Lewis acid-catalyzed conjugate additions of silyloxyallenes: A selective solution to the intermolecular Rauhut-Currier problem

Article abstract of DOI:10.1021/ol800745q

(Chemical Equation Presented) Silyloxyallenes serve as highly useful α-acylvinyl anion equivalents. These latent allenolates undergo conjugate additions to alkylidene malonates in the presence of 10 mol % Sc(OTf) ₃. The reaction delivers intermolecular Rauhut-Currier products in excellent yields and regioselectivities for a wide scope of substrates. Notably, the formal cross-coupling of two different α,β-unsaturated carbonyl compounds (a cross Rauhut-Currier reaction) is achieved. Preliminary investigations have demonstrated good levels of enantioselectivity for the addition of a racemic silyloxyallene with a chiral Lewis acid.

Full text of DOI:10.1021/ol800745q

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2449-2452
Lewis Acid-Catalyzed Conjugate
Additions of Silyloxyallenes: A Selective
Solution to the Intermolecular
Rauhut-Currier Problem
Troy E. Reynolds, Michael S. Binkley, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received April 2, 2008
ABSTRACT
Silyloxyallenes serve as highly useful r-acylvinyl anion equivalents. These latent allenolates undergo conjugate additions to alkylidene malonates
in the presence of 10 mol % Sc(OTf)3. The reaction delivers intermolecular Rauhut-Currier products in excellent yields and regioselectivities
for a wide scope of substrates. Notably, the formal cross-coupling of two different r,ꢀ-unsaturated carbonyl compounds (a cross Rauhut-Currier
reaction) is achieved. Preliminary investigations have demonstrated good levels of enantioselectivity for the addition of a racemic silyloxyallene
with a chiral Lewis acid.
R-Acylvinyl anion equivalents are atypical nucleophiles that
generate valuable R,ꢀ-unsaturated carbonyl compounds in a
Scheme 1. Intermolecular Rauhut-Currier Strategies
highly convergent manner.1 One method of interest that
employs this type of unconventional reactivity is the
Rauhut-Currier reaction in which the R-acylvinyl anion
undergoes a Michael addition.2,3 Similar to the Morita-
Baylis-Hillman reaction, the method involves the initial
conjugate addition of a Lewis base catalyst to generate a
zwitterionic enolate that then undergoes a conjugate addition
onto a second equivalent of an electron-deficient olefin
(Scheme 1, Option 1). While dimerizations of the activated
alkenes (e.g., acrylates) are well-known, the reaction between
two different R,ꢀ-unsaturated carbonyl compounds (a cross
Rauhut-Currier) is much more challenging with few re-
(1) Chinchilla, R.; Najera, C. Chem. ReV. 2000, 100, 1891–1928.
(2) Rauhut, M. M.; Currier, H. U.S. Patent 307499919630122, American
Cyanamid Co., 1963
.
(3) (a) McClure, J. D. J. Org. Chem. 1970, 35, 3045–3048. (b)
Basavaiah, D.; Gowriswari, V. V. L.; Bharathi, T. K. Tetrahedron Lett.
1987, 28, 4591–4592. (c) Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron
Lett. 1989, 30, 7381–7382. (d) Jenner, G. Tetrahedron Lett. 2000, 41, 3091–
ported examples.4 The key problem is that self-condensations
compete under the reaction conditions and the products,
which are electron-deficient alkenes as well, are susceptible
3094
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10.1021/ol800745q CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

