Preparation of 3-diazoindolin-2-imines via cascade reaction between indoles and sulfonylazides and their extensions to 2,3-diaminoindoles and imidazo[4,5-b]indoles

Article abstract of DOI:10.1021/ol502423k

3-Diazoindolin-2-imines were constructed from indoles and sulfonylazides via an electronically matched 1,3-dipolar cycloaddition and a subsequent dehydroaromatization/ring-opening cascade. The reaction between 3-substituted indoles and sulfonyl azides provided 2-aminoindoles, while 2-substituted indoles furnished 3-aminoindoles. Moreover, 2,3-diaminoindoles could be prepared from the resulting 3-diazoindolin-2-imines and secondary amines via a rhodium-catalyzed amination. Further extension of 2,3-diaminoindoles led to the formation of imidazo[4,5-b]indoles.

Full text of DOI:10.1021/ol502423k

Letter
pubs.acs.org/OrgLett
Preparation of 3‑Diazoindolin-2-imines via Cascade Reaction
between Indoles and Sulfonylazides and Their Extensions to 2,3-
Diaminoindoles and Imidazo[4,5‑b]indoles
Guorong Sheng, Kai Huang, Zhihao Chi, Hualong Ding, Yanpeng Xing, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: 3-Diazoindolin-2-imines were constructed from
indoles and sulfonylazides via an electronically matched 1,3-
dipolar cycloaddition and a subsequent dehydroaromatization/
ring-opening cascade. The reaction between 3-substituted
indoles and sulfonyl azides provided 2-aminoindoles, while 2-
substituted indoles furnished 3-aminoindoles. Moreover, 2,3-
diaminoindoles could be prepared from the resulting 3-
diazoindolin-2-imines and secondary amines via a rhodium-
catalyzed amination. Further extension of 2,3-diaminoindoles
led to the formation of imidazo[4,5-b]indoles.
mong the widely existing indole derivatives, compounds
A
with a 2-aminoindole,1 3-aminoindole,2 and 2,3-diami-
noindole moiety3 are much more attractive. Alkaloids
possessing the 2- or 3-aminoindole framework exhibit a broad
range of bioactivities, such as GSK-3β inhibiting,2c antibacterial,
antimalarial, antitumor, and tubulin-inhibiting activities.1,2,4
Due to their pharmaceutical importance and potential
applications in the synthesis of more complicated indole
derivatives, we became interested in the development of
feasible strategies for the construction of 2-amino-, 3-amino-,
and 2,3-diaminoindoles.
Recently, the fragile 1-sulfonyl-1,2,3-triazoles5 have been
demonstrated as α-imino metal carbene precursors in a variety
of synthetically useful transformations,6 such as transannula-
tions,7 ring expansions/rearrangements,8 cyclopropanations,9
C−H insertions,10 and arylations.11 Although Cu-catalyzed
alkyne−azide cycloaddition proved to be a feasible and practical
method in the preparation of 1-sulfonyl-1,2,3-triazoles with the
help of suitable ligands,12 development of metal-free formation
of 1-sulfonyl-1,2,3-triazoles or their α-diazo imine forms
remains formidably challenging.
In our previous work, we developed a Cu-catalyzed tandem
synthesis of indolotriazoles,13 which were later identified as 3-
diazoindolin-2-imines in solid states by single crystal analysis
(Figure 1, our previous work). We utilized them as rhodium
carbene precursors for the synthesis of a series of valuable
indole derivatives.
