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Study the reactions of fluoroalkanesulfonyl azides with N-alkylindoles
Journal of Fluorine Chemistry 126 (2005) 113–120 www.elsevier.com/locate/fluor
Study the reactions of fluoroalkanesulfonyl azides with N-alkylindoles Ping He, Shi-Zheng Zhu* Key Laboratory of Organofluorine Chemistry, Shanghai Institution of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China Received 21 March 2004; accepted 26 October 2004 Available online 7 December 2004
Abstract The reactions of fluoroalkanesulfonyl azides RfSO2N3 1 with N-alkylindoles 2 have been studied in detail. It was found that both solvent and the amount of the azides seriously affected the product distribution. 1 reacted with equimolar of 2 in ether or 1,4-dioxane affording 2-(Nsubstituted-indolinylidene)fluoroalkane sulfonylimines 3 as major product; While, treatment of 2 with 2 equiv. of 1 in ethanol, an unexpected product N-substituted-2-fluoroalkanesulfonimino-3-diazo-indolines 4 were obtained in good yield. The reaction mechanism was discussed. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluoroalkanesulfonyl azides; N-alkylindoles; Diazo transfer; 1,3-Dipolar cycloaddition; Carbanion process
1. Introduction As an important nucleus of many alkaloids and pigments, indole and its derivatives have achieved increased significance in medicinal chemistry in recent years [1]. Due to its special structural character, investigations of their chemical transformation also gained much attention [2]. Among them, the reactions of sulfonyl azides with indole and its derivatives were studied extensively. Fusco et al. had reported that benzensulfonyl azides add to open chain enamines in such a fashion that the enamine nitrogen and azide nitrogen are bonded to the same carbon atom in the product [3] (Scheme 1). During the past several years Bailey and coworkers have reported the reaction of arylsulfonyl azides with indole and alkylindoles and afforded similar results [4,5]. It is well known that replacement of hydrogen by fluorine in biologically active molecules often yield analogues with improved reactivity and selectivity due to the unique physical and chemical properties of fluorine and C–F bond * Corresponding author. Tel.: +86 21 641633003525; fax: +86 21 64166128. E-mail address: [email protected] (S.-Z. Zhu). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.10.039
[6]. Per (poly) fluroalkanesulfonyl azides RfSO2N3 1 are more reactive than other nonfluorinated organic azides due to the strong electron-withdrawing property of the RfSO2 group. However, their reactions are studied rarely. Recently we systematically studied their reactions with electron-rich olefin such as enamines, silyl enol ethers, etc. [7], as continuation of our investigation, the reactions of 1 with Nalkylindoles have been examined in detail. These reactions gave 2-(N-substituted-indolinylidene)fluoroalkane sulfonylimines (3), N-substituted-2-fluoroalkanesulfonimino-3diazo-indolines (4) and fluoroalkanesulfonylamide (5), the distribution of the products are dependent on the reaction conditions such as solvent, reaction time and molar ratio of the reactants. Herein we wish to report these results.
2. Results and discussion The reaction of equimolar fluoroalkanesulfonyl azides 1a with N-methylindoles 2a was first investigated. It proceeded smoothly in anhydrous diethyl ether at room temperature, TLC analysis showed that the azide 1a disappeared within 1 h and three products with close polarities formed. After removal of solvent, the residue was separated and purified by
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P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120 Table 1 Reaction results of fluoroalkanesulfonyl azides 1 with N-alkylindoles 2a
Scheme 1.
column chromatography over silica gel using petroleum ether/ether (4:1) as eluant. The first compound 3aa was isolated in 76% yield. In addition, an unexpected product 4aa was also separated in low yield (10%), accompanying with small amount of fluoroalkanesulfonylamide 5a (<3%). New products were fully characterized by spectra methods and elemental analysis. For instance, the MS spectrum of 3aa showed its strong molecular ion peak at m/z 552. Its 1H NMR consists of five peaks at d 7.55 (m), 7.26 (d), 7.11 (d), 4.30 (s), 3.50 (s), which can be assigned to the corresponding four Ar–H, the two benzylic protons at the 3 position and the N–CH3, respectively. Meanwhile, a typical strong absorption at 1552 cm1 in IR spectrum also confirmed the existence of C=N functional group. The mass spectra of 4aa also showed its molecular ion peak, the mass difference between 3aa and 4aa is 26, which should be assigned to the additional diazo group (N2). The major fragment ions observed in spectrum at m/z 235, 207,159 and 132 could be attributed to [M+ Rf], [M+ Rf N2], [M+ RfSO2N] and [M+ RfSO2N N2] respectively. In its 1H NMR spectrum, the peak of two benzylic protons at the 3 position disappeared, while their 19F NMR was similar to 3aa. A strong absorption at 2153 cm1 in IR spectrum was found, which is the typical absorption of C=N+=N. Thus, the molecular structure of compounds 3aa and 4aa were determined as 2-(N-methyl-indolinylidene)fluoroalkane sulfonylimines and N-methyl-2-fluoroalkanesulfonimino-3-diazo-indolines, respectively (Scheme 2). Other azides 1(b–e) that reacted with 2 gave similar results. All these results were summarized in Table 1. Comparing with arylsulfonyl azides, the mild reaction condition (r.t.) and shorter reaction time (1–8 h) both confirmed that fluoroalkanesulfonyl azides are more reactive in these reactions. From Table 1, it was found that when the azide 1b was used, the yields of 4ba or 4bb were increased (Table 1, entries 3 and 4). While in the case of the reaction of azide 1e with 2a or 2b, the yields of 3ea and 3eb were
Entry
Azides
Indoles
Time (h)
Products and yields (%)b
1 2 3 4 5 6 7 8 9
1a 1a 1b 1b 1c 1c 1d 1e 1e
2a 2b 2a 2b 2a 2b 2a 2a 2b
1 4 4 4 8 8 1 8 8
3aa (76) 3ab (54) 3ba (35) 3bb (33) 3ca (32) 3cb (30) 3da (35) 3ea (27) 3eb (26)
a b
4aa (10) 4ab (20) 4ba (23) 4bb (22) 4ca (–) 4cb (12) 4da (15) 4ea (–) 4eb (–)
5a (2) 5a (10) 5b (20) 5b (22) 5c (30) 5c (28) 5d (20) 5e (25) 5e (26)
1:2 = 1:1, reaction carried out in ether at room temperature. Isolated yield.
decreased obviously, even the corresponding 4ea and 4eb were not isolated from the system due to the very small amount but can be seen from the TLC analysis. As mentioned above, the reaction of 1a with 2a was completed within 1 h, however, under the same reaction conditions, the reaction of 1a with N-ethylindole 2b was finished after 4 h (monitored by TLC). Other azides 1, such as 1b, 1c, 1e, however, need more reaction time to complete their reactions. To control the product distribution, some influence factors were studied in detail. For convenience, the reaction of fluoroalkanesulfonyl azide 1a and N-methylindole 2a was chosen as a module reaction. The influence of different solvents was studied first at room temperature using equimolar reactants. The results of solvent effects on the product distribution were summarized in Table 2. From Table 2, it is clear that 1,4-dioxane and Et2O are the suitable solvent for the formation of product 3aa. MeanTable 2 Solvent effects of the product distribution in the reaction of 1a with 2a Entry
Solvent
T (8C)
Time (h)
1 2 3 4 5
Et2O CH2Cl2 C2H5OH 1,4-Dioxane CH3CN
20 20 20 20 20
1 4 0.5 4 4
Scheme 2.
a
Determined by
19
F NMR.
Products and yields (%)a 3aa
4aa
5a
87 88 36 93 81
10 9 32 6 8
3 3 32 1 11
P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120
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Table 3 Effect of the reactants molar ratio on the products distribution in the reaction of 1a with 2a
Table 4 Typical results of fluoroalkanesulfonyl azides 1 with N-alkylindoles 2 in different reaction conditions
Entry
Entry
Molar ratio, 1a/2a
1 1.5 2 3 1.5 2 3
1 2 3 4 5 6 7 a
Determined by
Time (h)
0.5 0.5 0.5 0.5 4 4 4 19
Products and yields (%)a 3aa
4aa
5a
36 20 16 5 0 0 0
32 37 39 44 49 45 44
32 43 45 52 51 55 56
F NMR.
