1,2- and 1,4-additions of 2-alkynylcyclohexadienimines with aromatic amines to access 4-amino- N -arylindoles and -azepinoindoles

Article abstract of DOI:10.1021/ol3029675

2-Alkynylcyclohexadienimines, derived from the oxidation of 2-alkynylanilines, react with aromatic amines leading to N-arylindoles with a 4-amino substitution. The reaction was metal-controlled, and Bi(OTf)₃ proved to be the best catalyst. The resulting 4-amino N-arylindoles could be converted to azepino[4,3,2-cd]indoles through condensation with aldehydes.

Full text of DOI:10.1021/ol3029675

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
1,2- and 1,4-Additions
of 2‑Alkynylcyclohexadienimines
with Aromatic Amines To Access
4‑Amino‑N‑arylindoles and -azepinoindoles
Li Zhang, Zhiming Li,* and Renhua Fan*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China
rhfan@fudan.edu.cn; zmli@fudan.edu.cn
Received October 28, 2012
ABSTRACT
2-Alkynylcyclohexadienimines, derived from the oxidation of 2-alkynylanilines, react with aromatic amines leading to N-arylindoles with a 4-amino
substitution. The reaction was metal-controlled, and Bi(OTf)3 proved to be the best catalyst. The resulting 4-amino N-arylindoles could be
converted to azepino[4,3,2-cd]indoles through condensation with aldehydes.
N-Arylindoles appear as central substructures in many
pharmaceutical and medicinal compounds.1 For example,
they are potential antipsychotic agents,2 angiotensin II
antagonists,3 melatonin receptor MT1 agonists,4 anti
HIV-1 agents,5 and COX-2 inhibitors.6 Transition-metal-
catalyzed CÀN cross-coupling of aryl halides with indoles
is a straightforward approach to prepare N-arylindoles.7
Recently, a variety of cascade reactions have been devel-
oped for the synthesis of N-arylindoles.8 In these elegant
tactics, a transition-metal-catalyzed coupling reaction also
plays a prominent role (Scheme 1). The development of an
alternative method to construct functionalized N-arylin-
doles is still desirable.
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r
10.1021/ol3029675
XXXX American Chemical Society

3aa in a 53% yield. When AuCl3 was used instead of AuCl,
the desired 4-amino-N-arylindole 4aa was isolated as the
major product in 39% yield. When PdCl2 was employed,
the yield of N-arylindole 4aa decreased to 7%. For a variety
of metal triflates, only AgOTf, Cu(OTf)2, and Bi(OTf)3
exhibited catalytic activities for the generation of
N-arylindole 4aa. Bi(OTf)3 proved to be the best catalyst.
Scheme 1. Strategies for the Synthesis of N-Arylindoles
Table 1. Evaluation of Catalysts
entry
catalyst
3aa (%)a
4aa (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
AuCl
AuCl3
PdCl2
53
11
64
0
0
0
0
0
0
0
0
39
7
0
0
0
0
0
0
Scheme 2. Our Strategy To Construct 4-Amino-N-arylindoles
Zn(OTf)2
Ni(OTf)2
Fe(OTf)2
Dy(OTf)3
Sc(OTf)3
Yb(OTf)3
In(OTf)3
AgOTf
0
47
7
7
36
35
62
Cu(OTf)2
Bi(OTf)3
Some of our recent efforts have been focused on extend-
ing the utilization of cyclohexadienimines,9,10 which are
formed from the oxidative dearomatization of aromatic
amines.11 2-Alkynyl cyclohexadienimines proved to be
potential precursors to 4-substituted indoles. Since there
are two reaction sites in the R,β-unsaturated imino group,
we envisaged that tandem 1,2- and 1,4-additions of aromatic
amines to 2-alkynylcyclohexadienimines might provide a
path to construct N-arylindoles with a 4-amino substitu-
tion (Scheme 2). The 4-aminoindole unit is also found in
many biologically active compounds, such as (À)-indo-
lactam V,12 pyrroloazaflavones,13 and SDZ-216525.14
Preliminary investigation revealed that the species of
catalyst had a significant influence on the reaction between
2-phenylethynylcyclohexadienimine (1a) and p-toluidine
(2a) (Table 1). In the presence of 10 mol % of AuCl, the
reaction only provided 4-amino-substituted N-Ts indole
a Reported yields are of the isolated product based on compound 1a.
To improve the yield of compound 4aa, various sol-
vents, temperatures, and ratios of cyclohexadienimine and
p-toluidine were examined. The best yield was obtained
when the reaction was conducted in t-BuOH with 3 equiv
of p-toluidine at room temperature for 48 h (eq 1).
With the optimized reaction conditions in hand, the
scope of this reaction was investigated. To simplify the
reaction procedure, the crude oxidative dearomatization
products were directly used in the Bi(OTf)3-catalyzed
reactions (Table 2). For 4-substituted 2-alkynylanilines
with a range of different substitutions, the two-step reac-
tions proceeded smoothly leading to the corresponding
4-amino-N-arylindoles in good to excellent yields (Table 2,
entries 1À7). When 2-ethynyl-4-methylbenzenamine (5h)
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Melton, D. Nat. Chem. Biol. 2009, 5, 258.
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B
Org. Lett., Vol. XX, No. XX, XXXX

