Regio- and enantioselective copper(I)-catalyzed hydroboration of borylalkenes: Asymmetric synthesis of 1,1-diborylalkanes

Article abstract of DOI:10.1002/anie.201208610

A bisphosphine/copper catalyst was used for the asymmetric hydroboration of 1,8-naphthalenediaminatoboryl (Bdan) substituted alkenes (see scheme; pin=pinacolato). Simple alkyl-substituted borylalkenes and styrene derivatives were hydroborated with high regio- and enantioselectivity. The electronic and steric properties of the Bdan group significantly affected the reactivity and regioselectivity of hydroboration.

Full text of DOI:10.1002/anie.201208610

Angewandte
Chemie
DOI: 10.1002/anie.201208610
Asymmetric Catalysis
Regio- and Enantioselective Copper(I)-Catalyzed Hydroboration of
Borylalkenes: Asymmetric Synthesis of 1,1-Diborylalkanes**
Xinhui Feng, Heekyung Jeon, and Jaesook Yun*
Efficient stereoselective transition-metal-catalyzed hydrobo-
ration reactions of alkenes have received much attention, and
are valuable synthetic methods for the preparation organo-
borane intermediates.[1] These reactions give products with
different selectivities to those obtained by traditional stoi-
chiometric hydroboration reactions, thus broadening the
scope of hydroboration reactions. Although rhodium catalysts
have predominantly been used in the hydroboration of
alkenes,[2] we recently reported that phosphine-coordinated
copper(I) complexes are effective catalysts for the hydro-
boration of vinyl arenes, with pinacolborane as the hydro-
borating reagent.[3]
high atom efficiency. This method uses a catalytic combina-
tion of CuCl, NaOtBu, and either (R)-dtbm-segphos or (R,S)-
josiphos as the chiral ligand.
In preliminary experiments, we evaluated the regioselec-
tivity of the hydroboration of pinacolboronate-substituted
styrene 1. By using a copper/dtbm-segphos catalyst[3b] and
pinacolborane (HBpin) as the hydroborane source, 1,2-
diboronyl (vic-1a) and 1,1-diboronyl (gem-1b) were gener-
ated in a 15:85 ratio with complete conversion (Scheme 1).
Multiborylated compounds, including 1,1-diboryl deriva-
tives, are interesting synthetic intermediates as polyfunctional
organometallic reagents.[4] The recent reports by the Shibata
group and Hall group[5] on 1,1-diborylalkanes made this type
of compounds containing two borons attached to the same sp3
carbon atom attractive for further functionalization.[6] How-
ever, previous reports have described the formation of
multiborylated compounds as a regioisomeric mixture by
hydroboration or diboration.[7]
We envisioned that regio- and stereoselective copper-
catalyzed hydroboration of borylalkenes with would provide
easy access to either 1,2- or 1,1-diboryl compounds. More-
over, enantiomerically enriched 1,1-diboryl derivatives pos-
sessing two different boryl groups at the stereogenic carbon
center might be obtained through the copper-catalyzed
reaction of appropriate borylalkenes in an atom-economical
fashion. Similar non-asymmetric hydroboration approaches
involving rhodium catalysis have been developed.[6c,8] How-
ever, these approaches have some limitations, such as low
regioselectivity and low to moderate yields as a result of side
reactions involving reduction and b-hydride elimination.
Furthermore, only one asymmetric synthesis of 1,1-diboryl
compounds through conjugate boration[9] has been reported
so far.[5b] Herein, we report a highly regio- and enantioselec-
tive copper-catalyzed hydroboration of borylalkenes to pro-
duce enantiomerically enriched 1,1,-diboryl compounds with
Scheme 1. Regioselectivity of the copper-catalyzed hydroboration of
borylalkenes.