while under the same condition, strong polar and protonic solvent ethanol gave nearly equal amount of 3aa, 4aa and 5a (entry 3), ethanol was the proper solvent to the formation of the diazo product 4aa. During our previous study in Et2O, we found that the molar ratio of the two reactants also affected the product distribution and the diazo products could be major product by control of the molar ratios. Then different molar ratio of the two reactants was investigated at room temperature in ethanol. The whole reaction process was followed by 19F NMR and the corresponding results were summarized in Table 3. It is evident that with the increasing of 1, the proportion of 3aa decreased from 36 to 5%, while the product 4aa increased from 32 to 44% (Table 3, entries 1–4). To our surprise, prolonging the reaction time to 4 h, the product 3aa disappeared and the product 4aa can be selectively formed (entries 2 and 5). From these results, we could assume that the products 4 and 5 were formed during the same process and they might be formed from the transformation of product 3, which also can be deduced from the TLC analysis. This point was confirmed during the following studies. Until now, the controlled reaction conditions to the formation of the product 3 or 4 are optimized. Some typical results of the formation of 3 and 4 are selected and summarized in Table 4.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Azides
1a 1a 1b 1b 1c 1c 1d 1d 1a 1a 1a 1b 1b 1b 1c 1c 1d 1d a
R in 2
2a 2b 2a 2b 2a 2b 2a 2b 2a 2b 2b 2a 2b 2b 2a 2b 2a 2b
Condition Sol. molar ratio
(1/2)
T (h)
1,4-Dioxane 1,4-Dioxane Et2O Et2O 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane Ethanol Ethanol Et2O Ethanol Ethanol Et2O Ethanol Ethanol Ethanol Ethanol
1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2
1 4 4 4 8 8 1 1 2 2 4 8 8 8 8 8 2 2
Product
Yield (%)a
3aa 3ab 3ba 3bb 3ca 3cb 3da 3db 4aa 4ab 4ab 4ba 4bb 4bb 4ca 4cb 4da 4db
73 60 35 33 63 51 70 76 81 90 46 52 89 84 59 52 67 89
Isolated yield and based on 2.
From Table 4, it was found that treatment RfSO2N3 1 with equimolar of 2 in 1,4-dioxane at room temperature, 3 were obtained as major products. Meanwhile, by mixing two equimolar of 1 with 2 in ethanol at room temperature the major products 4 were obtained in moderate to good yields within 2–8 h. Compared with the reaction carried out in Et2O (see Table 1), the yields of 4 were improved obviously. To the best of our knowledge, the transfer of the diazo group from arylsulfonyl azides to an active methylene compound has been known for quite some time [8]. Nearly all the reported examples have involved the transfer of diazo group from sulfonyl azides generally under basic reaction condition [8,9]. However, during the reactions of fluoroalkanesulfonyl azides 1 and N-alkylindoles 2 the diazo transfer reaction to an amidine occurred smoothly in the absence of
Scheme 3.
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base. The products 4 were yellowish stable solid which is different from the hydrocarbon analogues obtained from the reaction of arylsulfonyl azides with indoles studied by Harmon et al. [10]. They found that the corresponding diazo compounds 8 were light sensitive and difficult to isolate in pure form, but treated them with PPh3 affording stable crystalline triphenylphosphine derivatives 9. In addition, the diazo transfer product was not obtained under the same conditions using 1,4-dioxane as a solvent instead of ethanol, i.e., the 2-substituted compounds 6 are the major products and abnormal 3-substituted compounds 7 are the minor products in 1,4-dioxane, however, no the corresponding diazo compounds 8 are formed, which formed only in the ethanol (Scheme 3). During their studies on the reaction of sulfonyl azides with indoles, an amino–imino type of tautomeric equilibrium could be easily observed from the NMR spectra of 6 in DMSO-d6. However, in our case, the products 3 can dissolve in DMSO-d6 solution as well as CDCl3, their NMR spectra shown there is no corresponding amino tautomer exists, the imino tautomers were the sole type (Scheme 4). These results are opposite to those reported by Bailey et al. [11] in the case of 1,3-dimethylindole and are amenable to those
Scheme 4.
reported by Harmon et al. [12]. They found that in general electron-withdrawing substituents on the benzenesulfonamido group reduce the percentage of amino tautomer in solution. Thus, the strong electron-withdrawing ability of the fluorine-containing group perhaps can be used to explain why only the imino tautomers were found in their NMR spectra.
Scheme 5.
Scheme 6.
P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120
In our previous study on the fluoroalkanesulfonyl azides 1, the nitrene RfSO2N: formed thermally at 110 8C, thus in above reactions the nitrene intermediates were not involved. In the reactions of azides 1 with N-alkylindoles 2, the triazoline A should be formed first via 1,3-dipolar cycloaddition process. When the triazoline ring carries an electron-withdrawing group at the 1-position, it is very labile. Thus, the triazolines A are not isolated, it decomposed immediately after their formation in situ followed by elimination of N2 gas and 1,2-H shift to form amidines 3. Since the transfer of diazo group from sulfonyl azides was supposed to involve a carbanion as the reactive species, the formation of diazo compounds 4 may be explained well. The formed amidines 3 could be further reacted with 1 and following with the hydrogen abstraction to form product 4 and fluoroalkanesulfonamide 5, that is, the amidines 3 are the key intermediates to the formation of 4 (Scheme 5). This mechanism was further substantiated by the conversion of amidine 3ba with another equimolar amount of 1b to diazo compound 4ba in 82% yield. Meanwhile, we also obtained the compound 4ca by treatment equimolar of 3ca with 1a under the same condition with excellent yield up to 92%, which was not isolated successfully due to the small amount of formation in corresponding reaction in Et2O (Table 1, entry 5). In addition to 4ca, the formation of another product IRfSO2NH2 5a confirmed the mechanism again (Scheme 6).
3. Conclusions In summary, the reactions of fluoroalkanesulfonyl azides and N-alkylindoles under mild reaction condition were studied in detail. By control of the reactant molar ratio, the 2-(N-substituted-indolinylidene)fluoroalkane sulfonylimines 3 and N-substituted-2-fluoroalkanesulfonimino-3-diazo-indolines 4 were obtained selectively in 1,4-dioxane or ethanol in moderate to good yields, respectively. The obtained products are important synthons in many synthesis processes, their chemical transformations are under way.
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respectively. Elemental analyses were performed by this institute. All solvents were purified before use. Fluoroalkanesulfonyl azides 1 and N-substituted indoles 2 were prepared according to literature [13,14]. 4.1. Typical procedure for the preparation of 2-(N-substituted-indolinylidene) fluoroalkanesulfonylimines 3 To a 10 mL round-bottom flask containing N-substituted indoles 2a (2.0 equiv.) in 2 mL 1,4-dioxane or anhydrous ether was added slowly fluoroalkanesulfonyl azides 1a (2.0 equiv.) at room temperature within 2 min. Then the mixture was continuously stirred at room temperature within 1 h until TLC analysis shown the reaction finished. The solvent was evaporated and the residue was chromatographed on a silica column using petroleum ether/diethyl ether (4:1) as eluant to give pure product 3aa as a white solid. 4.1.1. 2-(N-Methyl-indolinylidene)(50 -iodo-30 -oxa-octafluoropentyl)sulfonyl imines (3aa) m.p. 79–80 8C. FT-IR (nmax, cm1): 1576, 1554 (s, C=N), 1499, 1334, 1177, 1135. 1H NMR d (ppm): 7.80–7.10 (m, 4H, ArH), 4.30 (s, 2H, CH2), 3.50 (s, 3H, CH3). 19F NMR d (ppm): 65.2 (t, 2F, ICF2), 81.7 (t, 2F, CF2O), 85.8 (m, 2F, OCF2), 117.3 (s, 2F, SCF2). MS m/z (ion, %): 552 (M+, 49), 425 (M+ I, 8), 227 (IC2F4+, 6), 209 (M+ Rf, 78), 177 (ICF2+, 6), 145 (M+ RfSO2, 98), 118 + (M RfSO2 HCN, 100). Anal. Calcd. for C13H9F8IN2O3S (%): C, 28.26; H, 1.63; N, 5.07; Found (%): C, 28.20; H, 1.64; N, 5.00.
4. Experimental
4.1.2. 2-(N-methyl-indolinylidene)(50 -chloro-30 -oxa-octafluoropentyl)sulfonyl imines (3ba) m.p. 129–130 8C. FT-IR (nmax, cm1): 1580 (s, C=N), 1384, 1313, 1200, 1167. 1H NMR d (ppm): 7.42–7.12 (m, 4H, ArH), 4.30 (s, 2H, CH2), 3.50 (s, 3H, CH3). 19F NMR d (ppm): 73.7 (s, 2F, ClCF2), 81.2 (t, 2F, CF2O), 86.7 (t, 2F, OCF2), 116.8 (s, 2F, SCF2). MS m/z (ion, %): 462/460 (M+, 13/34), 425 (M+ Cl, 8), 209 (M+ Rf, 69), 145 (M+ RfSO2, 91), 135 (ClC2F4+, 7), 118 (M+ RfSO2 HCN, 100). Anal. Calcd. for C13H9ClF8N2O3S (%): C, 33.91; H, 1.96; N, 6.09; Found (%): C, 33.76; H, 1.96; N, 5.86.