to polymerizations. In 2002, Krische and Roush indepen-
dentlyreportedanintramolecularversionoftheRauhut-Currier
employing bis-enone substrates.5 Miller has recently reported
an elegant enantioselective intramolecular Rauhut-Currier
variant with similar bis-enones using one equivalent of
N-acetyl cysteine as the promoter.5k Despite the progress of
the intramolecular manifold, a successful intermolecular
Rauhut-Currier reaction has not emerged to date. A useful
bimolecular process could indeed expand the utility of this
bond-forming process. In this Communication, we disclose
that the Lewis acid-catalyzed conjugate additions of
silyloxyallenes afford a wide variety of 1,5-dicarbonyl
compounds that map directly onto what would be products
of an intermolecular Rauhut-Currier process (Scheme 1,
Option 2).
would generate products from the apparent coupling of two
different R,ꢀ-unsaturated carbonyl compounds via an inter-
molecular Rauhut-Currier reaction.
Given the mild nucleophilicity of silyloxyallenes, alky-
lidene malonates were examined as conjugate acceptors with
racemic 1.10 After surveying potential Lewis acids at 10 mol
%, we discovered that scandium triflate promotes the addition
of 1 in only 9% yield (Table 1, entry 1). Although only
Table 1. Optimization of Michael Additiona
Silyloxyallenes have emerged as versatile and useful
R-acylvinyl anion equivalents.6,7 These latent enolates are
prepared readily from the corresponding acylsilanes by way
of the Kuwajima-Reich rearrangent of R-hydroxypropar-
gylsilanes.8 Recently, we have demonstrated that silyloxy-
allenes undergo additions to aldehydes in the presence of
Lewis acids and high yields are achieved for a wide scope
of substrates with excellent control over the resulting double
bond geometry. Encouaged by the full potential of these un-
usual nucleophiles, we have developed an enantioselective
variant of this reaction using racemic silyloxyallenes and a
chiral (salen)Cr(III) Lewis acid catalyst.9 In an effort to
broaden the use of silyloxyallenes as nontraditional nucleo-
philic reagents, we have explored conjugate additions of these
R-acylvinyl anion equivalents. This reaction, if successful,
entry
additive
none
solvent temp (°C) time (h) yield (%)b
1
2
3
4
5
6
7
8
9
CH2Cl2
23
23
18
18
24
48
24
18
18
18
18
9
54
0
(CF3)2CHOH CH2Cl2
(CF3)2CHOH THF
(CF3)2CHOH Et2O
(CF3)2CHOH PhCH3
(CF3)2CHOH MeCN
(CF3)2CHOH MeCN
(CF3)2CHOH MeCN
(CF3)2CHOH MeCN
23
23
23
23
0
-20
-40
71
55
61
77
95
71
a 1 (1.5 equiv), 1 equiv of alkylidene malonate. b Isolated yield.
weakly encouraging, we postulated that catalyst turnover was
rate limiting with these conditions. After surveying an
assortment of additives, the addition of hexafluoroisopropanol
(HFIP) improves the yield to 54% (entry 2). Changing the
solvent to acetonitrile provides the optimal balance of rate
and yield (entry 6).11 Finally, lowering the temperature to
-20 °C in acetonitrile with 10 mol % Sc(OTf)3 and HFIP
(1 equiv) delivers the Rauhut-Currier product in 95% yield
and >20:1 regioselectivity favoring the Z-isomer (entry 8).
With these optimized bond-forming conditions in hand,
the electrophilic scope of the transformation was explored
(Table 2). Various alkylidene malonates were found to be
reactive partners. A wide range of aromatic ꢀ-substituents
is tolerated in good to excellent yields (entries 1-4).
Aliphatic substituents are also accommodated with excellent
selectivities and yields including two examples of R-branched
substituents (entries 7 and 8). However, the more hindered
tert-butyl substituted alkylidene malonate is unreactive under
the reaction conditions (entry 9).
(4) (a) Hwu, J. R.; Hakimelahi, G. H.; Chou, C. T. Tetrahedron Lett.
1992, 33, 6469–6472. (b) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc.
2003, 125, 12394–12395. (c) Evans, C. A.; Cowen, B. J.; Miller, S. J.
Tetrahedron 2005, 61, 6309–6314. (d) Dadwal, M.; Mohan, R.; Panda, D.;
Mobin, S. M.; Namboothiri, I. N. N. Chem. Commun. 2006, 338–340. (e)
Yin, Y. B.; Zhang, Q.; Li, J.; Sun, S. G.; Liu, Q. Tetrahedron Lett. 2006,
47, 6071–6074.
(5) (a) Wang, L. C.; Luis, A. L.; Agapiou, K.; Jang, H. Y.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 2402–2403. (b) Frank, S. A.; Mergott,
D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404–2405. (c) Brown,
P. M.; Kappel, N.; Murphy, P. J. Tetrahedron Lett. 2002, 43, 8707–8710.
(d) Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett. 2002, 4, 3157–
3160. (e) Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737–1740. (f)
Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5, 4223–4226. (g) Couturier,
M.; Menard, F.; Ragan, J. A.; Riou, M.; Dauphin, E.; Andresen, B. M.;
Ghosh, A.; Dupont-Gaudet, K.; Girardin, M. Org. Lett. 2004, 6, 1857–
1860. (h) Luis, A. L.; Krische, M. J. Synthesis 2004, 2579–2585. (i) Mergott,
D. J.; Frank, S. A.; Roush, W. R. Proc. Nat. Acad. Sci. 2004, 101, 11955–
11959. (j) Brown, P. M.; Kappel, N.; Murphy, P. J.; Coles, S. J.; Hursthouse,
M. B. Tetrahedron 2007, 63, 1100–1106. (k) Aroyan, C. E.; Miller, S. J.
J. Am. Chem. Soc. 2007, 129, 256–257.
(6) (a) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2006, 128, 15382–15383. (b) Reynolds, T. E.; Stern, C. A.; Scheidt,
K. A. Org. Lett. 2007, 9, 2581–2584
.
(7) For previous examples of silyloxyallenes as nucleophiles, see: (a)
Merault, G.; Bourgeoi, P.; Dunogues, J.; Duffaut, N, J. Organomet. Chem.
1974, 76, 17–27. (b) Fleming, I.; Perry, D. A. Tetrahedron 1981, 37, 4027–
4034. (c) Kato, M.; Kuwajima, I. Bull. Chem. Soc. Jpn. 1984, 57, 827–
830. (d) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am.
Chem. Soc. 1986, 108, 7791–7800. (e) Stergiades, I. A.; Tius, M. A. J.
Org. Chem. 1999, 64, 7547–7551. (f) Li, G. G.; Wei, H. X.; Phelps, B. S.;
Purkiss, D. W.; Kim, S. H. Org. Lett. 2001, 3, 823–826. (g) Yoshizawa,
K.; Shioiri, T. Tetrahedron 2007, 63, 6259. (h) Mueller, A. J.; Jennings,
The effect of the silyloxyallene on the reaction was also
investigated (Table 3). A broad range of substituents was
(10) For selected additions to alkylidene malonates, see: (a) Evans, D. A.;
Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem.
Soc. 2000, 122, 9134–9142. (b) Lassaletta, J. M.; Vazquez, J.; Prieto, A.;
Fernandez, R.; Raabe, G.; Enders, D. J. Org. Chem. 2003, 68, 2698–2703.
(c) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas,
C. F. Synthesis 2004, 1509–1521. (d) Prieto, A.; Fernandez, R.; Lassaletta,
J. M.; Vazquez, J.; Alvarez, E. Tetrahedron 2005, 61, 4609–4613. (e) Cao,
C. L.; Sun, X. L.; Zhou, J. L.; Tang, Y. J. Org. Chem. 2007, 72, 4073–
4076.
M. P. Org. Lett. 2007, 9, 5327–5329
.
(8) (a) Kuwajima, I.; Kato, M. Tetrahedron Lett. 1980, 21, 623–626.
(b) Reich, H. J.; Olson, R. E.; Clark, M. C. J. Am. Chem. Soc. 1980, 102,
1423–1424.
(9) Reynolds, T. E.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
7806–7809.
(11) Although diethyl ether gave the highest yield, the reaction was
slower than with acetonitrile.
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Org. Lett., Vol. 10, No. 12, 2008

