Simple one-pot conversion of aldehydes and ketones to enals

Article abstract of DOI:10.1021/ol9005757

A simple and efficient method to convert aldehydes into α,β-unsaturated aldehydes with a two-carbon homologation is presented. Hydroboration of ethoxy acetylene with BH₃·SMe ₂ generates tris(ethoxyvinyl) borane. Transmetalation with

Full text of DOI:10.1021/ol9005757

ORGANIC
LETTERS
2009
Vol. 11, No. 10
2117-2119
Simple One-pot Conversion of
Aldehydes and Ketones to Enals
Petr Valenta, Natalie A. Drucker, Jeffrey W. Bode, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
pwalsh@sas.upenn.edu
Received March 18, 2009
ABSTRACT
A simple and efficient method to convert aldehydes into r,ꢀ-unsaturated aldehydes with a two-carbon homologation is presented. Hydroboration
of ethoxy acetylene with BH3·SMe2 generates tris(ethoxyvinyl) borane. Transmetalation with diethylzinc, addition to aldehydes or ketones, and
acidic workup affords enals. When the addition is quenched with anilinium hydrochloride, 1,2-dithioglycol, or acetic anhydride, the unsaturated
imine, dithiolane, or 1,1-diacetate is isolated in high yield. These transformations can be performed in a one-pot procedure.
The field of organocatalysis has witnessed explosive growth
in the past decade and will continue to be a dynamic area of
chemical research.1 A wide variety of organocatalysts and
reaction classes have been recently advanced, and many of
these are based on R,ꢀ-unsaturated aldehydes as substrates.
As a result, enals have arguably become the single most
important class of substrates for development and applica-
tions of organocatalytic transformations2 while remaining a
mainstay of metal-based catalytic asymmetric processes.1a,3
To keep pace with the ever-increasing demand for enals,
current synthetic methods must be reevaluated and optimized
or supplanted with new, direct, and more efficient ap-
proaches. Herein we disclose a simple and practical yet
broadly applicable one-pot method for the conversion of
aldehydes and ketones into R,ꢀ-unsaturated aldehydes.
A practical synthesis of enals would meet the following
criteria: it must be general, employ commercially available
and inexpensive reagents, use common laboratory techniques,
be functional group compatible, and be tolerant of R-ste-
reogenic centers in enantioenriched aldehydes and ketones.
Furthermore, the transformation should be amenable to a one-
pot procedure to enable rapid generation of an array of enals.
Existing methods for conversion of aldehydes and ketones
to enals do not satisfy these criteria (Scheme 1). For example,
cross aldol reactions with acetaldehyde enolates are not
general, yielding self-condensation products with aliphatic
aldehyde partners (Scheme 1, A).4 This difficulty can be
circumvented with C-silated imines (B and C),5 but these
imines must be prepared, silylated, and distilled, adding
(1) (a) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books: Sausalito, 2008. (b) Enders, D.;
Grondal, C.; Hu¨ttl, M. R. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (c)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175. (d)
Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87. (f)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724.
(2) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370–14371. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed.
2004, 43, 6205–6208. (c) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131–
3134. (d) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard, S.;
Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 12031–12037. (e) Huang,
Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 15051–15053. (f) Chen, Y. K.; Yoshida, M.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2006, 128, 9328–9329. (g) Wilson, R. M.;
Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616–
11617. (h) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem.
Soc. 2005, 127, 15036–15037.
(3) (a) Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2009, 131, 954–962. (b) Rowley Kelly, A.; Lurain, A. E.; Walsh, P. J.
J. Am. Chem. Soc. 2005, 127, 14668–14674.
(4) Mahata, P. K.; Barun, O.; Ila, H.; Junjappa, H. Synlett 2000, 9, 1345–
1347.
10.1021/ol9005757 CCC: $40.75
Published on Web 04/15/2009
 2009 American Chemical Society