Melting points were measured in Temp-Melt apparatus and were uncorrected. 1H and 19F NMR spectra were recorded in CDCl3 (unless mentioned in text), Bruker AM300 instruments with Me4Si and CFCl3 (with upfield negative) as the internal and external standards, respectively. IR spectra were obtained with a Nicolet AV-360 spectrophotometer. Lower resolution mass spectrum or high resolution mass spectra (HRMS) were obtained on a Finnigan GC-MS 4021 or a Finnigan MAT-8430 instrument using the electron impact ionization technique (70 eV),
4.1.3. 2-(N-methyl-indolinylidene)-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 octafluoro-30 -oxa-pentyl) sulfonyl imines (3ca) m.p. 108–110 8C. FT-IR (nmax, cm1): 1562 (s, C=N), 1338, 1199, 1180. 1H NMR d (ppm): 7.46–7.10 (m, 4H, ArH), 5.88 (t–t, J = 52.5 Hz, 3 Hz, 1H, HCF2), 4.31 (s, 2H, CH2), 3.51 (s, 3H, CH3). 19F NMR d (ppm): 81.2 (t, 2F, CF2O), 88.8 (s, 2F, OCF2), 117.3 (s, 2F, CF2S), 137.6 (d, J = 53 Hz, 2F, HCF2). MS m/z (ion, %): 426 (M+, 34), 209 (M+ Rf, 45), 177 (ICF2+, 6), 145 (M+ RfSO2, 75), 118 (M+ RfSO2 HCN, 100), 101 (HC2F4+, 14). Anal. Calcd.
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for C13H10F8N2O3S (%): C, 36.62; H, 2.35; N, 6.57; Found (%): C, 36.62; H, 2.54; N, 6.31%. 4.1.4. 2-(N-ethyl-indolinylidene)-(50 -iodo-30 -oxaoctafluoropentyl)-sulfonylimines (3ab) m.p. 88–90 8C. FT-IR (nmax, cm1): 2988, 1552 (s, C=N), 1494, 1331, 1290, 1143, 1089. 1H NMR d (ppm): 7.40–7.12 (m, 4H, ArH), 4.29 (s, 2H, CH2), 4.04 (q, J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, J = 7.2 Hz, 3H, CH2CH3). 1H NMR (DMSO-d6) d (ppm): 7.52–7.24 (m, 4H, ArH), 4.34 (s, 2H, CH2), 4.03 (q, J = 7.2 Hz, 2H, CH2CH3), 1.23 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 64.7(t, 2F, ICF2), 81.2 (t, 2F, CF2O), 85.4 (m, 2F, OCF2), 116.6 (s, 2F, CF2S). MS m/z (ion, %): 566 (M+, 22), 439 (M+ I, 4), 227 (IC2F4+, 5), 223 (M+ Rf, 50), 177 (ICF2+, 4), 159 (M+ RfSO2, 100), 132 (M+ RfSO2 HCN, 39). Anal. Calcd. for C14H11F8IN2O3S (%): C, 29.68; H, 1.94; N, 4.95; Found (%): C, 29.70; H, 1.94; N, 4.92. 4.1.5. 2-(N-ethyl-indolinylidene)-(50 -chloro-30 -oxaoctafluoropentyl)-sulfonyl imines (3bb) m.p. 106–108 8C. FT-IR (nmax, cm1): 1569 (s, C=N), 1372, 1317, 1204, 1168. 1H NMR d (ppm): 7.43–7.11 (m, 4H, ArH), 4.29 (s, 2H, CH2), 4.05 (q, J = 7.2 Hz, 2H, CH2CH3), 1.35 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 74.0 (s, 2F, ClCF2), 81.6 (t, 2F, CF2O), 87.0 (t, 2F, OCF2), 117.0 (s, 2F, CF2). MS m/z (ion, %): 476/474 (M+, 9/23), 439 (M+ Cl, 5), 223 (M+ Rf, 46), 159 (M+ RfSO2, 100), 135 (ClC2F4+, 27), 80 (M+ RfSO2 HCN, 100). Anal. Calcd. for C14H11ClF8N2O3S (%): C, 35.41; H, 2.32; N, 5.90; Found (%): C, 35.31; H, 2.54; N, 5.89. 4.1.6. 2-(N-ethyl-indolinylidene)-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 octafluoro-30 -oxa-pentyl)-sulfonylimines (3cb) m.p. 90–92 8C. FT-IR (nmax, cm1): 1568 (s, C=N), 1372, 1319, 1166, 1018. 1H NMR d (ppm): 7.44–7.10 (m, 4H, ArH), 5.88 (t–t, J = 52.8 Hz, 3 Hz, 1H, HCF2), 4.29 (s, 2H, CH2), 4.04 (q, J = 7.5 Hz, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H, CH2CH3). 19F NMR d (ppm): 80.9 (t, 2F, CF2O), 88.6 (t, 2F, OCF2), 116.9 (s, 2F, CF2S), 137.3 (d, J = 53 Hz, 2F, HCF2). MS m/z (ion, %): 440 (M+, 34), 223 (M+ Rf, 45), 159 (M+ RfSO2N, 100), 132 (M+ RfSO2N HCN, 43). HRMS for C14H12F8N2O3S Calcd.: 440.04354%; Found: 440.04393%. 4.1.7. 2-(N-methyl-indolinylidene)perfluorobutylsulfonylimines (3da) m.p. 171–173 8C. FT-IR (nmax, cm1): 1581 (s, C=N), 1504, 1384, 1317, 1163, 1138, 1077. 1H NMR d (ppm): 7.43–7.11 (m, 4H, ArH), 4.31 (s, 2H, CH2), 3.51 (s, 3H, CH3). 19F NMR d (ppm): 80.7 (t, 3F, CF3), 113.4 (t, 2F, CF2S), 120.9 (m, 2F, CF2), 125.9 (t, 2F, CF3CF2). MS m/ z (ion, %): 428 (M+, 14), 209 (M+ Rf, 41), 145 (M+ RfSO2N, 55), 118 (M+ RfSO2N HCN, 100). Anal. Calcd. for C13H9F9N2O2S (%): C, 36.45; H, 2.10; N, 6.54; Found (%): C, 36.70; H, 2.11; N, 6.41.
4.1.8. 2-(N-ethyl-indolinylidene)perfluorobutylsulfonylimines (3db) m.p. 48–50 8C. FT-IR (nmax, cm1): 1569 (s, C=N), 1374, 1317, 1200, 1140, 1046. 1H NMR d (ppm): 7.44–7.11 (m, 4H, ArH), 4.31 (s, 2H, CH2), 4.06 (q, J = 7.5 Hz, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H, CH2CH3). 19F NMR d (ppm): 81.0 (s, 3F, CF3), 113.6 (t, 2F, CF2S), 121.3 (s, 2F, CF2), 126.2 (t, 2F, CF3CF2). MS m/z (ion, %): 442 (M+, 13), 223 (M+ Rf, 39), 159 (M+ RfSO2, 100), 132 (M+ RfSO2 HCN, 43). HRMS for C14H11F9N2O2S Calcd.: 442.03920%; Found: 442.03940%. 4.1.9. 2-(N-methyl-indolinylidene)(20 -isopropoxylcarbonyl-10 -difluoromethyl) sulfonylimines (3ea) m.p. 138–140 8C. FT-IR (nmax, cm1): 2995, 1763, 1577 (s, C=N), 1381, 1318, 1156, 1100. 1H NMR d (ppm): 7.44– 7.08 (m, 4H, ArH), 5.26 (m, 1H, CH), 4.30 (s, 2H, CH2), 3.49 (s, 3H, CH3), 1.40 (d, J = 6.3 Hz, 6H, 2CH3). 19F NMR d (ppm): 109.8 (s, 2F, CF2). MS m/z (ion, %): 346 (M+, 32), 304 (M+ C3H6, 13), 209 (M+ Rf, 93), 145 (M+ RfSO2N, 100), 118 (M+ RfSO2N HCN, 89), 43 (C3H7+, 15). Anal. Calcd. for C14H16F2N2O4S (%): C, 48.55; H, 4.62; N, 8.09; Found (%): C, 48.48; H, 4.56; N, 8.18. 4.1.10. 2-(N-methyl-indolinylidene)(20 -isopropoxylcarbonyl-10 -difluoromethyl) sulfonylimines (3eb) m.p. 120–122 8C. FT-IR (nmax, cm1): 2991, 1765, 1568 (s, C=N), 1374, 1314, 1159, 1097. 1H NMR d (ppm): 7.42– 7.08 (m, 4H, ArH), 5.25 (m, 1H, CH), 4.29 (s, 2H, CH2), 4.02 (q, J = 7.5 Hz, 2H, CH2CH3), 1.40–1.34 (m, 9H, 3CH3). 19F NMR d (ppm): 109.4 (s, 2F, CF2). MS m/z (ion, %): 360 (M+, 26), 318 (M+ C3H6, 7), 223 (M+ Rf, 69), 159 (M+ RfSO2N, 100), 132 (M+ RfSO2N HCN, 32), 43 (C3H7+, 9). HRMS for C15H18F2N2O4S Calcd.: 360.09498%; Found: 360.09486%. 4.2. Typical procedure for the preparation of N-substituted-2-fluoroalkanesulfonimino3-diazo-indolines 4 To a 10 mL round-bottom flask containing N-substituted indoles 2 (1.0 equiv.) in 2 mL anhydrous ethanol was added slowly fluoroalkanesulfonyl azides 1 (2.0 equiv.) at room temperature within 2 min. Then the mixture was continuously stirred at r.t. within 1–8 h until TLC analysis shown that the reaction finished. The solvent was evaporated and the residue was chromatographed on a silica column using petroleum ether/diethyl ether (4:1) as eluant to give pure product 4 as a yellowish solid. 4.2.1. N-methyl-2-(50 -iodo-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4aa) m.p. 90–92 8C. FT-IR (nmax, cm1): 2147 (s, C=N+=N), 1541 (s, C=N), 1386, 1330, 1297, 1218. 1H NMR d (ppm):
