Highly effective vinylogous Mukaiyama-Michael reaction catalyzed by silyl methide species generated from 1,1,3,3-tetrakis(trifluoromethanesulfonyl)propane

Article abstract of DOI:10.1021/jo902641g

(Chemical Equation Presented) Silyl methide species in situ generated from 1,1,3,3-tetrakis(trifluoromethanesulfonyl)propane (Tf₂CHCH ₂CHTf₂) performed as an excellent acid catalyst for the vinylogousMukaiyama-Michael reaction of α,β-unsaturated ketones with 2-silyloxyfurans. Notably, the required loading of Tf₂CHCH ₂CHTf₂ to obtain the 1,4-adducts in reasonable yield was significantly low (from 0.05 to 1.0 mol%). This carbon acid-mediatedVMMreaction provides a powerful synthetic methodology to construct highly substituted γ-butenolide structure. 2010 American Chemical Society.

Full text of DOI:10.1021/jo902641g

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Highly Effective Vinylogous Mukaiyama-Michael Reaction
Catalyzed by Silyl Methide Species Generated from
1,1,3,3-Tetrakis(trifluoromethanesulfonyl)propane
Arata Takahashi,† Hikaru Yanai,† Min Zhang,‡ Takaaki Sonoda,‡ Masaaki Mishima,‡
and Takeo Taguchi*,†
†School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji,
Tokyo 192-0392, Japan, and ‡Institute for Materials Chemistry and Engineering, Kyushu University,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
taguchi@ps.toyaku.ac.jp
Received December 14, 2009
Silyl methide species in situ generated from 1,1,3,3-tetrakis(trifluoromethanesulfonyl)propane
(Tf2CHCH2CHTf2) performed as an excellent acid catalyst for the vinylogous Mukaiyama-Michael
reaction of R,β-unsaturated ketones with 2-silyloxyfurans. Notably, the required loading of
Tf2CHCH2CHTf2 to obtain the 1,4-adducts in reasonable yield was significantly low (from 0.05 to
1.0 mol %). This carbon acid-mediated VMM reaction provides a powerful synthetic methodology to
construct highly substituted γ-butenolide structure.
Introduction
(1) simple operation without handling of easily hydrolyzed
and fuming silicon Lewis acids3 and (2) notably low catalyst
loading of Bronsted acid through high catalyst activity4 and
“self-repairing” of generated silicon Lewis acids.5,6 In addi-
tion, high activation of reaction substrates by catalytically
active silicon Lewis acid would realize some bond formations
between less reactive substrates such as sterically hindered
substrates.
In general, it is known that the silylating activity (or Lewis
acidity) of “R3Si-A”, which is possibly generated from
Bronsted acid “H-A” with silylated nucleophiles “R3Si-
Nu”, depends on both the leaving group ability of ligand
Organic Bronsted acid such as carboxylic acid, phosphonic
acid, and sulfonic acid is one of the most useful and popular
catalysts in modern organic synthesis.1 These organic acids are
essentially green due to avoiding the use of metal salts, although
the catalyst loading of Bronsted acids is generally higher than
that of transition metal catalysts or Lewis acids. In addition, the
low catalyst activity of organic catalysts severely limits their
application to synthetic reactions.
As an alternative application of Bronsted acid to organic
synthesis, in situ generation of silicon Lewis acids “R3Si-A”
by the reaction of Bronsted acids “H-A” with silylated
nucleophiles “R3Si-Nu” also attracts much attention.2 This
procedure has the following two advantages (Scheme 1):
(3) (a) Takasu, K. Synlett 2009, 1905–1914. (b) Takasu, K.; Miyakawa,
Y.; Ihara, M.; Tokuyama, H. Chem. Pharm. Bull. 2008, 56, 1205–1206.
(4) (a) Hara, K.; Akiyama, R.; Sawamura, M. Org. Lett. 2005, 7, 5621–
5623. (b) Scott, V. J.; Celenligil-Cetin, R.; Ozerov, O. V. J. Am. Chem. Soc.
2005, 127, 2852–2853. (c) Douvris, C.; Ozerov, O. V. Science 2008, 321, 1188–
1190.
(5) (a) Boxer, M. B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48–49.
(b) Boxer, M. B.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 2762–2763.
(6) (a) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2005, 127,
3668–3669. (b) Takasu, K.; Hosokawa, N.; Inanaga, K.; Ihara, M. Tetra-
hedron Lett. 2006, 47, 6053–6056. (c) Jung, M. E.; Ho, D. G. Org. Lett. 2007,
9, 375–378. (d) Cheon, C. H.; Yamamoto, H. Tetrahedron Lett. 2009, 50,
3555–3558.
(1) (a) Acid Catalysis in Modern Organic Synthesis; Yamamoto, H.,
Ishihara, K., Eds.; Wiley-VCH: Weinheim, Germany, 2008. (b) Asymmetric
Organocatalysis; Berkessel, A., Groeger, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2005; (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138–5175.
