Chemoselective Cu(I) catalyzed bis(pinacolato)diboron conjugate addition and reduction onto α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2016.04.094

Ligand-free CuI-catalyzed bis(pinacolato)diboron (B₂(pin)₂) conjugate addition and reduction onto α,β-unsaturated carbonyl compounds in moderate to excellent yields has been demonstrated.

Full text of DOI:10.1016/j.tetlet.2016.04.094

Accepted Manuscript
Chemoselective Cu(I) Catalyzed Bis(pinacolato)diboron Conjugate Addition
and Reduction onto α,β -Unsaturated Carbonyl Compounds
Qing-Dong Wang, Jin-Ming Yang, Dong Fang, Jiangmeng Ren, Bin Dong, Bin
Zhou, Bu-Bing Zeng
PII:
S0040-4039(16)30468-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.094
TETL 47594
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 February 2016
23 April 2016
26 April 2016
Please cite this article as: Wang, Q-D., Yang, J-M., Fang, D., Ren, J., Dong, B., Zhou, B., Zeng, B-B., Chemoselective
Cu(I) Catalyzed Bis(pinacolato)diboron Conjugate Addition and Reduction onto α,β -Unsaturated Carbonyl
Compounds, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.094
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Graphical Abstract
Chemoselective Cu(I) Catalyzed
Bis(pinacolato)diboron Conjugate Addition
and Reduction onto -Unsaturated
Carbonyl Compounds
Leave this area blank for abstract info.
Qing-Dong Wang, Jin-Ming Yang, Dong Fang, Jiangmeng Ren, Bin Dong, Bin Zhou, Bu-Bing Zeng

1
Tetrahedron Letters
Chemoselective Cu(I) Catalyzed Bis(pinacolato)diboron Conjugate Addition and
Reduction onto-Unsaturated Carbonyl Compounds
Qing-Dong Wanga, b, Jin-Ming Yangb *, Dong Fangb , Jiangmeng Rena, Bin Donga, Bin Zhoua, Bu-Bing
Zenga, c, 
a School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China
b School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu 224051, PR China
c Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ligand-free CuI-catalyzed bis(pinacolato)diboron (B2(pin)2) conjugate addition and reduction
onto-unsaturated carbonyl compounds in moderate to excellent yields has been
demonstrated.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Bis(pinacolato)diboron
Ligand-free
Conjugate addition
Reduction
-Unsaturated carbonyl compounds
Organoboranes are extremely useful and versatile synthetic
intermediates for organic synthesis1 and can also display
T
-boration of methyl cinnamate was i
in the
presence of 2 mol% CuI. A range of reaction conditions were
examined as shown in Table 1. It was found that the desired -
boration product 3a could be preferentially obtained in 85% yield
in the presence of 1.7 equiv. of K2CO3 (Table 1, entry 1). To our
del
4a in 15% yield by using 2 equiv. of base (Table 1,
entry 3). Eventually, the use of 2.5 equiv. Cs2CO3 was found to
give the reduced product almost exclusively (Table 1, entry 6).12
The role of CuI and Methanol was also investigated. It was quite
obvious that reactions could not happen without CuI (Table 1,
entry 7) and gave low yield with the absence of methanol (Table
1, entry 8) as it should be a proton source in this kind of reactions.
It was interesting that when stronger or higher equivalent of base
was used, the ratio of -boration product to reduction of -
unsaturated carbonyl compounds was decreasing. This result
indicates that strong base leads to deborylation reaction of -
boration product.
biological
activities.2
1,4-Conjugate
addition
of
bis(pinacolato)diboron (B2(pin)2) to carbon–carbon double bond
is one of the most important tool for establish nest of new C-B
bond via transition-metal-catalysis. In comparison with electron-
rich alkene or alkyne substrates, the reaction with
unsaturated carbonyl compounds has not been studied
extensively.3 Since introduction of
a boronate group at
theposition of carbonyl using conventional hydroboration
methods is not possible, the metal-catalyzed -boration of-
unsaturated carbonyl compounds provides a viable approach.
Such reactions have been reported using catalyst systems based
on platinum,4 palladium,5 rhodium,6 nickel,7 copper8 and N-
Heterocyclic Carbenes9 however with limitations such as high
catalyst loading, high temperature, low to moderate yield, dry
box handling and narrow substrate scope. The development of
improved procedures using less expensive, easily handled and
more sustainable catalyst systems has remained an elusive goal.10
More recently, Song and co-worker have reported the reduction
of unsaturated ketones via hydroboration at 90 oC.11 In this paper,
we herein report the development of a simple, inexpensive, and
efficient catalytic system for the 1,4-conjugate addition and
reduction of -unsaturated carbonyl compounds via the base-
controlled transition-metal-catalysis under mild conditions at
With the optimized conditions in hand, a range of substrates
were firstly screened for -boration (Table 2). In the presence of
1.7 equiv. K2CO3, -unsaturated esters with both aromatic and
aliphatic



room temperature.

