Sp2 - Sp3 hybridized mixed diboron: Synthesis, characterization, and copper-catalyzed β-boration of α,β- unsaturated conjugated compounds

Article abstract of DOI:10.1021/ol901359n

A novel sp² - sp³ hybridized mixed diboron and its reactivity on the copper-catalyzed β-boration of α,β-unsaturated conjugated compounds to afford the corresponding β-borated compounds is reported. The presence of sp³-hybr

Full text of DOI:10.1021/ol901359n

ORGANIC
LETTERS
sp2-sp3 Hybridized Mixed Diboron:
Synthesis, Characterization, and
Copper-Catalyzed ꢀ-Boration of
r,ꢀ-Unsaturated Conjugated
Compounds
2009
Vol. 11, No. 15
3478-3481
Ming Gao, Steven B. Thorpe, and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061
santosw@Vt.edu
Received June 16, 2009
ABSTRACT
A novel sp2-sp3 hybridized mixed diboron and its reactivity on the copper-catalyzed ꢀ-boration of r,ꢀ-unsaturated conjugated compounds
to afford the corresponding ꢀ-borated compounds is reported. The presence of sp3-hybridized boron provides a mild ꢀ-boration condition in
the absence of phosphine and base additives. Finally, our investigations demonstrate that the sp2-hybridized boron of the mixed diboron is
selectively transferred to the ꢀ-carbon of conjugated substrates.
Organoboron compounds are important in medicine be-
cause of their diverse biological activities and in organic
synthesis due to their versatility as synthetic intermedi-
ates.1,2 One of the important methods for the synthesis of
organoboron derivatives is the transition-metal-catalyzed
addition of diboron reagents to R,ꢀ-unsaturated carbonyl
compounds. These boration reactions have been extensively
studied using platinum,3 rhodium,4 nickel,5 and copper6
catalyst systems. While these reactions provide a convenient
method for the installation of boron, some suffer from
limitations such as high catalyst loading, narrow substrate
scope, and high reaction temperature. In the copper-catalyzed
ꢀ-boration of R,ꢀ-unsaturated carbonyl compounds, Yun and
co-workers reported an improved procedure and a dramatic
rate acceleration in the presence of methanol.6d However,
additives such as phosphine ligand and base were still
(3) (a) Lawson, Y. G.; Lesley, M. J. G.; Marder, T. B.; Norman, N. C.;
Rice, C. R. Chem. Commun. 1997, 2051–2052. (b) Ali, H. A.; Goldberg,
I.; Srebnik, M. Organometallics 2001, 20, 3962–3965. (c) Bell, N. J.; Cox,
A. J.; Cameron, N. R.; Evans, J. S. O.; Marder, T. B.; Duin, M. A.; Elsevier,
C. J.; Baucherel, X.; Tulloch, A. A. D.; Tooze, R. P. Chem. Commun. 2004,
1854–1855.
(1) For reviews, see: (a) Boronic Acids-Preparation and Applications
in Organic Synthesis and Medicine; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, Germany, 2005. (b) Beletskaya, I.; Moberg, C. Chem. ReV. 2006,
106, 2320–2354. (c) Beletskaya, I.; Moberg, C. Chem. ReV. 1999, 99, 3435–
3461. (d) 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, 2685–2722. (e) Miyaura, N.; Suzuki, A. Chem. ReV.
(4) Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2002, 43,
2323–2325.
(5) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5031–
5033.
(6) (a) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett.
2000, 41, 6821–6825. (b) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem.
Lett. 2000, 982–983. (c) Takahashi, K.; Ishiyama, T.; Miyaura, N. J.
Organomet. Chem. 2001, 625, 47–53. (d) Mun, S.; Yun, J. Org. Lett. 2006,
8, 4887–4889. (e) Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 733–
734. (f) Lee, J. E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145–147. (g)
Sim, H.-S.; Feng, X.; Yun, J. Chem. Eur. J. 2009, 15, 1939–1943.
1995, 95, 2457–2483
.
(2) Irving, A. M.; Vogels, C. M.; Nikolcheva, L. G.; Edwards, J. P.;
He, X.-F.; Hamilton, M. G.; Baerlocher, M. O.; Baerlocher, F. J.; Decken,
A.; Westcott, S. A. New J. Chem. 2003, 27, 1419–1424
.
10.1021/ol901359n CCC: $40.75
Published on Web 07/13/2009
 2009 American Chemical Society

