Trifluoromethanesulfonic Acid, an Unusually Powerful Catalyst for the Michael Addition Reaction of β-Ketoesters under Solvent-Free Conditions

Full text of DOI:10.1021/jo982521z

3770
J . Org. Chem. 1999, 64, 3770-3773
knowledge. We accomplished this feat by incorporating
Tr iflu or om eth a n esu lfon ic Acid , a n
Un u su a lly P ow er fu l Ca ta lyst for th e
the novel feature of solvent-free conditions.6, 7
To find the optimum conditions, the Michael addition
reaction of â-keto ester 1a with 1.2 equiv of ethyl acrylate
(2a ) was carried out in the presence of a variety of Lewis
and Brønsted acids (Table 1). The highest catalytic
Mich a el Ad d ition Rea ction of â-Ketoester s
u n d er Solven t-F r ee Con d ition s
Hiyoshizo Kotsuki,*,† Koji Arimura, Takeshi Ohishi, and
Ryosuke Maruzasa
Ta ble 1. Effect of Va r iou s Lew is a n d Br øn sted Acid s for
th e Mich a el Ad d ition Rea ction of 1a w ith 2a
Department of Chemistry, Faculty of Science, Kochi
University, Akebono-cho, Kochi 780-8520, J apan
Received December 29, 1998
The Michael addition reaction is widely recognized as
one of the most important carbon-carbon bond forming
reactions in organic synthesis and can generally be
carried out with a strong base.1 However, the base-
catalyzed method sometimes suffers from disadvantages
of incompatibility with base-sensitive functionality and
the occurrence of other side reactions such as auto-
condensations and retro-Michael type decompositions. To
circumvent these problems, considerable attention has
recently been focused on the use of Lewis acid catalysts,
including transition metal complexes.2 We are generally
interested in the use of lanthanide(III) trifluoromethane-
sulfonates [Ln(OTf)3] as water-tolerant Lewis acid cata-
lysts and recently reported that the Michael addition
reactions of â-keto esters were efficiently catalyzed by
Yb(OTf)3 under high pressure or on silica gel supports.3
entry
catalyst
time (h)
yield (%)b
1c
2
3
Yb(OTf)3 (0.1 equiv)
TfOH
TfOH (0.1 equiv)
TfOH (0.2 equiv)
TfOH
24
5
81
92
25 (66)
63
72
72
72
72
72
72
72
72
4
5d
6
tracee
9 (76)
tracee
5 (90)
41 (44)
5 (70)
BF3‚OEt2
7
8
9
10
TiCl4
ZnCl2
H2SO4
60% HClO4
a
Unless otherwise noted, 1.2 equiv of 2a and 0.3 equiv of the
b
catalyst were used under solvent-free conditions. Isolated yields.
Yields in parentheses are recovery of 1a . c See ref 3. Solvent
d
(CH2Cl2) was used. e Unreacted 1a was mostly recovered.
activity was attained for the reaction using 0.3 equiv of
TfOH at room temperature: the reaction proceeded
smoothly within 5 h to give 3a in 92% yield (Table 1,
entry 2). This result clearly reflects the remarkable
activity of TfOH, since it is known that 2a is usually the
least reactive of several Michael acceptors under normal
Lewis acid-catalyzed conditions (except for our high-
pressure version).3,8 It should be pointed out that the use
of less TfOH retarded the reaction progress due to the
competitive polymerization of 2a (Table 1, entries 3 and
4) and no catalytic activity was observed in CH2Cl2
solution even after a prolonged reaction time (Table 1,
entry 5).