(2) (a) Oishi, M. Silicon(IV) Lewis Acids. In Lewis Acids in Organic
Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1,
pp 355-393; (b) Hosomi, A.; Miura, K. Si(IV) Lewis acids. In Acid Catalysis in
Modern Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH:
Weinheim, Germany, 2008; Vol. 1, pp 469-516.
DOI: 10.1021/jo902641g
r
Published on Web 01/19/2010
J. Org. Chem. 2010, 75, 1259–1265 1259
2010 American Chemical Society

Takahashi et al.
JOCArticle
SCHEME 1. In Situ Generation of Silicon Lewis Acid “R3Si-A”
and Its Self Repairing
TABLE 1. Survey of Effective Acids for the Reaction of 2a with TBSO-
Furan
entry
acid catalyst (mol %)
temp (°C) time (h) yielda (%)
1
2
3
4
5
6
7
8
9
Tf2CHCH2CHTf2 1 (0.25) -78
2
3
3
3
5
6
6
3
5
88
87
0
7
36
7
part “A” and I-strain between silyl part “R3Si” and ligand
part “A”.2b,7 Therefore, the design of Bronsted acid is a
promising approach to develop catalytically active silicon
species with high performance. Contrary to a design of
Bronsted acid structure, Yamamoto and co-workers has
already showed that the sterically bulky silyl part is an
important factor for the catalytic activity of in situ generated
silicon Lewis acid.5 That is, (Me3Si)3Si-NTf2 (Tf = CF3SO2)
generated by the in situ reaction of nitrogen acid Tf2NH with
tris(trimethylsilyl)silyl (TTMS) enol ethers nicely catalyzes
the Mukaiyama-aldol reaction of aldehydes with TTMS enol
ethers, while the use of t-BuMe2Si-NTf2 generated from tert-
butyldimethylsilyl (TBS) enol ethers instead of TTMS enol
ethers resulted in a significant decrease in the yield of aldol
products.
Recently, we reported aluminum methide complex Me2Al-
CHTf2 prepared by the reaction of Me3Al and bis(trifluoro-
methanesulfonyl)methane (Tf2CH2).8 Since the Tf2CH
structure acts as a good proton donor due to gem-disubsti-
tution by two triflyl groups, highly acidic Tf2CHC6F5 was
reported as a “super Bronsted acid” catalyst.9,10 We have
examined the synthetic applications of various carbon acids
having the Tf2CH group in the molecular structure. In this
paper, we would like to report the vinylogous Mukaiya-
ma-Michael (VMM) reaction11 catalyzed by silyl methide
species generated from 1,1,3,3-tetrakis(trifluoromethane-
sulfonyl)propane 112,13 (Tf2CHCH2CHTf2) having two
acidic protons attached on the 1,3-carbons.14 This is the first
example of synthetic reactions catalyzed by carbon acid 1.15
Tf2CHCH2CHTf2 1 (0.05) -78 to -24
Tf2CH2 (1.0)
Tf2CHMe (1.0)
Tf2CHC6F5 (0.05)
TfOH (0.25)
Tf2NH (0.25)
Me3Al (40)
-78
-78
-78 to rt
-78
-78
-78
rt
7
64
NRb
none
aIsolated yield. bNo reaction.
Results and Discussion
1,1,3,3-Tetrakis(trifluoromethanesulfonyl)propane-Mediated
VMM Reaction. At first, to survey the activity of the Tf group
containing Bronsted acids, the reaction of 4-methyl-3-penten-
2-one 2a with TBSO-furan (1.1 mol equiv) as a model reaction
was carried out (Table 1).16 In the presence of 0.25 mol % of
carbon acid 1, the reaction at -78 °C for 2 h provided Michael
adduct 3aa in 88% yield after desilylation of silyl enol ether
intermediate by aqueous HCl treatment (entry 1). The catalyst
loading of 1 could be reduced to 0.05 mol % without significant
decrease in the product yield (entry 2). Interestingly, Tf2CH2
did not catalyze this reaction (entry 3), while a weak catalyst
activity was observed by replacing a hydrogen of Tf2CH2 with a
methyl or C6F5 group. That is, the reactions in the presence of
Tf2CHMe (1.0 mol %) and Tf2CHC6F5 (0.05 mol %) gave
1,4-adduct 3aa in 7% and 36% yield, respectively (entries 4
and 5). Compared to the high activity of 1, the efficiency of
other Bronsted acids such as TfOH and Tf2NH was remarkably
lower. For instance, in the presence of 0.25 mol % of TfOH,
Michael adduct 3aa was obtained in only 7% yield (entry 6).
The use of Tf2NH also gave the essentially same result as in
the case of TfOH (entry 7). Additionally, the use of Me3Al
instead of carbon acid 1 required a notable increase in catalyst
loading, but resulted in a low yield of 3aa (40 mol %, 64% yield)
(entry 8). In the absence of acids, the reaction at room
temperature also resulted in no change of 2a and silyloxyfuran
(entry 9). Despite a number of reports demonstrating that
Lewis acid can promote 1,4-addition of silicon enolate to
sterically crowded β,β-disubstituted enones via single-electron
transfer mechanism,17 the construction of quaternary carbon
through Bronsted acid-mediated Michael-type addition to
β,β-disubstituted enones has been limited.
