- Email: [email protected]
Catalytic and enantioselective bromoetherification of olefinic 1,3-diols: mechanistic insight
Tetrahedron xxx (2015) 1e7
Contents lists available at ScienceDirect
Tetrahedron journal homepage: www.elsevier.com/locate/tet
Catalytic and enantioselective bromoetherification of olefinic 1,3-diols: mechanistic insight Zhihai Ke a, Chong Kiat Tan b, Yi Liu b, Keefe Guang Zhi Lee b, Ying-Yeung Yeung a, b, * a b
Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2015 Received in revised form 28 August 2015 Accepted 2 September 2015 Available online xxx
How can high enantioselectivity be achieved when the racemic background reaction proceeds at a rate comparable to that of the catalytic asymmetric reaction? We attempted to rationalize this counterintuitive observation by studying the effect of (1) catalyst structure, (2) temperature and addition sequence of components, (3) catalyst loading, and (4) Brønsted acid additives. In the course of our investigation, it was found that increasing the amount of catalyst used led to inhibition of the stoichiometric reaction. Olefinic 1,3-diol 1, 5 mol % of catalyst 3a, 1 equiv of MsOH, and NBS were added at low temperature in a specific sequence to provide the best performance for the enantioselective bromoetherification. Ó 2015 Published by Elsevier Ltd.
Keywords: Asymmetric halogenation Bromoetherification Chiral sulfide catalyst Lewis base Brønsted acid
1. Introduction Over the last couple of years, a range of new methods for asymmetric halocyclizations have been described. However, most of these methods are applicable only to halolactonizations or related amidations.1e3 On the other hand, suitable methods for asymmetric haloetherifications are rare, and are of general interest.4 Recently-published studies from our laboratory detailed the optimization and development of a novel organocatalytic method for catalytic enantioselective bromoetherification of olefinic 1,3diol 1 using a mono-functional C2-symmetric cyclic sulfide 3a as the catalyst (Scheme 1).5 In the course of optimizing the bromoetherification of olefinic 1,3-diol 1, several interesting phenomena were identified: (1) the protecting group of the catalyst is of great importance in controlling the er; (2) the er and dr are affected by the sequence in which the reagent, catalyst, and substrate are added; (3) an increase in catalyst loading leads to a reduction in reaction yield while the er and dr are maintained; (4) the MsOH additive (1 equiv) alone can catalyze the racemic bromoetherification with reaction rate similar to that of the MsOH/cyclic sulfide 3a catalyzed asymmetric reaction, while the cyclic ether product 2 can be still achieved in the catalytic asymmetric process with high er.
* Corresponding author. Tel.: þ852 39436377; fax: þ852 26035057; e-mail addresses: [email protected], [email protected] (Y.-Y. Yeung).
Despite the successful deployment of the optimized conditions for the catalytic and enantioselective bromoetherification of 1, it was nonetheless of significant interest to elucidate these interesting and unusual observations. In this article, the interesting phenomena and the mechanistic insights will be discussed. 2. Results 2.1. The effect of catalyst structure Based on the optimized conditions in our previous report, a combination of 10 mol % catalyst loading, reaction temperature at 78 C, and reaction time at 48 h was defined as the most general set of reaction parameters with which to examine a variety of catalysts (Scheme 1).5 Olefinic 1,3-diol 1a and NBS were used as the substrate and the halogen source, respectively. In addition, 1 equiv of MsOH was used as an additive. Catalyst 3ae3d, 3i, 3k, 3l, and 3m were synthesized using the method developed by our group.3g,5 The seven-membered ring cyclic sulfides 3ee3g could be prepared from the dimesylate6 which is derived from D-mannitol. The 1,2-diol protecting group in 3j could be modified using the procedure shown in Scheme 2. The key to this synthesis is the formation of the bis-epoxide7 which can be ring-opened by phenol derivatives to form analogs of the desired catalysts. The cyclization of the di-mesylate to form the strained 5,5-trans bicyclic ring system proved to be rather difficult, and required microwave conditions to perform this transformation.
http://dx.doi.org/10.1016/j.tet.2015.09.016 0040-4020/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
2
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
instead of cyclic selenide 3m (29% yield, 65.5:34.5 er). We observed that the sterically-bulkier 2,6-diisopropylphenol derived analogue 3b gave the desired substituted THF in a lower er (94% yield, 92:8 dr, 46.5:53.5 er). Catalysts with dimethyl and diisopropyl substituents directly linked to the bicyclic core (3c and 3d) gave the desired products 2a and 2a0 with 50:50 er, while maintaining moderate levels of conversion and yield. Cyclic sulfides in seven-membered rings (3ee3h) also performed poorly in the reaction. Unfortunately, a 2,5-diphenylpyrimidine derived group (3g) stymied the reaction, leading to 27% yield of the desired product. Changing the tert-butyl substituent in 3a into tert-amyl did not influence the selectivity (3i, 74% yield, 94:6 dr, 84:16 er). However, a significant effect on enantioselectivity was observed when the two methyl groups were removed from the 1,3-dioxolane (3j, 64% yield, 88:12 dr, 51:49 er). In a direct comparison, the deprotected diol derived catalyst (3k) delivered the product in 90% yield with 91:9 dr, 77.5:22.5 er. A further modification using 2,2-di-tert-butyl [1,3,2] dioxasilole (3l) led to a drop in reactivity (47% yield, 88:12 dr, 68.5:31.5 er). 2.2. The effect of addition sequence and reaction temperature
Scheme 1. Effect of catalyst structure on the asymmetric bromoetherification and desymmetrization of 1a.
During our reaction optimization study, it was observed that the addition sequence of the reagent, substrate, and catalyst is of critical importance to the reaction performance. The effect of the addition sequence in the bromoetherification of 1a was investigated as indicated in Scheme 3: (1) 1a and catalyst 3a were dissolved in CH2Cl2 at 78 C. A pre-cooled solution of MsOH in CH2Cl2 (freshly prepared for each experiment) was added to the reaction mixture. After the addition, solid NBS was added. The product 2a was obtained in 80% yield and 71% ee (2) NBS was added to a solution of 1a and catalyst 3a in CH2Cl2 at 78 C. After 5 min, a pre-cooled solution of MsOH in CH2Cl2 was added to the mixture. 61% ee of 2a was obtained. (3) A pre-cooled solution of MsOH in CH2Cl2 was added to a solution of NBS and catalyst in CH2Cl2 at 78 C. Substrate 1a was added and 2a was furnished in 50% ee (4) NBS and MsOH were pre-mixed in CH2Cl2 at 78 C. Following which, catalyst 3a and substrate 1a were added consecutively to yield 2a in 54% ee (5) Addition sequence was the same as that in equation (1) but the reaction was performed at 25 C. The substrate was consumed quickly. However, a complex mixture was obtained and the yield of the desired product 2a was low.
Scheme 2. Preparation of cyclic sulfide catalyst 3j.
Among a range of catalysts surveyed, increased reactivity and enantioselectivity were achieved when cyclic sulfide 3a was used
Scheme 3. Study of the addition sequence.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
We also studied reactions in the absence of the cyclic sulfide catalyst 3 (Scheme 4). It was found that MsOH alone could mediate the cyclization of 1a at room temperature to give 5 in 90% yield (Scheme 4, eq 1). When MsOH, NBS and 1a were mixed at room temperature, a mixture of 2a (90%) and 5 (8%) was obtained (Scheme 4, eq 2). The formation of 5 was totally suppressed when the reaction was conducted at 78 C (Scheme 4, eq 3).
3
Table 2-1 Effect of catalyst loading on the asymmetric bromoetherification and desymmetrization of 1aa
Entrya
3a (mol %)
Yield (%)b
drc
er
1 2 3 4 5
1 2 5 10 20
42 98 97 80 72
82:18 93:7 93:7 92:8 92:8
51:49 83:17 85.5:14.5 85.5:14.5 85.5:14.5
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a, methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
2.4. The effect of MsOH additive Scheme 4. Study of reaction without catalyst 3.
A survey on the effect of reaction temperature on the bromoetherification revealed that a low reaction temperature is important for good yield, er, and dr of the desired product 2a (Table 1).
2.3. The effect of catalyst loading For the asymmetric bromoetherification of 1a using 3a as the catalyst, 2a was obtained in low yield and er when 1 mol % of catalyst was used (Table 2-1, entry 1). The yield and er were dramatically improved when the catalyst loading was increased to 2 mol % (Table 2-1, entry 2). The performance was not improved significantly when 5 mol % of 3a was used (Table 2-1, entry 3). While the er and dr maintained when the catalyst loading was further increased (Table 2-1, entries 4 and 5), the yield unexpectedly dropped. We also examined the effect of catalyst loading on the bromoetherification of 1b and a similar trend was observed (Table 2-2). In a direct comparison, 10 mol % catalyst 3a delivered the product 2b in 93% yield with 95.5:4.5 er (Table 2-2, entry 4). We were able to decrease the catalyst loading to 2 mol % (Table 2-2, entry 2) with minimal effect on the yield. Furthermore, lowering the catalyst loading to 1 mol % (Table 2-2, entry 1) gave 2b in 83% yield, 55.5:44.5 er. Again, an increase in catalyst loading led to a reduction in product yield but same er and dr were obtained (Table 2-2, entries 4 and 5).
