Cyclization of Alkyne-Azide with Isonitrile/CO via Self-Relay Rhodium Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b03570

A self-relay rhodium(I)-catalyzed cyclization of alkyne-azides with two σ-donor/π-acceptor ligands (isonitriles and CO) to form sequentially multiple-fused heterocycle systems via tandem nitrene transformation and aza-Pauson-Khand cyclization has been dev

Full text of DOI:10.1021/acs.orglett.5b03570

Letter
pubs.acs.org/OrgLett
Cyclization of Alkyne−Azide with Isonitrile/CO via Self-Relay
Rhodium Catalysis
Zhen Zhang, Fan Xiao, Baoliang Huang, Jincheng Hu, Bin Fu, and Zhenhua Zhang*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
S
* Supporting Information
ABSTRACT: A self-relay rhodium(I)-catalyzed cyclization of
alkyne−azides with two σ-donor/π-acceptor ligands (isonitriles
and CO) to form sequentially multiple-fused heterocycle systems
via tandem nitrene transformation and aza-Pauson−Khand
cyclization has been developed. In this approach, an intriguing
chemoselective insertion process of isonitriles superior to CO was
observed. This reaction provides an alternative strategy to
synthesize functionalized pyrrolo[2,3-b]indole scaffolds.
olycyclic nitrogen heterocycles are among the most
important fused heterocycles, which are found in a range
the coupling reaction of nitrene precursors with σ-donor/π-
P
acceptor ligands, which provides an efficient route to activate and
reorganize unsaturated reactants. In our previous research, we
reported a palladium-catalyzed coupling reaction of azides with
isonitriles to furnish unsymmetrical carbodiimides.10 It is well-
known that isonitriles, as a class of significant σ-donor/π-
acceptor ligands, have been widely applied to constructing
versatile nitrogen-containing heterocycles due to their superior
reactivity since the pioneering work of Ugi and Passerini.11,12
Besides, it cannot be ignored that another σ-donor/π-acceptor
carbonmonoxide (CO),13 an isoelectronic species of isonitrile,
and π-donor alkynyl group,14 are also excellent and efficient
ligands for the preparation of heterocycles incorporating
carbonyl groups and unsaturated carbon−carbon bonds. In
particular, isonitriles12 and CO,13d,f as valuable C1 building
blocks, were also frequently used in transition-metal-catalyzed
cascade reactions to increase the molecular complexity of the
products and to construct numerous essential heterocycles
efficiently. Thus, we envisioned an atom economic assembly of
the three unsaturated ligands with an azide into multiple-fused
heterocyclic systems via a relay transition-metal-catalyzed
cascade nitrene-coupling/cyclization process. Herein, we report
a single rhodium(I)-catalyzed sequential installation of isonitrile
and/or CO with 2-azidoalkynylbenzenes to afford two different
pyrrolo[2,3-b]indole-based heterocyclic compounds (Scheme
1).
of bioactive natural products and pharmaceuticals. In particular,
the pyrrolo[2,3-b]indole framework is a key structural motif in a
series of medicinal natural products and biologically active
molecules,1 such as physostigmine,1c pseudophrynaminol,1a
flustramine C,1b nocardioazine B,1e and flustramine P1d (Figure
1). Consequently, numerous innovative methods have been
Figure 1. Selected examples of pyrrolo[2,3-b]indole-containing natural
products.
developed for constructing this important and attractive
structural motif.1f,2 Traditional strategies involve cyclizations of
indoles,3 tryptamines,4 and tryptophan derivatives.5 Recently,
Mukai6 and Saito7 independently reported a catalytic hetero-
cumulenic Pauson−Khand reaction of alkynylcarbodiimides to
prepare pyrrolo[2,3-b]indol-2-one ring systems. Moreover, Tu
and co-workers8 achieved a Co(acac)2-catalyzed double insertion
of two identical isonitriles into 2-ethynylanilines to obtain
functionalized pyrrolo[2,3-b]indoles. In spite of the considerable
progress that has been disclosed, given the ubiquity and
importance of pyrrolo[2,3-b]indole derivatives in bioactive
molecules and drugs, further exploration and development of
diverse and efficient methods for their synthesis are still in great
demand.
To our knowledge, unexpected side reactions are common
phenomena in late transition-metal-catalyzed nitrene trans-
formations. An intriguing issue is whether a single rhodium
catalyst can perform the sequential coupling/cyclization with
specific unsaturated ligands, namely isonitriles, CO, and alkynes.
We began our investigation by reacting azidobenzene with tert-
butyl isocyanide (2a) and CO, respectively, in the presence of
With the rapid development of nitrene chemistry in recent
years, transition-metal-mediated nitrene transformation has
become a convenient and promising approach for the synthesis
of N-containing compounds.9 Our interest has been focused on
Received: December 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03570
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Self-Relay Rh(I)-Catalyzed Cyclization of Alkyne−
Azides with Two Sequential σ-Donor/π-Acceptor Ligands
(Isonitriles and CO)
Table 1. Optimization of the Reaction Conditions
b
entry
ligand (mol %)
additive (mol %)
yield (%)
1
DPPM (5)
DPPP (5)
DPPE (5)
DPPB (5)
55
57
2
3
62
4
61
5
trace
trace
trace
72
6
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPP (5)
DPPE (5)
AgSbF6 (5)
Zn(OTf)2 (5)
CuI (5)
7
8
9
CuCl (5)
CuBr (5)
CuI (10)
CuI (10)
CuI (10)
65
Rh(PPh3)3Cl as catalyst (Scheme 2). To our delight, rhodium
catalysts showed remarkable reactivity and selectivity. Carbodii-
10
11
12
76
81
75
Scheme 2. Rh(I)-Catalyzed Coupling Reactions of Azide with
Isonitrile or CO
c
13
trace
a
Reaction conditions: 4a (0.1 mmol), PhMe (2 mL), and 2a (0.1
mmol) were added, the mixture was reacted at room temperature for 3
h, and then 2a (0.11 mmol, 0.1 M in PhMe) was added by syringe at
b
c
120 °C for 2 h. Isolated yields. No [Rh(cod)Cl]2 was added. DPPM
= bis(diphenylphosphino)-methane. DPPP = 1,3-bis(diphenylphos-
phino)propane. DPPE = 1,2-bis(diphenylphosphino)ethane. DPPB =
1,4-bis(diphenylphosphino)butane.
Having identified the optimal conditions, we next focused on
examining the generality of the catalytic bicycloaddition
involving two isonitriles (Scheme 3). A variety of substituted
1-azido-2-(phenylethynyl)benzenes bearing halogen, electron-
rich, and electron-poor groups on the aromatic ring gave the
desired products in good yields (5b−e). Notably, those
substituents at the C4 or C5 positions of the ring are well
tolerated (5f,g). For substrates bearing halogen and other
electron-donating or -withdrawing groups on the aromatic ring at
the end of the triple bond, desired products were obtained in
moderate to good yields (5h−l), and electron-donating groups
exhibit better reactivity than electron-withdrawing groups.
Besides aryl substituents, substrates containing heterocyclic
(5m) or simple alkyl groups (5n,o) on the alkyne moiety were
smoothly converted into the corresponding pyrrolo[2,3-b]indole
products. In addition, isocyanocyclohexane also gave a better
result (5p, 78%). More importantly, selective and sequential
installation of two different isonitriles proved to be amenable for
the process. As for the second isonitrile, bearing either a linear
alkyl group like n-Bu (5q) or aryl groups substituted by a
sterically encumbered 2,6-dimethyl group or electronic 4-Cl, 4-
CN, and 4-MeO groups, all could be introduced into the
pyrrolo[2,3-b]indole scaffold in comparable yields (5r−u).
When the first insertion was an aryl isonitrile, designed product
could also be obtained (5v,w).
mide (3a), the coupling product of azide (1a) and isonitrile (2a),
could be obtained in 91% yield (eq 1). Meanwhile, the three-
component reaction of azide, CO, and arylamine also gave urea
in good yield (eq 2). To further evaluate the relative reactivity of
isonitrile and CO, an intermolecular competition experiment was
conducted (eq 3). Surprisingly, the result revealed that isonitrile
showed vastly superior reactivity to CO for Rh(I)-catalyzed
transformation with azide, which presumably could be
rationalized in terms of stronger coordination of isonitrile to
transition-metal atoms as well as the heterogeneous nature of
carbonylation with CO.
Based on the results of these initial experiments and given the
diversity and flexibility of isonitrile, we chose tert-butyl
isocyanide (2a) and 2-azidoalkynylbenzene (4a) as the model
substrates to evaluate the feasibility of installation of two σ-
donor/π-acceptor ligands to afford pyrrolo[2,3-b]indoles (Table
1). At the initial investigation, we found that the combination of
[Rh(cod)Cl]2 and bidentate phosphine ligands could apparently
effect the reaction. After examination of several bidentate
phosphine ligands with different bite angles, the desired product
was obtained in modest yields (Table 1, entries 1−4). To
enhance the reactivity, we surveyed a number of additives. To our
delight, a noticeable improvement in yield was observed by
addition of Cu(I) salts, which facilitate more efficient reactions
than zinc and silver salts did (Table 1, entries 6−10). Finally,
pyrrolo[2,3-b]indole (5a) was obtained in 81% yield when DPPP
was used as ligand and CuI (10 mol %) as additive (Table 1, entry
11). Notably, without any ligands and additives the target
product could only be detected in trace amounts (Table 1, entry
5).