P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120
7.42–7.26 (m, 4H, ArH), 3.63 (s, 3H, CH3). 19F NMR d (ppm): 65.0 (t, 2F, ICF2), 81.6 (t, 2F, CF2O), 85.8 (m, 2F, OCF2), 116.9 (s, 2F, CF2S). MS m/z (ion, %): 578 (M+, 23), 451 (M+ I, 2), 235 (M+ Rf, 24), 227 (IC2F4+, 9), 207 (M+ Rf N2, 61), 177 (ICF2+, 15), 159 (M+ RfSO2N, 33), 132 (M+ RfSO2N N2, 100). Anal. Calcd. for C13H7F8IN4O3S (%): C, 26.99; H, 1.21; N, 9.69; Found (%): C, 27.27; H, 1.28; N, 9.33. 4.2.2. N-methyl-2-(50 -chloro-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4ba) m.p. 120–121 8C. FT-IR (nmax, cm1): 2152 (s, C=N+=N), 1544 (s, C=N), 1387, 1329, 1219, 1128. 1H NMR d (ppm): 7.42–7.26 (m, 4H, ArH), 3.63 (s, 3H, CH3). 19 F NMR d (ppm): 73.7 (s, 2F, ClCF2), 81.3 (t, 2F, CF2O), 86.7 (t, 2F, OCF2), 116.8 (s, 2F, CF2S). MS m/z (ion, %): 488/486 (M+, 11/28), 235 (M+ Rf, 28), 207 (M+ Rf N2, 61), 159 (M+ RfSO2N, 32), 135 (ClC2F4+, 9), 132 (M+ RfSO2N N2, 100). Anal. Calcd. for C13H7ClF8N4O3S (%): C, 32.10; H, 1.44; N, 11.52; Found (%): C, 31.79; H, 1.68; N, 11.43. 4.2.3. N-methyl-2-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 -octafluoro30 -oxa-pentyl)-sulfonimino-3-diazo-indolines (4ca) m.p. 114–116 8C. FT-IR (nmax, cm1): 2153 (s, C=N+=N), 1545 (s, C=N), 1388, 1329, 1141. 1H NMR d (ppm): 7.46–7.11 (m, 4H, ArH), 5.88 (t–t, J = 52.2 Hz, 3 Hz, 1H, HCF2), 3.60 (s, 3H, CH3). 19F NMR d (ppm): 81.3 (t, 2F, CF2O), 88.9 (s, 2F, OCF2), 117.1 (s, 2F, CF2S), 137.6 (d, J = 53 Hz, 2F, HCF2). MS m/z (ion, %): 452 (M+, 26), 235 (M+ Rf, 25), 207 (M+ Rf N2, 48), 159 (M+ RfSO2N, 33), 132 (M+ RfSO2N N2, 100), 101 (HC2F4+, 22). Anal. Calcd. for C13H8F8N4O3S (%): C, 34.51; H, 1.77; N, 12.39; Found (%): C, 34.58; H, 1.90; N, 12.41. 4.2.4. N-ethyl-2-(50 -iodo-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4ab) m.p. 85–86 8C. FT-IR (nmax, cm1): 2130 (s, C=N+=N), 1527 (s, C=N), 1398, 1332, 1291, 1213, 1138. 1H NMR d (ppm): 7.42–7.26 (m, 4H, ArH), 4.18 (q, J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 64.6 (t, 2F, ICF2), 81.3 (t, 2F, CF2O), 85.4 (m, 2F, OCF2), 116.5 (s, 2F, CF2S). MS m/z (ion, %): 592 (M+, 29), 465 (M+ I, 3), 249 (M+ Rf, 31), 227 (IC2F4+, 9), 221 (M+ Rf N2, 93), 177 (ICF2+, 24), 146 (M+ RfSO2N N2, 100). Anal. Calcd. for C14H9F8IN4O3S (%): C, 28.38; H, 1.52; N, 9.46; Found (%): C, 28.50; H, 1.62; N, 9.17. 4.2.5. N-ethyl-2-(50 -chloro-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4bb) m.p. 70–72 8C. FT-IR (nmax, cm1): 2964, 2155 (s, C=N+=N), 1531 (s, C=N), 1401, 1329, 1175, 1135. 1H NMR d (ppm): 7.41–7.26 (m, 4H, ArH), 4.18 (q, J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 73.7 (s, 2F, ClCF2), 81.3 (t, 2F, CF2O), 86.7 (t, 2F, OCF2), 116.6 (s, 2F, CF2S). MS m/z (ion, %): 502/500
119
(M+, 7/19), 249 (M+ Rf, 21), 221 (M+ Rf N2, 54), 146 (M+ RfSO2N N2, 100). Anal. Calcd. for C14H9ClF8N4O3S (%): C, 33.57; H, 1.80; N, 11.19; Found (%): C, 33.63; H, 1.95; N, 11.31. 4.2.6. N-ethyl-2-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 -octafluoro30 -oxa-pentyl)-sulfonimino-3-diazo-indolines (4cb) m.p. 86–88 8C. FT-IR (nmax, cm1): 2134 (s, C=N+=N), 1533 (s, C=N), 1397, 1322, 1210, 1138, 1059. 1H NMR d (ppm): 7.42–7.25 (m, 4H, ArH), 5.88 (t–t, J = 52.5 Hz, 3 Hz, 1H, HCF2), 4.17 (q, J = 7.5 Hz, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H, CH2CH3). 19F NMR d (ppm): 81.0 (t, 2F, CF2O), 88.6 (m, 2F, OCF2), 116.6 (s, 2F, CF2S), 137.3 (d, J = 52.5 Hz, 2F, HCF2,). MS m/z (ion, %): 466 (M+, 24), 249 (M+ Rf, 21), 221 (M+ Rf N2, 47), 146 (M+ RfSO2N N2, 100). HRMS for C14H10F8N4O3S Calcd.: 446.03404%; Found: 446.03532%. 4.2.7. N-methyl-2-perfluorobutylsulfonimino-3-diazoindolines (4da) m.p. 140–142 8C. FT-IR (nmax, cm1): 2138 (s, C=N+=N), 1562 (s, C=N), 1435, 1392, 1307, 1218, 1137. 1H NMR d (ppm): 7.41–7.26 (m, 4H, ArH), 3.64 (s, 3H, CH3). 19F NMR d (ppm): 80.9 (t, 3F, CF3), 113.4 (t, 2F, CF2S), 121.3 (s, 2F, CF2), 126.2 (t, 2F, CF3CF2). MS m/z (ion, %): 235 (M+ Rf, 14), 207 (M+ Rf N2, 23), 159 (M+ RfSO2N, 37), 132 (M+ RfSO2N N2, 100). Anal. Calcd. for C13H7F9N4O2S (%): C, 34.36; H, 1.54; N, 12.33; Found (%): C, 34.28; H, 1.60; N, 12.37. 4.2.8. N-ethyl-2-perfluorobutylsulfonimino-3-diazoindolines (4da) m.p. 58–60 8C. FT-IR (nmax, cm1): 2981, 2143 (s, C=N+=N), 1522 (s, C=N), 1460, 1395, 1333, 1216, 1165, 1061. 1H NMR d (ppm): 7.41–7.26 (m, 4H, ArH), 4.19 (q, J = 7.2 Hz, 2H, CH2CH3), 1.37 (t, J = 7.2 Hz, 3H, CH2CH3). 19 F NMR d (ppm): 81.0 (t, 3F, CF3), 113.4 (t, 2F, CF2S), 121.3 (s, 2F, CF2), 126.2 (t, 2F, CF3CF2). MS m/z (ion, %): 468 (M+, 43), 249 (M+ Rf, 32), 221 (M+ Rf N2, 46), 146 (M+ RfSO2N N2, 100). Anal. Calcd. for C14H9F9N4O2S (%): C, 35.90; H, 1.92; N, 11.96; Found (%): C, 35.86; H, 1.86; N, 12.08.
Acknowledgements The authors thank the National Natural Science Foundation of China (nos. 20032010, 20372077) and Innovation Foundation of Chinese Academy of Science for financial support.