Several examples demonstrating the general feasibilty
of the present method are shown in Table 2. Ethyl
acrylate (2a ) reacted with various â-keto esters in nearly
quantitative yields (Table 2, entries 5, 8, 11, 13, and 14),
and even with nonactivated cyclohexanones such as
2-methylcyclohexanone (1i) and 2,6-dimethylcyclohex-
anone (1j), reasonable yields of the product were obtained
(Table 2, entries 15 and 16).9 Due to the more reactive
nature of ethyl acetoacetate (1d ), the reaction with 2a
resulted in a complex mixture (Table 2, entry 9). Instead,
ethyl 2-methylacetoacetate (1e) reacted quite smoothly
Although these methods are useful for properly reac-
tive substrates, there are still some limitations. For
example, reactions between â-keto esters and ethyl
acrylate are only successful at high pressure and the
reactions using cyclic enones as Michael acceptors under
Yb(OTf)3/SiO2-catalyzed conditions invariably take a long
time. In our continuing efforts to overcome these difficul-
ties, we accidentally found that direct exposure of Michael
donors and acceptors to a Yb(OTf)3 catalyst provided the
desired adducts, albeit in somewhat lower yields.3 This
result prompted us to investigate the possibility of
whether trifluoromethanesulfonic acid (TfOH) itself can
act as an active catalyst for performing this type of
Michael addition reaction. Whereas this very strong acid
has been used for carbon-carbon bond formation, taking
advantage of its mildness, nonoxidative character, and
ease of handling,4,5 a TfOH-catalyzed Michael addition
reaction has not yet been reported, to the best of our
† Tel: +81-888-44-8298. Fax: +81-888-44-8360. E-mail: kotsuki@
cc.kochi-u.ac.jp.
(1) Bergman, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10,
595. House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A.
Benjamin, Inc.: Menlo Park, 1972; pp 595-623. J ung, M. E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 1-67. Perlmutter, P. Conjugate
Addition Reactions in Organic Synthesis; Pergamon Press: Oxford,
1992.
(2) Reviews: Kobayashi, S. Synlett 1994, 689. Mukaiyama, T.;
Kobayashi, S. Org. React. 1994, 46, 1. Moreno-Man˜as, M.; Marquet,
J .; Vallribera, A. Tetrahedron 1996, 52, 3377. Shibasaki, M.; Sasai,
H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236. Christoffers,
J . Eur. J . Org. Chem. 1998, 1259.
(6) For some recent examples of solvent-free Michael addition
reactions, see: (a) Ballini, R.; Marziali, P.; Mozzicafreddo, A. J . Org.
Chem. 1996, 61, 3209. (b) Christoffers, J . J . Chem. Soc., Perkin Trans.
1 1997, 3141. (c) Soriente, A.; Spinella, A.; De Rosa, M.; Giordano, M.;
Scettri, A. Tetrahedron Lett. 1997, 38, 289. (d) Baruah, B.; Boruah,
A.; Prajapati, D.; Sandhu, J . S. Tetrahedron Lett. 1997, 38, 1449. (e)
Ranu, B. C.; Saha, M.; Bhar, S. Synth. Commun. 1997, 27, 621. (f)
Loh, T.-P.; Wei, L.-L. Tetrahedron 1998, 54, 7615.
(3) Kotsuki, H.; Arimura, K. Tetrahedron Lett. 1997, 38, 7583.
(4) Reviews: Howells, R. D.; McCown, J . D. Chem. Rev. 1977, 77,
69. Stang, P. J .; White, M. R. Aldrichimica Acta 1983, 16, 15.
(5) Marson, C. M.; Fallah, A. Chem. Commun. 1998, 83.
(7) For a general review, see: Metzger, J . O. Angew. Chem., Int.
Ed. Engl. 1998, 37, 2975.
(8) See also: Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37,
1879. Keller, E.; Feringa, B. L. Synlett 1997, 842.
10.1021/jo982521z CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/16/1999

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3771
Ta ble 2. TfOH-Ca ta lyzed Mich a el Ad d ition Rea ction of
to afford the desired adduct 3j in 93% yield (Table 2,
entry 11). Conformationally flexible R-acetyl-γ-butyro-
lactone (1f) was exceptionally unreactive with 2a and,
after 42 h, 51% of 3k was isolated along with a consider-
able quantity of byproducts (Table 2, entry 12).
â-Keto Ester s (E ) COOEt)a
In contrast, when methyl vinyl ketone (2b) was used
as the Michael acceptor, the reaction of 1a took place
violently under TfOH-catalyzed solvent-free conditions,
giving 50% of adduct 3b along with a small amount (13%)
of a Robinson annulated compound (Table 2, entry 1).10
The use of less amount of TfOH could improve the yield
of 3b (79%), but the reaction was very slow (Table 2,
entry 2). Under these harsh conditions, polymerization
of 2b proved to be unavoidable. This was also true for
2-cyclopentenone (2c). Therefore, for these meaningly
sensitive substrates, the use of CH2Cl2 or CH3CN as the
solvent11 and the gradual addition of an excess of the
reagents were essential for improving the product yields
(Table 2, entries 3, 4, 6, 7, and 10).
