Copper-catalyzed conjugate additions of alkylboranes to aryl α,β-Unsaturated Ketones

Article abstract of DOI:10.1246/cl.2011.928

Conjugate addition of alkylboron compounds (alkyl-9-BBN) to aryl α,β-unsaturated ketones proceeded in the presence of a catalytic amount (10 mol%) of [(IPr)CuCl] and t-BuOK. The alkylboranes are available through alkene hydroboration, and thus the overall process represents a reductive conjugate addition of alkenes to enone derivatives. A variety of functional groups are tolerated in both the alkenes and the α,β- unsaturated ketones.

Full text of DOI:10.1246/cl.2011.928

doi:10.1246/cl.2011.928
928
Published on the web September 5, 2011
Copper-catalyzed Conjugate Additions of Alkylboranes to Aryl ¡,¢-Unsaturated Ketones
Hirohisa Ohmiya,* Yoshinori Shido, Mika Yoshida, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-0810
(Received April 13, 2011; CL-110311; E-mail: ohmiya@sci.hokudai.ac.jp, sawamura@sci.hokudai.ac.jp)
Conjugate addition of alkylboron compounds (alkyl-9-BBN)
to aryl ¡,¢-unsaturated ketones proceeded in the presence of
a catalytic amount (10 mol %) of [(IPr)CuCl] and t-BuOK. The
alkylboranes are available through alkene hydroboration, and
thus the overall process represents a reductive conjugate addition
of alkenes to enone derivatives. A variety of functional groups
are tolerated in both the alkenes and the ¡,¢-unsaturated
ketones.
Transition-metal (Rh, Pd, Ni, etc.)-catalyzed conjugate
additions of organoboron compounds to ¡,¢-unsaturated car-
bonyl compounds are useful carbon-carbon bond formation
methods because of their broad substrate scope, functional group
compatibility and applicability to asymmetric reactions.1-4
Unfortunately however, the organoboron reagents that are
generally usable for these methods are limited to aryl-,
alkenyl-, and allylboron compounds, and the reactions of
alkylboron derivatives are relatively unexplored.2-7
Scheme 1. Cu-catalyzed conjugate addition of alkylborane.
In this context, we reported recently that conjugate addition
of alkylboron compounds (alkyl-9-BBN) to imidazol-2-yl ¡,¢-
unsaturated ketones proceeded in the presence of a catalytic
amount (10 mol %) of a Cu/N-heterocyclic carbene (NHC) and
t-BuOK.8,9 Here we report that the copper-catalyzed conjugate
addition of alkylboranes has been expanded to the reaction with
aryl ¡,¢-unsaturated ketones.10-12 The wide and easy availabil-
ity of alkylboranes via the established alkene hydroboration is an
attractive feature of this transformation and thus the overall
process represents a reductive conjugate addition of alkenes to
enone derivatives. A variety of functional groups are tolerated in
both the alkenes and the ¡,¢-unsaturated ketones.
Specifically, alkylborane 2a in THF solution was prepared
via hydroboration of styrene (1a) with 9-borabicyclo[3.3.1]-
nonane dimer [9-BBN-H]2 (1a/B 1.05:1) at 60 °C (Scheme 1).
