Pictet-Spengler reaction of nitrones and imines catalyzed by Yb(OTf)3-TMSCI

Article abstract of DOI:10.1246/cl.2002.428

The Pictet-Spengler reaction of nitrones and imines prepared from N-hydroxytryptamine and tryptamine gave the corresponding tetrahydro-β-carbolines in excellent yields in the presence of Yb(OTf)₃-TMSCl in a mixture of CH₂Cl₂

Full text of DOI:10.1246/cl.2002.428

428
Chemistry Letters 2002
Pictet–Spengler Reaction of Nitrones and Imines Catalyzed by Yb(OTf)3–TMSCl
Riichiro Tsuji, Masamichi Yamanaka, Atsushi Nishida, and Masako NakagawaÃ
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Chiba 263-8522
(Received January 9, 2002;CL-020028)
The Pictet–Spengler reaction of nitrones and imines prepared
from N-hydroxytryptamine and tryptamine gave the correspond-
ing tetrahydro-ꢀ-carbolines in excellent yields in the presence of
Yb(OTf)3–TMSCl in a mixture of CH2Cl2 and THF.
The Pictet–Spengler reaction has been shown to be useful for
the synthesis of tetrahydro-ꢀ-carbolines and has often been
applied to the synthesis of natural products.1 We succeeded in the
total synthesis of natural products such as fumitremorgin2 and
eudistomins3 using a diastereoselective Pictet–Spengler reaction.
Although this reaction proceeds efficiently under the acidic
conditions, other type of promoters are required to use acid-
sensitive substrate and also to develop a chiral version of Pictet–
Spengler reaction.4
Rare-earth triflates have recently been recognized as stable,
less-toxic, and environmentally harmonious Lewis acid catalysts.
Various reactions have been developed using these catalysts,
including the reactions of imines.5 We have also reported that
Yb(OTf)3 is a powerful catalyst for imino-ene reaction in
combination with a catalytic amount of TMSCl.6;7 We report
here the Pictet–Spengler reaction of imines catalyzed by the
combination of Yb(OTf)3 and TMSCl.
First, we tested the effectiveness of the catalyst system,
Yb(OTf)3–TMSCl, in the Pictet–Spengler reaction of nitrones
(Scheme 1 and Table 1). The reaction of 1a in CH2Cl2-THF
(4 : 1) with only Yb(OTf)3 (1.2 equiv) gave 2a in 12% yield after
5 h at room temperature (entry 1). On the other hand, TMSCl
(1.0 equiv) by itself promoted this reaction to give 2a in 70% yield
(entry 2) within 20 min. However, the reaction was considerably
slow when only 0.12 equiv of TMSCl was used (entry 3). In
contrast to these results, the reaction with both Yb(OTf)3 and
TMSCl proceeded efficiently and 1a was cyclized to 2a in
quantitative yield within 20 min (entries 4 and 5).
Scheme 1.
Table 1. Pictet–Spengler reaction of nitrones promoted by
Yb(OTf)3–TMSCl
Entry Substrate Yb(OTf)3 TMSCl Time Yielda
/equiv
/equiv
/min
/%
12
70
30
>99
>99
36
84
98
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
1.2
- -
- -
1.0
0.25
0.25
0.25
0.25
0.25
- -
1.0
0.12
0.12
1.0
1.0
1.0
1.0
1.0
300
20
20
20
20
300
2
90
50
30
aIsolated yield.
Scheme 2.
Next, we investigated substituent effects under the conditions
used for entry 5 in Table 1. The cyclization of p-anisyl nitrone 1b
required a prolonged reaction time and gave 2b in only 36% yield
(entry 6). On the other hand, the reaction of nitrone 1c, which has
an electron-defficient CN double bond by substitution of a nitro
group, proceeded within 2 min and gave 2c in high yield (entry 7).
The methyl nitrone 1e gave 2e in only 30% yield (entry 9).
Then, we turned our attention to the Pictet–Spengler reaction
of imines prepared from tryptamine and various aldehydes
(Scheme 2 and Table 2). The Pictet–Spengler reaction of 3a using
1.0 equiv of Yb(OTf)3 gave only a trace amount of 3b. However,
the addition of 1.0 equiv of TMSCl together with Yb(OTf)3
promoted the reaction and ꢀ-carboline 3b was isolated in