Table 1 Effect of reaction temperature on bromoetherification and desymmetrization of 1aa
The effect of MsOH loading on the asymmetric reaction was studied (Table 3). 2a was obtained in 61% yield with moderate dr and negligible er in the absence of MsOH additive (Table 3, entry 1). The overall performance was improved when MsOH was added. It is particularly intriguing that the enantioselectivity of the reaction using 3a as the catalyst is strongly dependent on the presence of MsOH (85.5:14.5 er with 1 equiv MsOH and 52:48 er without MsOH), whereas the product yield is comparable in both cases (Table 3, entries 1e3). However, when 1.5 equiv of MsOH was used, the er showed a significant depreciation (Table 3, entry 4). Since it is known that different counterions exert an influence on the reactivity and selectivity of the halocyclization,8 we deemed it important to verify whether other carboxylic/Brønsted acids would perform comparably to MsOH. As such, we examined different achiral Brønsted acid sources, focusing on those providing a range of steric and electronic variation (Table 4). Aliphatic alkanesulfonic acids generally increased the enantioselection with increasing acidity (Table 4, entries 2e4). This effect did not extend to aromatic sulfonic acids, as the p-toluenesulfonic acid performed better than the more acidic triflic acid (Table 4, entries 7 and 8). We also considered that the carboxylate ion may be a more competitive counterion for the selective bromoetherification than succinimide (Table 4, entries 9 and 10), but that turned out not to be the case. Chiral organic acids, including both enantiomers of camphor sulfonic acid and BINOL-derived phosphoric acid, were proven to be inferior in inducing er as compared to MsOH (Table 4, entries 5e6, 11e12). In addition, the chirality of the counterion appears to play an unimportant role on the reaction performance. Table 2-2 Effect of catalyst loading on the asymmetric bromoetherification and desymmetrization of 1ba
Entrya
T ( C)
Yield (%)b
drc
er
Entrya
3a (mol %)
Yield (%)b
drc
ee %
1 2 3 4 5
78 60 40 20 0
80 78 68 65 62
92:8 89:11 88:12 85:15 83:17
85.5:14.5 78.5:21.5 77.5:22.5 73.5:26.5 71:29
1 2 3 4 5
1 2 5 10 20
83 92 98 93 77
88:12 93:7 >99:1 >99:1 >99:1
55.5:44.5 95.5:4.5 95.5:4.5 95.5:4.5 95.5:4.5
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a (10 mol %), methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
a Reactions were conducted with alkenoic diol 1b (0.05 mmol), catalyst 3a, methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
4
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
Table 3 Effect of methanesulfonic acid loading on the asymmetric bromoetherification and desymmetrization of 1aa
Entrya
MsOH (equiv)
Yield (%)b
drc
er
1 2 3 4
0 0.5 1.0 1.5
61 88 80 79
86:14 91:9 92:8 91:9
52:48 68:32 85.5:14.5 69.5:30.5
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a (0.005 mmol), methanesulfonic acid and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
The methaneseleninic acid was more effective in promoting the reaction but did so in a less selective manner (54:46 er; Table 4, entry 13). Interestingly, adamantine-1-sulfonic acid, which is much more sterically bulky than MsOH, caused a substantial decrease in enantioselection to 54.5:45.5 er (Table 4, entry 14). Use of 1adamantanol led to similar results (52:48 er; Table 4, entry 15). 3. Discussion
and structurally well-defined catalyst pocket. The locked conformation of the bicyclic core (acetonide fused cyclic sulfide) would affect the stereo control of the reaction. Acetonide, a common protecting group for 1,2-diols, is critical in obtaining high er. Removing the isopropylidene bridge (3k) led to a decrease of the enantioselectivity of the bromoetherification of 1a. The two methyl groups of the isopropylidene in 3a were also found to be responsible to the high enantioselectivity. The ee dropped significantly when changing the isopropylidene protecting group into a methylene (catalyst 3j) or a bis(tert-butyl) silyl ether (catalyst 3l). In particular, almost no ee was observed when 3j was used, suggesting that the isopropylidene in 3a might offer suitable steric bulkiness in the enantio-determining step. 3.2. The reaction efficiency It is surprising to see that a high catalyst loading led to a decrease in conversion, while the ee and dr are maintained. Based on the previous mechanistic study,5 a 3a-Br intermediate which contains a SeBr Lewis base-coordinated Br system might exist (Scheme 5). The olefin moiety in substrate 1 could then attack the activated electrophilic Br in 3a-Br to form the corresponding bromiranium intermediate A which could further undergo cyclization to yield the cyclic ether product 2.
3.1. The structureeactivity relationship Section 2.1 showed the results of our investigation on the catalyst structure and its influence on the enantioselectivity. It turned out that small changes in the catalyst structure led to fluctuations in the enantioselectivity. Five-membered cyclic sulfides without aromatic substituents (3c and 3d) and seven-membered cyclic sulfides (3ee3g) were ineffective in achieving asymmetric bromoetherification. Changing the 4-tert-butyl group on the phenyl rings in 3a into 2,6-diisopropyl (3b) led to a drop in the er, which might be due to the excessively sterically hindered system. The role of the transfused ring system in 3a and 3i was expected to lock the conformation of the cyclic sulfide five-membered ring, resulting in a rigid Table 4 Effect of various acid additives on the asymmetric bromoetherification and desymmetrization of 1aa
Entrya
Acid
Yield (%)b
drc
er
1 2 3 4 5 6 7 8 9 10 11
Nil MsOH Ethanesulfonic acid Propanesulfonic acid (S)-Camphor sulfonic acid (R)-Camphor sulfonic acid TsOH TfOH TFA Chloroacetic acid (S)-(þ)-1,10 -Binaphthyl-2,20 -diyl hydrogenphosphate (R)-(þ)-1,10 -Binaphthyl-2,20 -diyl hydrogenphosphate Methane seleninic acid Adamantane-1-sulfonic acid 1-Adamantanol
61 80 87 95 88 78 95 32 87 96 96
86:14 92:8 94:6 94:6 94:6 94:6 94:6 90:10 94:6 94:6 94:6
52:48 85.5:14.5 53.5:46.5 50.5:49.5 81:19 81:19 78.5:21.5 67.5:32.5 82:18 81.5:18.5 76:24
93
94:6
72.5:27.5
96 90 85
94:6 93:7 92:8
54:46 54.5:45.5 52:48
12 13 14 15
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a (0.005 mmol), acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
Scheme 5. Sulfide-Br complexes.
In a study by Brown in 2000, it was found that the collidine in the brominating reagent bis(sym-collidine)bromonium triflate would dissociate to form a mono-collidine-coordinated Br species before interacting with the olefin to form the bromiranium intermediate.9 In the case of 3a-catalyzed bromoetherification, we speculate that another molecule of Lewis basic sulfide 3a could also interact with the 3a-Br species (instead of the p-electron of 1a) to give a 3a-Br-3a complex that is similar to the bis(collidine)-Br system in Brown’s case. A higher loading of catalyst 3a might shift the equilibrium in favor of the formation of 3a-Br-3a, which might result in lower conversions due to the trapping of the electrophilic Br (Tables 2-1 and 2-2). Since the same bromiranium intermediate A is still involved, the er and dr should remain unaffected even at high catalyst loading. 3.3. Effect of addition sequence and temperature According to the results presented in Section 2.2, the performance of the catalytic bromoetherification was affected by the components’ addition sequence. The reaction was best performed when NBS was added at last and at 78 C. Other addition sequences led to lower enantioselectivities and/or reaction yields. When adding MsOH as the last component in the reaction (Scheme 3, eq 2), 3a alone could catalyze the reaction with low enantioselectivity as indicated in Table 3, entry 1. This might be the reason for the reduced ee of the overall reaction. Alternatively, when the substrate was added last, i.e., Scheme 3 equation (3) or (4), the prior incubation of catalyst 3a, NBS and MsOH might have led to catalyst decomposition. Indeed, a complex mixture was obtained when catalyst 3 was incubated with NBS for a few hours. When using such incubated catalyst 3 in the asymmetric bromoetherification of 1, 2 was obtained in dramatically diminished er.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
Lewis-basic sulfide catalysts are susceptible to decay by stoichiometric quantities of oxidants. It has been reported that tetrahydrothiophene could decompose through a thiocarbenium ion intermediate when it was treated with N-chlorosuccinimide.10 In our catalyst system, we suspect that a similar decomposition pathway might occur. Intermediate 3-Br, which was generated from 3 and NBS, could undergo de-hydrobromination to give the thiocarbenium ion B. Subsequent nucleophilic addition to B by nucleophiles such as water (from moisture) or the substrate’s hydroxyl group could give a mixture of thioacetals C and D. (Scheme 6).
Scheme 6. A possible decomposition pathway when incubating catalyst 3 with NBS and MsOH.
When the reaction was conducted at relatively high temperatures (e.g., room temperature) (Scheme 3, eq 5), we speculate that catalyst 3 might also decompose through ring-opening of the cyclic sulfide system10 in addition to the decomposition pathway shown in Scheme 7. Since 3-Br is a Swern-type intermediate,10 another possible explanation is that the substrate’s alcohol group might be oxidized (Scheme 6). These possible decomposition pathways could consume both the catalyst and substrate, leading to lower ers and yields of the desired product 2.
Scheme 7. Possible decomposition pathways of the catalyst 3 at relatively high temperature.
Based on the results in Scheme 4 and Table 1, one of the side reactions is the proton-mediated cyclization of 1 (Scheme 8). In addition, it appears that low temperature is beneficial to the reaction due to several aspects: (1) suppression of the protonmediated cyclization; (2) alleviation of catalyst decomposition through pathways shown in Schemes 6 and 7; (3) retardation of the substrate’s hydroxyl group oxidation (Scheme 6). We suspect that MsOH might react with NBS to give MsOBr in situ (together with the formation of the weakly acidic succinimide byproduct) which could be a highly active brominating agent.11 This proposal could explain bromoetherification being preferred over proton-mediated halocyclization when mixing 1a and MsOH, followed by the addition of NBS. Indeed, when mixing NBS and MsOH in CDCl3, NBS disappeared and molecular succinimide was formed. In addition, a new methyl signal at 2.78 ppm (vs MsOH’s methyl signal at 2.63 ppm) was observed which could be attributed to the formation of MsOBr.
Scheme 8. Plausible mechanism of the MsOH-mediated cyclization of 1a.
