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Synthesis, reactions, and applications of fluorine-containing multifunctional carbon compounds
Journal of Fluorine Chemistry 126 (2005) 941–955 www.elsevier.com/locate/fluor
Synthesis, reactions, and applications of fluorine-containing multifunctional carbon compounds Tomoya Fujiwara, Yoshio Takeuchi * Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan Received 10 March 2005; accepted 12 April 2005
Abstract The chemistry of compounds containing a carbon atom bearing three or four different labile functional groups has received little attention. These compounds should be of considerable significance in theoretical and synthetic organic chemistry. Among the compounds with multifunctional structures, those having both carbonyl and halogen groups in addition to other heteroatom groups seem especially valuable from a synthetic viewpoint. Their potential use as probes in pure and applied synthetic chemistry has not been exploited, presumably because of structural instability and a paucity of synthetic approaches. Keeping this background in mind, we focused on the synthesis of a new class of multifunctional carbon compounds in which ester carbonyl, halogen, and other heteroatom-derived functional groups are directly attached to the central carbon atom. Fluorine was chosen as the halogen because of the inherent stability of the C–F bond and because of the fundamental chemical and biological interest in fluorine-containing compounds. The synthesis, reactions, and some applications of various fluorinecontaining multifunctional carbon compounds are described. # 2005 Elsevier B.V. All rights reserved. Keywords: Fluorine-containing multifunctional carbon compound; Heteroatom; Monofluoro building block; Chiral derivatizing agent
1. Introduction The term ‘‘multifunctional carbon’’ means a carbon bearing plural heteroatom-containing functional groups in addition to a synthetically significant carbonyl group. We proposed that the compounds containing such multifunctional carbons should be categorized as ‘‘multifunctional carbon compounds’’ [1,2]. The a-amino acids, a-hydroxy aldehydes, and a-halo ketones are therefore classified into this category, and they may be called difunctional carbon compounds since two different functional groups are attached to the same carbon atom. Several compounds that we can call tri- or tetrafunctional carbon compounds in the sense mentioned above have been reported. However, we discovered that few compounds existed in which the four functional groups attached to the central carbon are different from each other when we started studying these kinds of * Corresponding author. Tel.: +81 76 434 7555; fax: +81 76 434 5053. E-mail address: [email protected] (Y. Takeuchi). 0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2005.04.008
compounds. Tetrafunctional carbon compounds containing both carbonyl and halogen groups (Fig. 1) were unknown. There was not even an indication in literature that the construction of such structures has ever been attempted. If one could reliably prepare members of this class of novel molecules, one could expect some interesting organic chemistry from them. First of all, these compounds have many functional groups that can be properly manipulated in chemical synthesis. For example, the difunctional a-amino acids have been converted into many natural products [3] and have been used as valuable tools in asymmetric reactions [4] by using either the amino or carboxylic acid group, or both of the two groups. Therefore, if there were more functional groups attached to an asymmetric carbon atom, such compounds would provide a much larger number of reactions by the proper manipulation of this combination of plural functional groups. Secondly, the chemical properties of each functional group presumably would be altered from its normal properties. Namely, one functional group in such circumstances would necessarily be destined to be
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Fig. 1. Structure of multifunctional carbon compounds.
affected both sterically and electronically by the combined effects of the plural functional groups placed adjacent to it. Therefore, novel chemical properties could be expected from such compounds, which might lead to the development of new reactions. Thirdly, when the four functional groups surrounding the central carbon atom are different from each other (Fig. 1), the carbon atom naturally plays the role of a novel type of asymmetric center. Optically active molecules with multifunctional carbon structure should have merits as useful precursors for the synthesis of various optically active compounds and as useful chiral auxiliaries in asymmetric synthesis. One can envisage several additional merits of these multifunctional carbon compounds, such as new materials, bioactive compounds, and convenient models for mechanistic and structural chemistry. Among the structures shown in Fig. 1, we focused our attention on those compounds in which the halogen atom is fluorine. We expected the fluorine to stabilize these unusual structures. Most of the so-called functional groups frequently used in synthetic chemistry are derived from heteroatoms having electronegativities greater than that of carbon. Therefore, attachment of the plural heteroatomderived labile groups to a single carbon atom would necessarily bring about the destabilization of the molecule. Since halogens possess generally greater leaving-group ability, their presence would be a major cause of destabilization. To overcome the problem, we thought we might be able to stabilize the multifunctional carbon structure by the introduction of the C–F bond with its known large bond energy. Another reason for the choice of the fluorine atom from among the halogens was that we anticipated the study of these organofluorine compounds to be applicable in the fields of synthetic and analytical chemistry. That is, fluorinecontaining multifunctional carbon compounds would serve as versatile building blocks [5], and therefore they would be intermediates in the synthesis of various organofluorine compounds. Much attention has been paid recently to fluorine-containing compounds from the viewpoint of new materials [6] and bioactive compounds [7]. Despite this attention, direct fluorination still generally requires special reagents and equipment. Moreover, only few fluorination methods are known which proceed with high selectivity. In consideration of this situation, the use of fluorine-containing building blocks should develop effective tools for the synthesis of various organofluorine compounds. By the use of these chiral fluorine compounds, we can also expect the development of new reagents for enantiomeric excess and absolute configuration determinations that
would surpass a-methoxy-a-trifluoromethylphenylacetic acid (MTPA, Mosher’s reagent) [8], since the fluorine atom is directly attached to the chiral center in our case. As mentioned above, fluorine-containing multifunctional carbon compounds are very significant. We would like to describe here the synthetic strategy leading to various fluorine-containing multifunctional carbon compounds, followed by some reactions and applications of these compounds.
2. Synthesis of multifunctional carbon compounds Since it seemed to be impossible and lacking synthetic generality to introduce two different functional groups simultaneously into a single carbon atom, our synthetic strategy was based on the stepwise introduction of various labile groups into readily available difunctional carbon compounds. The order of introducing functional groups turned out to be a big problem. However, we would here like to describe the synthetic methods according to the type of reaction for functionalization. The carbonyl group chosen as an indispensable group was the ester function because it is easily convertible to the other carbonyl groups such as carboxylic acid, amide, ketone, and aldehyde. 2.1. Electrophilic functionalization 2.1.1. Functionalization via enolates We first focused on the electrophilic functionalization of difunctional carbon compounds [2,9,10]. Treatment of several a-fluoro ketones or esters 1 having one or two additional fluorine or bromine atoms at the a-position of the carbonyl group, with zinc and trimethylsilyl chloride in acetonitrile gave the corresponding enol silylethers 2 (M = TMS) (Scheme 1) [11]. Although electrophilic nitration of the enol silylethers and the corresponding lithium or sodium enolates 2 (M = Li, Na) [12–14] was attempted, under various conditions (PrONO2/TBAF [15], O2NBF4/HF/Pyridine [16], or NH4ONO2/TFAA [17]), the desired compound 3 could not be obtained. Both electrophilic amination (R2NOR0 ) [18] and sulfenylation (PhSCl, PhSSPh) of them were also unsuccessful. These results are probably due to the low reactivity [19] of a-fluoro enolates. We then examined an approach that involved the halogenation of nitroacetic acid esters.
Scheme 1.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
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Scheme 2.
2.1.2. Utilization of nitroacetates Reaction of ethyl bromonitroacetate (4) derived from ethyl nitroacetate (5) with NaSPh produced the trifunctional carbon compound 6. We first expected that nucleophilic substitution by PhS would have occurred. However, we decided to examine the reaction pathway more carefully because the yield of 6 was disappointing (30–40%) and because debrominated compound 5 was always obtained in addition to the disubstituted derivatives 7 and 8. It was finally found, contrary to our expectation, that the electrophilic pathways shown in Scheme 2 produced the various products and no nucleophilic substitution occurred with nitroacetate compounds. Furthermore, to our extreme surprise, it was found subsequently that the tetrafunctional carbon compound 9 was formed in this reaction, although we did not pay any attention at that time to the isolation and characterization of this compound since its formation was entirely beyond our expectation. We have established a general method for the preparation of some nitro group-containing multifunctional carbon compounds by utilizing the chemical behavior of nitroacetate esters as follows (Scheme 3). Readily available nitroacetic esters 5 [20] were converted to the corresponding salts [21] by treatment with an equivalent amount of base, with which bromine or perchloryl fluoride (FClO3) were allowed to react in an electrophilic manner to produce 4a and 4b, respectively. The trifunctional carbon compounds 4a,b were converted again to the corresponding salts by treatment with KF and these salts were submitted to sulfenylation with PhSCl to produce the first tetrafunctional carbon compound 9 which has halogen, nitro, sulfenyl, and ester carbonyl groups [2,9]. Reverse functionalization, i.e., sulfenylation of 5 followed by electrophilic halogenation of the sulfides 6, also produced compound 9. Moreover,
bromination of 4b with N-bromosuccinimide (NBS) led to another tetrafunctional carbon compound 10, which has two different halogens. The method shown here, which involves the formation of potassium salts [21] of nitro compounds with spray-dried KF [22] and the direct fluorination of the salts with FClO3, is a laboratory-scale fluorination procedure devised in our laboratory [2,9]. Although F2 and CF3OF have been known for electrophilic fluorination, both of them are dangerous, and further, are not easily available. Also, efficient reagents such as N-fluoro-1,4-diazabicyclo[2.2.2]-octane derivatives [23], N-fluoropyridinium salts [24], and N-fluorosulfonamide(-imide) derivatives [25] have been recently developed. However, these reagents are rather expensive and are not atom-economical. Therefore, the development of a more convenient fluorination method has long been desired. The procedure that we adopted here has several advantages over the conventional ones; i.e., the reagent can be generated very easily and safely [26] from inexpensive fluorosulfonic acid and potassium perchlorate [27], normal glassware can be used, one can obtain the necessary amount of the reagent just before use, and the reaction proceeds with high selectivity in excellent yield. 2.2. Nucleophilic functionalization 2.2.1. Synthesis of trifunctional carbon compounds We focused our attention on ethyl bromofluoroacetate (11) as a versatile precursor because it seemed potentially difficult to nucleophilically introduce both ester and fluorine functionalities afterwards and because bromo derivatives are preferred considering the variety of functionalizations to be performed in the later stages of our syntheses [9,10]. Compound 11 could be easily
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Scheme 3.
obtained either by diazotization [28] of a-amino esters 12 followed by treatment with HF/pyridine and NBS [29] or by reaction of 1,2-dibromo-1,1,2-trifluoroethane (13) with NaOEt [30] followed by acid-catalyzed solvolysis (Scheme 4) [31]. Direct introduction of an amino group into 11 seemed very difficult from our preliminary work [32]. Therefore, we have chosen both azido and imido groups among several nitrogenous functionalities, which could be converted into an amino group in some later stage. Reaction of 11 with NaN3 readily produced ethyl azidofluoroacetate (14a) under phase transfer conditions. Treatment of 11 with potassium phthalimide or the analogous iminodicarboxylate nucleophiles in heated dimethylformamide (DMF) successfully
afforded the N-protected a-fluoro-a-amino acid derivatives 14b–d. We next attempted the introduction of an oxygenfunctionality into 11. Reaction of 11 with NaOEt and NaOPh gave a-fluoro ether derivatives 15a,b in excellent yields. Similarly, the reaction of 11 with potassium salts of some carboxylic acids gave the a-fluoro-a-acyloxyacetic ester derivatives 15c,d. The nucleophilic introduction of a sulfur-functionality was also attempted. When the bromoester 11 was treated with NaSEt and NaSPh, the sulfides 16a,b were obtained almost quantitatively. The a-fluoroacetic esters 14–16 having various heteroatom functionalities at the a-position thus prepared were
Scheme 4.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
945
Scheme 5.
unknown except for a few compounds that were obtained accidentally [33]. It is important to note that defluorination is not observed under these nucleophilic conditions. Our procedure is the first to establish general access to monofluorinated heteroatom-containing trifunctional carbon compounds. 2.2.2. Synthesis of tetrafunctional carbon compounds It is very difficult to generate a carbanion at the aposition to a fluorine atom because of p–p repulsion [34], which makes additional electrophilic functionalization at the fluorine-bearing carbon atom of 14–16 problematic. On the other hand, nucleophilic introduction of the fourth group into the trifunctional compounds would result in either the undesired detachment of fluorine or of the N, O, or S functionalities already introduced. Therefore, a further device was required for the introduction of another functional group into the trifunctional compounds. We first decided to investigate the free radical introduction of a bromine atom into 14–16. Bromination of 14 under various conditions was attempted and only apparently decomposed products were obtained. However, when the sulfides 16a,b were treated with NBS, the unstable bromo derivatives 17a,b were obtained successfully. Also, reaction of compound 15b with Br2 produced the unstable bromide 18 (Scheme 5). Only spectral data were obtained for 18 since it decomposed so readily. However, we succeeded in the conversion of 17a,b into the corresponding azido derivatives 19a,b by treatment with NaN3 or LiN3 under phase transfer conditions. The yield of the bromo- or azido-containing tetrafunctional carbon compounds thus obtained was unsatisfactory, ranging from 32 to 66%,
probably because of the loss of products during work up due to their unstable and unexpectedly volatile characteristics. We also attempted to obtain tetrafunctional carbon compounds using the available dibromoacetate derivatives. Treatment of ethyl dibromofluoroacetate (20) or ethyl dibromonitroacetate (21) with NaN3 under phase transfer conditions produced mono-azidated tetrafunctional carbon compounds, 22 and 23, although in low yields. Nucleophilic introduction of other groups into 20 and 21 was also attempted using reagents possessing less nucleophilicity than N3. However, only decomposed products were obtained since no mild reaction conditions were successful and since both starting materials and the
Scheme 6.
