Mild and general zinc-alkoxide-catalyzed allylations of ketones with allyl pinacol boronates

Article abstract of DOI:10.1021/ol101301s

A general and efficient zinc-alkoxide-catalyzed allylation of a diverse array of ketones with allyl boronates is presented. The methodology is effective with 2 mol % of catalyst and with relatively short reaction times. Studies of the key exchange process are presented, which support a cyclic transition state for the boron to zinc exchange.

Full text of DOI:10.1021/ol101301s

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3748-3751
Mild and General
Zinc-Alkoxide-Catalyzed Allylations of
Ketones with Allyl Pinacol Boronates
Keith R. Fandrick,* Daniel R. Fandrick, Joe J. Gao, Jonathan T. Reeves,
Zhulin Tan, Wenjie Li, Jinhua J. Song, Bruce Lu, Nathan K. Yee, and
Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368
keith.fandrick@boehringer-ingelheim.com
Received June 5, 2010
ABSTRACT
A general and efficient zinc-alkoxide-catalyzed allylation of a diverse array of ketones with allyl boronates is presented. The methodology is
effective with 2 mol % of catalyst and with relatively short reaction times. Studies of the key exchange process are presented, which support
a cyclic transition state for the boron to zinc exchange.
The allylation of ketones1 has emerged as one of the
fundamental methods for the synthesis of versatile tertiary
homoallylic alcohol building blocks.2 In this context, several
Barbier-type processes3 and catalytic examples have been
reported utilizing stoichiometric amounts of allyl stannanes4
and silanes.5 Although direct allylations with allyl boronates
of aldehydes6 and ketones bearing a coordinating functional
group7 have been reported, only recently have general
methodologies been realized with Cu,8 In,9 Ir,10 Ni,11 and
chiral diol catalysts.12 Recently, we reported the zinc-
(5) For selected recent examples of allylation of ketones employing allyl
silanes, see: (a) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 6536. (b) Wadamoto, M.; Yamamoto, H.
J. Am. Chem. Soc. 2005, 127, 14556. (c) Burns, N. Z.; Hackman, B. M.;
Ng, P. Y.; Powelson, I. A.; Leighton, J. L. Angew. Chem., Int. Ed. 2006,
45, 3811.
(1) For a recent review of asymmetric allylation of ketones, see: Hatano,
M.; Ishihara, K. Synthesis 2008, 11, 1647.
(2) For selected recent reviews on the allylation of aldehydes, see: (a)
Yanagisawa, A. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. 2,
p 965. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(3) For selected examples, see: (a) Nair, V.; Ros, S.; Jayan, C. N.; Viji,
S. Synthesis 2003, 16, 2546. (b) Nair, V.; Jayan, C. N.; Ros, S. Tetrahedron
2001, 57, 9453. (c) Kim, H. Y.; Choi, K. I.; Pae, A. N.; Koh, H. Y.; Choi,
J. H.; Cho, Y. S. Synth. Commun. 2003, 33, 1899.
(6) For a selected example, see: Carosi, L.; Hall, D. G. Angew. Chem.,
Int. Ed. 2007, 46, 5913.
(7) For selected allylation examples of R- and ꢀ-hydroxy ketones, see:
(a) Wang, Z.; Meng, X.-J.; Kabalka, G. W. Tetrahedron Lett. 1991, 32,
1945. (b) Kabalka, G. W.; Narayana, C.; Reddy, N. K. Tetrahedron Lett.
1996, 37, 2181.
(8) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 8910.
(4) For selected recent examples of allylation of ketones employing allyl
stannes, see: (a) Waltz, K. M.; Gavenonis, J.; Walsh, P. J. Angew Chem.,
Int. Ed. 2002, 41, 3697. (b) Yasuda, M.; Hirata, K.; Nishino, M.; Yamamoto,
A.; Baba, A. J. Am. Chem. Soc. 2002, 124, 13442. (c) Kim, J. G.; Walts,
K M.; Garcia, I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem. Soc. 2004,
126, 12580. (d) Teo, Y.-C.; Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743.
(9) (a) Schneider, U.; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46,
5909. (b) Schneider, U.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2008,
130, 13824.
(10) Barker, T. J.; Jarvo, E. R. Org. Lett. 2009, 11, 1047–1049.
(11) Zhang, P.; Morken, J. P. J. Am. Chem. Soc. 2009, 131, 12550.
10.1021/ol101301s  2010 American Chemical Society
Published on Web 08/04/2010

