A nickel catalyst for the addition of organoboronate esters to ketones and aldehydes

Article abstract of DOI:10.1021/ol9017613

A Ni(cod)₂/IPr catalyst promotes the intermolecular 1,2-addition of arylboronate esters to unactivated aldehydes and ketones. Dlaryl, alkyl aryl, and dialkyl ketones show good reactivity under mild reaction conditions (<80° C, nonpolar solvents, no strong base or acid additives). A dramatic ligand effect favors either carbonyl addition (IPr) or C-OR cross-coupling (PCy₃) with aryl ether substrates. A Ni(0)/Ni(II) catalytic cycle initiated by the oxidative cyclization of the carbonyl substrate Is proposed.

Full text of DOI:10.1021/ol9017613

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4410-4413
A Nickel Catalyst for the Addition of
Organoboronate Esters to Ketones and
Aldehydes
Jean Bouffard and Kenichiro Itami*
Department of Chemistry, Graduate School of Science, Nagoya UniVersity,
Nagoya 464-8602, Japan
itami@chem.nagoya-u.ac.jp
Received July 31, 2009
ABSTRACT
A Ni(cod)2/IPr catalyst promotes the intermolecular 1,2-addition of arylboronate esters to unactivated aldehydes and ketones. Diaryl, alkyl aryl,
and dialkyl ketones show good reactivity under mild reaction conditions (e80 °C, nonpolar solvents, no strong base or acid additives). A
dramatic ligand effect favors either carbonyl addition (IPr) or C-OR cross-coupling (PCy3) with aryl ether substrates. A Ni(0)/Ni(II) catalytic
cycle initiated by the oxidative cyclization of the carbonyl substrate is proposed.
Boronic acids and their derivatives have emerged as privi-
leged organometallic nucleophiles in a wide variety of late
transition metal-catalyzed reactions, including Suzuki-Miyaura
cross-couplings, 1,4-conjugate additions, and carbon-hetero-
atom bond formation.1 Despite substantial advances in C-X
and C-H metalation chemistry,2 the shelf-stability, func-
tional group compatibility, widespread commercial avail-
ability, and ease of functionalization3 of boronic acids confer
on them significant practical advantages over lithium,
magnesium, aluminum, or zinc organometallics. Unfortu-
nately, for the most prototypical of organometallic reactions,
1,2-addition to carbonyls, boronic acids remain limited
substrates. Since the first report of Rh-catalyzed addition of
boronic acids to aldehydes by the Miyaura group,4 and
despite recent developments,5 the 1,2-addition of boronic
acids to the less reactive ketones has to date been largely
limited to activated substrates and intramolecular reactions,
or must be preceded by boron-to-zinc transmetalation.6,7
Herein, we report that a simple Ni(cod)2/IPr·HCl system
(IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) cata-
lyzes the 1,2-addition of organoboronate esters to unactivated
ketones and aldehydes under mild conditions. For example,
phenylboronate ester 2a reacts with 2-acetylnaphthalene (1a)
in toluene at 80 °C in the presence of Ni(cod)2, IPr·HCl,
(4) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998, 37,
3279–3280.
(5) Selected references: Rh: (a) Batey, R. A.; Thadani, A. N.; Smil, D. V.
Org. Lett. 1999, 1, 1683–1686. (b) Ueda, M.; Miyaura, N. J. Org. Chem.
2000, 65, 4450–4452. (c) Fu¨rstner, A.; Krause, H. AdV. Synth. Catal. 2001,
343, 343–350. Pd: (d) Kuriyama, M.; Shimazawa, R.; Shirai, R. J. Org.
Chem. 2008, 73, 1597–1600. Ru: (e) Yamamoto, Y.; Kurihara, K.; Miyaura,
N. Angew. Chem., Int. Ed. 2009, 48, 4414–4416. Fe: (f) Zou, T.; Pi, S.-S.;
Li, J.-H. Org. Lett. 2009, 11, 453–456. Cu: (g) Tomita, D.; Kanai, M.;
Shibasaki, M. Chem. Asian J. 2006, 1, 161–166. Pt: (h) Liao, Y.-X.; Xing,
C.-H.; He, P.; Hu, Q.-S. Org. Lett. 2008, 10, 2509–2512. Ni: (i) Takahashi,
G.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y. Chem. Commun. 2005,
1459–1461. (j) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2005, 7,
4689–4691. (k) Arao, T.; Kondom, K.; Aoyama, T. Tetrahedron Lett. 2007,
48, 4115–4117.
(1) (a) Boronic Acids; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40,
275–286.
(2) Recent reviews: (a) Mulvey, R. E.; Mongin, F.; Uchiyama, M.;
Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802–3824. (b) Knochel, P.;
Dohle, W.; Gommermann, N.; Kniesel, F. F.; Kopp, F.; Korn, T.; Sapountzis,
I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302–4320.
(3) Recent examples: (a) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2008, 130, 14084–14085. (b) Ihara, H.; Suginome, M. J. Am. Chem. Soc.
2009, 131, 7502–7503.
10.1021/ol9017613 CCC: $40.75
Published on Web 08/26/2009
 2009 American Chemical Society

