Catalytic asymmetric pictet-spengler-type reaction for the synthesis of optically active indolo[3,4-cd][1]benzazepines

Article abstract of DOI:10.1021/ol202361t

A new strategy has been introduced to develop a catalytic asymmetric Pictet-Spengler-type reaction by replacing the aldehyde with an imine. A range of 4-(2-aminoaryl)indoles smoothly undergo the chiral phosphoric acid catalyzed asymmetric Pictet-Spengler-

Full text of DOI:10.1021/ol202361t

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5636–5639
Catalytic Asymmetric PictetÀSpengler-
Type Reaction for the Synthesis of
Optically Active Indolo[3,4-
cd][1]benzazepines
Dao-Juan Cheng, Hai-Bian Wu, and Shi-Kai Tian*
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, China
tiansk@ustc.edu.cn
Received August 31, 2011
ABSTRACT
A new strategy has been introduced to develop a catalytic asymmetric PictetÀSpengler-type reaction by replacing the aldehyde with an imine. A
range of 4-(2-aminoaryl)indoles smoothly undergo the chiral phosphoric acid catalyzed asymmetric PictetÀSpengler-type reaction with imines at
room temperature to give structurally diverse indolo[3,4-cd][1]benzazepines in good to excellent yields and ee.
The PictetÀSpengler reaction, discovered 100 years
ago,1 is now widely employed in the construction of various
nitrogen-containing heterocycles.2 This transformation is
generally accomplished by treatment of aldehydes with
β-(hetero)arylethylamines in the presence of acidic catalysts,
which promote imine formation and subsequent cyclization
through an intramolecular FriedelÀCrafts reaction (Scheme
1, path a). In recent years a number of catalytic asymmetric
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r
10.1021/ol202361t
Published on Web 09/26/2011
2011 American Chemical Society