(7) (a) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219–8226.
(b) Mathieu, B.; de Fays, L.; Ghosez, L. Tetrahedron Lett. 2000, 41, 9561–
9561.
(8) (a) Yanai, H.; Takahashi, A.; Taguchi, T. Tetrahedron 2007, 63,
12149–12159. (b) Yanai, H.; Takahashi, A.; Taguchi, T. Tetrahedron Lett.
2007, 48, 2993–2997.
(9) For examples of Brønsted acid catalysts equipped with an Tf2CH
group, see: (a) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem.,
Int. Ed. 2001, 40, 4077–4079. (b) Ishihara, K.; Hasegawa, A.; Yamamoto, H.
Synlett 2002, 1299–1301. (c) Kokubo, Y.; Hasegawa, A.; Kuwata, S.;
Ishihara, K.; Yamamoto, H.; Ikariya, T. Adv. Synth. Catal. 2005, 347,
220–224.
(10) For a chiral Brønsted acid catalyst equipped with an Tf2CH group,
see: Hasegawa, A.; Naganawa, Y.; Fushimi, M.; Ishihara, K.; Yamamoto,
H. Org. Lett. 2006, 8, 3175–3178.
(11) Mukaiyama, T.; Matsuo, J. Boron and Silicon Enolates in Crossed
Aldol Reaction. In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, Germany, 2004; Vol. 1, pp 127-160.
(12) (a) Nozari, M. S. Ger. Patent 2609148, 1976. (b) Siefken, M. W. Ger.
Patent 2609150, 1976. (c) Koshar, R. J.; Barber, L. L., Jr. U.S. Patent 4053519,
1977.
(13) Tf2CHCH2CHTf2 is a nonfuming and nonhydroscopic crystal. This
compound can be stored at room temperature for several months without
decomposition.
(14) Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385–
2387.
(15) Previously, in the field of polymer synthesis, carbon acid 1 had been
used as a strong Brønsted acid catalyst, see: Robins, J.; Young, C. Ring-
opening polymerization. In ACS Symp. Ser. 1985, 286, 263-274.
(16) For selected examples of the VMM reactions with heterocyclic
dienoxysilane, see: (a) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.
Synlett 2009, 1525–1542. (b) Scettri, A.; De Sio, V.; Villano, R.; Acocella, M.
R. Synlett 2009, 2629–2632. (c) Barluenga, J.; de Prado, A.; Santamarıa, J.;
ꢀ
Tomas, M. Angew. Chem., Int. Ed. 2005, 44, 6583–6585. (d) Brimble, M. A.;
Burgess, C.; Halim, R.; Petersson, M.; Ray, J. Tetrahedron 2004, 60, 5751–
5758. (e) Arroyo, Y.; de Paz, M.; Rodrıguez, J. F.; Sanz-Tejedor, M. A.;
Garcıa Ruano, J. L. J. Org. Chem. 2002, 67, 5638–5643. (f) Narasaka, K.;
Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223–1224.
(17) Otera, J.; Fujita, Y.; Sakuta, N.; Fujita, M.; Fukuzumi, S. J. Org.
Chem. 1996, 61, 2951–2962.
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TABLE 2. Carbon Acid-Mediated VMM Reaction of R,β-Enone 2a
aReaction temperature, -78 to -24 °C; reaction time 1-4 h. bIsolated yield. cBased on isolated yield. dAcidic workup by aq HCl in THF. eAcidic
workup by TfOH in CH2Cl2. f1,4-Adduct 5 was obtained in 25%. g1,4-Adduct 5 was obtained in 29%.
To see the scope of the present carbon acid-mediated
VMM reaction, we examined the reaction of various R,β-
enones with 2-TBSO-furans (Table 2). The reaction of
cyclohexylideneacetone 2b with 2-TBSO-furan was nicely
promoted by 0.25 mol % of 1 to give 1,4-adduct 3ba in 90%
yield (entry 1). Methyl vinyl ketone 2c and aryl vinyl ketone
derivatives 2d, 2e were also found as good substrates for the
present reaction (3ca 82% yield, 3da 89% yield, and 3ea
88% yield). Since catalyst loading was varied in a range from
0.05 to 0.25 mol % in these cases, excellent activity of
propane diacid 1 was clearly demonstrated. In the presence
of 0.25 mol % of 1, the reaction of 2a with 3-methyl-2-
TBSO-furan smoothly proceeded at -78 °C to give 1,4-
adduct 3ab in 84% yield along with a small amount of 1,2-
adduct 4ab (2% yield) after acidic workup (entry 5). As
shown in entry 6, in the case of 4-methyl-2-TBSO-furan, the
1,4-/1,2-selectivity was decreased to 10:1, although an ex-
cellent combined yield of 3ac and 4ac was observed (86%
yield). Surprisingly, in the presence of 1.0 mol % of 1, the
reaction with 5-methyl-2-TBSO-furan gave 1,4-adduct 3ad,
which has consecutive quaternary carbons, in 72% yield
without the formation of any 1,2-adducts. In this reaction,
isomer 5 was also formed as a major byproduct (∼25%
yield) (entry 7). Since, as shown in entry 8, lower catalyst
loading of 1 (0.25 mol %) resulted in a significant decrease
of the reaction rate and poor yield of 3ad, more than 1 mol %
of 1 was necessary to obtain a smooth reaction.
