Sc(OTf)3-catalyzed conjugate allylation of alkylidene meldrum's acids

Article abstract of DOI:10.1021/ol9003959

Alkylidene Meldrum's acids are allylated in a conjugate fashion by allyltin nucleophiles under mild Sc(OTf)₃-catalyzed conditions. The addition is functional group tolerant and reactions with nonracemic alkylidenes are highly diastereoselective

Full text of DOI:10.1021/ol9003959

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1919-1922
Sc(OTf)3-Catalyzed Conjugate Allylation
of Alkylidene Meldrum’s Acids
Aaron M. Dumas and Eric Fillion*
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario N2L 3G1, Canada
efillion@uwaterloo.ca
Received February 25, 2009
ABSTRACT
Alkylidene Meldrum’s acids are allylated in a conjugate fashion by allyltin nucleophiles under mild Sc(OTf)3-catalyzed conditions. The addition
is functional group tolerant and reactions with nonracemic alkylidenes are highly diastereoselective. Allylation of alkylidenes derived from
r-ketoesters yield all-carbon quaternary stereocenters.
Nucleophilic addition of an allyl group is a fundamental C-C
bond forming reaction. In particular, 1,2-addition of allyl
nucleophiles to carbonyls has been studied extensively and
a large selection of catalytic conditions for this process have
been developed.1 However, catalytic 1,4-conjugate allylation
of R,ꢀ-unsaturated carbonyls is significantly less developed
compared to other carbon nucleophiles, although methods
involving stoichiometric amounts of Lewis acids2 or nucleo-
philic activators3 are known.4 For example, in contrast to
the plethora of catalytic enantioselective 1,2-allylations5 there
are at present only two methods for catalytic enantioselective
1,4-allylation, as reported recently by Morken6 and Snapper.7
A major difficulty in investigating conjugate allylation is
competing 1,2- vs 1,4-addition, which is often dependent on
the combination of nucleophile and electrophile. In particular,
conjugate allylation of enones and enals remains a challeng-
ing objective.8,9 Therefore, development of a general,
catalytic conjugate allylation would be aided by the use of
electrophiles for which 1,2-addition can be suppressed but
are easily converted into a range of carbonyl derivatives.10
In this regard, recent work by Jarvo has shown that Pd-NHC
complexes catalyze the addition of allylboranes to unsatur-
ated N-acylpyrroles and alkylidene malononitriles in a
(1) Selected recent examples: (a) Barker, T. J.; Jarvo, E. R. Org. Lett.
2009, 11, 1047–1049. (b) Denmark, S. E.; Nguyen, S. T. Org. Lett. 2009,
11, 781–784. (c) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 14891–14899. (d) Raunyar, V.; Zhai, H.; Hall, D. G. J. Am.
Chem. Soc. 2008, 130, 8481–8490. (e) Lou, S.; Moquist, P. N.; Schaus,
S. E. J. Am. Chem. Soc. 2006, 128, 12660–12661. For a general review on
reactions of allyl metal reagents, see: (f) Yamamoto, Y.; Asao, N. Chem.
ReV. 1993, 93, 2207–2293.
(4) Conjugate allylation of nitroalkenes: (a) Shen, K.-H.; Liu, J.-T.; Wu,
Y.-R.; Yao, C.-F. Synth. Commun. 2007, 37, 3677–3687. (b) Kumar,
H. M. S.; Reddy, B. V. S.; Reddy, P. T.; Yadav, J. B. Tetrahedron Lett.
1999, 40, 5387–5388. (c) Barboni, L.; Bartoli, G.; Marcantoni, E.; Petrini,
M.; Dalpozzo, R. J. Chem. Soc., Perkin Trans. 1 1990, 2133–2138. (d)
Yamamoto, Y.; Nishii, S. J. Org. Chem. 1988, 53, 3597–3603. (e) Uno,
H.; Watanabe, N.; Fujiki, S.; Suzuki, H. Synthesis 1987, 471–474
.
(5) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763–2794
.
(2) Initial discovery using allylsilanes: (a) Hosomi, A.; Sakurai, H. J. Am.
Chem. Soc. 1977, 99, 1673–1675. Allylstannanes: (b) Hosomi, A.; Iguchi,
H.; Endo, M.; Sakurai, H. Chem. Lett. 1979, 8, 977–980.
(6) (a) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2008, 130, 4978–
4983. (b) Sieber, J. D.; Liu, S.; Morken, J. P. J. Am. Chem. Soc. 2007, 129,
2214–2215
(7) Shizuka, M.; Snapper, M. L. Angew. Chem., Int. Ed. 2008, 47, 5049–
5051
.
(3) Majetich, G.; Casares, A.; Chapman, D.; Behnke, M. J. Org. Chem.
1986, 51, 1745–1753.
.
10.1021/ol9003959 CCC: $40.75
Published on Web 04/02/2009
 2009 American Chemical Society