The copper/phosphine-catalyzed hydroboration of simple
styrene derivatives was exclusively a regioselective, whereas
the use of this catalyst resulted in inverse regioselectivity for
the reaction of borylalkene 1 to mainly give the gem-1b
product. We believe the electron-withdrawing nature of the
Bpin group possibly altered the regioselectivity of the hydro-
boration.[10]
In search of substrates giving better selectivity, we tested
a
substrate containing a 1,8-naphthalenediaminatoboryl
(Bdan) group instead of the Bpin group. Despite the lower
Lewis acidity of the Bdan group, owing to electron-donating
nitrogen atoms,[11] the reaction of 2a proceeded to 100%
conversion at room temperature in 24 h and produced 1,1-
diborylated product (3a) as the major regioisomer. The
enantiomeric excess of 3a was measured by HPLC analysis on
a chiral stationary phase and determined as 96% ee.
[*] X. Feng, H. Jeon, Prof. J. Yun
Department of Chemistry and Institute of Basic Science
Sungkyunkwan University
Suwon 440-746 (Korea)
E-mail: jaesook@skku.edu
To investigate the effect of other chiral bisphosphine
ligands on regioselectivity and enantioselectivity, a range of
chiral ligands were screened. With 2a as the model substrate,
all reactions showed complete regioselectivity to give 3a.
When the (R)-tol-binap ligand was used, the reaction did not
proceed to complete conversion (Table 1, entry 2; 72%),
[**] 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 (NRF-
20110009533).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208610.
Angew. Chem. Int. Ed. 2013, 52, 3989 –3992
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3989

.
Angewandte
Communications
Table 2: Copper-catalyzed enantioselective hydroboration of boryl-
alkenes (2).
whereas the use of the short-tethered quinoxP and Me-
duphos ligands, resulted in complete conversion and good
ee values (82–85% ee; Table 1, entries 3 and 4). Utilization of
(R,S)-josiphos as the ligand resulted in an efficient reaction
Table 1: Optimization of reaction conditions.
Entry
R
Ligand t [h] Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
o-FC6H4 (2b)
o-FC6H4 (2b)
m-FC6H4 (2c)
p-FC6H4 (2d)
p-MeC6H4 (2e)
2-naphthyl (2 f)
nBu (2g)
nBu (2g)
(CH3)2CHCH2CH2 (2h) L1
cyclohexyl (2i) L2
L1
L2
L1
L1
L1
L2
L1
L2
63
19
36
24
24
24
12
12
24
24
81
80
81
87
85
80
90
85
80
89
93
91
93
98
97
93
95
93
97
97
Entry Ligand
t [h] Conv. [%] Yield [%][a] ee [%][b]
1
2
3
4
5
(R)-dtbm-segphos 24
100
72
100
100
100
89
45
80
83
82
96(S)
62(S)
82(S)
85(R)
94(S)
(R)-tol-binap
24
24
12
6
(R,R)-quinoxP
(S,S)-Me-duphos
(R,S)-josiphos
9
10[c]
[a] Yield of the isolated product. [b] Determined by HPLC analysis on
a chiral stationary phase. [c] 5 mol% of CuCl, 5 mol% of L2, and
10 mol% of NaOtBu were used.
[a] Yield of the isolated product. [b] Determined by HPLC analysis on
a chiral stationary phase.
Avariety of Bdan-substituted alkene compounds could be
hydroborated with high levels of enantioselectivity when the
copper/bisphosphine catalysts were used. The ee values were
similar for all the substituted alkenes (R = aryl or primary or
secondary alkyl), thus indicating the minimal influence of the
R substituent (remote from the Bdan group) on enantiose-
lectivity with the current catalyst system.
Regarding the mechanism of the catalytic borylalkene
hydroboration, we postulated that the hydroboration is
À
initiated by a LCu H (L = chiral phosphine ligand) catalyst,
generated from the reaction of copper tert-butoxide with
pinacolborane;[14] this pathway is distinct from that of similar
copper-catalyzed formal hydroboration reactions involving
À
Cu B species generated from bis(pinacolato)diboron
(B2pin2; Scheme 2).[15] Subsequent Cu H addition to the
À
with full conversion achieved in 6 h, to afford (S)-3a in 82%
yield and 94% ee (Table 1, entry 5).
borylalkene would afford a chiral organocopper intermediate
À
I, the stereogenic center of which contains both C B and
À
À
With optimized reaction conditions including dtbm-seg-
phos or josiphos as the chiral ligand established, the hydro-
boration reactions of a variety of b-Bdan-substituted styrene
derivatives were examined (Table 2, entries 1–6). The hydro-
boration reactions provided the corresponding 1,1-diborylal-
kane compounds with excellent levels of regio- and enantio-
selectivity.[12] The steric and electronic properties of aryl
groups did not significantly affect enantioselectivity. Both
ligands could be used successfully, but the use of the josiphos
ligand generally resulted in shorter reaction times, although
with slightly reduced ee values, than use of the segphos ligand.