PictetÀSpengler reactions have been developed for the synth-
esis of optically active six-membered nitrogen-containing
heterocycles with high enantioselectivity.3,4 Nevertheless, to
our knowledge, there is no catalytic asymmetric PictetÀ
Spengler-type reaction reported previously for the construc-
tion of chiral seven-membered ring systems.
Figure 1. Chiral indole-fused ring systems based on the catalytic
asymmetric modification of the pyrrole ring of indole.
Scheme 1. Proposed PictetÀSpengler-Type Reaction
Our investigation is based on Kundu’s recent report on
the synthesis of racemic indolo[3,4-cd][1]benzazepines
through a trifluoroacetic acid catalyzed modified PictetÀ
Spengler reaction of 4-(2-aminoaryl)indoles with
aldehydes.11 Initially, we found that phosphoric acids were
effective in catalyzing this transformation.12 For example,
treatment of 4-(2-aminophenyl)indole (1a) with aldehyde
2aa (1.1 equiv) and 10 mol % of phosphoric acid 4a in
dichloromethane at room temperature resulted in the
formation of indolo[3,4-cd][1]benzazepine 3a in 99% yield
and with 33% ee (Table 1, entry 1). To improve the
enantioselectivity according to our aforementioned hy-
pothesis, we replaced aldehyde 2aa with imine 2ab in the
reaction and, gratifyingly, found thatthe enantioselectivity
was enhanced to 39% for the same product albeit a
decreased reaction rate was observed (Table 1, entry 2).
Screening of solvents revealed that the reaction exhibited
the best enantioselectivity in tetrahydrofuran (46% ee,
Table 1, entry 8). It was fruitless to improve the enantio-
selectivity by replacing the p-methoxyphenyl group of
imine 2ab with another aryl group, a sulfonyl group, or a
diphenylphosphinyl group (Table 1, entries 10À18).
Nevertheless, the reactivity and enantioselectivity were
dramatically affected by the structure of the chiral phos-
phoric acid (Table 1, entries 19À26), and the employment
of commercially available catalyst 4d enhanced the enan-
tioselectivity to 82% ee (Table 1, entry 21). Finally, the
Prompted by our recent exploration of new reactions
through the complete cleavage of carbonÀnitrogen double
bonds,5,6 we envisioned that a PictetÀSpengler-type reac-
tion could occur by replacing the aldehyde with an imine
because the same precursor for cyclization could be gen-
erated through transimination under acidic conditions
(Scheme 1, path b).7 Although the N-substituent of an
imine would not go to the final product, it might affect
reactivity and enantioselectivity through nonbonding in-
teractions with a chiral acidic catalyst. We hoped that the
formation of an amine or an ammonia equivalent, instead
of water, as the byproduct would be beneficial to enhance
enantioselectivity.
Much attention has been paid to the construction of
indole-fused ring systems due to their broad range of
interesting biological properties.8 Catalytic asymmetric
modification of the pyrrole ring of indole has recently
emerged as a powerful approach to the construction of
chiral indole-fused ring systems. However, they are limited
to 1,2- and 2,3-fused indole derivatives (Figure 1).9,3,10
Herein, we wish to report a catalytic asymmetric synthesis
of optically active 3,4-fused indole derivatives, indolo[3,4-
cd][1]benzazepines, through a chiral phosphoric acid cata-
lyzed PictetÀSpengler-type reaction of 4-(2-aminoaryl)indoles
with imines.
˚
addition of 3 A molecular sieves and decreasing the con-
centration allowed the synthesis of indolo[3,4-cd]-
[1]benzazepine 3a with up to 90% ee (Table 1, entry 27).
It is noteworthy that the enantioselectivity is much better
than that obtained from the reaction with aldehyde 2aa
under the same conditions (83% ee, Table 1, entry 28).
Under the optimized reaction conditions, a range of
4-(2-aminoaryl)indoles smoothly underwent the asym-
metric PictetÀSpengler-type reaction with various imines
in the presence of 10 mol % of chiral phosphoric acid 4d at
room temperature to give structurally diverse indolo[3,4-
cd][1]benzazepines in good to excellent yields and ee (Table
2). It is noteworthy that this reaction tolerated a variety of
functional groups, such as alkoxy, halide, sulfonate, and
(7) For examples, see: (a) Zajac, W. W.; Walters, T. R.; Darcy, M. G.
J. Org. Chem. 1988, 53, 5856–5860. (b) Giuseppone, N.; Schmitt, J.-L.;
Schwartz, E.; Lehn, J.-M. J. Am. Chem. Soc. 2005, 127, 5528–5539.
(8) For reviews, see: (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004,
21, 278–311. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–
103. (c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761–793. (d)
Ishikura, M.; Yamada, K.; Abe, T. Nat. Prod. Rep. 2010, 27, 1630–1680.
(9) (a) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2008, 47, 3238–3241. (b) Enders, D.; Wang, C.;
Raabe, G. Synthesis 2009, 4119–4124. (c) Hong, L.; Sun, W.; Liu, C.;
Wang, L.; Wang, R. Chem.;Eur. J. 2010, 16, 440–444. (d) Cai, Q.;
Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2010, 49, 8666–8669.
(10) (a) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi,
S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424–1425. (b) Han,
X.; Widenhoefer, R. A. Org. Lett. 2006, 8, 3801–3804. (c) Li, C.-F.; Liu,
H.; Liao, J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett. 2007, 9, 1847–
1850. (d) Huang, H.; Peters, R. Angew. Chem., Int. Ed. 2009, 48, 604–
(11) Saifuddin, M.; Agarwal, P. K.; Sharma, S. K.; Mandadapu,
A. K.; Gupta, S.; Harit, V. K.; Kundu, B. Eur. J. Org. Chem. 2010, 5108–
5117.
(12) For reviews of asymmetric catalysis with chiral phosphoric
acids, see: (a) Terada, M. Synthesis 2010, 1929–1982. (b) Terada, M.
Chem. Commun. 2008, 4097–4112. (c) Akiyama, T. Chem. Rev. 2007,
107, 5744–5758.
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(f) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew. Chem., Int. Ed. 2009, 48,
7428–7431. (g) Zhang, J.-W.; Cai, Q.; Shi, X.-X.; Zhang, W.; You, S.-L.
Synlett 2011, 1239–1242.
Org. Lett., Vol. 13, No. 20, 2011
5637