It was also reported that 1,2,3-triazoles could be constructed
by the secondary amine-catalyzed inverse-electron-demand
Huisgen 1,3-dipolar cycloadditions of ketones with azides.14
Although the regioselectivity of this reaction was well
controlled by the dipolar direction of enamines and azides,
the variety of substituents at the 1-position of 1,2,3-triazoles
was significantly limited to electron-donating groups. When
Figure 1. Our catalyst-free approach.
sulfonylazide was used for this 1,3-dipolar cycloaddition, the
ring of 1-sulfonyl-1,2,3-triazoles was opened, affording amidines
through a sequential alkyl shift.15,14d Only one exception was
presented (Figure 1, J. Wang’s work). In that case, the crowded
amidine was not formed because the steric hindrance of the
amine catalyst inhibited the alkyl shift as the authors claimed in
their article.14d
Based on these reports, we proposed a novel strategy to
prepare 3-diazoindolin-2-imines through a direct 1,3-dipolar
cycloaddition of indoles with tosylazide (Figure 1, this work). It
is anticipated that the dehydroaromatization of cycloaddition
product could help the formation of thermodynamically favored
indolotriazole and a catalyst could be reasonably avoided.
Received: August 18, 2014
Published: September 11, 2014
© 2014 American Chemical Society
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Letter
We initially examined the reaction between N-methylindole
(1a, 0.25 mmol) and p-tosylazide (2a, 0.5 mmol) in DMSO (2
mL). After the mixture was stirred at 40 °C under air for 16 h,
3a (Scheme 1) was isolated in 15% yield. We then screened the
azide (2d), and methane-sulfonylazide (2f). Thus, 3m−p were
obtained in 32%−65% yields. For the reaction between 4-
nitrobenzenesulfonylazide (2e) and 1a, we isolated the desired
product 3q13 (10% yield) along with 2-iminoindoline 4b16
(30% yield) as shown in Scheme 3. Single crystal analysis of 3d
and 3l confirmed the existence of the 3-diazoindolin-2-imine
skeleton.17
Scheme 1. Formation of 3a and 4a
Scheme 3. Reaction of 1a with 2e
Electronically matching indole and azide is essential to a
successful transformation. Neither phenyl azide nor benzyl
azide reacted with N-methylindole (1a). The reaction also did
not take place when N-tosylindole or N-acetylindole, instead of
N-methylindole, was used.
In order to gain further insights into the reaction mechanism,
we examined the 2- or 3- position blocked indoles 1b−f (Table
1). 1,3-Dimethylindole (1b) readily reacted with 2a to give 4c
reaction conditions (see Supporting Information, Table S1).
The optimal reaction conditions were obtained when the
reaction of 1a (0.25 mmol) and 2a (0.5 mmol) in DMSO (0.5
mL) was carried out under air at 50 °C for 12 h (Scheme 1,
path a; Table S1, entry 19). We also performed the reaction in
DCM under N2, but isolated 2-iminoindoline 4a16 in 7% yield
with 90% recovery of 1a (Scheme 1, path b).
a
Table 1. Preparation of 2-Aminoindoles 4
With the optimal reaction conditions, we examined the
substrate scope (Scheme 2). The alkyl group on the 1-position
a
Scheme 2. Substrate Scope for the Preparation of 3
4:4′
4/yield
(%)
entry 1 (R1)
2 (R2)
CDCl3 DMSO-d6
1
2
3
4
5
6
7
1b (Me) 2a (Ts)
4c/87
4d/90
4e/94
4f/89
4g/84
4h/83
37:63
25:75
100:0
29:71
100:0
100:0
46:64
0:100
0:100
0:100
0:100
0:100
0:100
0:100
1b
2b (SO2Ph)
1b
2c (SO2Np-β)
2d (SO2C6H4OMe-p)
2e (Ns)
1b
1b
1c (Et)
2c
b
1d (Bn) 2c
4i/64
a
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), DMSO (0.5 mL),
b
50 °C, 72 h; isolated yields were reported. 48 h.
a
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), DMSO (0.5 mL),
b
air, 50 °C, 12 h; isolated yields were reported. For gram scale
and its enamine form 4c′ in 87% total yield (Table 1, entry 1).
The ratio of 4c (37%) and 4c′ (63%) was determined on the
reaction: 1a (0.655 g, 5 mmol), 2a (1.97 g, 10 mmol), and DMSO (10
mL) were used, and 1.103 g (67% yield) of 3a was isolated.
