COMMUNICATION DOI: 10.1002/asia.201402458

Copper-Catalyzed Synthesis of 1,1-Diborylalkanes through Regioselective Dihydroboration of Terminal Alkynes Sumin Lee, Dingxi Li, and Jaesook Yun*[a]

Abstract: The copper-catalyzed sequential hydroboration of terminal alkynes with pinacolborane to prepare 1,1-diborylalkanes directly from alkynes was studied. Protected propargyl amines, propargyl alcohol derivatives, and simple alkynes regioselectively produced the desired 1,1-diborylalkanes in good yields with a copper/xantphos catalyst.

kynes would efficiently provide 1,1-diboryl compounds with more economical copper catalysts. While the copper-catalyzed hydroboration of terminal alkynes has not previously been reported, catalytic hydroborations of internal alkynes[9] and the formal hydroboration of terminal alkynes[5b, 10] with a diboron reagent and methanol producing anti-Markovnikov products have been reported. Herein, we report a regioselective copper-catalyzed sequential hydroboration of terminal alkynes including propargyl substrates and alkylalkynes, which constitutes a worthy alternative to the Rh-catalyzed synthesis of 1,1-diborylalkane compounds. We initiated our investigation with the copper-catalyzed reaction of phenylacetylene and pinacolborane using 1,2bis(diphenylphosphino)benzene (dppbz) as the ligand, which was an efficient ligand for the hydroboration of vinylarenes.[7a, 11] When 1.2 equivalents pinacolborane were used in an attempt to prepare the monohydroboration product, the reaction proceeded to partial conversion of the starting alkyne and produced a mixture of mono- and diborylated regioisomeric products. With an increase of pinacolborane to 2.2 equivalents, a similar product distribution was observed with complete conversion of the starting alkyne. Analysis of the products indicated poor regioselectivity, with a ratio of a- and b-hydroboration of approximately 1:1.[12] Using CuCl and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), however, the hydroboration resulted in predominantly b-hydroboration products (b-m, b-d; Scheme 1). In the absence of phosphine ligands, no reaction was observed at room temperature, which indicated that the hydroboration required a phosphine copper catalyst. Based on the proposed mechanism of the copper-catalyzed hydroboration,[11] a-hydroboration products were expected to form as a result of electronic control of the substrate reacting with the nucleophilic Cu H catalyst.[7a, 13] On the other hand, the b-hydroboration product (b-m) would result from steric interactions between the substrate and catalyst.

Stereoselective catalytic hydroboration reactions have proven to be valuable methods for the preparation of various organoboron derivatives.[1] Multiborylated compounds, including 1,1-diboryl compounds, are intriguing synthetic intermediates for further organic transformations, as evidenced by recent progress in their applications.[2] However, previous hydroboration or diboration reactions have been reported to generate multiborylated compounds as regioisomeric mixtures.[3] Only recently has the regio- and stereoselective synthesis of 1,1-diborylated compounds by hydroboration of appropriate alkenylboron derivatives been disclosed.[4, 5] Since alkenylboronates can be prepared from alkynes via hydroboration, the synthesis of 1,1-diboryl compounds directly from alkynes would be desirable and convenient. To date, only a single report of such a transformation using a rhodium catalyst has appeared, from the Shibata group.[6] A rhodium-based catalytic system produced the desired products from arylalkynes; however, the formation of side-products through reduction of intermediate alkenylboronates was unavoidable even under optimized Rh/ dppb catalytic conditions (dppb = 1,4-bis(diphenylphosphino)butane). The ratio of regioisomeric 1,1-diboryl products was highly variable depending on the rhodium/phosphine catalyst. Recently, we reported that a phosphine-ligated copper(I) catalyst was effective for the hydroboration of electrophilic alkenes using pinacolborane (HBpin) as the hydroborating reagent.[7] Since alkenylboronic esters can be prepared from alkyne substrates,[8] we envisioned that two successive regioand stereoselective hydroboration reactions of terminal al[a] S. Lee, D. Li, Prof. J. Yun Department of Chemistry and Institute of Basic Science Sungkyunkwan University Suwon 440-746 (Korea) Fax: (+ 82) 31-290-7075 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402458.

Chem. Asian J. 2014, 9, 2440 – 2443

Scheme 1. Hydroboration of phenylacetylene.

