Copper-catalyzed β-boration of α,β-unsaturated carbonyl compounds with tetrahydroxydiborane

Article abstract of DOI:10.1021/ol201900d

The copper-catalyzed β-boration of α,β-unsaturated carbonyl compounds with tetrahydroxydiborane has been developed. This diboron reagent allows direct, efficient access to boronic acids and their derivatives. Primary, secondary, and tertiary α,β-unsaturated amides are converted to the corresponding β-trifluoroboratoamides in good to excellent yields. The β-boration of a variety of α,β-unsaturated esters and ketones is also reported.

Full text of DOI:10.1021/ol201900d

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4684–4687
Copper-Catalyzed β-Boration of
r,β-Unsaturated Carbonyl Compounds
with Tetrahydroxydiborane
Gary A. Molander* and Silas A. McKee
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
gmolandr@sas.upenn.edu
Received July 13, 2011
ABSTRACT
The copper-catalyzed β-boration of R,β-unsaturated carbonyl compounds with tetrahydroxydiborane has been developed. This diboron
reagent allows direct, efficient access to boronic acids and their derivatives. Primary, secondary, and tertiary R,β-unsaturated amides are
converted to the corresponding β-trifluoroboratoamides in good to excellent yields. The β-boration of a variety of R,β-unsaturated esters
and ketones is also reported.
Boron homoenolates are versatile compounds that have
been developed as synthetic intermediates for a variety of
transformations,1 including Suzuki coupling reactions.2
Significantly, secondary β-trifluoroboratoamides have been
demonstrated to react stereospecifically with inversion of
configuration in palladium catalyzed cross-couplings.2b
These developments have greatly expanded the utility of
trifluoroborato homoenolates in organic synthesis.
using diboron reagents. The β-boration of R,β-unsaturated
carbonyl compounds with bis(pinacolato)diboron is
well established.3 Rhodium,4 platinum,5 palladium,6
nickel7 and copper6a,b,8 catalyzed methods have been
previously reported. Of these, the copper catalyzed
systems have received the most attention. Yun and co-
workers were instrumental in expanding the substrate
scope from the more traditional unsaturated ketones
and esters to include the more challenging R,β-unsa-
turated amides.9
Although previously reported catalytic systems provide
efficient access to pinacol boronate esters, they are less
convenient for the syntheses of other boronate derivatives.
Conversion of the pinacol esters to the corresponding
trifluoroborate can be problematic,10 as pinacol can be
difficult to remove from the crude reaction mixtures, requir-
ing tedious purification protocols. Additionally, in the inter-
est of atom economy, use of a borylating reagent that does
not require the intermediacy of the pinacol ester would prove
beneficial.
A particularly appealing approach to the synthesis of
these compounds is the transition metal-catalyzed β-boration
of readily available R,β-unsaturated carbonyl compounds
ꢀ
(1) Bonet, A.; Sole, C.; Gulyas, H.; Fernandez, E. Curr. Org. Chem.
2010, 14, 2531.
(2) (a) Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795.
ꢀ
(b) Sandrock, D. L.; Jean-Gerard, L.; Cheng-yi, C.; Dreher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108. (c) Molander,
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G. A.; Jean-Gerard, L. J. Org. Chem. 2009, 74, 1297. (d) Molander,
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G. A.; Jean-Gerard, L. J. Org. Chem. 2009, 74, 5446.
€
(3) For a current review see: Schifner, J. A.; Muther, K.; Oestreich
Angew. Chem., Int. Ed. 2010, 49, 1194.
(4) (a) Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2002,
43, 2323. (b) Shiomi, T.; Adachi, T.; Toribatake, K.; Zhou, L.; Nishiyama,
H. Chem. Commun. 2009, 5987.
(5) (a) Lawson, Y.; Lesly, G.; Marder, T.; Norman, N.; Rice, C.
Chem. Commun. 1997, 2051. (b) Bell, J.; Cox, A.; Cameron, N.; Evans,
J.; Marder, T.; Duin, M.; Elsevier, C.; Baucherel, X.; Tulloch, A.; Tooze,
R. Chem. Commun. 2004, 1854.
(7) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5031.
(8) (a) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000,
982. (b) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron
Lett. 2000, 41, 6821. (c) Chea, H.; Sim, H, S.; Yun, J. Adv. Synth. Catal.
2009, 351, 855.
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(6) (a) Lillo, V.; Geier, M. J.; Westcott, S. A.; Fernandez, E. Org.
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Biomol. Chem. 2009, 7, 4674. (b) Bonet, A.; Gulyas, H.; Koshevoy, I. O.;
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Estevan, F.; Sanau, M.; Ubeda, M. A.; Fernandez, E. Chem.;Eur. J.
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r
10.1021/ol201900d
Published on Web 08/05/2011
2011 American Chemical Society

