Copper-catalyzed conjugate additions of alkylboranes to imidazolyl α,β-unsaturated ketones: Formal reductive conjugate addition of terminal alkenes

Article abstract of DOI:10.1021/ol102819k

Conjugate addition of alkylboron compounds (alkyl-9-BBN) to imidazol-2-yl α,β-unsaturated ketones proceeded in the presence of a catalytic amount (10 mol %) of CuCl, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), and t-BuOK. The alkylboranes are

Full text of DOI:10.1021/ol102819k

ORGANIC
LETTERS
2011
Vol. 13, No. 3
482-485
Copper-Catalyzed Conjugate Additions
of Alkylboranes to Imidazolyl
r,ꢀ-Unsaturated Ketones: Formal
Reductive Conjugate Addition of
Terminal Alkenes
Hirohisa Ohmiya,* Mika Yoshida, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
ohmiya@sci.hokudai.ac.jp; sawamura@sci.hokudai.ac.jp
Received November 20, 2010
ABSTRACT
Conjugate addition of alkylboron compounds (alkyl-9-BBN) to imidazol-2-yl r,ꢀ-unsaturated ketones proceeded in the presence of a catalytic
amount (10 mol %) of CuCl, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes), 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 r,ꢀ-unsaturated ketones. The 2-acylimidazole moiety can easily be converted into the
corresponding carboxylic acid, ester, and amide derivatives.
Transition-metal-catalyzed conjugate additions of orga-
nometallic reagents to R,ꢀ-unsaturated carbonyl com-
pounds are important carbon-carbon bond formation
methods in view of their broad substrate scope and
applicability to asymmetric reactions.1 In particular, the
reactions of organoboron compounds under the influence
of transition metal catalysts, such as rhodium, palladium,
nickel, etc., have emerged at the frontier of the field given
their broad substrate scope and functional group compat-
ibility.2-5 Unfortunately, however, the organoboron reagents
that are usable for these methods are generally limited to
aryl-, alkenyl-, and allylboron compounds,2-5 and the
reactions of alkylboron derivatives are rare and underdevel-
(2) For selected references on Rh-catalyzed conjugate additions with
aryl- and alkenylboron compounds, see: (a) Sakai, M.; Hayashi, H.; Miyaura,
N. Organometallics 1997, 16, 4229–4231. (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579–
5580. (c) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508–11509. For reviews, see: (d) Fagnou, K.; Lautens,
M. Chem. ReV. 2003, 103, 169–196. (e) Hayashi, T.; Yamasaki, K. Chem.
ReV. 2003, 103, 2829–2844.
(3) For selected references on Pd-catalyzed conjugate additions with aryl-
and alkenylboron compounds, see: (a) Cho, C. S.; Tanabe, K.; Uemura, S.
Tetrahedron Lett. 1994, 35, 1275–1278. (b) Cho, C. S.; Motofusa, S.; Ohe,
K.; Uemura, S.; Shim, S. C. J. Org. Chem. 1995, 60, 883–888. (c) Cho,
C. S.; Motofusa, S.; Ohe, K.; Uemura, S. Bull. Chem. Soc. Jpn. 1996, 69,
2341–2348. (d) Gini, F.; Hessen, B.; Minnaard, A. J. Org. Lett. 2005, 7,
5309–5312. (e) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9,
343–346. (f) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651–9653. (g) Lin,
S.; Lu, X. Tetrahedron Lett. 2006, 47, 7167–7170. (h) Lin, S.; Lu, X. Org.
Lett. 2010, 12, 2536–2539. (i) Yamamoto, Y.; Nishikata, T.; Miyaura, N.
Pure Appl. Chem. 2008, 80, 807–817, and references therein.
(1) For reviews on transition-metal-catalyzed conjugate additions, see:
(a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171, 196. (b) Alexakis,
A.; Ba¨ckvall, J. E.; Krause, N.; Pa`mies, O.; Die´guez, M. Chem. ReV. 2008,
108, 2796–2823. (c) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. ReV. 2008, 108, 2824–2852. (d)
Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279,
1300. (e) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46, 7295–7306.
10.1021/ol102819k  2011 American Chemical Society
Published on Web 12/20/2010