2440

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Jaesook Yun et al.

www.chemasianj.org

To increase the regioselectivity of the first hydroboration and for an overall more efficient synthesis, the substrate was switched from an arylalkyne to less electronically biased simple alkynes and propargylic alkynes. The hydroboration of propargyl amide 1 a was investigated by screening the copper source, ligand, and base in the presence of pinacolborane at room temperature (Table 1). While CuTC/dppbz

Table 2. Synthesis of 1,1-diboryl compounds via hydroboration.

Entry

Table 1. Hydroboration of propargyl amide 1 a.

Entry

Cu/L

Base

Conversion [%][a]

Yield [%][b]

1 2 3 4 5[d] 6

CuTC[c]/dppbz CuTC/PCy3 CuCl/dppbz CuCl/xantphos CuCl/xantphos CuCl/xantphos

NaOtBu NaOtBu NaOtBu NaOtBu LiOtBu K3PO4

92 63 32 100 100 100

60 14 30 66 76 n.i.[e]

[a] Determined by GC analysis with an internal standard based on consumption of 1 a. [b] Yield of isolated 2 a. [c] CuTC = copper(I) thiophene2-carboxylate [d] 2.2 equiv HBpin was used. [e] Not isolated. A 4:1 ratio of 2 a and monodeboronated product (2 a’) was obtained by GC analysis of the crude mixture.

1[c]

1b

80

2[c]

1c

74

3[d]

1d

72

4

1e

32

5

1f

n.r.[e]

6

1g

83

7[f]

1h

56

8[g]

1i

63

9[d,f]

1j

61

10

1k

60

[a] The reaction was carried out with the combination of 5 mol % CuCl, 6 mol % xantphos, and 15 mol % NaOtBu in toluene using 2.2 equiv of pinacolborane at room temperature for 24 h. [b] Yield of isolated 2. [c] 2.4 equiv HBpin was used. [d] 10 mol % NaOtBu was used. [e] No reaction. [f] The reaction temperature was 50 8C. [g] 5 mol % CuTC and 5 mol % NaOtBu were used. TBDMSO = tert-butyldimethylsilyloxy.

catalyst gave the desired product in moderate yield (Table 1, entry 1), a copper/monophosphine catalyst gave the product in low yield together with deboronated product (Table 1, entry 2). Using CuCl/xantphos resulted in a superior conversion to the product, which was isolated in 66 % yield (Table 1, entry 4). In contrast to the hydroboration of phenylacetylene, a borylalkenyl intermediate was not detected during this reaction. Replacement of NaOtBu with LiOtBu gave a slightly increased isolated yield (Table 1, entry 5). The reaction with less basic K3PO4 proceeded to complete conversion, but deboronated product and impurities formed along with the diborylated product. With optimized reaction conditions including NaOtBu[14] as base, the dihydroboration of various terminal alkynes was examined (Table 2). The reaction of benzyl or methyl protected propargyl alcohols gave the desired products in good yields without the detection of other regioisomeric products (Table 2, entries 1 and 2). The reaction of silyl-protected propargyl ether (1 d) afforded the product in 72 % yield, but reaction of a propargyl ester (1 e) gave a poor yield of product, possibly due to SN2’ substitution[15] by the Cu H catalyst instead of addition. Unprotected propargyl alcohol (1 f) was not reactive under the reaction conditions. Simple aliphatic alkynes were suitable substrates for the reaction as well. For alkyl substituted substrates, the reaction temperature was increased to 50 8C to obtain a better yield of the target products.[16] Primary alkyl-substituted compounds (1 g–1 i) afforded the desired products in moderate to good yields. Secondary and tertiary alkyl-substituted alkyne substrates (1 j, 1 k) also produced the corresponding

Chem. Asian J. 2014, 9, 2440 – 2443

Yield [%][b]

Alkyne

diborylated products, which indicate that a sterically bulky substituent does not impede the reaction. Next, intermediate alkenylboronate compounds were prepared in a separate step,[10, 17] and these intermediates were subjected to hydroboration at room temperature to assess the efficiency of the copper/xantphos catalyst in the second hydroboration step (Scheme 2). The reactions proceeded smoothly at room temperature to afford the products with

Scheme 2. Hydroboration of alkenylboronates.

