Cross-Cycloaddition of Two Different Isocyanides: Chemoselective Heterodimerization and [3+2]-Cyclization of 1,4-Diazabutatriene

Article abstract of DOI:10.1002/anie.201600257

A new cross-cycloaddition reaction between a wide range of isocyanides and 2-isocyanochalcones (or analogues) was developed for the expeditious synthesis of pyrrolo[3,4-b]indoles under thermal conditions. On the basis of the experimental results and DFT c

Full text of DOI:10.1002/anie.201600257

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International Edition: DOI: 10.1002/anie.201600257
German Edition: DOI: 10.1002/ange.201600257
Dipolar Cycloadditions
Cross-Cycloaddition of Two Different Isocyanides: Chemoselective
Heterodimerization and [3+2]-Cyclization of 1,4-Diazabutatriene
Zhongyan Hu, Haiyan Yuan, Yang Men, Qun Liu,* Jingping Zhang,* and Xianxiu Xu*
Abstract: A new cross-cycloaddition reaction between a wide
range of isocyanides and 2-isocyanochalcones (or analogues)
was developed for the expeditious synthesis of
pyrrolo[3,4-b]indoles under thermal conditions. On the basis
of the experimental results and DFT calculations, a mechanism
for this domino reaction is proposed involving chemoselective
heterodimerization of two different isocyanides to form
1,4-diazabutatriene intermediates, followed by an intramolec-
ular [3+2]-cycloaddition and 1,3-proton shift.
I
socyanides are versatile building blocks in organic synthesis
because of their unique modes of reaction.[1] Accordingly,
ioscyanides are widely employed in valuable reactions that
require a-addition, a-acidity, and a readiness to react with
radicals. These include, Passerini[2] and Ugi reactions,[3]
transition-metal catalyzed isocyanide insertion,[4] [3+2]-cyclo-
addition of activated methylene isocyanides with polar multi-
ple bonds,[5] and radical insertions.[6] Recently, a new isocyano
group reactivity profile was realized by Zhu and co-workers
where the isocyano functional group formally acts as a polar-
ized triple bond, allowing synthesis of imidazoles (Scheme 1,
Eq. (1)).[7] This type of polarized reactivity is also exhibited in
the cross-cycloaddition of isocyanides with activated methyl-
ene isocyanides (Scheme 1, Eq. (2)).[8] In spite of these
intensive research efforts, exploiting the new reactivity profile
of the isocyano functional group remains highly desirable.
Scheme 1. New reactivity profile of the isocyano functional group.
isocyanides.[9,11] Heterodimerization of two different isocya-
nide moieties to generate a nonsymmetrical 1,4-diazabuta-
triene has not yet been established.[12] As a continuation of
our studies on isocyanide chemistry,[13] herein, we report
a new and general cross-cycloaddition based on the hetero-
dimerization between isocyanides 1 and 2-isocyanochalcones
(and analogues thereof) 2 (Scheme 1, Eq. (3)). In this
reaction, the highly reactive 1,4-diazabutatriene tautomers I
and I’ are 1,3-dipole equivalents, which allow the intra-
molecular [3+2]-cycloaddition to furnish pyrrolo[3,4-
b]indoles[11] under relatively mild thermal conditions.
Pyrrolo[3,4-b]indoles are valuable fused heterocycles with
broad synthetic applications.[14] Additionally, they are stable
analogues of indole-2,3-quinodimethanes used for prepara-
tion of carbazoles, carbolines, and related heterocyclic
systems, through cycloaddition reactions.[15,16] Moreover, the
pyrrolo[3,4-b]indole derivatives show a broad spectrum of
pharmacological activity.[13] Although many methods for the
construction of pyrrolo[3,4-b]indoles have been developed,
a preformed indole precursor is generally required.[14,17] Our
method provides an alternative approach, involving forma-
tion of two pyrrole rings from chalcone derivatives in
a tandem process (Scheme 1, Eq. (3)).