cases, the catalyst loading can be lowered to 1 mol % without
an appreciable reduction in yield, at the expense of extended
reaction times. The reaction proceeds best in toluene or
benzene, but acceptable yields can be achieved in MTBE,
THF, or n-hexane.8
Table 1. Discovery of Nickel Catalysis and Influence of
Parametersa
With an efficient catalyst system in hand, the scope of
applicable ketone substrates (1) as well as arylboronate esters
(2) was examined on a preparative scale (1 mmol), with 1
(1.0 equiv), 2 (1.5 equiv), Ni(cod)2 (5 mol %), IPr·HCl (10
mol %), and CsF (1.6 equiv) in toluene at 80 °C (Scheme
1). Unactivated diaryl (3e), aryl alkyl (3a-d), and dialkyl
Scheme 1.
Ni-Catalyzed Addition to Ketonesa
a See the Supporting Information for details. Standard conditions for
optimization studies: 1 (0.1 mmol), 2 (0.2 mmol), CsF (0.3 mmol), Ni(cod)2
(10 µmol), IPr·HCl (13 µmol), toluene (1 mL), 80-100 °C, 10-12 h.
b Determined by GC analysis.
and CsF to furnish the addition product 3a in quantitative
yield (Table 1). Under these conditions, neither R-arylation
of 1a nor homocoupling of 2a occurs. Listed in Table 1 are
some examples of variations from the standard conditions
(see the Supporting Information for an extensive list of
reaction conditions). Other nucleophiles such as trifluorobo-
rates and stannanes are essentially unreactive, while boronic
acids and pinacolboronate esters give lower yields. Catalysis
requires both a Ni(0) precatalyst and a bulky NHC ligand.
Comparable results are obtained with either the free carbene
or the more convenient air-stable IPr·HCl. The addition of
CsF, which presumably assists the transmetalation of the
organoboron reagent to the Ni catalyst, was required to reach
high conversions with ketone substrates.8 Addition also
proceeds at room temperature, albeit less rapidly. In some
a Reagents and conditions: carbonyl compound (1: 1.0 mmol), boronate
(2: 1.5 mmol), CsF (1.6 mmol), Ni(cod)2 (0.05 mmol), IPr·HCl (0.10 mmol),
toluene (3 mL). Isolated yields. b 10% Ni(cod)2. c IPr (1:1 L:Ni) in place
of IPr·HCl. d without CsF.
(3g-j) ketones, as well as activated trifluoromethyl ketones
(3f), react to give the corresponding tertiary alcohols in
moderate to excellent yields. Addition to a substituted
cyclohexanone (3h and 3i) takes place with virtually
complete diastereoselectivity. Addition of 2j to ethyl levuli-
nate was followed by intramolecular cyclization to give
lactone 3j.
(6) Selected references: Electronically activated ketones: (a) He, P.; Lu,
Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9, 343–346. (b) Shintani, R.;
Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353–3356. (c)
Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard,
A. J. Chem. Commun. 2006, 4093–4095. (d) Motoki, R.; Tomita, D.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 8083–8086. Strain-activated
ketones: (e) Matsuda, T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6,
1257–1259. Intramolecular additions: (f) Liu, G.; Lu, X. J. Am. Chem. Soc.
2006, 128, 16504–16505. B-to-Zn transmetalation: (g) Bolm, C.; Rudolph,
J. J. Am. Chem. Soc. 2002, 124, 14850–14851. Rare examples of
intermolecular additions to unactivated ketones, albeit limited in scope: (h)
Ueura, K.; Miyamura, S.; Satoh, T.; Miura, M. J. Organomet. Chem. 2006,
691, 2821–2826. (i) Facchetti, S.; Cavallini, I.; Funaioli, T.; Marchetti, F.;
Iuliano, A. Organometallics 2009, 28, 4150–4158.
As expected, aldehydes are considerably more reactive,
allowing the reaction to be performed at room temperature
with both aryl (3k-p, 3t) and alkyl (3q-s) aldehydes
(Scheme 2). Lower temperatures enable the addition to
(7) For recent progress in catalytic allylboration of carbonyls, see: (a)
Hall, D. G. Pure Appl. Chem. 2008, 80, 913–927. (b) Kanai, M.; Wada,
R.; Shibuguchi, T.; Shibasaki, M. Pure Appl. Chem. 2008, 80, 1055–1062.
(8) See the Supporting Information for details.
Org. Lett., Vol. 11, No. 19, 2009
4411