———
 Corresponding author. Tel. /fax: +86 (21) 64253689; e-mail: chemyjm@163.com (J.-M. Yang), zengbb@ecust.edu.cn (B.-B. Zeng).

2
Tetrahedron
a The reaction was conducted with substrate (1.0 eq.), B2(pin)2 (1.2 eq. ), CuI
(2 mol%), K2CO3 (1.7 eq.), MeOH (2.0 eq.), anhydrous THF (1.0 mL) for 30
h at room temperature. b n.d. = not detected.
-
-boration products.
boration product 3k was detected by LC-MS.
When
Next, the catalytic reduction of -unsaturated carbonyl
compounds was examined using 2.5 equiv. Cs2CO3 as the base
instead of K2CO3. As shown in Table 3, a range of -
unsaturated substrates bearing aromatic group were reduced at
room temperature in moderate to excellent yields. Methyl
cinnamate 1a afforded the corresponding products 4a in 75%
yield. To our delight, ethyl cinnamate afforded the corresponding
product in 75% yield. The reaction of cinnamate derivatives
bearing an electron-withdrawing group afforded the desired
reductive products 4d and 4e in 91% and 98% yield respectively.
In addition, -unsaturated esters generally give the desired
products at higher yields (75-98%, Table 3, entries 1-5)
compared with -unsaturated ketones (71-81%, Table 3, entry
6-9).
Table 1. Reaction condition optimization.
Entry
1a
Conditions
3a (%)
4a (%)
<1
<1
15
K2CO3 (1.7 eq.), 30h
K2CO3 (1.7 eq.), 24h
K2CO3 (2.0 eq.), 30h
Cs2CO3 (2.0 eq.), 24h
Cs2CO3 (2.0 eq.), 30h
Cs2CO3 (2.5 eq.), 30h
Cs2CO3 (2.5 eq.), 30h
Cs2CO3 (2.5 eq.), 30h
85
60
70
18
10
<1
0
2a
3a
4a
65
5a
69
6a
75
Table 3. Cu(I) Catalyzed Reduction of  Unsaturated
7b
0
Carbonyl Compounds.a
8c
trace
36
a The reaction was conducted with substrate (1.0 eq.), B2(pin)2 (1.2 eq. ), CuI
(2 mol%), base, MeOH (2.0 eq.), anhydrous THF (1.0 mL) at room
temperature.
b The reaction was conducted with substrate (1.0 eq.), B2(pin)2 (1.2 eq. ), base,
MeOH (2.0 eq.), anhydrous THF (1.0 mL) at room temperature.
c The reaction was conducted with substrate (1.0 eq.), B2(pin)2 (1.2 eq. ), CuI
(2 mol%), base, anhydrous THF (1.0 mL) at room temperature.
Table 2. Cu(I) Catalyzed B2(pin)2 Conjugate Addition of -
Unsaturated Carbonyl Compounds.a,b
a The reaction was conducted with substrate (1.0 eq.), B2(pin)2 (1.2 eq. ), CuI
(2 mol%), Cs2CO3 (2.5 eq.), MeOH (2.0 eq.), anhydrous THF (1.0 mL) for 30
h at room temperature.
In the following trails, compounds 3a, 3c, 3d and 3e were
subjected to the standard condition of 2 mol% CuI and 2.5 equiv.
Cs2CO3 at room temperature. Interestingly, 3a could transfer to
4a under current catalytic condition (Scheme 1). This suggests
that the reduction product was formed via the catalytic boration
of -unsaturated substrates followed by protodeboronation. At
the same time, compound 3c, 3d and 3e were found to resist to
this condition and no reduction products were detected. This
phenomenon may reveal that the functional group attached at the
-position of -unsaturated esters was essential for the
protodeboronation of the -boration products. The conversion of
the -borated products to their corresponding reduction products
required the presence of aromatic rings at the position of the
carbonyl group as it may activate the C-B bond.