Subsequently, the resulting THF solution of 2a (0.3 mmol) was
added to a THF solution of [(IPr)CuCl]13 (10 mol %) and
t-BuOK (10 mol %). Chalcone (3a) (0.2 mmol) was then added
to the mixture, which was heated at 80 °C for 8 h. After
hydrolytic workup, the conjugate addition product 4aa was
obtained in 83% isolated yield.14
Several observations concerning the optimum reaction con-
ditions are to be noted (Scheme 1). Unlike the conjugate addi-
tion of alkylboranes to imidazol-2-yl ¡,¢-unsaturated ketones,
IPr ligand was effective for the present protocol. While SIPr was
as effective as IPr (80% yield), other NHC ligands such as IMes
and ICy resulted in no reactions under otherwise identical
conditions.13 The reaction without a ligand afforded a complex
mixture with no addition product. The use of Cu(Ot-Bu)/
IPr instead of [(IPr)CuCl]/t-BuOK was also effective to produce
3aa in 85%, suggesting that KCl present in the optimal
conditions is not essential for the catalysis. No reaction occurred
when [(IPr)CuCl]/t-BuOK was omitted.15 Alkyl ¡,¢-unsaturat-
ed ketones did not afford the corresponding products under
similar reaction conditions: the lower reactivity of the alkyl
ketones would be attributed to their lower electrophilicity.16
Various alkenes 1 and aryl ¡,¢-unsaturated ketones 3
were subjected to the reductive conjugate addition protocol
(Table 1).17 Functional groups such as ester, acetal, silyl ether,
methoxy, trifluoromethyl, phthalimide, bromo, and amido moie-
ties were tolerated in the reaction (Entries 2-11). Both alkyl- and
aryl substituents were compatible at the ¢-position in the
¡,¢-unsaturated ketones. The substrate 3k bearing a 2-thienyl
group at the ¢-position underwent the conjugate addition
(Entry 11). The substitution of the aromatic ring of the aryl
ketone with either MeO or CF3 groups caused only marginal and
capricious effects on the reactivity (Entries 5 and 6). The
2-furyl ketone substrate 3g surved as a substrate (Entry 7).
The tolerance of the reaction toward steric demand in
alkylboranes 2 and ¡,¢-unsaturated ketones 3 is also shown in
Table 1. The sterically more demanding alkylborane 2e, which
was derived from a terminal alkene 1e with a tertiary alkyl
substituent, underwent coupling with 3i to afford the corre-
sponding product 4ei in good yield (Entry 9). The reaction of
the ¢-branched alkylborane 2h, which was prepared from
¡-methylstyrene 1h, also proceeded smoothly to produce 4ha
as a mixture of diastereomers (79:21) (Entry 12). No reaction
occurred with secondary alkylboranes (data not shown). A
sterically more demanding £-alkyl substituent such as an
cyclohexyl group was tolerated (Entry 3).
In summary, the scope of the copper-catalyzed conjugate
addition of alkylboranes (alkyl-9-BBN) has been expanded
toward aryl ¡,¢-unsaturated ketones. The alkylboranes are
easily and widely available through alkene hydroboration and
thus the overall process represents a reductive conjugate addition
of alkenes to enone derivatives. A variety of functional groups
Chem. Lett. 2011, 40, 928-930
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

929
Table 1. Substrate scope of the Cu-catalyzed conjugate addi-
tion of alkylboranesa
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
Entry Alkene
Ketone
Product
Yield/%b
Me
O
O
O
References and Notes
1
2
1a
73
Ph
Ph
O
Me
Ph
Ph
4ab
3b
3c
1
2
3
For reviews on transition-metal-catalyzed conjugate addi-
tions, see: a) N. Krause, A. Hoffmann-Röder, Synthesis
2001, 171. b) A. Alexakis, J. E. Bäckvall, N. Krause, O.
Pàmies, M. Diéguez, Chem. Rev. 2008, 108, 2796. c) S. R.
Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard,
B. L. Feringa, Chem. Rev. 2008, 108, 2824. d) J.
Christoffers, G. Koripelly, A. Rosiak, M. Rössle, Synthesis
2007, 1279. e) C. Hawner, A. Alexakis, Chem. Commun.
2010, 46, 7295.
For selected references on Rh-catalyzed conjugate additions
with aryl- and alkenylboron compounds, see: a) M. Sakai, H.
Hayashi, N. Miyaura, Organometallics 1997, 16, 4229. b) Y.
Takaya, M. Ogasawara, T. Hayashi, M. Sakai, N. Miyaura,
J. Am. Chem. Soc. 1998, 120, 5579. c) T. Hayashi, K.
Ueyama, N. Tokunaga, K. Yoshida, J. Am. Chem. Soc. 2003,
125, 11508. For reviews, see: d) K. Fagnou, M. Lautens,
Chem. Rev. 2003, 103, 169. e) T. Hayashi, K. Yamasaki,
Chem. Rev. 2003, 103, 2829.