Electrophilic alkene substrates are better for copper-
catalyzed hydroboration,[13] therefore simple alkyl-substituted
alkenes are often considered as less efficient substrates
because they contain electron-donating alkyl groups. How-
ever, the current catalytic system could be successfully
applied to alkyl-substituted borylalkenes (2g–i) to afford
products in good yield and excellent ee values (Table 2,
entries 7–10). For the hydroboration of 2i, bearing a secon-
dary alkyl group, the more-reactive L2 ligand was required to
obtain high conversion in a reasonable reaction time.
C Cu bonds. Stereoretentive transmetalation of the Cu C
bond with pinacolborane would produce the desired product
[3b,13]
À
À
and regenerate the active Cu H catalyst.
The Cu H
addition step determines the regioselectivity and the hydride
Scheme 2. A proposed catalytic cycle for hydroboration involving two
stereodetermining steps, hydrocupration, and subsequent transmetala-
tion.
3990 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3989 –3992

Angewandte
Chemie
anhydrous toluene (0.4 mL) was stirred for 10 min in a Schlenk tube
addition to the b-carbon atom from the Bdan (or Bpin) group
is considered to be mainly determined by the electronic
nature of the boronyl group.[10,16] In the case of activated
borylalkenes in which R = phenyl group (1 vs. 2a, Scheme 1),
the possible hydride addition to the b-carbon atom from the
under an atmosphere of nitrogen. Pinacolborane (0.6 mmol, 90 mL)
was added to the reaction mixture, which was stirred for another
10 min at room temperature. Substrate 2 (0.5 mmol) in toluene
(0.4 mL) and tetradecane (0.25 mmol), as an internal standard, were
added to the reaction mixture. The reaction tube was washed with
toluene (0.2 mL) and sealed. The reaction was monitored by TLC and
GC. When the reaction was complete, the reaction mixture was
filtered through a pad of Celite and the filtrate was concentrated
in vacuo. The product was purified by chromatography on silica gel
(hexanes/ethyl acetate = 10:1).
À
phenyl (or a-carbon atom from B) and L Cu addition to the
benzylic carbon atom can lower the regioselectivity, as was
the case with 1. The flat Bdan group, containing a naphthyl
À
moiety, presumably accommodates the L Cu moiety better
than the Bpin group, thus delivering higher regioselectivity.
Next, we briefly examined applications of these novel
chiral 1,1-diborylalkane compounds (Scheme 3). First,
a homologation reaction of 3a with 3-chloro-3-methylbut-1-
Received: October 26, 2012
Published online: February 26, 2013
Keywords: copper · 1,1-diborylalkanes · enantioselectivity ·
.
hydroboration · regioselectivity
[1] a) D. Mꢀnnig, H. Nçth, Angew. Chem. 1985, 97, 854 – 855;
Angew. Chem. Int. Ed. Engl. 1985, 24, 878 – 879; for reviews, see:
b) K. Burgess, M. J. Ohlmeyer, Chem. Rev. 1991, 91, 1179 – 1191;
c) C. M. Crudden, D. Edwards, Eur. J. Org. Chem. 2003, 4695 –
4712.
[2] a) A.-M. Carroll, T. P. OꢁSullivan, P. J. Guiry, Adv. Synth. Catal.
2005, 347, 609 – 631; b) T. Hayashi, Y. Matsumoto, Y. Ito,
Tetrahedron: Asymmetry 1991, 2, 601 – 612; c) C. M. Crudden,
Y. B. Hleba, A. C. Chen, J. Am. Chem. Soc. 2004, 126, 9200 –
9201; d) S. A. Moteki, D. Wu, K. L. Chandra, D. S. Reddy, J. M.
