Allylation and crotylation of ketones and aldehydes using potassium organotrifluoroborate salts under lewis acid and montmorillonite k10 catalyzed conditions

Article abstract of DOI:10.1021/ol900599q

Two convenient highly diastereoselective protocols for the allylation and crotylation of ketones using practical, air- and water-stable potassium allyl and crotyltrifluoroborate salts have been developed. BF₃-OEt ₂ and montmorillonit

Full text of DOI:10.1021/ol900599q

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2631-2634
Allylation and Crotylation of Ketones
and Aldehydes Using Potassium
Organotrifluoroborate Salts under Lewis
Acid and Montmorillonite K10 Catalyzed
Conditions
Farhad Nowrouzi, Avinash N. Thadani,† and Robert A. Batey*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received March 21, 2009
ABSTRACT
Two convenient highly diastereoselective protocols for the allylation and crotylation of ketones using practical, air- and water-stable potassium
allyl and crotyltrifluoroborate salts have been developed. BF3·OEt2 and montmorillonite clay are used as catalysts to promote additions. The
montmorillonite-catalyzed method in particular is very robust, providing a straightforward and scalable method for the allylation and crotylation
of a range of ketones and aldehydes.
The allylation and crotylation of carbonyl compounds is one
of the most important C-C bond formation methods in
organic synthesis.1 The resulting homoallylic alcohol prod-
ucts are versatile synthetic intermediates, as exemplified by
their application toward the synthesis of numerous natural
products.2 Classical methods that have been employed for
these transformations include reactions of allylic halides with
stoichiometric metals (e.g., Mg, Cr, Zn, In) under Barbier-
type conditions3 or the use of various allyl or crotyl
organometalloid derivatives (e.g., B, Si, Sn).4 Asymmetric
variants of the reaction have also been accomplished with
either chiral reagents or chiral catalysts.5 However, whereas
reactions of aldehydes are well established, the allylation and
(3) For selected recent examples of allylations of ketones under Barbier-
like conditions, see: (a) Zhao, L.; Burnell, D. J. Tetrahedron Lett. 2006,
47, 3291–3294. (b) Preite, M. D.; Perez-Carvajal, A. Synlett 2006, 3337–
3339. (c) Miller, J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752–
2753.
† Current address: Department of Chemistry and Biochemistry, University
of Windsor, 273-1 Essex Hall, 401 Sunset Ave., Windsor, ON, Canada.
(1) For reviews on allylations in general, see: (a) Yamamoto, Y.; Asao,
N. Chem. ReV. 1993, 93, 2207–2293. (b) Roush, W. R. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 1-53 and references therein. (c)
Matteson, D. S. Stereodirected Synthesis with Organoboranes; Springer-
Verlag: Berlin, 1995. (d) Kennedy, J. W. J.; Hall, D. G. Angew. Chem.,
Int. Ed. 2003, 42, 4732–4739. (e) Denmark, S. E.; Fu, J. P. Chem. ReV.
2003, 103, 2763–2793.
(4) Using allylsilanes, see: (a) Aoyama, N.; Hamada, T.; Manabe, K.;
Kobayashi, S. Chem. Commun. 2003, 676–677. (b) Wadamoto, M.;
Yamamoto, H. J. Am. Chem. Soc. 2005, 127, 14556–14557. Using
allylstannanes, see: (c) Waltz, K. M.; Gavenonis, J.; Walsh, P. J. Angew.
Chem., Int. Ed. 2002, 41, 3697–3699. (d) Lu, J.; Hong, M.-L.; Ji, S.-J.;
Teo, Y.-C.; Loh, T.-P. Chem. Commun. 2005, 4217–4218. (e) Gu, Y.;
Ogawa, C.; Kobayashi, J.; Mori, Y.; Kobayashi, S. Angew. Chem., Int. Ed.
2006, 45, 7217–7220. (f) Wooten, A. J.; Kim, J. G.; Walsh, P. J. Org. Lett.
2007, 9, 381–384.
(5) See for example: (a) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem.
Soc. 2008, 130, 8481–8490. (b) Wu, T. R.; Shen, L.; Chong, J. M. Org.
Lett. 2004, 6, 2701–2704. (c) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G.
J. Am. Chem. Soc. 2003, 125, 10160–10161. (d) Gravel, M.; Lachance, H.;
Lu, X.; Hall, D. G. Synthesis 2004, 1290–1302.
(2) See for example: (a) Nicolaou, K. C.; Kim, D. W.; Baati, R. Angew.
Chem., Int. Ed. 2002, 41, 3701–3704. (b) Felpin, F. X.; Lebreton, J. J.
Org. Chem. 2002, 67, 9192–9199. (c) Hornberger, K. R.; Hamblet, C. L.;
Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894–12895.
10.1021/ol900599q CCC: $40.75
Published on Web 05/27/2009
 2009 American Chemical Society