Scheme 2
.
Ni-Catalyzed Addition to Aldehydes at Room
Temperaturea
Scheme 3. Ligand-Controlled Orthogonal Arylation
Scheme 4. Proposed Mechanism
has in many cases been found to be favorable for ketones
(Scheme 4, left).10
a Reagents and conditions: carbonyl compound (1: 1.0 mmol), boronate
(2: 1.5 mmol), CsF (1.6 mmol), Ni(cod)2 (0.05 mmol), IPr·HCl (0.10 mmol),
toluene (3 mL). Isolated yields. b IPr (1:1 L:Ni) in place of IPr·HCl. c Without
CsF. d Slow addition of aldehyde.
Evidence from preliminary mechanistic investigations
argues against the involvement of a transmetalation-insertion
cycle for the Ni(cod)2/IPr system (see detailed experiments
and extended discussion in the Supporting Information): (i)
addition does not occur with Ni(II) precatalysts; (ii) reaction
of the carbonyl substrate with the catalyst precedes that of
the organoboron substrate;11 (iii) the observed rate law is
first order in catalyst, zeroth order in carbonyl substrate, and
approximately zeroth order in boronate ester, which is
inconsistent with a two-step transmetalation-insertion cycle;12
and (iv) byproducts that would arise from ꢀ-carbon elimina-
tion (aryl group scrambling) are not found in the reaction
mixture.
proceed selectively in the presence of other electrophiles
including aryl chlorides (3m), ketones (3l), and nitriles (3n).
Addition also takes place with alkenylboronate ester (2p) to
furnish allylic alcohol 3p in high yield. Synthetically useful
levels of diastereoselectivity can be obtained when R,R-
disubstituted aldehydes are used (3q). The addition to
aldehydes does not require the presence of CsF, allowing
fluoride-sensitive silyl ethers to participate in the reaction
(3s and 3t).
We rather favor an alternate mechanism based on the
oxidative cyclization of Ni(0) and substrate carbonyl(s) to
afford an oxanickelacycle, followed by transmetalation with
the boronate ester and reductive elimination (Scheme 4,
right).8 The 1,2-oxanickelirane pathway (n ) 1) has been
postulated in related reactions,5i-k,13 although formation of
The choice of the bulky and strongly donating IPr ligand
is critical not only for reactivity but also for the selectivity
of the 1,2-addition reaction.8 Tobisu, Chatani, and co-
workers have recently reported that Ni(cod)2/PCy3 cata-
lyzes the cross-coupling of arylboronate esters with aryl
ethers.9 Replacement of PCy3 for IPr, under essentially
identical reaction conditions, results in a complete reversal
of selectivity with substrate 1u to favor the carbonyl
addition product 3u in place of the C-OMe cross-coupling
product 4 (Scheme 3).
(10) Mechanistic studies: (a) Krug, C.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 1674–1679. (b) Krug, C.; Hartwig, J. F. Organometallics 2004,
23, 4594–4607. (c) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 3124–3125. (d) Zhao, P.; Hartwig, J. F. Organometallics
2008, 27, 4749–4757. Tertiary alcohols as organometallic surrogates through
ꢀ-carbon elimination: (e) Nishimura, T.; Katoh, T.; Hayashi, T. Angew.
Chem., Int. Ed. 2007, 46, 4937–4939. (f) Iwasaki, M.; Hayashi, S.; Hirano,
K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 4463–4469.
(11) Tsou, T. T.; Huffman, J. C.; Kochi, J. K. Inorg. Chem. 1979, 18,
2311–2316.
Addition of organoboron reagents to aldehydes and ketones
proceeds through a transmetalation-insertion mechanism for
d8 metal catalysts [Rh(I), Pd(II)], where the insertion is
reversible and the reverse reaction (ꢀ-carbon elimination)
(12) Kinetic data were obtained for the addition of phenylboronate 2a
to p-anisaldehyde in the absence of CsF. The observed lack of dependence
of the reaction rate on the concentration of both substrates within the range
of concentration relevant to catalytic reactions is likely indicative of
saturation kinetics. See the Supporting Information for a detailed discussion
of the catalytic reaction kinetics.
(9) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008,
47, 4866–4869.
4412
Org. Lett., Vol. 11, No. 19, 2009

