One-pot enol silane formation-Mukaiyama aldol-type addition to dimethyl acetals mediated by TMSOTf

Article abstract of DOI:10.1021/jo8001084

(Chemical Equation Presented) Various ketones, esters, amides, and thioesters add in high yield to dimethyl acetals in the presence of silyl trifluoromethanesulfonates and an amine base. Acetals derived from aryl, unsaturated, and aliphatic aldehydes are

Full text of DOI:10.1021/jo8001084

ably because enolization of the aldehyde electrophile competed
with the desired ketone enolization. We speculated that if the
effective concentration of the enolizable electrophile could be
lowered, this competition could be greatly reduced. Alterna-
tively, a highly electrophilic aldehyde surrogate might prefer
enol silane addition over enolization. Accordingly, we began
to examine the catalytic activation of dimethyl acetals as a
source of oxocarbenium ions, a class of electrophiles well
documented to undergo Mukaiyama-type addition.3 As a proof
of principle, we first investigated the addition of acetophenone
to benzaldehyde dimethyl acetal. We were gratified to find that
in the presence of 1.2 equiv of TMSOTf and 1.2 equiv of i-Pr2-
NEt, aldol-type addition occurs in exceptional yield in less than
2 h (eq 2).
One-Pot Enol Silane Formation-Mukaiyama
Aldol-Type Addition to Dimethyl Acetals
Mediated by TMSOTf
C. Wade Downey,* Miles W. Johnson, and Kathryn J. Tracy
Gottwald Center for the Sciences, UniVersity of Richmond,
Richmond, Virginia 23173
wdowney@richmond.edu
ReceiVed January 16, 2008
Various ketones, esters, amides, and thioesters add in high
yield to dimethyl acetals in the presence of silyl trifluoro-
methanesulfonates and an amine base. Acetals derived from
aryl, unsaturated, and aliphatic aldehydes are all effective
substrates. The reaction proceeds in a single reaction flask,
with no purification of the intermediate enol silane necessary.
Based on our previous work with the Mukaiyama aldol
reaction,2 we hypothesize that the mechanism involves the in
situ formation of an enol silane derived from acetophenone,
effected by stoichiometric amounts of TMSOTf and i-Pr2NEt
(Scheme 1). The remaining unreacted TMSOTf then activates
the dimethyl acetal, leading to the formation of a highly
electrophilic oxocarbenium intermediate.4 Mukaiyama-type ad-
dition of the enol silane to the oxocarbenium ion, followed by
silicon transfer to another acetal, provides the product. Although
a stoichiometric amount of silylating agent is necessary to
produce the enol silane, the carbon-carbon bond-forming event
is catalytic in TMSOTf.3a,b
The Mukaiyama aldol reaction continues to garner great inter-
est among organic chemists because of its versatility and mild
reaction conditions.1 We recently reported a modification of the
Mukaiyama aldol reaction wherein the requisite enol silane for-
mation was achieved in situ, achieving high yields with nonenoliz-
able aldehyde acceptors (eq 1).2 The key to this process was the
Table 1 shows the addition reactions of acetophenone and a
wide range of acetal electrophiles, including acetals derived from
enolizable aldehydes. As evidenced by entry 1, addition may
be mediated by either TMSOTf or triethylsilyl trifluoromethane-
sulfonate (TESOTf) with comparable yield. Electron-rich aro-
matic acetals react extremely well (entry 2).5 Several other
aromatic and heteroaromatic substrates were excellent electro-
philes (entries 3-5). Importantly, versatile styrenyl product 6
was synthesized in near-quantitative yield.6 Although enolizable
aldehydes were completely incompatible with our original aldol
conditions, we were gratified to find that their acetal deriVatiVes
were outstanding substrates (entries 7-9). These results, which
include the extremely unhindered and enolization-prone acetal-
dehyde dimethyl acetal, greatly expand the scope of our in situ
enol silane formation strategy. Finally, even relatively unreactive
dimethoxy methane provided good yield of the addition product
(entry 10). Despite this success with acetals, ketal electrophiles
ability of a silyl trifluoromethanesulfonate to act as both a silylat-
ing agent and a Lewis acid catalyst. To further expand the scope
of this reaction to include enolizable aldehyde surrogates, we
turned to dimethyl acetal electrophiles. We now report the
successful development of a one-pot enol silane formation-
Mukaiyama aldol-type addition to dimethyl acetals, where tri-
methylsilyl trifluoromethanesulfonate (TMSOTf) acts as both
a silylating agent and a Lewis acidic activator of the acetal
electrophile.3
In the course of our study of the in situ enol silane formation-
Mukaiyama aldol reaction, we discovered that enolizable alde-
hydes were incompatible with the reaction conditions, presum-
(3) For the use of silyl trifluoromethanesulfonates as Lewis acids in
Mukaiyama-type addition to acetals, see: (a) Murata, S.; Suzuki, M.; Noyori,
R. J. Am. Chem. Soc. 1980, 102, 3248-3249. (b) Murata, S.; Suzuki, M.;
Noyori, R. Tetrahedron 1988, 44, 4259-4275. For a strategy similar to
the one reported here, but with a boron Lewis acid, see: (c) Li, L.-S.; Das,
S.; Sinha, S. C. Org. Lett. 2004, 6, 127-130.
(4) Similar conditions (TESOTf/2,6-lutidine) have been used to convert
symmetric acetals to mixed acetals via a similar oxocarbenium intermediate.
See: Fujioka, H.; Okitsu, T.; Sawama, Y.; Murata, N.; Li, R.; Kita, Y. J.
Am. Chem. Soc. 2006, 128, 5930-5938.
(5) Synthesis of the dimethyl acetal derived from p-nitrobenzaldehyde
proved nontrivial, preventing its inclusion in this study.
(1) (a) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503-7509. For a review, see: (b) Carreira, E. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, Germany, 1999; Vol. 3, pp 997-1065. For more
recent examples, see: (c) Rech, J. C.; Floreancig, P. E. Org. Lett. 2005, 7,
5175-5178. (d) Jung, M. E.; Zhang, T.-H. Org. Lett. 2008, 10, 137-140.
(2) (a) Downey, C. W.; Johnson, M. W. Tetrahedron Lett. 2007, 48,
3559-3562. For intramolecular precedents for this reaction, see: (b) Hoye,
T. R.; Dvornikovs, V.; Sizova, E. Org. Lett. 2006, 8, 5191-5194. (c) Rassu,
G.; Auzzas, L.; Pinna, L.; Zombrano, V.; Battistini, L.; Zanardi, F.;
Marzocchi, L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2001, 66, 8070-
8075.
(6) Styrenyl bonds are easily cleaved by ozonolysis to yield an aldehyde.
For example, see: Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem.
Soc. 1988, 110, 2506-2526.
10.1021/jo8001084 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/12/2008
J. Org. Chem. 2008, 73, 3299-3302
3299

