Preparation of bisindolylalkanes from N-tert-butanesulfinyl aldimines

Article abstract of DOI:10.1016/j.tetlet.2004.12.140

A series of bisindolylalkanes were synthesized by nucleophilic addition reactions of indole with N-tert-butanesulfinyl aldimines in good to excellent yields catalyzed by either iodine, potassium hydrogen sulfate and amberlyst.

Full text of DOI:10.1016/j.tetlet.2004.12.140

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1751–1753
Preparation of bisindolylalkanes from N-tert-butanesulfinyl
aldimines
*
Bowen Ke, Yong Qin, Qinfei He, Zhiyan Huang and Fengpeng Wang
*
Department of Chemistry of Medicinal Natural Products, West China School of Pharmacy, Sichuan University,
Chengdu 610041, PR China
Received 2 November 2004; revised 31 December 2004; accepted 4 January 2005
Available online 29 January 2005
Abstract—A series of bisindolylalkanes were synthesized by nucleophilic addition reactions of indole with N-tert-butanesulfinyl
aldimines in good to excellent yields catalyzed by either iodine, potassium hydrogen sulfate and amberlyst.
Ó 2005 Elsevier Ltd. All rights reserved.
Bisindolylalkane 1 is an important class of bioactive
1
R
metabolite. With the continuing isolation of structur-
2
R
O
S
catalyst
ally more diverted bisindolylalkanes, the efficient syn-
theses of bisindolylalkanes become an increasing
+
N
N
H
N
H
N
H
3
interest in organic synthesis. Although bisindolylalk-
2
1
3
anes were usually prepared by the protic or Lewis
acid-catalyzed addition reactions of indole with alde-
hydes, the electron nucleophilic additions of indole to
Schiff bases are scarcely studied probably due to the
low reactivity of Schiff bases compared with aldehydes.
Banerji et al. reported that indole can react with aro-
Scheme 1. The addition reaction of indole with aldimine 3.
Since the carbon-3 of indole possesses certain nucleo-
philic characteristics, we were wondering whether the
addition reaction of indole with aldimine 3 could be
accomplished without any additives. As shown in Table
, when N-tert-butanesulfinyl p-methoxybenzal aldimine
a was used as a model compound, the reaction was not
4
5
matic aldimines and nitrones to afford bisindolylalk-
anes in low to moderate yields in the presence of BF3
etherate or Me SiCl. InCl was reported to be a catalyst
3
3
1
3
for the addition reaction of indole with aromatic aldi-
6
a
mines. the addition reaction of indole with aromatic
b
aldimine was extremely difficult.
successful without additive at room temperature in dry
CH CN, MeOH, CH Cl , THF, DMSO, toluene, and
6
3
2
2
xylene. The reaction was very sluggish at an elevated
temperature in toluene and xylene. Decomposition of
aldimine 3a occurred, and the desired bisindolylalkane
7
N-tert-Butanesulfinyl aldimine 3 is a new type of Schiff
base and has been found to have tremendous applica-
tions in the addition reactions of organometallic re-
1a was obtained in low yield (Table 1, entries 1 and 2).
8
agents in recent years, but its electrophilic reactivity
toward the weak nucleophilic indole remains unex-
plored. In this letter, we report that three agents,
iodine, potassium hydrogen sulfate and amberlyst, can
serve as mild and efficient catalysts for the addition reac-
tions of indole with aldimines 3 to give bisindolylalkanes
in moderate to excellent yields (Scheme 1).
Then we screened the effect of a variety of protic and
Lewis acids on the addition reaction. The reaction cata-
lyzed by 1 equiv of ammonium ceric nitrate proceeded
slowly to give 1a in 81% yield in MeOH and in 39% yield
in toluene (Table 1, entries 3 and 4). NBS promoted the
reaction in moderate yield in MeOH (entry 5). BF eth-
3
erate catalyzed the reaction in good yield in CH Cl , but
2
2
a lower temperature was necessary (Table 1, entry 6). At
room temperature, the reaction with aldimine 1a gave a
*
0
Corresponding authors. Tel./fax: +86 28 85503842; e-mail:
yanshuqin@yahoo.com
complicate mixture when BF etherate was used. Protic
3
acid H SO catalyzed the addition reaction in MeOH at
2
4
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.140

