Diastereoselective Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan catalyzed by bismuth triflate

Article abstract of DOI:10.1021/jo702085p

(Chemical Equation Presented) We have developed an efficient vinylogous Mukaiyama aldol reaction of 2-(trimethylsilyloxy)furan with various aromatic aldehydes mediated by bismuth triflate in low catalyst loading (1 mol %). The reaction proceeds rapidly and affords the corresponding 5-(hydroxy(aryl)methyl) furan-2(5H)-ones in high yields with good to very good diastereoselectivities (dr up to >98:2). Such selectivities, albeit previously reported with other Lewis acids, could this time be achieved with a much lower catalyst loading. 5-(Hydroxy(alkyl)methyl)furan-2(5H)-ones derived from ketones could also be obtained with good diastereoselectivities.

Full text of DOI:10.1021/jo702085p

described, using catalytic amounts of various chiral mediators.4
Recently, synthetic methods involving numerous lanthanide
triflates have been reported.5 High catalytic activity, moisture,
and air tolerance make lanthanide triflates attractive catalysts.
However, their cost often restricts their utilization.
Diastereoselective Mukaiyama Aldol Reaction of
2-(Trimethylsilyloxy)furan Catalyzed by Bismuth
Triflate
Thierry Ollevier,* Jean-Emmanuel Bouchard, and
Valerie Desyroy
To our knowledge, all racemic examples up to now of
vinylogous Mukaiyama aldol with silyloxyfurans have employed
Lewis acids such as SnCl4, ZnCl2, TiCl4, BF3‚OEt2, SiCl4, or
silyl triflates.6 Yet, moisture sensitivity of these catalysts and
the high cost of some of them often restrain their use. In
addition, all reported racemic reactions were involving the Lewis
acid in large amounts or even in stoichiometric amount.6 In view
of the versatile synthetic utility of 5-(hydroxy(aryl)methyl)furan-
2(5H)-ones and 5-(hydroxy(alkyl)methyl)furan-2(5H)-ones, for
example, for the preparation of γ-alkylidene-butenolides,7 there
is clearly a need for practical and efficient conditions that
involve a bench-stable catalyst, used in very low loading.
As a part of our ongoing interest in bismuth(III)-catalyzed
aldol condensation reactions,8 we report herein a bismuth(III)-
catalyzed vinylogous Mukaiyama aldol reaction. Aldols are
De´partement de chimie, UniVersite´ LaVal, Que´bec,
Canada G1K 7P4
thierry.olleVier@chm.ulaVal.ca
ReceiVed September 23, 2007
obtained efficiently in the presence of
1 mol % of
Bi(OTf)3‚4H2O. Bismuth compounds have attracted recent
attention due to their low toxicity, low cost, and high stability.9
Bismuth salts have been reported as catalysts for opening of
epoxides,10 Mannich-type reactions,11 formation and deprotec-
We have developed an efficient vinylogous Mukaiyama aldol
reaction of 2-(trimethylsilyloxy)furan with various aromatic
aldehydes mediated by bismuth triflate in low catalyst loading
(1 mol %). The reaction proceeds rapidly and affords the
corresponding 5-(hydroxy(aryl)methyl)furan-2(5H)-ones in
high yields with good to very good diastereoselectivities (dr
up to >98:2). Such selectivities, albeit previously reported
with other Lewis acids, could this time be achieved with a
much lower catalyst loading. 5-(Hydroxy(alkyl)methyl)furan-
2(5H)-ones derived from ketones could also be obtained with
good diastereoselectivities.
(4) (a) For a review on enantioselective vinylogous Mukaiyama aldol,
see: Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2005, 44, 4682-4698. (b) Matsuoka, Y.; Irie, R.; Katsuki, T. Chem.
Lett. 2003, 32, 584-585. (c) Szlozek, M.; Figade`re, B. Angew. Chem., Int.
Ed. 2000, 39, 1799-1801. (d) Szlozek, M.; Franck, X.; Figade`re, B.; Cave´,
A. J. Org. Chem. 1998, 63, 5169-5172. (e) Palombi, L.; Acocella, M. R.;
Celenta, N.; Massa, A.; Villano, R.; Scettri A. Tetrahedron: Asymmetry
2006, 17, 3300-3303. (f) For a recent organocatalytic approach, see: Nagao,
H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 8-9.