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Scheme 7.
products were unstable even under ambient conditions (Scheme 5). The tetrafunctional carbon compounds thus far obtained, 9, 10, 17–19, 22, and 23, are not only new but also interesting from the viewpoint of physical properties.
3. Some unusual reactions derived from multifunctional carbon structures Novel reactions could be expected for the multifunctional carbon compounds since various labile groups are placed geminal to each other. Even the strong C–F bonds were
sometimes cleaved and several unusual reactions have been observed. When ethyl bromofluoronitroacetate (10) was treated with MeLi, the bromine was subjected to nucleophilic attack to afford the reduced product 4b. When 10 was allowed to react with NaN3, however, the central carbon was attacked in a nucleophilic manner to produce the azido derivative 24. Usually, this type of reaction does not occur for nitroacetates. Compound 10 cannot assume the aciform because it has no acidic proton at the a-position. Therefore, the central carbon was attacked. On the other hand, when potassium phthalimide was used as a nucleophile, compound 25 was obtained as a result of the carbonyl carbon being attacked (Scheme 6) [10]. This is the first known example of three conjunctive atoms being attacked, depending on the identity of the nucleophile [35]. Reaction of ethyl dibromofluoroacetate (20) with nucleophiles such as NaOEt, NaOCH2Ph, NaSEt, and NaSPh yielded mainly the reduced compounds, 15a, 26, 27, and 16b, respectively (Scheme 7) [10]. It may be possible that the fluorine atom could be subjected to nucleophile attack at some initial reaction stage although the mechanism for the formation of 26 and 27 is unclear. Furthermore, when the trifunctional carbon compound 15a was heated for purification by distillation, the only obtainable compound was the glyoxylate acetal 28. The mechanism for this reaction is also unclear, but intermolecular disproportionation is a possible path since the yield of 28 was low (30–40%) and the residual compounds were unidentifiable decomposed substances.
Scheme 8.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
All of the unusual reactions mentioned above can be ascribed to the unique structure where plural labile groups are present on the same carbon atom.
4. Application of multifunctional carbon compounds 4.1. Preparation of optically active multifunctional carbon compounds 4.1.1. Optical resolution of multifunctional carbon compounds The central carbon of the tetrafunctional carbon compounds having three or four different labile groups features by definition an asymmetric center and therefore the corresponding optically active forms should exist [36]. If the optically active multifunctional carbon compounds are stable under ambient conditions, they can be used as versatile chiral auxiliaries for the synthesis of optically active natural products and building blocks for preparation
Fig. 2. Synthetic strategy of versatile building blocks for aliphatic monofluoro compounds.
947
of various organofluorine compounds. Furthermore, they can be convenient models for spectroscopic study and research on the steric aspects of reaction mechanisms. Thus, the attempts to prepare optically active multifunctional carbon compounds are of great significance. We first attempted to resolve ethyl a-fluoro-a-nitro-a(phenylthio)acetate [()-9b] [1,9]. Preparation of the carboxylic acid by the cleavage of the ester bond failed because the obtained carboxylic acid was easily decarboxylated [20]. We then attempted the transesterification of ()-9b with (R)-(+)-a-phenethylalcohol. This transesterification was carried out with catalytic Ti(OiPr)4 [37] to give the diastereomeric esters 29a,b, which could be resolved by column chromatography on silica gel (Scheme 8). Each diastereomer was successfully transesterified again with EtOH and catalytic Ti(OiPr)4 to afford the optically active ethyl ester (+)-9b and ()-9b in high yields. Optically active N-phthaloyl-a-fluoroglycine ethyl ester (14b) and ethyl a-fluoro-a-nitro-b-phenylpropionate (30) could also be obtained successfully in the same manner [1,9]. Several multifunctional carbon compounds could be resolved directly by chiral HPLC. For example, racemic ethyl 2-fluoro-2-nitro-5-oxohexanoate [()-31] was easily resolved on a Chiralcel OB column (Daicel Chemical Co. Ltd.) [38–40] to give (+)-31 and ()-31 in high yields [26c].
Scheme 9.
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4.1.2. Absolute configuration determination of multifunctional carbon compounds Optically active multifunctional carbon compounds are not of much value unless their absolute configurations are known. Thus, we attempted to determine the absolute configuration of the obtained optically active multifunctional carbon compounds, and the absolute configurations of 9b, 14b, 30, and 31 were assigned unambiguously by Xray crystallographic analysis as shown in Scheme 8 [41,42]. 4.2. Development of useful building blocks for aliphatic monofluoro compounds
Scheme 10.
While many building blocks for the synthesis of fluoroaromatic and di- or trifluoromethyl-containing compounds have been developed [43], there have been few examples of the developing of building blocks for aliphatic monofluoro compounds despite their significance for synthetic organic and medicinal chemistry [5]. Thus, we attempted to develop monofluoro building blocks that have multifunctionalized carbon structures.
Scheme 11.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
949
Scheme 12.
4.2.1. Molecular design of versatile building blocks Our basic strategy in designing these building blocks involved sequential introduction of two independent alkyl chains into the smallest fluorine-bearing carbon fragment (CHF), which is common to all secondary alkyl fluorides (Fig. 2) [26]. If two kinds of alkyl groups, R and R0 , are to be introduced one after another into the fragment, alkyl fluorides (R-CHF-R0 ) would be obtained that possess a fluorine atom at a position in an alkyl chain dependent on the choice of those two alkyl groups. Since electrophilic introduction of alkyl groups is far easier than the other modes of reaction from a synthetic viewpoint, the fragment should be an a-fluorocarbanion equivalent such as CHF(R) or CHF, which is derived from structures with two strong electron-withdrawing groups (EWG, EWG0 ) at the geminal position to fluorine. Considering the versatility in conversion and removal of the functional groups, four classes of compounds, 1-fluoro-1-nitro-1-(phenylsulfonyl)alkanes (32), 2-fluoro-2-(phenylsulfonyl)alkanoic esters (33), 2-fluoro-2-nitroalkanoic esters (34), and 1-fluoro-1(phenylsulfonyl)alkylphosphonic esters (35) were finally chosen as potentially practical building blocks that might meet our criteria (Scheme 9). 4.2.2. Preparation of building blocks 32–35 We employed difunctional carbon compounds 4, 36–38 as starting materials for the synthesis of 32–35, and the starting materials except commercially available 4 were prepared as shown in Scheme 9 [26]. The starting materials were treated with alkyl halides or active olefins by using appropriate bases and solvents to give the alkylated products. Fluorination of the alkylated products was
achieved by using diluted FClO3 to give the key compounds 32–35 quantitatively. In order to confirm the versatility of 32–35 as building blocks, we next attempted the conversion and removal of their various functional groups. 4.2.3. Attempted conversion and removal of functional groups of 32 and 33 Denitration of 32 with n-Bu3SnH [44], NaTeH [45], MeSNa [46], and 1-benzyl-1,4-dihydronicotinamide (BNAH) [47] did not give the desired compounds 39 (Scheme 10). Desulfonylation of 32 with Na-Hg [48], BNAH [49], and 1,3-dimethyl-2-phenylbenzimidazole (DMBI) [50] was also unsuccessful [26]. Saponificative hydrolysis (aqueous NaOH) of 33 gave the corresponding
Fig. 3. Structures of compounds 11, 14b–16b, 44a, and 61–66.
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carboxylic acids 41. However, attempted decarboxylation of the acids was unsuccessful. Treatment of 33 with LiAlH4 afforded the corresponding alcohols 43 successfully [26]. However, attempted deformylation of the alcohols failed.
We then attempted to extend the above methodology to the synthesis of tertiary alkyl fluorides, for which a general synthetic route has not yet been developed. Reaction of 34a– e with n-Bu3SnCH2CH CH2/AIBN [51] gave the allylated products 51p–t in 50–80% yields. Compounds 51p–t were reduced with LiAlH4 to give the alcohols 52p–t, which could be easily converted into tertiary alkyl fluorides [52]. Denitrative introduction of the third alkyl groups into 48j,k with n-Bu3SnH in the presence of a large excess of the Michael acceptors, methyl vinyl ketone and acrylonitrile, also gave 53u–w in low yields [26,53]. The synthesis of tertiary alkyl fluorides via radical alkylation of a-bromofluoroalkanes succeeded in moderate overall yields [53].
4.2.4. Conversion and removal of functional groups of 34 Denitration of 34a–c with n-Bu3SnH [44] successfully produced the fluoroalkanoic esters 44a–c (68–88%). Compounds 44a–c were readily converted to the 2fluoroalkanoic acids 45a–c and the 2-fluoroalkanols 46a– c in excellent yields using straightforward methods. Although we had anticipated the possibility of defluorination in the course of these reactions, none occurred (Scheme 11) [26]. Decarboethoxylation of 34a–e was performed either by alkaline hydrolysis and subsequent decarboxylation or by treatment with NaBH4 to give the 1-fluoro-1-nitroalkanes 47a–e (70–95%). Successive introduction of the second alkyl group (R0 ) into 47a–e was accomplished by Michaeltype additions to afford the desired dialkylated products 48f– m (43–82%) [26]. Denitration of 48k–m, the final stage of our pathway to the desired secondary alkyl fluorides, was successfully achieved by the use of n-Bu3SnH [44] to afford 49k–m (52–96%). Dehydronitration using MeSNa [46] was successful for those compounds that contained a benzyl structure, 48f,g. The (Z)-fluoroalkenes 50n,o were produced in a regio- and stereoselective manner in 75 and 55% yields, respectively [26]. We have thus developed the versatile building blocks 34 for general synthetic pathways leading to a wide variety of secondary fluorides. These building blocks are equivalent to the synthon of monofluoromethylene dicarbanion, CH(F).
4.2.5. Conversion and removal of functional groups of 35 Treatment of 35a with Na–Hg [48] did not give the desulfonylated products but, surprisingly, afforded 1-fluoro2-phenylethyl phenyl sulfone (54a) (Scheme 12). Compound 54b was also obtained from 35b under basic conditions. The instability of the P–C bond in compounds 35 under these conditions was attributable to the high electrophilic reactivity of the phosphoryl center due to the multifunctional structure of this compound containing a sulfonyl group and a fluorine atom. Thus, reaction of 35a with pyridine gave monoethyl hydrogenphosphonate (55). Treatment of 55 with Na–Hg successfully produced the desulfonylated product 56 [54]. Reaction of 35g with various carbonyl compounds gave fluoroolefins 57h–n (E/Z = 2/3 –100/0). Since these olefins could be converted into various kinds of monofluoro compounds 58–60 by Michael [54], Diels-Alder [54], and 1,3-dipole [55,56] addition reactions, they should be a fluoroethene equivalent. The above method has been applied to the synthesis of fluorine-containing amino acids [54] and tropanes [55].
Table 1 DdF values (in ppm) for diastereomeric derivatives of compounds 11, 14b–16b, 44a, and 61–66 R3
a
Not detectable.
H/Br (11)
H/NPhth (14b)
H/OPh (15b)
H/SPh (16b)
H/Ph (62)
H/Bn (44a)
Me/CBBCPh (63)
Ph/CBBCPh (64)
Me/Ph (65)
Bu/Ph (66)
(61, MTPA)
0.203
N.D.a
0.138
0.078
0.406
0.098
0.087
0.319
0.709
0.594
N.D.a
0.036
0.840
0.029
1.003
0.438
0.075
0.282
0.369
0.594
0.210
0.203
0.116
0.582
0.067
0.127
1.198
0.022
0.015
0.746
0.652
0.601
0.181
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
Fig. 4. Structures of compounds 67–73.
4.3. Development of versatile chiral derivatizing agents Recent advances in the development of the methodology of asymmetric synthesis and its application for the Table 2 DdF values (in ppm) for diastereomeric CFPA and MTPA derivatives R4
CF3/OMc/Ph (61, MTPA)
F/CN/Ph (67, CFPA)
N.D.a
0.241
0.203
1.048
0.181
1.006
0.029
0.752
951
synthesis of complex natural products have produced an increasing demand for convenient and reliable methods for the determination of enantiomeric excess (ee) of chiral compounds. The NMR spectroscopic analysis of the diastereomeric derivatives formed by reaction with chiral derivatizing agents (CDAs) is one of the convenient methods for this determination. Among many CDAs [57], MTPA (61) [8] (Fig. 3) has been widely employed for this purpose because the optically active form is commercially available and both 1H and 19F NMR can be used for the determination of ee. However, many examples have been also reported where the determination by this agent failed because of insufficient reactivity of the MTPA acid chloride [58] and poor signal-resolving ability of the agent [59]. Thus, we attempted to develop a highly versatile CDAs based on multifunctionalized carbon structures. 4.3.1. Feature and necessity of fluorine-containing chiral derivatizing agent Although many non fluorine-containing CDAs for determination of ee of chiral compounds have been developed [57], these CDAs as well as the above-mentioned MTPA have some critical problems in resolution ability, reactivity, etc. Fluorinecontaining chiral derivatizing agents [60] have some inherent advantages that enable these problems to be overcome. These advantages are: (i) the volatility of the derivatives is increased compared with the derivatives of non fluorine-containing CDAs—making gas chromatographic analysis easier and (ii) use of 19F NMR, which has a remarkably large range of chemical shift values (about 100 times larger than the 1H chemical shift range), a high sensitivity almost equal to 1H
Table 3 DdF valuesa (in ppm) for diastereomeric CFTA and MTPA esters 0.296
0.274
0.260
0.245
0.051
a
Not detectable.