required.3-6 The boron source in these transformations is
derived from diboron reagents such as B2cat2,3a B2neop2,4
and B2pin2 13-6 (cat ) catecholato ) 1,2-O2C6H4; neop )
OCH2CMe2CH2O, pin ) pinacolato ) OCMe2CMe2O); all
contain sp2-hybridized boron. Herein, we report the synthesis
and characterization of a novel sp2-sp3 hybridized mixed
diboron 2 and its reactivity on the copper-catalyzed boration
of R,ꢀ-unsaturated esters, ketones, nitriles, and amides at
room temperature. 2 allows the ꢀ-boration of R,ꢀ-unsaturated
conjugated compounds under mild reaction conditions with-
out the need for additives such as phosphine ligand and base.
Treatment of 1 with bis(2-hydroxypropyl)amine (cis/trans
mixture) in a combination of ether/CH2Cl2 readily provided
mixed diboron 2 (Figure 1a). This method can easily provide
Table 1. Cu-Catalyzed Addition of Mixed Diboron 2 to Benzyl
Acrylate under Various Conditionsa
equiv time % yieldb
entry
additive
of 2
(h)
(%)c
1
2
3
4
5
6
7
8
none
1.1
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
1.1
2.0
2.0
2.0
2.0
24
36
48
48
48
48
48
96
48
24
24
13
24
24
24
60(81)
67(82)
42(65)
76
30(36)
70
82(86)
82
80
95
65
94
94
none
DPEphosd
DPEphos, MeOHd,e
(nBu)3P, MeOHd,e
ICy, MeOHd,e
none
none
9
NaOtBuf
10
11
12
13
14
15
MeOHe
MeOHe
NaOtBu, MeOHe f
,
NaOtBu, DPEphos, MeOHd e f
,
,
MeOHe g
0
0
,
MeOHe h
,
a Each reaction was performed at least three times. General procedure:
2 in CH2Cl2 was added to a solution of CuCl (0.05 equiv) in CH2Cl2 at rt
followed by 3a (1 equiv) at 0 °C, then the mixture was allowed to warm to
rt. b Isolated yield. c Corrected yield with recovered 3a. d Ligand (0.03 equiv).
e MeOH (4 equiv). NaOtBu (0.05 equiv). g In the absence of CuCl. h 1
was used instead of 2.
f
Figure 1.
(a) Synthesis of mixed diboron 2 and (b) 11B NMR (160
MHz) of 2 in CD3CN at room temperature.
1.1 equiv of mixed diboron reagent 2 dissolved in CH2Cl2,
3a was found to undergo the ꢀ-boration to afford product
4a in moderate yield (entry 1). Analysis of 4a demon-
strated that the sp2-hybridized boron was selectively
transferred to the ꢀ-carbon of 3a. This finding is consistent
with the ꢀ-boration mechanism proposed by Miyaura,
where a base functions to activate a diboron reagent
generating, in situ, a mixed sp2-sp3 hybridized diboron.6c
Increasing the equiv of 2 to 1.5 provided a slight increase
in yield (67%, entry 2). Addition of DPEphos9 led to a
decrease in yield (entry 3), but the concomitant addition
of MeOH provided a higher yield (entry 4). Encouraged
by these results, we changed the ligand to (nBu)3P and a
better σ donor N-heterocyclic carbene ICy.9 However, both
ligands provided unsatisfactory yields (entries 5 and 6).
Increasing the equivalency of 2 as well as the reaction
time to 96 h afforded 4a in good yield (entries 7 and 8).
Attempts with added base did not improve the yield (entry
9). Surprisingly, optimum conditions were found when
using MeOH (4 equiv) and 2 (2 equiv) to provide the
ꢀ-boration product in 95% yield within 24 h (entry 10).
A lower equiv of 2 provided the product in moderate yield
(entry 11). No further improvement in yield was observed
when adding either base only or base with ligand (entries
12 and 13). As expected, the reaction did not work when
gram-scale amounts of 2 with 31% recovered starting
material (1) that can be recycled. Analysis of the 11B NMR
of 2 shows the appearance of two distinct peaks at δ 35.51
and 8.95 and the loss of starting material signal (δ 31.14),
consistent with the presence of tri- and tetracoordinate
boron centers, respectively (Figure 1b).7 To our knowl-
edge, this is the first report of an sp2-sp3 hybridized
diboron. Both 1D (1H, 13C) and 2D (COSY, HMQC) NMR
studies indicate the structure of 2 to be a diastereomeric
mixture of trans/cis form (1:1.2), as expected from the
starting diol.8
We were intrigued by a report that addition of base improved
the copper-catalyzed boration of unsaturated carbonyl com-
pounds with 1.6c It has been suggested that the base acts to
activate the B-B bond by complexation prior to transfer at the
copper center, in effect generating an sp2-sp3 hybridized
diboron. We hypothesized that a “preactivated” diboron can
undergo the same transformation without the need for an
alkoxide, providing a milder reaction condition.
With mixed diboron 2 in hand, we examined its
reactivity in the ꢀ-boration of benzyl acrylate 3a (Table
1). Using a catalytic amount of CuCl in the presence of
(7) Wrackmeyer, B. Nuclear Magnetic Resonance Spectroscopy of Boron
Compounds Containing Two-, Three-, and Four-Coordinate Boron. In
Annual Reports in NMR Spectroscopy; Webb, G. A., Ed.; Academic Press:
San Diego, CA, 1988; pp 205-314.
(9) DPEphos ) bis(2-diphenylphosphinophenyl)ether, ICy ) 1,3-
dicyclohexylimidazoline-2-ylidene.
(8) See the Supporting Information for details.
Org. Lett., Vol. 11, No. 15, 2009
3479