We next sought to reduce the catalyst loading. Interest-
ingly, initial attempts to reduce the catalyst load resulted in
incomplete conversion even at long reaction times (Table
1, entries 1À3), despite the relatively short reaction times at
high catalyst load. Consequently, attention was focused on
the mechanism of the process and specifically the role of
the base in these transformations (Scheme 1).9,14
Table 1. Catalyst Load Optimizationa
CuCl
CyJohnPhos
(mol %)
NaOtBu
reaction
time (h)
P:
SMb
entry
(mol %)
(mol %)
Scheme 1. Proposed Mechanism
1
2
3
4
5
6
7
8
9
10
5
10
5
30
15
9
18
18
18
18
18
18
1
>20:1
1.4:1
3
3
0.4:1
5
5
30
30
30
30
30
30
>20:1
>20:1
>20:1
>18:1
>19:1
>19:1
3
3
1
1
1
1
1
1
2
1
1
3
a All reactions were carried out on a 0.3 mmol scale in 3 mL of EtOH
with 1.2 equiv of BBA. b Ratio of product to starting material calculated
by 1H NMR.
Despite the interest in copper catalyzed beta-boration,
there have been only a few publications examining alter-
native diboron reagents,11 each of which provides access to
a single boronate ester. Our group has recently established
tetrahydroxydiborane (bisboronic acid, BBA)12 as an ef-
fective replacement for bis(pinacolato)diboron in palla-
dium catalyzed Miyaura borylation reactions.13 This
reagent offers direct access to boronic acids, simplifying
purification and providing access to a variety of boronate
derivatives through a single intermediate. Herein we report
a method for the β-boration of R,β-unsaturated carbonyl
compounds using BBA as an effective and atom economic-
al source of boron. To our knowledge, this is the first
example of the β-boration of R,β-unsaturated carbonyl
compounds with BBA, as well as the first copper-catalyzed
reaction of this reagent.
Reaction conditions for the β-borylation were optimized
on (E)-N-cyclohexylbut-2-enamide. For ease of analysis, the
initially formed boronic acid was converted in situ to the
corresponding alcohol by oxidation with NaOH/H2O2. A
screen of various solvents, alkoxide bases, copper(I) sources
and phosphine ligands established EtOH, NaOt-Bu, CuCl,
and 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos) as the
preferred conditions. A 1:1 ratio of ligand to copper and 1.2
equiv of BBA was effective for >90% conversion after 4 h.
Previous studies have established that the base is critical
in the formation of an sp2-sp3 species (I), creating a
more nucleophilic intermediate that facilitates trans-
metalation to the active borylcopper species II.11c In-
sertion of the R,β-unsaturated carbonyl compound into
the copper boron bond of II gives a copper enolate (III),
which accepts a proton from EtOH to give the bory-
lated product IV, regenerating a copper alkoxide cata-
lyst. We hypothesized that the formation of a borate
ester byproduct V sequestered the NaOt-Bu necessary
for catalyst regeneration as the reaction proceeded
toward completion. Therefore, the incomplete conver-
sion at low catalyst loads could be due to insufficient
quantities of base rather than of catalyst.
(11) (a) Gao, M.; Thorpe, S. B.; Santos, W. L. Org. Lett. 2009, 11,
1899. (b) Thorpe, S. B.; Guo, X.; Santos, W. L. Chem. Commun. 2011,
47, 424. (c) Gao, M.; Thorpe, S. B.; Kleeberk, C.; Slebodnick, C.;
Marder, T. B.; Santos, W. L. J. Org. Chem. 2011, 76, 3997.
(12) BBA reactions in the literature: (a) Sebelius, S.; Olsson, V.;
Szabo, K. J. Am. Chem. Soc. 2005, 127, 10478. (b) Olsson, V.; Sebelius,
S.; Selander, N.; Szabo, K. J. Am. Chem. Soc. 2006, 128, 4588. (c)
Selander, N.; Kipke, A.; Sebelius, S.; Szabo, K. J. Am. Chem. Soc. 2007,
129, 13723. (d) Selander, N.; Szabo, K. Chem. Commun. 2008, 3420. (e)
Pilarski, L. T.; Szabo, K. J. Angew. Chem., Int. Ed. 201110.1002/
anie.201102384 .
Encouragingly, we found that keeping 30 mol % of
NaOt-Bu allowed a reduction in the amount of CuCl and
CyJohnPhos to 1 mol % while retaining efficient conver-
sion to the product (Table 1, entries 4À6). Reactions run
with 2 mol % of CuCl and CyJohnPhos were found to be
more reproducible, and thus, 2 mol % of both catalyst and
ligand were used as the general conditions for subsequent
(13) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc.
2010, 132, 17701.
(14) Dang, Li,; Lin, Z.; Marder, T. Organometallics 2008, 27, 4443.
Org. Lett., Vol. 13, No. 17, 2011
4685