R4
R5
CF3/OMe/Ph (61, MTPA)
F/CN/p-Tol (73, CFTA)
Me Me Me Me Me
Et Hex Ph COOMe CH2COOtBu
+0.00 0.05 0.20 0.48 +0.01
+0.08 +0.32 +0.87 +1.28 +0.59
+0.10 –b 0.11 +0.02 +0.22
+0.74 +0.92 +0.59 +0.11 +0.79
0.623
N.D.a
0.224
N.D.a
0.014
N.D.a
0.094
Bornyl 10-Bromoisobornyl Menthyl Isomenthyl Neomenthyl a
DdF = dRS(or SR) dSS(or RR). The (R, S)-derivatives derived from (R)CFTA [or (R)-MTPA] and (S)-alcohols are designated as RS and the (S, S)derivatives derived from (S)-CFTA [or (S)-MTPA] and (S)-alcohols are designated as SS. b MTPA esters were not obtained.
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NMR, and a simple spectrum relative to 1H NMR. All these advantages enable the determination of ee easily and exactly compared with the case of non fluorine-containing CDAs. Thus, fluorine-containing CDAs are necessary for the practical determination of the ees of various kinds of chiral molecules.
4.3.2. Evaluation of multifunctional carbon compounds as CDA The major structural imperfections of 61 for NMR spectroscopic analysis seemed to lie in the presence of the fluorine atoms being not on the chiral center but on the carbon atom adjacent to it. Thus, we first focused on
Fig. 5. DdH values (in ppm) for diastereomeric CFTA and MTPA esters. The diastereomeric MTPA esters of (1S,2R)-10-bromoisoborneol were not obtained.
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trifunctional carbon compounds having a single fluorine atom and an appropriate heteroatom-centered functionality or a bulky group directly attached to the a-position of the acetate structure and attempted to prepare the diastereomeric esters and amides of compounds 11, 14b–16b, 62, and 44a (Fig. 3) to investigate the electronic and the steric effects of the functional group on the diastereomeric chemical shift differences (Dd) [61]. The 19F chemical shift differences (DdF) for the diastereomeric 2-butyl,1-phenethyl esters, and 1-phenethylamides of 11, 14b–16b, 62, 44a, and 61 are shown in Table 1. Heteroatom-substituted acetates 11 and 14b–16b generally showed greater DdF values when compared with the corresponding carbon-substituted analog 44a. The DdF values for diastereomeric derivatives of 14b and 16b were greater than those observed for the corresponding MTPA derivatives. However, further investigations of 14b and 16b were stymied because the preparation of the corresponding carboxylic acids proved rather difficult. Although compound 62, which has both fluorine and phenyl group on the chiral center, had advantages over the other compounds examined, further investigations of this compound were not possible because of the unfortunate problem of racemization at the benzylic position. Considering the above problems, we next focused on the structure that has no hydrogen on the chiral center, and we therefore prepared the diastereomeric esters and amides of compounds 63–66 (Fig. 3) [62]. The DdF values for the diastereomeric derivatives of 63– 66 were generally greater than those observed for the corresponding MTPA derivatives (Table 1). These results also indicated that the existence of three different sizes of substituents, RL (Ph), RM (CBBCPh, Me, or Bu), and RS (F), appeared to be essential in obtaining these larger DdF values. However, the fluorine signals of the diastereomeric derivatives of 63, 65, and 66 were split as a result of coupling with the a-protons of the methyl or butyl group. 4.3.3. Properties of a-cyano-a-fluorophenylacetic acid (CFPA) as CDA Based on the results for compounds 11, 14b–16b, 44a, and 62–66, we then designed and prepared a-cyano-afluorophenylacetic acid (CFPA) (67) (Fig. 4), which has three different sizes of substituents and no hydrogen on the chiral center [63]. The DdF and DdH values for the diastereomeric derivatives of 67 were much greater than those observed for the corresponding MTPA derivatives, and this greater signal-resolving ability enabled even the ee determination of the alcohols and amines having remotely disposed chiral centers (Table 2) [63]. Moreover, compound 67 showed a much higher reactivity than MTPA because of the strong electron-withdrawing groups such as fluorine and the cyano group on the chiral center [64]. Therefore, neither racemization nor kinetic resolution, which is a critical problem for ee determination, was observed during the derivatization. Despite these advantages, however, the general use and further investigation on CFPA was retarded
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because of the rather involved synthetic route required for the preparation of the agent. 4.3.4. Properties of a-cyano-a-fluoro-p-tolylacetic acid (CFTA) as CDA To overcome problems about the preparation of CFPA, we focused on some CFPA analogs 68–72 (Fig. 4) [65], which would retain the inherent structural advantages and be easily prepared. However, the approach using these compounds failed because these carboxylic acids could not be obtained. Success was obtained by the use of a-cyano-a-fluoro-ptolylacetic acid (CFTA) (73) (Fig. 4) [66]. The acid chloride of this agent was shown to have a high reactivity, similar to CFPA-Cl, and was easily prepared via electrophilic fluorination using FClO3. The DdF values for the CFTA diastereomers were much greater than those for the corresponding MTPA derivatives (Table 3) [66,67]. Therefore, CFTA can be used for the determination of the ee of even alcohols and amines having a remotely disposed chiral center. It should also be noted that the relationship between the relative position of the 1H NMR chemical shifts (DdH) for diastereomeric CFTA esters of chiral secondary alcohols and their absolute configurations was consistent without exception (Fig. 5) [67]. This relationship strongly indicates that the absolute configuration of chiral secondary alcohols can be determined through the 1H chemical shift differences (DdH) between their CFTA esters in the same procedure as the modified Mosher’s method. The applicability of CFTA for determining absolute configurations using 1H NMR is much wider than that of MTPA. The relationship between the sign of DdF and the absolute configuration of chiral secondary alcohols was also consistent without exception while no consistent correlation was found with the MTPA esters (Table 3) [67]. Thus this relationship of CFTA derivatives seems to be applicable for the determination of the absolute configurations of chiral secondary alcohols.
5. Conclusion The novel notion of a multifunctional carbon structure was introduced. The first synthesis of some tri- and tetrafunctional carbon compounds was achieved successfully by electrophilic and/or nucleophilic introduction of various heteroatom-containing labile groups into appropriate difunctional carbon compounds. This multifunctionality led to some unusual reactions, which suggest the possibility of the development of novel and efficient reactions based on multifunctional carbon structures. The synthetic methodology of monofluoro building blocks was developed by manipulating multifunctional carbon structure. Versatile chiral derivatizing agents having multifunctional carbon structures were also developed and were showed to be superior to existing chiral derivatizing agents with respect both to reactivity and resolution efficiency.
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References [1] Y. Takeuchi, M. Asahina, K. Nagata, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1987) 2203–2207. [2] Y. Takeuchi, A. Murayama, T. Hagi, T. Koizumi, Chem. Ind. Chem. (1985) 2029–2033. [3] (a) P.N. Confalone, E.M. Huie, J. Am. Chem. Soc. 106 (1984) 7175– 7178; (b) C.G. Chavdarian, E.B. Sanders, R.L. Bassfield, J. Org. Chem. 47 (1982) 1069–1073; (c) M. Otsuka, A. Kittaka, T. Iimori, H. Yamashita, S. Kobayashi, M. Ohno, Chem. Pharm. Bull. 33 (1985) 509–514; (d) F.J. Vinick, S. Jung, J. Org. Chem. 48 (1983) 392–393; (e) S. Tsuji, S. Kusumoto, T. Shiba, Chem. Lett. (1975) 1281–1284; (f) L. Faber, W. Wiegrebe, Helv. Chim. Acta. 56 (1973) 2882–2884; (g) R.B. Woodward, K. Heusler, J. Gosteli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, H. Vorbru¨ ggen, J. Am. Chem. Soc. 88 (1966) 852–853. [4] (a) K. Drauz, A. Kleeman, J. Martens, Angew. Chem. Int. Ed. Engl. 21 (1982) 584–608; (b) M. Larcheveque, Y. Petit, Tetrahedron Lett. 25 (1984) 3705–3706; (c) L. Broek, P. Porskamp, R. Haltiwanger, B. Zwanenburg, J. Org. Chem. 49 (1984) 1691–1695; (d) D. Seebach, M. Boes, R. Naef, W.B. Schweizer, J. Am. Chem. Soc. 105 (1983) 5390–5398; (e) Y. Nagao, T. Ikeda, M. Yagi, E. Fujita, J. Am. Chem. Soc. 104 (1982) 2079–2081; (f) P.J. Maurer, H. Takahata, H. Rapoport, J. Am. Chem. Soc. 106 (1984) 1095–1098; (g) D.A. Evans, Aldrichim. Acta 15 (1982) 23–32. [5] (a) Y. Takeuchi, J. Org. Synth. Chem. 46 (1988) 145–159; (b) K. Tanaka, Synthesis and Function of Fluorinated Compounds, CMC, Tokyo, 1987. [6] (a) R.E. Banks, Preparation and Properties and Industrial Applications of Organofluorine Compounds, Ellis Horwood Ltd., Chichester, 1982; (b) N. Ishikawa, Synthesis Function of Fluorinated Compounds, CMC, Tokyo, 1987; (c) T. Satokawa, Functional Fluorine-containing Polymers, Nikkan Kogyo Press, Tokyo, 1982; (d) N. Ishikawa, J. Org. Synth. Chem. 42 (1984) 770–774; (e) M. Yamabe, H. Matsuo, J. Org. Synth. Chem. 45 (1987) 526–535; (f) H. Kobayashi, J. Org. Synth. Chem. 45 (1987) 561–570; (g) N. Ishikawa, Chemistry Industry of Fluorinated Compounds, CMC, Tokyo, 1977; (h) N. Ishikawa, The Newest Applied Technology of Fluorine Chemistry, CMC, Tokyo, 1981; (i) J.G. Riess, M.L. Blanc, Angew. Chem. Int. Ed. Engl. 17 (1978) 621–634; (j) K. Yokoyama, K. Yamanouchi, T. Suyama, Life Chemistry Reports 2 (1983) 35–93; (k) D.D. Dixon, D.G. Holland, Fed. Proc. 34 (1975) 1444–1448. [7] (a) R. Filler, Biochemistry Involving Carbon-Fluorine Bonds, American Chemical Society, Washington DC, 1976; (b) R. Filler, Y. Kobayashi, Biomedicinal Aspects of Fluorine Chemistry, Kodansha Ltd., Tokyo, 1982; (c) K. Sakauchi, S. Kurozumi, J. Org. Synth. Chem. 42 (1984) 794– 808; (d) I. Kumadaki, J. Org. Synth. Chem. 42 (1984) 786–793; (e) K. Yoshioka, C. Takayama, N. Matsuo, J. Org. Synth. Chem. 42 (1984) 809–821. [8] (a) J.A. Dale, D.L. Dull, H.S. Mosher, J. Org. Chem. 34 (1969) 2543– 2549; (b) J.A. Dale, H.S. Mosher, J. Am. Chem. Soc. 95 (1973) 512– 519; (c) G.R. Sullivan, J.A. Dale, H.S. Mosher, J. Org. Chem. 38 (1973) 2143–2147;