In 1977, Lange and Hçfle proposed
a transient
À
1,4-diazabutatriene intermediate after C C homodimeriza-
tion of two imidoyl isocyanides and formation of 4,4’-bis-
(quinazolines).[9] Subsequently, only a few examples have
dealt with this highly unstable intermediate. In 1999, Beckert
provided evidence for the existence of 1,4-diazabutatriene by
reduction of bis-imidoyl chlorides of oxalic acid.[10] Subse-
quently, Cheng and co-workers reported the homodimeriza-
tion of 2-pyridylisonitriles.[11] To date, the reactivity mode of
dimerization has been restricted to the homodimerization of
[*] Z. Hu, Dr. H. Yuan, Y. Men, Prof. Dr. Q. Liu, Prof. Dr. J. Zhang,
Prof. Dr. X. Xu
Department of Chemistry, Northeast Normal University
Changchun, 130024 (China)
E-mail: liuqun@nenu.edu.cn
zhangjp162@nenu.edu.cn
xuxx677@nenu.edu.cn
Prof. Dr. X. Xu
College of Chemistry and Molecular Engineering (SCME), Institute of
Advanced Synthesis (IAS), Jiangsu National Synergetic Innovation
Centre for Advanced Materials (SICAM), Nanjing Tech University
(Nanjing Tech), Nanjing, 211816 (China)
Herein, the reaction of ethyl 4-isocyanobenzoate 1a with
2-isocyanochalcone 2a was employed as a model to optimize
the reaction conditions (Table 1). When a mixture of 1a
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600257.
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Table 1: Optimization of reaction conditions.[a]
isocyanides 1 with p-phenyl (1b), electron-donating (1c and
1d) or withdrawing groups (1e–g), a-naphthyl isocyanide
(1h), 2-pyridyl isocyanide (1i), isocyanoacetate (1j), TosMIC
(1k), 4-chlorobenzyl isocyanide (1l), and 3-(2-isocyanoethyl)-
1H-indole (1m) were effective isocyanide components. In
cases involving reaction of tert-butyl isocyanide 1n and
cyclohexyl isocyanide 1o with 2-isocyanochalcone 2a, the
corresponding products 3na and 3oa could not be detected,
possibly because of the steric disruption imposed by tert-butyl
and cyclohexyl groups during reactivity. Additionally, when 2-
isocyanocinnamate 2s was treated with 4-methoxyphenyl
isocyanide 1c, the desired pyrrolo[3,4-b]indole 3cs was
obtained in 66% yield (Table 2). In contrast, in the absence
of 1c, pyrrolo[3,4-b]indole 3ss[18] was produced in 43% yield
after homodimerization of 2s (Table 2).
Subsequently, the scope of the reaction was evaluated
with respect to 2-isocyanochalcones and analogues 2; results
are summarized in Table 3. The reaction tolerates a wide
range of isocyanides 2 bearing various R1 groups, such as
para- (3ab–af), ortho- (3ag), or meta-substituted aryl (3ah),
disubstituted aryl (3ai and 3aj), a- or b-naphthyl (3ak and
3al), hetereoaryl (3am and 3an), ferrocenyl (Fc, 3ao), p-tolyl
vinyl (3ap), alkyl (3aq and 3ar), and alkyloxy groups (3as).
Entry
T [8C]
Conc. [m]
Yield [%][b] of 3aa
Yield [%][b] of 4a
1
2
3
4
120
120
120
100
140
120
120
0.1
0.2
0.05
0.2
0.2
0.2
0.2
76
81
61
74
80
83
64
20
14
28
17
16
13
22
5
6[c]
7[d]
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), air atmosphere,
1208C, in a sealed tube for 1.5 h. [b] Yield of isolated products. [c] 1a
(3.0 equiv) was used. [d] 1a (1.0 equiv) was used.
(0.4 mmol) and 2a (0.2 mmol) was heated at 1208C in
1,4-dioxane (2 mL, c = 0.1m) for 1.5 h, the tricyclic product
pyrrolo[3,4-b]indole 3aa was obtained in 76% yield, along
with pyrrolo[1,2-a:3,4-b’]diindole 4a in 20% yield (Table 1,
entry 1). Selected solvents, such as ethanol, acetonitrile,
N,N-dimethylformamide (DMF), 1,2-dichloroethane, and
tert-butanol, were also examined but gave 3aa in lower
yields (Supporting Information, Table S1). When the reaction
was conducted at a higher concentration (0.2m), the yield of
3aa increased up to 81% (Table 1, entry 2 and entry 6 (with
3.0 equiv of 1a)). In comparison, lower concentration led to
a decreased yield of 3aa (61%; Table 1, entry 3 and entry 7
(with 1.0 equiv of 1a)). When the reaction was performed at
1008C, 3aa was produced in 74% yield (Table 1, entry 4).
With the optimal conditions in hand (Table 1, entry 2), the
scope of viable isocyanide substrates 1 was examined; the
results are summarized in Table 2. In general, the reaction
tolerated a wide range of substrates 1, producing a series of
polysubstituted pyrrolo[3,4-b]indoles (3ba–ma, 3cs, 3ss) in
good to high yields within 1.5 h by reactions of isocyanides
1 with 2-isocynochalcone 2a and its analogue 2s. Aryl
Table 3: Scope of isocyanides 2.[a,b]
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), in dry 1,4-dioxane
(1 mL), air atmosphere, at 1208C, in a sealed tube. [b] Yield of isolated
products.