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Study the reactions of fluoroalkanesulfonyl azides with N-alkylindoles Ping He, Shi-Zheng Zhu* Key Laboratory of Organofluorine Chemistry, Shanghai Institution of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China Received 21 March 2004; accepted 26 October 2004 Available online 7 December 2004
Abstract The reactions of fluoroalkanesulfonyl azides RfSO2N3 1 with N-alkylindoles 2 have been studied in detail. It was found that both solvent and the amount of the azides seriously affected the product distribution. 1 reacted with equimolar of 2 in ether or 1,4-dioxane affording 2-(Nsubstituted-indolinylidene)fluoroalkane sulfonylimines 3 as major product; While, treatment of 2 with 2 equiv. of 1 in ethanol, an unexpected product N-substituted-2-fluoroalkanesulfonimino-3-diazo-indolines 4 were obtained in good yield. The reaction mechanism was discussed. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluoroalkanesulfonyl azides; N-alkylindoles; Diazo transfer; 1,3-Dipolar cycloaddition; Carbanion process
1. Introduction As an important nucleus of many alkaloids and pigments, indole and its derivatives have achieved increased significance in medicinal chemistry in recent years [1]. Due to its special structural character, investigations of their chemical transformation also gained much attention [2]. Among them, the reactions of sulfonyl azides with indole and its derivatives were studied extensively. Fusco et al. had reported that benzensulfonyl azides add to open chain enamines in such a fashion that the enamine nitrogen and azide nitrogen are bonded to the same carbon atom in the product [3] (Scheme 1). During the past several years Bailey and coworkers have reported the reaction of arylsulfonyl azides with indole and alkylindoles and afforded similar results [4,5]. It is well known that replacement of hydrogen by fluorine in biologically active molecules often yield analogues with improved reactivity and selectivity due to the unique physical and chemical properties of fluorine and C–F bond * Corresponding author. Tel.: +86 21 641633003525; fax: +86 21 64166128. E-mail address: [email protected] (S.-Z. Zhu). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.10.039
[6]. Per (poly) fluroalkanesulfonyl azides RfSO2N3 1 are more reactive than other nonfluorinated organic azides due to the strong electron-withdrawing property of the RfSO2 group. However, their reactions are studied rarely. Recently we systematically studied their reactions with electron-rich olefin such as enamines, silyl enol ethers, etc. [7], as continuation of our investigation, the reactions of 1 with Nalkylindoles have been examined in detail. These reactions gave 2-(N-substituted-indolinylidene)fluoroalkane sulfonylimines (3), N-substituted-2-fluoroalkanesulfonimino-3diazo-indolines (4) and fluoroalkanesulfonylamide (5), the distribution of the products are dependent on the reaction conditions such as solvent, reaction time and molar ratio of the reactants. Herein we wish to report these results.
2. Results and discussion The reaction of equimolar fluoroalkanesulfonyl azides 1a with N-methylindoles 2a was first investigated. It proceeded smoothly in anhydrous diethyl ether at room temperature, TLC analysis showed that the azide 1a disappeared within 1 h and three products with close polarities formed. After removal of solvent, the residue was separated and purified by
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P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120 Table 1 Reaction results of fluoroalkanesulfonyl azides 1 with N-alkylindoles 2a
Scheme 1.
column chromatography over silica gel using petroleum ether/ether (4:1) as eluant. The first compound 3aa was isolated in 76% yield. In addition, an unexpected product 4aa was also separated in low yield (10%), accompanying with small amount of fluoroalkanesulfonylamide 5a (<3%). New products were fully characterized by spectra methods and elemental analysis. For instance, the MS spectrum of 3aa showed its strong molecular ion peak at m/z 552. Its 1H NMR consists of five peaks at d 7.55 (m), 7.26 (d), 7.11 (d), 4.30 (s), 3.50 (s), which can be assigned to the corresponding four Ar–H, the two benzylic protons at the 3 position and the N–CH3, respectively. Meanwhile, a typical strong absorption at 1552 cm1 in IR spectrum also confirmed the existence of C=N functional group. The mass spectra of 4aa also showed its molecular ion peak, the mass difference between 3aa and 4aa is 26, which should be assigned to the additional diazo group (N2). The major fragment ions observed in spectrum at m/z 235, 207,159 and 132 could be attributed to [M+ Rf], [M+ Rf N2], [M+ RfSO2N] and [M+ RfSO2N N2] respectively. In its 1H NMR spectrum, the peak of two benzylic protons at the 3 position disappeared, while their 19F NMR was similar to 3aa. A strong absorption at 2153 cm1 in IR spectrum was found, which is the typical absorption of C=N+=N. Thus, the molecular structure of compounds 3aa and 4aa were determined as 2-(N-methyl-indolinylidene)fluoroalkane sulfonylimines and N-methyl-2-fluoroalkanesulfonimino-3-diazo-indolines, respectively (Scheme 2). Other azides 1(b–e) that reacted with 2 gave similar results. All these results were summarized in Table 1. Comparing with arylsulfonyl azides, the mild reaction condition (r.t.) and shorter reaction time (1–8 h) both confirmed that fluoroalkanesulfonyl azides are more reactive in these reactions. From Table 1, it was found that when the azide 1b was used, the yields of 4ba or 4bb were increased (Table 1, entries 3 and 4). While in the case of the reaction of azide 1e with 2a or 2b, the yields of 3ea and 3eb were
Entry
Azides
Indoles
Time (h)
Products and yields (%)b
1 2 3 4 5 6 7 8 9
1a 1a 1b 1b 1c 1c 1d 1e 1e
2a 2b 2a 2b 2a 2b 2a 2a 2b
1 4 4 4 8 8 1 8 8
3aa (76) 3ab (54) 3ba (35) 3bb (33) 3ca (32) 3cb (30) 3da (35) 3ea (27) 3eb (26)
a b
4aa (10) 4ab (20) 4ba (23) 4bb (22) 4ca (–) 4cb (12) 4da (15) 4ea (–) 4eb (–)
5a (2) 5a (10) 5b (20) 5b (22) 5c (30) 5c (28) 5d (20) 5e (25) 5e (26)
1:2 = 1:1, reaction carried out in ether at room temperature. Isolated yield.
decreased obviously, even the corresponding 4ea and 4eb were not isolated from the system due to the very small amount but can be seen from the TLC analysis. As mentioned above, the reaction of 1a with 2a was completed within 1 h, however, under the same reaction conditions, the reaction of 1a with N-ethylindole 2b was finished after 4 h (monitored by TLC). Other azides 1, such as 1b, 1c, 1e, however, need more reaction time to complete their reactions. To control the product distribution, some influence factors were studied in detail. For convenience, the reaction of fluoroalkanesulfonyl azide 1a and N-methylindole 2a was chosen as a module reaction. The influence of different solvents was studied first at room temperature using equimolar reactants. The results of solvent effects on the product distribution were summarized in Table 2. From Table 2, it is clear that 1,4-dioxane and Et2O are the suitable solvent for the formation of product 3aa. MeanTable 2 Solvent effects of the product distribution in the reaction of 1a with 2a Entry
Solvent
T (8C)
Time (h)
1 2 3 4 5
Et2O CH2Cl2 C2H5OH 1,4-Dioxane CH3CN
20 20 20 20 20
1 4 0.5 4 4
Scheme 2.
a
Determined by
19
F NMR.
Products and yields (%)a 3aa
4aa
5a
87 88 36 93 81
10 9 32 6 8
3 3 32 1 11
P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120
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Table 3 Effect of the reactants molar ratio on the products distribution in the reaction of 1a with 2a
Table 4 Typical results of fluoroalkanesulfonyl azides 1 with N-alkylindoles 2 in different reaction conditions
Entry
Entry
Molar ratio, 1a/2a
1 1.5 2 3 1.5 2 3
1 2 3 4 5 6 7 a
Determined by
Time (h)
0.5 0.5 0.5 0.5 4 4 4 19
Products and yields (%)a 3aa
4aa
5a
36 20 16 5 0 0 0
32 37 39 44 49 45 44
32 43 45 52 51 55 56
F NMR.
while under the same condition, strong polar and protonic solvent ethanol gave nearly equal amount of 3aa, 4aa and 5a (entry 3), ethanol was the proper solvent to the formation of the diazo product 4aa. During our previous study in Et2O, we found that the molar ratio of the two reactants also affected the product distribution and the diazo products could be major product by control of the molar ratios. Then different molar ratio of the two reactants was investigated at room temperature in ethanol. The whole reaction process was followed by 19F NMR and the corresponding results were summarized in Table 3. It is evident that with the increasing of 1, the proportion of 3aa decreased from 36 to 5%, while the product 4aa increased from 32 to 44% (Table 3, entries 1–4). To our surprise, prolonging the reaction time to 4 h, the product 3aa disappeared and the product 4aa can be selectively formed (entries 2 and 5). From these results, we could assume that the products 4 and 5 were formed during the same process and they might be formed from the transformation of product 3, which also can be deduced from the TLC analysis. This point was confirmed during the following studies. Until now, the controlled reaction conditions to the formation of the product 3 or 4 are optimized. Some typical results of the formation of 3 and 4 are selected and summarized in Table 4.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Azides
1a 1a 1b 1b 1c 1c 1d 1d 1a 1a 1a 1b 1b 1b 1c 1c 1d 1d a
R in 2
2a 2b 2a 2b 2a 2b 2a 2b 2a 2b 2b 2a 2b 2b 2a 2b 2a 2b
Condition Sol. molar ratio
(1/2)
T (h)
1,4-Dioxane 1,4-Dioxane Et2O Et2O 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane 1,4-Dioxane Ethanol Ethanol Et2O Ethanol Ethanol Et2O Ethanol Ethanol Ethanol Ethanol
1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2
1 4 4 4 8 8 1 1 2 2 4 8 8 8 8 8 2 2
Product
Yield (%)a
3aa 3ab 3ba 3bb 3ca 3cb 3da 3db 4aa 4ab 4ab 4ba 4bb 4bb 4ca 4cb 4da 4db
73 60 35 33 63 51 70 76 81 90 46 52 89 84 59 52 67 89
Isolated yield and based on 2.