(5) (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem.
ReV. 2002, 102, 2227-2302. (b) Kobayashi, S.; Hamada, T.; Nagayama,
S.; Manabe, K. Org. Lett. 2001, 3, 165-167. (c) Kobayashi, S.; Hachiya,
I.; Takahori, T. Synthesis 1993, 371-373. (d) Kobayashi, S.; Hachiya, I.
Tetrahedron Lett. 1992, 33, 1625-1628.
The aldol reaction is well recognized as one of the most
powerful synthetic tools for a fast carbon-carbon bond con-
nection. This route provides rapid access to â-hydroxy carbonyl
compounds, which have attracted much synthetic efforts and
enjoyed widespread use in natural products and bioactive
molecules synthesis.1 The Mukaiyama aldol reaction and its
variants are probably the most notable achievements that have
been made in the field by focusing on the addition of enolsilanes
to aldehydes in the presence of catalytic amounts of Lewis
acids.2
(6) For reviews on vinylogous aldol reaction with silyloxyfurans, see:
(a) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999, 1333-
1350. (b) Casiraghi, G.; Rassu, G. Synthesis 1995, 607-626. For original
reports: (c) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett.
1987, 28, 4037-4040. (d) Acocella, M. R.; De Rosa, M.; Massa, A.;
Palombi, L.; Villano, R.; Scettri A. Tetrahedron 2005, 61, 4091-4097. (e)
Kong, K.; Romo, D. Org. Lett. 2006, 8, 2909-2912. (f) Yoshii, E.; Koizumi,
T.; Kitatsuji, E.; Kawazoe, T.; Kaneko, T. Heterocycles 1976, 4, 1663-
1668. (g) Boukouvalas, J.; Maltais, F.; Lachance, N. Tetrahedron Lett. 1994,
35, 7897-7900. (h) Lo´pez, C. S.; AÄ lvarez, R.; Vaz, B.; Faza, O. N.; de
Lera, A. R. J. Org. Chem. 2005, 70, 3654-3659. (i) Sarma, K. D.; Zhang,
J.; Curran, T. T. J. Org. Chem. 2007, 72, 3311-3318. (j) For a recent
organocatalytic approach, see: De Rosa, M.; Citro, L.; Soriente, A.
Tetrahedron Lett. 2006, 47, 8507-8510.
(7) (a) von der Ohe, F.; Bru¨ckner, R. New J. Chem. 2000, 24, 659-669.
(b) von der Ohe, F.; Bru¨ckner, R. Tetrahedron Lett. 1998, 39, 1909-1910.
(c) Go¨rth, F. C.; Umland, A.; Bru¨ckner, R. Eur. J. Org. Chem. 1998, 1055-
1062. (d) Go¨rth, F. C.; Bru¨ckner, R. Synthesis 1999, 1520-1528.
(8) (a) Ollevier, T.; Desyroy, V.; Debailleul, B.; Vaur, S. Eur. J. Org.
Chem. 2005, 4971-4973. (b) Ollevier, T.; Desyroy, V.; Nadeau, E.
ARKIVOC 2007, x, 10-20.
The vinylogous Mukaiyama aldol reaction rapidly provides
5-(hydroxy(aryl)methyl)furan-2(5H)-ones by addition of the γ
carbon of a dienolate on a carbonyl framework.3 Over past years,
some elegant enantioselective versions of this reaction have been
(1) Shiina, I. In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, 2004; Vol. 2, pp 105-166.
(2) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011-
1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503-7509. For reviews of catalytic Mukaiyama aldol reactions: (c)
Mukaiyama, T.; Matsuo, J.-i. In Modern Aldol Reactions; Mahrwald, R.,
Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 127-160. (d) Carreira, E.
M. in ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, Germany, 1999; Vol. 3,
pp 997-1065.