Carbon Acid-Mediated Diastereoselective VMM Reaction.
Next, to realize an acyclic stereoselection in the carbon acid-
catalyzed VMM reaction, we examined the reaction of
benzalacetone 2f with several 2-silyloxyfurans.18,19 Selected
results are summarized in Table 3. In the presence of
1.0 mol % of carbon acid 1, the reaction of 2f with 1.1 mol
equiv of 2-TBSO-furan at -78 °C completed within 2 h to
give 1,4-adduct 3fa in 91% yield with poor anti selectivity
(anti/syn = 1.8:1) (entry 1). Under the same conditions,
3-methyl-2-TBSO-furan and 3-bromo-2-TBSO-furan gave
a better anti selectivity (entry 2, anti/syn = 4.9:1; entry 3,
anti/syn = 16:1). Interestingly, the diastereoselectivity also
(18) For enantioselective and diastereoselective 1,4-addition of silyloxy-
furans catalyzed by chiral Lewis acids, see: (a) Kitajima, H.; Ito, K.; Katsuki,
T. Tetrahedron 1997, 53, 17015–17028. (b) Kitajima, H.; Ito, K.; Katsuki, T.
Synlett 1997, 568–570. (c) Desimoni, G.; Faita, G.; Filippone, S.; Mella, M.;
Zampori, M. G.; Zema, M. Tetrahedron 2001, 57, 10203–10212. (d) Suga, H.;
Kitamura, T.; Kekahi, A.; Baba, T. Chem. Commun. 2004, 1414–1415.
(e) Yang, H.; Kim, S. Synlett 2008, 555–560.
(19) For enantioselective and diastereoselective 1,4-addition of silyloxy-
furans catalyzed by chiral organocatalyst, see: Brown, S. P.; Goodwin, N. C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192–1194.
J. Org. Chem. Vol. 75, No. 4, 2010 1261

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TABLE 3. Substituent Effects of Silyloxyfuran on Diastereoselectivity
TABLE 4. Anti-Selective VMM Reaction of 2 with 3-Bromo-2-TESO-
Furan
1 (mol %) 3fx yielda (%) anti/synb
entry
2
R1
R2 1 (mol %)
3
yielda (%) anti/synb
entry
SiR3
TBS
TBS
X
1c
2c,d
3c
H
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.25
0.25
3fa
3fb
3fe
3fa
3fa
3fe
3fe
3fe
3fe
91
87
92
91
93
93
95
90
89
1.8:1
4.9:1
16:1
3.6:1
5.0:1
20:1
>30:1
anti only
>30:1
1
2
3
2g Me Me
2h CH2CH2Ph Me
2i c-Hex
0.5
3ge
3he
3ie
3ie
3je
3ke
3me
3ne
76
91
93
0
12:1
>30:1
anti only
Me
Br
H
0.25
0.25
0.25
1.0
1.0
0.5
TBS
Me
Me
t-Bu
Ph
Me
Me
4c
SiEt2i-Pr
TES
TES
TES
TES
4c 2i c-Hex
5d 2j c-Hex
6e 2k Ph
5c
H
66
95
96
80
8.5:1
>30:1
5.6:1
6.5:1
6c
Br
Br
Br
Br
7e
7f 2m CO2Et
8f 2n CO2i-Pr
8e
0.5
9e
TES
aIsolatedyield. bBasedon1H NMR ofcrude mixture. cTf2NHwasused
aIsolated yield. Based on H NMR. Concentration of 2f: 0.25 M.
b
1
c
d
instead of carbon acid 1. Reaction was carried out at -24 °C for 1 h.
d1,2-Adduct was obtained in 6% yield. eConcentration of 2f: 0.5 M.
eDesilylation: TfOH, CH2Cl2, -78 °C, 0.5 h. Stereochemistry is not
determined
f
depended on the steric bulkiness of the silyl group. Thus,
2-silyloxyfuran having a relatively less hindered silyl group
such as 2-TESO-furan gave better diastereoselectivity (anti/
syn = 3.6-5.0:1, entry1vs. entries4and5). Inthereactionwith
3-bromo-2-silyloxyfurans, a similar tendency for the improve-
ment of the diastereoselectivity by the relatively less hindered silyl
group was also observed and 3-bromo-2-TESO-furan was found
as a nice nucleophile for the anti-selective VMM reaction.20
That is, in the presence of 1.0 mol % of carbon acid 1, the
reaction with 3-bromo-2-TESO-furan gave the 1,4-adduct 3fe in
93% yield with excellent anti-selectivity (anti/syn = 20:1, entry 6).
