Highly stereoselective asymmetric pummerer reactions that incorporate intermolecular and intramolecular nonbonded S...O interactions

Article abstract of DOI:10.1021/ja056649r

New chiral sulfoxides (R_S,S)-3, (S_S,S)-3, (R _S,S)-4, and (S_S,S)-4 and known chiral sulfoxides (R _S)-5, (R_S)-6, and (R_S)-7 were synthesized, and the stereochemistry of the new sulfoxides (R_S,S)-3 and (R _S,S)-4 was determined by X-ray crystallographic analysis. In their crystallographic structures, the intramolecular nonbonded S...O close contacts were recognized. Analyses of several sulfoxide complexes including rac-11 with N,N-dimethylacetamide (DMAC) or N-methyl-2-pyrrolidone (NMP) in a MeOH solution utilizing cold-spray ionization mass spectrometry provided, for the first time, direct information for intermolecular nonbonded S...O interactions between sulfoxides and amide (or lactam) in a solution. Highly diastereoselective and enantioselective Pummerer reactions based on the concept of intermolecular and intramolecular nonbonded S...O interactions were performed by treatment of several chiral sulfoxides (R_S, S)-3, (S_S, S)-3, (R_S, S)-4, (S_S, S)-4, (R _S)-5, (R_S)-6, and (R_S)-7 with acetic anhydride and trimethylsilyl triflate (TMSOTf) in DMAC, NMP, N,N-dimethylformamide, and N-formylpiperidine. Mechanistic studies on these facile stereoselective Pummerer reactions revealed the necessity for the amide/TMSOTf complex, such as 26 or 27, to be an efficient activation reagent for Ac₂O and a trapping reagent for the released acetate ion, and that DMAC and NMP had a positive effect on this highly stereoselective chiral transfer reaction.

Full text of DOI:10.1021/ja056649r

Published on Web 07/11/2006
Highly Stereoselective Asymmetric Pummerer Reactions That
Incorporate Intermolecular and Intramolecular Nonbonded
S‚‚‚O Interactions
Yoshimitsu Nagao,*,† Satoshi Miyamoto,† Motoyuki Miyamoto,† Hiroe Takeshige,†
Kazuhiko Hayashi,† Shigeki Sano,† Motoo Shiro,‡ Kentaro Yamaguchi,§ and
Yoshihisa Sei§
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of
Tokushima, Sho-machi, Tokushima 770-8505, Japan, Rigaku Corporation,
3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan, and Faculty of Pharmaceutical
Sciences at Kagawa Campus, Tokushima Bunri UniVersity,
1314-1 Shido, Sanuki-city, Kagawa 769-2193, Japan
Received September 28, 2005; E-mail: ynagao@ph.tokushima-u.ac.jp
Abstract: New chiral sulfoxides (RS,S)-3, (SS,S)-3, (RS,S)-4, and (SS,S)-4 and known chiral sulfoxides (RS)-
5, (RS)-6, and (RS)-7 were synthesized, and the stereochemistry of the new sulfoxides (RS,S)-3 and (RS,S)-4
was determined by X-ray crystallographic analysis. In their crystallographic structures, the intramolecular
nonbonded S‚‚‚O close contacts were recognized. Analyses of several sulfoxide complexes including rac-
11 with N,N-dimethylacetamide (DMAC) or N-methyl-2-pyrrolidone (NMP) in a MeOH solution utilizing cold-
spray ionization mass spectrometry provided, for the first time, direct information for intermolecular
nonbonded S‚‚‚O interactions between sulfoxides and amide (or lactam) in a solution. Highly diastereo-
selective and enantioselective Pummerer reactions based on the concept of intermolecular and intramo-
lecular nonbonded S‚‚‚O interactions were performed by treatment of several chiral sulfoxides (RS, S)-3,
(SS, S)-3, (RS, S)-4, (SS, S)-4, (RS)-5, (RS)-6, and (RS)-7 with acetic anhydride and trimethylsilyl triflate
(TMSOTf) in DMAC, NMP, N,N-dimethylformamide, and N-formylpiperidine. Mechanistic studies on these
facile stereoselective Pummerer reactions revealed the necessity for the amide/TMSOTf complex, such
as 26 or 27, to be an efficient activation reagent for Ac2O and a trapping reagent for the released acetate
ion, and that DMAC and NMP had a positive effect on this highly stereoselective chiral transfer reaction.
Introduction
be unsatisfactory from the viewpoint of optical yield due to the
formation of an achiral sulfurane intermediate, 1, or a sulfonium
Asymmetric Pummerer reactions,1 which provide various
chiral R-substituted sulfides from the corresponding chiral
sulfoxides, have attracted considerable attraction in regard to
their value in the synthesis of natural products and biologically
active compounds2 and in regard to their reaction mechanisms.3
In general, asymmetric Pummerer reactions of chiral sulfoxides
with acetic anhydride (Ac2O) under heating have turned out to
ion, 2, involving the resultant acetate ion.4 To resolve this issue,
some fascinating and elaborate methods have been explored,
such as using Ac2O and 1,3-dicyclohexylcarbodiimide for
trapping the acetate ion5 or using ethoxy vinyl acetate without
the release of an acetate ion.6 O-Methyl-O-tert-butyldimethyl-
silyl ketene acetal was also developed for highly stereoselective
silicon-induced Pummerer-type reactions by Kita et al.7 Fur-
thermore, enantioselective Pummerer-type reactions of the chiral
† The University of Tokushima.