(9) (a) Organobismuth Chemistry; Suzuki, H.; Matano, Y., Eds.;
Elsevier: Amsterdam, 2001. (b) Gaspard-Iloughmane, H.; Le Roux, C. Eur.
J. Org. Chem. 2004, 2517-2532. (c) Leonard, N. M.; Wieland, L. C.;
Mohan, R. S. Tetrahedron 2002, 58, 8373-8397.
(10) (a) Ogawa, C.; Azoulay, S.; Kobayashi, S. Heterocycles 2005, 66,
201-206. (b) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2004, 45,
49-52. (c) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett. 2002, 43,
7891-7893.
(3) For a recent review, see: Casiraghi, G.; Zanardi, F.; Appendino, G.;
Rassu, G. Chem. ReV. 2000, 100, 1929-1972.
10.1021/jo702085p CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/11/2007
J. Org. Chem. 2008, 73, 331-334
331

tion of acetals,12 Friedel-Crafts reactions,13 Fries and Claisen
rearrangements,14 and Sakurai reactions.15 Bi(OTf)3 is particu-
larly attractive because it is commercially available or can be
easily prepared from commercially available starting materials.16
Bismuth triflate has been reported by Dubac as an efficient
catalyst for the Mukaiyama aldol reaction with silyl enol ethers17
and was recently used with a chiral ligand as reported by
Kobayashi in an elegant enantioselective method.18 The
Bi(OTf)3‚4H2O-catalyzed vinylogous Mukaiyama aldol reaction
has been studied only with dioxinone-derived silyl dienol ethers
and proceeded regioselectively (γ-attack only).19 In regard to
the importance of a diastereoselective synthesis of 5-(hydroxy-
(aryl)methyl)furan-2(5H)-ones, the Bi(OTf)3‚4H2O-catalyzed-
vinylogous Mukaiyama aldol has been investigated with 2-
(trimethylsilyloxy)furans and various carbonyl compounds.
Initially, various solvents were screened for the Mukaiyama
aldol reaction of benzaldehyde 1a with 2-(trimethylsilyloxy)-
furan 2a in the presence of 1 mol % of Bi(OTf)3‚4H2O. Among
the various polar solvents tested, acetonitrile, dichloromethane,
and tetrahydrofuran afforded good yields of the expected product
although with moderate diastereoselectivity (Table 1, entries
1-3). The most suitable solvent was found to be diethyl ether.
5-(Hydroxy(phenyl)methyl)furan-2(5H)-one 3a was obtained in
best yield and diastereoselectivity (Table 1, entry 4). With
further optimization of the reaction conditions, we found that a
lower catalyst loading (0.5 mol %) did not allow the reaction
to proceed (Table 1, compare entry 5 and entry 4), although a
higher catalyst loading (5 mol %) afforded the product with
close diastereoselectivity but decreased yield (Table 1, compare
entry 6 and entry 4).
TABLE 1. Vinylogous Bi(OTf)3-catalyzed Mukaiyama Aldol
Reactions Involving Benzaldehyde 1a and 2-(Trimethylsilyloxy)furan
2aa
entry
solvent
x mol %
dr (syn/anti)b
yield 3a (%)c
1
2
3
4
5
6
MeCN
CH2Cl2
THF
Et2O
Et2O
1
1
1
1
0.5
5
60:40
87:13
89:11
94:6
nd
75d
81
87
91
-
Et2O
93:7
80
a Conditions: benzaldehyde 1a (1.0 equiv), 2-(trimethylsilyloxy)furan
2a (1.2 equiv), Bi(OTf)3‚4H2O (x mol %). b Determined from 1H NMR of
the crude reaction mixture. c Isolated yield. d Reaction was run at 0 °C.
TABLE 2. Vinylogous Bi(OTf)3-Catalyzed Mukaiyama Aldol
Reactions Involving Various Aromatic or Unsaturated Aldehydes 1
with 2-(Trimethylsilyloxy)furan 2aa
Encouraged by our results in the reaction with benzaldehyde
1a, we studied the scope and limitations of this reaction with
(11) (a) Ollevier, T.; Nadeau, E. Org. Biomol. Chem. 2007, 5, 3126-
3134. (b) Ollevier, T.; Nadeau, E. J. Org. Chem. 2004, 69, 9292-9295.