Takacs, Org. Lett. 2006, 8, 3097 – 3100; e) K. Endo, M. Hirokami,
T. Shibata, Organometallics 2008, 27, 5390 – 5393; f) M. Rubina,
M. Rubin, V. Gevorgyan, J. Am. Chem. Soc. 2003, 125, 7198 –
7199.
[3] a) D. Noh, H. Chea, J. Ju, J. Yun, Angew. Chem. 2009, 121, 6178 –
6180; Angew. Chem. Int. Ed. 2009, 48, 6062 – 6064; b) D. Noh,
S. K. Yoon, J. Won, J. Y. Lee, J. Yun, Chem. Asian J. 2011, 6,
1967 – 1969; for early examples of copper-catalyzed hydrobora-
Scheme 3. Reactions of chiral alkylborane 3a. [a] The yield was deter-
mined by GC analysis.
ynyllithium provided allenylboronate 4, and the ee value was
retained. Next, we tried Suzuki–Miyaura cross-coupling
reactions of compounds 3 (see the Supporting Information
for details). Compared to Suzuki–Miyaura cross-coupling
3
À
reactions of alkylboron (C(sp ) B) compounds containing
=
=
tion of C N and C C bonds with catecholborane, see: c) R. T.
Baker, J. C. Calabrese, S. A. Westcott, J. Organomet. Chem.
1995, 498, 109 – 117; d) V. Lillo, M. R. Fructos, J. Ramꢂrez,
A. A. C. Braga, F. Maseras, M. M. Dꢂaz-Requejo, P. J. Pꢃrez, E.
Fernꢄndez, Chem. Eur. J. 2007, 13, 2614 – 2621.
a coordinating carbonyl group,[5b,17] the coupling reactions of
the current compounds led to a low yield of the product with
a decrease in ee value. Interestingly, the absolute configura-
tion of the major enantiomer of 6 was determined to be R,
thus indicating the reaction proceeded with retention of
configuration. This result clearly shows the importance of the
activating carbonyl group for the transmetalation in the
previous couplings.[5b,17] While further improvement is
needed, this example constitutes the first stereoretentive
coupling of an enantioenriched 1,1-diborylalkane that does
not contain an additional coordinating group. Further inves-
tigation of this coupling is underway in our laboratory.
In summary, we have described a copper-catalyzed hydro-
boration of borylalkene compounds for the atom-economical
preparation of enantiomerically enriched 1,1-diborylalkane
compounds. The reaction was highly regio- and enantioselec-
tive to form the desired compounds with high efficiency.
Investigations into further applications of the products are
underway.
[4] a) T. Kurahashi, T. Hata, H. Masai, H. Kitagawa, M. Shimizu, T.
Hiyama, Tetrahedron 2002, 58, 6381 – 6395; b) M. Shimizu, C.
Nakamaki, K. Shimono, M. Schelper, T. Kurahashi, T. Hiyama, J.
Am. Chem. Soc. 2005, 127, 12506 – 12507; c) N. Iwadate, M.
Suginome, J. Am. Chem. Soc. 2010, 132, 2548 – 2549; d) R. B.
Coapes, F. E. S. Souza, R. L. Thomas, J. J. Hall, T. B. Marder,
Chem. Commun. 2003, 614 – 615; e) J. Takaya, N. Iwasawa, ACS
Catal. 2012, 2, 1993 – 2006; f) M. Tobisu, N. Chatani, Angew.
Chem. 2009, 121, 3617 – 3620; Angew. Chem. Int. Ed. 2009, 48,
3565 – 3568.
[5] a) K. Endo, T. Ohkubo, M. Hirokami, T. Shibata, J. Am. Chem.
Soc. 2010, 132, 11033 – 11035; b) J. C. H. Lee, R. McDonald,
D. G. Hall, Nat. Chem. 2011, 3, 894 – 899.
[6] a) M. Shimizu, M. Schelper, I. Nagao, K. Shimono, T. Kurahashi,
T. Hiyama, Chem. Lett. 2006, 35, 1222 – 1223; b) K. Endo, M.
Hirokami, T. Shibata, J. Org. Chem. 2010, 75, 3469 – 3472; c) K.
Endo, M. Hirokami, T. Shibata, Synlett 2009, 1331 – 1335.
[7] 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) H. C.