[9] [10] [11] [12] [13] [14]
[15] [16]
[17] [18]
[19] [20] [21]
[22] [23]
[24]
[25]
(d) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc. 113 (1991) 4092–4096; (e) T. Kusumi, T. Fukushima, I. Ohtani, H. Kakisawa, Tetrahedron Lett. 32 (1991) 2939–2942. Y. Takeuchi, M. Asahina, A. Murayama, K. Hori, T. Koizumi, J. Org. Chem. 51 (1986) 955–956. Y. Takeuchi, M. Asahina, K. Hori, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1988) 1149–1153. M. Yamana, T. Ishihara, T. Ando, Tetrahedron Lett. 24 (1983) 507– 510. E. Elkik, M. Imbeaux-Oudotte, Tetrahedron Lett. 19 (1978) 3793– 3796. R.L. Buchanan, F.H. Dean, F. Pattison, Can. J. Chem. 40 (1962) 1571– 1575. (a) J.T. Welch, S. Eswarakrishnan, J. Chem. Soc., Chem. Commun. (1985) 186–188; (b) J.T. Welch, K. Seper, S. Eswarakrishnan, J. Samarino, J. Org. Chem. 49 (1984) 4720–4721. F.E. Elfehail, W.W. Zajac Jr., J. Org. Chem. 46 (1981) 5151–5155. (a) G.A. Olah, Aldrichim. Acta 12 (1979) 43–48; (b) G.A. Olah, J.G. Shih, G.K.S. Prakash, J. Fluorine Chem. 33 (1986) 377–396. P. Dampawan, W.W. Zajac Jr., Synthesis (1983) 545–546. (a) T. Sheradsky, Z. Nir, Tetrahedron Lett. 10 (1969) 77–78; (b) E.W. Colvin, G.W. Kirby, A.C. Wilson, Tetrahedron Lett. 23 (1982) 3835–3836; (c) M. Bernheim, G. Boche, Angew. Chem. Int. Ed. Engl. 19 (1980) 1010–1011. P. Brownbridge, Synthesis (1983) 1–28. M.T. Shipchandler, Synthesis (1979) 666–686. (a) A. Ostaszynski, J. Wielgat, T. Urbanski, Tetrahedron 25 (1969) 1929–1938; (b) A.V. Fokin, V.S. Galakhov, V.P. Radchenko, Zh. Obsh. Khim. 39 (1969) 1345–1346. N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida, T. Tatsuno, Chem. Lett. (1981) 761–764. (a) A.G. Gilicinski, G.P. Pez, R.G. Syvret, G.S. Lal, J. Fluorine Chem. 59 (1992) 157–162; (b) R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif, R.G. Syvret, J. Chem. Soc., Chem. Commun. (1992) 595–596; (c) G.S. Lal, J. Org. Chem. 58 (1993) 2791–2796; (d) R.E. Banks, N.J. Lawrence, A.L. Popplewell, J. Chem. Soc., Chem. Commun. (1994) 343–344. (a) T. Umemoto, K. Tomita, Tetrahedron Lett. 27 (1986) 3271–3274; (b) T. Umemoto, K. Kawada, K. Tomita, Tetrahedron Lett. 27 (1986) 4465–4468; (c) T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomita, J. Am. Chem. Soc. 112 (1990) 8563–8575; (d) T. Umemoto, G. Tomizawa, Bull. Chem. Soc. Jpn. 59 (1986) 3625–3629; (e) T. Umemoto, G. Tomizawa, J. Org. Chem. 60 (1995) 6563–6570; (f) T. Umemoto, K. Harasawa, G. Tomizawa, K. Kawada, K. Tomita, Bull. Chem. Soc. Jpn. 64 (1991) 1081–1092; (g) M. Ihara, T. Kai, N. Taniguchi, K. Fukumoto, J. Chem. Soc., Perkin Trans. 1 (1990) 2357–2358. (a) W.E. Barnette, J. Am. Chem. Soc. 106 (1984) 452–454; (b) S.H. Lee, J. Schwartz, J. Am. Chem. Soc. 108 (1986) 2445–2447; (c) E. Differding, R.W. Lang, Helv. Chim. Acta 72 (1989) 1248–1252; (d) E. Differding, G.M. Ru¨ egg, R.W. Lang, Tetrahedron Lett. 32 (1991) 1779–1782; (e) F.A. Davis, W. Han, Tetrahedron Lett. 32 (1991) 1631–1634; (f) F.A. Davis, W. Han, Tetrahedron Lett. 33 (1992) 1153–1156; (g) F.A. Davis, W. Han, C.K. Murphy, J. Org. Chem. 60 (1995) 4730– 4737; (h) F.A. Davis, P.V.N. Kasu, G. Sundarababu, H. Qi, J. Org. Chem. 62 (1997) 7546–7547; (i) E. Differding, H. Ofner, Synlett (1991) 187–189;
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
[26]
[27] [28] [29] [30] [31] [32] [33]
[34] [35]
[36] [37]
[38] [39] [40] [41] [42]
[43] [44]
(j) S. Singh, D.D. DesMarteau, S.S. Zuberi, M. Witz, H.-N. Huang, J. Am. Chem. Soc. 109 (1987) 7194–7196; (k) G. Resnati, D.D. DesMarteau, J. Org. Chem. 56 (1991) 4925– 4929; (l) D.D. DesMarteau, Z.-Q. Xu, M. Witz, J. Org. Chem. 57 (1992) 629–635; (m) G. Resnati, D.D. DesMarteau, J. Org. Chem. 57 (1991) 4281– 4284; (n) Z.-Q. Xu, D.D. DesMarteau, S.S. Zuberi, M. Witz, H.-N. Huang, J. Fluorine Chem. 58 (1992) 71–79; (o) W. Ying, D.D. DesMarteau, Y. Gotoh, Tetrahedron 52 (1996) 15– 22. (b) Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 54 (1989) 5453–5459; (b) Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 53 (1988) 4160; (c) Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 52 (1987) 5061–5063. G.B. Wehrenalp, J. Inorg. Nucl. Chem. 2 (1956) 266. N.E. Searle, Org. Synth. Col., vol. 4, Wiley, New York, 1963, pp. 424– 426. G.A. Olah, J. Welch, Synthesis (1974) 896–898. B. Englund, Org. Synth. Col., vol. 4, Wiley, New York, 1963, pp. 184– 220. B. Englund, Org. Synth. Col., vol. 4, Wiley, New York, 1963, pp. 423– 429. Y. Takeuchi, M. Nabetani, K. Takagi, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1991) 49–53. (a) R. Sauvetre, J. Normant, J. Villieras, Tetrahedron 31 (1975) 897– 903; (b) J.F. Normant, R. Sauvetre, J. Villieras, C. R. Acad. Sci. Ser. C 277 (1973) 515–517; (c) A.V. Fokin, V.I. Zimin, Y.N. Studnev, A.I. Rapkin, Zh. Org. Khim. 7 (1971) 249–251; (d) V.V. Berrenblit, V.A. Nikitin, V.P. Sass, L.N. Senyushov, Y.K. Starobin, Y.V. Tsyganov, Zh. Org. Khim. 15 (1979) 284–292; (e) P.R. Ortiz de Montellano, W.A. Vinson, J. Am. Chem. Soc. 101 (1979) 2222–2224. R.D. Chambers, Fluorine in Organic Chemistry, Wiley, New York, 1973. K. Nagata, Y. Takeuchi, T. Koizumi, in: Proceedings of the 68th Hokuriku Branch Meeting of Pharmaceutical Society of Japan, Kanazawa, 1986, p. 4 (Book of Abstract). H. Hirschmann, K.R. Hanson, Top. Stereochem. 14 (1983) 183–229. (a) P. Schnurrenberger, M.F. Zu¨ ger, D. Seebach, Helv. Chim. Acta 65 (1982) 1197–1201; (b) B. Weidmann, D. Seebach, Angew. Chem. Int. Ed. Engl. 22 (1983) 31–45. Y. Okamoto, M. Kawashima, K. Yamamoto, K. Hatada, Chem. Lett. (1984) 739–742. A. Ichida, T. Shibata, I. Okamoto, Y. Yuki, H. Namikoshi, Y. Toga, Chromatographia 19 (1984) 280–284. T. Shibata, I. Okamoto, K. Ishii, J. Liq. Chromatogr. 9 (1986) 313–340. Y. Takeuchi, M. Nojiri, T. Koizumi, Y. Iitaka, Tetrahedron Lett. 29 (1988) 4727–4730. Y. Takeuchi, H. Note, M. Nojiri, T. Koizumi, Y. Iitaka, p. 68 (Book of Abstract), in: Proceedings of the 13th Fluorine Conference of Japan, Sendai, 1988. I.L. Knunyants, G.G. Yakobson, Synthesis of Fluoroorganic Compounds, Springer–Verlag, New York, 1985. (a) D.D. Tanner, E.V. Blackburn, G.E. Diaz, J. Am. Chem. Soc. 103 (1981) 1557–1559; (b) N. Ono, H. Miyake, R. Tamura, A. Kaji, Tetrahedron Lett. 22 (1981) 1705–1708; (c) N. Ono, H. Miyake, A. Kamimura, I. Hashimoto, R. Tamura, A. Kaji, Tetrahedron 41 (1985) 4013–4023; (d) N. Ono, T. Hamamoto, T.X. Jun, A. Kaji, Tetrahedron Lett. 28 (1987) 2277–2280.
955
[45] (a) H. Suzuki, K. Takaoka, A. Osuka, Bull. Chem. Soc. Jpn. 58 (1985) 1067–1068; (b) D.H.R. Barton, S.W. McCombie, J. Chem. Soc., Perkin Trans. 1 (1975) 1574–1585. [46] (a) N. Kornblum, S.C. Carlson, R.G. Smith, J. Am. Chem. Soc. 100 (1978) 289–290; (b) N. Kornblum, S.C. Carlson, R.G. Smith, J. Am. Chem. Soc. 101 (1979) 647–657; (c) N. Kornblum, J. Widmer, S.C. Carlson, J. Am. Chem. Soc. 101 (1979) 658–664. [47] (a) N. Ono, R. Tamura, A. Kaji, J. Am. Chem. Soc. 102 (1980) 2851– 2852; (b) N. Ono, R. Tamura, A. Kaji, J. Am. Chem. Soc. 105 (1983) 4017– 4022. [48] B.M. Trost, H.C. Arndt, P.E. Strege, T.R. Verhoeven, Tetrahedron Lett. 17 (1976) 3477–3478. [49] N. Ono, R. Tamura, R. Tanikawa, A. Kaji, J. Chem. Soc., Chem. Commun. (1981) 71–72. [50] J. Chen, D.D. Tanner, J. Org. Chem. 53 (1988) 3897–3900. [51] N. Ono, K. Zinsmeister, A. Kaji, Bull. Chem. Soc. Jpn. 58 (1985) 1069–1070. [52] A. Kaneda, Y. Takeuchi, K. Nagata, T. Koizumi, p. 5 (Book of Abstract), in: Proceedings of the 77th Hokuriku Branch Meeting of Pharmaceutical Society of Japan, Kanazawa, 1989. [53] Y. Takeuchi, A. Kanada, S. Kawahara, T. Koizumi, J. Org. Chem. 58 (1993) 3483–3485. [54] T. Koizumi, T. Hagi, Y. Horie, Y. Takeuchi, Chem. Pharm. Bull. 35 (1987) 3959–3962. [55] T. Takahashi, T. Hagi, K. Kitano, Y. Takeuchi, T. Koizumi, Chem. Lett. (1989) 593–596. [56] T. Takahashi, K. Kitano, T. Hagi, H. Nihonmatsu, T. Koizumi, Chem. Lett. (1989) 597–598. [57] (a) J.M. Seco, E. Quin˜ oa´ , R. Riguera, Chem. Rev. 104 (2004) 17–118; (b) T.J. Wenzel, J.D. Wilcox, Chirality 15 (2003) 256–270. [58] (a) J.S. Dutcher, J.G. Macmillan, C.H. Heathcock, J. Org. Chem. 41 (1976) 2663–2669; (b) L. Hietaniemi, E. Pohjala, P. Malkonen, M.L. Riekkola, Finn. Chem. Lett. 16 (1989) 67–73; (c) A. Svatos, I. Valterova, D. Samon, J. Vrkoc, Collect. Czech. Chem. Commun. 55 (1990) 485–490; (d) H.C. Brown, A.M. Salunkhe, B. Singaram, J. Org. Chem. 56 (1991) 1170–1175. [59] S.K. Latypov, J.M. Seco, E. Quin˜ oa´ , R. Riguera, J. Org. Chem. 61 (1996) 8569–8577. [60] Y. Takeuchi, T. Takahashi, Enantiocontrolled Synthesis of Fluoroorganic Compounds, Wiley, Chichester, 1999, pp. 497–534. [61] Y. Takeuchi, H. Ogura, Y. Ishii, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1989) 1721–1725. [62] Y. Takeuchi, H. Ogura, Y. Ishii, T. Koizumi, Chem. Pharm. Bull. 38 (1990) 2404–2408. [63] (a) Y. Takeuchi, N. Itoh, H. Note, T. Koizumi, K. Yamaguchi, J. Am. Chem. Soc. 113 (1991) 6318–6320; (b) Y. Takeuchi, N. Itoh, T. Satoh, T. Koizumi, K. Yamaguchi, J. Org. Chem. 58 (1993) 1812–1820. [64] (a) Y. Takeuchi, N. Itoh, T. Koizumi, J. Chem. Soc., Chem. Commun. (1992) 1514–1515; (b) Y. Takeuchi, N. Itoh, S.-I. Kawahara, T. Koizumi, Tetrahedron 49 (1993) 1861–1870. [65] Y. Takeuchi, H. Iwashita, K. Yamada, M. Gotaishi, N. Kurose, T. Koizumi, K. Kabuto, T. Kometani, Chem. Pharm. Bull. 43 (1995) 1668–1673. [66] (a) Y. Takeuchi, M. Konishi, H. Hori, T. Takahashi, T. Kometani, K.L. Kirk, Chem. Commun. (1998) 365–366; (b) Y. Takeuchi, M. Konishi, H. Hori, T. Takahashi, K.L. Kirk, Enantiomer 4 (1999) 339–344. [67] T. Takahashi, A. Fukushima, Y. Tanaka, Y. Takeuchi, K. Kabuto, C. Kabuto, Chem. Commun. (2000) 788–789.