crotylation reactions of ketones are more challenging because
of their lower reactivity and the difficulty in achieving
stereoselective additions. Recently the allylation of ketones
has been the focus of renewed attention using organoboron
compounds.6 We now report two convenient ambient tem-
perature protocols for the allylation and crotylation of ketones
using practical, air- and water-stable potassium allyl and
crotyltrifluoroborate salts 1a-c (Figure 1).
to consider alternative protocols. The use of Lewis acid
activation using BF3·OEt2 could be accomplished. Thus,
reaction of 4-bromoacetophenone with 1a (2.0 equiv) using
catalytic BF3·OEt2 (5 mol %) in CH2Cl2 at room temperature
for 24 h afforded homoallylic alcohol 2a in 98% yield
(Method A, Table 1, entry 1). Reaction using catalytic
Table 1. Optimization of Reaction Conditions for Allylation and
Crotylation of 4-Bromoacetophenone using Potassium
Allyltrifluoroborate 1a and Crotyltrifluoroborate Salts 1b and 1c
Figure 1. Potassium allyl and crotyltrifluoroborate salts 1a-c.
Organotrifluoroborate salts are air- and moisture-stable
compounds that are readily formed by the reaction of boronic
7
,
acids with KHF2 and are now widely used as equivalents
entry RBF3K
additivea
BF3·OEt2
solvent (mL)
CD2Cl2
yieldb c
to the corresponding organoboronic acids.8 We have previ-
ously demonstrated the synthesis and use of 1a-c as mild
allylation/crotylation reagents for aldehydes in the presence
of Lewis acids (e.g., BF3·OEt2) in organic solvents or in the
presence of phase-transfer catalysts (i.e., Bu4NI in CH2Cl2/
H2O).9 The salts 1a-c avoid some of the problems typically
associated with tricoordinate allyl- and crotylboron com-
pounds, which can be sensitive to air and/or moisture and
have poor storage properties. Further to these studies we were
interested in expanding the scope of these reactions to include
other carbonyl compounds such as ketones and pyruvates.
Initial experiments revealed that the reaction of potassium
allyl- and crotyltrifluoroborates with ketones was much
slower than with aldehydes. For example, the only substrates
that would react completely with 1a using the previously
reported phase-transfer catalyzed conditions (CH2Cl2/H2O
with 1.0 equiv of nBu4NI for 16 h)9c were the more reactive
cyclic ketones such as cyclohexanone. Noncyclic ketones
such as acetophenone gave only a moderate yield (30%) of
the corresponding homoallylic alcohol product under these
conditions even when an excess of 1a (5 equiv) was used.
The inapplicability of the previously developed phase-
transfer catalyzed conditions toward ketones prompted us
1
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
98
28
2
3
4
5
BF3·OEt2
CD2Cl2
montmorillonite D2O (0.1)/CDCl3 (1.4) 96
montmorillonite CDCl3 (1.5) 66
alumina(N)
charcoal
D2O (0.1)/CDCl3 (1.4) quant
D2O (0.1)/CDCl3 (1.4) 11
D2O (0.1)/CDCl3 (1.4) 37
6
7
8
9
silica gel
montmorillonite D2O (0.1)/CDCl3 (1.4) 98
alumina(N) D2O (0.1)/CDCl3 (1.4) 98
montmorillonite D2O (0.1)/CDCl3 (1.4) 73
alumina(N) D2O (0.1)/CDCl3 (1.4)
montmorillonite D2O (0.1)/CD2Cl2 (1.4) 98
10
11
12
5
a 0.1 g of solid additives were used, with reaction times of 3 h, except
for entries 1 and 2 where 5 mol % of BF3·OEt2 was used for 24 h and 3 h,
respectively. b Yield of the product determined by 1H NMR using an internal
standard. c Entries 1-7 gave product 2a, entries 8 and 9 gave 2b (dr g98:
2), and entries 10-12 gave 2c (dr g95:5).
BF3·OEt2 for a shorter time (3 h) gave a much lower yield
of 2a (Table 1, entry 2). The reaction rate was much slower
than for aldehydes, which typically react within 3 h using
catalytic conditions or within 15 min using stoichiometric
BF3·OEt2 at -78 °C.9a,b
Although the use of BF3·OEt2 was successful, a more
experimentally convenient protocol that would achieve faster
additions and higher yields was desirable. A screen of a
variety of other solid reagents (Table 1, entries 3-7) revealed
that montmorillonite K1010 and neutral alumina had the most
beneficial effect on reactivity using a water/chloroform
solvent system. The most effective additives were applied
for the crotylation using 1b under identical conditions.
Reactions using montmorillonite K10 and neutral alumina
were effective, giving 2b in excellent diastereoselectivity
(Table 1, entries 8 and 9). However, only montmorillonite
K10 gave satisfactory results with the more sensitive (Z)-
(6) For selected recent examples of allylborations of ketones, see: (a)
Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8910–8911. (b) Canales, E.; Prasad, K. G.; Soderquist, J. A. J. Am.
Chem. Soc. 2005, 127, 11572–11573. (c) Lou, S.; Moquist, P. N.; Schaus,
S. E. J. Am. Chem. Soc. 2006, 128, 12660–12661. (d) Schneider, U.;
Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 5909–5912. (e) Carosi, L.;
Hall, D. G. Angew. Chem., Int. Ed. 2007, 46, 5913–5915. (f) Schneider,
U.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13824–13825.
(7) Vedejs, E.; Fields, S. C.; Shrimpf, M. R. J. Am. Chem. Soc. 1993,
117, 11612–11613.
(8) For reviews of organotrifluoroborates and other leading references,
see: (a) Darses, S.; Geneˆt, J. P. Eur. J. Org. Chem. 2003, 4313–4327. (b)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286. (c) Stefani,
H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623–3658. (d) Darses,
S.; Geneˆt, J.-P. Chem. ReV. 2008, 108, 288–325.
(9) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett. 1999,
40, 4289–4292. (b) Batey, R. A.; Thadani, A. N.; Smil, D. V. Synthesis
2000, 990–998. (c) Thadani, A. N.; Batey, R. A. Org. Lett. 2002, 4, 3827–
3830. (d) Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003, 44, 8051–
8055. (e) Li, S.-W.; Batey, R. A. Chem. Commun. 2004, 1382–1383.
(10) For reviews on the use of clay-catalyzed reactions, see: (a) Dasgupta,
S.; To¨ro¨k, B. Org. Prep. Proced. Int. 2008, 40, 1–65. (b) Varma, R. S.
Tetrahedron 2002, 58, 1235–1255. (c) Nikalje, M. D.; Phukan, P.; Sudalai,
A. Org. Prep. Proced. Int. 2002, 32, 1–40.
2632
Org. Lett., Vol. 11, No. 12, 2009