2441

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Jaesook Yun et al.

www.chemasianj.org

excellent regioselectivity and high yield. The hydroboration of simple alkenylboronates proceeded at room temperature to form the product in high yield (Scheme 2 (1)). The absence of detectable intermediate alkenylboronates in the dihydroboration of alkyl-substituted alkynes (Table 2) together with this result suggests that the first hydroboration is less energetically favorable than the second hydroboration, especially for alkylalkynes under the dihydroboration conditions. A possible catalytic cycle for the sequential hydroboration of terminal alkynes is proposed in Scheme 3. A ligand-coordinated Cu H moiety, generated in situ from CuOtBu and

was stirred for 10 min at room temperature. The alkyne substrate (0.5 mmol) was added to the reaction mixture, and the reaction tube was washed with toluene (0.5 mL), sealed, and stirred at room temperature. The reaction was monitored by TLC and GC. After 24 h, the reaction mixture was filtered through a pad of Celite and concentrated. The product was purified by chromatography on silica gel.

Acknowledgements This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2011-0009533, 2013R1A1A2058160).

Keywords: alkynes · copper · homogeneous catalysis · hydroboration · regioselectivity

[1] a) K. Burgess, M. J. Ohlmeyer, Chem. Rev. 1991, 91, 1179 – 1191; b) C. M. Crudden, D. Edwards, Eur. J. Org. Chem. 2003, 4695 – 4712; c) A.-M. Carroll, T. P. OSullivan, P. J. Guiry, Adv. Synth. Catal. 2005, 347, 609 – 631; d) T. Hayashi, Y. Matsumoto, Y. Ito, Tetrahedron: Asymmetry 1991, 2, 601 – 612; e) H. Doucet, E. Fernandez, T. P. Layzell, J. M. Brown, Chem. Eur. J. 1999, 5, 1320 – 1330. [2] a) K. Endo, T. Ohkubo, M. Hirokami, T. Shibata, J. Am. Chem. Soc. 2010, 132, 11033 – 11035; b) K. Endo, M. Hirokami, T. Shibata, J. Org. Chem. 2010, 75, 3469 – 3472; c) K. Endo, T. Ohkubo, T. Shibata, Org. Lett. 2011, 13, 3368 – 3371; d) J. C. H. Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894 – 899. [3] a) D. J. Pasto, J. Am. Chem. Soc. 1964, 86, 3039 – 3047; b) P. Nguyen, R. B. Coapes, A. D. Woodward, N. J. Taylor, J. M. Burke, J. A. K. Howard, T. B. Marder, J. Organomet. Chem. 2002, 652, 77 – 85; c) V. V. R. Rao, S. K. Agarwal, I. Mehrotra, D. Devaprabhakara, J. Organomet. Chem. 1979, 166, 9 – 16; d) J. Ramrez, A. M. Segarra, E. Fernndez, Tetrahedron: Asymmetry 2005, 16, 1289 – 1294. [4] X. Feng, H. Jeon, J. Yun, Angew. Chem. Int. Ed. 2013, 52, 3989 – 3992; Angew. Chem. 2013, 125, 4081 – 4084; 1,1-diboryl compounds via conjugate borylation, see ref. [2d]. [5] For the synthesis of 1,2-diboryl compounds from alkenylboronates via hydroboration, a) C. Wiesauer, W. Weissensteiner, Tetrahedron: Asymmetry 1996, 7, 5 – 8; via formal hydroboration b) Y. Lee, H. Jang, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 18234 – 18235; c) H.-Y. Jung, J. Yun, Org. Lett. 2012, 14, 2606 – 2609. [6] K. Endo, M. Hirokami, T. Shibata, Synlett 2009, 1331 – 1335. [7] a) D. Noh, H. Chea, J. Ju, J. Yun, Angew. Chem. Int. Ed. 2009, 48, 6062 – 6064; Angew. Chem. 2009, 121, 6178 – 6180; b) D. Noh, S. K. Yoon, J. Won, J. Y. Lee, J. Yun, Chem. Asian J. 2011, 6, 1967 – 1969. [8] a) C. Gunanathan, M. Hçlscher, F. Pan, W. Leitner, J. Am. Chem. Soc. 2012, 134, 14349 – 14352; b) C. E. Tucker, J. Davidson, P. Knochel, J. Org. Chem. 1992, 57, 3482 – 3485; c) S. Pereira, M. Srebnik, Tetrahedron Lett. 1996, 37, 3283 – 3286; d) H. C. Brown, S. K. Gupta, J. Am. Chem. Soc. 1972, 94, 4370 – 4373. [9] K. Semba, T. Fujihara, J. Terao, Y. Tsuji, Chem. Eur. J. 2012, 18, 4179 – 4184. [10] a) J.-E. Lee, J. Kwon, J. Yun, Chem. Commun. 2008, 733 – 734; b) M. Gao, S. B. Thorpe, W. L. Santos, Org. Lett. 2009, 11, 3478 – 3481. [11] J. Won, D. Noh, J. Yun, J. Y. Lee, J. Phys. Chem. A 2010, 114, 12112 – 12115. [12] The ratio was determined by NMR spectroscopic analysis of a crude reaction mixture. The deboronated form of a-d (Y = H) was obtained under the reaction conditions. [13] For in situ generation of Cu H from copper precursors with pinacolborane, see: a) D. Zhao, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 14440 – 14441; b) B. H. Lipshutz, Zˇ. V. Bosˇkovicˇ, D. H. Aue, Angew. Chem. Int. Ed. 2008, 47, 10183 – 10186;