Table 1. Optimization of Reaction Conditionsa
Table 2. Catalytic Asymmetric Synthesis of Indolo[3,4-cd][1]-
benzazepinesa
yield/ ee/
b
%
c
%
entry
2a
X
solvent
catalyst
1d
2
2aa
O
CH2Cl2
CH2Cl2
CHCl3
PhMe
EtOAc
Et2O
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
99
98
98
83
95
91
86
96
95
79
80
83
76
95
77
78
88
75
83
90
90
92
60
62
84
88
90
99
33
39
39
28
39
42
43
46
6
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
3
4
5
6
7
dioxane
THF
8
9
MeCN
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27e,f
28f
2ac
NPh
41
30
33
34
45
31
32
25
16
49
74
82
33
29
14
34
11
90
83
2ad NC6H4Br-4
THF
2ae
2af
NC6H4Cl-4
NC6H4Cl-2
THF
THF
2ag NC6H4OH-2
THF
2ah NC6H4OMe-2 THF
2ai
2aj
NNp-1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NSO2Me
2ak NPOPh2
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
2ab NPMP
4g
4h
4i
4d
4d
2aa
O
a Reaction conditions: 1 (0.050 mmol), 2 (1.1 equiv), catalyst 4d (10
mol %), 3 A molecular sieves (30 mg), THF (1.5 mL), rt, 70 h. b Isolated
˚
a Reaction conditions: 1a (0.050 mmol), 2a (1.1 equiv), catalyst 4 (10
mol %), solvent (1.0 mL), rt, 24 h. b Isolated yield. c Determined by chiral
stationary phase HPLC analysis. d The reaction was run for 5 h. e The
reaction was run for 70 h. f The reaction was run in 1.5 mL of THF in the
yield. c Determined by chiral stationary phase HPLC analysis. d The
absolute configuration of product 3i was determined by single crystal
X-ray analysis, and that of the rest of the products was assigned by
analogy.
˚
presence of 3 A molecular sieves (30 mg).
ester, and bulky groups next to the amino groups of 4-(2-
aminoaryl)indoles.
Significantly inferior reactivity was observed with a 4-(2-
aminoaryl)-7-azaindole under the same reaction condi-
tions. For example, the PictetÀSpengler-type reaction
did not take place between 4-(2-aminophenyl)-7-azaindole
(5) and imine 2ab in the presence of 10 mol % of chiral
phosphoric acid 4d at room temperature (eq 1). Never-
theless, replacement of imine 2ab with aldehyde 2aa resulted
in the formation of 7-azaindolo[3,4-cd][1]benzazepine 6 in
77% yield and with 90% ee.
To gain insight into the origin of enantioselectivity, the
PictetÀSpengler-type reaction of 4-(2-aminophenyl)-1-meth-
ylindole (7) with imine 2ab was carried out in the presence of
5638
Org. Lett., Vol. 13, No. 20, 2011

10 mol % of chiral phosphoric acid 4d at room temperature
(eq 2). In direct contrast to the results summarized in Table 2,
this reaction only afforded 3% ee. This result clearly indicates
that the indole NH moieties of 4-(2-aminoaryl)indoles are
essential for the high enantioselectivity with regard to the
formation of indolo[3,4-cd][1]benzazepines.13
Figure 2. A possible complex for the formation of indolo[3,4-
cd][1]benzazepine 3.
replacing the aldehyde with an imine. A range of 4-(2-
aminoaryl)indoles smoothly undergo the asymmetric Pic-
tetÀSpengler-type reaction with imines in the presence of
10 mol % of a commercially available chiral phosphoric
acid at room temperature to give structurally diverse
indolo[3,4-cd][1]benzazepines in good to excellent yields
and ee. This strategy extends the catalytic asymmetric
PictetÀSpengler reaction, for the first time, to constructing
seven-membered ring systems in a highly enantioselective
manner.
Our experimental results suggest that the arylamine
byproduct and the indole NH moiety should play impor-
tant roles to determine the enantioselectivity in the step of
chiral phosphoric acid catalyzed asymmetric 7-endo-trig
cyclization of the precursor generated through the transi-
mination of imine 2 with 4-(2-aminoaryl)indole 1. Although
there is no direct evidence available at present, a possible
complex is illustrated in Figure 2 for the formation of
indolo[3,4-cd][1]benzazepine 3. The cyclization precursor,
the chiral phosphoric acid, and the arylamine byproduct are
tentatively organized through hydrogen bonding interac-
tions,13 and such an organization should facilitate the
cyclization step in a highly enantioselective manner.
Acknowledgment. We are grateful for the financial sup-
port from the National Natural Science Foundation of China
(20972147 and 20732006) and the National Basic Research
Program of China (973 Program 2010CB833300).
In summary, we have presented a new strategy to extend
the catalytic asymmetric PictetÀSpengler reaction to
the construction of nitrogen-containing heterocycles by
Supporting Information Available. Experimental pro-
1
cedures; characterization data; copies of H NMR, 13C
NMR, and HPLC spectra for products; and crystal data
for compound 3i. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) For related examples, see: (a) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.;
Zhang, C.-M.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46, 5565–5567.
(b) Lin, J.-H.; Xiao, J.-C. Eur. J. Org. Chem. 2011, 4536–4539.
Org. Lett., Vol. 13, No. 20, 2011
5639