3.4. The role of MsOH Earlier experiments demonstrated that a stoichiometric amount of MsOH with respect to the substrate is an essential requirement
5
for high enantioselectivity to be achieved. A possible reason for this observation could be that a more configurationally-stable bromiranium ion A, containing a relatively stable and dissociative mesylate counter-anion, was formed. It would lead to less racemization and higher enantioselectivity. As shown in Table 3, the addition of less or more than 1 equiv of MsOH resulted in much reduced enantioselectivity of the bromoether products (Table 3, entries 2 and 4). In the absence of MsOH additive (Table 3, entry 1), bromiranium ion intermediate E would be formed (Scheme 9). As it contains a relatively more associative succinimide counter-anion, it might be less configurationallystable as compared to A. Therefore, the reaction pathway involving intermediate E would lead to poorer enantioselectivity due to the racemization of the bromiranium ion through an olefin-toolefin degeneration.12 When adding 0.5 equiv of MsOH in the reaction (Table 3, entry 2), a mixture of A and E would be present in the reaction, leading to a lower overall er as compared to the result in Table 3, entry 3. When adding 1.5 equiv of MsOH in the reaction (Table 3, entry 4), excess amount of MsOH could catalyze the racemic bromoetherification, which would then reduce the er of the reaction.
Scheme 9. Counteranions of the bromiranium intermediate.
In the course of our experiments, we found that the addition of MsOH to the reaction mixture provided the best selectivities, even when compared to other Brønsted acids. The possible reasons for this observation were discussed below.13 Based on the acid additive screening results shown in Table 4, several observations can be summarized as follows: (1) the pKa of the acid seems to be important to the overall performance of the cyclization, and the acidity of MsOH might be an optimal case which could promote the reaction with high er; (2) the stereochemistry of the counter-anion partner might not play a crucial role in the enantio-determining step (Table 4, entries 5e6, 11e12); (3) the er is significantly affected by the size of the counter-anion, and a higher er could be obtained with a smaller size sulfonate (Table 4, entries 2e4, 14). A possible explanation is that a larger-sized counter-anion (e.g., adamantane sulfonate) might hinder the nucleophilic attack of the hydroxyl group on the bromiranium ion. Thus, the background uncatalyzed cyclization process might proceed well to give racemic products in the presence of a large counteranion. MsOH is a competent Brønsted acid for promoting both the catalyzed and the uncatalyzed cyclization reactions. However, it was observed that the catalyzed and uncatalyzed cyclizations have similar reaction rates (Scheme 3 eq 1 vs Scheme 4 eq 3). If the rate of the uncatalyzed racemic background reaction is comparable to that of the reaction catalyzed by the chiral Lewis base, highly enantiomerically enriched 2a should not be obtainable. Counterintuitively, we obtained 2a in high enantioselectivity using the above system.14 The striking behavior of this catalytic system is reminiscent of Jacobsen’s analysis of the asymmetric catalytic pathway in the Povarov reaction.15 In that study, a similar observation was made in that a Brønsted acid catalyzed racemic background reaction was suppressed, a phenomenon that they ascribed to ‘negative catalysis’.16 Very recently, Denmark and co-workers reported an interesting phenomenon on ‘negative catalysis’ in the asymmetric carbosulfenylation reaction promoted by Lewis basic selenide and
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
6
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
ethanesulfonic acid.14 In their study, it was found that the rate of the Lewis basic selenide-catalyzed reaction is similar to the uncatalyzed reaction, which is highly similar to our observation in the bromoetherification of 1. A possible explanation for the inhibition of the racemic background reaction under catalytic conditions may be found in the buffering effect of the sulfonate ‘triple ion’. In devising the mechanistic proposal of the bromoetherification of 1, we attempted to rationalize our observations in line with critical insights from Denmark’s studies: The true background reaction under ‘catalytic conditions’ was significantly slower than the uncatalyzed background reaction, and is therefore not accurately represented by simply removing the catalyst. Based on Denmark’s proposal, we believe that both sulfonate and succinimide ions (necessary consequences of the formation of the catalytically active species) were effective inhibitors of the racemic background reaction. On the basis of the aforementioned details, a mechanistic proposal is constructed as depicted in Scheme 10. NBS is activated by chiral cyclic sulfide catalyst 3 to give active species 3-Br through a Lewis base activated Lewis acid mechanism. 3-Br then delivers the Br asymmetrically to the olefin to give A. We propose that MsOH facilitates the formation of the cyclic sulfide-Br complex 3-Br through the protonation of succinimide (also see Section 3.3) and enhances the turnover as described in Denmark’s proposal.14 For the uncatalyzed reaction through intermediate G, the pathway could be suppressed by the buffering effect of succinimide and sulfonate anions.
uncatalyzed processes being similar, and (b) that excessive catalyst loading leads to a decrease in yield without affecting enantioselectivity. 5. Experimental section 5.1. General All reactions that required anhydrous conditions were carried by standard procedures under nitrogen atmosphere. Commercially available reagents were used as received. The solvents were dried over a solvent purification system from Innovative Technology. Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrophotometer and reported in wave numbers (cm1). Melting points € were determined on a BUCHI B-540b melting point apparatus. 1H 13 NMR and C NMR spectra were recorded on a Bruker ACF300 (300 MHz), Bruker DPX300 (300 MHz) or AMX500 (500 MHz) spectrometer. Chemical shifts (d) are reported in ppm relative to TMS (d 0.00) for the 1H NMR and to chloroform (d 77.0) for the 13C NMR measurements. Optical rotations were recorded on a Jasco DIP-1000 polarimeter. Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash chromatography separations were performed on Merck 60 (0.040e0.063 mm) mesh silica gel. 5.2. (3aS,4S,6S,6aS)-2,2,4,6-Tetramethyltetrahydrothieno[3,4d][1,3]dioxole 3c A solution of the known dimesylate (916 mg, 2.64 mmol) and sodium sulfide nonahydrate (freshly recrystallized in EtOH, 2.54 g, 10.58 mmol) were both charged into a biotage microwave vessel (20 mL) and dissolved in DMF (15 mL). The reaction mixture was then microwaved at 135 C for 5 min. The reaction was monitored by thin layer chromatography (TLC). Water (35 mL) was then added to the mixture at room temperature and the aqueous layer was extracted with diethyl ether (235 mL). The combined organic layers were washed with water (235 mL) and dried over MgSO4. After filtration, the solution was concentrated in vacuo (the evaporation was realized carefully at room temperature). Purification by flash column chromatography (hexane/ethyl acetate 25:1) afforded 3c (355 mg, 71%) as a colorless oil. ½a25 D 245 (c 1.0, CHCl3); IR (KBr): 2975, 2893, 1453, 1241, 1184, 1077 cm1; 1H NMR (300 MHz, CDCl3): d 4.44 (dd, J¼4.3, 2.1 Hz, 2H), 3.27 (m, 2H), 1.47 (s, 6H), 1.32 (d, J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 119.7, 81.5, 34.7, 27.1, 18.0; HRMS (EI) calcd for C9H16O2S [M]þ: 188.0871; found: 188.0870. 5.3. (3aR,4S,8S,8aR)-2,2-Dimethylhexahydrothiepino[4,5-d] [1,3]dioxole-4,8-diol 3e
Scheme 10. Plausible mechanism of the bromoetherification of 1.
4. Conclusion Research into the enantioselective Lewis base catalyzed, Brønsted acid promoted bromoetherification reaction has offered insights which account for previously observed interesting phenomena. The effect of (1) catalyst structure, (2) temperature and addition sequence of components, (3) catalyst loading, and (4) MsOH additive were discussed. The possible reasons of some unusual observations are (a) the inclusion of MsOH affords high enantioselectivity, despite the rate of the catalyzed reaction and
3e was prepared using a literature procedure.6 White solid, mp 1 93e94 C; ½a25 D 122 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d 4.27 (m, 4H), 3.05 (br s, 2H), 2.95 (dd, J¼15.0, 4.8 Hz, 2H), 2.54 (dd, J¼15.0, 5.8 Hz, 2H), 1.38 (s, 6H); 13C NMR (75 MHz, CDCl3): d 108.5, 75.7, 66.0, 37.3, 26.8; HRMS (EI) calcd for C9H16O4S [M]þ: 220.0769; found: 220.0770. 5.4. (3aS,4S,8S,8aS)-4,8-Bis(benzyloxy)-2,2dimethylhexahydrothiepino[4,5-d][1,3]dioxole 3f To 125 mg (3.12 mmol) of 60% NaH was added under nitrogen 7 mL of THF and 568 mg (2.58 mmol) of the thiepane derivative 3e. The reaction mixture was stirred for 30 min and treated with a solution of 0.3 mL of benzyl bromide and 2 mg (0.012 mmol) of KI in 1.8 mL of THF. After 7 h, 125 mg (3.12 mmol) of 60% NaH and 0.3 mL (2.71 mmol) of benzyl bromide were added. Stirring was continued for 12 h, then H2O was added and the mixture extracted
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