Scheme 3. Proposed catalytic cycle for the copper-catalyzed sequential hydroboration of alkynes.

pinacolborane, is considered as the active catalyst, and its addition to the alkyne and subsequent transmetalation with pinacolborane affords the hydroboration product I by steric control. Subsequent hydroboration of the alkenyl product produces the desired 1,1-diborylalkane product. Since the hydroboration of isolated alkenylboronates produced 1,1-diborylated products as the only detectable isomer (Scheme 2), it could be concluded that the initial hydroboration of the alkyne controls the overall regioisomeric product distribution of the diborylated products. The examples in Scheme 2 also provide an alternative stepwise access to 1,1diborylalkane products from arylalkynes, which are difficult to obtain in pure regioisomeric form due to the moderate regioselectivity of the first hydroboration of these substrates under the copper-catalyzed conditions. In summary, we have developed a sequential copper-catalyzed hydroboration of terminal alkynes with pinacolborane for the preparation of 1,1-diborylalkane compounds. Protected propargyl amines, propargyl alcohol derivatives, and simple alkynes reacted to give the desired 1,1-diborylalkanes in good yields and high regioselectivity. This current method that utilizes copper catalysis constitutes an alternative to the previously reported Rh/dppb catalyzed protocol.

Experimental Section A mixture of CuCl (2.5 mg, 0.025 mmol), NaOtBu (7.2 mg, 0.075 mmol), and xantphos (17.4 mg, 0.03 mmol) in anhydrous toluene (1 mL) was stirred for 15 min in a Schlenk tube under a nitrogen atmosphere. Pinacolborane (160 mL, 1.1 mmol) was added to the reaction, and the mixture

Chem. Asian J. 2014, 9, 2440 – 2443

2442

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org

Angew. Chem. 2008, 120, 10337 – 10340; for reviews of Cu H catalyzed reactions, see: c) C. Deutsch, N. Krause, B. H. Lipshutz, Chem. Rev. 2008, 108, 2916 – 2927; d) S. Rendler, M. Oestreich, Angew. Chem. Int. Ed. 2007, 46, 498 – 504; Angew. Chem. 2007, 119, 504 – 510. [14] LiOtBu was less effective for simple alkynes and protected propargyl alcohol derivatives. [15] a) J. F. Daeuble, C. McGettigan, J. M. Stryker, Tetrahedron Lett. 1990, 31, 2397 – 2400; b) C. Deutsch, B. H. Lipshutz, N. Krause, Angew. Chem. Int. Ed. 2007, 46, 1650 – 1653; Angew. Chem. 2007,

Chem. Asian J. 2014, 9, 2440 – 2443

Jaesook Yun et al.

119, 1677 – 1681; c) C. Zhong, Y. Sasaki, H. Ito, M. Sawamura, Chem. Commun. 2009, 5850 – 5852. [16] For example, reactions of 1 h and 1 j at room temperature for 24 h gave products in lower yields, 26 % and 48 %, respectively. [17] a) H. R. Kim, J. Yun, Chem. Commun. 2011, 47, 2943 – 2945; b) J. Takagi, K. Takahashi, T. Ishiyama, N. Miyaura, J. Am. Chem. Soc. 2002, 124, 8001 – 8006. Received: April 30, 2014 Published online: June 24, 2014

2443

 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim