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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Am Chem Soc. Author manuscript; available in PMC 2010 December 30.
Published in final edited form as:
PMCID: PMC2797564
NIHMSID: NIHMS163868

Vicinal Diboronates in High Enantiomeric Purity through Tandem Site-Selective NHC–Cu-Catalyzed Boron-Copper Additions to Terminal Alkynes

Abstract

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A Cu-catalyzed protocol for conversion of terminal alkynes to enantiomerically enriched diboronates is reported. In a single vessel, a site-selective hydroboration of an alkyne leads to the corresponding terminal vinylboronate, which undergoes a second site-selective and enantioselective hydroboration. Reactions proceed in the presence of two equivalents of commercially available bis(pinacolato)diboron [B2(pin)2] and 5–7.5 mol % of a chiral bidentate imidazolinium salt, affording diboronates in 60–93% yield and up to 97.5:2.5 enantiomeric ratio (er). The enantiomerically enriched products can be functionalized to afford an assortment of versatile organic molecules. Enynes are converted to unsaturated diboronates with high chemo- (>98% reaction of alkyne; <2% at alkene) and enantioselectivity (e.g., 94.5:5.5 er).

We recently reported a site- and enantioselective Cu-catalyzed method for boron-copper addition to olefins carried out with bis(pinacolato)diboron [B2(pin)2; 1].1 Transformations involve N-heterocyclic carbene (NHC) complexes and are performed in the presence of MeOH, which promotes in situ protonation of the C–Cu bond to regenerate the catalyst and deliver the hydroboration product. Aryl-substituted alkenes serve as effective substrates, since a low-lying π* orbital is likely required for association of the substrate with the nucleophilic NHC–Cu complex.2 We reasoned that if vinylboronates can be induced to undergo site-selective hydroborations, an efficient Cu-catalyzed protocol for enantioselective synthesis of the highly versatile vicinal diboronates would be in hand.3,4,5 Since vinylboronates might be prepared by alkyne hydroboration, we further envisioned a single-vessel Cu-catalyzed process for conversion of terminal alkynes to diboronates of high enantiomeric purity (eq 1).6,7 Herein, we disclose the realization of the strategy outlined above. Through the use of a Cu complex derived from a chiral bidentate NHC,8,9 a wide range of terminal alkynes are converted to vicinal diboronates in >98% site selectivity, 60–93% yield and up to 97.5:2.5 enantiomeric ratio (er).

equation image
(1)

We began by examining the efficiency and site selectivity of alkyne hydroboration under conditions that would likely be optimal for the second enantioselective process [−15 °C, tetrahydrofuran (thf)].1 We established that, as illustrated in Scheme 1a, reaction of Cl-substituted alkyne 2 with 5.0 mol % chiral imidazolinium salt 3 and CuCl in the presence of 20 mol % NaOt-Bu and 0.9 equiv of 1 leads to >98% conv (based on 1) in 24 hours, affording vinylboronate 4 with >98% site selectivity (<2% 5 by 400 MHz 1H NMR analysis). Subjection of pure 4 to the same conditions (except with 1.1 equiv 1) furnishes diboronate 6 with >98% site selectivity (<2% geminal diboronate) and in 94:6 er. As illustrated in Scheme 1, Cu-catalyzed tandem double-hydroboration of 2 with 2.1 equivalents of 1 leads to 90% conversion to 6, which is formed in 95:5 er.

Scheme 1
Initial Investigations

In addition to terminal alkynes bearing a halogen-substituted alkyl group (entry 1, Table 1), those carrying an O- or an N-based unit (entries 2–3), or an n-alkyl group (entry 4) undergo diboration to afford the desired products in 72–93% yield and up to 96.5:3.5 er. Comparison of the data in entries 5–6 with 7–8 (Table 1) indicates that transformations of alkynes containing a β-branched side chain (entries 5–6), where 7.5 mol % 3 is required for high conversion, proceed more slowly than those with the corresponding α-branched substituents (entries 7–8). In all cases, however, the desired products are isolated in 96.5:3.5 er.

Table 1
Cu-Catalyzed Enantloselective Diboration of Terminal Alkynesa

Cu-catalyzed diborations presented in eq 23 demonstrate that the reaction can be carried out with terminal alkynes bearing a propargylic heteroatom, affording 15 and 16 in 71% and 82% yield and 97:3 and 95:5 er, respectively. These transformations, as well as those in Table 1, highlight a critical – and not immediately evident – attribute of the bidentate NHC–Cu complex derived from 3: high site selectivity in alkyne hydroborations. This point is elucidated below.

equation image
(2)
equation image
(3)

The first-stage hydroboration of alkynes 14ab proceeds readily with 1.0 mol % monodentate NHC–Cu complex 17 (Scheme 2), which result in the formation of secondary vinylboronates 19a and 19b as major isomers (18:19 = 17:83 and 10:90, respectively). In contrast, when imidazolinium sulfonate 3 is used, 18a and 18b are produced predominantly (18:19 = 89:11).10 Control experiments indicate that secondary boronates (e.g., 19) undergo Cu-catalyzed hydroboration less readily and afford products of substantially lower enantiomeric purity (with Cu complex of 3). For example, treatment of a pure sample of 5 to the conditions in Scheme 1 results in 13% conversion to 6, which is formed in only 55:45 er. The high enantioselectivity afforded by the Cu derived from 3 is thus partly due to its ability to promote preferential formation of the terminal vinylboronates selectively. Consistent with the above findings, chiral monodentate NHC–Cu complexes 20 and 21 (Scheme 2) give rise to less efficient and nonselective transformations. The basis for site selectivity in NHC–Cu-catalyzed alkyne hydroborations is under investigation.

Scheme 2
Influence of NHC Structure on Site Selectivity and Enantioselectivity of Boron–Copper Additionsa

The diboronates obtained through the present method are versatile, providing access to other useful enantiomerically enriched molecules. The example in eq 4 involving diboronate 15 and β-bromoenone 22 is illustrative; site-selective Pd-catalyzed cross-coupling11 of the less hindered C–B bond followed by

equation image
(4)

oxidation of the remaining alkylboronate delivers 23 in 72% yield without loss of enantiomeric purity (96.5:3.5 er).

Enantiomerically enriched diboronates can be synthesized with through catalytic diborations of terminal alkenes with one equivalent of 1 or the derived biscatecholate3,6 (vs two equiv used in this study). Bis(pinacolato)diboron is, however, commercially available in ample quantities and inexpensive. The alternative protocols require the use of chiral phosphines and salts of precious metals (e.g., Pt-, Pd- or Rh-based), which are significantly more costly than CuCl. Finally, as demonstrated through synthesis of unsaturated diboronate 25 in eq 5, the present approach complements the abovementioned protocols involving alkene substrates;3,6 the Cu-catalyzed reaction thus allows for chemoselective diboration of an alkyne in the presence of an olefin (<2% reaction of the alkene).

equation image
(5)

Development of other NHC–Cu-catalyzed boron-copper additions and examination of mechanistic issues are in progress.

Supplementary Material

1_si_001

Acknowledgment

Financial support was provided by the NSF (CHE-0715138) and the NIH (GM-47480). Y. L. is an AstraZeneca Graduate Fellow. We thank Frontier Scientific, Inc. for generous gifts of reagent 1. Mass spectrometry facilities at Boston College are supported by the NSF (DBI-0619576).

Footnotes

Supporting Information Available: Experimental procedures and spectral, analytical data for all products (PDF). This material is available on the web: http://www.pubs.acs.org

References

(1) Lee Y, Hoveyda AH. J. Am. Chem. Soc. 2009;131:3160–3161. [PMC free article] [PubMed]
(2) Dang L, Lin Z, Marder TB. Organometallics. 2008;27:4443–4454. and references cited therein.
(3) For selected reviews regarding catalytic diboron additions to alkenes (including enantioselective variants), see: (a) Beletskaya I, Moberg C. Chem. Rev. 2006;106:2320–2354. [PubMed]. (b) Burks HE, Morken JP. Chem. Commun. 2007:4717–4725. [PubMed]. (c) Dang L, Lin Z, Marder TB. Chem. Commun. 2009:3987–3995. [PubMed]. See the SI for additional reviews.
(4) For Rh-catalyzed enantioselective hydroborations (up to 89.5:10.5 er) of a vinylboronate [(E)-2-(phenylethenyl)-1,3,2-dioxaborolane], see: Wiesauer C, Weissensteiner W. Tetrahedron: Asymm. 1996;7:5–8.
(5) For Pt- and Pd-catalyzed double-hydrosilylation of arylacetylenes, see: Shimada T, Mukaide K, Shinohara A, Han JW, Hayashi T. J. Am. Chem. Soc. 2002;124:1584–1585. [PubMed]
(6) For selected recent reports regarding catalytic enantioselective diboration of terminal alkenes, see: Rh-catalyzed: (a) Morgan JB, Miller SP, Morken JP. J. Am. Chem. Soc. 2003;125:8702–8703. [PubMed]. (b) Trudeau S, Morgan JB, Shrestha M, Morken JP. J. Org. Chem. 2005;70:9538–9544. [PubMed]. Pt-catalyzed: (c) Kliman LT, Mlynarski SN, Morken JP. J. Am. Chem. Soc. 2009;131:13210–13211. [PubMed]. Enantiomerically enriched diboronates have been prepared by Rh- or Ir-catalyzed hydrogenations of bis-borylalkenes; see: (d) Morgan JB, Morken JP. J. Am. Chem. Soc. 2004;126:15338–15339. [PubMed]. (e) Paptchikhine A, Cheruku P, Engman M, Andersson PG. Chem. Commun. 2009:5996–5998. [PubMed]
(7) For a recent review on Rh- and Ir-catalyzed enantioselective alkene hydroboration, see: (a) Carroll A-M, O'Sullivan TP, Guiry PJ. Adv. Synth. Catal. 2005;347:609–631.. For a recent Cu-catalyzed hydroboration of monosubstituted styrenes (with pinacolborane), see: (b) Noh D, Chea H, Ju J, Yun J. Angew. Chem., Int. Ed. 2009;48:6062–6064. [PubMed]
(8) Glorious F, editor. N-Heterocyclic Carbenes in Transition Metal Catalysis. Springer-Verlag; Berlin, Heidelberg: 2007.
(9) For representative examples where bidentate Cu-based NHC-sulfonates have been utilized in enantioselective C–C bond formation, see: (a) Brown MK, Hoveyda AH. J. Am. Chem. Soc. 2008;130:12904–12906. [PubMed]. (b) Lee Y, Akiyama K, Gillingham DG, Brown MK, Hoveyda AH. J. Am. Chem. Soc. 2008;130:446–447. [PubMed]. For structural attributes of related Zn- and Al-based complexes, see: (c) Lee Y, Li B, Hoveyda AH. J. Am. Chem. Soc. 2009;131:11625–11633. [PubMed]
(10) For a study regarding variations in site selectivity of boron-copper additions to terminal alkynes (not catalytic), see: Takahashi K, Ishiyama T, Miyaura N. J. Organomet. Chem. 2001;625:47–53.
(11) Doucet H. Eur. J. Org. Chem. 2008:2013–2030.