crotyltrifluoroborate 1c, giving full conversion to 2c in
CD2Cl2 solvent (Table 1, entries 10-12).11
A series of ketones were then allylated under the two sets
of conditions: BF3·OEt2 (5 mol %)/CH2Cl2/rt (Method A),
and montmorillonite K10/CH2Cl2/H2O/rt (Method B) (Table
2). Aromatic, aliphatic, and R,ꢀ-unsaturated ketones were
High-yielding stereoselective allylations of cyclic and
acyclic ketones were also accomplished using both allylation
protocols (Table 3, entries 1-3). Diastereoselective croty-
lations of ketones are, in general, much more difficult than
reactions with aldehydes. Nevertheless, crotylations of ac-
Table 3. Diastereoselective Allylation and Crotylation of
Ketones using 1a-c under Lewis Acid or Montmorillonite K10
Catalyzed Conditionsa
Table 2. Substrate Generality for the Lewis Acid and
Montmorillonite K10 Catalyzed Allylation of Ketones with
Potassium Allyltrifluoroborate 1a
a Yield of product isolated after silica gel chromatography.
efficiently allylated using each of these methods. Overall,
the use of montmorillonite K10 (Method B) was the most
general, giving better results with more hindered ketones
(Table 2, entry 6). In addition, reactions using Method B
were faster than those of Method A. Purification was
straightforward and avoided problems associated with the
removal of phase transfer catalysts.9c Also, the use of an
inert atmosphere or other special requirements were not
necessary.6 Moreover, Method B was more scaleable, as
exemplified by the allylation of 4-bromoacetophenone to 2a
on a 20 mmol scale, which occurred without any changes in
reaction time or yield.
a Method A: BF3·OEt2 (5 mol %), CH2Cl2, rt, 24 h. Method B:
Montmorillonite K10 (0.1 g), CH2Cl2/H2O, rt, 3-5 h. b Yield of isolated
product after silica gel chromatography. c Diastereomeric ratio determined
by 1H NMR or GC analysis of the crude products before column
chromatography. d Crude conversion with 1b and 1c was 75% and 62%,
respectively.
(11) CH2Cl2 was used as solvent for both allylation and crotylation
because the observed conversion or diastereoselectivity was lower using
other solvents such as toluene, H2O, THF, MeCN, CHCl3, DMF, or MeOH.
Org. Lett., Vol. 11, No. 12, 2009
2633