with Et2O (330 mL). The organic layer was dried and evaporated to give 0.99 g (2.39 mmol, 96%) of 3f as a yellow solid which was purified by flash chromatography (SiO2; CH2Cl2/hexane 3:1), giving a solid with mp 56e57 C. ½a25 D 40.1 (c 1.0, CHCl3); IR (KBr): 2945, 1246, 1184, 1078 cm1; 1H NMR (300 MHz, CDCl3): d 7.40 (m, 10H), 4.93 (d, J¼12.0 Hz, 2H), 4.72 (d, J¼12.0 Hz, 2H), 4.70 (m, 2H), 4.20 (m, 2H), 2.93 (dd, J¼15.1, 5.1 Hz, 2H), 2.63 (dd, J¼15.1, 6.1 Hz, 2H), 1.56 (s, 6H); 13C NMR (75 MHz, CDCl3): d 138.7, 128.3, 127.6, 127.5, 109.3, 77.6, 74.1, 73.5, 36.8, 26.9; HRMS (EI) calcd for C23H28O4S [M]þ: 400.1708; found: 400.1710. 5.5. 6,60 -((3aS,4S,8S,8aS)-2,2-Dimethylhexahydrothiepino[4,5d][1,3]dioxole-4,8-diyl)bis(oxy)bis(4-chloro-2,5diphenylpyrimidine) 3g 3g was prepared in analogy to above procedure for 3f. White solid, mp 142e143 C; ½a25 D 52.3 (c 1.0, CHCl3); IR (KBr): 2949, 1246, 1183, 1078 cm1; 1H NMR (300 MHz, CDCl3): d 8.42 (m, 4H), 7.45 (m, 16H), 5.98 (t, J¼5.1 Hz, 2H), 4.44 (m, 2H), 3.31 (dd, J¼15.6, 5.1 Hz, 2H), 3.01 (dd, J¼15.6, 5.7 Hz, 2H), 0.76 (s, 6H); 13C NMR (75 MHz, CDCl3): d 166.5, 162.3, 159.7, 135.9, 131.5, 131.4, 130.2, 128.5, 128.3, 128.1, 118.5, 109.5, 75.3, 71.5, 35.6, 25.8; HRMS (EI) calcd for C41H34Cl2N4O4S [M]þ: 748.1678; found: 748.1678. 5.6. (S)-3,5-Dihydrodinaphtho[2,1-c:10,20 -e]thiepine 3h 3h was prepared using a literature procedure.17 Brown solid, mp 177e178 C; ½a25 D þ280 (c 0.2, CHCl3); IR (KBr): 2915, 2833, 677 cm1; 1H NMR (500 MHz, CDCl3): d 3.43 (s, 4H), 7.20e8.02 (m, 12H); 13C NMR (125 MHz, CDCl3): d 133.4, 133.2, 132.5, 131.2, 128.9, 127.8, 126.4, 126.1, 125.7, 125.1, 31.9; HRMS (EI) calcd for C22H16S [M]þ: 312.0973; found: 312.0971. 5.7. (3aS,4S,6S,6aS)-2,2-Dimethyl-4,6-bis((4-tert-pentylphenoxy)methyl) tetrahydrothieno[3,4-d][1,3]dioxole 3i 3i was prepared in analogy to above procedure for 3c. White solid, mp 130e131 C; ½a25 D 33.4 (c 1.0, CHCl3); IR (KBr): 2964, 2363, 1608, 1512, 1245, 1183, 1079 cm1; 1H NMR (500 MHz, CDCl3): d 7.29 (d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H), 4.70 (dd, J¼4.5, 1.9 Hz, 2H), 4.46 (dd, J¼10.0, 5.7 Hz, 2H), 4.13 (dd, J¼10.0, 7.0 Hz, 2H), 3.66 (m, 2H), 1.67 (q, J¼7.5, 4H), 1.57 (s, 6H), 1.32 (s, 12H), 0.74 (t, J¼7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3): d 156.2, 142.1, 126.8, 120.4, 114.4, 81.6, 68.7, 38.8, 37.2, 36.9, 28.5, 27.1, 9.1; HRMS (EI) calcd for C31H44O4S [M]þ: 512.2960; found: 512.2962. 5.8. (3aS,4S,6S,6aS)-4,6-Bis((4-tert-pentylphenoxy)methyl) tetrahydrothieno[3,4-d][1,3]dioxole 3j 3j was prepared in analogy to above procedure for 3c. White solid, mp 101e102 C; ½a25 D 98.5 (c 1.0, CHCl3); IR (KBr): 2965, 2393, 1508, 1241, 1184, 1027 cm1; 1H NMR (500 MHz, CDCl3): d 7.30 (d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H), 5.65 (s, 2H), 4.62 (dd, J¼4.4, 1.9 Hz, 2H), 4.47 (dd, J¼9.8, 5.7 Hz, 2H), 4.15 (dd, J¼9.8, 7.2 Hz, 2H), 3.69 (m, 2H), 1.68 (q, J¼7.5 Hz, 4H), 1.33 (s, 12H), 0.75 (t, J¼7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3): d 156.0, 142.1, 126.8, 114.1, 104.8, 82.6, 68.4, 38.1, 37.2, 36.8, 28.5, 9.0; HRMS (EI) calcd for C29H40O4S [M]þ: 484.2647; found: 484.2641. 5.9. (2S,3S,4S,5S)-2,5-Bis((4-tert-butylphenoxy)methyl)tetrahydrothiophene-3,4-diol 3k 3k was prepared by conventional hydrolysis of the ketal. White solid, mp 134e135 C; ½a25 D 136 (c 1.0, CHCl3); IR (KBr): 3360, 2965, 2363, 1608, 1241, 1184, 1027 cm1; 1H NMR (500 MHz, CDCl3): d 7.30 (d, J¼8.8 Hz, 4H), 6.86 (d, J¼8.8 Hz, 4H), 5.63 (s, 2H), 4.50 (d,
7
J¼3.2 Hz, 2H), 4.33 (dd, J¼9.5, 8.2 Hz, 2H), 4.17 (dd, J¼9.5, 5.7 Hz, 2H), 4.08 (m, 2H), 1.29 (s, 18H); 13C NMR (125 MHz, CDCl3): d 156.0, 144.1, 126.3, 114.1, 78.3, 66.8, 48.0, 34.1, 31.5; HRMS (EI) calcd for C26H36O4S [M]þ: 444.2334; found: 444.2330. Acknowledgements We thank the financial support from National University of Singapore (grant no. 143-000-605-112), A*STAR-Public Sector Funding (grant no. 143-000-536-305), and GSK-EDB (grant no. 143000-564-592). Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2015.09.016. References and notes 1. For recent reviews, see: (a) Chen, G. F.; Ma, S. M. Angew. Chem., Int. Ed. 2010, 49, 8306; (b) Castellanos, A.; Fletcher, S. P. Chem.dEur. J. 2011, 17, 5766; (c) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335; (d) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. Aldrichimica Acta 2011, 44, 27; (e) Hennecke, U. Chem.dAsian. J. 2012, 7, 456; (f) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938; (g) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763; (h) Tan, C. K.; Yeung, Y.-Y. Chem. Commun. 2013, 7985. 2. For selected recent examples, see: (a) Huang, D.; Liu, X.; Li, L.; Cai, Y.; Liu, W.; Shi, Y. J. Am. Chem. Soc. 2013, 135, 8101; (b) Zeng, X.; Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem. Commun. 2013, 2418; (c) Jaganathan, A.; Staples, R. J.; Borhan, B. J. Am. Chem. Soc. 2013, 135, 14806; (d) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, O.; Ilupeju, J.; Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.; Gouverneur, V. Angew. Chem., Int. Ed. 2013, 52, 9796; (e) Romanov-Michailidis, ne e, L.; Alexakis, A. Angew. Chem., Int. Ed. 2013, 52, 9266; (f) Tripathi, C. F.; Gue B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013, 52, 8450; (g) Brindle, C. S.; Yeung, C. S.; Jacobsen, E. N. Chem. Sci. 2013, 4, 2100; (h) Zhang, W.; Liu, N.; Schienebeck, C. M.; Zhou, X.; Izhar, I. I.; Guzei, I. A.; Tang, W. Chem. Sci. 2013, 4, 2652; (i) Hu, D. X.; Shibuya, G. M.; Burns, N. Z. J. Am. Chem. Soc. 2013, 135, 12960; (j) Zhang, Y.; Xing, H.; Xie, W.; Wan, X.; Lai, Y.; Ma, D. Adv. Synth. Catal. 2013, 355, 68; (k) Yin, Q.; You, S.-L. Org. Lett. 2013, 15, 4266; (l) Mori, K.; Ichikawa, Y.; Kobayashi, M.; Shibata, Y.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135, 3964. 3. (a) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738; (b) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164; (c) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem. Commun. 2012, 5793; (d) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51, 7771; (e) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492; (f) Zhou, L.; Tay, D. W.; Chen, J.; Leung, G. Y. C.; Yeung, Y.-Y. Chem. Commun. 2013, 4412; (g) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2013, 135, 1232. 4. For other haloetherifications, see: (a) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am. Chem. Soc. 2003, 125, 15748; (b) Kwon, H. Y.; Park, C. M.; Lee, S. B.; Youn, J. H.; € ller, C. H.; Kang, S. H. Chem.dEur. J. 2008, 14, 1023; (c) Hennecke, U.; Mu €hlich, R. Org. Lett. 2011, 13, 860; (d) Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li, Fro L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350; (e) Denmark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256. 5. Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014, 136, 5627. 6. (a) Depezay, J. C.; Fuzier, M.; LeMerrer, Y. Heterocycles 1987, 25, 541; (b) LeMerrer, Y.; Fuzier, M.; Dosbaa, I.; Foglietti, M.-J.; Depezay, J.-C. Tetrahedron 1997, 53, 16731. ault, A.; Gravier, C.; Languin, D.; Depezay, J. C. Tetrahedron 7. LeMerrer, Y.; Dure Lett. 1985, 26, 319. 8. Well-established role of the achiral counteranion in determining the enantioselectivity in analogous iodocyclization reactions was reported. See Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068. 9. Cui, X. L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653. 10. Schmidt, D. L.; Heeschen, J. P.; Klingler, T. C.; McCarty, L. P. J. Org. Chem. 1985, 50, 2840. 11. It has been proposed that AcOH could react with NBS to give AcOBr. For references, see: (a) Chen, K.; Baran, P. S. Nature 2009, 459, 824; (b) Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247; (c) Levine, S. G.; Wall, M. E. J. Am. Chem. Soc. 1959, 81, 2826; (d) Lauer, G.; Oberdorfer, F. Angew. Chem., Int. Ed. 1993, 32, 272. 12. Brown, R. S. Acc. Chem. Res. 1997, 30, 131. 13. For sulfetherification, see Wang, H.; Huang, D.; Cheng, D.; Li, L.; Shi, Y. Org. Lett. 2011, 13, 1650. 14. Denmark, S. E.; Chi, H. M. J. Am. Chem. Soc. 2014, 136, 3655. 15. (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986; (b) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678. 16. (a) Retey, J. Angew. Chem., Lnt. Ed. Engl. 1990, 29, 355; (b) Breslow, R. Acc. Chem. Res. 1991, 24, 317; (c) Abel, E. Adv. Catal. 1957, 9, 330. 17. Foubelo, F.; Moreno, B.; Soler, T.; Yus, M. Tetrahedron 2005, 61, 9082.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Contents lists available at ScienceDirect
Tetrahedron journal homepage: www.elsevier.com/locate/tet
Catalytic and enantioselective bromoetherification of olefinic 1,3-diols: mechanistic insight Zhihai Ke a, Chong Kiat Tan b, Yi Liu b, Keefe Guang Zhi Lee b, Ying-Yeung Yeung a, b, * a b
Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 June 2015 Received in revised form 28 August 2015 Accepted 2 September 2015 Available online xxx
How can high enantioselectivity be achieved when the racemic background reaction proceeds at a rate comparable to that of the catalytic asymmetric reaction? We attempted to rationalize this counterintuitive observation by studying the effect of (1) catalyst structure, (2) temperature and addition sequence of components, (3) catalyst loading, and (4) Brønsted acid additives. In the course of our investigation, it was found that increasing the amount of catalyst used led to inhibition of the stoichiometric reaction. Olefinic 1,3-diol 1, 5 mol % of catalyst 3a, 1 equiv of MsOH, and NBS were added at low temperature in a specific sequence to provide the best performance for the enantioselective bromoetherification. Ó 2015 Published by Elsevier Ltd.