catalyzed propargylations of aldehydes based on a boron-zinc
exchange mechanism wherein the zinc alkoxide product from
the addition can participate in an exchange with the boronate
reagent to regenerate the active nucleophile.13 Although
related catalytic cycles have been proffered for the zinc-
catalyzed allylation of hydrazones14 and copper-catalyzed
allylation of ketones,8 the extension to the zinc-catalyzed
allylation of ketones has been elusive. Herein, we report a
general and mild zinc-alkoxide-catalyzed allylation of ke-
tones with allyl boronates.
rides14 and zinc hydroxides are competent for the exchange
with allyl boronates,16 we felt that the use of zinc alkoxides
as a catalyst might be better suited for the B/Zn exchange
and promote the turnover of the zinc from the tertiary alcohol
product to generate a catalytic process. An initial experiment
for the allylation with an in situ generated diethoxide zinc
catalyst generated from diethyl zinc (10 mol %) and excess
ethanol (1.25 equiv) proceeded to complete conversion within
2.5 h. This effect is more evident when 2 mol % of diethyl
zinc is utilized, which proceeds to complete conversion
within 2.5 h when 1 equiv of ethanol is utilized in the reaction
(97% isolated yield, entry 10). However, the corresponding
reaction without the alcohol additive led to poor conversion
(3% conversion, entry 9). As a control experiment, a reaction
with 1 equiv of ethanol and without diethyl zinc proceeds
with no conversion (entry 12).
Initial exploration of the process was performed by
evaluating selected Lewis acids for the allylation of 4-chlo-
roacetophenone 1a with allyl boronate 2a (Table 1). In
Table 1. Survey of Catalysts for the Allylation of
The effects of solvent and alcohol additives in the model
system were studied (Table 2). The allylation was found to
p-Chloroacetophenone 1a with Allyl Pinacol Boronate 2aa
Table 2. Survey of Additives and Solvents for the
Zinc-Catalyzed Allylation of p-Chloroacetophenone 1a with
Allyl Pinacol Boronate 2aa
additive
(equiv)
convnb
(%)
entry
catalyst
time (h)
1
2
3
4
5
6
7
8
none
InCl3 (100 mol %)
CuBr (100 mol %)
none
none
none
18
18
48
48
20
48
2.5
2.5
2.5
2
0
4
0
Sc(OTf)3 (10 mol %) none
0
ZnCl2 (10 mol %)
ZnBr2 (100 mol %)
ZnEt2 (10 mol %)
ZnEt2 (10 mol %)
ZnEt2 (2 mol %)
ZnEt2 (2 mol %)
ZnEt2 (2 mol %)
none
none
none
none
EtOH (1.25)
none
EtOH (0.02)
EtOH (1.0)
EtOH (1.0)
12
55
40
97
3
entry
additive (equiv)
solvent
time (h)
convnb (%)
1
2
3
4
5
6
7
8
9
10
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
EtOH (1)
none
none
H2O (2)
tBuOH (1)
THF
2.5
22
22
22
22
22
22
18
18
18
99c
89
74
1
toluene
DCM
MeCN
MTBE
EtOAc
EtOH
H2O
9
10
11
12
99c
99d
0
97
4
2.5
2.5
99d
3
a Typical reaction conditions: ketone 1 (3 mmol), catalyst and additive,
allyl boronate 2 (1.1 equiv), 4 mL of THF. b Molar % conversion as
determined by HPLC analysis. c Isolated yield (92%). d Isolated yield (97%).
THF
THF
4
97
a Typical reaction conditions: ketone 1 (3 mmol), catalyst and additive,
allyl boronate 2 (1.1 equiv), 4 mL of THF. b Molar % conversion as
determined by HPLC analysis. c Isolated yield (97%). d Isolated yield (99%).
contrast to indium(III) chloride, copper bromide and scan-
dium triflate, which provided poor conversions for the model
system, employing stoichiometric zinc bromide proceeded
in moderate conversion (entry 6, 55% conversion). Consider-
ing that the zinc reagent could also be operating via an
exchange process, the reaction was attempted with diethyl
zinc as it has precedence for promoting the B/Zn exchange
with other organoboronates.13,15 The corresponding reaction
with catalytic amounts of diethyl zinc (10 mol %, entry 7)
proceeded to 40% conversion. Considering that zinc fluo-
perform well in several solvent systems. In particular,
toluene, dichloromethane, or methyl tert-butyl ether (MTBE)
provided the desired product in g74% molar conversions.
Noteworthy, the reaction also proceeds well when ethanol
is employed as the solvent, providing the product in complete
conversion and 99% yield. However, excess moisture led to
low yields in this process (2 equiv of water, entry 9). The
allylation does not appear to be affected by the alcohol
additive, as the reaction with the sterically demanding tert-
butanol additive provides the product in 97% conversion.
After establishing the optimized conditions, the effect of
different substitution patterns on the ketone substrate (Table
(12) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006,
128, 12660.
(13) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Johnson,
C. S.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2010,
12, 88.
(14) Fujita, M.; Nagano, T.; Schneider, U.; Hamada, T.; Ogawa, C.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 2914.
(15) For a recent review, see: Knochel, P.; Leuser, H.; Gong, L.-Z.;
Perrone, S.; Kneisel, F. F. In Handbook of Functionalized Organometallics;
Knochel, P., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vol. 1, pp
251-346.
(16) For the zinc fluoride exchange with allyl trimethoxysilanes, see:
Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed. 2003, 42,
3927.
Org. Lett., Vol. 12, No. 17, 2010
3749