For selected references on Pd-catalyzed conjugate additions
with aryl- and alkenylboron compounds, see: a) C. S. Cho,
K. Tanabe, S. Uemura, Tetrahedron Lett. 1994, 35, 1275. b)
C. S. Cho, S. Motofusa, K. Ohe, S. Uemura, S. C. Shim,
J. Org. Chem. 1995, 60, 883. c) C. S. Cho, S. Motofusa, K.
Ohe, S. Uemura, Bull. Chem. Soc. Jpn. 1996, 69, 2341. d) F.
Gini, B. Hessen, A. J. Minnaard, Org. Lett. 2005, 7, 5309. e)
P. He, Y. Lu, C.-G. Dong, Q.-S. Hu, Org. Lett. 2007, 9, 343.
f) X. Lu, S. Lin, J. Org. Chem. 2005, 70, 9651. g) S. Lin,
X. Lu, Tetrahedron Lett. 2006, 47, 7167. h) S. Lin, X. Lu,
Org. Lett. 2010, 12, 2536. i) Y. Yamamoto, T. Nishikata, N.
Miyaura, Pure Appl. Chem. 2008, 80, 807, and references
therein.
PivO
O
O
3
PivO
69
3
O
3
O
Ph
3
4bc
1b
O
3
1a
62c
Ph
O
3d
Ph
Ph
4ad
Ph
O
TIPSO
3
TIPSO
4
5
3a
84
Ph
3
1c
4ca
O
Ph
O
93d
TIPSO
1c
Ph
3
3
3e
4ce
OMe
OMe
O
Ph
O
O
TIPSO
6
7
1c
1a
82
78
Ph
3f
4cf
CF3
CF3
O
Ph
O
O
Ph
Ph
3g
4ag
OMe
O
O
O
N
O
8
9
93
74
71
Ph
N
O
3
3h
MeO
1d
1e
1f
O
Ph
3
4dh
Br
O
MeO
Ph
O
O
3i
MeO
Br
Ph
4ei
O
O
Boc
N
O
O
MeO
10
Bn
MeO
Ph
Boc
N
O
3j
O
Bn
Ph
4
5
For Ni-catalyzed conjugate additions with arylboron com-
pounds, see: E. Shirakawa, Y. Yasuhara, T. Hayashi, Chem.
Lett. 2006, 35, 768.
For conjugate additions with allylboron compounds, see: a)
J. D. Sieber, S. Liu, J. P. Morken, J. Am. Chem. Soc. 2007,
129, 2214. b) J. D. Sieber, J. P. Morken, J. Am. Chem. Soc.
2008, 130, 4978. c) M. B. Shaghafi, B. L. Kohn, E. R. Jarvo,
Org. Lett. 2008, 10, 4743.
For conjugate additions with alkylboron compounds, see: a)
N. Miyaura, M. Itoh, A. Suzuki, Tetrahedron Lett. 1976, 17,
255. b) K. Hirano, H. Yorimitsu, K. Oshima, Org. Lett. 2007,
9, 1541.
For a review on transition-metal-catalyzed cross-coupling
reactions using alkyl-organometallic reagents, see: R. Jana,
T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417.
H. Ohmiya, M. Yoshida, M. Sawamura, Org. Lett. 2011, 13,
482.
4fj
O
O
OAc
S
OAc
75d
74e
S
O
11
12
Ph
3k
1g
Ph
4gk
Ph
O
Ph
3a
Ph
Ph
1h
4ha
aThe reaction was carried out with 3 (0.4 mmol, E/Z > 99:1),
alkylborane 2 (Entries 1-3, 0.6 mmol; Entries 4-12, 0.48
mmol), [(IPr)CuCl] (10 mol %) and t-BuOK (10 mol %) in
THF (0.8 mL) at 80 °C for 8 h. Alkylborane 2 was prepared in
advance from 1. bIsolated yield based on 3. cNMR yield. dThe
isolated product was contaminated with a trace amount of an
6
7
e
unidentified material. Diastereomer ratio 79:21.