oped. Specifically, more than 30 years ago Suzuki et al.
reported the copper-mediated conjugate addition of lithium
trialkylmethylborates prepared from trialkylboranes and
methyllithium to acrylonitrile or ethyl acrylate.6 Recently,
Oshima, Yorimitsu and co-workers reported the nickel-
catalyzed conjugate addition of trialkylboranes to R,ꢀ-
unsaturated esters, but functionalized alkylboranes (alkyl-
9-BBN) were only used for the addition to the specific
substrate benzyl (E)-crotonate. Furthermore, the system
required the use of a difficult-to-handle catalyst precursor
[Ni(cod)2/PtBu3] and large excess amounts of alkylboron
reagents and base.7
nonane dimer [9-BBN-H]2 (1a/B 1.05:1) at 60 °C (Scheme
1). Subsequently, the resulting THF solution of 2a (0.48
Scheme 1
Herein, we report a copper-catalyzed conjugate addition
of alkylboron compounds (alkyl-9-BBN) to imidazol-2-yl
R,ꢀ-unsaturated ketones.8-10 Several aspects of this trans-
formation are noteworthy: (1) Cu, which is relatively
abundant in the Earth’s crust and thus cheap and environ-
mentally benign, is used as a metal; (2) alkyl-9-BBN reagents
are widely available via alkene hydroboration; (3) a variety
of functional groups are tolerated in both the alkene and the
R,ꢀ-unsaturated ketones; and (4) the 2-acylimidazole moiety
is a practical equivalent to various carbonyl-based functional
groups, such as carboxylic acids, esters, and amides, via the
protocols developed by Ohta.11,12 The overall molecular
transformation represents a formal reductive conjugate ad-
dition of terminal alkenes to R,ꢀ-unsaturated carbonyl
compounds.9,13
mmol) was added to a brown suspension of CuCl (10 mol
%), 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes)
(10 mol %), and t-BuOK (10 mol %). Imidazolyl R,ꢀ-
unsaturated ketone (3a) (0.4 mmol) was then added to the
mixture, which was heated at 80 °C for 12 h. After hydrolytic
workup, the conjugate addition product 4aa was obtained
in 82% isolated yield.14 Unlike the copper-catalyzed γ-selec-
tive allyl-alkyl coupling between allylic phosphates and
alkylboranes,8a the present protocol uses alkylboranes directly
without converting them into alkylborates.
Several observations concerning the optimum reaction
conditions are to be noted. Ligand screening for the reaction
between 2a and 3a revealed that N-heterocyclic carbene
(NHC) ligands were useful, with IMes being most effective.
Other NHC ligands such as IPr (27%), SIPr (0%), and SIMes
(26%) were less effective.15,16 The reaction without a ligand
Specifically, alkylborane 2a in THF solution was prepared
via hydroboration of alkene (1a) with 9-borabicyclo[3.3.1]-
(4) For Ni-catalyzed conjugate additions with arylboron compounds, see:
(a) Shirakawa, E.; Yasuhara, Y.; Hayashi, T. Chem. Lett. 2006, 35, 768–
769.
(5) For conjugate additions with allylboron compounds, see: (a) Sieber,
J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007, 129, 2214–2215. (b)
Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130, 4978–4983. (c)
Shaghafi, M. B.; Kohn, B. L.; Jarvo, E. R. Org. Lett. 2008, 10, 4743–
4746.
(6) Miyaura, N.; Itoh, M.; Suzuki, A. Tetrahedron Lett. 1976, 255, 258.
(7) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1541–
1544.
(12) For examples of the conversion of 2-acylimidazoles to other groups
such as carboxylic acids, esters, amides, ketone derivatives, etc., see: (a)
Evans, D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351–3354.
(b) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am.
Chem. Soc. 2007, 129, 10029–10041. (c) Trost, B. M.; Lehr, K.; Michaelis,