3) was explored. The methodology performs well with a
diverse array of functional groups including both electron-
deficient and rich aromatic acetophenones providing the
desired products in >90% isolated yields with 2 mol % of
the zinc catalyst within 2 h at ambient temperature. Even an
unprotected phenol (1i) and aniline (1h) substrates are
tolerated in the chemistry, providing the homoallylic sub-
strates in 92 and 96% yield, respectively. Apparently, the
allylation of the carbonyl effectively competes with proto-
nolysis of the allyl zinc species with either the ethanol
additive or the phenol substrate. The allylation is competent
with ethyl (1c), chloromethyl (1e), and ꢀ-chloroethyl (1d)
substrates, providing the corresponding products in 91-96%
isolated yields. It should be noted that no observable
intramolecular cyclizations with the appended chloromethyl
and chloroethyl side chains of 2d and 2e were observed.
Unsaturated ketones, in particular, substrates 1o and 1p,
perform well in the parent methodology, providing access
to the 1,2-addition products (96 and 81% yields). Also, an
R-keto ester (1q) is a competent substrate for the allylation,
allowing access to this important class of compounds (92%
isolated yield).
Table 3. Survey of Ketones for the Zinc-Catalyzed Allylations
with Allyl Pinacol Boronate 2aa
The allylation with a series of substituted allyl boronates
(eqs 1-4) was also explored. The allylation was found to
be competent with the R-methyl-substituted boronate 2b (eq
1), in which good selectivity is obtained by performing the
reaction at -25 °C, providing the syn-product 4a in 5:1 dr
and in good yield. The selectivity reverses with the corre-
sponding phenyl-substituted boronate, providing the product
in 91% yield and 10:1 diastereoselectivity favoring the anti-
product 4b (eq 2). Interestingly, the chemistry fails to proceed
to any significant conversion with a terminally methyl-
substituted boronate 2d. However, the 2-methylallyl boronate
2e performs well in the allylation, providing access to the
corresponding homoallyl alcohol 4c in near quantitative yield
(eq 4).
In order to elucidate the effect of the alcohol additive with
the parent methodology, the reaction between the boronate
reagent and the zinc catalyst was studied. The zinc-boron
exchange process and the stability of the allyl pinacol
boronate 2a under typical reaction conditions (Figure 1) were
a Typical reaction conditions: ketone 1 (3 mmol), diethyl zinc (2 mol
% 0.06 mmol), ethanol (1.2 equiv), allyl boronate 2 (1.1 equiv), 4 mL of
c
THF. b Isolated yield. 96% assay yield determined by H NMR.
1
3750
Org. Lett., Vol. 12, No. 17, 2010