The relative configuration of the major diastereomer was deter-
mined as the anti relationship by an X-ray crystallographic
analysis (see the Supporting Information). The loading of
carbon acid catalyst also influenced the diastereoselectivity
and, under higher substrate concentration conditions, a perfect
anti-selectivity was realized by using 0.25 mol % of 1 without
significant decreases in the product yield (entries 7 and 8). On the
other hand, the use of 3-bromo-2-TBSO-furan instead of
3-bromo-2-TESO-furan resulted in a slight decrease in the
anti-selectivity (entry 9).
To reveal the scope of the present anti-selective VMM
reaction, we also conducted the reaction of various R,β-
enones with 3-bromo-2-TESO-furan in the presence of
1.0 mol % or less than 1.0 mol % of carbon acid 1 (Table 4).
In the reactions of methyl ketones (R2 = Me) 2g-i, less than
1.0 mol % of carbon acid 1 was effective enough to complete
the reaction and 1,4-adducts 3ge-ie were obtained in good
yields with excellent anti-selectivities (entries 1-3). On the other
hand, the reaction of enone 2i with 3-bromo-2-TESO-furan did
not proceed in the presence of Tf2NH instead of 1 under the
same conditions (entry 4). These results clearly showed the high
activity of carbon acid 1.21 Since the silylation activity of “Et3Si-A”
is elevated by elongating the Si-A bond through steric repul-
sion between the relatively less hindered Et3Si group and
FIGURE 1. Possible transition state models of the VMM reaction.
ligand part “A”, highly hindered carbon acid 1 possibly
performed as a better Bronsted acid precatalyst for this system.
While the reactivity of tert-butyl ketone 2j was notably lower
than that of methyl ketone 2i, the desired 1,4-adduct 3je was
formed in 66% yield with reasonable diastereoselectivity by the
reaction at -24 °C for 2 h in the presence of 1.0 mol % of
1,3-propane diacid 1 (entry 5). The use of at least 1.0 mol % of 1
was required for the reaction of phenyl ketone 2k to give
1,4-adduct 3ke in 95% yield with excellent anti-selectivity
(anti/syn=>30:1, entry 6). Since Heathcock and co-workers
reported that, in the TiCl4-catalyzed Mukaiyama-Michael
reaction of R,β-enone with simple ketene silyl acetals, good
syn-selectivity was observed in the reaction of tert-butyl ke-
tone,22 the present anti-selectivity showed a sharp contrast in
the substituent effect of the R2 part. β-Alkoxycarbonylated
R,β-enones 2m and 2n, which are susceptible to polymerization
under acidic conditions, were also found to be nice substrates
for this VMM reaction. By using 0.5 mol % of carbon acid 1,
1,4-adducts 3me and 3ne were obtained in 96% and 80% yield,
(20) For the Lewis acid-catalyzed vinylogous Mukaiyama-aldol reaction
ꢀ
with 3-bromo-2-silyloxyfuran, see: Lopez, C. S.; Alvarez, R.; Vaz, B.; Faza,
ꢀ
O. N.; de Lera, A. R. J. Org. Chem. 2005, 70, 3654–3659.
ꢀ
(21) In the presence of 1 mol % of 2,6-di-tert-butylpyridine, the VMM
reaction of 2i was catalyzed by 1.0 mol % of carbon acid 1. This finding also
supports that in situ generated silyl methide acts as a catalytically active
species, see: Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117,
4570-4581 and refs 4a and 6d.
(22) (a) Heathcock, C. H.; Norman, M. H.; Uehling, D. E. J. Am. Chem.
Soc. 1985, 107, 2797–2799. (b) Heathcock, C. H.; Uehling, D. E. J. Org.
Chem. 1985, 51, 279–280.
1262 J. Org. Chem. Vol. 75, No. 4, 2010

Takahashi et al.
JOCArticle
respectively (entries 7 and 8). In each reaction, a high level of
acyclic stereocontrol was observed.
SCHEME 2. Synthetic Applications of R-Bromo-γ-butenolide 3if
As an extension using more complex substrates, we tried
the reactions as shown in eqs 1 and 2. The reaction of 2o,
which has a stereogenic carbon center at the carbonyl
γ-position, with 3-bromo-2-TESO-furan was nicely pro-
moted by only 0.25 mol % of carbon acid 1 to give anti,
syn-3oe and anti,anti-3oe in 65% and 26% yield, respectively,
without the formation of the other diastereomers (eq 1). This
result suggested that the VMM reaction of 2o proceeds with
perfect 4,5-anti selectivity and with moderate 5,10-syn selec-
tivity. Under the same conditions, the reaction of enone 2i
with 3-bromo-5-methyl-2-TESO-furan also gave the 1,4-
adduct 3if in 97% yield as a mixture of anti/syn isomers in
a ratio of 6.6:1 (eq 2). In consequence, the present carbon
acid-mediated VMM reaction is a highly effective methodo-
logy for the diastereoselective C-C bond formation between
quaternary carbon and tertiary carbon.