Synthesis, reactions, and applications of fluorine-containing multifunctional carbon compounds Tomoya Fujiwara, Yoshio Takeuchi * Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan Received 10 March 2005; accepted 12 April 2005
Abstract The chemistry of compounds containing a carbon atom bearing three or four different labile functional groups has received little attention. These compounds should be of considerable significance in theoretical and synthetic organic chemistry. Among the compounds with multifunctional structures, those having both carbonyl and halogen groups in addition to other heteroatom groups seem especially valuable from a synthetic viewpoint. Their potential use as probes in pure and applied synthetic chemistry has not been exploited, presumably because of structural instability and a paucity of synthetic approaches. Keeping this background in mind, we focused on the synthesis of a new class of multifunctional carbon compounds in which ester carbonyl, halogen, and other heteroatom-derived functional groups are directly attached to the central carbon atom. Fluorine was chosen as the halogen because of the inherent stability of the C–F bond and because of the fundamental chemical and biological interest in fluorine-containing compounds. The synthesis, reactions, and some applications of various fluorinecontaining multifunctional carbon compounds are described. # 2005 Elsevier B.V. All rights reserved. Keywords: Fluorine-containing multifunctional carbon compound; Heteroatom; Monofluoro building block; Chiral derivatizing agent
1. Introduction The term ‘‘multifunctional carbon’’ means a carbon bearing plural heteroatom-containing functional groups in addition to a synthetically significant carbonyl group. We proposed that the compounds containing such multifunctional carbons should be categorized as ‘‘multifunctional carbon compounds’’ [1,2]. The a-amino acids, a-hydroxy aldehydes, and a-halo ketones are therefore classified into this category, and they may be called difunctional carbon compounds since two different functional groups are attached to the same carbon atom. Several compounds that we can call tri- or tetrafunctional carbon compounds in the sense mentioned above have been reported. However, we discovered that few compounds existed in which the four functional groups attached to the central carbon are different from each other when we started studying these kinds of * Corresponding author. Tel.: +81 76 434 7555; fax: +81 76 434 5053. E-mail address: [email protected] (Y. Takeuchi). 0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2005.04.008
compounds. Tetrafunctional carbon compounds containing both carbonyl and halogen groups (Fig. 1) were unknown. There was not even an indication in literature that the construction of such structures has ever been attempted. If one could reliably prepare members of this class of novel molecules, one could expect some interesting organic chemistry from them. First of all, these compounds have many functional groups that can be properly manipulated in chemical synthesis. For example, the difunctional a-amino acids have been converted into many natural products [3] and have been used as valuable tools in asymmetric reactions [4] by using either the amino or carboxylic acid group, or both of the two groups. Therefore, if there were more functional groups attached to an asymmetric carbon atom, such compounds would provide a much larger number of reactions by the proper manipulation of this combination of plural functional groups. Secondly, the chemical properties of each functional group presumably would be altered from its normal properties. Namely, one functional group in such circumstances would necessarily be destined to be
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Fig. 1. Structure of multifunctional carbon compounds.
affected both sterically and electronically by the combined effects of the plural functional groups placed adjacent to it. Therefore, novel chemical properties could be expected from such compounds, which might lead to the development of new reactions. Thirdly, when the four functional groups surrounding the central carbon atom are different from each other (Fig. 1), the carbon atom naturally plays the role of a novel type of asymmetric center. Optically active molecules with multifunctional carbon structure should have merits as useful precursors for the synthesis of various optically active compounds and as useful chiral auxiliaries in asymmetric synthesis. One can envisage several additional merits of these multifunctional carbon compounds, such as new materials, bioactive compounds, and convenient models for mechanistic and structural chemistry. Among the structures shown in Fig. 1, we focused our attention on those compounds in which the halogen atom is fluorine. We expected the fluorine to stabilize these unusual structures. Most of the so-called functional groups frequently used in synthetic chemistry are derived from heteroatoms having electronegativities greater than that of carbon. Therefore, attachment of the plural heteroatomderived labile groups to a single carbon atom would necessarily bring about the destabilization of the molecule. Since halogens possess generally greater leaving-group ability, their presence would be a major cause of destabilization. To overcome the problem, we thought we might be able to stabilize the multifunctional carbon structure by the introduction of the C–F bond with its known large bond energy. Another reason for the choice of the fluorine atom from among the halogens was that we anticipated the study of these organofluorine compounds to be applicable in the fields of synthetic and analytical chemistry. That is, fluorinecontaining multifunctional carbon compounds would serve as versatile building blocks [5], and therefore they would be intermediates in the synthesis of various organofluorine compounds. Much attention has been paid recently to fluorine-containing compounds from the viewpoint of new materials [6] and bioactive compounds [7]. Despite this attention, direct fluorination still generally requires special reagents and equipment. Moreover, only few fluorination methods are known which proceed with high selectivity. In consideration of this situation, the use of fluorine-containing building blocks should develop effective tools for the synthesis of various organofluorine compounds. By the use of these chiral fluorine compounds, we can also expect the development of new reagents for enantiomeric excess and absolute configuration determinations that
would surpass a-methoxy-a-trifluoromethylphenylacetic acid (MTPA, Mosher’s reagent) [8], since the fluorine atom is directly attached to the chiral center in our case. As mentioned above, fluorine-containing multifunctional carbon compounds are very significant. We would like to describe here the synthetic strategy leading to various fluorine-containing multifunctional carbon compounds, followed by some reactions and applications of these compounds.
2. Synthesis of multifunctional carbon compounds Since it seemed to be impossible and lacking synthetic generality to introduce two different functional groups simultaneously into a single carbon atom, our synthetic strategy was based on the stepwise introduction of various labile groups into readily available difunctional carbon compounds. The order of introducing functional groups turned out to be a big problem. However, we would here like to describe the synthetic methods according to the type of reaction for functionalization. The carbonyl group chosen as an indispensable group was the ester function because it is easily convertible to the other carbonyl groups such as carboxylic acid, amide, ketone, and aldehyde. 2.1. Electrophilic functionalization 2.1.1. Functionalization via enolates We first focused on the electrophilic functionalization of difunctional carbon compounds [2,9,10]. Treatment of several a-fluoro ketones or esters 1 having one or two additional fluorine or bromine atoms at the a-position of the carbonyl group, with zinc and trimethylsilyl chloride in acetonitrile gave the corresponding enol silylethers 2 (M = TMS) (Scheme 1) [11]. Although electrophilic nitration of the enol silylethers and the corresponding lithium or sodium enolates 2 (M = Li, Na) [12–14] was attempted, under various conditions (PrONO2/TBAF [15], O2NBF4/HF/Pyridine [16], or NH4ONO2/TFAA [17]), the desired compound 3 could not be obtained. Both electrophilic amination (R2NOR0 ) [18] and sulfenylation (PhSCl, PhSSPh) of them were also unsuccessful. These results are probably due to the low reactivity [19] of a-fluoro enolates. We then examined an approach that involved the halogenation of nitroacetic acid esters.
Scheme 1.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
943
Scheme 2.
2.1.2. Utilization of nitroacetates Reaction of ethyl bromonitroacetate (4) derived from ethyl nitroacetate (5) with NaSPh produced the trifunctional carbon compound 6. We first expected that nucleophilic substitution by PhS would have occurred. However, we decided to examine the reaction pathway more carefully because the yield of 6 was disappointing (30–40%) and because debrominated compound 5 was always obtained in addition to the disubstituted derivatives 7 and 8. It was finally found, contrary to our expectation, that the electrophilic pathways shown in Scheme 2 produced the various products and no nucleophilic substitution occurred with nitroacetate compounds. Furthermore, to our extreme surprise, it was found subsequently that the tetrafunctional carbon compound 9 was formed in this reaction, although we did not pay any attention at that time to the isolation and characterization of this compound since its formation was entirely beyond our expectation. We have established a general method for the preparation of some nitro group-containing multifunctional carbon compounds by utilizing the chemical behavior of nitroacetate esters as follows (Scheme 3). Readily available nitroacetic esters 5 [20] were converted to the corresponding salts [21] by treatment with an equivalent amount of base, with which bromine or perchloryl fluoride (FClO3) were allowed to react in an electrophilic manner to produce 4a and 4b, respectively. The trifunctional carbon compounds 4a,b were converted again to the corresponding salts by treatment with KF and these salts were submitted to sulfenylation with PhSCl to produce the first tetrafunctional carbon compound 9 which has halogen, nitro, sulfenyl, and ester carbonyl groups [2,9]. Reverse functionalization, i.e., sulfenylation of 5 followed by electrophilic halogenation of the sulfides 6, also produced compound 9. Moreover,
bromination of 4b with N-bromosuccinimide (NBS) led to another tetrafunctional carbon compound 10, which has two different halogens. The method shown here, which involves the formation of potassium salts [21] of nitro compounds with spray-dried KF [22] and the direct fluorination of the salts with FClO3, is a laboratory-scale fluorination procedure devised in our laboratory [2,9]. Although F2 and CF3OF have been known for electrophilic fluorination, both of them are dangerous, and further, are not easily available. Also, efficient reagents such as N-fluoro-1,4-diazabicyclo[2.2.2]-octane derivatives [23], N-fluoropyridinium salts [24], and N-fluorosulfonamide(-imide) derivatives [25] have been recently developed. However, these reagents are rather expensive and are not atom-economical. Therefore, the development of a more convenient fluorination method has long been desired. The procedure that we adopted here has several advantages over the conventional ones; i.e., the reagent can be generated very easily and safely [26] from inexpensive fluorosulfonic acid and potassium perchlorate [27], normal glassware can be used, one can obtain the necessary amount of the reagent just before use, and the reaction proceeds with high selectivity in excellent yield. 2.2. Nucleophilic functionalization 2.2.1. Synthesis of trifunctional carbon compounds We focused our attention on ethyl bromofluoroacetate (11) as a versatile precursor because it seemed potentially difficult to nucleophilically introduce both ester and fluorine functionalities afterwards and because bromo derivatives are preferred considering the variety of functionalizations to be performed in the later stages of our syntheses [9,10]. Compound 11 could be easily
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Scheme 3.
obtained either by diazotization [28] of a-amino esters 12 followed by treatment with HF/pyridine and NBS [29] or by reaction of 1,2-dibromo-1,1,2-trifluoroethane (13) with NaOEt [30] followed by acid-catalyzed solvolysis (Scheme 4) [31]. Direct introduction of an amino group into 11 seemed very difficult from our preliminary work [32]. Therefore, we have chosen both azido and imido groups among several nitrogenous functionalities, which could be converted into an amino group in some later stage. Reaction of 11 with NaN3 readily produced ethyl azidofluoroacetate (14a) under phase transfer conditions. Treatment of 11 with potassium phthalimide or the analogous iminodicarboxylate nucleophiles in heated dimethylformamide (DMF) successfully
afforded the N-protected a-fluoro-a-amino acid derivatives 14b–d. We next attempted the introduction of an oxygenfunctionality into 11. Reaction of 11 with NaOEt and NaOPh gave a-fluoro ether derivatives 15a,b in excellent yields. Similarly, the reaction of 11 with potassium salts of some carboxylic acids gave the a-fluoro-a-acyloxyacetic ester derivatives 15c,d. The nucleophilic introduction of a sulfur-functionality was also attempted. When the bromoester 11 was treated with NaSEt and NaSPh, the sulfides 16a,b were obtained almost quantitatively. The a-fluoroacetic esters 14–16 having various heteroatom functionalities at the a-position thus prepared were
Scheme 4.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
945
Scheme 5.
unknown except for a few compounds that were obtained accidentally [33]. It is important to note that defluorination is not observed under these nucleophilic conditions. Our procedure is the first to establish general access to monofluorinated heteroatom-containing trifunctional carbon compounds. 2.2.2. Synthesis of tetrafunctional carbon compounds It is very difficult to generate a carbanion at the aposition to a fluorine atom because of p–p repulsion [34], which makes additional electrophilic functionalization at the fluorine-bearing carbon atom of 14–16 problematic. On the other hand, nucleophilic introduction of the fourth group into the trifunctional compounds would result in either the undesired detachment of fluorine or of the N, O, or S functionalities already introduced. Therefore, a further device was required for the introduction of another functional group into the trifunctional compounds. We first decided to investigate the free radical introduction of a bromine atom into 14–16. Bromination of 14 under various conditions was attempted and only apparently decomposed products were obtained. However, when the sulfides 16a,b were treated with NBS, the unstable bromo derivatives 17a,b were obtained successfully. Also, reaction of compound 15b with Br2 produced the unstable bromide 18 (Scheme 5). Only spectral data were obtained for 18 since it decomposed so readily. However, we succeeded in the conversion of 17a,b into the corresponding azido derivatives 19a,b by treatment with NaN3 or LiN3 under phase transfer conditions. The yield of the bromo- or azido-containing tetrafunctional carbon compounds thus obtained was unsatisfactory, ranging from 32 to 66%,
probably because of the loss of products during work up due to their unstable and unexpectedly volatile characteristics. We also attempted to obtain tetrafunctional carbon compounds using the available dibromoacetate derivatives. Treatment of ethyl dibromofluoroacetate (20) or ethyl dibromonitroacetate (21) with NaN3 under phase transfer conditions produced mono-azidated tetrafunctional carbon compounds, 22 and 23, although in low yields. Nucleophilic introduction of other groups into 20 and 21 was also attempted using reagents possessing less nucleophilicity than N3. However, only decomposed products were obtained since no mild reaction conditions were successful and since both starting materials and the
Scheme 6.