etophenone, 4-bromoacetophenone, and ethyl pyruvate by
potassium crotyltrifluoroborates 1b,c gave adducts in good
yields and excellent diastereoselectivities (Table 3, entries
4-6). As anticipated from previous crotylation reactions of
organometalloid reagents,1 the reaction of a less sterically
differentiated linear substrate, 2-heptanone, gave products
with modest diasteroselectivy under both sets of conditions
(Table 3, entry 7).
high (g98:2), with 1b giving the anti-adducts 3d,f, and 1c
giving syn-adduct 3e. This method thus provides one of the
most operationally simple approaches to the allylation/
crotylation of aldehydes.
The diastereospecific additions achieved with the (E)- and
(Z)-crotyl reagents 1b and 1c afforded anti and syn diaster-
eomeric adducts, respectively. This selectivity is consistent
with reaction of tricoordinate allylboron species through
cyclic Zimmerman-Traxler-like transition states.9 The req-
uisite tricoordinate allylboron species can be formed by
fluoride ion abstraction from 1 under Lewis acidic or
montmorillonite based conditions.
Method B was also applied toward the allylation and
crotylation of various aldehydes (Figure 2). The much higher
In summary, we have developed mild and practical
methods for the allylation and crotylation of ketones and
aldehydes using organotrifluoroborate salts, under either
Lewis acidic or montmorillonite K10 catalysis. The latter
method in particular is very robust, providing a remarkably
straightforward and simple method for allylation and cro-
tylation using an inexpensive and environmentally benign
catalyst. Further applications of these methods and related
chemistry will be reported in due course.
Acknowledgment. The Natural Science and Engineering
Research Council (NSERC) of Canada funded this research.
We also thank Dr. Alex Young (University of Toronto) for
mass spectral analysis and Dr. Tim Burrow (University of
Toronto) for NMR assistance.
Figure 2. Examples of products of allylation and crotylation of
aldehydes using montmorillonite K10 catalysis (Method B).
reactivity of aldehydes compared to that of ketones allowed
the use of just 1.2 equiv of the trifluoroborate salts 1a-c,
rather than the 2.0 equiv necessary for the reactions with
ketones. Under these conditions full conversions were
achieved in less than 10 min to give the adducts 3a-f in
high yields. The diastereoselectivity of the crotylations was
Supporting Information Available: Spectroscopic data
of all the new compounds and detailed descriptions of
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL900599Q
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Org. Lett., Vol. 11, No. 12, 2009