TABLE 5. Chemical Shifts of 2a in the Presence of Brønsted Acids in 13
NMRa
C
chemical shiftsb
entry
Brønsted acid
none
TfOH
Tf2CHCH2CHTF2 199.3 þ0.6 124.2 -0.1 155.5 þ0.5
Tf2CH2
CCdO ΔCCdO CR ΔCR Cβ
198.7 124.3 155.0
210.6 þ11.9 122.8 -1.5 186.8 þ31.8
ΔCβ
1
2
3
4
199.0 þ0.3 124.2 -0.1 155.5 þ0.5
a0.5 M solution of 2a and Brønsted acid in CDCl3 at room tempera-
ture. b100 MHz, ppm.
FIGURE 2. Space-filling projection of carbon acid 1 on the basis of
X-ray crystallographic analysis: (A) top view and (B) side view.
mixture of 1,4-adduct 6 and 1,2-adduct 7 (eq 3), we assume
that the complete 1,4-selectivity observed in the reaction using
2-silyloxyfurans should be attributed to the secondary orbital
interaction between silylated R,β-enone substrate and 2-silyl-
oxyfuran in the transition state. That is, as shown in Figure 1,
major anti-3xe was possibly formed via endo transition state A,
similar to the Diels-Alder reaction under kinetic conditions. In
addition, the electrostatic interaction between the electronically
negative 3-bromo group on silyloxyfuran and the electronically
positive oxocarbenium moiety of enone substrate should
stabilize this endo transition state.
Unfortunately, both theoretical and experimental studies
on diastereoselectivity in the VMM reaction are limited.23
However, since we found that, in the presence of carbon acid
1, the reaction of benzalacetone 2f with acyclic ketene silyl
acetal proceeded in a nonregioselective manner to give a
To show the synthetic applications of R-bromo-γ-buteno-
lide products, we carried out some transformations of
anti-3if (Scheme 2).24 For example, the Suzuki-Miyaura
(24) For synthetic applications of R-bromo-γ-butenolides, see: (a) Takei,
H.; Fukuda, Y.; Sugaya, K.; Taguchi, T.; Kawahara, T. Chem. Lett. 1980,
1307–1310. (b) Takei, H.; Fukuda, Y.; Taguchi, T.; Kawahara, T.; Mizutani,
(23) (a) Sartori, A.; Curti, C.; Battistini, L.; Burreddu, P.; Rassu, G.;
Pelosi, G.; Casiraghi, G.; Zanardi, F. Tetrahedron 2008, 64, 11697–11705.
(b) Yadav, J. S.; Reddy, B. V. S.; Narasimhulu, G.; Reddy, N. S.; Reddy, P. J.
Tetrahedron Lett. 2009, 50, 3760–3762.
€
H.; Mukuta, T. Chem. Lett. 1980, 1311–1314. (c) Olpp, T.; Bruckner, R.
Angew. Chem., Int. Ed. 2005, 44, 1553–1557. (d) Vaz, B.; Domınguez, M.;
Alvarez, R.; de Lera, A. R. Chem.;Eur. J. 2007, 13, 1273–1290.
J. Org. Chem. Vol. 75, No. 4, 2010 1263

Takahashi et al.
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FIGURE 3. Proposed catalyst cycle of the carbon acid-mediated VMM reaction.
cross-coupling reaction of anti-3if with phenylboronic acid
nicely proceeded under the standard conditions to give
R-phenyl-γ-butenolide anti-8 in 95% yield without epimeri-
zation.25 Furthermore, the hydrogenation of anti-3if in
the presence of palladium on carbon gave debrominated
γ-butanolide 9 in quantitative yield.
The Origin of High Efficiency of Tetrakis(trifluoromethane-
sulfonyl)propane. Regarding excellent efficiency of 1,1,3,3-
tetrakis(trifluoromethanesulfonyl)propane 1 for the VMM
reaction of R,β-enones with 2-silyloxyfurans, we measured its
acidity26 to reveal the origin of the activity.
R,β-enone substrates resulted in a rapid polymerization of
the temporarily formed γ-butenolides,29 the catalytically
active species in the VMM reaction system would be the silyl
methide species generated by the reaction of 1 with 2-silyl-
oxyfurans (external Bronsted acid catalyzed reaction).30
Next, we also conducted an X-ray crystallographic ana-
lysis of carbon acid 1. As shown in Figure 2, the space-filling
model of 1 demonstrated that, in the solid state, acidic
protons Ha and Hb locate in the inside of the molecular
structure, meanwhile, electronically negative atoms such as
fluorines and oxygens occupy the outside. Carbon acid 1
totally formed the bowl-like structure equipped with two
acidic protons in a cavity. Thus, the steric crowding around
acidic protons in carbon acid 1 would be larger than those of
commonly used Bronsted acids such as Tf2NH and TfOH,
and this would be similar even in the solution state.
On the basis of these facts, we propose a catalyst cycle of
the present VMM reaction as shown in Figure 3. That is, in
situ generated silyl methide species D or disilylated derivative
E activates R,β-enone substrate 2 through carbonyl silylation
to form oxocarbenium intermediate F.30 The sequential
C-C bond formation with 2-silyloxyfuran provides the
Michael adduct G along with the regeneration of silyl
methide D or E. Since catalytically active species D or E
derived from sterically hindered carbon acid 1 should be
highly destabilized by an appreciable I-strain between the
R3Si part and the methide ligand part, this carbonyl silyla-
tion step would proceed even under the significant low
concentration of silyl methide species. In addition, a self-
repairing pathway of catalytically active D or E would assist
to realize the low loading of carbon acid 1.