‡ Rigaku Corporation.
§ Tokushima Bunri University.
(3) (a) Oae, S.; Numata, T. In Isotopes in Organic Chemistry, Buncel, E., Lee,
C. C., Ed., Elsevier: New York, 1980; pp 45-102. (b) Oae, S.; Numata,
T.; Yoshimura, T. In The Chemistry of the Sulphonium Group, Part 2;
Stirling, C. J. M., Patai, S., Ed.; John Wiley and Sons: New York, 1981;
pp 571-672. (c) Numata, T.; Itoh, O.; Yoshimura, T.; Oae, S. Bull. Chem.
Soc. Jpn. 1983, 56, 257. (d) Kita, Y.; Shibata, N. Synlett 1996, 289.
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Chem. Soc. Jpn. 1970, 43, 1416. (c) Wolfe, S.; Kazmaier, P. M. Can. J.
Chem. 1979, 57, 2397. (d) Shimada, K.; Kikuta, Y.; Koganebuchi, H.;
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(5) Numata, T.; Itoh, O.; Oae, S. Tetrahedron Lett. 1979, 1869.
(6) (a) Kita, Y.; Shibata, N.; Kawano, N.; Fukui, S.; Fujimori, C. Tetrahedron
Lett. 1994, 35, 3575. (b) Shibata, N.; Matsugi, M.; Kawano, N.; Fukui, S.;
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1997, 8, 303.
(1) (a) Stridsberg, B.; Allenmark, S. Acta Chem. Scand. 1974, B28, 591. (b)
Stridsberg, B.; Allenmark, S. Acta Chem. Scand. 1976, B30, 219. (c)
Numata, T.; Itoh, O.; Oae, S. Chem. Lett. 1977, 909. (d) Masuda, T.;
Numata, T.; Furukawa, N.; Oae, S. Chem. Lett. 1977, 903. (e) Numata, T.;
Oae, S. Tetrahedron Lett. 1977, 1337. (f) Mikolajczyk, M.; Zatorski, A.;
Grzejszczak, S.; Costisella, B.; Midura, W. J. Org. Chem. 1978, 43, 2518.
(g) Wolfe, S.; Kazmaier, P. M.; Auksi, H. Can. J. Chem. 1979, 57, 7, 2404.
(h) Kosugi, H.; Tagami, K.; Takahashi, A.; Kanna, H.; Uda, H. J. Chem.
Soc., Perkin Trans. 1 1989, 935. (i) Ferreira, J. T. B.; Marques, J. A.;
Marino, J. P. Tetrahedron: Asymmetry 1994, 5, 641. (j) Abe, H.; Itani, J.;
Masunari, C.; Kashino, S.; Harayama, T. J. Chem. Soc., Chem. Commun.
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(b) Kita, Y.; Shibata, N.; Yoshida, N.; Fujita, S. J. Chem. Soc., Perkin
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9
9722
J. AM. CHEM. SOC. 2006, 128, 9722-9729
10.1021/ja056649r CCC: $33.50 © 2006 American Chemical Society

Highly Stereoselective Asymmetric Pummerer Reactions
A R T I C L E S
Figure 1. Intramolecular nonbonded S‚‚‚O interactions in the crystal
structures 8-10.
sulfoxides and an amide oxygen atom, especially after acety-
lation of the sulfinyl moiety. However, to our knowledge, there
has been no attempt to detect an intermolecular nonbonded
S‚‚‚O interaction between a sulfoxide compound and an amide
compound in a solution, possibly because there has been no
method for detecting such a weak charge-charge attraction.
We have attempted detection of weak complexes (nonbonded
interactions) of several sulfoxides with N,N-dimethylacetamide
(DMAC) or N-methyl-2-pyrrolidone (NMP) in a MeOH solution
by utilizing cold-spray ionization mass spectrometry (CSI-MS),
a variant of electrospray ionization (ESI) MS operating at low
temperature. This particular CSI-MS method allows facile and
precise characterization of labile organic species bearing non-
covalent bonding interactions such as hydrogen bonding,9g
chelation involving a metal ion, and electrostatic interactions.11
CSI-MS spectra of mixtures (1:1) of selected chiral sulfoxides
(RS,S)-3, (RS)-5, and (RS)-7 with an equimolecular amount of
either DMAC or NMP in MeOH at -10 °C were determined
as follows. The corresponding molecular ion peaks, m/z 389
due to [(RS,S)-3‚‚‚DMAC complex + H]+ (for C21H28N2O3S
+ H) and m/z 411 due to [(RS,S)-3‚‚‚DMAC complex + Na]+
(for C21H28N2O3S + Na), m/z 401 due to [(RS,S)-3‚‚‚NMP
complex + H]+ (for C22H28N2O3S + H) and m/z 423 due to
[(RS,S)-3‚‚‚NMP complex + Na]+ (for C22H28N2O3S + Na),
m/z 314 due to [(RS)-5‚‚‚DMAC complex + H]+ (for C15H23-
NO4S + H), m/z 326 due to [(RS)-5‚‚‚NMP complex + H]+
(for C16H23NO4S + H) and m/z 348 due to [(RS)-5‚‚‚NMP
complex + Na]+ (for C16H23NO4S + Na), m/z 375 due to [(RS)-
7‚‚‚DMAC complex + H]+ (for C20H26N2O3S + H) and m/z
397 due to [(RS)-7‚‚‚DMAC complex + Na]+ (for C20H26N2O3S
+ Na), and m/z 387 due to [(RS)-7‚‚‚NMP complex + H]+ (for
C21H26N2O3S + H) and m/z 409 due to [(RS)-7‚‚‚NMP complex
+ Na]+ (for C21H26N2O3S + Na) on each respective CSI-MS
spectrum were clearly observed (Supporting Information). To
confirm the exclusive participation of the sulfinyl moiety in this
particular intermolecular nonbonded S‚‚‚O interaction, we
examined the CSI-MS determination of a known racemic ethyl
methyl sulfoxide, rac-11,12 as a molecule without aromatic,
amide, and ester groups, in the presence of DMAC or NMP
under the same conditions as those used for the determination
of several chiral sulfoxides. Thus, the corresponding molecular
ion peak m/z 202 due to (rac-11‚‚‚DMAC complex + Na)+
aryl(substituted-methyl) sulfoxides bearing electron-withdrawing
groups such as CO2Et and CONMe2, when developed using
these well-established methods, have never exceeded 90% ee.