To further explore the diversity of products generated by our
reaction, we turned our attention to another prominent σ-
donor/π-acceptor ligand carbon monoxide, which has become a
common carbonylation reagent due to its low cost and ready
availability, and has even been applied in industry. In our method,
CO was employed as a crucial synthon to build intricate
heterocyclic compounds containing carbonyl groups. As
mentioned above, compared with its isoelectronic isonitriles
counterparts, CO exhibits inferior reactivity in coupling reactions
B
DOI: 10.1021/acs.orglett.5b03570
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. [Rh(cod)Cl]2-Catalyzed Reactions of Alkyne−
Scheme 4. [Rh(cod)Cl]2-Catalyzed Reactions of Alkyne−
a
a
Azides with Two Isonitriles
Azides with Isonitriles or CO
a
Reaction conditions: 4 (0.15 mmol), 2 (0.15 mmol), o-xylene (2 mL)
reacted at 110 °C for 10 h under CO (1 atm). Isolated yields were
given.
Scheme 5. Proposed Mechanism
a
Reaction conditions: 4 (0.15 mmol), PhMe (2 mL), and 2 (0.15
mmol) were added, the mixture was reacted at rt for 3 h, and then
another portion of 2 (0.165 mmol, 0.1 M in PhMe) was added by
b
syringe at 120 °C for 2 h. Isolated yields were given. 4 (0.15 mmol),
dioxane (2 mL), and 2 (0.15 mmol) were added without CuI, the
mixture was reacted at rt for 10 min, and then another portion of 2
(0.165 mmol, 0.1 M in dioxane) was added by syringe at 120 °C for 2
h.
with azides. Taking advantage of this difference in reaction rates,
we achieved selective incorporation of both isonitrile and CO
into the product in a single operation. Next, we explored the
substrate scope of our strategies involving the cyclization of
isonitriles and CO. The results were summarized in Scheme 4.
Compared with two isonitriles, the introduction of two kinds of
σ-donor/π-acceptor ligands gave the corresponding products
with relatively lower yield. Variation of electronic nature or
positions at the phenyl ring of aryl azides did not affect the
reactivity significantly (6a−e). Azidoalkynylbenzenes bearing
different substituents (including Me, Cl, F, and OMe) at the
aromatic alkyne moieties could react well to deliver products
(6g−j) in moderate yields. Moreover, isocyanocyclohexane is
also compatible in the transformation, albeit in low yield (6f).
However, though heterocyclic substituents at the alkynyl
terminal position were well tolerated under the conditions
(6k), aliphatic substituents showed little reactivity (6l).
A plausible mechanism for the formation of pyrrolo[2,3-
b]indoles is shown in Scheme 5, which generally involves two
processes including Rh(I)-catalyzed cross-coupling of azides
with isonitriles and an aza-Pauson−Khand cyclization. Initially,
an important intermediate alkynyl carbodiimide A was generated
with release of N2.15 Next, the alkynyl carbodiimides
intermediate A, through π-complexation with Rh(I) and an
oxidative cyclometalation step, could form a new intramolecular
C−C bond and afford rhodacycle species B. Further insertion of
another σ-donor/π-acceptor ligand (isonitrile or CO) into the
Rh−C bond of species B results in the generation of rhodium
complex C. Finally, the two different pyrrolo[2,3-b]indole
derivatives were produced following a reductive elimination
process with regeneration of the active rhodium(I) catalyst.
In summary, we have developed a self-relay Rh(I)-catalyzed
cascade reaction that enabled the assembly of two different σ-
donor/π-acceptor ligands sequentially to form multiple-fused
heterocyclic systems via relay-catalyzed nitrene transformation
and sequential cyclization processes. This protocol provides an
alternative and facile strategy to construct the pyrrolo[2,3-
b]indole scaffold, which served as a pivotal structural motif of
many useful natural products and drug molecules. Moreover, we
have examined the reactivity of isonitriles and CO in this
reaction. The result shows that isonitriles possess superior
reactivity to their isoelectronic counterpart CO in either coupling
C
DOI: 10.1021/acs.orglett.5b03570
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03570.
Experimental procedures along with characterization data
and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhangzhh@cau.edu.cn.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This project is supported by the National Natural Science
Foundation of China (No. 21302219), the National S&T Pillar
Program of China (2015BAK45B01), the Fundamental Research
Funds for the Central Universities (China Agricultural
University 2016QC040), and the Beijing National Laboratory
of Molecular Sciences (BNLMS).
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