Keywords: Asymmetric halogenation Bromoetherification Chiral sulfide catalyst Lewis base Brønsted acid
1. Introduction Over the last couple of years, a range of new methods for asymmetric halocyclizations have been described. However, most of these methods are applicable only to halolactonizations or related amidations.1e3 On the other hand, suitable methods for asymmetric haloetherifications are rare, and are of general interest.4 Recently-published studies from our laboratory detailed the optimization and development of a novel organocatalytic method for catalytic enantioselective bromoetherification of olefinic 1,3diol 1 using a mono-functional C2-symmetric cyclic sulfide 3a as the catalyst (Scheme 1).5 In the course of optimizing the bromoetherification of olefinic 1,3-diol 1, several interesting phenomena were identified: (1) the protecting group of the catalyst is of great importance in controlling the er; (2) the er and dr are affected by the sequence in which the reagent, catalyst, and substrate are added; (3) an increase in catalyst loading leads to a reduction in reaction yield while the er and dr are maintained; (4) the MsOH additive (1 equiv) alone can catalyze the racemic bromoetherification with reaction rate similar to that of the MsOH/cyclic sulfide 3a catalyzed asymmetric reaction, while the cyclic ether product 2 can be still achieved in the catalytic asymmetric process with high er.
* Corresponding author. Tel.: þ852 39436377; fax: þ852 26035057; e-mail addresses: [email protected], [email protected] (Y.-Y. Yeung).
Despite the successful deployment of the optimized conditions for the catalytic and enantioselective bromoetherification of 1, it was nonetheless of significant interest to elucidate these interesting and unusual observations. In this article, the interesting phenomena and the mechanistic insights will be discussed. 2. Results 2.1. The effect of catalyst structure Based on the optimized conditions in our previous report, a combination of 10 mol % catalyst loading, reaction temperature at 78 C, and reaction time at 48 h was defined as the most general set of reaction parameters with which to examine a variety of catalysts (Scheme 1).5 Olefinic 1,3-diol 1a and NBS were used as the substrate and the halogen source, respectively. In addition, 1 equiv of MsOH was used as an additive. Catalyst 3ae3d, 3i, 3k, 3l, and 3m were synthesized using the method developed by our group.3g,5 The seven-membered ring cyclic sulfides 3ee3g could be prepared from the dimesylate6 which is derived from D-mannitol. The 1,2-diol protecting group in 3j could be modified using the procedure shown in Scheme 2. The key to this synthesis is the formation of the bis-epoxide7 which can be ring-opened by phenol derivatives to form analogs of the desired catalysts. The cyclization of the di-mesylate to form the strained 5,5-trans bicyclic ring system proved to be rather difficult, and required microwave conditions to perform this transformation.
http://dx.doi.org/10.1016/j.tet.2015.09.016 0040-4020/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
2
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
instead of cyclic selenide 3m (29% yield, 65.5:34.5 er). We observed that the sterically-bulkier 2,6-diisopropylphenol derived analogue 3b gave the desired substituted THF in a lower er (94% yield, 92:8 dr, 46.5:53.5 er). Catalysts with dimethyl and diisopropyl substituents directly linked to the bicyclic core (3c and 3d) gave the desired products 2a and 2a0 with 50:50 er, while maintaining moderate levels of conversion and yield. Cyclic sulfides in seven-membered rings (3ee3h) also performed poorly in the reaction. Unfortunately, a 2,5-diphenylpyrimidine derived group (3g) stymied the reaction, leading to 27% yield of the desired product. Changing the tert-butyl substituent in 3a into tert-amyl did not influence the selectivity (3i, 74% yield, 94:6 dr, 84:16 er). However, a significant effect on enantioselectivity was observed when the two methyl groups were removed from the 1,3-dioxolane (3j, 64% yield, 88:12 dr, 51:49 er). In a direct comparison, the deprotected diol derived catalyst (3k) delivered the product in 90% yield with 91:9 dr, 77.5:22.5 er. A further modification using 2,2-di-tert-butyl [1,3,2] dioxasilole (3l) led to a drop in reactivity (47% yield, 88:12 dr, 68.5:31.5 er). 2.2. The effect of addition sequence and reaction temperature
Scheme 1. Effect of catalyst structure on the asymmetric bromoetherification and desymmetrization of 1a.
During our reaction optimization study, it was observed that the addition sequence of the reagent, substrate, and catalyst is of critical importance to the reaction performance. The effect of the addition sequence in the bromoetherification of 1a was investigated as indicated in Scheme 3: (1) 1a and catalyst 3a were dissolved in CH2Cl2 at 78 C. A pre-cooled solution of MsOH in CH2Cl2 (freshly prepared for each experiment) was added to the reaction mixture. After the addition, solid NBS was added. The product 2a was obtained in 80% yield and 71% ee (2) NBS was added to a solution of 1a and catalyst 3a in CH2Cl2 at 78 C. After 5 min, a pre-cooled solution of MsOH in CH2Cl2 was added to the mixture. 61% ee of 2a was obtained. (3) A pre-cooled solution of MsOH in CH2Cl2 was added to a solution of NBS and catalyst in CH2Cl2 at 78 C. Substrate 1a was added and 2a was furnished in 50% ee (4) NBS and MsOH were pre-mixed in CH2Cl2 at 78 C. Following which, catalyst 3a and substrate 1a were added consecutively to yield 2a in 54% ee (5) Addition sequence was the same as that in equation (1) but the reaction was performed at 25 C. The substrate was consumed quickly. However, a complex mixture was obtained and the yield of the desired product 2a was low.
Scheme 2. Preparation of cyclic sulfide catalyst 3j.
Among a range of catalysts surveyed, increased reactivity and enantioselectivity were achieved when cyclic sulfide 3a was used
Scheme 3. Study of the addition sequence.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
We also studied reactions in the absence of the cyclic sulfide catalyst 3 (Scheme 4). It was found that MsOH alone could mediate the cyclization of 1a at room temperature to give 5 in 90% yield (Scheme 4, eq 1). When MsOH, NBS and 1a were mixed at room temperature, a mixture of 2a (90%) and 5 (8%) was obtained (Scheme 4, eq 2). The formation of 5 was totally suppressed when the reaction was conducted at 78 C (Scheme 4, eq 3).
3
Table 2-1 Effect of catalyst loading on the asymmetric bromoetherification and desymmetrization of 1aa
Entrya
3a (mol %)
Yield (%)b
drc
er
1 2 3 4 5
1 2 5 10 20
42 98 97 80 72
82:18 93:7 93:7 92:8 92:8
51:49 83:17 85.5:14.5 85.5:14.5 85.5:14.5
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a, methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
2.4. The effect of MsOH additive Scheme 4. Study of reaction without catalyst 3.
A survey on the effect of reaction temperature on the bromoetherification revealed that a low reaction temperature is important for good yield, er, and dr of the desired product 2a (Table 1).
2.3. The effect of catalyst loading For the asymmetric bromoetherification of 1a using 3a as the catalyst, 2a was obtained in low yield and er when 1 mol % of catalyst was used (Table 2-1, entry 1). The yield and er were dramatically improved when the catalyst loading was increased to 2 mol % (Table 2-1, entry 2). The performance was not improved significantly when 5 mol % of 3a was used (Table 2-1, entry 3). While the er and dr maintained when the catalyst loading was further increased (Table 2-1, entries 4 and 5), the yield unexpectedly dropped. We also examined the effect of catalyst loading on the bromoetherification of 1b and a similar trend was observed (Table 2-2). In a direct comparison, 10 mol % catalyst 3a delivered the product 2b in 93% yield with 95.5:4.5 er (Table 2-2, entry 4). We were able to decrease the catalyst loading to 2 mol % (Table 2-2, entry 2) with minimal effect on the yield. Furthermore, lowering the catalyst loading to 1 mol % (Table 2-2, entry 1) gave 2b in 83% yield, 55.5:44.5 er. Again, an increase in catalyst loading led to a reduction in product yield but same er and dr were obtained (Table 2-2, entries 4 and 5).