From Table 4, it was found that treatment RfSO2N3 1 with equimolar of 2 in 1,4-dioxane at room temperature, 3 were obtained as major products. Meanwhile, by mixing two equimolar of 1 with 2 in ethanol at room temperature the major products 4 were obtained in moderate to good yields within 2–8 h. Compared with the reaction carried out in Et2O (see Table 1), the yields of 4 were improved obviously. To the best of our knowledge, the transfer of the diazo group from arylsulfonyl azides to an active methylene compound has been known for quite some time [8]. Nearly all the reported examples have involved the transfer of diazo group from sulfonyl azides generally under basic reaction condition [8,9]. However, during the reactions of fluoroalkanesulfonyl azides 1 and N-alkylindoles 2 the diazo transfer reaction to an amidine occurred smoothly in the absence of
Scheme 3.
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base. The products 4 were yellowish stable solid which is different from the hydrocarbon analogues obtained from the reaction of arylsulfonyl azides with indoles studied by Harmon et al. [10]. They found that the corresponding diazo compounds 8 were light sensitive and difficult to isolate in pure form, but treated them with PPh3 affording stable crystalline triphenylphosphine derivatives 9. In addition, the diazo transfer product was not obtained under the same conditions using 1,4-dioxane as a solvent instead of ethanol, i.e., the 2-substituted compounds 6 are the major products and abnormal 3-substituted compounds 7 are the minor products in 1,4-dioxane, however, no the corresponding diazo compounds 8 are formed, which formed only in the ethanol (Scheme 3). During their studies on the reaction of sulfonyl azides with indoles, an amino–imino type of tautomeric equilibrium could be easily observed from the NMR spectra of 6 in DMSO-d6. However, in our case, the products 3 can dissolve in DMSO-d6 solution as well as CDCl3, their NMR spectra shown there is no corresponding amino tautomer exists, the imino tautomers were the sole type (Scheme 4). These results are opposite to those reported by Bailey et al. [11] in the case of 1,3-dimethylindole and are amenable to those
Scheme 4.
reported by Harmon et al. [12]. They found that in general electron-withdrawing substituents on the benzenesulfonamido group reduce the percentage of amino tautomer in solution. Thus, the strong electron-withdrawing ability of the fluorine-containing group perhaps can be used to explain why only the imino tautomers were found in their NMR spectra.
Scheme 5.
Scheme 6.
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In our previous study on the fluoroalkanesulfonyl azides 1, the nitrene RfSO2N: formed thermally at 110 8C, thus in above reactions the nitrene intermediates were not involved. In the reactions of azides 1 with N-alkylindoles 2, the triazoline A should be formed first via 1,3-dipolar cycloaddition process. When the triazoline ring carries an electron-withdrawing group at the 1-position, it is very labile. Thus, the triazolines A are not isolated, it decomposed immediately after their formation in situ followed by elimination of N2 gas and 1,2-H shift to form amidines 3. Since the transfer of diazo group from sulfonyl azides was supposed to involve a carbanion as the reactive species, the formation of diazo compounds 4 may be explained well. The formed amidines 3 could be further reacted with 1 and following with the hydrogen abstraction to form product 4 and fluoroalkanesulfonamide 5, that is, the amidines 3 are the key intermediates to the formation of 4 (Scheme 5). This mechanism was further substantiated by the conversion of amidine 3ba with another equimolar amount of 1b to diazo compound 4ba in 82% yield. Meanwhile, we also obtained the compound 4ca by treatment equimolar of 3ca with 1a under the same condition with excellent yield up to 92%, which was not isolated successfully due to the small amount of formation in corresponding reaction in Et2O (Table 1, entry 5). In addition to 4ca, the formation of another product IRfSO2NH2 5a confirmed the mechanism again (Scheme 6).
3. Conclusions In summary, the reactions of fluoroalkanesulfonyl azides and N-alkylindoles under mild reaction condition were studied in detail. By control of the reactant molar ratio, the 2-(N-substituted-indolinylidene)fluoroalkane sulfonylimines 3 and N-substituted-2-fluoroalkanesulfonimino-3-diazo-indolines 4 were obtained selectively in 1,4-dioxane or ethanol in moderate to good yields, respectively. The obtained products are important synthons in many synthesis processes, their chemical transformations are under way.
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respectively. Elemental analyses were performed by this institute. All solvents were purified before use. Fluoroalkanesulfonyl azides 1 and N-substituted indoles 2 were prepared according to literature [13,14]. 4.1. Typical procedure for the preparation of 2-(N-substituted-indolinylidene) fluoroalkanesulfonylimines 3 To a 10 mL round-bottom flask containing N-substituted indoles 2a (2.0 equiv.) in 2 mL 1,4-dioxane or anhydrous ether was added slowly fluoroalkanesulfonyl azides 1a (2.0 equiv.) at room temperature within 2 min. Then the mixture was continuously stirred at room temperature within 1 h until TLC analysis shown the reaction finished. The solvent was evaporated and the residue was chromatographed on a silica column using petroleum ether/diethyl ether (4:1) as eluant to give pure product 3aa as a white solid. 4.1.1. 2-(N-Methyl-indolinylidene)(50 -iodo-30 -oxa-octafluoropentyl)sulfonyl imines (3aa) m.p. 79–80 8C. FT-IR (nmax, cm1): 1576, 1554 (s, C=N), 1499, 1334, 1177, 1135. 1H NMR d (ppm): 7.80–7.10 (m, 4H, ArH), 4.30 (s, 2H, CH2), 3.50 (s, 3H, CH3). 19F NMR d (ppm): 65.2 (t, 2F, ICF2), 81.7 (t, 2F, CF2O), 85.8 (m, 2F, OCF2), 117.3 (s, 2F, SCF2). MS m/z (ion, %): 552 (M+, 49), 425 (M+ I, 8), 227 (IC2F4+, 6), 209 (M+ Rf, 78), 177 (ICF2+, 6), 145 (M+ RfSO2, 98), 118 + (M RfSO2 HCN, 100). Anal. Calcd. for C13H9F8IN2O3S (%): C, 28.26; H, 1.63; N, 5.07; Found (%): C, 28.20; H, 1.64; N, 5.00.
4. Experimental
4.1.2. 2-(N-methyl-indolinylidene)(50 -chloro-30 -oxa-octafluoropentyl)sulfonyl imines (3ba) m.p. 129–130 8C. FT-IR (nmax, cm1): 1580 (s, C=N), 1384, 1313, 1200, 1167. 1H NMR d (ppm): 7.42–7.12 (m, 4H, ArH), 4.30 (s, 2H, CH2), 3.50 (s, 3H, CH3). 19F NMR d (ppm): 73.7 (s, 2F, ClCF2), 81.2 (t, 2F, CF2O), 86.7 (t, 2F, OCF2), 116.8 (s, 2F, SCF2). MS m/z (ion, %): 462/460 (M+, 13/34), 425 (M+ Cl, 8), 209 (M+ Rf, 69), 145 (M+ RfSO2, 91), 135 (ClC2F4+, 7), 118 (M+ RfSO2 HCN, 100). Anal. Calcd. for C13H9ClF8N2O3S (%): C, 33.91; H, 1.96; N, 6.09; Found (%): C, 33.76; H, 1.96; N, 5.86.