catalyst-controlled, highly regioselective manner.11 Herein
we report that alkylidene Meldrum’s acids are excellent
acceptors for Sc(OTf)3-catalyzed conjugate allylation under
mild reaction conditions.12 The use of alkylidene Meldrum’s
acids for conjugate allylation provides a number of advan-
tages, owing to their ease of preparation,13 high electrophi-
licity,14 and the versatility of the Meldrum’s acid group in
subsequent transformations. Importantly, Meldrum’s acid
derivatives can be converted directly into both ketones15 and
aldehydes,16 as well as carboxylic acids, esters, and amides.17
In order to minimize potential 1,2-addition and allow
maximum functional group compatibility, a goal of the
investigation was to use the least nucleophilic allylating agent
possible.18 Initial attempts using benzylidene Meldrum’s acid
1a as electrophile and allyltrimethylsilane as nucleophile
were unsuccesful. In the presence of a variety of Lewis acid
catalysts no reaction occurred and the starting materials were
unchanged. Increasing the nucleophilicity by switching to
allyltriphenylstannane revealed a slow uncatalyzed reaction;
addition of 10 mol % Sc(OTf)3 resulted in a substantial
increase in conversion (Scheme 1).
of allylSnPh3 and 5 mol % of Sc(OTf)3; using 1a as
electrophile, 2a was obtained in 85% yield after 21 h at room
temperature (entry 1).
Table 1. Sc(OTf)3-Catalyzed Allylation of Alkylidene
Meldrum’s Acids
entry
R
product
% yielda
1
2
3
C6H5 (1a)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
85
87
91
82
83
85
74
80
91
88
86
89
76
73
83
77
4-MeC6H4 (1b)
4-(CN)C6H4 (1c)
4-(OMe)C6H4 (1d)
4-(NO2)C6H4 (1e)
4-ClC6H4 (1f)
4b
5b
6
7
8
9
2-FC6H4 (1g)
3-(OTIPS)C6H4 (1h)
2-naphthyl (1i)
1-naphthyl (1j)
2-thienyl (1k)
3-(N-Ts)indolyl (1l)
2-(N-Ts)pyrrolyl (1m)
Me (1n)
10c
11d
12c
13d
14
15
16d
a
Scheme 1. Conjugate Allylation of 1a with AllylSnPh3
i-Pr (1o)
t-Bu (1p)
a Isolated yield. b Reactions conditions: 1,2-dichloroethane, 50 °C, 21 h.
c Sc(OTf)3 (0.1 mmol) used. d Reaction ran for 36 h with 0.15 mmol
Sc(OTf)3.
a Ratio 1a:2a determined by analysis of the 1H NMR of the crude
The reaction is general across a range of substituted and
functionalized benzylidene Meldrum’s acids (Table 1, entries
1-8); in the case of 1d, running the reaction at higher
temperature allowed complete conversion of the less reactive
electron-rich starting material (entry 4). Higher temperature
was also useful for 1e, which reacts slowly due to its low
solubility at rt (entry 5). As an alternative to running reactions
at higher temperature, increased catalyst loading and reaction
reaction mixture following acidic workup.19
Further optimization of reaction conditions allowed reduc-
tion of both the catalyst loading and the amount of allyl-
SnPh3. As shown in Table 1, standard reaction conditions
involve 1.0 mmol of alkylidene Meldrum’s acid, 1.3 mmol
(8) For recent examples of 1,2-allylation of enals and enones using
allyltin reagents, see: (a) Zhang, T.; Shi, M.; Zhao, M. Tetrahedron 2008,
64, 2412–2418. (b) Lingaiah, B. V.; Ezikiel, G.; Yakaiah, T.; Reddy, G. V.;
Rao, P. S. Tetrahedron Lett. 2006, 47, 4315–4318. Enones: (c) Wooten,
A. J.; Kim, J. G.; Walsh, P. J. Org. Lett. 2007, 9, 381–384. (d) Teo, Y.-C.;
Goh, J.-D.; Loh, T.-P. Org. Lett. 2005, 7, 2743–2745.
(13) Dumas, A. M.; Seed, A.; Zorzitto, A. K.; Fillion, E. Tetrahedron
Lett. 2007, 48, 7072–7074.
(14) Alkylidene Meldrum’s acids are significantly more electrophilic
than the corresponding diethyl alkylidenemalonates, see: Kaumanns, O.;
Mayr, H. J. Org. Chem. 2008, 73, 2738–2745.
(9) Conjugate allylation of cinnamaldehyde with allyllithium in the
presence of a bulky aluminum phenoxide reagent has been reported: Ooi,
T.; Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 1997, 36, 1183–
1185.
(15) For transformations into arylketones, see: (a) Fillion, E.; Dumas,
A. M. J. Org. Chem. 2008, 73, 2920–2923. (b) Fillion, E.; Fishlock, D.;
Wilsily, A.; Goll, J. M. J. Org. Chem. 2005, 70, 1316–1327. (c) Fillion,
E.; Fishlock, D. Org. Lett. 2003, 5, 4653–4656.
(10) Conjugate allylation of enones with catalytic indium and excess
TMSCl: Lee, P. H.; Seomoon, D.; Kim, S.; Nagaiah, K.; Damle, S. V.;
Lee, K. Synthesis 2003, 2189–2193.
(16) Frost, C. G.; Hartley, B. C. Org. Lett. 2007, 9, 4259–4261.
(17) For reviews on transformations of Meldrum’s acid derivatives, see:
(a) Ivanov, A. S. Chem. Soc. ReV. 2008, 37, 789–811. (b) Chen, B. C.
´
(11) (a) Shaghafi, M. B.; Kohn, B. L.; Jarvo, E. R. Org. Lett. 2008, 10,
4743–4746. (b) Waetzig, J. D.; Swift, E. C.; Jarvo, E. R. Tetrahedron 2009,
65, 3197–3201.
Heterocycles 1991, 32, 529–597. (c) Strozhev, M. F.; Lielbriedis, I. E.;
Neiland, O. Ya. Khim. Geterotsikl. Soedin. 1991, 579–599. (d) McNab, H.
Chem. Soc. ReV. 1978, 7, 345–358.
(12) Isolated examples of conjugate allylation in the presence of Lewis
acids to alkylidene Meldrum’s acids containing metallated dienes have been
reported, see: (a) Wada, C. K.; Roush, W. R. Tetrahedron Lett. 1994, 35,
7351–7354. (b) Paley, R. S.; Estroff, L. A.; Gauguet, J.-M.; Hunt, D. K.;
Newlin, R. C. Org. Lett. 2000, 2, 365–368. For an intramolecular example,
see: (c) Tietze, L. F.; Ruther, M. Chem. Ber. 1990, 123, 1387–1395.
(18) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am.
Chem. Soc. 2001, 123, 9500–9512.
(19) The initial product formed by allylation is a triphenyltin enolate of
Meldrum’s acid that is protonated by acidic workup. See Supporting
Information.
1920
Org. Lett., Vol. 11, No. 9, 2009