8
9
are tolerated in both the alkenes and the ¡,¢-unsaturated
ketones.
For Cu-catalyzed conjugate addition of arylboronic acid to
alkynoates, see: Y. Yamamoto, N. Kirai, Y. Harada, Chem.
Commun. 2008, 2010.
This work was supported by Grants-in-Aid for Scientific
Research (B) and for Young Scientists (B), JSPS. We thank
MEXT for financial support in the form of a Global COE grant
(Project No. B01: Catalysis as the Basis for Innovation in
Materials Science).
10 For Cu-catalyzed £-selective and stereospecific allyl-alkyl
and allyl-aryl couplings with organoboron compounds, see:
a) H. Ohmiya, U. Yokobori, Y. Makida, M. Sawamura,
J. Am. Chem. Soc. 2010, 132, 2895. b) H. Ohmiya, N.
Chem. Lett. 2011, 40, 928-930
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

930
Yokokawa, M. Sawamura, Org. Lett. 2010, 12, 2438. c)
15 The reaction between 2a and 3a in the presence of the radical
inhibitor, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl)
under otherwise identical conditions afforded 3aa in 83%
yield. Thus, the radical mechanism should be ruled out. For
a conjugate addition of trialkylboranes to ¡,¢-unsaturated
aldehydes and ketones under radical conditions, see: H. C.
Brown, G. W. Kabalka, J. Am. Chem. Soc. 1970, 92, 714.
16 A reaction mechanism should include the formation of
alkylcopper(I) species through B/Cu transmetalation be-
tween an alkylborane and a copper(I) alkoxide and sub-
sequent conjugate addtion of the alkylcopper(I) species to an
enone. See, refs. 8, 10a, and 10d.
A. M. Whittaker, R. P. Rucker, G. Lalic, Org. Lett. 2010, 12,
3216. For Cu-catalyzed carboxylations with alkylboron
compounds (alkyl-9-BBN) to carbon dioxide, see: d) H.
Ohmiya, M. Tanabe, M. Sawamura, Org. Lett. 2011, 13,
1086.
11 Knochel et al. reported the copper-mediated conjugate
addition of dialkylzinc reagents, prepared by a hydrobora-
tion/boron-zinc exchange sequence, to ethyl acrylate, but
the application to ¢-substituted ¡,¢-unsaturated esters is
underdeveloped while benzylidene malonate has success-
fully been used. Furthermore, the cumbersome procedure
and low atom efficiency, using large excess substrate and
reagents, hampers the wide application of this method. See:
a) F. Langer, L. Schwink, A. Devasagayaraj, P.-Y. Chavant,
P. Knochel, J. Org. Chem. 1996, 61, 8229. b) E. Hupe, M. I.
Calaza, P. Knochel, Tetrahedron Lett. 2001, 42, 8829. c) E.
Hupe, M. I. Calaza, P. Knochel, Chem.®Eur. J. 2003, 9,
2789. d) E. Hupe, M. I. Calaza, P. Knochel, J. Organomet.
Chem. 2003, 680, 136.
12 For selected references on Cu-catalyzed enantioselective
conjugate additions with alkylmagnesium- or alkylzinc
reagents, see: a) K.-s. Lee, M. K. Brown, A. W. Hird,
A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 7182. b) D.
Martin, S. Kehrli, M. d’Augustin, H. Clavier, M. Mauduit,
A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416. c) S. R.
Harutyunyan, F. López, W. R. Browne, A. Correa, D. Peña,
R. Badorrey, A. Meetsma, A. J. Minnaard, B. L. Feringa,
J. Am. Chem. Soc. 2006, 128, 9103. d) S.-Y. Wang, S.-J. Ji,
T.-P. Loh, J. Am. Chem. Soc. 2007, 129, 276. See also
refs. 1b and 1c.