TABLE 2. Addition of Various Substrates to Benzaldehyde
Dimethyl Acetald
SCHEME 1. Proposed Mechanistic Scheme
TABLE 1. Addition of Acetophenone to Various Dimethyl Acetalsc
a Isolated yield after chromatography. b TESOTf was used instead of
TMSOTf. c Product contaminated with <5% starting amide. d See the
Supporting Information for experimental procedures.
occurred in 48% yield (eq 3). Analysis of the unpurified reaction
mixture by 1H NMR spectroscopy revealed multiple unidentified
side products, perhaps due to competing enolization of the cyclic
oxocarbenium intermediate. Side products also complicated ini-
tial attempts to add acetophenone to the diethyl acetal of acetal-
dehyde. Fortunately, the use of mildly basic 2,6-lutidine sup-
pressed the side reactions for this case, possibly by inhibiting com-
petitive deprotonation of the oxocarbenium intermediate (eq 4).
a Isolated yield after chromatography. b Reaction performed with TESOTf
instead of TMSOTf. c See the Supporting Information for experimental
procedures.
derived from acetone and cyclohexanone provided no desired
product under similar reaction conditions.7
In addition to dimethyl acetals, other acetal eletrophiles were
examined in the course of this study. When 2-methoxy pyran was
subjected to the reaction conditions, a glycosidation-type reaction
Concurrent with the investigation of various acetal reaction
partners, we probed the ability of a range of enolate precursors
to add to benzaldehyde dimethyl acetal under similar reaction
conditions (Table 2). As expected, aromatic methyl ketones reac-
ted exceptionally well, providing high yields of â-methoxy
(7) Ketals were generally converted to enol ethers under the reaction
conditions.
3300 J. Org. Chem., Vol. 73, No. 8, 2008