Melting points were measured in Temp-Melt apparatus and were uncorrected. 1H and 19F NMR spectra were recorded in CDCl3 (unless mentioned in text), Bruker AM300 instruments with Me4Si and CFCl3 (with upfield negative) as the internal and external standards, respectively. IR spectra were obtained with a Nicolet AV-360 spectrophotometer. Lower resolution mass spectrum or high resolution mass spectra (HRMS) were obtained on a Finnigan GC-MS 4021 or a Finnigan MAT-8430 instrument using the electron impact ionization technique (70 eV),
4.1.3. 2-(N-methyl-indolinylidene)-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 octafluoro-30 -oxa-pentyl) sulfonyl imines (3ca) m.p. 108–110 8C. FT-IR (nmax, cm1): 1562 (s, C=N), 1338, 1199, 1180. 1H NMR d (ppm): 7.46–7.10 (m, 4H, ArH), 5.88 (t–t, J = 52.5 Hz, 3 Hz, 1H, HCF2), 4.31 (s, 2H, CH2), 3.51 (s, 3H, CH3). 19F NMR d (ppm): 81.2 (t, 2F, CF2O), 88.8 (s, 2F, OCF2), 117.3 (s, 2F, CF2S), 137.6 (d, J = 53 Hz, 2F, HCF2). MS m/z (ion, %): 426 (M+, 34), 209 (M+ Rf, 45), 177 (ICF2+, 6), 145 (M+ RfSO2, 75), 118 (M+ RfSO2 HCN, 100), 101 (HC2F4+, 14). Anal. Calcd.
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for C13H10F8N2O3S (%): C, 36.62; H, 2.35; N, 6.57; Found (%): C, 36.62; H, 2.54; N, 6.31%. 4.1.4. 2-(N-ethyl-indolinylidene)-(50 -iodo-30 -oxaoctafluoropentyl)-sulfonylimines (3ab) m.p. 88–90 8C. FT-IR (nmax, cm1): 2988, 1552 (s, C=N), 1494, 1331, 1290, 1143, 1089. 1H NMR d (ppm): 7.40–7.12 (m, 4H, ArH), 4.29 (s, 2H, CH2), 4.04 (q, J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, J = 7.2 Hz, 3H, CH2CH3). 1H NMR (DMSO-d6) d (ppm): 7.52–7.24 (m, 4H, ArH), 4.34 (s, 2H, CH2), 4.03 (q, J = 7.2 Hz, 2H, CH2CH3), 1.23 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 64.7(t, 2F, ICF2), 81.2 (t, 2F, CF2O), 85.4 (m, 2F, OCF2), 116.6 (s, 2F, CF2S). MS m/z (ion, %): 566 (M+, 22), 439 (M+ I, 4), 227 (IC2F4+, 5), 223 (M+ Rf, 50), 177 (ICF2+, 4), 159 (M+ RfSO2, 100), 132 (M+ RfSO2 HCN, 39). Anal. Calcd. for C14H11F8IN2O3S (%): C, 29.68; H, 1.94; N, 4.95; Found (%): C, 29.70; H, 1.94; N, 4.92. 4.1.5. 2-(N-ethyl-indolinylidene)-(50 -chloro-30 -oxaoctafluoropentyl)-sulfonyl imines (3bb) m.p. 106–108 8C. FT-IR (nmax, cm1): 1569 (s, C=N), 1372, 1317, 1204, 1168. 1H NMR d (ppm): 7.43–7.11 (m, 4H, ArH), 4.29 (s, 2H, CH2), 4.05 (q, J = 7.2 Hz, 2H, CH2CH3), 1.35 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 74.0 (s, 2F, ClCF2), 81.6 (t, 2F, CF2O), 87.0 (t, 2F, OCF2), 117.0 (s, 2F, CF2). MS m/z (ion, %): 476/474 (M+, 9/23), 439 (M+ Cl, 5), 223 (M+ Rf, 46), 159 (M+ RfSO2, 100), 135 (ClC2F4+, 27), 80 (M+ RfSO2 HCN, 100). Anal. Calcd. for C14H11ClF8N2O3S (%): C, 35.41; H, 2.32; N, 5.90; Found (%): C, 35.31; H, 2.54; N, 5.89. 4.1.6. 2-(N-ethyl-indolinylidene)-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 octafluoro-30 -oxa-pentyl)-sulfonylimines (3cb) m.p. 90–92 8C. FT-IR (nmax, cm1): 1568 (s, C=N), 1372, 1319, 1166, 1018. 1H NMR d (ppm): 7.44–7.10 (m, 4H, ArH), 5.88 (t–t, J = 52.8 Hz, 3 Hz, 1H, HCF2), 4.29 (s, 2H, CH2), 4.04 (q, J = 7.5 Hz, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H, CH2CH3). 19F NMR d (ppm): 80.9 (t, 2F, CF2O), 88.6 (t, 2F, OCF2), 116.9 (s, 2F, CF2S), 137.3 (d, J = 53 Hz, 2F, HCF2). MS m/z (ion, %): 440 (M+, 34), 223 (M+ Rf, 45), 159 (M+ RfSO2N, 100), 132 (M+ RfSO2N HCN, 43). HRMS for C14H12F8N2O3S Calcd.: 440.04354%; Found: 440.04393%. 4.1.7. 2-(N-methyl-indolinylidene)perfluorobutylsulfonylimines (3da) m.p. 171–173 8C. FT-IR (nmax, cm1): 1581 (s, C=N), 1504, 1384, 1317, 1163, 1138, 1077. 1H NMR d (ppm): 7.43–7.11 (m, 4H, ArH), 4.31 (s, 2H, CH2), 3.51 (s, 3H, CH3). 19F NMR d (ppm): 80.7 (t, 3F, CF3), 113.4 (t, 2F, CF2S), 120.9 (m, 2F, CF2), 125.9 (t, 2F, CF3CF2). MS m/ z (ion, %): 428 (M+, 14), 209 (M+ Rf, 41), 145 (M+ RfSO2N, 55), 118 (M+ RfSO2N HCN, 100). Anal. Calcd. for C13H9F9N2O2S (%): C, 36.45; H, 2.10; N, 6.54; Found (%): C, 36.70; H, 2.11; N, 6.41.
4.1.8. 2-(N-ethyl-indolinylidene)perfluorobutylsulfonylimines (3db) m.p. 48–50 8C. FT-IR (nmax, cm1): 1569 (s, C=N), 1374, 1317, 1200, 1140, 1046. 1H NMR d (ppm): 7.44–7.11 (m, 4H, ArH), 4.31 (s, 2H, CH2), 4.06 (q, J = 7.5 Hz, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H, CH2CH3). 19F NMR d (ppm): 81.0 (s, 3F, CF3), 113.6 (t, 2F, CF2S), 121.3 (s, 2F, CF2), 126.2 (t, 2F, CF3CF2). MS m/z (ion, %): 442 (M+, 13), 223 (M+ Rf, 39), 159 (M+ RfSO2, 100), 132 (M+ RfSO2 HCN, 43). HRMS for C14H11F9N2O2S Calcd.: 442.03920%; Found: 442.03940%. 4.1.9. 2-(N-methyl-indolinylidene)(20 -isopropoxylcarbonyl-10 -difluoromethyl) sulfonylimines (3ea) m.p. 138–140 8C. FT-IR (nmax, cm1): 2995, 1763, 1577 (s, C=N), 1381, 1318, 1156, 1100. 1H NMR d (ppm): 7.44– 7.08 (m, 4H, ArH), 5.26 (m, 1H, CH), 4.30 (s, 2H, CH2), 3.49 (s, 3H, CH3), 1.40 (d, J = 6.3 Hz, 6H, 2CH3). 19F NMR d (ppm): 109.8 (s, 2F, CF2). MS m/z (ion, %): 346 (M+, 32), 304 (M+ C3H6, 13), 209 (M+ Rf, 93), 145 (M+ RfSO2N, 100), 118 (M+ RfSO2N HCN, 89), 43 (C3H7+, 15). Anal. Calcd. for C14H16F2N2O4S (%): C, 48.55; H, 4.62; N, 8.09; Found (%): C, 48.48; H, 4.56; N, 8.18. 4.1.10. 2-(N-methyl-indolinylidene)(20 -isopropoxylcarbonyl-10 -difluoromethyl) sulfonylimines (3eb) m.p. 120–122 8C. FT-IR (nmax, cm1): 2991, 1765, 1568 (s, C=N), 1374, 1314, 1159, 1097. 1H NMR d (ppm): 7.42– 7.08 (m, 4H, ArH), 5.25 (m, 1H, CH), 4.29 (s, 2H, CH2), 4.02 (q, J = 7.5 Hz, 2H, CH2CH3), 1.40–1.34 (m, 9H, 3CH3). 19F NMR d (ppm): 109.4 (s, 2F, CF2). MS m/z (ion, %): 360 (M+, 26), 318 (M+ C3H6, 7), 223 (M+ Rf, 69), 159 (M+ RfSO2N, 100), 132 (M+ RfSO2N HCN, 32), 43 (C3H7+, 9). HRMS for C15H18F2N2O4S Calcd.: 360.09498%; Found: 360.09486%. 4.2. Typical procedure for the preparation of N-substituted-2-fluoroalkanesulfonimino3-diazo-indolines 4 To a 10 mL round-bottom flask containing N-substituted indoles 2 (1.0 equiv.) in 2 mL anhydrous ethanol was added slowly fluoroalkanesulfonyl azides 1 (2.0 equiv.) at room temperature within 2 min. Then the mixture was continuously stirred at r.t. within 1–8 h until TLC analysis shown that the reaction finished. The solvent was evaporated and the residue was chromatographed on a silica column using petroleum ether/diethyl ether (4:1) as eluant to give pure product 4 as a yellowish solid. 4.2.1. N-methyl-2-(50 -iodo-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4aa) m.p. 90–92 8C. FT-IR (nmax, cm1): 2147 (s, C=N+=N), 1541 (s, C=N), 1386, 1330, 1297, 1218. 1H NMR d (ppm):