Scheme 1
.
Synthesis of Enals
Scheme 2. Our Synthesis of Enals
tion to aldehydes, and elimination provides enals (F).
Although this method has advantages over those outlined
above, it is not economically viable because Schwartz’s
reagent is prohibitively expensive (>$2,000/mol from Ald-
rich).
Our approach to R,ꢀ-unsaturated aldehydes involves
hydroboration of ethoxy acetylene with BH3·SMe2 to generate
the tris(vinyl) borane (Scheme 2).11 This intermediate can
be prepared on scale and stored for months under a nitrogen
atmosphere or used directly in situ. Transmetalation from
boron to zinc at -78 °C and addition to aldehydes or ketones
affords zinc alkoxy enol ethers,12 which readily undergo
elimination on workup with 2 M HCl.
additional steps. Wittig,6 Horner-Emmons,7 and Peterson-
type reagents8 are generally not compatible with base-
sensitive functional groups and/or can require additional
synthetic steps to generate enals (D).
The broad substrate scope of this tandem reaction is
illustrated in Table 1. Aliphatic (entries 1-3), aromatic
(entries 4 and 8), and heteroaromatic aldehydes (entries 5-7)
and conjugated enals (entries 9 and 10) and ynals (entry 11)
undergo homologation to afford enals with 72-96% yield.
Particularly noteworthy is the successful conversion of
phenyl acetaldehyde to the expected enal in 89% yield,
despite the acidic nature of its R-hydrogens (entry 3).
Ketone substrates were more challenging and exhibited
variable results. Cyclohexanone (entry 12) was an excellent
substrate and furnished the enal in 86% yield. Given the low
reactivity of benzophenone and the mild nature of organozinc
reagents,13 we were surprised to isolate 54% yield of the
enal (entry 13). Unsymmetrical ketones, such as acetophe-
none (entry 14), gave little E:Z selectivity (3:1) unless the
two groups flanking the carbonyl were significantly different
in size, such as tert-butyl versus methyl (E:Z ) 15:1, 53%
yield, entry 15). To examine the selectivity of the vinylzinc
intermediate toward aldehydes versus ketones, a 1:1 mixture
of cyclohexane carboxaldehyde and cyclohexanone were
subjected to 1 equiv of ethoxy vinylzinc reagent. The more
reactive aldehyde was converted to the enal product, and
the ketone was left untouched.
Methods employing commercially available ethoxy acety-
lene are most attractive (Scheme 1, E and F). Hydrostan-
nylation of ethoxy acetylene provides a vinylstannane.
Transmetalation with n-BuLi leads to a highly reactive
vinyllithium that readily adds to aldehydes and ketones to
afford enals on acidic workup.9 The drawback of such
methods is the incompatibility of the vinyllithium with most
functional groups. Suzuki introduced a method that combines
the two steps above into one and circumvents the highly
reactive vinyllithium intermediate in E.10 Thus, hydrozir-
conation of ethoxy acetylene, in situ transmetalation of the
vinylzirconocene intermediate with catalytic AgClO4, addi-
(5) (a) Gaudemar, M.; Bellassoued, M. Tetrahedron Lett. 1990, 31, 349–
352. (b) Bellassoued, M.; Majidi, A. J. Org. Chem. 1993, 58, 2517–2522.
(6) (a) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979–
3982. (b) Hudson, R. D. A.; Manning, A. R.; Gallagher, J. F.; Garcia, M. H.;
Lopes, N.; Asselberghs, I.; Boxel, R. V.; Persoons, A.; Lough, A. J. J.
Organomet. Chem. 2002, 655, 70–88. (c) Mladenova, M.; Ventelon, L.;
Blanchard-Desce, M. Tetrahedron Lett. 1999, 40, 6923–6926. (d) Daubresse,
N.; Francesch, C.; Rolando, C. Tetrahedron 1998, 54, 10761–10770. (e)
Cristau, H.-J.; Gasc, M.-B. Tetrahedron Lett. 1990, 31, 341–344. (f) Fraser-
Reid, B.; Molino, B. F.; Magdzinski, L.; Mootoo, D. R. J. Org. Chem.
1987, 52, 4505–4511. (g) Cresp, T. M.; Sargent, M. V.; Vogel, P. J. Chem.
Soc., Perkin Trans. 1974, 1, 37–41.
In the case of p-phthalaldehyde the di(enal) was isolated
in 70% yield (entry 16). The o-derivative (entry 17),
(7) (a) Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem.
2000, 65, 8908–8918. (b) Paterson, I.; Cumming, J. G.; Ward, R. A.;
Lamboley, S. Tetrahedron 1995, 51, 9393–9412. (c) Nicolaou, K. C.; Harter,
M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann.-Recl. 1997, 7, 1283–1301.
(d) Still, W. C.; Gennari, C. Tet. Lett. 1983, 24, 4405–4408. (e) Ando, K.
Tetrahedron Lett. 1995, 36, 4105–4108.
(10) (a) Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron
Lett. 1992, 33, 5965–5968. (b) Maeta, H.; Suzuki, K. Tetrahedron Lett.
1993, 34, 341–344.
(11) Miyaura, N.; Maeda, K.; Suginome, H. J. Org. Chem. 1982, 47,
2117–2120.
(8) (a) Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976, 1,
7–10. (b) Martin, S. F.; Dodge, J. A.; Burgess, L. E.; Limberakis, C.;
Hartmann, M. Tetrahedron 1996, 52, 3229–3246.
(12) Jeon, S.-J.; Chen, Y. K.; Walsh, P. J. Org. Lett. 2005, 7, 1729–
1732.
(9) Wollenberg, R. H.; Albizati, K. F.; Peries, R. J. Am. Chem. Soc.
1977, 99, 7365–7367.
(13) Garc´ıa, C.; Libra, E. R.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2003, 125, 3210–3211.
2118
Org. Lett., Vol. 11, No. 10, 2009