TABLE 3. Addition of Various Substrates to Acetaldehyde
Dimethyl Acetalc
(Table 3). Again, aromatic methyl ketones provided aldol-type
products in high yields (entries 1-3), even though the elimina-
tion of â-methoxy adduct 20 in the presence of Lewis acids is
precedented.8 Indeed, preliminary results indicated that if more
than a 1% excess of TMSOTf relative to i-Pr2NEt was present
in the reaction mixture, elimination of the methoxy group
became a competing reaction.
Although thioester substrates again performed well (entries 6
and 7), the less acidic ester and amide substrates proved problem-
atic when used in conjunction with acetaldehyde dimethyl acetal.
No conversion to the desired product was observed with ester
nucleophiles, probably due to competing enolization of the
acetal-derived oxocarbenium ion (entry 4). Similarly,
N,N-diphenylacetamide suffered from low conversion, and the
product was chromatographically inseparable from the starting
material (entry 5).10 Furthermore, when one of the phenyl groups
on the amide was removed, the resultant secondary amide
underwent N-alkylation rather than aldol-type addition (eq 5).11
Given the success of this one-pot addition procedure with
simple nucleophiles, we next investigated the diastereoselectivity
of the reaction. Propiophenone was reacted with both benzal-
dehyde dimethyl acetal and acetaldehyde dimethyl acetal. The
yield for both reactions was 82%, with a modest but promising
syn:anti ratios of 3.1:1 and 3.7:1, respectively (eq 6).12
a Isolated yield after chromatography. b Conversion as determined by 500
MHz 1H NMR spectroscopy. c See the Supporting Information for experi-
mental procedures.
ketones (entries 1-3). Attempts to employ alkyl-alkyl ketones
as nucleophiles resulted in many side reactions and intractable
product mixtures. Ester substrates generally suffered from poor
yields when TMSOTf was employed as the silylating agent; anal-
ysis of the reaction mixture suggested that the â-methoxy group
in the product was being eliminated to yield a cinnamate ester.8
Furthermore, elimination was observed when the ethyl acetate-
derived product was resubjected to the reaction conditions. Fortu-
nately, when TMSOTf was replaced with the bulkier TESOTf,
the elimination reaction was suppressed (entries 4 and 5).
In conclusion, the use of dimethyl acetal electrophiles has
expanded the scope of our one-pot enol silane formation-
Mukaiyama aldol process to include aliphatic aldehyde sur-
rogates. A wide range of dimethyl acetals is compatible with
the reaction conditions. Future work in this area includes the
use of chiral auxiliaries to achieve greater control of the
stereochemical outcome of these promising reactions.
Experimental Section
Typical Procedure for One-Pot Enol Silane-Formation
Mukaiyama Aldol-Type Addition. Synthesis of Product 1.13 To
an oven-dried 10 mL round-bottomed flask under N2 was added
CH2Cl2 (2.5 mL). The flask was cooled to 0 °C, and acetophenone
As shown in entry 6, diphenylamide product 17 was formed in
good yield but was inseparable from trace amounts of the starting
material. Thioesters performed very well in the reaction, providing
convenient building blocks in excellent yield (entries 7 and 8).9
Upon completion of the benzaldehyde dimethyl acetal study,
we turned to a representative and challenging substrate derived
from an enolizable aldehyde, acetaldehyde dimethyl acetal
1
(10) Analysis by 500 MHz H NMR suggests that enolization of ester
and amide substrates is slow under the reaction conditions, typically less
than 10% after 15 min at ambient temperature. In contrast, conversion of
aromatic ketones to enol silanes under identical conditions is >90%
complete after 15 min.
1
(8) â-Methoxy carbonyl compounds are known to undergo elimination
under Lewis acidic conditions. See: Ramirez, F.; Rubin, M. B. J. Am. Chem.
Soc. 1955, 77, 2905-2907.
(9) For an example of a thioester aldol adduct used as a building block
in the asymmetric total synthesis of pectenotoxin, see: Evans, D. A.;
Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002,
41, 4573-4576. For the direct conversion of thioesters to aldehydes by
Fukuyama reduction, see: Fukuyama, T.; Lin, S.-L.; Li, L. J. Am. Chem.
Soc. 1990, 112, 7050-7051.
(11) Product structure assigned on the basis of H NMR spectrum. No
yield was determined. Methoxymethyl protection of amides is known to
occur under similar conditions. For example, see: Szmigielski, R.;
Danikiewicz, W. Synlett 2003, 372-376.
(12) Assignment of relative stereochemistry for product 26 is based on
literature precedent (ref 3b). Assignment for product 27 is by analogy.
(13) For a literature synthesis of product 1, see: Torii, S.; Inokuchi, T.;
Takagishi, S.; Horike, H.; Kuroda, H.; Uneyama, K. Bull. Chem. Soc. Jpn.
1987, 60, 2173-2188.
J. Org. Chem, Vol. 73, No. 8, 2008 3301