Table 1 Effect of reaction temperature on bromoetherification and desymmetrization of 1aa
The effect of MsOH loading on the asymmetric reaction was studied (Table 3). 2a was obtained in 61% yield with moderate dr and negligible er in the absence of MsOH additive (Table 3, entry 1). The overall performance was improved when MsOH was added. It is particularly intriguing that the enantioselectivity of the reaction using 3a as the catalyst is strongly dependent on the presence of MsOH (85.5:14.5 er with 1 equiv MsOH and 52:48 er without MsOH), whereas the product yield is comparable in both cases (Table 3, entries 1e3). However, when 1.5 equiv of MsOH was used, the er showed a significant depreciation (Table 3, entry 4). Since it is known that different counterions exert an influence on the reactivity and selectivity of the halocyclization,8 we deemed it important to verify whether other carboxylic/Brønsted acids would perform comparably to MsOH. As such, we examined different achiral Brønsted acid sources, focusing on those providing a range of steric and electronic variation (Table 4). Aliphatic alkanesulfonic acids generally increased the enantioselection with increasing acidity (Table 4, entries 2e4). This effect did not extend to aromatic sulfonic acids, as the p-toluenesulfonic acid performed better than the more acidic triflic acid (Table 4, entries 7 and 8). We also considered that the carboxylate ion may be a more competitive counterion for the selective bromoetherification than succinimide (Table 4, entries 9 and 10), but that turned out not to be the case. Chiral organic acids, including both enantiomers of camphor sulfonic acid and BINOL-derived phosphoric acid, were proven to be inferior in inducing er as compared to MsOH (Table 4, entries 5e6, 11e12). In addition, the chirality of the counterion appears to play an unimportant role on the reaction performance. Table 2-2 Effect of catalyst loading on the asymmetric bromoetherification and desymmetrization of 1ba
Entrya
T ( C)
Yield (%)b
drc
er
Entrya
3a (mol %)
Yield (%)b
drc
ee %
1 2 3 4 5
78 60 40 20 0
80 78 68 65 62
92:8 89:11 88:12 85:15 83:17
85.5:14.5 78.5:21.5 77.5:22.5 73.5:26.5 71:29
1 2 3 4 5
1 2 5 10 20
83 92 98 93 77
88:12 93:7 >99:1 >99:1 >99:1
55.5:44.5 95.5:4.5 95.5:4.5 95.5:4.5 95.5:4.5
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a (10 mol %), methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
a Reactions were conducted with alkenoic diol 1b (0.05 mmol), catalyst 3a, methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
4
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
Table 3 Effect of methanesulfonic acid loading on the asymmetric bromoetherification and desymmetrization of 1aa
Entrya
MsOH (equiv)
Yield (%)b
drc
er
1 2 3 4
0 0.5 1.0 1.5
61 88 80 79
86:14 91:9 92:8 91:9
52:48 68:32 85.5:14.5 69.5:30.5
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a (0.005 mmol), methanesulfonic acid and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
The methaneseleninic acid was more effective in promoting the reaction but did so in a less selective manner (54:46 er; Table 4, entry 13). Interestingly, adamantine-1-sulfonic acid, which is much more sterically bulky than MsOH, caused a substantial decrease in enantioselection to 54.5:45.5 er (Table 4, entry 14). Use of 1adamantanol led to similar results (52:48 er; Table 4, entry 15). 3. Discussion
and structurally well-defined catalyst pocket. The locked conformation of the bicyclic core (acetonide fused cyclic sulfide) would affect the stereo control of the reaction. Acetonide, a common protecting group for 1,2-diols, is critical in obtaining high er. Removing the isopropylidene bridge (3k) led to a decrease of the enantioselectivity of the bromoetherification of 1a. The two methyl groups of the isopropylidene in 3a were also found to be responsible to the high enantioselectivity. The ee dropped significantly when changing the isopropylidene protecting group into a methylene (catalyst 3j) or a bis(tert-butyl) silyl ether (catalyst 3l). In particular, almost no ee was observed when 3j was used, suggesting that the isopropylidene in 3a might offer suitable steric bulkiness in the enantio-determining step. 3.2. The reaction efficiency It is surprising to see that a high catalyst loading led to a decrease in conversion, while the ee and dr are maintained. Based on the previous mechanistic study,5 a 3a-Br intermediate which contains a SeBr Lewis base-coordinated Br system might exist (Scheme 5). The olefin moiety in substrate 1 could then attack the activated electrophilic Br in 3a-Br to form the corresponding bromiranium intermediate A which could further undergo cyclization to yield the cyclic ether product 2.
3.1. The structureeactivity relationship Section 2.1 showed the results of our investigation on the catalyst structure and its influence on the enantioselectivity. It turned out that small changes in the catalyst structure led to fluctuations in the enantioselectivity. Five-membered cyclic sulfides without aromatic substituents (3c and 3d) and seven-membered cyclic sulfides (3ee3g) were ineffective in achieving asymmetric bromoetherification. Changing the 4-tert-butyl group on the phenyl rings in 3a into 2,6-diisopropyl (3b) led to a drop in the er, which might be due to the excessively sterically hindered system. The role of the transfused ring system in 3a and 3i was expected to lock the conformation of the cyclic sulfide five-membered ring, resulting in a rigid Table 4 Effect of various acid additives on the asymmetric bromoetherification and desymmetrization of 1aa
Entrya
Acid
Yield (%)b
drc
er
1 2 3 4 5 6 7 8 9 10 11
Nil MsOH Ethanesulfonic acid Propanesulfonic acid (S)-Camphor sulfonic acid (R)-Camphor sulfonic acid TsOH TfOH TFA Chloroacetic acid (S)-(þ)-1,10 -Binaphthyl-2,20 -diyl hydrogenphosphate (R)-(þ)-1,10 -Binaphthyl-2,20 -diyl hydrogenphosphate Methane seleninic acid Adamantane-1-sulfonic acid 1-Adamantanol
61 80 87 95 88 78 95 32 87 96 96
86:14 92:8 94:6 94:6 94:6 94:6 94:6 90:10 94:6 94:6 94:6
52:48 85.5:14.5 53.5:46.5 50.5:49.5 81:19 81:19 78.5:21.5 67.5:32.5 82:18 81.5:18.5 76:24
93
94:6
72.5:27.5
96 90 85
94:6 93:7 92:8
54:46 54.5:45.5 52:48
12 13 14 15
a Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a (0.005 mmol), acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the absence of light. b Isolated yield. c Determined by 1H NMR.
Scheme 5. Sulfide-Br complexes.
In a study by Brown in 2000, it was found that the collidine in the brominating reagent bis(sym-collidine)bromonium triflate would dissociate to form a mono-collidine-coordinated Br species before interacting with the olefin to form the bromiranium intermediate.9 In the case of 3a-catalyzed bromoetherification, we speculate that another molecule of Lewis basic sulfide 3a could also interact with the 3a-Br species (instead of the p-electron of 1a) to give a 3a-Br-3a complex that is similar to the bis(collidine)-Br system in Brown’s case. A higher loading of catalyst 3a might shift the equilibrium in favor of the formation of 3a-Br-3a, which might result in lower conversions due to the trapping of the electrophilic Br (Tables 2-1 and 2-2). Since the same bromiranium intermediate A is still involved, the er and dr should remain unaffected even at high catalyst loading. 3.3. Effect of addition sequence and temperature According to the results presented in Section 2.2, the performance of the catalytic bromoetherification was affected by the components’ addition sequence. The reaction was best performed when NBS was added at last and at 78 C. Other addition sequences led to lower enantioselectivities and/or reaction yields. When adding MsOH as the last component in the reaction (Scheme 3, eq 2), 3a alone could catalyze the reaction with low enantioselectivity as indicated in Table 3, entry 1. This might be the reason for the reduced ee of the overall reaction. Alternatively, when the substrate was added last, i.e., Scheme 3 equation (3) or (4), the prior incubation of catalyst 3a, NBS and MsOH might have led to catalyst decomposition. Indeed, a complex mixture was obtained when catalyst 3 was incubated with NBS for a few hours. When using such incubated catalyst 3 in the asymmetric bromoetherification of 1, 2 was obtained in dramatically diminished er.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
Lewis-basic sulfide catalysts are susceptible to decay by stoichiometric quantities of oxidants. It has been reported that tetrahydrothiophene could decompose through a thiocarbenium ion intermediate when it was treated with N-chlorosuccinimide.10 In our catalyst system, we suspect that a similar decomposition pathway might occur. Intermediate 3-Br, which was generated from 3 and NBS, could undergo de-hydrobromination to give the thiocarbenium ion B. Subsequent nucleophilic addition to B by nucleophiles such as water (from moisture) or the substrate’s hydroxyl group could give a mixture of thioacetals C and D. (Scheme 6).
Scheme 6. A possible decomposition pathway when incubating catalyst 3 with NBS and MsOH.
When the reaction was conducted at relatively high temperatures (e.g., room temperature) (Scheme 3, eq 5), we speculate that catalyst 3 might also decompose through ring-opening of the cyclic sulfide system10 in addition to the decomposition pathway shown in Scheme 7. Since 3-Br is a Swern-type intermediate,10 another possible explanation is that the substrate’s alcohol group might be oxidized (Scheme 6). These possible decomposition pathways could consume both the catalyst and substrate, leading to lower ers and yields of the desired product 2.
Scheme 7. Possible decomposition pathways of the catalyst 3 at relatively high temperature.
Based on the results in Scheme 4 and Table 1, one of the side reactions is the proton-mediated cyclization of 1 (Scheme 8). In addition, it appears that low temperature is beneficial to the reaction due to several aspects: (1) suppression of the protonmediated cyclization; (2) alleviation of catalyst decomposition through pathways shown in Schemes 6 and 7; (3) retardation of the substrate’s hydroxyl group oxidation (Scheme 6). We suspect that MsOH might react with NBS to give MsOBr in situ (together with the formation of the weakly acidic succinimide byproduct) which could be a highly active brominating agent.11 This proposal could explain bromoetherification being preferred over proton-mediated halocyclization when mixing 1a and MsOH, followed by the addition of NBS. Indeed, when mixing NBS and MsOH in CDCl3, NBS disappeared and molecular succinimide was formed. In addition, a new methyl signal at 2.78 ppm (vs MsOH’s methyl signal at 2.63 ppm) was observed which could be attributed to the formation of MsOBr.
Scheme 8. Plausible mechanism of the MsOH-mediated cyclization of 1a.