1752
B. Ke et al. / Tetrahedron Letters 46 (2005) 1751–1753
a
9
Table 1. Catalyst screening for the addition of indole to aldimine 3
Table 2. Addition reaction of indole with aldimine 3
b
a
Entry 1 R = 4-MeOPh Catalyst
Solvent Time (h) Yield
1,R
Entry Reagent
Solvent Time (h) Yield
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
None
None
Can
Toluene 48
Xylene 48
Toluene 48
36
34
39
81
1b
Ph
1
2
3
Amberlyst MeCN 3091
MeOH 16
d
KHSO
4
95
97
I
2
MeCN
6
Can
NBS
MeOH
MeOH
CH Cl
48
1054
16
6
1c
4-MePh
4
5
6
Amberlyst MeCN
24
MeOH 24
94
95
95
e
f
KHSO
4
BF
SO
3
2
2
71
61
0
I
2
MeCN
5
H
2
4
MeOH
MeOH
MeOH
MeOH
TFA
TFA
24
24
12
24
1d
4-NO Ph
7
8
9
Amberlyst MeCN
KHSO4
I2
24
MeOH 15
93
94
97
43
53
89
91
2
f
0
1
2
3
4
TsOH
MeCN
5
Amberlyst MeOH
Amberlyst CH
KHSO MeOH
CH CN
b
1
e
-CIPh
10Amberlyst MeCN
11 KHSO
12
MeOH 12
91
81
87
3
CN 24
b
4
4
4
2093
5
1
2
I
2
MeCN
5
I
2
3
94
b
a
1f
13
Ph 14
15
Amberlyst MeCN
KHSO
24
MeOH 15
73
94
72
The reaction was conducted at room temperature except the one
indicated in the table with 1 equiv additive.
b
3
,4-(MeO)
2
4
b
c
d
e
f
I
2
MeCN
5
Isolated yield.
At 110 °C.
At 140 °C.
At ꢀ20 °C.
At 60 °C.
1g
2-Furyl
16
17
18
Amberlyst MeCN
KHSO4
I2
12
MeOH 3044
81
51
MeCN
5
1
h
19
Amberlyst MeCN
1081
Ph–(CH
2
)
2
–
20KHSO
4
MeOH 3069
2
1
I
2
MeCN
4
90
81
room temperature to afford 1a in moderate yield, while
TFA and TsOH required a higher temperature (entries
1
n-Butyl
i
22
23
Amberlyst MeCN
EtOH
MeCN
12
KHSO
4
3076
5
7
–10). The observation that a simple protic acid can
2
4
I
2
95
81
effectively promote the addition reaction encouraged
us to test different acidic additives such as amberlyst
1j
Isopropyl
25
26
Amberlyst MeCN
KHSO
12
MeOH 200
MeCN
(
ment of indole and aldimine 3a with amberlyst or
strong sulfonic acid form) and KHSO . Direct treat-
4
4
2
7
I
2
5
90
a
KHSO4 at room temperature in MeOH or CH CN
3
Isolated yields.
At 60 °C.
b
afforded the desired 1a in 89–93% yields (entries 11–
1
3). Further examination of additives led us to find that
iodine promoted the addition reaction more effectively
in short time (94% yield, entry 14).
the addition reaction of indole with more hindered iso-
propylal aldimine 3k (Table 2, entry 26).
Having found that amberlyst, KHSO , and I are effec-
2
4
From the mechanistic point of view, the first step for the
formation of bisindolylalkane 1 involves a nucleophilic
attack of indole to aldimine activated by a catalyst. Both
tive catalysts in the addition reaction of indole with
aldimine 3a, we then tested the applicable scope of cur-
rent method in the addition reaction of indole with dif-
0
10
coordination of aldimine with iodine (intermediate 3
and acidification of aldimine by amberlyst and KHSO
)
ferent aldimines in MeOH and CH CN. As shown in
3
4
Table 2, the addition reactions of indole with aldimines
3 catalyzed by iodine were unexceptionably faster than
the reactions catalyzed by amberlyst and KHSO . Three
00
(intermediate 3 ) make the aldimine more electrophilic
and more eligible to the attack of indole to give interme-
diate 4. Consequent loss of tert-butanesulfinamide moi-
ety provides the azafulvenium salts 5. The azafulvenium
4
of these catalysts were able to catalyze the reactions of
aromatic aldimines 3 bearing both electron-donating
and electron-withdrawing groups smoothly in over
8
The exception was that the addition reactions of aldim-
0% yields (entries 1–9 and 12) at room temperature.
R
O
S
R
O
S
N+
N
ine 3e and aldimine 3f catalyzed by amberlyst and
KHSO were very slow at room temperature, a higher
catalyst
N
H
+
H
3'
4
N
H
R
O
temperature was required to promote the reaction (Ta-
ble 2, entries 10–11 and 13–14). In the case of aldimine
3f, the addition reaction with KHSO was better than
4
that with amberlyst (Table 2, entries 13 and 14). In con-
N
H
4
S
2
O
S
I2
3''
H N
2
R
R
trast, amberlyst was superior to KHSO in the addition
4
reaction of aldimine 3g (Table 2, entries 16 and 17). For
the addition reaction with aliphatic aldimines 3, iodine
was the best choice of catalyst, which was still capable
to catalyze the reactions in over 90% yields, while
N+
N
H
N
H
5
1
H
amberlyst and KHSO promoted the reactions in good
4
yields (Table 2, entries 19–27). KHSO failed to catalyze
4
Scheme 2. A plausible mechanism for the addition reaction.