The role of TfOH in these Michael addition reactions
can be attributed to its strong proton-donating ability
(pKa value is <-11),12 which enhances both the nucleo-
philicity of â-keto esters via their enol forms and the
electrophilicity of the acceptor molecules.4 In the latter
case, the polymerization side reaction becomes a serious
drawback. However, this difficulty can be overcome by
conducting the reaction under carefully controlled condi-
tions in the presence of an appropriate organic solvent.
This newly discovered method apparently shows a re-
markable contrast with the Lewis acid-catalyzed method.
The catalytic activity of Lewis acids mainly relies on their
coordinating character to assemble both Michael donors
and acceptors on their coordination surface. On the other
hand, TfOH, in principle, can activate these substrates
through protonation, so that the reactivity of Michael
acceptors is essentially independent of their s-cis or
s-trans conformation. Despite the extreme activity of
TfOH, however, no reaction was observed with acryloni-
trile, ethyl methacrylate, ethyl crotonate, or ethyl cin-
namate.13
Finally, the above technique was applied to the dias-
tereoselective Michael addition reaction using 1k ,14 1l,
2d , and 2e15 as the chiral substrates with (-)-menthol
or (-)-8-phenylmenthol as the common chiral auxiliary16
(Table 3). In these examples, the Michael addition
reactions were considerably slower than the standard
reaction employing 1a and 2a . This is probably due to
the rather sterically crowded menthyl moiety. Although
essentially no asymmetric induction was observed for the
combination of 1a and 2d or 1k and 2a (Table 3, entries
(9) GC analyses revealed that only a trace amount of the regioisomer
was formed in the reaction of 1i and 2a . A similar phenomenon was
also observed for the reaction using NaOEt. The results indicate that
in this acid-catalyzed alkylation well-known Saytzeff-type orientation
of an enolic double bond was predominant. See: Ingold, C. K. Structure
and Mechanism in Organic Chemistry, 2nd ed.; Cornell University
Press: Ithaca, 1969; p 819.
(10) The use of 0.3 equiv of TfOH/Tf2O (1:1) as a cocatalyst under
similar conditions (rt, 6 h) gave a somewhat better yield (23%) of the
Robinson adduct but 3b in 24% yield.
(11) No significant differences in product yields were observed in
these solvents.
(12) Hendrickson, J . B.; Sternbach, D. D.; Bair, K. W. Acc. Chem.
Res. 1977, 10, 306.
a
Unless otherwise noted, 1.2 equiv of the Michael acceptor and
0.3 equiv of TfOH were used under solvent-free conditions.
b
Isolated yield based on the starting Michael donor. Yields in
parentheses are recovery of the Michael donor. c A Robinson
d
annulated compound (13%) was also obtained. See ref 10. 0.02
equiv of TfOH was used. e Solvent (CH2Cl2) was used, and in total
2.7-3.3 equiv of 2b was added. f Solvent (CH3CN) was used, and
in total 1.5 equiv of 2c was added. g A 1:1 diastereomeric mixture.
(13) The use of a larger amount (0.7-0.8 equiv) of TfOH was also
ineffective.
(14) Decicco, C. P.; Buckle, R. N. J . Org. Chem. 1992, 57, 1005.
(15) Corey, E. J .; Ensley, H. E. J . Am. Chem. Soc. 1975, 97, 6908.
(16) Review: Whitesell, J . K. Chem. Rev. 1992, 92, 953.
h
i
A complex mixture of products was obtained. Considerable
amounts of byproducts were formed. Only a trace amount of the
regioisomer was detected by GC. See ref. 9.
j

3772 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
see our previous paper.20 The structures of the Michael adducts
3a ,21 3b,6b 3d ,22 3e,6b 3g,23 3i,24 3j,25 3m ,26 and 3n 27 were
confirmed by comparison with published data.