3.4. The role of MsOH Earlier experiments demonstrated that a stoichiometric amount of MsOH with respect to the substrate is an essential requirement
5
for high enantioselectivity to be achieved. A possible reason for this observation could be that a more configurationally-stable bromiranium ion A, containing a relatively stable and dissociative mesylate counter-anion, was formed. It would lead to less racemization and higher enantioselectivity. As shown in Table 3, the addition of less or more than 1 equiv of MsOH resulted in much reduced enantioselectivity of the bromoether products (Table 3, entries 2 and 4). In the absence of MsOH additive (Table 3, entry 1), bromiranium ion intermediate E would be formed (Scheme 9). As it contains a relatively more associative succinimide counter-anion, it might be less configurationallystable as compared to A. Therefore, the reaction pathway involving intermediate E would lead to poorer enantioselectivity due to the racemization of the bromiranium ion through an olefin-toolefin degeneration.12 When adding 0.5 equiv of MsOH in the reaction (Table 3, entry 2), a mixture of A and E would be present in the reaction, leading to a lower overall er as compared to the result in Table 3, entry 3. When adding 1.5 equiv of MsOH in the reaction (Table 3, entry 4), excess amount of MsOH could catalyze the racemic bromoetherification, which would then reduce the er of the reaction.
Scheme 9. Counteranions of the bromiranium intermediate.
In the course of our experiments, we found that the addition of MsOH to the reaction mixture provided the best selectivities, even when compared to other Brønsted acids. The possible reasons for this observation were discussed below.13 Based on the acid additive screening results shown in Table 4, several observations can be summarized as follows: (1) the pKa of the acid seems to be important to the overall performance of the cyclization, and the acidity of MsOH might be an optimal case which could promote the reaction with high er; (2) the stereochemistry of the counter-anion partner might not play a crucial role in the enantio-determining step (Table 4, entries 5e6, 11e12); (3) the er is significantly affected by the size of the counter-anion, and a higher er could be obtained with a smaller size sulfonate (Table 4, entries 2e4, 14). A possible explanation is that a larger-sized counter-anion (e.g., adamantane sulfonate) might hinder the nucleophilic attack of the hydroxyl group on the bromiranium ion. Thus, the background uncatalyzed cyclization process might proceed well to give racemic products in the presence of a large counteranion. MsOH is a competent Brønsted acid for promoting both the catalyzed and the uncatalyzed cyclization reactions. However, it was observed that the catalyzed and uncatalyzed cyclizations have similar reaction rates (Scheme 3 eq 1 vs Scheme 4 eq 3). If the rate of the uncatalyzed racemic background reaction is comparable to that of the reaction catalyzed by the chiral Lewis base, highly enantiomerically enriched 2a should not be obtainable. Counterintuitively, we obtained 2a in high enantioselectivity using the above system.14 The striking behavior of this catalytic system is reminiscent of Jacobsen’s analysis of the asymmetric catalytic pathway in the Povarov reaction.15 In that study, a similar observation was made in that a Brønsted acid catalyzed racemic background reaction was suppressed, a phenomenon that they ascribed to ‘negative catalysis’.16 Very recently, Denmark and co-workers reported an interesting phenomenon on ‘negative catalysis’ in the asymmetric carbosulfenylation reaction promoted by Lewis basic selenide and
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
6
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
ethanesulfonic acid.14 In their study, it was found that the rate of the Lewis basic selenide-catalyzed reaction is similar to the uncatalyzed reaction, which is highly similar to our observation in the bromoetherification of 1. A possible explanation for the inhibition of the racemic background reaction under catalytic conditions may be found in the buffering effect of the sulfonate ‘triple ion’. In devising the mechanistic proposal of the bromoetherification of 1, we attempted to rationalize our observations in line with critical insights from Denmark’s studies: The true background reaction under ‘catalytic conditions’ was significantly slower than the uncatalyzed background reaction, and is therefore not accurately represented by simply removing the catalyst. Based on Denmark’s proposal, we believe that both sulfonate and succinimide ions (necessary consequences of the formation of the catalytically active species) were effective inhibitors of the racemic background reaction. On the basis of the aforementioned details, a mechanistic proposal is constructed as depicted in Scheme 10. NBS is activated by chiral cyclic sulfide catalyst 3 to give active species 3-Br through a Lewis base activated Lewis acid mechanism. 3-Br then delivers the Br asymmetrically to the olefin to give A. We propose that MsOH facilitates the formation of the cyclic sulfide-Br complex 3-Br through the protonation of succinimide (also see Section 3.3) and enhances the turnover as described in Denmark’s proposal.14 For the uncatalyzed reaction through intermediate G, the pathway could be suppressed by the buffering effect of succinimide and sulfonate anions.
uncatalyzed processes being similar, and (b) that excessive catalyst loading leads to a decrease in yield without affecting enantioselectivity. 5. Experimental section 5.1. General All reactions that required anhydrous conditions were carried by standard procedures under nitrogen atmosphere. Commercially available reagents were used as received. The solvents were dried over a solvent purification system from Innovative Technology. Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrophotometer and reported in wave numbers (cm1). Melting points € were determined on a BUCHI B-540b melting point apparatus. 1H 13 NMR and C NMR spectra were recorded on a Bruker ACF300 (300 MHz), Bruker DPX300 (300 MHz) or AMX500 (500 MHz) spectrometer. Chemical shifts (d) are reported in ppm relative to TMS (d 0.00) for the 1H NMR and to chloroform (d 77.0) for the 13C NMR measurements. Optical rotations were recorded on a Jasco DIP-1000 polarimeter. Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash chromatography separations were performed on Merck 60 (0.040e0.063 mm) mesh silica gel. 5.2. (3aS,4S,6S,6aS)-2,2,4,6-Tetramethyltetrahydrothieno[3,4d][1,3]dioxole 3c A solution of the known dimesylate (916 mg, 2.64 mmol) and sodium sulfide nonahydrate (freshly recrystallized in EtOH, 2.54 g, 10.58 mmol) were both charged into a biotage microwave vessel (20 mL) and dissolved in DMF (15 mL). The reaction mixture was then microwaved at 135 C for 5 min. The reaction was monitored by thin layer chromatography (TLC). Water (35 mL) was then added to the mixture at room temperature and the aqueous layer was extracted with diethyl ether (235 mL). The combined organic layers were washed with water (235 mL) and dried over MgSO4. After filtration, the solution was concentrated in vacuo (the evaporation was realized carefully at room temperature). Purification by flash column chromatography (hexane/ethyl acetate 25:1) afforded 3c (355 mg, 71%) as a colorless oil. ½a25 D 245 (c 1.0, CHCl3); IR (KBr): 2975, 2893, 1453, 1241, 1184, 1077 cm1; 1H NMR (300 MHz, CDCl3): d 4.44 (dd, J¼4.3, 2.1 Hz, 2H), 3.27 (m, 2H), 1.47 (s, 6H), 1.32 (d, J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 119.7, 81.5, 34.7, 27.1, 18.0; HRMS (EI) calcd for C9H16O2S [M]þ: 188.0871; found: 188.0870. 5.3. (3aR,4S,8S,8aR)-2,2-Dimethylhexahydrothiepino[4,5-d] [1,3]dioxole-4,8-diol 3e
Scheme 10. Plausible mechanism of the bromoetherification of 1.
4. Conclusion Research into the enantioselective Lewis base catalyzed, Brønsted acid promoted bromoetherification reaction has offered insights which account for previously observed interesting phenomena. The effect of (1) catalyst structure, (2) temperature and addition sequence of components, (3) catalyst loading, and (4) MsOH additive were discussed. The possible reasons of some unusual observations are (a) the inclusion of MsOH affords high enantioselectivity, despite the rate of the catalyzed reaction and
3e was prepared using a literature procedure.6 White solid, mp 1 93e94 C; ½a25 D 122 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d 4.27 (m, 4H), 3.05 (br s, 2H), 2.95 (dd, J¼15.0, 4.8 Hz, 2H), 2.54 (dd, J¼15.0, 5.8 Hz, 2H), 1.38 (s, 6H); 13C NMR (75 MHz, CDCl3): d 108.5, 75.7, 66.0, 37.3, 26.8; HRMS (EI) calcd for C9H16O4S [M]þ: 220.0769; found: 220.0770. 5.4. (3aS,4S,8S,8aS)-4,8-Bis(benzyloxy)-2,2dimethylhexahydrothiepino[4,5-d][1,3]dioxole 3f To 125 mg (3.12 mmol) of 60% NaH was added under nitrogen 7 mL of THF and 568 mg (2.58 mmol) of the thiepane derivative 3e. The reaction mixture was stirred for 30 min and treated with a solution of 0.3 mL of benzyl bromide and 2 mg (0.012 mmol) of KI in 1.8 mL of THF. After 7 h, 125 mg (3.12 mmol) of 60% NaH and 0.3 mL (2.71 mmol) of benzyl bromide were added. Stirring was continued for 12 h, then H2O was added and the mixture extracted