We have developed highly diastereoselective and enantioselec-
tive Pummerer reactions of the chiral sulfoxides (RS,S)-3, (SS,S)-
3, (RS,S)-4, (SS,S)-4, (RS)-5, (RS)-6, and (RS)-7 based on the
concept of intermolecular and intramolecular nonbonded S‚‚‚
O interactions; this novel simple procedure and the related
nonbonded S‚‚‚O interactions are herein described.
Results and Discussion
Various intramolecular nonbonded 1,4 and 1,5 types of S‚‚
‚O interactions (the S‚‚‚O distances being shorter than the sum
(S + O ) 3.32 Å) of the van der Waals radii) in the sulfoxides
(e.g., compounds 8-10,8 Figure 1), and numerous other
organosulfur compounds9 have been observed in their crystal
structures. Specifically, in molecular structure 88b bearing the
1,5-type S‚‚‚O interaction, the amide carbonyl oxygen atom is
seen to be close to the S atom on the opposite site of the oxide
ion. In the amide moiety of crystalline structure 9, an intramo-
lecular nonbonded 1,4-type S‚‚‚O interaction (2.723 Å) that is
stronger than that (2.884 Å) in the ester moiety can be
recognized, as represented in Figure 1.8d,e Such an intramolecular
nonbonded S‚‚‚O interaction in the crystalline state of the
sulfoxides bearing the CO2R or CONR2 group may be possible
even in a solution, based on the information of similar
organosulfur and organoselenium compounds.9g,10
Thus, we anticipated the possibility of an intermolecular
nonbonded S‚‚‚O interaction between a sulfonium ion of
(8) (a) Kucksman, A.; Kapovits, I. Organic Sulfur Chemistry: Theoretical and
Experimental AdVances; Bernardi, F., Csizmadia, I. G., Mangini, A., Eds.;
Elsevier: Amsterdam, 1985; pp 191-245 and references therein. (b)
Iwasaki, F.; Toyoda, N.; Yamazaki, N. Acta Crystallogr. 1989, C45, 1914.
(c) Zhang, J.; Saito, S.; Koizumi, T. J. Am. Chem. Soc. 1998, 120, 1631.
(d) Nagao, Y.; Miyamoto, S.; Hayashi, K.; Mihira, A.; S. Sano, Tetrahedron
Lett. 2002, 43, 1519. (e) Nagao, Y.; Miyamoto, S.; Hayashi, K.; Mihira,
A.; Sano, S. Chem. Pharm. Bull. 2002, 50, 558.
(9) (a) Kapecki, J. A.; Baldwin, J. E.; Paul, I. C. J. Am. Chem. Soc. 1968, 90,
5800. (b) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi, A.; Iizuka, K.;
Shiro, M. J. Am. Chem. Soc. 1998, 120, 3104 and references therein. (c)
Kumagai, T.; Tamai, S.; Abe, T.; Matsunaga, H.; Hayashi, K.; Kishi, I.;
Shiro, M.; Nagao, Y. J. Org. Chem. 1998, 63, 8145. (d) Nagao, Y.;
Nishijima, H.; Iimori, H.; Ushirogochi, H.; Sano, S.; Shiro, M. J.
Organomet. Chem. 2000, 611, 172. (e) Nagao, Y.; Iimori, H.; Nam, K. H.;
Sano, S.; Shiro, M. Chem. Pharm. Bull. 2001, 49, 1660. (f) Nagao, Y.;
Iimori, H.; Goto, S.; Hirata, T.; Sano, S.; Chuman, H.; Shiro, M.
Tetrahedron Lett. 2002, 43, 1709. (g) Nagao, Y.; Honjo, T.; Iimori, H.;
Goto, S.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y. Tetrahedron Lett.
2004, 45, 8757.
(10) (a) Komatsu, H.; Iwaoka, M.; Tomoda, S. Chem. Commun. 1999, 205. (b)
Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. J. Am. Chem. Soc.
2004, 126, 5309.
(11) Yamaguchi, K. J. Mass. Spectrom. 2003, 38, 473 and references therein.
(12) Bulman Page, P. C.; Graham, A. E.; Bethell, R.; Kevin Park, B. Synth.