(117 µL, 1.00 mmol), i-Pr2NEt (210 µL, 1.21 mmol), and TMSOTf
(217 µL, 1.20 mmol) were added sequentially. After 15 min,
benzaldehyde dimethyl acetal (210 µL, 1.40 mmol) was added, and
the reaction was removed from the ice bath and allowed to warm
to room temperature. After 2 h, the reaction mixture was filtered
through a plug of silica (2 cm × 5 cm) with Et2O, and the solvent
was removed by rotary evaporation. Silica gel chromatography (2-
10% EtOAc/Hexanes) provided the product as a colorless oil (99%
yield): IR (film) 3055, 3023, 2925, 2822, 1681, 1595, 1459, 1356,
1269, 1198, 1095, 992, 748, 699 cm-1; 1H NMR (500 MHz, CDCl3)
δ 8.00-7.95 (m, 2H), 7.59-7.55 (m, 1H), 7.49-7.37 (m, 6H),
7.35-7.30 (m, 1H), 4.91 (dd, J ) 4.5, 8.6 Hz, 1H), 3.62 (dd, J )
8.5, 16.8 Hz, 1H), 3.26 (s, 3H), 3.41 (dd, J ) 4.4, 16.2 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 197.7, 141.5, 137.3, 133.1, 128.6,
128.5, 128.2, 127.9, 126.1, 79.6, 56.9, 47.2; HRMS (ESI): Exact
mass calcd for C16H16O2Na [M + Na]+, 263.1043. Found 263.1040.
Acknowledgment. We thank Research Corporation and the
Thomas F. Jeffress and Kate Miller Jeffress Memorial Trust
for funding. M.W.J. acknowledges the Howard Hughes Medical
Institute for a research fellowship. K.J.T. acknowledges the
University of Richmond College of Arts and Sciences for a
summer research fellowship. We thank Dr. Robert Miller for
useful discussions and Dr. Timothy Smith for assistance with
mass spectral data.
Supporting Information Available: Experimental procedures,
compound characterization data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8001084
3302 J. Org. Chem., Vol. 73, No. 8, 2008