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
with Et2O (330 mL). The organic layer was dried and evaporated to give 0.99 g (2.39 mmol, 96%) of 3f as a yellow solid which was purified by flash chromatography (SiO2; CH2Cl2/hexane 3:1), giving a solid with mp 56e57 C. ½a25 D 40.1 (c 1.0, CHCl3); IR (KBr): 2945, 1246, 1184, 1078 cm1; 1H NMR (300 MHz, CDCl3): d 7.40 (m, 10H), 4.93 (d, J¼12.0 Hz, 2H), 4.72 (d, J¼12.0 Hz, 2H), 4.70 (m, 2H), 4.20 (m, 2H), 2.93 (dd, J¼15.1, 5.1 Hz, 2H), 2.63 (dd, J¼15.1, 6.1 Hz, 2H), 1.56 (s, 6H); 13C NMR (75 MHz, CDCl3): d 138.7, 128.3, 127.6, 127.5, 109.3, 77.6, 74.1, 73.5, 36.8, 26.9; HRMS (EI) calcd for C23H28O4S [M]þ: 400.1708; found: 400.1710. 5.5. 6,60 -((3aS,4S,8S,8aS)-2,2-Dimethylhexahydrothiepino[4,5d][1,3]dioxole-4,8-diyl)bis(oxy)bis(4-chloro-2,5diphenylpyrimidine) 3g 3g was prepared in analogy to above procedure for 3f. White solid, mp 142e143 C; ½a25 D 52.3 (c 1.0, CHCl3); IR (KBr): 2949, 1246, 1183, 1078 cm1; 1H NMR (300 MHz, CDCl3): d 8.42 (m, 4H), 7.45 (m, 16H), 5.98 (t, J¼5.1 Hz, 2H), 4.44 (m, 2H), 3.31 (dd, J¼15.6, 5.1 Hz, 2H), 3.01 (dd, J¼15.6, 5.7 Hz, 2H), 0.76 (s, 6H); 13C NMR (75 MHz, CDCl3): d 166.5, 162.3, 159.7, 135.9, 131.5, 131.4, 130.2, 128.5, 128.3, 128.1, 118.5, 109.5, 75.3, 71.5, 35.6, 25.8; HRMS (EI) calcd for C41H34Cl2N4O4S [M]þ: 748.1678; found: 748.1678. 5.6. (S)-3,5-Dihydrodinaphtho[2,1-c:10,20 -e]thiepine 3h 3h was prepared using a literature procedure.17 Brown solid, mp 177e178 C; ½a25 D þ280 (c 0.2, CHCl3); IR (KBr): 2915, 2833, 677 cm1; 1H NMR (500 MHz, CDCl3): d 3.43 (s, 4H), 7.20e8.02 (m, 12H); 13C NMR (125 MHz, CDCl3): d 133.4, 133.2, 132.5, 131.2, 128.9, 127.8, 126.4, 126.1, 125.7, 125.1, 31.9; HRMS (EI) calcd for C22H16S [M]þ: 312.0973; found: 312.0971. 5.7. (3aS,4S,6S,6aS)-2,2-Dimethyl-4,6-bis((4-tert-pentylphenoxy)methyl) tetrahydrothieno[3,4-d][1,3]dioxole 3i 3i was prepared in analogy to above procedure for 3c. White solid, mp 130e131 C; ½a25 D 33.4 (c 1.0, CHCl3); IR (KBr): 2964, 2363, 1608, 1512, 1245, 1183, 1079 cm1; 1H NMR (500 MHz, CDCl3): d 7.29 (d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H), 4.70 (dd, J¼4.5, 1.9 Hz, 2H), 4.46 (dd, J¼10.0, 5.7 Hz, 2H), 4.13 (dd, J¼10.0, 7.0 Hz, 2H), 3.66 (m, 2H), 1.67 (q, J¼7.5, 4H), 1.57 (s, 6H), 1.32 (s, 12H), 0.74 (t, J¼7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3): d 156.2, 142.1, 126.8, 120.4, 114.4, 81.6, 68.7, 38.8, 37.2, 36.9, 28.5, 27.1, 9.1; HRMS (EI) calcd for C31H44O4S [M]þ: 512.2960; found: 512.2962. 5.8. (3aS,4S,6S,6aS)-4,6-Bis((4-tert-pentylphenoxy)methyl) tetrahydrothieno[3,4-d][1,3]dioxole 3j 3j was prepared in analogy to above procedure for 3c. White solid, mp 101e102 C; ½a25 D 98.5 (c 1.0, CHCl3); IR (KBr): 2965, 2393, 1508, 1241, 1184, 1027 cm1; 1H NMR (500 MHz, CDCl3): d 7.30 (d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H), 5.65 (s, 2H), 4.62 (dd, J¼4.4, 1.9 Hz, 2H), 4.47 (dd, J¼9.8, 5.7 Hz, 2H), 4.15 (dd, J¼9.8, 7.2 Hz, 2H), 3.69 (m, 2H), 1.68 (q, J¼7.5 Hz, 4H), 1.33 (s, 12H), 0.75 (t, J¼7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3): d 156.0, 142.1, 126.8, 114.1, 104.8, 82.6, 68.4, 38.1, 37.2, 36.8, 28.5, 9.0; HRMS (EI) calcd for C29H40O4S [M]þ: 484.2647; found: 484.2641. 5.9. (2S,3S,4S,5S)-2,5-Bis((4-tert-butylphenoxy)methyl)tetrahydrothiophene-3,4-diol 3k 3k was prepared by conventional hydrolysis of the ketal. White solid, mp 134e135 C; ½a25 D 136 (c 1.0, CHCl3); IR (KBr): 3360, 2965, 2363, 1608, 1241, 1184, 1027 cm1; 1H NMR (500 MHz, CDCl3): d 7.30 (d, J¼8.8 Hz, 4H), 6.86 (d, J¼8.8 Hz, 4H), 5.63 (s, 2H), 4.50 (d,
7
J¼3.2 Hz, 2H), 4.33 (dd, J¼9.5, 8.2 Hz, 2H), 4.17 (dd, J¼9.5, 5.7 Hz, 2H), 4.08 (m, 2H), 1.29 (s, 18H); 13C NMR (125 MHz, CDCl3): d 156.0, 144.1, 126.3, 114.1, 78.3, 66.8, 48.0, 34.1, 31.5; HRMS (EI) calcd for C26H36O4S [M]þ: 444.2334; found: 444.2330. Acknowledgements We thank the financial support from National University of Singapore (grant no. 143-000-605-112), A*STAR-Public Sector Funding (grant no. 143-000-536-305), and GSK-EDB (grant no. 143000-564-592). Supplementary data Supplementary data associated with this article can be found in the online version, at http://dx.doi.org/10.1016/j.tet.2015.09.016. References and notes 1. For recent reviews, see: (a) Chen, G. F.; Ma, S. M. Angew. Chem., Int. Ed. 2010, 49, 8306; (b) Castellanos, A.; Fletcher, S. P. Chem.dEur. J. 2011, 17, 5766; (c) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335; (d) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. Aldrichimica Acta 2011, 44, 27; (e) Hennecke, U. Chem.dAsian. J. 2012, 7, 456; (f) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed. 2012, 51, 10938; (g) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763; (h) Tan, C. K.; Yeung, Y.-Y. Chem. Commun. 2013, 7985. 2. For selected recent examples, see: (a) Huang, D.; Liu, X.; Li, L.; Cai, Y.; Liu, W.; Shi, Y. J. Am. Chem. Soc. 2013, 135, 8101; (b) Zeng, X.; Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem. Commun. 2013, 2418; (c) Jaganathan, A.; Staples, R. J.; Borhan, B. J. Am. Chem. Soc. 2013, 135, 14806; (d) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano, O.; Ilupeju, J.; Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.; Gouverneur, V. Angew. Chem., Int. Ed. 2013, 52, 9796; (e) Romanov-Michailidis, ne e, L.; Alexakis, A. Angew. Chem., Int. Ed. 2013, 52, 9266; (f) Tripathi, C. F.; Gue B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013, 52, 8450; (g) Brindle, C. S.; Yeung, C. S.; Jacobsen, E. N. Chem. Sci. 2013, 4, 2100; (h) Zhang, W.; Liu, N.; Schienebeck, C. M.; Zhou, X.; Izhar, I. I.; Guzei, I. A.; Tang, W. Chem. Sci. 2013, 4, 2652; (i) Hu, D. X.; Shibuya, G. M.; Burns, N. Z. J. Am. Chem. Soc. 2013, 135, 12960; (j) Zhang, Y.; Xing, H.; Xie, W.; Wan, X.; Lai, Y.; Ma, D. Adv. Synth. Catal. 2013, 355, 68; (k) Yin, Q.; You, S.-L. Org. Lett. 2013, 15, 4266; (l) Mori, K.; Ichikawa, Y.; Kobayashi, M.; Shibata, Y.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135, 3964. 3. (a) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738; (b) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164; (c) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem. Commun. 2012, 5793; (d) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51, 7771; (e) Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492; (f) Zhou, L.; Tay, D. W.; Chen, J.; Leung, G. Y. C.; Yeung, Y.-Y. Chem. Commun. 2013, 4412; (g) Chen, F.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2013, 135, 1232. 4. For other haloetherifications, see: (a) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am. Chem. Soc. 2003, 125, 15748; (b) Kwon, H. Y.; Park, C. M.; Lee, S. B.; Youn, J. H.; € ller, C. H.; Kang, S. H. Chem.dEur. J. 2008, 14, 1023; (c) Hennecke, U.; Mu €hlich, R. Org. Lett. 2011, 13, 860; (d) Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li, Fro L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350; (e) Denmark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256. 5. Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014, 136, 5627. 6. (a) Depezay, J. C.; Fuzier, M.; LeMerrer, Y. Heterocycles 1987, 25, 541; (b) LeMerrer, Y.; Fuzier, M.; Dosbaa, I.; Foglietti, M.-J.; Depezay, J.-C. Tetrahedron 1997, 53, 16731. ault, A.; Gravier, C.; Languin, D.; Depezay, J. C. Tetrahedron 7. LeMerrer, Y.; Dure Lett. 1985, 26, 319. 8. Well-established role of the achiral counteranion in determining the enantioselectivity in analogous iodocyclization reactions was reported. See Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc. 2012, 134, 6068. 9. Cui, X. L.; Brown, R. S. J. Org. Chem. 2000, 65, 5653. 10. Schmidt, D. L.; Heeschen, J. P.; Klingler, T. C.; McCarty, L. P. J. Org. Chem. 1985, 50, 2840. 11. It has been proposed that AcOH could react with NBS to give AcOBr. For references, see: (a) Chen, K.; Baran, P. S. Nature 2009, 459, 824; (b) Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247; (c) Levine, S. G.; Wall, M. E. J. Am. Chem. Soc. 1959, 81, 2826; (d) Lauer, G.; Oberdorfer, F. Angew. Chem., Int. Ed. 1993, 32, 272. 12. Brown, R. S. Acc. Chem. Res. 1997, 30, 131. 13. For sulfetherification, see Wang, H.; Huang, D.; Cheng, D.; Li, L.; Shi, Y. Org. Lett. 2011, 13, 1650. 14. Denmark, S. E.; Chi, H. M. J. Am. Chem. Soc. 2014, 136, 3655. 15. (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986; (b) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678. 16. (a) Retey, J. Angew. Chem., Lnt. Ed. Engl. 1990, 29, 355; (b) Breslow, R. Acc. Chem. Res. 1991, 24, 317; (c) Abel, E. Adv. Catal. 1957, 9, 330. 17. Foubelo, F.; Moreno, B.; Soler, T.; Yus, M. Tetrahedron 2005, 61, 9082.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016