(c) Ollevier, T.; Nadeau, E.; Eguillon, J.-C. AdV. Synth. Catal. 2006, 348,
2080-2084. (d) Ollevier, T.; Nadeau, E. Synlett 2006, 219-222. (e)
Ollevier, T.; Nadeau, E.; Guay-Be´gin, A.-A. Tetrahedron Lett. 2006, 47,
8351-8354.
(12) (a) Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier, B. A.;
Smith, R. C.; Mohan, R. S. J. Org. Chem. 2002, 67, 5202-5207. (b)
Carrigan, M. D.; Sarapa, D.; Smith, R. C.; Wieland, L. C.; Mohan, R. S. J.
Org. Chem. 2002, 67, 1027-1030.
(13) (a) Le Roux, C.; Dubac, J. Synlett 2002, 181-200. (b) Desmurs, J.
R.; Labrouille`re, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac, J.
Tetrahedron Lett. 1997, 38, 8871-8874. (c) Re´pichet, S.; Le Roux, C.;
Dubac, J.; Desmurs, J. R. Eur. J. Org. Chem. 1998, 2743-2746.
(14) (a) Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004,
2794-2796. (b) Ollevier, T.; Mwene-Mbeja, T. M. Synthesis 2006, 3963-
3966. (c) Ollevier, T.; Mwene-Mbeja, T. M. Tetrahedron Lett. 2006, 47,
4051-4055.
(15) (a) Komatsu, N.; Uda, M.; Suzuki, H.; Takahashi, T.; Domae, T.;
Wada, M. Tetrahedron Lett. 1997, 38, 7215-7218. (b) Wieland, L. C.;
Zerth, H. M.; Mohan, R. S. Tetrahedron Lett. 2002, 43, 4597-4600. (c)
Ollevier, T.; Ba, T. Tetrahedron Lett. 2003, 44, 9003-9005. (d) Leroy, B.;
Marko´, I. E. Org. Lett. 2002, 4, 47-50. (e) Sreekanth, P.; Park, J. K.; Kim,
J. W.; Hyeon, T.; Kim, B. M. Catal. Lett. 2004, 96, 201-204. (f) Choudary,
B. M; Chidara, S.; Raja Sekhar, C. V. Synlett 2002, 1694-1696. (g) Ollevier,
T.; Li, Z. Org. Biomol. Chem. 2006, 4, 4440-4443.
a Conditions: aldehyde 1 (1.0 equiv), 2-(trimethylsilyloxy)furan 2a (1.2
equiv), Bi(OTf)3‚4H2O (1 mol %), Et2O, -78 °C. b Determined from 1H
NMR of the crude reaction mixture. c Isolated yield. d Warmed to -45 °C.
e Using 2 mol % of Bi(OTf)3‚4H2O.
(16) (a) Re´pichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J.
Tetrahedron Lett. 2002, 43, 993-995. (b) Labrouille`re, M.; Le Roux, C.;
Gaspard, H.; Laporterie, A.; Dubac, J.; Desmurs, J. R. Tetrahedron Lett.
1999, 40, 285-286. (c) Peyronneau, M.; Arrondo, C.; Vendier, L.; Roques,
N.; Le Roux, C. J. Mol. Cat. A 2004, 211, 89-91. (d) Bi(OTf)3‚4H2O has
been prepared from Bi2O3 according to ref 16a.
respect to the aldehyde employed in the process. The results
are summarized in Table 2. The addition of 2-(trimethylsilyl-
oxy)furan 2a to various aldehydes 1 proceeded readily employ-
ing Bi(OTf)3‚4H2O as the Lewis acid (Scheme 2, Table 2).
Generally, excellent yields of 5-(hydroxy(aryl)methyl)furan-
2(5H)-ones were obtained with 1.2 equiv of 2-(trimethylsilyl-
oxy)furan 2a and 1 mol % of Bi(OTf)3‚4H2O at -78 °C in
Et2O. Heteromatic aldehydes as well as an R,â-unsaturated
aldehyde reacted smoothly to give the corresponding substituted
(17) Le Roux, C.; Ciliberti, L.; Laurent-Robert, H.; Laporterie, A.; Dubac,
J. Synlett 1998, 1249-1251.
(18) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.;
Manabe, K. Org. Lett. 2005, 7, 4729-4731.