Table 2. β-Boration of R,β-Unsaturated Amides with Bisboro-
Table 3. β-Boration of R,β-Unsaturated Carbonyl Compounds
nic Acida
with Bisboronic Acida
a General conditions: Carbonyl substrate (1.0 equiv), BBA (1.2 equiv),
CuCl (2 mol %), CyJohnPhos (2 mol %), NaOt-Bu (30 mol %), EtOH (0.1
M), rt. After filtration and solvent removal, MeOH, KHF2 (8.2 equiv), 0 °C
to rt, 20 min. b Yield is given for isolated products.
of BBA for efficient conversion (Table 2, entry 5). Effective
conversion could not be obtained, however, for compounds
containing multiple substituents at the beta position, pre-
sumably for steric reasons (Table 2, entry 6). Next we exa-
mined the effect of the amine portion of the amide on the
borylation reaction. Primary, secondary and tertiary amides
were all tolerated, although primary amides (Table 2, entry 12)
required longer reaction times. The reaction could be run
on gram scale with only a slight reduction in yield (Table 2,
entry 1). Unfortunately, attempts to isolate the boronic acid
intermediate synthesized from 1a yielded an inseparable
mixture of boronic acid and what appears to be boroxine,
along with ligand and traces of starting material.
We were gratified to find that R,β-unsaturated esters and
ketones were also efficiently borylated under the standard
reaction conditions (Table 3). A variety of substitution
patterns were effective for ketones, with cyclic and acyclic sub-
strates proving to be good substrates for the reaction. Even
sterically hindered ketones were borylated in good yield, albeit
with a longer reaction time (Table 3, entry 3). Esters were
equally effective coupling partners (Table 3, entries 5À8), and
notably lactone 4g was a competent substrate.
a General conditions: Amide (1.0 equiv), BBA (1.2 equiv), CuCl
(2 mol %), CyJohnPhos (2 mol %), NaOt-Bu (30 mol %), EtOH (0.1 M), rt.
After filtration and solvent removal, MeOH, KHF2 (8.2 equiv), 0 °C to rt,
20 min. b Yield is given for isolated products. c Gram scale. d Used 2.0 equiv
BBA, CuCl (10 mol %), NaOt-Bu (50 mol %) CyJohnPhos (10 mol %).
reactions. Increasing the amount of NaOt-Bu beyond
30 mol % provided no advantage.
With optimized conditions in hand, we examined the
substrate scope of this reaction (Table 2). We first varied the
substitution on a series on N-cyclohexyl amides. Methyl
substitution at the R position was well tolerated, as was
monoalkyl or phenyl substitution at the beta position.
Branching at the gamma position was tolerated but required
a longer reaction time, increased catalyst loading, and 2 equiv
In summary, we have developed an efficient copper
catalyzed method for the synthesis of β-trifluoroborato
4686
Org. Lett., Vol. 13, No. 17, 2011

carbonyl compounds using bisboronic acid as a source
of boron;the first copper-catalyzed process for this
atom economical reagent. This method uses EtOH as
an environmentally benign solvent, avoids purification
difficulties encountered in the conversion of pinacol
esters to the corresponding trifluoroborates, and pro-
vides efficient access to β-amido trifluoroborates. Ef-
forts toward an enantioselective variant are ongoing in
our laboratory.
Acknowledgment. This research was supported by the
NIGMS (R01 GM-035249). Dr. RakeshKohli(University
of Pennsylvania) is acknowledged for obtaining HRMS
data. We thank BASF for a generous donation of
tetrahydroxydiborane.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
4687