Abstract
A stereoconvergent method for the catalytic asymmetric Negishi cross-coupling of racemic secondary propargylic halides with arylzinc reagents has been developed. Neither family of compounds has previously been shown to be a suitable partner in such coupling processes. From a practical point of view, it is noteworthy that the catalyst components (NiCl2·glyme and pybox ligand 1) are commercially available.
We have recently described the use of chiral nickel complexes to achieve catalytic asymmetric cross-couplings of organozinc,1,2 -silicon,3 and -boron4 reagents with racemic secondary alkyl electrophiles, specifically, α-halocarbonyl compounds and allylic, benzylic, and homobenzylic halides.5,6,7 In order to fully exploit the tremendous potential of enantioselective cross-couplings, it is necessary to expand the scope to other families of reaction partners. With respect to electrophiles, propargylic halides are attractive substrates, since an alkyne is an extremely versatile functional group.8 In this report, we establish that, in the presence of a chiral Ni/pybox complex, a wide array of racemic propargylic halides can be cross-coupled with arylzinc reagents in a stereoconvergent process (eq 1).
 |
(1) |
In previous investigations of nickel-catalyzed asymmetric Negishi9 reactions, we observed that alkylzincs can be coupled with α-bromoesters, 1-haloindanes, and allylic chlorides in good yield and ee.1 Unfortunately, under the same conditions we were not able to efficiently cross-couple arylzinc reagents with these electrophiles. After extensive studies, we have now determined that enantioselective Negishi reactions of diarylzincs can in fact be achieved by NiCl2·glyme/110 (both of which are commercially available) in glyme at −20 °C, and that a new family of electrophiles, propargylic halides, are suitable coupling partners (eq 2).
 |
(2) |
We next turned our attention to exploring the scope of the catalytic asymmetric arylation of propargylic halides. Few diarylzinc reagents are commercially available, and diarylzincs generated in situ by transmetalation of arylmagnesium or aryllithium compounds did not furnish results comparable to eq 2, due in part to interference by the residual magnesium or lithium salts.11 Since arylzinc halides also were not suitable coupling partners under these conditions, we examined the use of arylzinc reagents produced by treatment of readily available arylboronic acids with diethylzinc.12 Although the published procedure was not effective (eq 3), we were pleased to determine that, by employing a modified protocol, the coupling of an arylzinc with a propargylic halide can be achieved in very good yield and ee (eq 4).
 |
(3) |
 |
(4) |
With straightforward access to a useful family of arylzinc reagents, we examined the scope of this method for enantioselective Negishi cross-coupling, focusing initially on TMS-substituted propargylic bromides (Table 1), due to their ready deprotection. We have established that asymmetric carbon–carbon bond formation occurs smoothly in the presence of functional groups such as acetals, ethers, esters, and olefins. Reactions of hindered substrates proceed in modest yield (but high ee; e.g., entry 4).
Table 1.
Asymmetric Cross-Couplings of TMS-Protected Propargylic Bromides with Arylzinc Reagents.
 | ||||
|---|---|---|---|---|
| entry | alkyl | Ar | yield (%)a | ee (%) |
| 1 | Me |
|
71 | 93 |
| 2 | n-Bu |
|
92 | 93 |
| 3b | n-Bu |
|
70 | 93 |
| 4 | n-Bu |
|
39 | 92 |
| 5 |
|
|
76 | 94 |
| 6 |
|
|
79 | 94 |
| 7 | i-Bu |
|
71 | 93 |
All data are the average of two experiments.
Yield of purified product.
6.0% NiCl2 · glyme, 7.8% (−)-1, and 3.0 equiv of ArZnEt were used.
Ni/1 can be applied to asymmetric Negishi reactions of propargylic bromides that bear silyl protecting groups other than TMS (eq 5 and eq 6). Thus, under the same conditions, Me2PhSi- and TIPS-substituted electrophiles also undergo enantioselective cross-coupling in good yield and ee.
 |
(5) |
 |
(6) |
Furthermore, without modification this stereoconvergent method can be employed for asymmetric Negishi couplings of alkyl- and aryl-substituted propargylic bromides (Table 2); the alkyl substituent can range in size from methyl to t-butyl (entries 1–5). Carbon-carbon bond formation proceeds in generally good yield and enantioselectivity with an array of functionalized arylzinc reagents, including compounds that contain heterocycles. An unactivated primary alkyl chloride is essentially inert to these conditions (entry 5).13,14
Table 2.
Asymmetric Cross-Couplings of Propargylic Bromides with Arylzinc Reagents.
All data are the average of two experiments.
Yield of purified
· product. 6.0% NiCl2 glyme, 7.8% (−)-1, and 3.0 equiv of ArZnEt were used.
Not only propargylic bromides, but also chlorides, undergo cross-coupling under our standard conditions (eq 7). Although the yield is somewhat lower, the ee is essentially identical to that observed for the reaction of the corresponding bromide (see eq 4).
 |
(7) |
Wright and Anderson recently described a series of novel inhibitors of dihydrofolate reductase (from Cryptosporidium hominis and Toxoplasma gondii, two parasitic protozoa), the most active of which was pyrimidine 2 (Scheme 1).15 They synthesized target compound 2 via a Sonogashira reaction of alkyne 3, which was prepared in five steps (22% yield) from arylacetic acid 4, by attachment and then removal of an Evans chiral oxazolidinone.
Scheme 1.
Catalytic Asymmetric Synthesis of a Potent Dihydrofolate Reductase Inhibitor (2)
As a demonstration of our new Negishi cross-coupling method, we have applied it to a catalytic asymmetric synthesis of alkyne 3. Thus, on a gram-scale, the propargylic bromide derived from commercially available 4-trimethylsilyl-3-butyn-2-ol was coupled with arylzinc reagent 4 (generated from a commercially available arylboronic acid) to furnish the key carbon–carbon bond in 93% ee.
In conclusion, we have developed a stereoconvergent method for the catalytic asymmetric Negishi cross-coupling of racemic secondary propargylic halides with arylzinc reagents. Neither family of compounds has previously been shown to be a suitable partner in such coupling processes. From a practical point of view, it is noteworthy that the catalyst components (NiCl2·glyme and pybox ligand 1) are commercially available. Additional studies of enantioselective nickel-catalyzed cross-coupling reactions are underway.
Supplementary Material
Experimental procedures and compound characterization data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgments
We thank Frontier Scientific for a generous gift of boronic acids. Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences, grant R01-GM62871), Merck Research Laboratories, and Novartis. Funding for the MIT Department of Chemistry Instrumentation Facility has been provided in part by the National Science Foundation (CHE-0234877, CHE-9808061 and DBI-9729592) and the National Institutes of Health (1S10RR13886-01).
References
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Supplementary Materials
Experimental procedures and compound characterization data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.