1
1
basis of H NMR in CDCl3. When the H NMR spectra were
recorded in DMSO-d6, the imine form 4c disappeared and the
enamine form 4c′ was dominant. 1b−d did react with sulfonyl
azides 2b−e to furnish 4d−i in 64%−94% yields (Table 1,
entries 2−7). In the cases of 4e and 4g, the 1H NMR spectra in
CDCl3 presented a single imine form, while they showed a
complete enamine form in DMSO-d6. The solid structure of
imine form 4g was established by its single crystal analysis.17
Tautoumerism occurred in some circumstances in CDCl3, but
all products existed in the enamine form in DMSO-d6.
For 1,2-dimethylindole (1e), reactions with sulfonyl azides
2a−e gave the corresponding 3-aminoindoles 5a−e in excellent
yields (Scheme 4). In these cases, the sulfonamide group
migrated from the 2-position to the 3-position. Similar
phenomena were observed in the reaction of 1-methyl-2-
phenylindole (1f) with 2a−e, which furnished 5f−j.
of indole could be varied from methyl (3a), ethyl (3b),
isopropyl (3c), allyl (3d), and benzyl (3e) with moderate
yields. It was worth noting that indole reacted with 2a to afford
3f (29% yield), which could not be prepared by our previous
method.13 The electronic effect of the substituent on the 5-
position of indole was apparent. Electron-donating groups
benefited the reaction and gave a higher yield (3j, 78%), but
electron-withdrawing groups decreased the yields accordingly.
As a result, 5-fluoro-, 5-chloro-, and 5-bromo-1-methylindoles
produced 3g, 3h, and 3i in 36%, 45%, and 51% yields,
respectively. A substituent on the 7-position of indole
presented a similar electronic effect. Compounds 3k and 3l
were prepared in 25% and 59% yields, respectively. p-
Tosylazide could be altered into benzenesulfonyl azide (2b),
naphthalene-2-sulfonylazide (2c), 4-methoxybenzenesulfonyl-
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Scheme 4. Preparation of 3-Aminoindoles 5
Scheme 6. Possible Mechanism for the Formation of 5a
Scheme 7. Preparation of 2,3-Diaminoindoles 7
Based on these results, we proposed a possible mechanism
(Scheme 5). Despite the participation of the oxidant, the
Scheme 5. Possible Mechanism To Form 3a and 4a
amination with 6a, furnishing the corresponding 2,3-diami-
noindoles 7a−l in good to excellent yields. Substituents on the
1-position of 3 could be methyl (7a), ethyl (7b), isopropyl
(7c), allyl (7d), benzyl (7e), or even hydrogen (7f). The
substituent effect on the phenyl ring of indoles was not
apparent (7g−k). Other secondary amines, such as N-
methylaniline (6b), N-isopropylaniline (6c), N-benzylaniline
(6d), and diphenylamine (6e) were also examined, and 7m−t
were obtained in 71% −91% yields.
The 2,3-diaminoindoles 7o, 7q, 7r, and 7t derived from N-
benzylamine are stable in solid at room temperature, but
instable in the solution under air at high temperature. By
refluxing these compounds in toluene under O2 for 18 h,
imidazo[4,5-b]indoles 8a−c were formed in yields varying from
31% to 36% (Scheme 8).
electronically matched Huisgen cycloaddition between 1a and
2a does occur to form A that can equilibrate with starting
materials in the solution. Dehydroaromatization of A in the
presence of O2 generates B (path a). Subsequent ring opening
of B leads to the formation of 3a. Alternatively, the ring
opening of A forms diazonium salt C, which undergoes
dehydrogenation to give 3a (path b). In the absence of an
oxidant, C undergoes a 1,2-H shift with a loss of N2 to afford 4a
(path c). In the case of 4-nitrobenzenesulfonylazide (2f,
Scheme 3), the strong electron-withdrawing effect of the
nitro group can facilitate the ring opening of the cycloaddition
product A and the resulting diazonium salt C undergoes a 1,2-
H shift to afford 4b. When the 3-position of indole is blocked
with methyl (Table 1), a 1,2-H shift occurs to generate 4.18
For 2-methylindole 1e or 2-phenylindole 1f, a 1,2-N shift
occurs through an aziridine intermediate C (Scheme 6).18 This
rearrangement affords 3-aminoindole 5.