B. Ke et al. / Tetrahedron Letters 46 (2005) 1751–1753
1753
salts 5 can undergo further addition with second indole
to afford 1 (Scheme 2).
4. (a) Banerji, J.; Kumar, M.; Sarkar, S. Indian J. Chem.
983, 22B, 27–29; (b) Banerji, J.; Saha, M.; Chakrabarti,
1
R.; Das, A. K.; Pandit, U. K.; Chatterjee, A. Indian J.
Chem. 1986, 25B, 1204–1208.
. (a) Banerji, A.; Mukhopadhyay, A. Indian J. Chem. 1982,
21B, 239–241; (b) Denis, J. N.; Mauger, H.; Vallee, Y.
Tetrahedron Lett. 1997, 38, 8515–8518.
. (a) Babu, G.; Sridhar, N.; Perumal, P. T. Synth. Commun.
In summary, we have described a new procedure for the
preparation of bisindolylalkanes through a nucleophilic
attack of indole to N-tert-butanesulfinyl aldimine cata-
lyzed by amberlyst, iodine and KHSO4.
5
6
2
000, 30, 1609–1614; (b) Wynne, J. H.; Stalick, W. M.
J. Org. Chem. 2002, 67, 5850–5853.
7. (a) For the preparation of N-tert-butanesulfinyl aldimines
, see: Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem.
Acknowledgements
3
Soc. 1997, 119, 9913–9914; (b) Liu, G.; Cogan, D. A.;
Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278–
Supports from Ministry of Education (NCET, RFDP,
EYTP, SRF for ROCS), the Excellent Youth Founda-
tion of Sichuan Province (No. 04ZQ026-011), and the
National Natural Science Foundation of China (No.
1
4
284, The racemic tert-butanesulfinamide was prepared in
0–45% yield in three steps by oxidization of tert-butyl
disulfide with H
with SO Cl , followed by amination of the resulting tert-
2 2
O , chlorization of tert-butanetiosulfinate
2
0372048) are gratefully acknowledged.
2
2
4
butanesulfinate chloride with NH OH; (c) For the prep-
aration of optically pure tert-butanesulfinamide, see: Han,
Zh.-X.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.;
Senanayake, Ch. H. J. Am. Chem. Soc. 2002, 124, 7880–
7881; (d) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5,
1317–1320; (e) Qin, Y.; Wang, C.; Huang, Z.; Xiao, X.;
Jiang, Y. J. Org. Chem. 2004, 69, 8533–8536.
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3
9. General procedure: Indole (1 mmoL)and N-tert-but-
(0.5 mmol) were mixed with
4
, or 450mg of amberlyst (strong
anesulfinyl aldimine
0.5 mmol of I or KHSO
3
2
sulfonic acid form) in 10mL of dry solvent (as indicated in
Table 2). The reaction mixture was stirred for 4–30h at
room temperature until 3 was completely consumed
1
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checked by TLC. For the I
solution of Na was added to the reaction mixture to
destroy the excess I . For the KHSO catalyzed reaction,
the KHSO was removed by a simple filtration. For the
amberlyst catalyzed reaction, the amberlyst was recycled
by a simple filtration. After removing the solvent, the
mixture was subjected to chromatography to afford the
corresponding bisindolylalkane 1.
2
catalyzed reaction, a saturated
2 2 4
S O
2
4
4
3
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10. Aldehyde can be activated by the coordination of iodine
with oxygen atom of aldehyde, see Refs. 3c and g.
3
4, 275–280.