quantitative yield, whereas the reaction with 1.0 equiv of TMSCl
gave 3b in only 7% yield. TMSOTf did not promote the reaction.
The similar reaction of 3b, 3c, and 3d in the presence of Yb(OTf)3
and TMSCl (1.0 equiv of each) gave the corresponding ꢀ-
carbolines, 4b, 4c and 4d, in quantitative yields. While 3e gave
Table 2. Pictet–Spengler reaction of imines promoted by
Yb(OTf)3–TMSCl
Entry Substrate Yb(OTf)3 TMSCl
/equiv
Time
/h
Yielda
/%
/equiv
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
3d
3e
3e
1.0
- -
- -
1.0
1.0
1.0
1.0
1.0
1.0
10.0
41
1.3
5
trace
7
1.0
1.0
1.0
1.0
1.0
1.0
>99
>99
>99
>99
trace
>99
4
10 min
16
2
20
aIsolated yield.
only a trace amount of 4e under the above conditions, the addition
of 10 equiv of TMSCl improved the reaction.
A two-component Pictet–Spengler reaction, which should
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
429
proceed without isolation of an imine, is desirable when the imine
is unstable. However, most Lewis acids arenoteffective forsuch a
two-component reaction because the reaction involves highly
reactive amines and water. Thus, using a water-tolerant Lewis
acid, Yb(OTf)3,8 we examined two-component coupling between
tryptamine (5) and p-nitrobenzaldehyde (6) in the presence of
Yb(OTf)3 and TMSCl (Scheme 3 and Table 3).
Mukaiyama on the occasion of his 75th birthday.
References and Notes
1
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3
4
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Table 3. Two-component Pictet–Spengler reaction
Entry
Yb(OTf)3
/equiv
TMSCl
/equiv
Time
/h
Yielda
/%
1
2
3
4
5
6
1.0
0.3
0.2
0.1
0.05
- -
1.0
1.0
1.0
1.0
1.0
1.0
10
25
40
56
61
76
16
3.5
3.5
3.5
3.5
18
aIsolated yield.
5
a) S. Kobayashi, H. Ishitani, and S. Nagayama, Synthesis,
1995, 1195. b) S. Kobayashi and H. Ishitani, J. Chem. Soc.,
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Chem. Soc., 114, 4418 (1992).
When a mixture of 5 and 6 (1 : 1) was stirred under the same
conditions as for entry 2 in Table 2, the reaction proceeded slowly
and gave ꢀ-carboline 4c in 25% yield after 10 h. When 1.0 equiv
of Yb(OTf)3 is used, tryptamine may coordinate with Yb(OTf)3
and prevent imine formation. Therefore, reactions using less than
1.0 equiv of Yb(OTf)3 were examined. The yield of 4c increased
dramatically up to 76%. The reaction without Yb(OTf)3 gave the
product in only 16% yield, and the two-component reaction was
only successful using 6.9
In summary, we have developed an efficient Yb(OTf)3–
TMSCl-mediated Pictet–Spengler reaction using mild condi-
tions. Further studies toinvestigate the mechanism of this reaction
and its application in asymmetric processes are under in-
vestigation.10
6
M. Yamanaka, A. Nishida, and M. Nakagawa, Org. Lett., 2,
159 (2000).
7
8
M. Nakagawa, and M. Kawahara, Org. Lett., 2, 953 (2000).
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Soc. Chem. Commun., 1976, 1060. b) J. Forsberg, V.
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52, 1017 (1987).
This research was supported by a Grant-in-Aid for Scientific
Research in Priority Areas (A) ‘‘Exploitation of Multi-Element
Cyclic Molecules’’ from the Ministry of Education, Culture,
Sports, Science, and Technology. Financial support from the
Uehara Memorial Foundation is also acknowledged. We also
thank Ms. R. Hara at the Analytical Center, Chiba University, for
performing mass spectroscopy.
9
The same reaction using bezaldehyde was unsuccessful.
10 The mechanism of this synergistic effect between Yb(OTf)3
and TMSCl is under investigations. A previous report on the
activation of CN double bond by TMSCl;C. Jimeno, A.
`
Vidal-Ferran, A. Moyano, M. A. Pericas, and A. Riera,
Tetrahedron Lett., 40, 777 (1999).
The present work is dedicated to Professor Teruaki