Scheme 8. Preparation of Imidazo[4,5-b]indoles 8
As a synthetic application of 3-diazoindolin-2-imines (3), we
tested the Rh-catalyzed amination of 3a with N-ethylaniline
(6a). After the mixture of 3a (0.25 mmol), 6a (0.5 mmol), and
Rh2(Oct)4 (0.0025 mmol) reacted in toluene at 110 °C for 2.5
h, 2,3-diaminoindole 7a was isolated in 96% yield (Scheme 7).
No reaction was observed in the absence of the Rh catalyst.
Toluene was the best solvent in comparison with others, such
as benzene (81%), DCE (50%), and CHCl3 (40%). With this
satisfying result, we tested the reactivity of 3 with a series of
secondary amines 6. A variety of 3 were suitable to the
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Letter
(c) Schultz, E. E.; Sarpong, R. J. Am. Chem. Soc. 2013, 135, 4696.
(d) Chattopadhyay, B.; Gevorgyan, V. Org. Lett. 2011, 13, 3746.
(e) Shi, Y.; Gevorgyan, V. Org. Lett. 2013, 15, 5394.
In conclusion, we developed a general and practical approach
to 3-diazoindolin-2-imines via the cascade reaction of indoles
with sulfonyl azides. In comparison with Cu-catalyzed alkyne−
azide cycloaddition, as well as the secondary amine-catalyzed
enamine-azide cycloaddition, this method presented several
advantages. First, the reaction is catalyst-free with excellent
regioselectivity. Second, the starting materials are readily
available with nice substrate diversity. Third, and most
importantly, the electronically matched indoles and sulfonyl
azides make the formation of diazoindolinimines feasible.
Besides these featured characteristics, 2- and 3-aminoindoles
could be prepared through the reactions of 3- or 2-substituted
indoles with sulfonyl azides. Furthermore, the resulting 3-
diazoindolin-2-imines could be applied as α-imino rhodium
carbene precursors for the synthesis of diverse 2,3-diaminoin-
doles, which could be further extended into imidazo[4,5-
b]indoles.
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ASSOCIATED CONTENT
* Supporting Information
■
S
(13) Xing, Y. P.; Sheng, G. R.; Wang, J.; Lu, P.; Wang, Y. G. Org. Lett.
2014, 16, 1244.
Experimental procedures and characterization data for all new
compounds, and crystallographic information files (CIF) for
compounds 3d, 3l, and 4g. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) (a) Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. Chem.
Eur. J. 2008, 14, 9143. (b) Belkheira, M.; Abed, D. E.; Pons, J. M.;
Bressy, C. Chem.Eur. J. 2011, 17, 12917. (c) Danence, L. J. T.; Gao,
Y. J.; Li, M. G.; Huang, Y.; Wang, J. Chem.Eur. J. 2011, 17, 3584.
(d) Wang, L.; Peng, S. Y.; Danence, L. J. T.; Gao, Y. J.; Wang, J.
Chem.Eur. J. 2012, 18, 6088. (e) Wang, L.; Huang, J. Y.; Gao, X. J.;
Wang, J. Chem.Eur. J. 2013, 19, 7555.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pinglu@zju.edu.cn.
*E-mail: orgwyg@zju.edu.cn.
(15) Contini, A.; Eraba, E. RSC Adv. 2012, 2, 10652.
(16) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163.
(17) CCDC 1000725 (3d), CCDC 1004672 (3l), and CCDC
1002178 (4g) contain supplementary crystallographic data for this
paper.
Notes
The authors declare no competing financial interest.
(18) For similar examples, see: (a) He, P.; Zhu, S. Z. J. Fluorine Chem.
2005, 126, 825. (b) Bahadur, G. A.; Bailey, A. S.; Middleton, N. W.;
Peach, J. M. J. Chem. Soc., Perkin Trans. 1 1980, 1689.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Nos. 21032005, 21272203, and J1210042) for the
financial support.
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