Ta ble 3. Dia ster eoselective Mich a el Ad d ition Rea ction
Usin g Ch ir a l Men th yl Ester s
Typ ica l Exp er im en ta l P r oced u r e for th e Syn th esis of
3a . TfOH (0.6 mmol) was added dropwise to a mixture of ethyl
2-oxocyclohexanecarboxylate (1a ) (2.0 mmol) and ethyl acrylate
(2a ) (2.4 mmol) at 0 °C, and the resultant yellow mixture was
allowed to stand at room temperature for 5 h. When the reaction
was finished, the mixture turned brown. The cooled mixture was
diluted with CH2Cl2 and neutralized by the addition of the
minimum amount of Et3N. Concentration and purification by
silica gel column chromatography gave the desired Michael
adduct 3a 21 in 92% yield.
ratio of
The followings are new compounds.
entry
1
2
product time (h) yield (%)a diastereomers
Eth yl 2-oxo-1-(3-oxocyclopen tyl)cycloh exan ecar boxylate
(3c): a 1:1 mixture of the two diastereomers; colorless oil; IR
1
2
3
4
1a 2d
1a 2e
1k 2a
1l 2a
3p
3q
3r
11
38
7
86
49 (42)
87
52:48b
69:31c
50:50c
68:32c
1
(neat) 1742, 1711 cm-1; H NMR (CDCl3, 400 MHz) δ 1.28 and
1.29 (totally 3H, t, J ) 7.1 Hz), 1.48-1.70 (3H, m), 1.77-1.87
(2H, m), 1.93-2.11 (2H, m), 2.12-2.25 (2H, m), 2.27-2.38 (2H,
m), 2.40-2.60 (3H, m), 2.62-2.77 (1H, m), 4.17-4.31 (2H, m);
13C NMR (CDCl3, 100 MHz) δ 14.1, 22.6, 24.1 and 25.0 (pair),
27.2(7) and 27.3(3) (pair), 34.2 and 34.3 (pair), 38.3 and 38.6
(pair), 40.2 and 40.8 (pair), 40.9(0) and 40.9(2) (pair), 41.4, 61.4-
(8) and 61.4(9) (pair), 62.3 and 62.6 (pair), 170.8 and 170.9 (pair),
207.0(7) and 207.1(0) (pair), 217.7 and 217.9 (pair); HRMS calcd
for C14H20O4 + H 253.1439, found 253.1429.
3s
8
78 (18)
a
Isolated yields. Yields in parentheses are recovery of 1.
b
Determined by chiral HPLC analysis (Chiralcel OD) after
conversion to 3a . c Determined by 1H and 13C NMR analyses.
1 and 3), the moderate diastereoselectivity could be
attained for the reaction between 1a and 2e or 1l and
2a (Table 3, entries 2 and 4). This is in striking contrast
to cases utilizing alumina-supported reactions17 or chiral
imine technology.18 The results imply that no significant
electrostatic interaction between those reagents was
present in our system.
Eth yl 2-oxo-1-(3-oxocyclopen tyl)cyclopen tan ecar boxylate
(3f): a 1:1 mixture of the two diastereomers; colorless oil; IR
1
(neat) 1744, 1726 cm-1; H NMR (CDCl3, 400 MHz) δ 1.26 and
1.27 (totally 3H, t, J ) 7.1 Hz), 1.54-1.83 (1H, m), 1.91-2.06
(4H, m), 2.10-2.40 (5H, m), 2.42-2.56 (2H, m), 2.83-2.94 (1H,
m), 4.18, 4.20 (totally 2H, q, J ) 7.1 Hz); 13C NMR (CDCl3, 100
MHz) δ 14.1, 19.6 (1) and 19.6 (5) (pair), 24.3 and 25.2 (pair),
30.4 and 30.8 (pair), 38.3 and 38.4 (pair), 38.5 and 38.7 (pair),
40.1, 40.2 and 40.9 (pair), 61.7, 61.8 and 62.1 (pair), 170.5, 214.0
and 214.1 (pair), 217.3 and 217.4 (pair); HRMS calcd for
C13H18O4 + H 239.1283, found 239.1302.
Eth yl 3-(1-a cetyl-2-oxo-3-oxola n yl)p r op a n oa te (3k ): col-
orless oil; IR (neat) 1767, 1732, 1715 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.26 (3H, t, J ) 7.1 Hz), 2.05 (1H, dt, J ) 12.9, 9.0 Hz),
2.16-2.28 (3H, m), 2.35 (3H, s), 2.40-2.47 (1H, m), 2.88 (1H,
ddd, J ) 12.9, 7.1, 3.4 Hz), 4.14 (2H, q, J ) 7.1 Hz), 4.17 (1H,
dt, J ) 9.0, 7.1 Hz), 4.33 (1H, dt, J ) 9.0, 3.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 14.1, 25.6, 29.2, 29.3, 29.7, 60.5, 60.9, 66.1,
171.8, 175.0, 202.0; HRMS calcd for C11H16O5 + H 229.1076,
found 229.1062.