D. J.; Xu, J.; Buckl, A. K. J. Am. Chem. Soc. 2010, 132, 8915–8917. (d)
Davies, D. H.; Haire, N. A.; Hall, J.; Smith, E. H. Tetrahedron 1992, 48,
7839–7856. (e) Bakhtiar, C.; Smith, E. H. J. Chem. Soc., Perkin Trans. 1
1994, 239, 243. (f) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science
2010, 328, 1376–1379.
(8) For Cu-catalyzed γ-selective and stereospecific allyl-alkyl and
allyl-aryl couplings with organoboron compounds, see: (a) Ohmiya, H.;
Yokobori, U.; Makida, Y.; Sawamura, M. J. Am. Chem. Soc. 2010, 132,
2895–2897. (b) Ohmiya, H.; Yokokawa, N.; Sawamura, M. Org. Lett. 2010,
12, 2438–2440. (c) Whittaker, A. M.; Rucker, R. P.; Lalic, G. Org. Lett.
2010, 12, 3216–3218
.
(9) Knochel et al. reported the copper-mediated conjugate addition of
dialkylzinc reagents, prepared by a hydroboration/boron-zinc exchange
sequence, to ethyl acrylate, but the application to ꢀ-substituted R,ꢀ-
unsaturated esters is underdeveloped while benzylidene malonate has
successfully been used. Furthermore, the cumbersome procedure and its
low atom efficiency, using a large excess of substrate and reagents, hampers
the wide application of this method. See: (a) Langer, F.; Schwink, L.;
Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61,
8229–8243. (b) Hupe, E.; Calaza, M. I.; Knochel, P. Tetrahedron. Lett.
2001, 42, 8829–8831. (c) Hupe, E.; Calaza, M. I.; Knochel, P. Chem.sEur.
J. 2003, 9, 2789–2796. (d) Hupe, E.; Calaza, M. I.; Knochel, P. J.
(13) Cu-catalyzed conjugate additions of alkenylmetal compounds
prepared through carbo- or hydrometalation of terminal alkynes, to R,ꢀ-
unsaturated carbonyl compounds, have been developed. However, the use
of alkylmetal compounds generated from alkenes is not well explored. See:
(a) Lipshutz, B. H.; Dimock, S. H. J. Org. Chem. 1991, 56, 5761–5763.
(b) Vuagnoux-d’Augustin, M.; Alexakis, A. Chem.sEur. J. 2007, 13, 9647–
9662. (c) Lipshutz, B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112,
7440–7441.
Organomet. Chem. 2003, 680, 136–142
.
(14) Even when the conjugate addition was quenched with D2O or
benzaldehyde instead of H2O, only the protonated product 4aa was
obtained.
(10) For selected references on Cu-catalyzed enantioselective conjugate
additions with alkylmagnesium or alkylzinc reagents, see: (a) Lee, K.-S.;
Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128,
7182–7184. (b) Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit,
M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–8417. (c) Harutyunyan,
S. R.; Lo´pez, F.; Browne, W. R.; Correa, A.; Pen˜a, D.; Badorrey, R.;
Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006,
128, 9103–9118. (d) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc.
(15) IPr: 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene; SIPr: 1,3-
Bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene; SIMes: 1,3-Bis(2,4,6-
trimethylphenyl)imidazolidin-2-ylidene. For reviews on N-heterocyclic
carbenes (NHCs), see: (a) N-Heterocyclic Carbenes in Transition Metal
Catalysis; Glorius, F., Ed.; Topics in Organometallic Chemistry; Springer:
Heidelberg, 2007; Vol. 21. (b) N-Heterocyclic Carbenes in Synthesis; Nolan,
S. P., Ed.; Wiley-VCH: Weinheim, 2006. (c) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1290–1309. (d) D´ıez-Gonza´lez, S.; Marion, N.;
2007, 129, 276–277, See also refs 1b and c
(11) Ohta, S.; Hayakawa, S.; Nishimura, K.; Okamoto, M. Chem. Pharm.
Bull. 1987, 35, 1058–1069
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Org. Lett., Vol. 13, No. 3, 2011
483