Brown, C. G. Scouten, R. Liotta, J. Am. Chem. Soc. 1979, 101,
96 – 99.
Experimental Section
General procedure for the enantioselective hydroboration with (R,S)-
josiphos ligand: A mixture of CuCl (0.015 mmol, 1.5 mg), NaOtBu
(0.03 mmol, 3.0 mg), and (R,S)-josiphos (0.015 mmol, 9.6 mg) in
Angew. Chem. Int. Ed. 2013, 52, 3989 –3992
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3991

.
Angewandte
Communications
[8] a) C. Wiesauer, W. Weissensteiner, Tetrahedron: Asymmetry
1996, 7, 5 – 8; for regioselective formation of 1,2-diboronate by
borylcupration, see: 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.
[9] a) S. Mun, J.-E. Lee, J. Yun, Org. Lett. 2006, 8, 4887 – 4889; b) J.-
E. Lee, J. Yun, Angew. Chem. 2008, 120, 151 – 153; Angew.
Chem. Int. Ed. 2008, 47, 145 – 147; c) H.-S. Sim, X. Feng, J. Yun,
Chem. Eur. J. 2009, 15, 1939 – 1943; d) H. Chea, H.-S. Sim, J.
Yun, Adv. Synth. Catal. 2009, 351, 855 – 858; e) X. Feng, J. Yun,
Chem. Commun. 2009, 6577 – 6579; f) I.-H. Chen, L. Yin, W.
Itano, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
11664 – 11665; g) J. M. OꢁBrien, K.-s. Lee, A. H. Hoveyda, J.
Am. Chem. Soc. 2010, 132, 10630 – 10663; h) X. Feng, J. Yun,
Chem. Eur. J. 2010, 16, 13609 – 13612.
[10] K. Sasaki, T. Hayashi, Angew. Chem. 2010, 122, 8321 – 8323;
Angew. Chem. Int. Ed. 2010, 49, 8145 – 8147.
[11] a) D. G. Hall in Boronic acids, 2nd ed. (Ed.: D. G. Hall), Wiley,
Weinheim, 2011, chap. 1; b) H. Noguchi, K. Hojo, M. Suginome,
J. Am. Chem. Soc. 2007, 129, 758 – 759.
[12] The major enantiomer of the products (3b–i) was assumed to
have the same configuration as 3a based on the fact that the R
substituent of 2 had little influence on enantioselectivity.
[13] J. Won, D. Noh, J. Yun, J. Y. Lee, J. Phys. Chem. A 2010, 114,
12112 – 12115.
À
[14] For in situ generation of Cu H from copper precursors by using
pinacolborane, see: a) D. Zhao, K. Oisaki, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2006, 128, 14440 – 14441; b) Y.
Du, L.-W. Xu, Y. Shimizu, K. Oisaki, M. Kanai, M. Shibasaki, J.
ˇ
Am. Chem. Soc. 2008, 130, 16146 – 16147; c) B. H. Lipshutz, Z. V.
ˇ
ˇ
Boskovic, D. H. Aue, Angew. Chem. 2008, 120, 10337 – 10340;
Angew. Chem. Int. Ed. 2008, 47, 10183 – 10186; d) H. Kim, J.
Yun, Adv. Synth. Catal. 2010, 352, 1881 – 1885; for theoretical
DFT calculations of related mechanisms, see also Ref. [3b] and
[13].
[15] a) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 3160 –
3161; b) R. Corberꢄn, N. W. Mszar, A. H. Hoveyda, Angew.
Chem. 2011, 123, 7217 – 7220; Angew. Chem. Int. Ed. 2011, 50,
7079 – 7082.
[16] The reaction of simple Bpin alkenes having an alkyl substituent
under the same reaction conditions exclusively produced 1,1-
diboronyl compounds; the other regioisomer was not detected.
[17] a) T. Ohmura, T. Awano, M. Suginome, J. Am. Chem. Soc. 2010,
132, 13191 – 13193; b) D. Sandrock, L. Jean-Gꢃrard, C. Chen,
S. D. Dreher, G. A. Molander, J. Am. Chem. Soc. 2010, 132,
17108 – 17110.
3992 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3989 –3992