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Scheme 7.
products were unstable even under ambient conditions (Scheme 5). The tetrafunctional carbon compounds thus far obtained, 9, 10, 17–19, 22, and 23, are not only new but also interesting from the viewpoint of physical properties.
3. Some unusual reactions derived from multifunctional carbon structures Novel reactions could be expected for the multifunctional carbon compounds since various labile groups are placed geminal to each other. Even the strong C–F bonds were
sometimes cleaved and several unusual reactions have been observed. When ethyl bromofluoronitroacetate (10) was treated with MeLi, the bromine was subjected to nucleophilic attack to afford the reduced product 4b. When 10 was allowed to react with NaN3, however, the central carbon was attacked in a nucleophilic manner to produce the azido derivative 24. Usually, this type of reaction does not occur for nitroacetates. Compound 10 cannot assume the aciform because it has no acidic proton at the a-position. Therefore, the central carbon was attacked. On the other hand, when potassium phthalimide was used as a nucleophile, compound 25 was obtained as a result of the carbonyl carbon being attacked (Scheme 6) [10]. This is the first known example of three conjunctive atoms being attacked, depending on the identity of the nucleophile [35]. Reaction of ethyl dibromofluoroacetate (20) with nucleophiles such as NaOEt, NaOCH2Ph, NaSEt, and NaSPh yielded mainly the reduced compounds, 15a, 26, 27, and 16b, respectively (Scheme 7) [10]. It may be possible that the fluorine atom could be subjected to nucleophile attack at some initial reaction stage although the mechanism for the formation of 26 and 27 is unclear. Furthermore, when the trifunctional carbon compound 15a was heated for purification by distillation, the only obtainable compound was the glyoxylate acetal 28. The mechanism for this reaction is also unclear, but intermolecular disproportionation is a possible path since the yield of 28 was low (30–40%) and the residual compounds were unidentifiable decomposed substances.
Scheme 8.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
All of the unusual reactions mentioned above can be ascribed to the unique structure where plural labile groups are present on the same carbon atom.
4. Application of multifunctional carbon compounds 4.1. Preparation of optically active multifunctional carbon compounds 4.1.1. Optical resolution of multifunctional carbon compounds The central carbon of the tetrafunctional carbon compounds having three or four different labile groups features by definition an asymmetric center and therefore the corresponding optically active forms should exist [36]. If the optically active multifunctional carbon compounds are stable under ambient conditions, they can be used as versatile chiral auxiliaries for the synthesis of optically active natural products and building blocks for preparation
Fig. 2. Synthetic strategy of versatile building blocks for aliphatic monofluoro compounds.
947
of various organofluorine compounds. Furthermore, they can be convenient models for spectroscopic study and research on the steric aspects of reaction mechanisms. Thus, the attempts to prepare optically active multifunctional carbon compounds are of great significance. We first attempted to resolve ethyl a-fluoro-a-nitro-a(phenylthio)acetate [()-9b] [1,9]. Preparation of the carboxylic acid by the cleavage of the ester bond failed because the obtained carboxylic acid was easily decarboxylated [20]. We then attempted the transesterification of ()-9b with (R)-(+)-a-phenethylalcohol. This transesterification was carried out with catalytic Ti(OiPr)4 [37] to give the diastereomeric esters 29a,b, which could be resolved by column chromatography on silica gel (Scheme 8). Each diastereomer was successfully transesterified again with EtOH and catalytic Ti(OiPr)4 to afford the optically active ethyl ester (+)-9b and ()-9b in high yields. Optically active N-phthaloyl-a-fluoroglycine ethyl ester (14b) and ethyl a-fluoro-a-nitro-b-phenylpropionate (30) could also be obtained successfully in the same manner [1,9]. Several multifunctional carbon compounds could be resolved directly by chiral HPLC. For example, racemic ethyl 2-fluoro-2-nitro-5-oxohexanoate [()-31] was easily resolved on a Chiralcel OB column (Daicel Chemical Co. Ltd.) [38–40] to give (+)-31 and ()-31 in high yields [26c].
Scheme 9.
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4.1.2. Absolute configuration determination of multifunctional carbon compounds Optically active multifunctional carbon compounds are not of much value unless their absolute configurations are known. Thus, we attempted to determine the absolute configuration of the obtained optically active multifunctional carbon compounds, and the absolute configurations of 9b, 14b, 30, and 31 were assigned unambiguously by Xray crystallographic analysis as shown in Scheme 8 [41,42]. 4.2. Development of useful building blocks for aliphatic monofluoro compounds
Scheme 10.
While many building blocks for the synthesis of fluoroaromatic and di- or trifluoromethyl-containing compounds have been developed [43], there have been few examples of the developing of building blocks for aliphatic monofluoro compounds despite their significance for synthetic organic and medicinal chemistry [5]. Thus, we attempted to develop monofluoro building blocks that have multifunctionalized carbon structures.
Scheme 11.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
949
Scheme 12.
4.2.1. Molecular design of versatile building blocks Our basic strategy in designing these building blocks involved sequential introduction of two independent alkyl chains into the smallest fluorine-bearing carbon fragment (CHF), which is common to all secondary alkyl fluorides (Fig. 2) [26]. If two kinds of alkyl groups, R and R0 , are to be introduced one after another into the fragment, alkyl fluorides (R-CHF-R0 ) would be obtained that possess a fluorine atom at a position in an alkyl chain dependent on the choice of those two alkyl groups. Since electrophilic introduction of alkyl groups is far easier than the other modes of reaction from a synthetic viewpoint, the fragment should be an a-fluorocarbanion equivalent such as CHF(R) or CHF, which is derived from structures with two strong electron-withdrawing groups (EWG, EWG0 ) at the geminal position to fluorine. Considering the versatility in conversion and removal of the functional groups, four classes of compounds, 1-fluoro-1-nitro-1-(phenylsulfonyl)alkanes (32), 2-fluoro-2-(phenylsulfonyl)alkanoic esters (33), 2-fluoro-2-nitroalkanoic esters (34), and 1-fluoro-1(phenylsulfonyl)alkylphosphonic esters (35) were finally chosen as potentially practical building blocks that might meet our criteria (Scheme 9). 4.2.2. Preparation of building blocks 32–35 We employed difunctional carbon compounds 4, 36–38 as starting materials for the synthesis of 32–35, and the starting materials except commercially available 4 were prepared as shown in Scheme 9 [26]. The starting materials were treated with alkyl halides or active olefins by using appropriate bases and solvents to give the alkylated products. Fluorination of the alkylated products was
achieved by using diluted FClO3 to give the key compounds 32–35 quantitatively. In order to confirm the versatility of 32–35 as building blocks, we next attempted the conversion and removal of their various functional groups. 4.2.3. Attempted conversion and removal of functional groups of 32 and 33 Denitration of 32 with n-Bu3SnH [44], NaTeH [45], MeSNa [46], and 1-benzyl-1,4-dihydronicotinamide (BNAH) [47] did not give the desired compounds 39 (Scheme 10). Desulfonylation of 32 with Na-Hg [48], BNAH [49], and 1,3-dimethyl-2-phenylbenzimidazole (DMBI) [50] was also unsuccessful [26]. Saponificative hydrolysis (aqueous NaOH) of 33 gave the corresponding
Fig. 3. Structures of compounds 11, 14b–16b, 44a, and 61–66.
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carboxylic acids 41. However, attempted decarboxylation of the acids was unsuccessful. Treatment of 33 with LiAlH4 afforded the corresponding alcohols 43 successfully [26]. However, attempted deformylation of the alcohols failed.
We then attempted to extend the above methodology to the synthesis of tertiary alkyl fluorides, for which a general synthetic route has not yet been developed. Reaction of 34a– e with n-Bu3SnCH2CH CH2/AIBN [51] gave the allylated products 51p–t in 50–80% yields. Compounds 51p–t were reduced with LiAlH4 to give the alcohols 52p–t, which could be easily converted into tertiary alkyl fluorides [52]. Denitrative introduction of the third alkyl groups into 48j,k with n-Bu3SnH in the presence of a large excess of the Michael acceptors, methyl vinyl ketone and acrylonitrile, also gave 53u–w in low yields [26,53]. The synthesis of tertiary alkyl fluorides via radical alkylation of a-bromofluoroalkanes succeeded in moderate overall yields [53].
4.2.4. Conversion and removal of functional groups of 34 Denitration of 34a–c with n-Bu3SnH [44] successfully produced the fluoroalkanoic esters 44a–c (68–88%). Compounds 44a–c were readily converted to the 2fluoroalkanoic acids 45a–c and the 2-fluoroalkanols 46a– c in excellent yields using straightforward methods. Although we had anticipated the possibility of defluorination in the course of these reactions, none occurred (Scheme 11) [26]. Decarboethoxylation of 34a–e was performed either by alkaline hydrolysis and subsequent decarboxylation or by treatment with NaBH4 to give the 1-fluoro-1-nitroalkanes 47a–e (70–95%). Successive introduction of the second alkyl group (R0 ) into 47a–e was accomplished by Michaeltype additions to afford the desired dialkylated products 48f– m (43–82%) [26]. Denitration of 48k–m, the final stage of our pathway to the desired secondary alkyl fluorides, was successfully achieved by the use of n-Bu3SnH [44] to afford 49k–m (52–96%). Dehydronitration using MeSNa [46] was successful for those compounds that contained a benzyl structure, 48f,g. The (Z)-fluoroalkenes 50n,o were produced in a regio- and stereoselective manner in 75 and 55% yields, respectively [26]. We have thus developed the versatile building blocks 34 for general synthetic pathways leading to a wide variety of secondary fluorides. These building blocks are equivalent to the synthon of monofluoromethylene dicarbanion, CH(F).
4.2.5. Conversion and removal of functional groups of 35 Treatment of 35a with Na–Hg [48] did not give the desulfonylated products but, surprisingly, afforded 1-fluoro2-phenylethyl phenyl sulfone (54a) (Scheme 12). Compound 54b was also obtained from 35b under basic conditions. The instability of the P–C bond in compounds 35 under these conditions was attributable to the high electrophilic reactivity of the phosphoryl center due to the multifunctional structure of this compound containing a sulfonyl group and a fluorine atom. Thus, reaction of 35a with pyridine gave monoethyl hydrogenphosphonate (55). Treatment of 55 with Na–Hg successfully produced the desulfonylated product 56 [54]. Reaction of 35g with various carbonyl compounds gave fluoroolefins 57h–n (E/Z = 2/3 –100/0). Since these olefins could be converted into various kinds of monofluoro compounds 58–60 by Michael [54], Diels-Alder [54], and 1,3-dipole [55,56] addition reactions, they should be a fluoroethene equivalent. The above method has been applied to the synthesis of fluorine-containing amino acids [54] and tropanes [55].
Table 1 DdF values (in ppm) for diastereomeric derivatives of compounds 11, 14b–16b, 44a, and 61–66 R3
a
Not detectable.
H/Br (11)
H/NPhth (14b)
H/OPh (15b)
H/SPh (16b)
H/Ph (62)
H/Bn (44a)
Me/CBBCPh (63)
Ph/CBBCPh (64)
Me/Ph (65)
Bu/Ph (66)
(61, MTPA)
0.203
N.D.a
0.138
0.078
0.406
0.098
0.087
0.319
0.709
0.594
N.D.a
0.036
0.840
0.029
1.003
0.438
0.075
0.282
0.369
0.594
0.210
0.203
0.116
0.582
0.067
0.127
1.198
0.022
0.015
0.746
0.652
0.601
0.181
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Fig. 4. Structures of compounds 67–73.
4.3. Development of versatile chiral derivatizing agents Recent advances in the development of the methodology of asymmetric synthesis and its application for the Table 2 DdF values (in ppm) for diastereomeric CFPA and MTPA derivatives R4
CF3/OMc/Ph (61, MTPA)
F/CN/Ph (67, CFPA)
N.D.a
0.241
0.203
1.048
0.181
1.006
0.029
0.752
951
synthesis of complex natural products have produced an increasing demand for convenient and reliable methods for the determination of enantiomeric excess (ee) of chiral compounds. The NMR spectroscopic analysis of the diastereomeric derivatives formed by reaction with chiral derivatizing agents (CDAs) is one of the convenient methods for this determination. Among many CDAs [57], MTPA (61) [8] (Fig. 3) has been widely employed for this purpose because the optically active form is commercially available and both 1H and 19F NMR can be used for the determination of ee. However, many examples have been also reported where the determination by this agent failed because of insufficient reactivity of the MTPA acid chloride [58] and poor signal-resolving ability of the agent [59]. Thus, we attempted to develop a highly versatile CDAs based on multifunctionalized carbon structures. 4.3.1. Feature and necessity of fluorine-containing chiral derivatizing agent Although many non fluorine-containing CDAs for determination of ee of chiral compounds have been developed [57], these CDAs as well as the above-mentioned MTPA have some critical problems in resolution ability, reactivity, etc. Fluorinecontaining chiral derivatizing agents [60] have some inherent advantages that enable these problems to be overcome. These advantages are: (i) the volatility of the derivatives is increased compared with the derivatives of non fluorine-containing CDAs—making gas chromatographic analysis easier and (ii) use of 19F NMR, which has a remarkably large range of chemical shift values (about 100 times larger than the 1H chemical shift range), a high sensitivity almost equal to 1H
Table 3 DdF valuesa (in ppm) for diastereomeric CFTA and MTPA esters 0.296
0.274
0.260
0.245
0.051
a
Not detectable.
