Catalytic activation of the leaving group in the SN2 reaction

Article abstract of DOI:10.1021/ol701737x

A novel catalytic activation of the leaving group in the S_N2 reaction is achieved as an extension of our mercuric triflate-catalyzed reactions. Derivatives of anilinoethyl 4-pentynoate reacted smoothly with catalytic amounts of Hg(OTf)₂ to give indoline derivatives in excellent yield with efficient catalytic turnovers under very mild conditions. The reaction of optically pure secondary alcohol derivatives resulted in inversion of stereochemistry, which is a definitive feature of the S _N2 reaction. The procedure is applicable for benzoazepine synthesis.

Full text of DOI:10.1021/ol701737x

ORGANIC
LETTERS
2007
Vol. 9, No. 20
4029-4032
Catalytic Activation of the Leaving
Group in the SN2 Reaction§
Hirofumi Yamamoto, Ghanshyam Pandey, Yumiko Asai, Mayo Nakano,
Atsushi Kinoshita, Kosuke Namba, Hiroshi Imagawa, and Mugio Nishizawa*
Faculty of Pharmaceutical Sciences, Tokushima Bunri UniVersity, Yamashiro-cho,
Tokushima 770-8514, Japan
mugi@ph.bunri-u.ac.jp
Received July 20, 2007
ABSTRACT
A novel catalytic activation of the leaving group in the SN2 reaction is achieved as an extension of our mercuric triflate-catalyzed reactions.
Derivatives of anilinoethyl 4-pentynoate reacted smoothly with catalytic amounts of Hg(OTf)2 to give indoline derivatives in excellent yield with
efficient catalytic turnovers under very mild conditions. The reaction of optically pure secondary alcohol derivatives resulted in inversion of
stereochemistry, which is a definitive feature of the SN2 reaction. The procedure is applicable for benzoazepine synthesis.
The SN2 reaction is a single-step reaction via a transition
state as formulated by Hughes and Ingold in 1937, and it is
a principal backbone of organic chemistry.1 Mitsunobu
developed the second generation of SN2 reactions of alcohol
using diethylazodicarboxylate, benzoic acid, and triphen-
ylphosphine, the so-called Mitsunobu reaction.2,3 So far, the
SN2 reaction has been recognized as a stoichiometric
bimolecular reaction between a nucleophile and a substrate.
Herein we report a novel catalytic activation of the leaving
group for the SN2 reaction as an extension of our original
mercury(II) trifluoromethanesulfonate [hereafter Hg(OTf)2]-
catalyzed reactions.4,5 Recently, we found that the Hg(OTf)2
complex showed highly efficient catalytic activity based upon
a significant affinity for the alkynyl group as well as an
efficient protodemercuration sequence resulting in regenera-
tion of Hg(OTf)2.6 We found that the Hg(OTf)2‚tetra-
(4) (a) Nishizawa, M.; Takenaka, H.; Nishide, H.; Hayashi, Y. Tetra-
hedron Lett. 1983, 24, 2581-2584. (b) Nishizawa, M.; Morikuni, E.; Asoh,
K.; Kan, Y.; Uenoyama, K.; Imagawa, H. Synlett 1995, 169-170. (c)
Nishizawa, M. Studies in Natural Product Chemistry.; Vol. 1, Stereoselective
Synthesis, Part A; Rahman, A. u., Ed.; Elsevier: Amsterdam, Holland, 1988;
pp 655-676. (d) Nishizawa, M. J. Syn. Org. Chem. Jpn. 1999, 57, 677-
688. (e) Nishizawa, M.; Imagawa, H. J. Syn. Org. Chem. Jpn. 2006, 64,
744-751.
(5) (a) Nishizawa, M.; Takenaka, H.; Hirotsu, K.; Higuchi, T.; Hayashi,
Y. J. Am. Chem. Soc. 1984, 106, 4290-4291. (b) Nishizawa, M.; Takenaka,
H.; Hayashi, Y. J. Am. Chem. Soc. 1985, 107, 522-523. (c) Nishizawa,
M.; Takenaka, H.; Hayashi, Y. J. Org. Chem. 1986, 51, 806-813. (d)
Nishizawa, M.; Yamada, H.; Hayashi, Y. Tetrahedron Lett. 1986, 27, 187-
190. (e) Nishizawa, M.; Yamada, H.; Hayashi, Y. J. Org. Chem. 1987, 52,
4878-4884. (f) Nishizawa, M.; Takao, H.; Kanoh, N.; Asoh, K.; Hatakeya-
ma, S.; Yamada, H. Tetrahedron Lett. 1994, 35, 5693-5696. (g) Nishizawa,
M.; Morikuni, E.; Takeji, M.; Asoh, K.; Hyodo, I.; Imagawa, H.; Yamada,
H. Synlett 1996, 927-928. (h) Nishizawa, M.; Takao, H.; Iwamoto, Y.;
Yamada, H.; Imagawa, H. Synlett 1998, 76-78. (i) Nishizawa, M.; Imagawa,
H.; Hyodo, I.; Takeji, M.; Morikuni, E.; Asoh, K.; Yamada, H. Tetrahedron
Lett. 1998, 39, 389-392.
§ In memory of the late Professor Yoshihiko Ito.
(1) (a) Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K. Nature 1936, 138,
759. (b) Hughes, E. D.; Ingold, C. K.; Scott, A. D. J. Chem. Soc. 1937,
1201-1208. (c) Hughes, E. D.; Ingold, C. K.; Martin, L. R. J.; Meigh, D.
F. Nature 1950, 166, 679-680.
(2) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380-2382. (b) Mitsunobu, O. Synthesis 1981, 1-28.
(3) (a) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34,
1639-1642. (b) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem. Lett.
1994, 539-542. (c) Tsunoda, T.; Ozaki, F.; Ito, S. Tetrahedron Lett. 1994,
35, 5081-5082. (d) Tsunoda, T.; Yamamiya, Y.; Kawamura, Y.; Ito, S.
Tetrahedron Lett. 1995, 36, 2529-2530. (e) Tsunoda, T.; Nagino, C.; Oguri,
M.; Ito, S. Tetrahedron Lett. 1996, 37, 2459-2462.
10.1021/ol701737x CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007

methylurea (hereafter TMU)-catalyzed cyclization of alky-
-noic acid 1 to γ-methylene-γ-lactone 2 is extremely rapid,7a
and we used the alkynoic acid residue as the leaving group
for Hg(OTf)2-catalyzed glycosylations such as 3 to 4, i.e.,
the typical SN1 reaction.7b Now, we have turned our attention
to the Hg(OTf)2-catalyzed SN2 reaction using the alkynoic
acid residue as the leaving group. An anilinoethanol deriva-
tive 5 was designed as a substrate, which underwent a novel
catalytic SN2 reaction that generated indoline 6 in high yield
with excellent catalytic turnover under very mild reaction
conditions. We also found that the Hg(OTf)2-catalyzed SN2
reaction of the optically pure secondary alcohol derivative
(S)-16 proceeded with inversion of configuration to give (R)-
13 in >99% ee. Furthermore, the procedure was shown to
be applicable to the syntheses of tetrahydroquinoline, tet-
rahydrobenzoazepin, and chroman.
Table 1. Hg(OTf)2-Catalyzed SN2 Reaction of 5 To Give 6
yield (%)a
Hg(OTf)2
(mol %)
time
(h)
entry
solvent
6
5
1
2
3
4
5
6
7
8
9
5
5
5
1
5
1
5
1
CH3CN
0.5
0.5
0.5
24
0.5
0.5
0.5
0.5
0.5
0.5
24
10
8
90
trace
88
trace
96
32
96
96
62
53
-
MeO-t-Bu
CH3NO2
CH3NO2
C6H5CH3
C6H5CH3
(CH2Cl)2
(CH2Cl)2
CH2Cl2
94
96
59
5
1
0.2
10
11
CH2Cl2
CH2Cl2
trace
95
a Isolated yield.
sample. Catalyst at 0.2 mol % afforded only trace amounts
of product even in CH2Cl2 (entry 11). Mercuric acetylide
formation is a possible catalyst suicide mechanism but the
level of this possible side product was too low to detect.9
Scheme 1. Hg(OTf)2-Catalyzed Reactions
The reaction of 5 is thought to be initiated by π-complex-
ation of an alkynyl group with Hg(OTf)2 as seen in 8
(Scheme 2). Nucleophilic participation of the carbonyl group
Scheme 2. Proposed Mechanism of Hg(OTf)2-Catalyzed SN2
Reaction
Reactions of 4-pentynoate 5 with 5 and 1 mol % of
Hg(OTf)2 (prepared in CH3CN and employed as CH3CN
solutions) were examined in various solvents such as
CH3CN, MeO-t-Bu, CH3NO2, C6H5CH3, (CH2Cl)2, and
CH2Cl2, at 25 °C for 30 min (Table 1). The optimum
conditions were found to be using 1 mol % of Hg(OTf)2
and CH2Cl2 giving rise to indoline 68 in 96% yield (Table
1, entry 10). Enol lactone 7 was identified in the NMR
spectrum of the crude extract by comparison with authentic
leads to oxocarbenium cation 9 and this cationic residue acts
as the highly efficient leaving group for the SN2 reaction.
Nucleophilic attack of the nitrogen group produces indoline
6 and an enol lactone 10 containing a vinylmercury group.
Protonation of 10 by in situ generated TfOH results in a
second oxocarbenium cation intermediate 11 that yields
γ-methylene-γ-lactone (2) along with regenerated catalyst
Hg(OTf)2. Finally, Hg(OTf)2 induces isomerization of 2 into
more stable enol lactone 7.10
(6) (a) Nishizawa, M.; Skwarczynski, M.; Imagawa, H.; Sugihara, T.
Chem. Lett. 2002, 12-13. (b) Nishizawa, M.; Yadav, V. K.; Skwarczynski,
M.; Takao, H.; Imagawa, H.; Sugihara, T. Org. Lett. 2003, 5, 1609-1611.
(c) Nishizawa, M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T.
Org. Lett. 2003, 5, 4563-4565. (d) Imagawa, H.; Kurisaki, T.; Nishizawa,
M. Org. Lett. 2004, 6, 3679-3681. (e) Imagawa, H.; Iyenaga, T.; Nishizawa,
M. Org. Lett. 2005, 7, 451-453. (f) Imagawa, H.; Iyenaga, T.; Nishizawa,
M. Synlett 2005, 703-705. (g) Imagawa, H.; Asai, Y.; Takano, H.;
Hamagaki, H.; Nishizawa, M. Org. Lett. 2006, 8, 447-450. (h) Kurisaki,
T.; Naniwa, T.; Yamamoto, H.; Imagawa, H.; Nishizawa, M. Tetrahedron
Lett. 2006, 47, 1871-1874. (i) Yamamoto, H.; Nishiyama, M.; Imagawa,
H.; Nishizawa, M. Tetrahedron Lett. 2006, 47, 8369-8373.
Since the reaction of 5 to 6 is a nucleophilic substitution
on the primary carbon center, there is no doubt that it is an
(7) (a) Imagawa, H.; Fujikawa, Y.; Tsuchihiro, A.; Kinoshita, A.;
Yoshinaga, T.; Takao, H.; Nishizawa, M. Synlett 2006, 639-641. (b)
Imagawa, H.; Kinoshita, A.; Fukuyama, T.; Yamamoto, H.; Nishizawa, M.
Tetrahedron Lett. 2006, 47, 4729-4731.
(8) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525-7546.
(9) Camps, M.; Montheard, J. P.; Benzaid, A. Bull. Soc. Chim. Fr. 1989,
123-129.
(10) Lactonization of 1 with Hg(OTf)2 in CH3CN results in isomerization
to conjugated lactone 7, whereas, Hg(OTf)2‚3TMU gives enol lactone 2
selectively. See ref 7a.
4030
Org. Lett., Vol. 9, No. 20, 2007

Scheme 3
Table 3. Hg(OTf)2-Catalyzed SN2 Reaction in CH2Cl2
SN2 reaction. However, SN2 reactions can also take place
on secondary carbons. Thus, we next examined the secondary
alcohol derivatives. Treatment of (()-12 with 1 mol % of
Hg(OTf)2 in CH2Cl2 at 25 °C for 30 min afforded (()-1311
in only 10% yield leaving 70% unreacted starting material
(Scheme 3). However, the reaction in CH2Cl2 under reflux
conditions for 30 min afforded (()-13 in 86% yield. The
butyl homologue (()-14 was also converted to (()-15 under
the same conditions in 72% yield.
Table 2. Hg(OTf)2-Catalyzed Reaction in CH2Cl2 To Give
(R)-13
Hg(OTf)2
(mol %)
temp
(°C)
time
(h)
yielda
(%)
entry
% ee
1
2
3
4
1b
1c
43
25
0
25
0
25
0
-10
0.5
3
24
3
2
2
86
94
27
94
95
82
80
66
93
95
97
93
94
97
98
>99
1c
5c
5
10c
1c
6d
7d
8d
1c
1c
3
14
a Isolated yield. b CH3CN solution of Hg(OTf)2 was employed. c CH3CN
was completely evacuated. d Reaction of (S)-16.
A signature feature of the SN2 reaction is the stereochem-
ical inversion. Thus, the reaction of optically pure (S)-1212
with 1 mol % of Hg(OTf)2 in CH2Cl2 at 43 °C for 30 min
was examined. The product obtained in 86% yield was shown
to be (R)-13 as determined by [R]D data with 93% ee based
on the chiral HPLC analysis (Table 2, entry 1).13 Then, we
found that complete removal of CH3CN from the reaction
a Isolated yield. b NMR yield with CH2Br2 as an internal standard.
Scheme 4
mixture increases the reactivity of Hg(OTf)2, and the reaction
of (S)-12 with 1 mol % of Hg(OTf)2 was completed within
3 h even at 25 °C, affording (R)-13 in 94% yield and 95%
ee (entry 2). Although the reaction at 0 °C afforded the
product in 97% ee, the yield was only 27% after 24 h (entry
3). Increased catalyst loading did not increase the optical
purity of product (entries 4 and 5). Finally, we changed the
(12) Absolute structure of (S)-N-(2-(2-hydroxypropyl)phenyl)-4-meth-
ylbenzene sulfonamide [(S)-23] was established by the Kusumi method by
preparing (R)- and (S)-MTPA derivatives. Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092-4096.
(11) Liu, X. Y.; Li, C. H.; Che, C. M. Org. Lett. 2006, 8, 2707-2710.
Org. Lett., Vol. 9, No. 20, 2007
4031

leaving group to 2-ethynylbenzoate and prepared (S)-16
(Scheme 4). Reaction of (S)-16 with 1 mol % of Hg(OTf)2
in CH2Cl2 at 25 °C for 2 h afforded (R)-13 in 82% yield
with 97% ee (entry 6) along with exomethylene lactone 17.
Furthermore, the same reaction at 0 °C for 3 h also afforded
(R)-13 in 80% yield with 98% ee (entry 7), while the reaction
at -10 °C for 14 h afforded (R)-13 in 66% yield with >99%
ee (entry 8). In the latter case we detected the occurrence of
hydrated product 18 in 27% yield. Thus, we obtained the
stereochemical inversion with this novel catalytic activated
SN2 reaction.