Commun. 1993, 23, 1507.
9
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A R T I C L E S
Nagao et al.
Scheme 1. Asymmetric Pummerer Reaction Based on the Inter-
and Intramolecular Nonbonded S‚‚‚O Interactions
(for C7H17NO2S + Na) or m/z 214 due to (rac-11‚‚‚NMP
complex + Na)+ (for C8H17NO2S + Na) was clearly recognized.
Consequently, we propose that the CSI-MS detection method
can provide significant direct evidence for evaluation of the
intermolecular nonbonded S‚‚‚O interaction in a solution. The
peaks assigned to [dimeric DMAC + H (or Na)]+, [dimeric
NMP + H (or Na)]+, [dimeric (RS,S)-3 + H]+, [dimeric (RS)-5
+ H]+, [dimeric (RS)-7 + H]+, and [dimeric rac-11 + Na]+
were also recognized on the CSI-MS charts of the corresponding
sulfoxide and DMAC (or NMP). Although the sulfoxide itself
(compounds 3, 4, 6, and 7) has an internal amide, the
participation of this amide in association with another identical
molecule of sulfoxide [“dimerization” in MeOH (CSI-MS
analysis)] should be negligible in an excess amount of amide
solvent such as DMAC or NMP that has a stronger electron-
donating character than the amides having an electron-
withdrawing R-sulfinyl group.
The molecular structure characteristics of sulfoxides 8-10
involving an intramolecular nonbonded S‚‚‚O interaction in their
crystalline structures and the possible intermolecular nonbonded
S‚‚‚O interaction of chiral and achiral sulfoxides, (RS,S)-3, (RS)-
5, (RS)-7, and rac-11 with DMAC or NMP in a MeOH solution
prompted us to investigate a novel approach to the asymmetric
Pummerer reactions. Thus, we envisioned a unique and simple
design involving a chiral sulfurane-type intermediate that can
be generated by treatment of chiral sulfoxides with Ac2O-
TMSOTf (trimethylsilyl triflate) in amide and lactam solvents
such as DMAC, N,N-dimethylformamide (DMF), NMP, N-
formylpiperidine (NFP), etc. (vide infra), as illustrated in
Scheme 1.
Scheme 2 represents a synthetic route for the new chiral
sulfoxides, (RS,S)-3, (SS,S)-3, (RS,S)-4, and (SS,S)-4, employed
for the asymmetric Pummerer reactions. Namely, treatment of
thiols 12 and 13 with sodium hydride and then ethyl bromoac-
etate gave thioethers 14 in 91% yield and 15 in 96% yield,
respectively. Alkaline hydrolysis of 14 with NaOH in H2O-
EtOH followed by oxidation with 30% H2O2 in 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) afforded racemic sulfinyl car-
boxylic acid 16 in 97% yield. Dehydrative condensation of 16
with (S)-R-methylbenzylamine in the presence of 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDC‚HCl)
and 4-(dimethylamino)pyridine (DMAP) and then chromato-
graphic separation of the resulting diastereomeric mixture on a
silica gel column with n-hexane-AcOEt furnished optically pure
(RS,S)-3 and (SS,S)-3 each in 44% yield. Carboxylic acid 17
(89% yield) obtained by alkaline hydrolysis of 15 was subjected
to dehydrative amidation with (S)-R-methylbenzylamine to give
amide 18 in 85% yield. Oxidation of 18 with 30% H2O2 in HFIP
followed by chromatographic separation on a silica gel column
with n-hexane-AcOEt afforded pure chiral sulfoxides (RS,S)-4
and (SS,S)-4 in 48% and 50% yields, respectively. Known chiral
sulfoxides (RS)-5 and (RS)-6 were prepared by the previously
reported methods.3c,7b Chiral sulfoxide (RS)-7 was prepared by
dehydrative condensation of the carboxylic acid, which was
obtained by alkaline hydrolysis of (RS)-5, with benzylamine.
The stereochemistry of new chiral sulfoxides, (RS,S)-3, (SS,S)-
3, (RS,S)-4, and (SS,S)-4, was determined on the basis of X-ray
crystallographic analysis of (RS,S)-3 and (RS,S)-4; the crystal
structures are shown in Figure 2. In the represented crystalline
structures, significant 1,4-type S‚‚‚O close contact [3.142(4) Å
for (RS,S)-3 or 2.925(2) Å for (RS,S)-4] was recognized, as we
expected. Such a difference of the S‚‚‚O distances in these two
sulfoxides may be due to the fact that the electron density of
the sulfur atom with the electron-withdrawing p-nitrophenyl
group in (RS,S)-4 was lower than that of the sulfur atom with
the electron-donating p-tolyl group in (RS,S)-3.
First, to compare the new procedures (vide infra), the
Pummerer reactions of (RS,S)-3, (SS,S)-3, (RS,S)-4, and (SS,S)-4
were attempted utilizing our reagent system,8d,e as summarized
in Table 1. Namely, the chiral sulfoxides were treated with Ac2O
(2.0 mol equiv) in the presence of TMSOTf (2.0 mol equiv)8d,e
in CH2Cl2 at -40 or 0 °C to give the corresponding R-acetoxy
sulfides, (R,S)-19, (S,S)-19, (R*,S)-20, and (S*,S)-20, as dia-
stereomeric mixtures in 83-89% yields but with low de (0.3-
20%) of each major diastereomer (Table 1). The stereochemistry
of (R,S)-19 and (S,S)-19 will be described later. These poor
diastereoselectivities can be attributed to racemization of the
chiral sulfoxides involving an achiral sulfurane intermediate and
the Pummerer products via enolization in the use of the Ac2O-
TMSOTf reagent system in CH2Cl2 (vide infra). The magnitude
of the racemization is dependent upon the reaction time (entries
1 and 2 vs 3 and 4).