no copper catalyst was present (entry 14). Under the same
reaction conditions as entry 10, no reaction products were
detected when 1 instead of 2 was used (entry 15).
Scheme 1. Copper-Catalyzed Diboration of 3-Butyn-2-one
With the optimal reaction conditions determined (entry 10,
Table 1), the generality of this copper-catalyzed boration was
demonstrated by reaction with various R,ꢀ-unsaturated
conjugated compounds (Table 2). Simple esters such as
Table 2. Copper-Catalyzed ꢀ-Boration of Various Unsaturated
Conjugated Compoundsa
to an R,ꢀ-acetylenic ketone affording ꢀ,ꢀ-diborated prod-
uct.10 We can envision the transformation of these types of
products into other useful functional groups.
On the basis of the above experimental results, a possible
catalytic cycle for the copper-catalyzed boration is shown
in Scheme 2. The activated sp2-sp3 hybridized mixed
time % yieldb
(h)
entry substrate
R1
R2
EWG
(%)c
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
CO2Bn
CO2Me
CO2Et
CO2 Bu
CO2nBu
24
15
18
24
24
36
72
72
48
72
72
48
95
92
96
96
91
41
47(53)
40(87)
76(84)
81(94)
85(93)
52
Scheme 2. Proposed Catalytic Cycle
t
Me CO2Me
Me CO2Et
Me CO2Bn
H
H
9
COMe
COMe
10
11
12
13
3j
3k
3l
2-cyclopentenone
H
H
H
H
CN
3m
CONMe2 48
80(90)
a Each reaction was performed at least three times. Conditions: 2 (2.0
equiv), CuCl (0.05 equiv), 3 (1 equiv), and MeOH (4 equiv), 0 °Cfrt.
b Isolated yield. c Corrected yield with recovered 3.
benzyl acrylate 3a, methyl acrylate 3b, ethyl acrylate 3c,
tert-butyl acrylate 3d, and n-butyl acrylate 3e afforded the
corresponding products 4a-e in excellent yields (91-96%)
within 24 h (entries 1-5). However, methacrylate esters
3f-h were converted to the desired products 4f-h only in
moderate yields, although some starting material was recov-
ered (entries 6-8). Fortunately, R,ꢀ-unsaturated ketones were
borated in good yields. Treatment of methyl vinyl ketone
with mixed diboron 2 under optimal conditions afforded 4i
in 76% yield (entry 9). Sterically encumbered substrate 3j
and 2-cyclopentenone 3k were also borated in high yields,
although an increase in reaction time was necessary (entries
10 and 11). The difference in reactivity between esters and
ketones can arise from the decreased electrophilicity of the
ester. Interestingly, acrylonitrile 3l and N,N-dimethylacry-
lamide 3m also underwent the ꢀ-boration reaction smoothly
in good yield (entries 12 and 13).
diboron 2 initially reacts with CuCl to generate oxazaborole
6 and boryl-cuprate intermediate 5 that undergoes conju-
gate addition to R,ꢀ-unsaturated conjugated compounds. The
resulting organocuprate 7/8 undergoes protolytic cleavage
by MeOH to form product 4, and a copper alkoxide, which
regenerates 5 in the presence of mixed diboron 2.6d
In summary, we disclose the first synthesis and characteriza-
tion of a novel mixed sp2-sp3 hybridized diboron reagent 2.
We also demonstrated its reactivity, in the absence of phosphine
or alkoxide additives, toward copper-catalyzed ꢀ-boration of
R,ꢀ-unsaturated conjugated compounds (up to 96% yield
achieved). Finally, our results established that the sp2-hybridized
boron of the mixed diboron reagent is selectively transferred
Finally, we attempted the ꢀ-boration reaction with mixed-
diboron 2 to 3-butyn-2-one 3n. Surprisingly, 3n undergoes
the boration twice to furnish ꢀ,ꢀ-diborated product 4n in
79% yield (Scheme 1). To the best of our knowledge, this
is the first example of catalytic addition of a diboron reagent
(10) Recently, Yun et al. reported the addition of bis(pinacolato)diboron
to R,ꢀ-acetylenic esters providing the corresponding monoborated products.
See reference 6e.
3480
Org. Lett., Vol. 11, No. 15, 2009

to the ꢀ-carbon of conjugated substrates. The mechanism,
synthetic utility, and synthesis of chiral mixed diboron com-
pounds are currently under investigation.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. We gratefully acknowledge financial sup-
port from the Department of Chemistry at Virginia Tech and the
Thomas F. Jeffress and Kate Miller Jeffress Memorial Trust.
OL901359N
Org. Lett., Vol. 11, No. 15, 2009
3481