3
2.
3.
Byun, Y.; Yan, J.; Al-Madhoun, A. S.; Johnsamuel, J.; Yang, W.;
Barth, R. F.; Eriksson, S.; Tjarks, W. J. Med. Chem. 2005, 48,
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Pierson, N. A.; Hoyt, J. M.; Campeau, L.-C.; Chirik, P. J. J. Am.
Chem. Soc. 2016, 138, 3562.
Scheme 1. Protonation of the -boration products.
According to the results mentioned above and the related
literature10, a tentative catalytic cycle was proposed as shown in
Scheme 1. Under basic condition, B2(pin)2 and CuI was firstly
transferred to a Cu-B(pin)2 I species. It was then went through a
1,4-addition of  unsaturated carbonyl compound to form a
borylated copper enolate II which could convert into conjugate
adduct and gave CuI back to complete the catalytic cycle. It
needs to be emphasized that added base and the R group attached
at the -position of the substrates played a key role in the
following protodeboronation process. Reaction trails showed that
this process could happen when a phenyl group attached at the -
position of the substrates as the phenyl group might activate the
C-B bond. The results in Table 1 also demonstrated the
protodeboronation process also affected by the added base type
and the amount.
4.
(a) Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. ; J. Am.
Chem. Soc. 1993, 115, 11018; (b) Iverson, C. N.; Smith, M. R. III.
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C.; Rice, C. R. Tetrahedron Lett. 1998, 39, 155.
Pelz, N. F.; Woodward, A. R. ; Burks, H. E.; Sieber, J. D.;
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2003, 125, 8702; (b) Nguyen, P.; Coapes, R. B.; Woodward, A.
D.; Taylor, N. J.; Burke, J. M.; Howard, J. A. K.; Marder, T. B. J.
Organomet. Chem. 2002, 652, 77; (c) Dai, C.; Robins, E. G.;
Scott, A. J.; Clegg, W.; Yufit, D. S.; Howard, J. A. K.; Marder, T.
B. Chem. Commun., 1998, 1983;
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Chem.Commun. 2009,
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(a) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9,
5031; (b) Lillo, V.; Gei
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Org. Biomol. Chem. 2009 7
(a) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron
Lett., 2000, 41, 6821; (b) Takahashi, K.; Ishiyama, T.; Miyaura, N.
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Chem.-Eur.
J. 2009, 15
2009 351
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Adv. Synth. Catal.
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7
J. Am. Chem.
Soc. 2009 131
9.
(a)Lee, K.-S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem.
Soc., , 131, 7253;(b)Wang, L.; Chen, Z.; Ma, M.;Duan, W.;
Song, C.;Ma, Y. Org. Biomol. Chem. 2015, 13, 10691;(c) Niu,
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2015, 80, 602.
Scheme 1. Proposed reaction mechanism.
10.
J. Am. Chem. Soc. 2010, 132, 5544.
In conclusions, we have discovered and optimized the “base-
controlled” and ligand free CuI catalyzed B2(pin)2 conjugate
addition and reduction of α,β-unsaturated carbonyl compounds.
In both cases, α,β-unsaturated esters generally give better yields
compared with α,β-unsaturated ketones. The formation of
reduction products requires the presence of aromatic groups at
the β-position and the proposed reaction mechanism was also
discussed.
11. Ding, W.; Song, Q. ; Org. Chem. Fornt. 2016, 3,14.
12. General Procedure : To an oven dried 10 mL round bottom flask
equipped with a magnetic stirring bar, CuI (0.015 mmol, 2.9 mg)
and an appropriate amount of base were azeotropically dried with
anhydrous THF twice. Then 1 mL of anhydrous THF was added
and the mixture was stirred for 20 min at room temperature. Then
bis(pinacolato)diboron (0.36 mmol, 91.4 mg) in 0.5 mL anhydrous
THF was added. After 5 min, the substrate (0.3 mmol) in 0.5 mL
anhydrous THF was added, followed by MeOH (0.03 mL). The
mixture was stirred for 30 h at room temperature. After reaction,
the mixture was extracted with ethyl acetate for three times. The
combined organic phases were washed with brine, dried over
Na2SO4, filtered, concentrated and purified by flash
chromatography to afford the desired product.
Acknowledgments
We thank the National High Technology Research and
Development Program of China (2007AA02Z301), Natural
Science Foundation of Jiangsu Province (BK20141257), Natural
Science Foundation of Yancheng Teachers University
(14YCKL001) and the Fundamental Research Funds for the
Central University (WY111307) for the generous financial
support.
Supplementary data
Supplementary data associated with this letter can be found in
the online version, at http://dx.doi.org/10.1016/ /j.tetlet.000000
References and notes
1.
(a) Beletskaya, I.; Moberg, C. Chem. Rev. 2006, 106, 2320; (b)
Irvine, G. J.; Lesley, M. J. G.; Marder, T. B.; Norman, N. C.; Rice,
C. R.; Robins, E. G.; Roper, W. R.; Whittell, G. R.; Wright, L. J.
Chem. Rev. 1998, 98, 2685; (c) Beletskaya, I.; Moberg, C. Chem.
Rev. 1999, 99, 3435; (d) Contemporary Boron Chemistry;
Davidson, M.; Hughes, A. K.; Marder, T. B.; Wade, K., Ed.; RSC:
Cambridge, 2000.

4
Tetrahedron
Highlights
A CuI-catalyzed B2(pin)2 conjugate addition and
reduction of-unsaturated carbonyl compounds.
This process was controlled by the substrates and
added base.
The reaction mechanism was proposed.