Subsequently, the asymmetric Pummerer reactions of (RS,S)-4
with Ac2O (2.0 mol equiv) and TMSOTf (2.0 mol equiv) were
investigated in detail in CH2Cl2 and several aprotic dipolar
solvents at room temperature, and the results are summarized
in Table 2. Interestingly, when the electron-donation number
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9724 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Highly Stereoselective Asymmetric Pummerer Reactions
A R T I C L E S
Scheme 2. Synthesis of New Chiral Sulfoxidesa
Table 1. Asymmetric Pummerer Reactions of Chiral Sulfoxides
Using Ac2O and TMSOTf in CH2Cl2
entry
sulfoxide
temp (
°
C)
time (h)
product
yielda/deb (%)
1
2
3
4
(RS,S)-3
(SS,S)-3
(RS,S)-4
(SS,S)-4
-40
-40
0
18
18
5
(R,S)-19
(S,S)-19
(R*,S)-20
(S*,S)-20
87/0.5
86/0.3
83/20
0
5
89/2.8
a Total isolated yield of a mixture of diastereomers. b Determined by 1H
NMR (400 MHz, CDCl3 or C6D6) analysis.
Table 2. Solvent Effect on Asymmetric Pummerer Reaction of
(RS, S)-4
yieldb/dec (%)
entry
solvent (EDNa)
time (h)
of (R*,S)-20
1
2
3
4
5
6
CH2Cl2 (-)
MeCN (14.1)
AcOEt (17.1)
Et2O (19.2)
DMF (26.6)
DMAC (27.8)
1
3
0.5
5
48
48
85/28
69/30
84/16
79/28
84/66
80/82
a EDN ) -∆H (kcal/mol): Complexation enthalpies of basic solvents
with SbCl5 in 1,2-dichloroethane.13 b Total isolated yield of a mixture of
diastereomers. c Determined by 1H NMR (400 MHz, CDCl3 or C6D6)
analysis.
a Reagents and conditions: (a) NaH, BrCH2CO2Et, THF; (b) NaOH,
H2O-EtOH; (c) 30% H2O2, HFIP; (d) (S)-R-methylbenzylamine, EDC‚HCl,
DMAP, CH2Cl2; (e) silica gel column (n-hexane-AcOEt).
Table 3. Diastereoselective Asymmetric Pummerer Reactions of
Chiral Sulfoxides in DMAC
entry
sulfoxide
time (h)
product
yielda/deb (%)
1
2
3
4
(RS,S)-3
(SS,S)-3
(RS,S)-4
(SS,S)-4
6
6
24
24
(R,S)-19
(S,S)-19
(R*,S)-20
(S*,S)-20
73/94 (97:3)c
79/96 (2:98)c
82/84 (92:8)c
78/92 (4:96)c
a Total isolated yield of a mixture of diastereomers. b Determined by 1H
NMR (400 MHz, CDCl3 or C6D6) analysis. c Diastereomer ratio.
or (SS,S)-3 with Ac2O (2.0 mol equiv) and TMSOTf (3.0 mol
equiv) in DMAC at room temperature for 6 h proceeded highly
diastereoselectively to afford R-acetoxy sulfides (R,S)-19 in 73%
yield with 94% de (entry 1 in Table 3) or (S,S)-19 in 79% yield
with 96% de (entry 2 in Table 3), as we expected. A similar
treatment of (RS,S)-4 and (SS,S)-4 in DMAC for 24 h gave
(R*,S)-20 in 82% yield with 84% de (entry 3 in Table 3) or
(S*,S)-20 in 78% yield with 92% de (entry 4 in Table 3),
respectively. These excellent diastereoselectivities obtained in
DMAC (Table 3) contrast significantly with the disappointing
results in CH2Cl2 (Table 1).
Figure 2. Computer-generated drawings derived from the X-ray coordinates
of (RS,S)-3 and (RS,S)-4.
(EDN) of the solvent was considered [e.g., AcOEt (EDN 17.1),
Et2O (EDN 19.2), DMF (EDN 26.6), and DMAC (EDN 27.8)],13
the de% value of the major product (R*,S)-20 appeared to
increase in near-dependence upon the EDN, as shown in Table
2 (entries 3-6).
As shown in Table 3, treatment of chiral sulfoxides (RS,S)-3
Consequently, a range of amide and lactam solvents were
utilized in enantioselective reactions as follows. Chiral sulfoxides
(13) Gutmann, V. Electrochim. Acta 1976, 21, 661.
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A R T I C L E S
Nagao et al.