afforded a complex mixture with no coupling product. The
use of Cu(O-t-Bu)/IMes instead of CuCl/IMes/t-BuOK was
also effective, but the yield decreased to 60%, suggesting
that KCl present in the optimal conditions is not essential
for the catalysis. The reaction with the corresponding R,ꢀ-
unsaturated esters, amides, or aldehydes resulted in the
formation of complex mixtures.
Various alkenes (1) and imidazolyl R,ꢀ-unsaturated ke-
tones (3) were subjected to the reductive conjugate addition
protocol (Table 1). Functional groups such as ester, chloro,
substituents were tolerated at the ꢀ-position in the R,ꢀ-
unsaturated ketones. The substrate 3g bearing a fur-2-yl
group at the ꢀ-position underwent the conjugate addition
(entry 10). The alkylation of fumaric acid derivative 3h
occurred with complete regioselectivity at the ꢀ-position of
the 2-acylimidazole moiety (entry 11).
The tolerance of the reaction toward steric demand in both
the alkylboranes (2) and R,ꢀ-unsaturated ketones (3) is also
shown in Table 1. The sterically more demanding alkylbo-
rane (2c), which was derived from a terminal alkene (1c)
with a tertiary alkyl substituent, served as a coupling partner
for 3a to afford the corresponding product (4c) in good yield
(entry 2). The use of secondary alkylboranes and ꢀ-branched
alkylboranes resulted in no reaction (data not shown).
Although the copper catalysis tolerated an Et group as a
ꢀ-substituent of the R,ꢀ-unsaturated ketone (3b), with the
corresponding i-Bu-substituted substrate (3c), the product
yield was low (17%) (entries 5 and 6, respectively).
The conjugate addition products with the 2-acylimidazole
moiety were readily derivatized into various carbonyl
compounds (eqs 1-3).11,12 The treatment of 4ab with
MeOTf and MS 4 Å in MeCN followed by addition of
MeOH and DBU afforded the corresponding methyl ester
derivative 5 in 92% yield (eq 1). Using H2O instead of
MeOH under similar conditions, 4aa was converted into
carboxylic acid 6 in 86% yield (eq 2). An amide (7) was
also obtainable in high yield (91%) by employing morpholine
as a nucleophilic reagent (eq 3).
Table 1. Copper-Catalyzed Conjugate Additionsa
In summary, we have developed a copper-catalyzed
conjugate addition of alkylboranes (alkyl-9-BBN) to imida-
zol-2-yl R,ꢀ-unsaturated ketones. This transformation has
(16) For selected references on catalytic reactions with NHC-copper(I)
alkoxide systems, see: (a) Diez-Gonza´lez, S.; Nolan, S. P. Synlett 2007,
2158, 2167. (b) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett.
2003, 5, 2417–2420. (c) Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P.
Organometallics 2004, 23, 1157–1160. (d) Laitar, D. S.; Mu¨ller, P.; Sadighi,
J. P. J. Am. Chem. Soc. 2005, 127, 17196–17197. (e) Mankad, N. P.; Gray,
T. G.; Laitar, D. S.; Sadighi, J. P. Organometallics 2004, 23, 1191–1193.
(f) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008, 47,
5792–5795. (g) O’Brien, J. M.; Lee, K.-S.; Hoveyda, A. H. J. Am. Chem.
Soc. 2010, 132, 10630–10633. (h) Lee, K.-S.; Hoveyda, A. H. J. Am. Chem.
Soc. 2010, 132, 2898–2900. (i) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 3160–3161. (j) Lee, Y.; Jang, H.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 18234–18235. (k) Guzman-Martinez, A.; Hoveyda, A. H.
J. Am. Chem. Soc. 2010, 132, 10634–10637. (l) Boogaerts, I. I. F.; Fortman,
G. C.; Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem., Int. Ed.
2010, 49, 8674–8677. (m) Zhang, L.; Cheng, C.; Ohishi, T.; Hou, Z. Angew.
Chem., Int. Ed. 2010, 49, 8670–8673. (n) Shintani, R.; Takatsu, K.; Hayashi,
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a The reaction was carried out with 3 (0.4 mmol, E/Z > 20:1), alkylborane
2 (0.48 mmol), CuCl (10 mol %), IMes (10 mol %), and t-BuOK (10 mol
%) in THF (0.8 mL) at 80 °C for 12 h. Alkylborane 2 was prepared in
advance by hydroboration of 1 with 9-BBN dimer at 60 °C for 1 h and
used without purification. b Isolated yield based on 3. c The isolated product
was contaminated with a trace amount of an unidentified material. d An
isomeric mixture was used as a substrate (3c, E/Z 87:13). e The reaction
was carried out in toluene (0.8 mL) at 80 °C. f The reaction was carried
out in toluene (1.75 mL) at 80 °C. g The reaction was carried out in toluene
(0.8 mL) at 100 °C. h The reaction was carried out at 60 °C.
cyano, acetal, and phthalimide moieties were compatible with
the reaction (entries 1-4 and 7-11). Both alkyl and aryl
484
Org. Lett., Vol. 13, No. 3, 2011

expanded the scope of transition-metal-catalyzed conjugate
additions of organoboron reagents to R,ꢀ-unsaturated car-
bonyl compounds, making versatile sp3-alkylation at the
ꢀ-position possible. 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 are
tolerated in both the alkenes and the R,ꢀ-unsaturated ketones.
In addition, the 2-acylimidazole moiety is a practical
equivalent to various carbonyl-based functional groups such
as carboxylic acid, esters, and amides. Studies on enanti-
oselective conjugate additions using chiral copper catalysts
are ongoing in our laboratory.
Acknowledgment. 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).
Supporting Information Available: Experimental details
and characterization data for new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL102819K
Org. Lett., Vol. 13, No. 3, 2011
485