was used as substrate, the reaction was complex. No
desired product 4ha was obtained(entry 8). Withrespect to
other aromatic amines, both electron-rich and electron-
poor anilines are suitable partners for this process (Table 2,
entries 9À15). For example, the reaction of 4-methoxy-
benzenamine (2b) gave rise to product 4ab in a 95% yield
(Table 2, entry 9), while the reaction of fluoro- or chloro-
substituted aniline 2g or 2h afforded compound 4ag or 4ah
in a 68 or a 75% yield, respectively (Table 2, entries 14 and 15).
The reaction of 5-amino-1,3-dimethyl-1H-pyrazole or
4-aminopyridine was very complex, and product 4ai or
4aj was not isolated (Table 2, entries 16 and 17).
the Bi(OTf)3-catalyzed reaction provided N-(4-meth-
oxyphenyl)cyclohexadienimine (7) in a 96% yield. No
reaction was observed with PdCl2 or AuCl as catalyst
(Scheme 3).
To shed some light on the reaction pathway, a primary
DFT calculation was performed using Gaussian 09
package.15 We located the ground states of the intermedi-
ates formed from the metal catalyst activation of 2-alkynyl
cyclohexadienimine 1a. As a matter of convenience, the
counteranion is not considered. The results indicated that,
when bismuth salt was used as catalyst, the direct coordi-
nation with the nitrogen atom of imine is most stable
(Figure 1, intermediate I). When palladium was used, the
activation of the triple bond leading to intermediate II was
most favored. On the basis of the NBO (natural bond
orbital) analysis, the C-3 position of 2-alkynylcyclohexa-
dienimine is more positively charged compared with the
C-5 position in both intermediates (Figure 1), which is in
line with our experimental results.
Table 2. Scope Investigation
Scheme 3
entry
R1
C6H5
R2
R3
4 (%)a
1
2
Me
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4aa (90)
4ba (73)
4ca (68)
4da (71)
4ea (65)
4fa(76)
4-MeOC6H4 Me
3
4-ClC6H4
n-Bu
t-Bu
Me
Me
Me
Et
4
5
6
C6H5
C6H5
H
7
n-Bu 4-MeC6H4
4ga (85)
4ha (0)
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-MeC6H4
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeOC6H4
4ab (95)
4ac (92)
4ad (88)
4ae (64)
4af (73)
4ag (68)
4ah (75)
4ai (0)
10
11
12
13
14
15
16
17
3,5-(Me)2C6H3
4-iPrC6H4
C6H5
4-BrC6H4
4-ClC6H4
4-FC6H4
4-pyridyl
1,3-(CH3)2-1H-pyrazol-5-yl 4aj (0)
a Reported yields are of the isolated product based on compound 5.
When 4-amino-N-Ts-indole 3aa was treated with
p-toluidine and Bi(OTf)3, it could not be converted to
4-amino-N-arylindole 4aa. When cyclohexadienimine 6
was used instead of 2-alkynylcyclohexadienimines to react
with 4-methoxybenzenamine under the standard conditions,
(15) Gaussian 09, Revision A.02: Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro,
F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov,
V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam,
J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Figure 1. Optimized structures of intermediate I with Bi(III) as
catalyst (upper) and intermediate II with Pd(II) as catalyst
(down). The number in parentheses is NBO charges on atoms.
€
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford, CT, 2009.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Synthesis of Azepino[4,3,2-cd]indolesa
Scheme 4. Plausible Reaction Pathway
entry
R3
R4
9b (%)