R4
R5
CF3/OMe/Ph (61, MTPA)
F/CN/p-Tol (73, CFTA)
Me Me Me Me Me
Et Hex Ph COOMe CH2COOtBu
+0.00 0.05 0.20 0.48 +0.01
+0.08 +0.32 +0.87 +1.28 +0.59
+0.10 –b 0.11 +0.02 +0.22
+0.74 +0.92 +0.59 +0.11 +0.79
0.623
N.D.a
0.224
N.D.a
0.014
N.D.a
0.094
Bornyl 10-Bromoisobornyl Menthyl Isomenthyl Neomenthyl a
DdF = dRS(or SR) dSS(or RR). The (R, S)-derivatives derived from (R)CFTA [or (R)-MTPA] and (S)-alcohols are designated as RS and the (S, S)derivatives derived from (S)-CFTA [or (S)-MTPA] and (S)-alcohols are designated as SS. b MTPA esters were not obtained.
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NMR, and a simple spectrum relative to 1H NMR. All these advantages enable the determination of ee easily and exactly compared with the case of non fluorine-containing CDAs. Thus, fluorine-containing CDAs are necessary for the practical determination of the ees of various kinds of chiral molecules.
4.3.2. Evaluation of multifunctional carbon compounds as CDA The major structural imperfections of 61 for NMR spectroscopic analysis seemed to lie in the presence of the fluorine atoms being not on the chiral center but on the carbon atom adjacent to it. Thus, we first focused on
Fig. 5. DdH values (in ppm) for diastereomeric CFTA and MTPA esters. The diastereomeric MTPA esters of (1S,2R)-10-bromoisoborneol were not obtained.
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
trifunctional carbon compounds having a single fluorine atom and an appropriate heteroatom-centered functionality or a bulky group directly attached to the a-position of the acetate structure and attempted to prepare the diastereomeric esters and amides of compounds 11, 14b–16b, 62, and 44a (Fig. 3) to investigate the electronic and the steric effects of the functional group on the diastereomeric chemical shift differences (Dd) [61]. The 19F chemical shift differences (DdF) for the diastereomeric 2-butyl,1-phenethyl esters, and 1-phenethylamides of 11, 14b–16b, 62, 44a, and 61 are shown in Table 1. Heteroatom-substituted acetates 11 and 14b–16b generally showed greater DdF values when compared with the corresponding carbon-substituted analog 44a. The DdF values for diastereomeric derivatives of 14b and 16b were greater than those observed for the corresponding MTPA derivatives. However, further investigations of 14b and 16b were stymied because the preparation of the corresponding carboxylic acids proved rather difficult. Although compound 62, which has both fluorine and phenyl group on the chiral center, had advantages over the other compounds examined, further investigations of this compound were not possible because of the unfortunate problem of racemization at the benzylic position. Considering the above problems, we next focused on the structure that has no hydrogen on the chiral center, and we therefore prepared the diastereomeric esters and amides of compounds 63–66 (Fig. 3) [62]. The DdF values for the diastereomeric derivatives of 63– 66 were generally greater than those observed for the corresponding MTPA derivatives (Table 1). These results also indicated that the existence of three different sizes of substituents, RL (Ph), RM (CBBCPh, Me, or Bu), and RS (F), appeared to be essential in obtaining these larger DdF values. However, the fluorine signals of the diastereomeric derivatives of 63, 65, and 66 were split as a result of coupling with the a-protons of the methyl or butyl group. 4.3.3. Properties of a-cyano-a-fluorophenylacetic acid (CFPA) as CDA Based on the results for compounds 11, 14b–16b, 44a, and 62–66, we then designed and prepared a-cyano-afluorophenylacetic acid (CFPA) (67) (Fig. 4), which has three different sizes of substituents and no hydrogen on the chiral center [63]. The DdF and DdH values for the diastereomeric derivatives of 67 were much greater than those observed for the corresponding MTPA derivatives, and this greater signal-resolving ability enabled even the ee determination of the alcohols and amines having remotely disposed chiral centers (Table 2) [63]. Moreover, compound 67 showed a much higher reactivity than MTPA because of the strong electron-withdrawing groups such as fluorine and the cyano group on the chiral center [64]. Therefore, neither racemization nor kinetic resolution, which is a critical problem for ee determination, was observed during the derivatization. Despite these advantages, however, the general use and further investigation on CFPA was retarded
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because of the rather involved synthetic route required for the preparation of the agent. 4.3.4. Properties of a-cyano-a-fluoro-p-tolylacetic acid (CFTA) as CDA To overcome problems about the preparation of CFPA, we focused on some CFPA analogs 68–72 (Fig. 4) [65], which would retain the inherent structural advantages and be easily prepared. However, the approach using these compounds failed because these carboxylic acids could not be obtained. Success was obtained by the use of a-cyano-a-fluoro-ptolylacetic acid (CFTA) (73) (Fig. 4) [66]. The acid chloride of this agent was shown to have a high reactivity, similar to CFPA-Cl, and was easily prepared via electrophilic fluorination using FClO3. The DdF values for the CFTA diastereomers were much greater than those for the corresponding MTPA derivatives (Table 3) [66,67]. Therefore, CFTA can be used for the determination of the ee of even alcohols and amines having a remotely disposed chiral center. It should also be noted that the relationship between the relative position of the 1H NMR chemical shifts (DdH) for diastereomeric CFTA esters of chiral secondary alcohols and their absolute configurations was consistent without exception (Fig. 5) [67]. This relationship strongly indicates that the absolute configuration of chiral secondary alcohols can be determined through the 1H chemical shift differences (DdH) between their CFTA esters in the same procedure as the modified Mosher’s method. The applicability of CFTA for determining absolute configurations using 1H NMR is much wider than that of MTPA. The relationship between the sign of DdF and the absolute configuration of chiral secondary alcohols was also consistent without exception while no consistent correlation was found with the MTPA esters (Table 3) [67]. Thus this relationship of CFTA derivatives seems to be applicable for the determination of the absolute configurations of chiral secondary alcohols.
5. Conclusion The novel notion of a multifunctional carbon structure was introduced. The first synthesis of some tri- and tetrafunctional carbon compounds was achieved successfully by electrophilic and/or nucleophilic introduction of various heteroatom-containing labile groups into appropriate difunctional carbon compounds. This multifunctionality led to some unusual reactions, which suggest the possibility of the development of novel and efficient reactions based on multifunctional carbon structures. The synthetic methodology of monofluoro building blocks was developed by manipulating multifunctional carbon structure. Versatile chiral derivatizing agents having multifunctional carbon structures were also developed and were showed to be superior to existing chiral derivatizing agents with respect both to reactivity and resolution efficiency.
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References [1] Y. Takeuchi, M. Asahina, K. Nagata, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1987) 2203–2207. [2] Y. Takeuchi, A. Murayama, T. Hagi, T. Koizumi, Chem. Ind. Chem. (1985) 2029–2033. [3] (a) P.N. Confalone, E.M. Huie, J. Am. Chem. Soc. 106 (1984) 7175– 7178; (b) C.G. Chavdarian, E.B. Sanders, R.L. Bassfield, J. Org. Chem. 47 (1982) 1069–1073; (c) M. Otsuka, A. Kittaka, T. Iimori, H. Yamashita, S. Kobayashi, M. Ohno, Chem. Pharm. Bull. 33 (1985) 509–514; (d) F.J. Vinick, S. Jung, J. Org. Chem. 48 (1983) 392–393; (e) S. Tsuji, S. Kusumoto, T. Shiba, Chem. Lett. (1975) 1281–1284; (f) L. Faber, W. Wiegrebe, Helv. Chim. Acta. 56 (1973) 2882–2884; (g) R.B. Woodward, K. Heusler, J. Gosteli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, H. Vorbru¨ ggen, J. Am. Chem. Soc. 88 (1966) 852–853. [4] (a) K. Drauz, A. Kleeman, J. Martens, Angew. Chem. Int. Ed. Engl. 21 (1982) 584–608; (b) M. Larcheveque, Y. Petit, Tetrahedron Lett. 25 (1984) 3705–3706; (c) L. Broek, P. Porskamp, R. Haltiwanger, B. Zwanenburg, J. Org. Chem. 49 (1984) 1691–1695; (d) D. Seebach, M. Boes, R. Naef, W.B. Schweizer, J. Am. Chem. Soc. 105 (1983) 5390–5398; (e) Y. Nagao, T. Ikeda, M. Yagi, E. Fujita, J. Am. Chem. Soc. 104 (1982) 2079–2081; (f) P.J. Maurer, H. Takahata, H. Rapoport, J. Am. Chem. Soc. 106 (1984) 1095–1098; (g) D.A. Evans, Aldrichim. Acta 15 (1982) 23–32. [5] (a) Y. Takeuchi, J. Org. Synth. Chem. 46 (1988) 145–159; (b) K. Tanaka, Synthesis and Function of Fluorinated Compounds, CMC, Tokyo, 1987. [6] (a) R.E. Banks, Preparation and Properties and Industrial Applications of Organofluorine Compounds, Ellis Horwood Ltd., Chichester, 1982; (b) N. Ishikawa, Synthesis Function of Fluorinated Compounds, CMC, Tokyo, 1987; (c) T. Satokawa, Functional Fluorine-containing Polymers, Nikkan Kogyo Press, Tokyo, 1982; (d) N. Ishikawa, J. Org. Synth. Chem. 42 (1984) 770–774; (e) M. Yamabe, H. Matsuo, J. Org. Synth. Chem. 45 (1987) 526–535; (f) H. Kobayashi, J. Org. Synth. Chem. 45 (1987) 561–570; (g) N. Ishikawa, Chemistry Industry of Fluorinated Compounds, CMC, Tokyo, 1977; (h) N. Ishikawa, The Newest Applied Technology of Fluorine Chemistry, CMC, Tokyo, 1981; (i) J.G. Riess, M.L. Blanc, Angew. Chem. Int. Ed. Engl. 17 (1978) 621–634; (j) K. Yokoyama, K. Yamanouchi, T. Suyama, Life Chemistry Reports 2 (1983) 35–93; (k) D.D. Dixon, D.G. Holland, Fed. Proc. 34 (1975) 1444–1448. [7] (a) R. Filler, Biochemistry Involving Carbon-Fluorine Bonds, American Chemical Society, Washington DC, 1976; (b) R. Filler, Y. Kobayashi, Biomedicinal Aspects of Fluorine Chemistry, Kodansha Ltd., Tokyo, 1982; (c) K. Sakauchi, S. Kurozumi, J. Org. Synth. Chem. 42 (1984) 794– 808; (d) I. Kumadaki, J. Org. Synth. Chem. 42 (1984) 786–793; (e) K. Yoshioka, C. Takayama, N. Matsuo, J. Org. Synth. Chem. 42 (1984) 809–821. [8] (a) J.A. Dale, D.L. Dull, H.S. Mosher, J. Org. Chem. 34 (1969) 2543– 2549; (b) J.A. Dale, H.S. Mosher, J. Am. Chem. Soc. 95 (1973) 512– 519; (c) G.R. Sullivan, J.A. Dale, H.S. Mosher, J. Org. Chem. 38 (1973) 2143–2147;