(19) Ollevier, T.; Desyroy, V.; Catrinescu, C.; Wischert, R. Tetrahedron
Lett. 2006, 47, 9089-9092.
332 J. Org. Chem., Vol. 73, No. 1, 2008

TABLE 3. Vinylogous Bi(OTf)3-Catalyzed Mukaiyama Aldol
Reactions Involving Various Aliphatic Aldehydes and Ketones with
2-(Trimethylsilyloxy)furan 2a
At this point, we were curious to verify if our methodology
could be extended to ketones. It was surprising to find very
limited number of examples in the literature for the construction
of tertiary alcohols by nucleophilic addition on unsymmetrical
ketones.6e,20 Clearly, this widely studied approach for aldehydes
has not led to similar levels of success when employed with
ketones. Apparently, low reactivity and low selectivity is the
origin of this disparity.6c,21 Romo’s recent study does show that
high diastereoselectivities could be obtained with ketones when
choosing 3-methyl-2-(tert-butyldimethylsilyloxy)furan; however,
high quantities of Lewis acids (0.4-3.0 equiv) were necessary.6e
When our conditions using 5 mol % of Bi(OTf)3‚4H2O were
applied to ketones, such as cyclohexanone or the more hindered
2-methyl-cyclohexanone, we were delighted to isolate the aldol
3m in good yield and 3n with good diastereoselectivity albeit
moderate yield (Table 3, entries 3 and 4). The reaction of
3-methyl-2-(trimethylsilyloxy)furan 2b7a with 2-methyl-cyclo-
hexanone afforded a very major diastereoisomer 3n′ in good
yield (Table 3, entry 5).
In summary, we have found the vinylogous Mukaiyama aldol
reaction proceeds smoothly with silyloxyfurans and a catalytic
amount of Bi(OTf)3‚4H2O. This method offers several advan-
tages including mild reaction conditions, highly catalytic (1 mol
%) process, no formation of byproducts, as well as air-tolerance.
Yet the process does not involve strictly anhydrous conditions
as, although solvents were distilled prior to use, no inert
atmosphere was required for the reaction to proceed with the
same yield and diastereoselectivity. High yields and good
diastereoselectivities were obtained with aromatic aldehydes.
Moreover, our methodology efficiently promotes the vinylogous
Mukaiyama aldol reaction with ketones providing one major
diastereoisomer with good diastereoselectivity. Because of its
numerous benefits, the Bi(OTf)3‚4H2O protocol should find
utility in the synthesis of biologically active compounds.
Development of other Bi(OTf)3‚4H2O-catalyzed Mukaiyama
aldol reactions and related mechanistic studies will be reported
in due course.
a
Conditions: carbonyl compound 1 (1.0 equiv), 2-(trimethylsilyloxy)-
furan 2a or 3-methyl-2-(trimethylsilyloxy)furan 2b (1.5 equiv), Bi(OTf)3‚4H2O
(x mol %), Et2O, -45 °C, 0.5--3 h. b Determined from 1H NMR of the
crude reaction mixture. c Syn/anti ratio. d Isolated yield. e Relative stereo-
1
chemistry of 3n was tentatively assigned by comparison of H NMR with
3n′ of known relative stereochemistry.6e f Reaction was stirred for an
additional hour at 0 °C.
furan-2(5H)-one 3 in high yield (Table 2, entries 8-10).