Scheme 1
.
Exchange Pathways for the Allylation of Ketones
Catalyzed by Zinc Alkoxides
Figure 1. Monitoring of the consumption of allyl pinacol boronate
2a by GC under various reaction conditions.
studied by monitoring the consumption of 2a by GC analysis.
The allyl boronate 2a is stable in the presence of 1.1 equiv
of ethanol over 2.3 h at ambient temperature. However,
treatment of the boronate 2a with 1.1 equiv of diethyl zinc
afforded partial consumption of the boronate over a 3 h
period. 1H NMR studies of the zinc reagent show that diethyl
zinc is quickly converted to the alkoxide species when treated
with excess ethanol (5 equiv). Under the typical reaction
conditions with catalytic zinc (20 mol %) and the presence
of 1.1 equiv of ethanol, the boronate 2a is rapidly consumed
within 60 min. Accordingly, the allylation of the ketone must
be considerably faster than the corresponding protonolysis
in order to provide excellent yields while only employing a
slight excess of the boronate. Interestingly, the corresponding
experiment with tert-butanol (20 mol % of diethyl zinc and
1 equiv of 2a) shows a slower rate of consumption of the
boronate 2a, which is either an artifact of the slower
exchange process with the zinc tert-butoxide or subsequent
protonolysis.
change processes, the reactivity of boronate 2d with the zinc
alkoxide catalyst was studied (eq 5). Treatment of allyl
boronate 2d with 20 mol % of zinc alkoxide led to less than
1% consumption of the allyl boronate 2d over a 3 h period.
However, the unsubstituted counterpart 2a is consumed
within 1 h under identical conditions. The lack of reactivity
of boronate 2d in the zinc alkoxide process is consistent with
the cyclic exchange process (pathway 1, Scheme 1) as the
increased steric requirements of the allyl group and the zinc
metal would hinder the exchange in transition state 5. This
effect should not be present if the allyl is transferred through
a noninversion process via pathway 2 (Scheme 1).
There are two reported mechanisms for the boron to zinc
exchange process (Scheme 1), and each can be differentiated
by whether the substituents on the allyl group are inverted
or retained during the exchange process with the metal.
Kobayashi proposed a cyclic transition structure for the boron
to zinc allyl exchange with zinc fluorides,12 wherein the allyl
group is inverted upon the transfer to the zinc metal. The
substitution pattern of the allyl group is retained upon the
addition to the ketone via a double overall inversion process.
Alternately, the allyl group can be transferred directly to the
zinc metal17 without inversion to form 9 that then undergoes
an isomerization to form the less sterically encumbered zinc
reagent, which is more consistent with a type 1 allylation
process.18 To differentiate between the two proposed ex-
In conclusion, the zinc-alkoxide-catalyzed allylation of
ketones provides an operationally simple method for the
preparation of synthetically useful homoallylic tertiary al-
cohols. Although the allyl boronate was found to be unstable
with the alcohol additive under the reaction conditions, the
allylation of the ketones effectively competes with proto-
nolysis and thus renders this process practical. The effect of
the allyl boronate substituent is consistent with an inversion
exchange mechanism.
Supporting Information Available: Experimental pro-
cedures and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(17) Jimeno, C.; Sayalero, S.; Fjermestad, T.; Colet, G.; Maseras, F.;
Pericas, M. P. Angew. Chem., Int. Ed. 2008, 47, 1098.
(18) (a) Carreira, E. M.; Kvaerno, L. Classics In StereoselectiVe
Synthesis; Wiley-VCH: Weinheim, Germany, 2009; pp 153-185. (b)
Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1.
OL101301S
Org. Lett., Vol. 12, No. 17, 2010
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