Hg(OTf)2-catalyzed cyclization of N-tosylanilinoallylic alcohols to 2-vinylindolines

Article abstract of DOI:10.1055/s-2008-1077881

The Hg(OTf)₂-catalyzed cyclization of N-tosylanilinoallylic alcohols giving rise to vinyl-substituted indolines has been developed. The reaction takes place with a highly efficient catalytic turnover (up to 1000 times) under mild conditions. The hydroxyl group of the organomercuric intermediate is protonated by in situ formed TfOH generating an oxonium cation, which regenerates the catalyst after demercuration. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1077881

LETTER
1719
Hg(OTf)2-Catalyzed Cyclization of N-Tosylanilinoallylic Alcohols to
2-Vinylindolines
H
g(OTf) -Catalyze
o
dCyclizatio
s
nof
N
-To
u
sylanilinoall
k
ylic
A
lcohol
e
s
to 2-Vinylindoli
N
ne
s
amba,* Yuki Nakagawa, Hirofumi Yamamoto, Hiroshi Imagawa, Mugio Nishizawa*
2
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Fax +81(88)6553051; E-mail: mugi@ph.bunri-u.ac.jp
Received 21 March 2008
Hg(OTf)2
(1 mol%)
C4H9
Abstract: The Hg(OTf)2-catalyzed cyclization of N-tosylanilino-
allylic alcohols giving rise to vinyl-substituted indolines has been
developed. The reaction takes place with a highly efficient catalytic
turnover (up to 1000 times) under mild conditions. The hydroxyl
group of the organomercuric intermediate is protonated by in situ
formed TfOH generating an oxonium cation, which regenerates the
catalyst after demercuration.
C4H9
CH2Cl2
r.t., 15 min
N
Ts
NHTs
1
2
97%
H
HgOTf
HOTf
HgOTf
C4H9
Key words: Hg(OTf)2, N-tosylanilinoallylic alcohol cyclization,
2-vinylindoline, 2-vinylpyrrolidine, 2-vinylpiperidine
2
C4H9
N
N +
Ts
Hg(OTf)2
Ts
3
4
Transition-metal-catalyzed cyclization of alkynyl and alk-
enyl amine derivatives leading to nitrogen heterocycles is
of great interest for both academic and industrial re-
search.1 In particular, catalytic hydroamination2 as well as
indole syntheses have been intensively investigated.3 Re-
cently, we also reported the Hg(OTf)2-catalyzed cyclo-
isomerization of alkynyl aniline derivatives giving rise to
indoles, with very high catalytic turnover (up to 400
times), under very mild reaction conditions.4 For example
the reaction of alkynyl aniline derivative 1 with 1 mol%
of Hg(OTf)2 in dichloromethane at room temperature for
15 minutes generates indole 2 in 97% yield. When vinyl
mercuric intermediate 3 is formed, it is protonated with in
situ formed TfOH generating iminium ion 4, which under-
goes smooth demercuration to give 2 while regenerating
catalyst Hg(OTf)2.5 If the corresponding alkenyl aniline
derivatives were treated with Hg(OTf)2, a stable sp3 C–Hg
bond would be formed in an essentially stoichiometric re-
action.6 We expected to overcome this drawback by intro-
ducing an oxygen-containing group as a protonation site
thereby triggering a smooth demercuration step. There-
fore, the reaction of anilino allyl alcohol 5 with a catalytic
amount of Hg(OTf)2 afforded indoline derivative 6 in
quantitative yield. An organomercuric intermediate 7
should be protonated by in situ formed TfOH and generate
oxonium ion 8. The latter leads to a smooth demercuration
step giving rise to indoline 6 and the regenerated catalyst
(Scheme 1). Described herein is the synthesis of 2-vinyl-
substituted indoline derivatives as well as tetrahydroquin-
oline, pyrrolidine, and piperidine derivatives by means of
Hg(OTf)2-catalyzed cyclization of N-tosylanilino- and
N-tosylaminoallylic alcohol derivatives. The vinyl func-
tionality maintained in the product should be useful for
Hg(OTf)2
r.t.
NH
Ts
OH
N
Ts
5
6
HgOTf
HgOTf
OH
6
+
N
N
OH2
Hg(OTf)2
HOTf
Ts
Ts
8
7
Scheme 1 Hg(OTf)2-catalyzed cyclization of alkynyl and alkenyl
aniline derivatives
further molecular modification such as hydroboration,
ozonolysis, and metathesis. Although Pd and Ni complex
catalyzed nitrogen allyl alcohol cyclizations were report-
ed, catalytic turnover was not very high.7,8 Quite recently
Au-salt-catalyzed cyclization of monoallylic diol to give
2-vinylpyrane has reported by Aponick and co-workers.9
First, we examined the reaction of (E)-N-[2-(4-hydroxy-
2-butenyl)phenyl]benzenesulfonamide (5)10 with 1 mol%
of Hg(OTf)2 in MeCN at room temperature for 20 hours,
and the expected vinylindoline derivative 6 was obtained
in 84% yield after column chromatography on silica gel
(Table 1, entry 1).10 This reaction was sensitive to solvent
effect, and MeNO2 and CHCl3 were shown to not be sat-
isfactory enough (entries 2 and 3). Since the substrate 5
was not soluble at all in toluene, the reaction did not pro-
ceed in this solvent (entry 4). CH2Cl2 was shown to be the
solvent of choice, and afforded 6 in quantitative yield
within 30 minutes using 1 mol% of Hg(OTf)2 (entry 5).
Although catalyst loading of 0.1 mol% gave rise to 6 in
98% yield within an acceptable reaction time (24 h),11
0.05 mol% was not enough to complete the reaction (en-
tries 6 and 7). The reactions were also examined using 2
SYNLETT 2008, No. 11, pp 1719–1723
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1077881; Art ID: U02408ST
© Georg Thieme Verlag Stuttgart · New York

1720
K. Namba et al.
LETTER
mol% of Hg(OTf)2 in (CH2Cl)2 at room temperature was
examined and the expected 2-vinylpyrrolidine 21 was ob-
tained in quantitative yield after 30 minutes.10 Amino allyl
alcohol 22 reacted with 0.3 mol% of Hg(OTf)2 affording
2-vinylpiperidine 23 in 65% yield.7 Reaction of amino al-
lyl alcohol 24 with 1 mol% of Hg(OTf)2 was also exam-
ined, however instead of the expected 2-vinylazetidine,
1-tosyl-1,2,3,6-tetrahydropyridine (25) was obtained as
the major product in 41% yield. Hg(OTf)2 probably acts
as the catalyst for the ring enlargement as seen in 26 and
following smooth demercuration from the cation 27
(Scheme 2) leads to 25.
Table 1 Hg(OTf)2-Catalyzed Cyclization of 5 to 6
Hg(OTf)2
Yield (%)a
Entry
Solvent
MeCN
MeNO2
CHCl3
(mol%)
Time
20 h
48 h
24 h
24 h
30 min
24 h
24 h
24 h
24 h
6
5
1
2
3
4
5
6
7
8
9
1
84
53
88
–
–
1
42
11
95
–
1
tolueneb
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
1
99
98
14
3
If aniline derivatives such as 28, containing a vinyl-
methoxy moiety, are cyclized by reaction with Hg(OTf)2,
generating intermediate 30, the methoxy group should act
as the protonation site. Thus, in situ generated TfOH
could protonate 30 leading to oxonium cation 31
(Scheme 3). The latter should undergo smooth demercu-
ration to regenerate Hg(OTf)2 and afford indole 29. Thus,
an E/Z (1:1) mixture of 28 was treated with 1 mol% of
Hg(OTf)2 in CH2Cl2, and 3-methylindole derivative 29
was obtained in 82% yield after three hours at room tem-
perature.
0.1
0.05
1c
1d
–
80
84
63
27
a Isolated yield.
b Compound 5 did not dissolve at all in toluene.
c Reaction was carried out with 2 mol% of Hg(OTFA)2.
d Reaction was carried out with 1 mol% of TfOH.
mol% of Hg(OTFA)2 and 1 mol% of TfOH as catalyst at
room temperature for 24 hours in CH2Cl2, but the yield of
6 were only 3% and 27%, respectively (entries 8 and 9).
These results suggested that the transformation of 5 to 6 in
the presence of Hg(OTf)2 is not an acid-catalyzed SN2¢ re-
action, and involves organomercuric intermediates 7 and
8.
HgOTf
Hg(OTf)2
+
NTs
N
Ts
27
26
Scheme 2 Reaction intermediates to give 25
The second substrate to be examined was (E)-N-
[2-(4-methoxy-2-butenyl)phenyl]-4-methylbenzenesul-
fonamide (9). Although the reaction of 9 with 1 mol% of
Hg(OTf)2 at room temperature was slower than the reac-
tion of 5, 2-vinylindoline 6 was obtained in 87% yield af-
ter one hour at room temperature (Table 2). The
corresponding acetate 10,12 however, did not react with
Hg(OTf)2 (2 mol%) at room temperature, and most of the
starting materials were recovered after two days. Reaction
of methyl-substituted E-allylalcohol 11 with 1 mol% of
Hg(OTf)2 at room temperature for two hours afforded 12
in 79% yield. Thus the procedure is suitable for the forma-
tion of a quaternary carbon center. Z-Isomer 13 also af-
forded 12 in 88% yield indicating that the reactivity is not
dependent on the stereochemistry of the double bond. Al-
though the reaction of 5-hydroxy-3-pentenyl derivative
14 with 1 mol% of Hg(OTf)2 at room temperature was
slower than the reaction of 5, tetrahydroquinoline deriva-
tive 15 was obtained in 52% yield after two hours at room
temperature.13 Reaction at reflux temperature in CH2Cl2,
however, afforded 15 in 96% yield after one hour. In con-
trast, reaction of the corresponding 6-hydroxy-3-hexenyl
derivative 16 in (CH2Cl)2 at 80 °C for 30 minutes afforded
the seven-membered ring product 17 in only 25% yield,12
together with an unexpected carbocyclization product 18
in 30% yield and an alternative tetrahydroquinoline 19 in
34% yield.13 Reaction of amino allyl alcohol 20 with 0.1
Hg(OTf)2
(1 mol%)
OMe
CH2Cl2
r.t., 3 h
NH
N
Ts
Ts
82%
28
29
HgOTf
HgOTf
H
O+
O
HOTf
N
Me
N
Me
Ts
Ts
30
31
Scheme 3 Hg(OTf)2-catalyzed cyclization of methoxyvinyl aniline
The corresponding butyl homologue 32 afforded 33 in
quantitative yield under similar conditions (Table 3). Re-
action of 34 with 1 mol% of Hg(OTf)2 afforded the six-
membered ring product 35 in 40% yield after heating to
120 °C for three hours in toluene. Attempted synthesis of
the corresponding seven-membered ring by the reaction
of 36 with 2 mol% of Hg(OTf)2 in toluene at room tem-
perature for five minutes resulted in the methoxylated
product 38 as the major product (66%), while the same re-
action in toluene at 100 °C for ten minutes afforded 37 in
52% yield along with 15% of 38. Neither eight- nor nine-
membered rings were accessible using this methodology.
Synlett 2008, No. 11, 1719–1723 © Thieme Stuttgart · New York

LETTER
Hg(OTf)2-Catalyzed Cyclization of N-Tosylanilinoallylic Alcohols to 2-Vinylindolines
1721
Table 2 Hg(OTf)2-Catalyzed Cyclization of Amino Allylic Alcohols
Substrate
Hg(OTf)2
(mol%)
Solvent
CH2Cl2
Temp
r.t.
Time
1 h
Product
(Yield%)a
1
2
6
87%
0
OMe
OAc
OH
NH
Ts
9
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
r.t.
r.t.
2 d
2 h
3 h
6
NH
Ts
10
1
1
79
88
NH
Ts
N
Ts
12
11
OH
12
NH
Ts
13
1
1
CH2Cl2
CH2Cl2
r.t.
2 h
1 h
52
96
NH
Ts
N
40 °C
14
Ts
15
OH
1
(CH2Cl)2
80 °C
30 min
25
NH
Ts
N
17
16
Ts
OH
30
34
18
NHTs
N
19
Ts
OH
20
0.1
0.3
(CH2Cl)2
(CH2Cl)2
r.t.
r.t.
30 min
10 h
99
65
NTs
NHTs
21
OH
NTs
NHTs
22
23
OH
1
CH2Cl2
r.t.
66 h
41
NTs
25
24
NHTs
a Isolated yield.
Thus, we have established a Hg(OTf)2-catalyzed anilino Acknowledgment
olefin cyclization reaction using neighboring oxygen
This study was financially 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.
functionality as the protonation site, facilitating the regen-
eration of the catalyst. The procedure should be of use in
a wide variety of carbocyclizations as well as heterocycle
synthesis.
Synlett 2008, No. 11, 1719–1723 © Thieme Stuttgart · New York

1722
K. Namba et al.
LETTER
Table 3 Hg(OTf)2-Catalyzed Cyclization of Methoxyvinyl Anilines
Substrate
Hg(OTf)2
(mol%)
Solvent
CH2Cl2
Temp
40 °C
Time
16 h
Product
Yield (%)a
C4H9
OMe
C4H9
1
2
99
40
NH
N
33
32
Ts
Ts
toluene
120 °C
3 h
N
NH OMe
Ts
35
34
Ts
1
1
toluene
toluene
r.t.
100 °C
5 min
10 min
0 (37), 66 (38)
52 (37), 15 (38)
N
NH
OMe
Ts
N
OMe
36
37
38
Ts
Ts
a Isolated yield.
Nishiyama, M.; Imagawa, H.; Nishizawa, M. Tetrahedron
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(0.01 M solution in MeCN, 6.3 mL, 0.063 mmol) at r.t., and
the mixture was stirred for 24 h. After addition of sat.
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a colorless powder; mp 111 °C. IR (neat): 3066, 1598, 1354,
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Hz, 1 H), 7.57 (d, J = 8.1 Hz, 2 H), 7.21 (m, 1 H), 7.17 (d,
J = 8.1 Hz, 1 H), 7.01–7.07 (m, 2 H), 6.99 (dd, J = 0.9, 7.5
Hz, 1 H), 5.91 (ddd, J = 6.3, 10.2, 16.8 Hz, 1 H), 5.39 (dt,
J = 1.2, 16.8 Hz, 1 H), 5.15 (dt, J = 1.5, 10.2 Hz, 1 H), 4.74
(m, 1 H), 2.95 (dd, J = 9.9, 15.9 Hz, 1 H), 2.64 (dd, J = 3.3,
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Synlett 2008, No. 11, 1719–1723 © Thieme Stuttgart · New York

LETTER
Hg(OTf)2-Catalyzed Cyclization of N-Tosylanilinoallylic Alcohols to 2-Vinylindolines
1723
15.9 Hz, 1 H), 2.36 (s, 3 H). 13C NMR (75 MHz, CDCl3):
(12) Hara, O.; Koshizawa, T.; Makino, K.; Kunimune, I.; Namiki,
A.; Hamada, Y. Tetrahedron 2007, 63, 6170.
(13) Larock, R. C.; Berrios-Pena, N. G.; Fried, C. A.; Yum, E. K.;
Tu, C.; Leong, W. J. Org. Chem. 1993, 58, 4509.
d = 143.8, 141.4, 137.6, 135.3, 131.2, 129.5, 127.7, 127.1,
125.1, 124.5, 116.8, 115.7, 63.8, 34.9, 21.5. HRMS (EI):
m/z [M]+ calcd for C17H19NO3S+: 299.0980; found:
299.0999.
Synlett 2008, No. 11, 1719–1723 © Thieme Stuttgart · New York