Electron-rich p-, or m-methoxybenzaldehyde led to the desired
product in good yield (Table 2, entries 4 and 5). The reaction
worked well with a variety of aldehydes including those bearing
an electron-withdrawing group, and the expected product 3 was
obtained with excellent yield (Table 2, entry 6), except
p-trifluoromethyl derivative 1g leading to a moderate yield of
product due to low conversion even at higher temperature (Table
2, entry 7). Such high diastereoselectivity (90:10 up to >98:2)
had only been previously reported with aromatic aldehydes
usually requiring high catalyst loadings or even stoichiometric
amounts of a Lewis acid (1 equiv of SiCl4, 2-(trimethylsilyloxy)-
furan, benzaldehyde, dr ) 75:25;6d 0.5 equiv of TBSOTf,
3-benzyl-2-(tert-butyldimethylsilyloxy)-4-isopropylfuran, 4-(tert-
butyldimethylsilyloxy)-3,5-dichlorobenzaldehyde, dr ) 73 :27;6g
1 equiv of BF3‚OEt2, 3-bromo-2-(trimethylsilyloxy)furan, ben-
zaldehyde, 72%, dr >99:1).6h In addition, heteroaromatic
aldehydes such as furfural or thiophene 3-carboxaldehyde can
also serve as a substrate in this reaction, giving the correspond-
ing aldol in a very good yield (Table 2, entries 8 and 9).
Conjugated aldehydes were good substrates as well (Table 2,
entry 10).
Experimental Section
Typical Procedure for the Bismuth Triflate-Catalyzed Mu-
kaiyama Aldol Reaction with Aromatic Aldehydes. To a solution
of the aldehyde (0.71 mmol) in diethyl ether (0.5 mL) was added
Bi(OTf)3‚4H2O (0.007 mmol). The mixture was brought to -78
°C, stirred at this temperature for 0.25 h, and a solution of
2-(trimethylsilyloxy)furan 2a (0.85 mmol) in 0.5 mL of diethyl ether
was added dropwise. The mixture was stirred at -78 °C until the
reaction was completed as indicated by TLC. The reaction was
diluted in tetrahydrofuran (1.0 mL) and quenched with 10% aqueous
HCl (1.0 mL). The mixture was stirred for 0.25 h at room
temperature, neutralized by addition of a saturated aqueous NaHCO3
solution, and extracted with ethyl acetate. The organic phases were
combined, dried over Na2SO4, and concentrated under reduced
pressure (rotary evaporator). The syn/anti ratio of the product was
determined by 1H NMR analysis of the crude reaction mixture. The
relative configurations of the products were assigned according to
the literature.4b-c The crude products were purified by silica gel
chromatography (ethyl acetate/hexanes). 3a, 3d, 3e, 3h, and 3j
Our conditions were then applied to aliphatic aldehydes
(Table 3). When n-butyraldehyde or cyclohexylcarboxaldehyde
were reacted, the corresponding aldols 3k and 3l were obtained
in moderate diastereoselectivity and poor yield due to low
conversion (Table 3, entries 1 and 2).
(20) Naito, S.; Escobar, M.; Kym, P. R.; Liras, S.; Martin, S. F. J. Org.
Chem. 2002, 67, 4200-4208.
(21) (a) Pelter, A.; Al-Bayati, R.; Lewis, W. Tetrahedron Lett. 1982,
23, 353-356. (b) Asaoka, M.; Yanagida, N.; Ishibashi, K.; Takei, H.
Tetrahedron Lett. 1981, 22, 4269-4270.
J. Org. Chem, Vol. 73, No. 1, 2008 333

accord exactly with those that have been previously reported in
the literature.4c,6d,22
1H NMR analysis of the crude reaction mixture. The crude product
was purified by silica gel chromatography (ethyl acetate/hexanes).