time can be used in the case of sterically hindered (entry
10) or electron-rich acceptors (entries 11-13). The reaction
proceeds equally well for methylidene Meldrum’s acids
(entries 14-15), even those possessing a bulky t-Bu group
(entry 16). Of note are successful reactions with substrates
containing functional groups incompatible with Pd-
catalyzed11a (entries 6 and 7) or fluoride-activated (entry 8)
conjugate allylation protocols.3
Scheme 3
.
Conjugate Allylation to Generate All-Carbon
Quaternary Centersa
Conjugate allylation of chiral, nonracemic alkylidene
Meldrum’s acid 1q20 proceeded equally well at rt, and in
high diastereoselectivity by analysis of the crude reaction
mixture, however the allylated Meldrum’s acid derivative
proved unstable and could not be isolated cleanly.21,22
Therefore a one-pot procedure involving Sc(OTf)3-catalyzed
conjugate allylation followed by treatment with HCl in
MeOH; which deprotected the acetonide and promoted
lactonization/esterification to furnish 3 with a dr > 20:1
(Scheme 2). Similar treatment of 1r, derived from Garner’s
aldehyde, gave the δ-lactone 4 in 19:1 dr.23
a Ratio 4a:5a determined by analysis of the 1H NMR of the crude
reaction mixture following acidic workup.
Scheme 2. Diastereoselective Conjugate Allylation/Lactonization
the allylating agent by using allylSnBu3, a Sc(OTf)3-catalyzed
addition to 6a was observed. The conversion could be
increased by performing the reactions at 50 °C in 1,2-
dichloroethane (Scheme 3b). No addition occurred to the less
reactive 5a under either of these conditions.
By increasing the amount of allylSnBu3 and the reaction
time, catalyst loading was reduced to 5 mol %; on a 1 mmol
scale reaction of 6a gave allylated product 7a in 81% yield
(Table 2, entry 1). The reaction was tolerant of electron-
Table 2. Conjugate Allylation of Tetrasubstituted Alkylidene
Meldrum’s Acids 5
The above reactions formed tertiary centers through
allylation of alkylidene Meldrum’s acids derived from
aldehydes. A more difficult transformation is addition to
tetrasubstituted alkylidenes to form all-carbon quaternary
stereocenters. Precedent from our group has shown that
alkylidenes of type 5 and 6 are excellent substrates to access
this challenging motif.24 Subjecting 5a and 6a to allylSnPh3
under conditions optimized for alkylidenes 1 resulted in no
conversion (Scheme 3a). Increasing the nucleophilicity of
entry alkylidene
R1
R2
product (% yielda)
1
2
3
4
5
6a
6b
6c
6d
6e
Ph
4-BrC6H4
4-(t-Bu)C6H4 Me
2-naphthyl
Ph
Me
Me
7a (81)
7b (76)
7c (82)
7d (85)
7e (78)
Me
allyl
(20) Fujimori, S.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4964–
4967.
a Isolated yield.
(21) For other examples of diastereselective conjugate allylation not
found in refs 2 and 3, see: (a) Groaning, M. D.; Meyers, A. I. Tetrahedron
Lett. 1999, 40, 8071–8074. (b) Sato, M.; Aoyagi, S.; Yago, S.; Kibayashi,
C. Tetrahedron Lett. 1996, 37, 9063–9066. (c) Pan, L.-R.; Tokoroyama, T.
donating and electron-withdrawing groups (entries 2 and 3,
respectively), increased steric hindrance (entry 4), and
Tetrahedron Lett. 1992, 33, 1469–1472
.
(22) For conjugate addition of indole to 1q and 1r formed in situ, see:
´
(a) Boisbrun, M.; Kova´cs-Kulyassa, A.; Jeannin, L.; Sapi, J.; Toupet, L.;
Laronze, J.-Y. Tetrahedron Lett. 2000, 41, 9771–9775. (b) Dardennes, E.;
(23) Relative stereochemistry was determined by analysis of coupling
constants and proceeds with the same facial selectivity as the addition of
indole (ref 22).
´
Kova´cs-Kulyassa, A.; Boisbrun, M.; Petermann, C.; Laronze, J.-Y.; Sapi,
J. Tetrahedron: Asymmetry 2005, 16, 1329–1339
.
Org. Lett., Vol. 11, No. 9, 2009
1921