P. He, S.-Z. Zhu / Journal of Fluorine Chemistry 126 (2005) 113–120
7.42–7.26 (m, 4H, ArH), 3.63 (s, 3H, CH3). 19F NMR d (ppm): 65.0 (t, 2F, ICF2), 81.6 (t, 2F, CF2O), 85.8 (m, 2F, OCF2), 116.9 (s, 2F, CF2S). MS m/z (ion, %): 578 (M+, 23), 451 (M+ I, 2), 235 (M+ Rf, 24), 227 (IC2F4+, 9), 207 (M+ Rf N2, 61), 177 (ICF2+, 15), 159 (M+ RfSO2N, 33), 132 (M+ RfSO2N N2, 100). Anal. Calcd. for C13H7F8IN4O3S (%): C, 26.99; H, 1.21; N, 9.69; Found (%): C, 27.27; H, 1.28; N, 9.33. 4.2.2. N-methyl-2-(50 -chloro-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4ba) m.p. 120–121 8C. FT-IR (nmax, cm1): 2152 (s, C=N+=N), 1544 (s, C=N), 1387, 1329, 1219, 1128. 1H NMR d (ppm): 7.42–7.26 (m, 4H, ArH), 3.63 (s, 3H, CH3). 19 F NMR d (ppm): 73.7 (s, 2F, ClCF2), 81.3 (t, 2F, CF2O), 86.7 (t, 2F, OCF2), 116.8 (s, 2F, CF2S). MS m/z (ion, %): 488/486 (M+, 11/28), 235 (M+ Rf, 28), 207 (M+ Rf N2, 61), 159 (M+ RfSO2N, 32), 135 (ClC2F4+, 9), 132 (M+ RfSO2N N2, 100). Anal. Calcd. for C13H7ClF8N4O3S (%): C, 32.10; H, 1.44; N, 11.52; Found (%): C, 31.79; H, 1.68; N, 11.43. 4.2.3. N-methyl-2-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 -octafluoro30 -oxa-pentyl)-sulfonimino-3-diazo-indolines (4ca) m.p. 114–116 8C. FT-IR (nmax, cm1): 2153 (s, C=N+=N), 1545 (s, C=N), 1388, 1329, 1141. 1H NMR d (ppm): 7.46–7.11 (m, 4H, ArH), 5.88 (t–t, J = 52.2 Hz, 3 Hz, 1H, HCF2), 3.60 (s, 3H, CH3). 19F NMR d (ppm): 81.3 (t, 2F, CF2O), 88.9 (s, 2F, OCF2), 117.1 (s, 2F, CF2S), 137.6 (d, J = 53 Hz, 2F, HCF2). MS m/z (ion, %): 452 (M+, 26), 235 (M+ Rf, 25), 207 (M+ Rf N2, 48), 159 (M+ RfSO2N, 33), 132 (M+ RfSO2N N2, 100), 101 (HC2F4+, 22). Anal. Calcd. for C13H8F8N4O3S (%): C, 34.51; H, 1.77; N, 12.39; Found (%): C, 34.58; H, 1.90; N, 12.41. 4.2.4. N-ethyl-2-(50 -iodo-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4ab) m.p. 85–86 8C. FT-IR (nmax, cm1): 2130 (s, C=N+=N), 1527 (s, C=N), 1398, 1332, 1291, 1213, 1138. 1H NMR d (ppm): 7.42–7.26 (m, 4H, ArH), 4.18 (q, J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 64.6 (t, 2F, ICF2), 81.3 (t, 2F, CF2O), 85.4 (m, 2F, OCF2), 116.5 (s, 2F, CF2S). MS m/z (ion, %): 592 (M+, 29), 465 (M+ I, 3), 249 (M+ Rf, 31), 227 (IC2F4+, 9), 221 (M+ Rf N2, 93), 177 (ICF2+, 24), 146 (M+ RfSO2N N2, 100). Anal. Calcd. for C14H9F8IN4O3S (%): C, 28.38; H, 1.52; N, 9.46; Found (%): C, 28.50; H, 1.62; N, 9.17. 4.2.5. N-ethyl-2-(50 -chloro-30 -oxa-octafluoropentyl)sulfonimino-3-diazo-indolines (4bb) m.p. 70–72 8C. FT-IR (nmax, cm1): 2964, 2155 (s, C=N+=N), 1531 (s, C=N), 1401, 1329, 1175, 1135. 1H NMR d (ppm): 7.41–7.26 (m, 4H, ArH), 4.18 (q, J = 7.2 Hz, 2H, CH2CH3), 1.36 (t, J = 7.2 Hz, 3H, CH2CH3). 19F NMR d (ppm): 73.7 (s, 2F, ClCF2), 81.3 (t, 2F, CF2O), 86.7 (t, 2F, OCF2), 116.6 (s, 2F, CF2S). MS m/z (ion, %): 502/500
119
(M+, 7/19), 249 (M+ Rf, 21), 221 (M+ Rf N2, 54), 146 (M+ RfSO2N N2, 100). Anal. Calcd. for C14H9ClF8N4O3S (%): C, 33.57; H, 1.80; N, 11.19; Found (%): C, 33.63; H, 1.95; N, 11.31. 4.2.6. N-ethyl-2-(10 ,10 ,20 ,20 ,40 ,40 ,50 ,50 -octafluoro30 -oxa-pentyl)-sulfonimino-3-diazo-indolines (4cb) m.p. 86–88 8C. FT-IR (nmax, cm1): 2134 (s, C=N+=N), 1533 (s, C=N), 1397, 1322, 1210, 1138, 1059. 1H NMR d (ppm): 7.42–7.25 (m, 4H, ArH), 5.88 (t–t, J = 52.5 Hz, 3 Hz, 1H, HCF2), 4.17 (q, J = 7.5 Hz, 2H, CH2CH3), 1.36 (t, J = 7.5 Hz, 3H, CH2CH3). 19F NMR d (ppm): 81.0 (t, 2F, CF2O), 88.6 (m, 2F, OCF2), 116.6 (s, 2F, CF2S), 137.3 (d, J = 52.5 Hz, 2F, HCF2,). MS m/z (ion, %): 466 (M+, 24), 249 (M+ Rf, 21), 221 (M+ Rf N2, 47), 146 (M+ RfSO2N N2, 100). HRMS for C14H10F8N4O3S Calcd.: 446.03404%; Found: 446.03532%. 4.2.7. N-methyl-2-perfluorobutylsulfonimino-3-diazoindolines (4da) m.p. 140–142 8C. FT-IR (nmax, cm1): 2138 (s, C=N+=N), 1562 (s, C=N), 1435, 1392, 1307, 1218, 1137. 1H NMR d (ppm): 7.41–7.26 (m, 4H, ArH), 3.64 (s, 3H, CH3). 19F NMR d (ppm): 80.9 (t, 3F, CF3), 113.4 (t, 2F, CF2S), 121.3 (s, 2F, CF2), 126.2 (t, 2F, CF3CF2). MS m/z (ion, %): 235 (M+ Rf, 14), 207 (M+ Rf N2, 23), 159 (M+ RfSO2N, 37), 132 (M+ RfSO2N N2, 100). Anal. Calcd. for C13H7F9N4O2S (%): C, 34.36; H, 1.54; N, 12.33; Found (%): C, 34.28; H, 1.60; N, 12.37. 4.2.8. N-ethyl-2-perfluorobutylsulfonimino-3-diazoindolines (4da) m.p. 58–60 8C. FT-IR (nmax, cm1): 2981, 2143 (s, C=N+=N), 1522 (s, C=N), 1460, 1395, 1333, 1216, 1165, 1061. 1H NMR d (ppm): 7.41–7.26 (m, 4H, ArH), 4.19 (q, J = 7.2 Hz, 2H, CH2CH3), 1.37 (t, J = 7.2 Hz, 3H, CH2CH3). 19 F NMR d (ppm): 81.0 (t, 3F, CF3), 113.4 (t, 2F, CF2S), 121.3 (s, 2F, CF2), 126.2 (t, 2F, CF3CF2). MS m/z (ion, %): 468 (M+, 43), 249 (M+ Rf, 32), 221 (M+ Rf N2, 46), 146 (M+ RfSO2N N2, 100). Anal. Calcd. for C14H9F9N4O2S (%): C, 35.90; H, 1.92; N, 11.96; Found (%): C, 35.86; H, 1.86; N, 12.08.
Acknowledgements The authors thank the National Natural Science Foundation of China (nos. 20032010, 20372077) and Innovation Foundation of Chinese Academy of Science for financial support.
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