Table 4. Enantioselective Pummerer Reactions of Chiral
Scheme 3. Attempt at Asymmetric Pummerer Reaction of (RS)-24
Sulfoxides in DMAC, DMF, NMP, and NFP
entry
sulfoxide
solvent
time (h)
product
yielda/ee (%)
1
2
3
4
5
6
7
(RS)-5
(RS)-5
(RS)-5
(RS)-6
(RS)-7
(RS)-7
(RS)-7
DMAC
DMF
NMP
DMAC
DMAC
NMP
1.5
4
4
4
6
(R*)-21
(R*)-21
(R*)-21
(R)-22
(R)-23
(R)-23
(R)-23
47/90b
76/90b
80/92b
58/82c
46/93d
61/95d
75/86d
4
4
NFP
a Isolated yield. b Determined by HPLC [CHIRALCEL OD, n-hexane-
propan-2-ol (50:1)] analysis. c Determined by HPLC [CHIRALCEL AD,
n-hexane-ethanol (6:1)] analysis. d Determined by HPLC [CHIRALCEL
OD, n-hexane-propan-2-ol (4:1)] analysis.
Figure 4. Possible structures for DMAC/TMSOTf complex 26 and NMP/
TMSOTf complex 27 based on their 1H NMR analysis (400 MHz, CDCl3).
entries 4-7 in Table 4). This stereoselective outcome was
thought to have resulted from intramolecular nonbonded 1,4
types of S‚‚‚O interaction in the chiral sulfoxides and the
intermolecular nonbonded S‚‚‚O interaction between the chiral
sulfoxides and DMAC (or NMP) (vide infra).
A chiral sulfoxide (RS)-24 without the â-carbonyl group was
synthesized by a method described in the literature.14 Then, this
chiral compound [>99% ee (HPLC analysis)] was similarly
treated with Ac2O (2.0 mol equiv) and TMSOTf (3.0 mol equiv)
in DMAC or NMP at room temperature for 40 or 45 h to give
a Pummerer reaction product, 25, as each racemate in 12% or
15% yield (Scheme 3). The same reaction of (RS)-24 with Ac2O
(2.0 mol equiv) and TMSOTf (3.0 mol equiv) in CH2Cl2 for 44
h resulted in recovery (50%) of the starting sulfoxide. Thus, in
highly diastereo- and enantioselective amide-promoted Pum-
merer reactions employing the chiral sulfoxides such as (RS,S)-
3, (SS,S)-3, (RS,S)-4, (SS,S)-4, (RS)-5, (RS)-6, and (RS)-7, the
existence of the â-carbonyl group in their molecules is thought
to be essential. On the basis of the unsuccessful asymmetric
Pummerer reaction of (RS)-24, which probably included an
intermolecular nonbonded S‚‚‚O (amide solvents) interaction
[cf. CSI-MS of a mixture of rac-11 and DMAC (or NMP)], a
fairly strong intramolecular nonbonded S‚‚‚O (ester or amide
group) interaction should play an important role [e.g., restriction
of the free rotation of the CH2COX group (Scheme 1 and Figure
6)] in the highly stereoselective Pummerer reactions in an amide
solvent.
Figure 3. Computer-generated drawings derived from the X-ray coordinates
of (S,S)-19 and (R)-23.
(RS)-5, (RS)-6, and (RS)-7 were allowed to react with Ac2O (2.0
mol equiv) and TMSOTf (3.0 mol equiv) in an amide or a
lactam solvent (DMAC, DMF, NMP, or NFP) at room tem-
perature for 1.5-6 h. The experimental results are summarized
in Table 4. In all cases, the highly enantioselective Pummerer
reaction proceeded to give known chiral R-acetoxy sulfides (R*)-
21,1c-e,3c (R)-22,1c-e,3c and (R)-23 in 82-95% ee. The results
obtained using NMP were superior in both chemical yield and
ee to those obtained using DMAC and DMF (entries 3 and 6
vs entries 1, 2, and 5 in Table 4).
Fortunately, the stereochemistries of unstable (S,S)-19 and
(R)-23 were clarified by their X-ray crystallographic analyses;
the crystal structures are shown in Figure 3. On the basis of the
structure of (S,S)-19, the stereochemistry of its diastereomer
(R,S)-19 was also precisely determined.
Although the absolute configuration of the newly formed
chiral carbon atom (R* or S*) of (R*,S)-20, (S*,S)-20, and (R*)-
21 has not yet been determined, it is expected to be identical to
the corresponding sulfinyl chirality because the sulfinyl chirality
of (RS,S)-3, (SS,S)-3, (RS,S)-4, and (SS,S)-4 explicitly reflects
the corresponding diastereomer ratio mode of the Pummerer
products (all entries in Tables 1-3), and the same chirality
(RSfR or SSfS) has been transferred from (RS,S)-3, (SS,S)-3,
(RS)-6, and (RS)-7 to the corresponding (R,S)-19, (S,S)-19, (R)-
22, and (R)-23, respectively (entries 1 and 2 in Table 3 and
TMSOTf (Lewis acid) instantly reacted exothermically with
an equimolecular amount of DMAC (Lewis base) or NMP
(Lewis base) at room temperature to give the corresponding
complex, 26 or 27, as a colorless oil or a colorless hygroscopic
(14) (a) Mikolajczyk, M.; Perlikowska, W. J. Org. Chem. 1998, 63, 9716. (b)
Alexandre, C.; Belkadi, O.; Maignan, C. Synthesis 1992, 547.