Table 1. Two-Carbon Homologation of Aldehydes and Ketones
Scheme 3.
One-Pot Synthesis of Derivatized Enalsa
a Isolated yield.
enals proceeds via oxocarbenium ions, we rationalized that
these intermediates could be trapped by other nucleophiles.
Thus, after addition of cinnamaldehyde to the vinylzinc to
generate the alkoxide, 3 equiv of anilinium hydrochloride
was added, leading to the imine in 90% isolated yield
(Scheme 3). Likewise, trapping with 2 equiv of 1,2-
dithioglycol afforded the unsaturated 1,3-dithiolane in 98%
yield. Unsaturated 1,1-diacetates are useful intermediates in
palladium allylation chemistry.14 The diacetate was isolated
in 92% yield after treatment of the alkoxide intermediate
with aqueous HCl, removal of the volatile materials under
reduced pressure and addition of 7 equiv of acetic anhydride
and catalytic FeCl3 (5 mol %).
In summary, we have developed a simple and efficient
one-pot procedure that enables rapid access to R,ꢀ-unsatur-
ated aldehydes from aldehydes and ketones. The advantages
of this method include its extensive substrate scope, func-
tional group compatibility, tolerance of stereocenters R to
carbonyl groups, and low cost. The method can also be
employed in the one-pot synthesis of synthetically valuable
unsaturated aldimines, dithiolanes, and 1,1-diacetates. We
anticipate this method will facilitate advances in organoca-
talysis with enal substrates.
a Isolated yield. b E:Z ratio 3:1 (1H NMR). c E:Z ratio >15:1 (1H NMR).
d ee determined by HPLC.
however, furnished the monoenal in 54% yield, most likely
because the second aldehyde forms an internal hemiacetal
derivative after the first addition, preventing further reaction.
Enantioenriched aldehydes are important starting materials
and intermediates in synthesis. We therefore examined two
optically active aldehyde substrates each with a stereocenter
flanking the carbonyl. Benzyl-protected 2-hydroxy propanal
and Garner’s aldehyde were converted to enals in 88% and
94% yield, respectively (entries 18 and 19). Both enals had
>98% ee after isolation and purification, indicating the
organozinc intermediate in this process is indeed mild.
In the development of practical and useful methods,
scalability must be demonstrated. The homologation of
cyclohexenecarboxaldehyde was therefore performed on a
10 mmol scale, affording the dienal in 95% yield (entry 9).
Although enals are very important synthetic intermediates,
derivatized enals are often desired. Under the assumption
that the mechanism of conversion of hydroxy enol ethers to
Acknowledgment. This work was supported by the NIH
(National Institute of General Medical Sciences, GM58101)
and NSF (CHE-065210). P.V. thanks the Isabel and Alfred
Bader Foundation for a graduate fellowship.
Supporting Information Available: Procedures and full
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL9005757
(14) Trost, B. M.; Lee, C. B.; Weiss, J. M. J. Am. Chem. Soc. 1995,
117, 7247–7248.
Org. Lett., Vol. 11, No. 10, 2009
2119