Table 2. Addition of Silyloxyallene 1 to Alkylidene Malonates
Table 3. Silyloxyallene Scope
a Determined by 500 MHz 1H NMR spectroscopy. b Isolated yield.
c Reaction performed at 23 °C.
R1 substituents were explored with a heptyl and iso-propyl
silyloxyallene undergoing addition in excellent yield and E/Z
selectivity (entries 5 and 6).
To render this highly selective reaction with alkylidene
malonates enantioselective, our preliminary investigations
have focused on the additions of racemic silyloxyallenes with
chiral Lewis acids. After a survey of chiral ligands and
reaction conditions,12 silyloxyallene 1 adds to alkylidene
Scheme 2. Enantioselective Addition of Silyloxyallene 1
a Determined by 500 MHz 1H NMR spectroscopy. b Isolated yield. c Not
applicable.
incorporated at the ꢀ-position of the allene (R2) providing
products in excellent yields and regioselectivities. A long
chain alkyl group is tolerated as well as sterically encumbered
trimethylsilyl and tert-butyl groups (entries 1-3). A sily-
loxyallene with a protected alcohol at the ꢀ-position was also
demonstrated to be reactive (entry 4). In addition, various
malonate 17 with 10 mol % Sc(OTf)3•(R,R)-Ph-Pybox in
72% yield and 70% ee (Scheme 2).13
Org. Lett., Vol. 10, No. 12, 2008
2451