In conclusion, we succeeded in developing a novel
method to effect the Michael addition reaction of â-keto
esters (1) with ethyl acrylate (2a ) in the presence of TfOH
as a strong Brønsted acid catalyst under solvent-free
conditions. For relatively reactive Michael acceptors such
as methyl vinyl ketone (2b) and 2-cyclopentenone (2c),
the reactions occurred best in CH2Cl2 or CH3CN. It
should be noted that the method does not require any
metal salts and hence it might be of great value as an
environmentally friendly process.19 We believe that the
method offers considerable advantages for producing
several types of Michael adducts in view of its high
efficiency, operational simplicity, and convenient workup
procedure, although there are some limitations for the
usable substrates having no acid sensitive functionality.
Work is in progress to expand the synthetic utility of this
method.
Eth yl 3-(2-(eth oxyca r bon yl)-1-oxoin da n -2-yl)pr op a n oa te
(3l): colorless oil; IR (neat) 1738, 1713, 1609 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.21, 1.23 (each 3H, t, J ) 7.3 Hz), 2.21-
2.47 (4H, m), 3.07, 3.70 (each 1H, d, J ) 17.3 Hz), 4.10, 4.17
(each 2H, q, J ) 7.1 Hz), 7.41 (1H, dt, J ) 7.8, 0.7 Hz), 7.49
(1H, dt, J ) 7.8, 1.0 Hz), 7.64 (1H, dt, J ) 7.8, 1.0 Hz), 7.77
(1H, dt, J ) 7.8, 0.7 Hz); 13C NMR (CDCl3, 100 MHz) δ 13.8,
13.9, 29.5, 29.6, 37.0, 59.3, 60.3, 61.4, 124.5, 126.2, 127.7, 134.8,
135.3, 152.5, 170.4, 172.4, 201.7; HRMS calcd for C17H20O5
304.1311, found 304.1327.
Eth yl 3-(1,3-d im eth yl-2-oxocycloh exyl)p r op a n oa te (3o):
a 1:1 mixture of the two diastereomers; colorless oil; IR (neat)
1736, 1703 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.98(6) (1.5H, d,
J ) 6.6 Hz), 0.99(2) (1.5H, d, J ) 6.3 Hz), 1.00 and 1.18 (totally
3H, s), 1.24(9) and 1.25(0) (totally 3H, t, J ) 7.1 Hz), 1.22-1.38
(1H, m), 1.49-2.00 (6H, m), 2.00-2.10 (1H, m), 2.24-2.42 (2H,
(20) Kotsuki, H.; Nishikawa, H.; Mori, Y.; Ochi, M. J . Org. Chem.
1992, 57, 5036.
(21) Green, S. P.; Whiting. D. A. J . Chem. Soc., Perkin Trans. 1 1996,
1027.
Exp er im en ta l Section
(22) Ravid, U.; Ikan, R.; Sachs, R. M. J . Agric. Food Chem. 1975,
23, 835.
(23) J acob, T. M.; Vatakencherry, P. A.; Dev, S. Tetrahedron 1964,
20, 2815.
Gen er a l Rem a r k s. Commercially available reagents were
used without purification. For general experimental information,
(17) Ranu, B. C.; Sarkar, A.; Saha, M.; Bhar, S. Pure Appl. Chem.
1996, 68, 775.
(18) Review: d′Angelo, J .; Desmae¨le, D.; Dumas, F.; Guingant, A.
Tetrahedron: Asymmetry 1992, 3, 459. Guingant, A. In Advances in
Asymmetric Synthesis; Hassner, A., Ed.; J AI Press: Greenwich, 1997;
Vol. 2, p 119.
(24) Momose, T.; Muraoka, O. Chem. Pharm. Bull. 1978, 26, 288.
(25) Willer, R. L.; Eliel, E. L. J . Am. Chem. Soc. 1977, 99, 1925.
(26) Tatsuoka, T.; Sumoto, K.; Suzuki, K.; Satoh, F.; Miyano, S. Eur.
Pat. Appl. EP 322248; Chem. Abstr. 1990, 112, 35683h.
(27) Pfau, M.; Revial, G.; Guingant, A.; d′Angelo, J . J . Am. Chem.
Soc. 1985, 107, 273. Milligan, G. L.; Mossman, C. J .; Aube´, J . J . Am.
Chem. Soc. 1995, 117, 10449.