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Br
4-NO2C6H4
4-CF3C6H4
4-FC6H4
9aaa (99)
9aab (92)
9aac (98)
9aad (98)
9aae (97)
9aaf (95)
9aag (94)
9aah (85)
9aai (85)
9aaj (90)
9aak (97)
9aal (80)
9aam (98)
9aan (91)
9afa (74)
9aga (73)
9aha (70)
3
4
4-ClC6H4
4-BrC6H4
4-CNC6H4
C6H5
5
6
7
8
4-MeOC6H4
4-HOC6H4
2-thiophyl
2-furyl
9
10
11
12
13
14
15
16
17
C6H5CHdCH
C6H5CH2
n-Pr
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Cl
F
a Freshly distilled trifluoromethanesulfonic acid was used. b Isolated
yield based on compound 4.
As illustrated in Scheme 4, when a suitable Lewis acid
such as Bi(OTf)3 was used, the coordination with the
carbonÀnitrogen double bond promotes 1,2- and 1,4-addi-
tions simultaneously.16 In path a, the 1,2 addition with
aromatic amines follows by elimination of TsNH2 to form
N-aryl 2-alkynylcyclohexadienimine C. With the aid of
Bi(OTf)3, this intermediate undergoes 1,4-addition to generate
intermediate F. In path b, the 1,4 addition generates inter-
mediate D. Its direct cyclization leads to 4-amino N-Ts indole 3.
When the 1,2-addition takes place before the cyclization,
intermediate D is converted to intermediate E, followed by
elimination of TsNH2 to afford intermediate F. After cycliza-
tion and aromatization, 4-amino-N-arylindole 4 is formed.
It is noteworthy that, compared with 4-amino-N-Ts-
indole 3, 4-amino-N-arylindole 4 has a more electron-rich
indolering. Thisproperty makesituseful inthe synthesis of
azepinoindole derivatives.17 As shown in Table 3, in the
presence of 2 equiv of trifluoromethanesulfonic acid (TfOH),
treatment of 4-amino-N-arylindoles with aldehydes in
dichloromethane at 0 °C led to azepino[4,3,2-cd]indoles 9.
Various aldehydes including aromatic aldehydes bearing an
electron-withdrawing or an electron-donating group, hetero-
aromatic aldehydes, cinnamaldehyde, 2-phenylacetaldehyde,
and butyraldehyde were suitable substrates for this reaction.
The corresponding azepino[4,3,2-cd]indoles were formed
in good to excellent yields. When 4-amino-N-arylindoles
bearing an electron-withdrawing substituent were used,
the corresponding products were formed in moderated
yields. The structure of compound 9 was confirmed by
single-crystal diffraction analysis of compound 9aak.
In summary, a new strategy for accessing 4-amino--
arylindoles through dearomatization and Bi(OTf)3-cata-
lyzed tandem reaction has been developed. 4-Amino-N-
arylindoles could be converted to azepino[4,3,2-cd]indoles.
Work is currently ongoing to extend its scope by exploring
its reaction mechanism and possiblesynthetic applications,
and these results will be reported in due course.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 21072033 and
21102019) is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, copies of H NMR and
13C NMR of new compounds, computational details,
X-ray crystal structure, and crystallographic data of
compound 9aak (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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J. B., Jr. J. Org. Chem. 1967, 32, 4095. (c) Hester, J. B., Jr.; Tang, A. H.;
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The authors declare no competing financial interest.
D
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