the cyclic intermediate can require the assistance of an
oxophilic Lewis acid.14 The Ogoshi group has recently
reported a Ni(cod)2/IPr-catalyzed Tishchenko reaction that
proceeds through a 1,4,2-dioxanickelolane intermediate
(n ) 2),15 which supports its plausible participation in the
1,2-addition reaction. Both Ni(0)/Ni(II) redox cycles are
nevertheless consistent with the experimental evidence, and
their viability has been confirmed by kinetic modeling.8
Although these preliminary experiments remain insuf-
ficient to establish the reaction mechanism unequivocally,
the Ni(cod)2/IPr·HCl system constitutes a simple, practical,
and comparatively inexpensive catalyst for the intermolecular
1,2-addition of boronic acid derivatives to unactivated
ketones and aldehydes under remarkably mild conditions.
Expansion of the scope of this reaction, elucidation of the
reaction mechanism, and the development of catalytic
asymmetric variants16 are the object of ongoing efforts in
our laboratory.
Acknowledgment. This work was funded in part by a
Grant-in-Aid for Scientific Research (MEXT) and a post-
doctoral fellowship to J.B. (JSPS). We thank Prof. Susumu
Saito and Masakazu Nambo (Nagoya University) for chiral
HPLC assistance.
(13) (a) Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 7826–
7827. (b) Ochiai, H.; Jang, M.; Hirano, K.; Yorimitsu, H.; Oshima, K. Org.
Lett. 2008, 10, 2681–2683.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004,
126, 11802–11803. (b) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am.
Chem. Soc. 2005, 127, 12810–12811. (c) Ogoshi, S.; Tonomori, K.; Oka,
M.; Kurosawa, H. J. Am. Chem. Soc. 2006, 128, 7077–7086. (d) Ogoshi,
S.; Kamada, H.; Kurosawa, H. Tetrahedron 2006, 62, 7583–7588. (e)
McCarren, P. R.; Liu, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N.
J. Am. Chem. Soc. 2009, 131, 6654–6655.
OL9017613
(16) To date, best results have been obtained with chiral NHC ligand 5:
(15) (a) Hoshimoto, Y.; Ogoshi, S. Nickel-catalyzed Coupling Reactions
of Aldehydes. Abstracts of Papers, 89th Meeting of the Chemical Society
of Japan, Chiba; The Chemical Society of Japan: Tokyo, Japan, 2009;
2-F3-20. See also: (b) Stone, F. G. A. Pure Appl. Chem. 1972, 30, 551–
573. (c) Stone, F. G. A. J. Organomet. Chem. 1975, 100, 257–271. (d)
Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119, 8135–8136. (e)
Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem. Commun. 2008,
1347–1349.
For synthesis and applications of 5·HBF4 see: Chaulagain, M. R.; Sormunen,
G. J.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 9568–9569.
Org. Lett., Vol. 11, No. 19, 2009
4413