different esters (entry 5). No products of 1,2-allylation of
either the Meldrum’s acid or ester groups were detected in
the H NMR of the crude reaction mixture.
Scheme 5.
Chemoselective Allylation of 1ia
1
As mentioned above, the presence of Meldrum’s acid in
the allylated products 2 is useful as it provides a highly
reactive handle for further transformations. As shown in
Scheme 4, the crude reaction mixture following allylation
Scheme 4. Transformations of Allylated Meldrum’s Acid 2a
a Yields in brackets determined by 1H NMR integrations versus an
internal standard of mesitylene. See Supporting Information.
control reaction between 11 and allylSnPh3 with catalytic
Sc(OTf)3 did provide homoallylic alcohol,26 it seems likely
that the selectivity arises primarily from the enhanced
electrophilicity of the alkylidenes.
Alkylidene Meldrum’s acids have been shown to be
excellent acceptors for conjugate allylation. The high reactiv-
ity of the alkylidenes combined with the versatility of the
Meldrum’s acid moiety makes this an attractive method for
accessing a variety of δ,ꢀ-unsaturated carbonyl compounds,
including those bearing the challenging all-carbon quaternary
center. Highly diastereoselective additions to nonracemic
alkylidenes affords chiral lactones with synthetically useful
handles for further transformations. Efforts to develop an
enantioselective version of this method are underway.
of 1a was treated with weak base and allyl bromide to
provide 5,5-disubstituted Meldrum’s acid derivative 8 in 82%
yield over two steps. Similarly crude 2a was converted into
methyl ester 9 by Cu-catalyzed esterification/decarboxy-
lation.24a The transformed products can themselves be reacted
further, as shown by the ring-closing metathesis of 8 to give
cyclohexene 10.25
In terms of chemoselectivity, the reactivity of alkylidene
Meldrum’s acids 1 is exceptional. Of note, a competition
experiment between 2-naphthaldehyde (11) and the corre-
sponding alkylidene 1i demonstrated complete selectivity for
formation of 2i over 1,2-allylation (Scheme 5). Since a
Acknowledgment. This work was supported by the Merck
Frosst Center for Therapeutic Research, the Natural Sciences
and Engineering Research Council of Canada (NSERC), the
Canadian Foundation for Innovation, the Ontario Innovation
Trust, and the University of Waterloo. A.M.D. thanks the
Government of Canada for a graduate scholarship (NSERC
CGS-D), and Ashraf Wilsily and Alexander K. Zorzitto,
University of Waterloo, for generously sharing alkylidene
Meldrum’s acids.
Supporting Information Available: Experimental details
and characterization of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) (a) Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801–2804. (b)
Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774–2775.
(25) Similar products have been obtained by the reaction of alkylidene
Meldrum’s acids with butadiene sulfone: Fillion, E.; Dumas, A. M.; Hogg,
S. A. J. Org. Chem. 2006, 71, 9899–9902.
OL9003959
(26) See Supporting Information for details.
1922
Org. Lett., Vol. 11, No. 9, 2009