The gas-phase acidities established with use of the FT-ICR
technique27 were used as an extensive scale for strong
Bronsted acids. In this scale, the acidities are expressed as
ΔGacid value of proton dissociation equilibrium and ΔGacid
values (kcal/mol) of some strong Bronsted acids are as
follows: H2SO4 (302.2), TfOH (299.5), Tf2NH (286.5), and
Tf2CH2 (300.6).27a,28 Since the experimental ΔGacid value of
carbon acid 1 was 295.7 kcal/mol, the acidity of 1 is stronger
than those of H2SO4 and TfOH at the gas phase. However, a
1:1 mixture of carbon acid 1 and 4-methyl-3-penten-2-one 2a
in CDCl3 did not show significant shifts of each signal in 13
C
NMR compared to the case of TfOH (Table 5). For example,
while the upfield shifts of CCdO and Cβ were observed
(entry 2: ΔCCdO=þ11.9 ppm, ΔCβ=þ31.8 ppm) in the pre-
sence of a stoichiometric amount of TfOH, the upfield shifts
of these signals in the cases of carbon acid 1 and Tf2CH2 were
particularly small (entries 3 and 4). A similar tendency was
also observed in 1H NMR analysis (see the Supporting
Information).
These results suggest that the electrophilic activation of
R,β-enone substrates through hydrogen bonding or proton-
ation by 1 is not a major factor to promote the present VMM
reaction. In addition, since the stoichiometric reaction
of carbon acid 1 with 2-silyloxyfuran in the absence of
Conclusions
We found that 1,1,3,3-tetrakis(trifluoromethanesulfonyl)-
propane 1 is an excellent Bronsted acid precatalyst for the
VMM reaction of R,β-unsaturated ketones with 2-silyloxy-
furans. The present reaction would be an external Bronsted
acid catalyzed C-C bond forming reaction and in situ
generated silyl methide species “R3Si-CTf2R” probably per-
forms as a catalytically active species for this reaction. Under
the present conditions, significantly low loading of carbon
(25) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(26) Although it is possible that carbon acid 1 performs as a diprotic acid
having two Tf2CH groups, the first proton dissociation constant Ka1 would
play a central role in its acidity.
(27) (a) Koppel, I. A.; Taft, R. W.; Anvia, F.; Zhu, S.-Z.; Hu, L.-Q.; Sung,
K.-S.; DesMarteau, D. D.; Yagupolskii, L. M.; Yagupolskii, Y. L.; Ignat’ev,
N. V.; Kondratenko, N. V.; Volkonskii, A. Y.; Vlasov, V. M.; Notario, R.;
Maria, P.-C. J. Am. Chem. Soc. 1994, 116, 3047–3057. (b) Koppel, I. A.;
Burk, P.; Koppel, I.; Leito, I.; Sonoda, T.; Mishima, M. J. Am. Chem. Soc.
2000, 122, 5114–5124.
(29) For this reason, we could not observe silyl methide species by 1H and
13C NMR studies.
(30) For the generation of silyl methide “Me3Si-C(C6F5)Tf2” by the
reaction of C6F5CHTf2 with allyltrimethylsilane, see: Hasegawa, A.; Ishi-
hara, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2003, 42, 5731–5733.
(28) The ΔGacid values of Tf2NH and Tf2CH2 were recently revised, see:
Leito, I.; Raamat, E.; Kutt, A.; Saame, J.; Kipper, K.; Koppel, I. A.; Koppel,
I.; Zhang, M.; Mishima, M.; Yagupolskii, L. M.; Garlyauskayte, R. Y.;
Filatov, A. A. J. Phys. Chem. A 2009, 113, 8421–8424.
1264 J. Org. Chem. Vol. 75, No. 4, 2010

Takahashi et al.
JOCArticle
acid 1 was realized in a range from 0.05 to 1.0 mol %.
This result is one of the most important advantages com-
pared to the other acid-catalyzed or -mediated C-C bond
forming reactions with silicon enolates. In addition, the
present carbon acid-mediated conditions can be applied
to the C-C bond formation between sterically hindered
substrates.
found 183.1012. Anal. Calcd for C10H14O3: C, 65.91; H, 7.74.
Found: C, 65.74; H, 7.70.