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9726 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Highly Stereoselective Asymmetric Pummerer Reactions
A R T I C L E S
Scheme 5. Investigation of Racemization of Chiral Pummerer
Table 5. Asymmetric Pummerer Reactions of (RS)-5 with/without
26 or 27
Product (R*)-21 and Chiral Sulfoxide (RS)-5
yielda/eeb (%)
entry
reagent
solvent
temp (
°
C)
time
of (R*)-21
1
2
3
4
5
26
27
27
TMSOTf
none
DMAC
NMP
CH2Cl2
CH2Cl2
DMAC
r.t.
r.t.
r.t.
r.t.
110
4 h
4 h
5 min
3.5 h
48 h
47/89
83/91
85/72
61/0
46/72
a Isolated yield. b Determined by HPLC [CHIRALCEL OD, n-hexane-
propan-2-ol (50:1)] analysis.
powder in a quantitative yield, respectively.15 These complex
1
structures could be rationalized by comparing their H NMR
chemical shifts with those of DMAC or NMP itself in CDCl3,
as shown in Figure 4. The amide carbonyl moiety of R-sulfinyl
amides [e.g., (RS)-7] should less coordinated to TMSOTf than
that of DMAC in excess DMAC. We experienced previously
the interesting chemoselective Pummerer reactions in DMF to
prove that the amide carbonyl group of DMF can more
predominantly coordinated to TMSOTf than that of a sulfoxide
substrate like compound 9.8d This may be because the nucleo-
philicity of DMF, DMAC, and NMP is stronger than that of
the R-sulfinyl amides bearing an electron-withdrawing sulfinyl
group (vide supra).
To confirm the activity of the complexes 26 and 27 to Ac2O,
the following acetylation reactions were examined. Treatment
of l-menthol 28 with Ac2O in the presence of 26 or 27 in CH2-
Cl2 smoothly gave acetoxy compound 2916 in excellent yield,
as we expected (Scheme 4).
intermolecular nonbonded S‚‚‚O interaction (just like an inter-
molecular OfS coordination) between the resulting acetox-
ysulfonium intermediate and the NMP released by acetylation
of (RS)-5 with 27. The reaction results of entry 3 involving the
rapid reaction time (5 min) and the high chemical yield (85%)
of (R*)-21 (72% ee) are very similar to those of the experiment
[reaction time (5 min) and 74% ee and 99% yield of (R*)-21]
in Figure 5 (vide infra).
Interestingly, the Pummerer reaction of (RS)-5 with Ac2O (2.0
mol equiv) in DMAC, even without the use of TMSOTf, under
heating at 110 °C for 48 h gave (R*)-21 [46% yield with
recovery (13%) of (RS)-5] in 72% ee (entry 5 in Table 5). Hence,
DMAC and NMP should greatly benefit this highly stereose-
lective chiral transfer reaction based on the intermolecular
nonbonded S‚‚‚O interaction, as described above. On the other
hand, treatment of (RS)-5 with TMSOTf (3 mol equiv) and Ac2O
(2 mol equiv) in CH2Cl2 at room temperature gave a racemic
product, 21 (0% ee), in 61% yield (entry 4 in Table 5). This
outcome seemed to be due to racemization of the chiral product
(R*)-21 and/or the starting chiral sulfoxide (RS)-5.
Scheme 4. Acetylation of l-Menthol 28 with Ac2O in the Presence
of 26 or 27
Then, we investigated some important reactions in order to
inspect the racemization reaction of (R*)-21 and (RS)-5 as
follows (Scheme 5). The chiral product (R*)-21 (91% ee) was
readily racemized by its treatment with a mixture of Ac2O and
TMSOTf to afford rac-21 in 85% recovery and 0% ee. This
racemization is likely attributable to the fact that (R*)-21 is
enolized with TMSOTf (strong Lewis acid) in the presence of
Ac2O. Treatment of (RS)-5 (>99% ee) with TMSOTf alone in
CH2Cl2 gave the starting chiral sulfoxide (RS)-5 (98% ee) in
70% recovery. Hence, TMSOTf is not responsible for the
racemization of (RS)-5. However, when (RS)-5 (>99% ee) was
treated with a mixture of Ac2O and TMSOTf in CH2Cl2 for 1
h, rac-5 (0% ee) and rac-21 (0% ee) were obtained in 37% and
61% yields, respectively. In particular, facile racemization of
the chiral Pummerer reaction product should be a serious
problem.
Thus, treatment of (RS)-5 with Ac2O (2.0 mol equiv) and a
3 mol equiv of 26 or 27 in DMAC, NMP, or CH2Cl2 gave the
product (R*)-21 in 47-85% yields with 72-91% ee, as shown
in Table 5 (entries 1-3). The results of entries 1 and 2 in Table
5 were almost the same as those for entries 1 and 3 in Table 4.
Hence, in the facile Pummerer reactions employing Ac2O and
TMSOTf in an amide solvent, the amide/TMSOTf complex such
as 26 or 27 generated in situ must become a real active species
for Ac2O and a trapping reagent for the released acetate ion.
The stereochemical outcome (72% ee) of entry 3 employing
27 even in CH2Cl2 can be understood in terms of the
(15) Djuric, S. W. J. Org. Chem. 1984, 49, 1311.
(16) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1996,
61, 4560.
(17) Rigaku 1998 PROCESS-AUTO: Automatic data acquisition and processing
package for imaging plate diffractometer; Rigaku Corporation: Tokyo.
(18) Sheldrick, G. M. SHELXS97, Program for the solution of crystal structures.
University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(19) Sheldrick, G. M. SHELXL97; University of Go¨ttingen: Go¨ttingen, Germany,
1997.