Table 2: Scope of isocyanides 1.[a,b]
Besides the carbonyl- and alkoxycarbonyl-substituted sub-
strates 2, cyano-substituted isocyanide 2t was also well-
tolerated and 1-cyanopyrrolo[3,4-b]indole 3at was obtained
in
high
yield.
Additionally,
the
trisubstituted
pyrrolo[3,4-b]indoles 3au and 3av were produced in high
yields from the corresponding substrates 2, bearing either
electron-donating or electron-withdrawing R2 groups.
Control experiments were performed so as to shed light
on the reaction mechanism taking place. When a reaction
mixture containing isocyanide 1a with 2-isocyanochalcone 2a
was subjected to Fukuyamaꢀs conditions (nBu3SnH/AIBN),[19]
a complex mixture was obtained containing trace amounts of
the desired product 3aa (Supporting Information, Scheme S2,
Eq. (1)). Additionally, the desired pyrrolo[3,4-b]indole 3aw
was not observed upon reaction of 1a with isocyanide 2w
[a] Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), in dry 1,4-dioxane
(1 mL), air atmosphere, at 1208C, in a sealed tube. [b] Yield of isolated
products.
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the intrinsic driving force that
promotes H-shifts via Int3,
Int4, and Int5, even in the
presence of trace amounts of
water.[20,21]
In summary, we have devel-
oped
tandem
a
new and practical
cross-cycloaddition
between
two
isocyanides
under thermal conditions. In
this reaction, both the hetero-
dimerization of two different
isocyanides and the [3+2]-
cycloaddition of the highly
reactive
1,4-diazabutatriene
intermediate with polarized
=
C C double bonds, are unpre-
cedented. The new domino
reaction was used to efficiently
construct highly functionalized
pyrrolo[3,4-b]indoles
from
a series of isocyanides and iso-
cyanochalcones (and ana-
logues) by formation of three
new bonds and two pyrrole
rings. Further studies on this
new reactivity mode are in
progress.
Figure 1. DFT computed energy surface for the cross-cycloaddition of isocyanides 1a and 2a. Relative free
energies are given in kcalmolÀ1
.
under our standard conditions (Supporting Information,
Scheme S2, Eq. (2)); in Fukuyamaꢀs indole synthesis, the
corresponding product was produced in 83% yield upon
reaction of 2w via a radical pathway.[19b] These results
demonstrate that the mechanism of cross-cycloaddition of
two isocyanides proceeds by a non-radical pathway (Table 2
and Table 3).
Acknowledgements
Financial support provided by the NNSFC (21172030 and
21572031) is gratefully acknowledged.
To gain further insight into the mechanism involved,
density functional theory calculations were conducted at
a B3LYP-D2/6-31 + G** level and interrogated computation-
ally. A heterodimerization and [3+2]-cycloaddition cascade
was proposed in which 1,4-diazabutatriene serves as a reactive
intermediate, in close comparison with the homodimerization
of isocyanides.[9,11] As shown in Figure 1, the free-energy
profile indicates that the reaction initiating from complex
Com1 (1a and 2a), proceeds through nucleophilic attack of
the isocyanide carbon of 1a on the isocyanide carbon of 2a, to
form 1,4-diazabutatriene Int1 via TS1 (TS = transition state)
with an activation barrier of 27.0 kcalmolÀ1. Subsequent
intramolecular [3+2]-cyclization takes place from Int1 by way
of TS2 to form adduct Int2 with an activation barrier of
15.9 kcalmolÀ1. Subsequently, three-water molecules[20,21]
associate with Int2 to form Int3, which undergoes successive
1,3-proton shifts via transition states TS3 and TS4, with
activation barriers of 16.8 and 17.5 kcalmolÀ1, respectively.
Finally, the water-cluster is released from Int5 to afford
product 3aa. Although Int4 coverts to Int5 endergonically
with a relative free energy of 4.7 kcalmolÀ1 during the
conversion of Int3 into product 3aa, Int5 is favored for the
subsequent Ha deprotonation and imidoyl anion protonation
process. Thus, hydrogen bonding interactions are likely to be
Keywords: 1,4-diazabutatriene · cross-cycloaddition ·
heterodimerization · isocyanides · pyrrolo[3,4-b]indoles
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7077–7080
Angew. Chem. 2016, 128, 7193–7196
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Received: January 9, 2016
Revised: March 3, 2016
Published online: May 2, 2016
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