(19) Dittmer, D. C. Chem. Ind. 1997, 779.

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3773
m), 2.62 (0.5H, sextet, J ) 6.3 Hz), 2.65 (0.5H, sextet, J ) 6.6
Hz), 4.11 and 4.12 (totally 2H, q, J ) 7.1 Hz); 13C NMR (CDCl3,
100 MHz) δ 14.1 and 14.2 (pair), 14.8(8) and 14.9(0) (pair), 21.0
and 21.2 (pair), 22.1 and 23.0 (pair), 29.1 and 29.5 (pair), 32.4
and 33.3 (pair), 36.4 and 36.6 (pair), 38.9 and 40.8 (pair), 41.0
and 41.2 (pair), 47.5 and 48.1 (pair), 60.2 and 60.5 (pair), 173.3
and 174.1 (pair), 216.2 and 216.3 (pair); HRMS calcd for
C13H22O3 + H 227.1647, found 227.1651.
E t h yl 3-(1-m en t h yloxyca r b on yl-2-oxocycloh exyl)p r o-
p a n oa te (3r ): a 1:1 mixture of the two diastereomers; colorless
oil; IR (neat) 1736, 1713 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.74
and 0.75 (totally 3H, d, J ) 7.1 Hz), 0.88 (3H, d, J ) 6.8 Hz),
0.92 (3H, d, J ) 6.6 Hz), 0.90-1.10 (2H, m), 1.24 and 1.25 (totally
3H, t, J ) 7.1 Hz), 1.36-1.56 (3H, m), 1.60-1.74 (4H, m), 1.74-
2.06 (6H, m), 2.12-2.28 (2H, m), 2.30-2.54 (4H, m), 4.11(9) and
4.12(1) (totally 2H, q, J ) 7.1 Hz), 4.72(0) and 4.72(3) (totally
1H, dt, J ) 10.7, 4.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.2,
15.5(7) and 15.6(3) (pair), 20.7(8) and 20.8(3) (pair), 21.9, 22.5,
22.7(8) and 22.8(3) (pair), 25.8 and 26.0 (pair), 27.5, 29.5(5) and
29.5 (9) (pair), 29.7 and 29.8 (pair), 31.4, 34.1, 36.0 and 36.1
(pair), 40.4 and 40.5 (pair), 41.0 and 41.1 (pair), 46.6 and 46. 7
(pair), 60.2 and 60.3 (pair), 60.4, 75.6(8) and 75.7(3) (pair), 171.2
and 171.3 (pair), 173.0 and 173.1 (pair), 207.4(8) and 207.5(2)
(pair); HRMS calcd for C22H36O5 380.2563, found 380.2546.
(1R,2S,5R)-(+)-8-P h en ylm en th yl 2-Oxocycloh exa n eca r -
boxyla te (1l). This compound was prepared from 1a and (-)-
8-phenylmenthol in a similar manner to that described in the
literature for the preparation of 1k :14 mp 73.5-74.5 °C; [R]25
D
+3.0 (c 1.0, CHCl3). Anal. Calcd for C23H32O3: C, 77.49; H, 9.05.
Found: C, 77.84; H, 9.17.
Men t h yl
p a n oa te (3p ): a mixture of the two diastereomers; colorless oil;
IR (neat) 1732, 1717 cm-1 1H NMR (CDCl3, 400 MHz) δ 0.74
3-(1-et h oxyca r b on yl-2-oxocycloh exyl)p r o-
1
The diastereoselectivity was determined by H and 13C NMR
;
analyses.