3k and 3l accord exactly with those that have been previously
reported in the literature.4c,23
5-(Hydroxy(2-tolyl)methyl)furan-2(5H)-one (3c). Reagents:
o-tolualdehyde (90 mg, 0.75 mmol), 2a (140 mg, 0.89 mmol), and
Bi(OTf)3‚4H2O (5.3 mg, 0.0075 mmol). The reaction was stirred
for 0.25 h at -78 °C and quenched according to the typical
5-(1-Hydroxycyclohexyl)furan-2(5H)-one (3 m). Reagents:
cyclohexanone (70 mg, 0.71 mmol), 2a (167 mg, 1.1 mmol), and
Bi(OTf)3‚4H2O (25 mg, 0.036 mmol). The mixture was stirred at
-45 °C for 3 h and then quenched according to the typical
procedure. The crude product was then purified on silica gel (20%
ethyl acetate/hexanes) to afford 97 mg (75%) of 3m as a white
solid: mp 51 °C; Rf ) 0.18 (20% ethyl acetate/hexanes); 1H NMR
(400 MHz, CDCl3): δ ) 7.50 (dq, J ) 5.9, 0.9 Hz, 1H); 6.17 (m,
1H), 4.85 (m, 1H), 2.12 (br s, 1H), 1.40-1.65 (m, 9H), 1.16-1.25
(m, 1H); 13C NMR (100 MHz, CDCl3): δ ) 173.6, 154.1, 122.9,
1
procedure. The syn/anti ratio (94:6) was determined by H NMR
analysis of the crude product (δ major: 4.95 ppm, δ minor: 5.12
ppm). The residue was purified by silica gel chromatography (20%
ethyl acetate/hexane) to afford 138 mg (90%) of 3c as the pure syn
diastereoisomer (colorless oil): Rf ) 0.15 (30% ethyl acetate/
1
hexane); H NMR (400 MHz, CDCl3): δ ) 7.48-7.52 (m, 1H),
7.26 (t, J ) 1.5 Hz, 2H), 7.18 (m, 1H), 7.10 (dd, J ) 5.9, 1.6 Hz,
1H), 6.13 (dd, J ) 5.9, 2.0 Hz, 1H), 5.19-5.21 (m, 1H), 4.95 (d,
J ) 7.3 Hz, 1H), 3.20 (br s, 1H), 2.29 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ ) 172.6, 153.2, 136.0, 135.5, 131.1, 129.0,
89.8, 72.8, 33.8, 33.5, 25.6, 21.3; IR (KBr): 3459, 1810 cm-1
HRMS: Calcd for C10H14O3 (M+) 182.0943, found 182.0947.
;
126.9, 123.4, 87.5, 72.2, 19.7; IR (film): 3459, 1756 cm-1
HRMS: Calcd for C12H12O3 (M+) 204.0786, found 204.0779.
;
Acknowledgment. This work was financially supported by
the Natural Sciences and Engineering Research Council of
Canada (NSERC), the Fonds Que´be´cois de la Recherche sur la
Nature et les Technologies (FQRNT, Que´bec, Canada), the
Canada Foundation for Innovation, and Universite´ Laval. V.
D. thanks NSERC for a postgraduate scholarship. We thank
Rhodia (Lyon, France) and Sidech s.a. (Tilly, Belgium) for a
generous gift of chemicals.
Typical Procedure for the Bismuth-Catalyzed Mukaiyama
Aldol Reaction with Aliphatic Aldehydes and Ketones. To a
solution of Bi(OTf)3‚4H2O (0.036 mmol) in diethyl ether (0.5 mL)
at room temperature was added the aldehyde or the ketone
(0.71 mmol). The mixture was brought to -45 °C, stirred at this
temperature for 0.25 h, and a solution of 2-(trimethylsilyloxy)furan
2 (1.1 mmol) in diethyl ether (0.5 mL) was added dropwise. The
mixture was stirred at -45 °C for 3 h. The mixture was diluted in
tetrahydrofuran (1.0 mL) and quenched with 10% aqueous HCl
(1.0 mL). The mixture was stirred for 0.25 h at room temperature,
neutralized by addition of a saturated aqueous NaHCO3 solution,
and extracted with ethyl acetate. The organic phases were combined,
dried over Na2SO4, and concentrated under reduced pressure (rotary
evaporator). The syn/anti ratio of the product was determined by
Supporting Information Available: Experimental details,
characterization data, and NMR spectra for compounds 3a-n, 3n′.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702085P
(22) Pohmakotr, M.; Tuchinda, P.; Premkaisorn, P.; Reutrakul, V.
Tetrahedron 1998, 54, 11297-11304.
(23) Hjelmgaard, T.; Persson, T.; Rasmussen, T. B.; Givskov, M.;
Nielsen, J. Bioorg. Med. Chem. 2003, 11, 3261-3271.
334 J. Org. Chem., Vol. 73, No. 1, 2008