In the reactions (Table 1, entry 4 in Table 5, and Scheme 5)
without the use of any amide solvent or compound, the existence
of the intermolecular nonbonded S‚‚‚O interaction between the
chiral acetoxysulfonium intermediate and the amide should be
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9727

A R T I C L E S
Nagao et al.
molecular amounts of DMAC with respect to TMSOTf pro-
ceeded more slowly than when equimolecular amounts were
used. These results suggested that an excess amount of TMSOTf
may disturb acetylation of the sulfinyl group by its coordination
to the Si atom. An excess amount of DMAC may also disturb
acetylation of the sulfinyl group by coordination of DMAC to
the Si atom of the DMAC/TMSOTf complex 26 generated in
situ. However, excess DMAC and the DMAC released from
26 by its acetylation of (RS)-5 participate in an intermolecular
nonbonded S‚‚‚O interaction and an intermolecular coordination
ÃfS interaction between the S+ atom of the starting sulfinyl
compound and the acetoxysulfonium intermediate and the Oδ+
atom of DMAC, as shown in Figure 6.
Through the asymmetric Pummerer reactions (e.g., entries 1
and 2 in Table 5), we realized that the amide/TMSOTf complex
in the corresponding amide solvent does not readily promote
racemization of the chiral product probably due to deactivation
of the Lewis acidity of the original TMS group by exchange of
TfO- for the amide. Thus, solvent amide silylation in situ should
be very important in order to prevent this particular asymmetric
Pummerer reaction from racemizing the chiral product and the
starting chiral sulfoxide.
Figure 5. Effect of DMAC on the asymmetric Pummerer reaction [(RS)-
5f(R*)-21] in CH2Cl2. Isolated yield.
a
impossible. Therefore, racemization of (RS)-5 may be caused
by formation of the achiral diacetoxy sulfurane 1 on the basis
of participation of the acetate ion obtained from a possible
equilibrium condition, as shown in eq 1.2a,4a
Finally, we propose a plausible mechanism of the highly
stereoselective Pummerer reaction in an amide or lactam solvent
involving intermolecular and intramolecular nonbonded S‚‚‚O
interactions and solvent amide silylation, as shown in Figure 6.
The solvent amide or lactam instantly coordinates to TMSOTf
to generate an amide (or lactam)/TMSOTf complex A and also
approaches to the S+ atom of a chiral sulfoxide substrate to
form the structures B and C bearing the intermolecular and
intramolecular nonbonded S‚‚‚O interactions. However, structure
B (see the X-ray structures in Figure 2) should be more stable
than structure C since the steric repulsion between the aryl group
and the carbonyl group in C is absent in B. Then, acetylation
of the sulfinyl oxygen atom of B with Ac2O in the presence of
the real active species A affords a chiral sulfurane-type
intermediate, D, in which fairly strong and tight coordination
of the amide or lactam to the S+ atom of acetoxysulfonium must
Furthermore, the effect of DMAC on the asymmetric Pum-
merer reactions of (RS)-5 was examined by using Ac2O (2 mol
equiv) and TMSOTf (3 mol equiv) in the presence of different
mol equivs of DMAC in CH2Cl2 at room temperature. The
results are graphically illustrated in Figure 5. They reveal a clear
trend toward higher %ee value for production of (R*)-21 as the
amount of DMAC increases. Interestingly, when an equimo-
lecular amount (each 3 mol equiv) of TMSOTf and DMAC in
the presence of Ac2O (2 mol equiv) was employed, the reaction
proceeded to completion within 5 min to furnish (R*)-21 in 99%
yield with 74% ee. This result strongly supports the likelihood
that there is rapid and quantitative generation of the active
species 26 (vide supra, entry 1 in Table 5), which makes an
important contribution to acetylation of the sulfinyl group and
trapping of the released acetate ion, as shown in Figure 6. The
Pummerer reactions of (RS)-5 with Ac2O using greater or smaller
Figure 6. Possible mechanism of the highly stereoselective Pummerer reaction with TMSOTf and Ac2O in an amide or lactam solvent.
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9728 J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006

Highly Stereoselective Asymmetric Pummerer Reactions
A R T I C L E S
be possible. Antiperiplanar-mode abstraction3d of the methylene
R-hydrogen atom with a base (e.g., TfO-) in intermediate D
would generate a rigid ylide intermediate E fixed by both
nonbonded S‚‚‚O interactions. Stereoselective 1,2-acetoxy trans-
fer in E may proceed via three kinds of plausible modes based
on the Oae-proposed cyclic and/or sliding modes3c and/or the
Kita-proposed intimate ion-pair mode6b,3d to furnish the desired
chiral Pummerer product.
In conclusion, we have presented the first evidence for the
intermolecular nonbonded S‚‚‚O interactions between several
sulfoxides and DMAC (or NMP) in a solution by utilizing the
CSI-MS analytical method and have demonstrated a novel
simple procedure for highly stereoselective Pummerer reactions
based on the concept of inter- and intramolecular nonbonded
S‚‚‚O interactions and the solvent amide silylation with TM-
SOTf.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (B) (2) (14370723 and
16390008) from the Japan Society for the Promotion of Science.
Supporting Information Available: Experimental procedures;
characterization of the products; X-ray data (CIF); and CSI-
MS experiments including CSI mass spectral charts. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA056649R
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J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9729