and 0.75 (totally 3H, d, J ) 6.8 Hz), 0.80-1.40 (3H, m), 0.88
(3H, d, J ) 6.6 Hz), 0.90 (3H, d, J ) 5.9 Hz), 1.27 (3H, t, J ) 7.1
Hz), 1.31-1.40 (1H, m), 1.42-1.52 (2H, m), 1.60-1.71 (4H, m),
1.74-2.04 (5H, m), 2.12-2.26 (2H, m), 2.32-2.54 (4H, m), 4.18-
4.23 (2H, m), 4.66 (1H, dt, J ) 11.0, 4.4 Hz); 13C NMR (CDCl3,
100 MHz) δ 14.1, 16.3, 20.7, 22.0, 22.5, 23.5, 26.2(3) and 26.2(5)
(pair), 27.5, 29.6, 29.8, 31.3, 34.2, 36.1(5) and 36.1(9) (pair), 40.9,
41.0, 47.0, 60.0, 61.4, 74.2, 171.7, 172.6, 207.5; HRMS calcd for
E t h yl 3-(1-(8-p h en ylm en t h yloxyca r b on yl)-2-oxocyclo-
h exyl)p r op a n oa te (3s): a 68:32 mixture of the two diastere-
omers; colorless oil; [R]27 +33.6 (c 1.1, CHCl3); IR (neat) 1736,
D
1711, 1601 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.85-2.55 (23H,
m), 0.86 and 0.88 (totally 3H, d, J ) 6.8 Hz), 1.24 and 1.26
(totally 3H, s), 1.30 and 1.31 (totally 3H, s), 4.12 (2H, q, J ) 7.1
Hz), 4.88 (1H, dt, J ) 10.7, 4.1 Hz), 7.16 (minor) and 7.26 (major)
(totally 5H, m); 13C NMR (CDCl3, 100 MHz) δ 14.2(0) and 14.2-
(3) (pair), 21.7 and 21.8 (pair), 22.1 and 22.5 (pair), 24.0 and
25.4 (pair), 27.1 and 27.2 (pair), 27.3 and 27.4 (pair), 28.4 and
28.7 (pair), 29.5 and 29.7 (pair), 30.0, 31.4, 34.3(7) and 34.4(3)
(pair), 34.7 and 35.4 (pair), 40.0 and 40.2 (pair), 40.8 and 41.1
(pair), 41.4 and 41.5 (pair), 49.8 and 50.0 (pair), 60.0 and 60.3-
(9) (pair), 60.4(2) and 60.5 (pair), 77.1 and 77.2 (pair), 125.3 and
125.4 (pair), 125.5 and 125.6 (pair, ×2), 128.0 and 128.1 (pair,
×2), 150.3 and 150.9 (pair), 171.2(1) and 171.2(4) (pair), 173.1,
207.3 and 207.4 (pair); HRMS calcd for C28H40O5 + H 457.2954,
found 457.2965.
C
22H36O5 380.2563, found 380.2567.
The diastereoselectivity was determined after conversion to
the corresponding ethyl ester 3a (p-TsOH, EtOH, reflux, 24 h),
which was further analyzed by chiral HPLC (Chiralcel OD,
elution with hexane/2-propanol ) 99:1).28
8-P h en ylm en th yl 3-(1-eth oxyca r bon yl-2-oxocycloh exyl)-
p r op a n oa te (3q): a 69:31 mixture of the two diastereomers;
colorless oil; [R]25 +27.8 (c 1.1, CHCl3); IR (neat) 1734, 1711,
D
1601 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 0.86 (3H, d, J ) 6.6
Hz), 1.20, 1.30 (each 3H, s), 0.85-2.05 (20H, m), 2.35-2.50 (3H,
m), 4.10-4.25 (2H, m), 4.80 (1H, m), 7.14 (minor) and 7.26
(major) (totally 5H, m); 13C NMR (CDCl3, 100 MHz) δ 14.1, 21.8,
22.5, 25.0, 26.6, 27.4, 27.9, 29.1 and 29.2 (pair), 29.3(6) and 29.4-
(2) (pair), 31.2, 34.5, 35.8 and 36.0 (pair), 39.6, 41.0, 41.7, 50.2-
(9) and 50.3(1) (pair), 59.8 and 59.9 (pair), 61.2(8) and 61.3(1)
(pair), 74.1 and 74.2 (pair), 125.0, 125.4 (×2), 127.9 (×2), 151.5,
171.5(5) and 171.6(0) (pair), 172.2(2) and 172.2(4) (pair), 207.3
and 207.4 (pair); HRMS calcd for C28H40O5 + H, 457.2954, found
457.2959.
1
The diastereoselectivity was determined by H and 13C NMR
analyses.
Ack n ow led gm en t. This work was partially sup-
ported by Scientific Research Grants from the Ministry
of Education, Science, Sports and Culture of J apan. We
are grateful to Prof. Y. Fukuyama of Tokushima Bunri
University for MS/HRMS measurements. We also thank
Central Glass Co., Ltd., for generously supplying TfOH.
1
The diastereoselectivity was determined by H and 13C NMR
analyses.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett.
1996, 37, 5561. See also: Hervouet, K.; Guingant, A. Tetrahedron:
Asymmetry 1996, 7, 421.
J O982521Z