To widen the scope of this new process, we examined
additional conjugate acceptors. Less reactive R,ꢀ-unsaturated
ketones do not afford desired products with the scandium(III)
conditions, but the combination of a stronger Lewis acid (1
equiv of TiCl4) and 1 in the presence of cyclohexenone,
cyclopentenone or chalcone affords good yields of the desired
Rauhut-Currier products (19, 20, 21, respectively) with
excellent to good Z-alkene selectivity (Figure 1).
addition followed by aldol condensation. Employing a chiral
scandium complex as the Lewis acid affords good levels of
enantioselectivity and using titanium(IV) promotes the reac-
tion with R,ꢀ-unsaturated ketones. Further studies of sily-
loxyallenes as R-acylvinyl anion equivalents and applications
of the 1,5-dicarbonyl products are currently underway.
Acknowledgment. Financial support for this work has
been provided by the NIGMS (GM73072) and the NSF
(CAREER). K.A.S. thanks the Sloan Foundation, Abbott,
Amgen, AstraZeneca, GlaxoSmithKline, and Boehringer-
Ingelheim for unrestricted support and Wacker Chemical and
FMCLithium for generous reagent support. T.E.R. is a
recipient of a 2007-2008 ACS Division of Organic Chem-
istry fellowship sponsored by Bristol-Myers Squibb. M.S.B.
thanks Northwestern for a Summer Research Fellowship.
Funding for the NU Integrated Molecular Structure Education
and Research Center (IMSERC) has been furnished in part
by the NSF (CHE-9871268).
Figure 1. Additions to R,ꢀ-Unsaturated Ketones.
In conclusion, silyloxyallenes undergo conjugate additions
to alkylidene malonates in excellent yields and Z-alkene
selectivity. The process accommodates wide substitution
patterns for both silyloxyallenes and conjugate acceptors.
Importantly, this new Lewis acid-catalyzed bond-forming
reaction is the first general and selective solution to access
compounds arriving from an intermolecular Rauhut-Currier
reaction. These unique products cannot be generated cleanly
or efficiently using traditional Rauhut-Currier conditions nor
by using a more stepwise approach such as a Michael
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800745Q
(12) See Supporting Information.
(13) Ph-pybox ) (+)-2,6-bis[(4R)-4-phenyl-2-oxazolin-2-yl]pyridine.
Cu(OTf)2 or Cu(SbF6)2 bis-oxazoline complexes as the Lewis acid afforded
no desired products.
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Org. Lett., Vol. 10, No. 12, 2008