(R*)-3-Bromo-5-[(S*)-3-oxo-1-phenylbutyl]furan-2(5H)-one
(anti-3fe) and (S*)-3-Bromo-5-[(S*)-3-oxo-1-phenylbutyl]furan-
2(5H)-one (syn-3fe). According to the synthetic procedure for
3aa, 1,4-adduct 3fe was obtained in 93% yield (anti-3fe, 136 mg,
0.45 mmol; syn-3fe, 0.02 mmol, 7 mg) (Table 3, entry 6) by the
reaction of 2f (73 mg, 0.50 mmol) with (3-bromofuran-2-yloxy)-
triethylsilane (166 mg, 0.60 mmol) in the presence of carbon acid
1 (2.8 mg, 5.2 μmol) in CH2Cl2 (1.0 mL) at -78 °C for 2 h. The
stereochemistry of 3fe was determined by an X-ray crystal-
lographic analysis of anti-3fe. For anti-3fe: colorless crystals;
mp 114.0-114.6 °C; IR (KBr) ν 3087, 3029, 1761, 1712, 1609,
Experimental Section
Preparation of 1,1,3,3-Tetrakis(trifluoromethanesulfonyl)-
propane (1). This compound was prepared by the reported
procedure.12b 1H NMR (400 MHz, CDCl3) δ 3.46 (2H, t, J =
7.0 Hz), 5.83 (2H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ
22.8, 72.5, 119.3 (q, JC-F = 329.6 Hz); 19F NMR (282 MHz,
CDCl3) δ -9.5 (12F, s). The structure was confirmed by X-ray
crystallographic analysis.
1
1497, 1454, 984, 767, 703 cm-1; H NMR (400 MHz, CDCl3)
δ 2.00 (3H, s), 2.84 (1H, dd, J = 17.5, 8.0 Hz), 2.96 (1H, dd, J =
17.5, 5.4 Hz), 3.41 (1H, td, J = 7.7, 5.4 Hz), 5.03 (1H, dd, J =
7.7, 1.6 Hz), 7.07-7.16 (6H, m); 13C NMR (100 MHz, CDCl3) δ
30.6, 44.3, 44.8, 85.0, 113.7, 128.0, 128.1, 129.1, 138.7, 151.8, 167.9,
205.5; MS (ESI-TOF) m/z 331 [M þ Na]þ, 333 [M þ 2 þ Na]þ;
HRMS calcd for C14H13BrNaO3 [M þ Na]þ 330.9946, found
330.9953. Anal. Calcd for C14H13BrO3: C, 54.39; H, 4.24. Found:
C, 54.24; H, 4.35. For syn-3fe: colorless oil; IR (neat) ν 1771, 1714,
1606, 1454, 1153, 981, 765, 701 cm-1;1H NMR (400 MHz, CDCl3)
δ 2.18 (3H, s), 2.92 (1H, dd, J = 18.2, 5.8 Hz), 3.20 (1H, dd, J =
18.2, 8.3 Hz), 3.74 (1H, ddd, J = 8.3, 5.8, 3.4 Hz), 5.28 (1H, dd,
J = 3.4, 1.8 Hz), 7.08-7.13 (2H, m), 7.22-7.32 (3H, m), 7.34 (1H,
d, J = 1.8 Hz); 13C NMR (100 MHz, CDCl3) δ 30.5, 42.7, 44.2,
83.6, 113.2, 128.0, 128.2, 128.9, 136.3, 151.5, 168.1, 206.2; MS
(ESI-TOF) m/z 331 [M þ Na]þ; HRMS calcd for C14H13BrNaO3
[M þ Na]þ 330.9946, found 330.9956.
5-(1,1-Dimethyl-3-oxobutyl)furan-2(5H)-one (3aa). To a solu-
tion of carbon acid 1 in CH2Cl2 (0.25 mM solution, 1.0 mL,
0.25 μmol) was added a solution of 2a (49 mg, 0.50 mmol) and
tert-butyl(furan-2-yloxy)dimethylsilane (109 mg, 0.55 mmol) in
CH2Cl2 (1 mL) at -78 °C over 10 min. After being stirred for 2 h
at -24 °C, the reaction mixture was quenched with saturated
NaHCO3 aqueous solution and extracted with EtOAc (3 ꢀ
20 mL). The organic layer was dried over anhydrous MgSO4,
then it was concentrated under reduced pressure. The resulting
residue was treated by 1 M HCl aqueous solution (10 mL) in
THF (10 mL) for 30 min at room temperature. The reaction
mixture was diluted with H2O (10 mL), extracted with EtOAc
(3 ꢀ 20 mL), dried over anhydrous MgSO4, and evaporated.
Purification of the resulting residue by column chromatography
on silica gel (hexane/EtOAc = 2:1) gave 3aa (80.1 mg, 0.44
mmol, 88% yield). Colorless oil; IR (neat) ν 1754, 1713 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.91 (3H, s), 1.17 (3H, s), 2.14 (3H, s),
2.40 (1H, d, J = 17.1 Hz), 2.69 (1H, d, J = 17.1 Hz), 5.26-5.28
(1H, m), 6.15 (1H, dd, J = 5.8, 2.1 Hz), 7.47 (1H, dd, J = 5.8,
1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 22.3, 22.9, 31.7, 36.7,
50.2, 88.1, 122.3, 154.3, 172.8, 207.3; MS (ESI-TOF) m/z 183
[M þ H]þ; HRMS calcd for C10H15O3 [M þ H]þ 183.1021,
Acknowledgment. The authors thank Mr. Haruhiko Fu-
kaya (Tokyo University of Pharmacy and Life Sciences) for
X-ray crystallographic analysis of the VMM products.
Supporting Information Available: Detailed experimental
1
procedure, compound characterization data, and H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 4, 2010 1265