yield after 2.5 h at reflux temperature,17 while 2-ethynyl-
benzoate 29 afforded 28 in 69% yield even after 10 h at
room temperature. Tetrahydrobenzoazepin synthesis by the
reaction with 4-pentynoate 3015 failed; however, the reaction
of 2-ethynylbenzoate 32 with 1 mol % of Hg(OTf)2 at reflux
temperature in dichloroethane afforded 31 in 36% yield along
with hydrated ketonic product and starting material in 34%
and 19% yield, respectively, even though the reaction was
carried out under extra dry conditions. A 89% yield of 31
was accomplished by using 10 mol % of catalyst at reflux
in dichloroethane for 14 h.18 Although the procedure is not
suitable for benzofuran synthesis from 2-ethynylbenzoate as
33 afforded 3419 in only 29% NMR yield along with hydrated
ketone formation, synthesis of chroman 36 was achieved in
acceptable yield (NMR yield 59%, isolated yield 50%) by
using 1 mol % of catalyst in CDCl3.20
Scheme 5
Thus, we have developed a novel catalytic activation of
the leaving group for a SN2 reaction using 4-pentynoate or
2-ethynylbenzoate as the leaving groups and our original
reagent, Hg(OTf)2, as the catalyst, which proceeds with high
catalytic turnover under very mild reaction conditions.
Although partial epimerization occurred when the leaving
group was 4-pentynoate, the problem was lessened by using
2-ethynylbenzoate. The procedure was shown to be applic-
able for tetrahydroquinoline, benzoazepine, and chroman
syntheses, but not for the synthesis of dihydrobenzofuran.
We are now working on the application of this process to
intermolecular SN2 reactions.
4-Pentynoates 5, (()-12, and (()-14 were prepared from
corresponding aminoalcohols 19,14 (()-20,15 and (()-2116
via tosylation followed by esterification (Scheme 5). Opti-
cally pure (S)-12 (>99% ee) and (S)-16 were prepared by
HPLC separation of diastereomeric menthol derivatives 22,
followed by hydrolysis to (S)-2312 and re-esterification with
4-pentynoic acid and 2-ethynylbenzoic acid, respectively.
The applicability of the procedure to the preparation of
other ring systems was also examined and the results are
summarized in Table 3. Reaction of 4-pentynoate 2415 with
1 mol % of Hg(OTf)2 in CH2Cl2 at room temperature for
2.5 h afforded tetrahydroquinoline derivative 25 in 91%
yield.17 Alternatively, 2-ethynylbenzoate 26 also provided
25 in 99% yield under similar conditions. 4-Pentynoate 27,
derived from a secondary alcohol,15 gave methyl homologue
28 in 33% yield after 12 h at room temperature, and 53%
Acknowledgment. We are grateful to Ms. Kie Masui of
this institute for technical assistance. This study was finan-
cially supported by a Grant-in-Aid from the Ministry of
Education, Culture, Sports, Science, and Technology of the
Japanese Government, and a MEXT.HAITEKU, 2003-2007.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701737X
(18) Cromarty, A.; Proctor, G. R. Chem. Commun. 1968, 842-843.
(19) Pouchert, C. J.; Behnke, J. The Aldrich Library of 13C and 1H NMR
Spectra, 1st ed.; Aldrich Chemical CO.: Milwaukee, IL, 1993; Vol. 2, p
226-A. Although the NMR signals corresponding to 34 overlapped with
those of the authentic sample, isolation of 34 was not successful due to the
small quantity of material and its high volatility.
(20) Boyd, D. R.; Sharma, N. D.; Bowers, N. I.; Boyle, R.; Harrison, J.
S.; Lee, K.; Bugg, D. H.; Gibson, D. T. Org. Biomol. Chem. 2003, 1, 1298-
1307.
(13) (a) Sakata, T.; Ueshima, Y.; Muro, H.; Maruyama, S.; Tetsuo, M.;
Okamoto, K. Iyakuhin Kenkyu 1980, 11, 388-394. (b) Kuwano, R.;
Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron:
Asymmetry 2006, 17, 521-535.
(14) Minin, P. L.; Walton, J. C. J. Org. Chem. 2003, 68, 2960-2963.
(15) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002, 4, 2691-
2694.
(16) Torii, S.; Tanaka, H.; Murakami, Y.; Okamoto, K. Jpn. Kokai Tokkyo
Koho 1988, 8.
(17) Fisher, G. H.; Schultz, H. P. J. Org. Chem. 1974, 39, 635-640.
(21) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D. F.; Smith,
G. M. J. Chem. Soc., Perkin Trans. 1 1996, 2249-2256.
4032
Org. Lett., Vol. 9, No. 20, 2007