17 Typical experimental procedure for the copper-catalyzed
conjugate addition (Table 1, Entry 10): In a glove box,
(9-BBN-H)2 (58.6 mg, 0.24 mmol), alkene 1f (145.5 mg,
0.504 mmol), and THF (0.20 mL) were placed in a vial
containing a magnetic stirring bar. Then, the vial was sealed
with a cap equipped with a Teflon-coated silicon rubber
septum. The vial was removed from the glove box. The
mixture was stirred at 60 °C for 1 h to prepare alkylborane 2f.
Also in the glove box, [(IPr)CuCl] (19.5 mg, 0.04 mmol),
t-BuOK (4.5 mg, 0.04 mmol), and THF (0.20 mL) were
placed in another vial and the vial was sealed with a cap
equipped with a Teflon-coated silicon rubber septum. After
the vial was removed from the glove box, the mixture was
stirred at 25 °C for 1 h. Next, the alkylborane was transferred
to the vial containing a Cu-IPr complex. Finally, aryl
¡,¢-unsaturated ketone 3j (106.5 mg, 0.40 mmol) in THF
(0.4 mL) was added. After 8 h stirring at 80 °C, H2O was
added to the reaction mixture. Then, the mixture was diluted
and extracted with EtOAc (2 mL © 3). The combined
organic layer was dried over MgSO4. Then, the drying
agent was removed by filtration, and the resulting solution
was evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel (5-15%
EtOAc/hexanes) to afford 4fj in 71% yield (158.4 mg,
0.284 mmol). White solid. Rf 0.3 (20% EtOAc/hexanes).
1H NMR (300 MHz, CDCl3): ¤ 1.11-1.31 (m, 2H), 1.38 (s,
9H), 1.53-1.85 (m, 4H), 2.82 (t, J = 7.5 Hz, 2H), 3.27-3.30
(m, 2H), 3.40 (m, 1H), 3.91 (s, 3H), 4.84 (s, 2H), 7.20-7.26
(m, 5H), 7.35 (m, 1H), 7.41-7.46 (m, 3H), 7.54 (m, 1H),
7.84-7.91 (m, 4H). 13C NMR (75.4 MHz, CDCl3): ¤ 24.92,
26.99, 27.72, 36.11, 38.02, 40.82, 45.48, 47.15, 51.97,
83.03, 127.07, 127.51, 127.69, 128.07, 128.30, 128.40,
128.52, 128.60, 130.36, 132.79, 133.08, 137.10, 138.41,
145.28, 153.16, 167.31, 176.10, 198.79. Mp 102.1-103.5 °C.
Anal. Calcd for C34H39NO6: C, 73.23; H, 7.05%. Found: C,
73.40; H, 7.30%.
13 IPr:
SIPr: 1,3-Bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene;
IMes: 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene;
1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene;
ICy: 1,3-Dicyclohexylimidazol-2-ylidene; For reviews on
N-heterocyclic carbenes (NHCs), see: a) N-Heterocyclic
Carbenes in Transition Metal Catalysis in Topics in
Organometallic Chemistry, ed. by F. Glorius, Springer,
Heidelberg, 2007, Vol. 21. doi:10.1007/978-3-540-36930-1
b) N-Heterocyclic Carbenes in Synthesis, ed. by S. P. Nolan,
Wiley-VCH, Weinheim, 2006. c) W. A. Herrmann, Angew.
Chem., Int. Ed. 2002, 41, 1290. d) S. Díez-González, N.
Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612.
14 When the catalytic conjugate addition was quenched with
D2O instead of H2O, 77% deuterium was incorporated at the
¡-position of 4aa. This suggests that the product of the
catalytic reaction is in a form of an enolate, but the attempted
enolate trap with aldehydes was unsuccessful.
Chem. Lett. 2011, 40, 928-930
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/