[9] [10] [11] [12] [13] [14]
[15] [16]
[17] [18]
[19] [20] [21]
[22] [23]
[24]
[25]
(d) I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc. 113 (1991) 4092–4096; (e) T. Kusumi, T. Fukushima, I. Ohtani, H. Kakisawa, Tetrahedron Lett. 32 (1991) 2939–2942. Y. Takeuchi, M. Asahina, A. Murayama, K. Hori, T. Koizumi, J. Org. Chem. 51 (1986) 955–956. Y. Takeuchi, M. Asahina, K. Hori, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1988) 1149–1153. M. Yamana, T. Ishihara, T. Ando, Tetrahedron Lett. 24 (1983) 507– 510. E. Elkik, M. Imbeaux-Oudotte, Tetrahedron Lett. 19 (1978) 3793– 3796. R.L. Buchanan, F.H. Dean, F. Pattison, Can. J. Chem. 40 (1962) 1571– 1575. (a) J.T. Welch, S. Eswarakrishnan, J. Chem. Soc., Chem. Commun. (1985) 186–188; (b) J.T. Welch, K. Seper, S. Eswarakrishnan, J. Samarino, J. Org. Chem. 49 (1984) 4720–4721. F.E. Elfehail, W.W. Zajac Jr., J. Org. Chem. 46 (1981) 5151–5155. (a) G.A. Olah, Aldrichim. Acta 12 (1979) 43–48; (b) G.A. Olah, J.G. Shih, G.K.S. Prakash, J. Fluorine Chem. 33 (1986) 377–396. P. Dampawan, W.W. Zajac Jr., Synthesis (1983) 545–546. (a) T. Sheradsky, Z. Nir, Tetrahedron Lett. 10 (1969) 77–78; (b) E.W. Colvin, G.W. Kirby, A.C. Wilson, Tetrahedron Lett. 23 (1982) 3835–3836; (c) M. Bernheim, G. Boche, Angew. Chem. Int. Ed. Engl. 19 (1980) 1010–1011. P. Brownbridge, Synthesis (1983) 1–28. M.T. Shipchandler, Synthesis (1979) 666–686. (a) A. Ostaszynski, J. Wielgat, T. Urbanski, Tetrahedron 25 (1969) 1929–1938; (b) A.V. Fokin, V.S. Galakhov, V.P. Radchenko, Zh. Obsh. Khim. 39 (1969) 1345–1346. N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida, T. Tatsuno, Chem. Lett. (1981) 761–764. (a) A.G. Gilicinski, G.P. Pez, R.G. Syvret, G.S. Lal, J. Fluorine Chem. 59 (1992) 157–162; (b) R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif, R.G. Syvret, J. Chem. Soc., Chem. Commun. (1992) 595–596; (c) G.S. Lal, J. Org. Chem. 58 (1993) 2791–2796; (d) R.E. Banks, N.J. Lawrence, A.L. Popplewell, J. Chem. Soc., Chem. Commun. (1994) 343–344. (a) T. Umemoto, K. Tomita, Tetrahedron Lett. 27 (1986) 3271–3274; (b) T. Umemoto, K. Kawada, K. Tomita, Tetrahedron Lett. 27 (1986) 4465–4468; (c) T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K. Tomita, J. Am. Chem. Soc. 112 (1990) 8563–8575; (d) T. Umemoto, G. Tomizawa, Bull. Chem. Soc. Jpn. 59 (1986) 3625–3629; (e) T. Umemoto, G. Tomizawa, J. Org. Chem. 60 (1995) 6563–6570; (f) T. Umemoto, K. Harasawa, G. Tomizawa, K. Kawada, K. Tomita, Bull. Chem. Soc. Jpn. 64 (1991) 1081–1092; (g) M. Ihara, T. Kai, N. Taniguchi, K. Fukumoto, J. Chem. Soc., Perkin Trans. 1 (1990) 2357–2358. (a) W.E. Barnette, J. Am. Chem. Soc. 106 (1984) 452–454; (b) S.H. Lee, J. Schwartz, J. Am. Chem. Soc. 108 (1986) 2445–2447; (c) E. Differding, R.W. Lang, Helv. Chim. Acta 72 (1989) 1248–1252; (d) E. Differding, G.M. Ru¨ egg, R.W. Lang, Tetrahedron Lett. 32 (1991) 1779–1782; (e) F.A. Davis, W. Han, Tetrahedron Lett. 32 (1991) 1631–1634; (f) F.A. Davis, W. Han, Tetrahedron Lett. 33 (1992) 1153–1156; (g) F.A. Davis, W. Han, C.K. Murphy, J. Org. Chem. 60 (1995) 4730– 4737; (h) F.A. Davis, P.V.N. Kasu, G. Sundarababu, H. Qi, J. Org. Chem. 62 (1997) 7546–7547; (i) E. Differding, H. Ofner, Synlett (1991) 187–189;
T. Fujiwara, Y. Takeuchi / Journal of Fluorine Chemistry 126 (2005) 941–955
[26]
[27] [28] [29] [30] [31] [32] [33]
[34] [35]
[36] [37]
[38] [39] [40] [41] [42]
[43] [44]
(j) S. Singh, D.D. DesMarteau, S.S. Zuberi, M. Witz, H.-N. Huang, J. Am. Chem. Soc. 109 (1987) 7194–7196; (k) G. Resnati, D.D. DesMarteau, J. Org. Chem. 56 (1991) 4925– 4929; (l) D.D. DesMarteau, Z.-Q. Xu, M. Witz, J. Org. Chem. 57 (1992) 629–635; (m) G. Resnati, D.D. DesMarteau, J. Org. Chem. 57 (1991) 4281– 4284; (n) Z.-Q. Xu, D.D. DesMarteau, S.S. Zuberi, M. Witz, H.-N. Huang, J. Fluorine Chem. 58 (1992) 71–79; (o) W. Ying, D.D. DesMarteau, Y. Gotoh, Tetrahedron 52 (1996) 15– 22. (b) Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 54 (1989) 5453–5459; (b) Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 53 (1988) 4160; (c) Y. Takeuchi, K. Nagata, T. Koizumi, J. Org. Chem. 52 (1987) 5061–5063. G.B. Wehrenalp, J. Inorg. Nucl. Chem. 2 (1956) 266. N.E. Searle, Org. Synth. Col., vol. 4, Wiley, New York, 1963, pp. 424– 426. G.A. Olah, J. Welch, Synthesis (1974) 896–898. B. Englund, Org. Synth. Col., vol. 4, Wiley, New York, 1963, pp. 184– 220. B. Englund, Org. Synth. Col., vol. 4, Wiley, New York, 1963, pp. 423– 429. Y. Takeuchi, M. Nabetani, K. Takagi, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1991) 49–53. (a) R. Sauvetre, J. Normant, J. Villieras, Tetrahedron 31 (1975) 897– 903; (b) J.F. Normant, R. Sauvetre, J. Villieras, C. R. Acad. Sci. Ser. C 277 (1973) 515–517; (c) A.V. Fokin, V.I. Zimin, Y.N. Studnev, A.I. Rapkin, Zh. Org. Khim. 7 (1971) 249–251; (d) V.V. Berrenblit, V.A. Nikitin, V.P. Sass, L.N. Senyushov, Y.K. Starobin, Y.V. Tsyganov, Zh. Org. Khim. 15 (1979) 284–292; (e) P.R. Ortiz de Montellano, W.A. Vinson, J. Am. Chem. Soc. 101 (1979) 2222–2224. R.D. Chambers, Fluorine in Organic Chemistry, Wiley, New York, 1973. K. Nagata, Y. Takeuchi, T. Koizumi, in: Proceedings of the 68th Hokuriku Branch Meeting of Pharmaceutical Society of Japan, Kanazawa, 1986, p. 4 (Book of Abstract). H. Hirschmann, K.R. Hanson, Top. Stereochem. 14 (1983) 183–229. (a) P. Schnurrenberger, M.F. Zu¨ ger, D. Seebach, Helv. Chim. Acta 65 (1982) 1197–1201; (b) B. Weidmann, D. Seebach, Angew. Chem. Int. Ed. Engl. 22 (1983) 31–45. Y. Okamoto, M. Kawashima, K. Yamamoto, K. Hatada, Chem. Lett. (1984) 739–742. A. Ichida, T. Shibata, I. Okamoto, Y. Yuki, H. Namikoshi, Y. Toga, Chromatographia 19 (1984) 280–284. T. Shibata, I. Okamoto, K. Ishii, J. Liq. Chromatogr. 9 (1986) 313–340. Y. Takeuchi, M. Nojiri, T. Koizumi, Y. Iitaka, Tetrahedron Lett. 29 (1988) 4727–4730. Y. Takeuchi, H. Note, M. Nojiri, T. Koizumi, Y. Iitaka, p. 68 (Book of Abstract), in: Proceedings of the 13th Fluorine Conference of Japan, Sendai, 1988. I.L. Knunyants, G.G. Yakobson, Synthesis of Fluoroorganic Compounds, Springer–Verlag, New York, 1985. (a) D.D. Tanner, E.V. Blackburn, G.E. Diaz, J. Am. Chem. Soc. 103 (1981) 1557–1559; (b) N. Ono, H. Miyake, R. Tamura, A. Kaji, Tetrahedron Lett. 22 (1981) 1705–1708; (c) N. Ono, H. Miyake, A. Kamimura, I. Hashimoto, R. Tamura, A. Kaji, Tetrahedron 41 (1985) 4013–4023; (d) N. Ono, T. Hamamoto, T.X. Jun, A. Kaji, Tetrahedron Lett. 28 (1987) 2277–2280.
955
[45] (a) H. Suzuki, K. Takaoka, A. Osuka, Bull. Chem. Soc. Jpn. 58 (1985) 1067–1068; (b) D.H.R. Barton, S.W. McCombie, J. Chem. Soc., Perkin Trans. 1 (1975) 1574–1585. [46] (a) N. Kornblum, S.C. Carlson, R.G. Smith, J. Am. Chem. Soc. 100 (1978) 289–290; (b) N. Kornblum, S.C. Carlson, R.G. Smith, J. Am. Chem. Soc. 101 (1979) 647–657; (c) N. Kornblum, J. Widmer, S.C. Carlson, J. Am. Chem. Soc. 101 (1979) 658–664. [47] (a) N. Ono, R. Tamura, A. Kaji, J. Am. Chem. Soc. 102 (1980) 2851– 2852; (b) N. Ono, R. Tamura, A. Kaji, J. Am. Chem. Soc. 105 (1983) 4017– 4022. [48] B.M. Trost, H.C. Arndt, P.E. Strege, T.R. Verhoeven, Tetrahedron Lett. 17 (1976) 3477–3478. [49] N. Ono, R. Tamura, R. Tanikawa, A. Kaji, J. Chem. Soc., Chem. Commun. (1981) 71–72. [50] J. Chen, D.D. Tanner, J. Org. Chem. 53 (1988) 3897–3900. [51] N. Ono, K. Zinsmeister, A. Kaji, Bull. Chem. Soc. Jpn. 58 (1985) 1069–1070. [52] A. Kaneda, Y. Takeuchi, K. Nagata, T. Koizumi, p. 5 (Book of Abstract), in: Proceedings of the 77th Hokuriku Branch Meeting of Pharmaceutical Society of Japan, Kanazawa, 1989. [53] Y. Takeuchi, A. Kanada, S. Kawahara, T. Koizumi, J. Org. Chem. 58 (1993) 3483–3485. [54] T. Koizumi, T. Hagi, Y. Horie, Y. Takeuchi, Chem. Pharm. Bull. 35 (1987) 3959–3962. [55] T. Takahashi, T. Hagi, K. Kitano, Y. Takeuchi, T. Koizumi, Chem. Lett. (1989) 593–596. [56] T. Takahashi, K. Kitano, T. Hagi, H. Nihonmatsu, T. Koizumi, Chem. Lett. (1989) 597–598. [57] (a) J.M. Seco, E. Quin˜ oa´ , R. Riguera, Chem. Rev. 104 (2004) 17–118; (b) T.J. Wenzel, J.D. Wilcox, Chirality 15 (2003) 256–270. [58] (a) J.S. Dutcher, J.G. Macmillan, C.H. Heathcock, J. Org. Chem. 41 (1976) 2663–2669; (b) L. Hietaniemi, E. Pohjala, P. Malkonen, M.L. Riekkola, Finn. Chem. Lett. 16 (1989) 67–73; (c) A. Svatos, I. Valterova, D. Samon, J. Vrkoc, Collect. Czech. Chem. Commun. 55 (1990) 485–490; (d) H.C. Brown, A.M. Salunkhe, B. Singaram, J. Org. Chem. 56 (1991) 1170–1175. [59] S.K. Latypov, J.M. Seco, E. Quin˜ oa´ , R. Riguera, J. Org. Chem. 61 (1996) 8569–8577. [60] Y. Takeuchi, T. Takahashi, Enantiocontrolled Synthesis of Fluoroorganic Compounds, Wiley, Chichester, 1999, pp. 497–534. [61] Y. Takeuchi, H. Ogura, Y. Ishii, T. Koizumi, J. Chem. Soc., Perkin Trans. 1 (1989) 1721–1725. [62] Y. Takeuchi, H. Ogura, Y. Ishii, T. Koizumi, Chem. Pharm. Bull. 38 (1990) 2404–2408. [63] (a) Y. Takeuchi, N. Itoh, H. Note, T. Koizumi, K. Yamaguchi, J. Am. Chem. Soc. 113 (1991) 6318–6320; (b) Y. Takeuchi, N. Itoh, T. Satoh, T. Koizumi, K. Yamaguchi, J. Org. Chem. 58 (1993) 1812–1820. [64] (a) Y. Takeuchi, N. Itoh, T. Koizumi, J. Chem. Soc., Chem. Commun. (1992) 1514–1515; (b) Y. Takeuchi, N. Itoh, S.-I. Kawahara, T. Koizumi, Tetrahedron 49 (1993) 1861–1870. [65] Y. Takeuchi, H. Iwashita, K. Yamada, M. Gotaishi, N. Kurose, T. Koizumi, K. Kabuto, T. Kometani, Chem. Pharm. Bull. 43 (1995) 1668–1673. [66] (a) Y. Takeuchi, M. Konishi, H. Hori, T. Takahashi, T. Kometani, K.L. Kirk, Chem. Commun. (1998) 365–366; (b) Y. Takeuchi, M. Konishi, H. Hori, T. Takahashi, K.L. Kirk, Enantiomer 4 (1999) 339–344. [67] T. Takahashi, A. Fukushima, Y. Tanaka, Y. Takeuchi, K. Kabuto, C. Kabuto, Chem. Commun. (2000) 788–789.