Rh-Catalyzed Reaction of Vinyl Azides with Isonitriles and Alkynes/Benzynes

Article abstract of DOI:10.1021/acs.orglett.8b03115

In contrast to well-known transformations of vinyl azides via azirine intermediates or initiating at the alkene moiety, herein we report a Rh(I)-catalyzed coupling reaction of vinyl azides with isonitriles at the azide moiety to form active vinyl carbodiimide intermediates and following tandem cyclization with unsaturated compounds, such as alkynes and benzynes, to give different classes of azaheterocycles. Mechanistically, controlled experiments and DFT calculations disclose that Rh-nitrene is the vital species in the first coupling step, and the Rh(I) catalyst can also play an important role in the cyclization step of alkynes.

Full text of DOI:10.1021/acs.orglett.8b03115

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh-Catalyzed Reaction of Vinyl Azides with Isonitriles and Alkynes/
Benzynes
Zongyang Li,† Tongyu Huo,† Li Li,‡ Shuo Feng,† Qian Wang,† Zhen Zhang,† Sen Pang,†
Zhiyuan Zhang,‡ Peng Wang,† and Zhenhua Zhang*,†
†Beijing Advanced Innovation Center for Food Nutrition and Human Health, and Department of Applied Chemistry, China
Agricultural University, Beijing 100193, China
‡National Institute of Biological Sciences (NIBS), Beijing 102206, China
S
* Supporting Information
ABSTRACT: In contrast to well-known transformations of vinyl azides via
azirine intermediates or initiating at the alkene moiety, herein we report a
Rh(I)-catalyzed coupling reaction of vinyl azides with isonitriles at the azide
moiety to form active vinyl carbodiimide intermediates and following tandem
cyclization with unsaturated compounds, such as alkynes and benzynes, to give
different classes of azaheterocycles. Mechanistically, controlled experiments and
DFT calculations disclose that Rh-nitrene is the vital species in the first
coupling step, and the Rh(I) catalyst can also play an important role in the
cyclization step of alkynes.
-Containing heterocycles are important structural
components in natural products, pharmaceuticals, and
electrophiles/radicals/nucleophiles to generate the corre-
sponding intermediates (Scheme 1b).5 Although vinyl azides
have shown multifaceted reactivities, transition-metal-catalyzed
sequential reactions that initiate at the azido group are not
common.6 On the other hand, vinyl carbodiimides, which have
two unsaturated functionalities, hold great potentials for
constructing azaheterocycles. However, the lack of facile access
to a vinyl carbodiimide intermediate and its instability in
isolation and storage limit its application.7 Herein, we report a
Rh(I)-catalyzed coupling reaction of vinyl azides with
isonitriles to form different substituted vinyl carbodiimide
intermediates in a facile access and following tandem
cyclization with unsaturated compounds, such as alkynes and
benzynes, to give different classes of azaheterocycles, i.e.,
aminopyridine, isoquinoline, and pyrroleimine (Scheme 1c).
Controlled experiments/DFT calculations reveal that Rh-
nitrene is the vital species in the first coupling step, and
Rh(I) catalyst also plays an important role in the cyclization of
alkynes.
N
functional materials. The construction of azaheterocycles is a
prominent field in organic synthesis.1 As an efficient nitrogen
source, the transformations of organic azides have been
explored.2 In particular, vinyl azides, which contain two
distinct functional groups, have received considerable attention
in the synthesis of different types of azaheterocycles.3 The
most common pathway of vinyl azide transformations proceeds
through azirine intermediates (Scheme 1a).4 Another pathway
initiates at the alkene moiety of vinyl azides, which react with
Scheme 1. Cyclization Pathway of Vinyl Azide
At the outset, (1-azidovinyl)benzene (1a) was used to react
with t-BuNC (2a) under [Rh(COD)Cl]2 catalyst, and then the
addition of diethyl but-2-ynedioate (3a) could furnish
aminopyridine (5a) in 44% yield (eq 1). To our delight, the
isolation and characterization of the unstable vinyl carbodii-
mide intermediate (4a) was also achieved.
Based on the above result, the formation and isolation of
active vinyl carbodiimide intermediates were studied (Scheme
2). In the presence of [Rh(COD)Cl]2, the isolated yield of 4a
was 86%, and the NMR yield was up to 92%. The addition of
the 2,2′-bpy ligand gave a similar 93% NMR yield. However,
Received: October 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03115
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Letter
a
Scheme 2. Substrate Scope of Vinyl Azide with Isonitrile
a
Reaction conditions: 1 (0.30 mmol), 2 (0.30 mmol), [Rh(COD)-
Cl]2 (2.5 mol %), 1,4-dioxane (2 mL), isolated yield, 2′-bpy = 2,2′-
b
bipyridine. NMR yield with mesitylene as the internal standard.
the addition of phosphine PPh3 ligand decreased the NMR
yield to 75%.8 For different vinyl azides and isonitriles, NMR
yields were all excellent (>80%), but some isolated yields were
relatively low because of their instability. Aryl-substituted vinyl
azides gave better isolated yields (4a−4d, 70−90%), whereas
benzyl- and alkyl-substituted vinyl azides gave only 54% and
60% isolated yields (4e−4f). For different isonitriles, the
desired vinyl carbodiimides were obtained in 51−86% isolated
yields (4a, 4g, 4h).
To gain insight into the mechanistic details of this reaction,
several control experiments were carried out (Figure 1a).
When 1a was stirred under standard conditions, no 3-phenyl-
2H-azirine was detected, and 95% of 1a was recovered after 8
h. Then, 3-phenyl-2H-azirine was subjected to the reaction
under the standard conditions, and no vinyl carbodiimide was
detected, even when heated to 120 °C. Mixing 3-phenyl-2H-
azirine with isonitrile and alkyne under the cyclization
conditions also could not give the aminopyridine product.
These results ruled out azirine as an intermediate in this
coupling/cyclization reaction. Additionally, the vinyl carbodii-
mide product could not be accessed in the absence of Rh
catalyst.
To further understand the mechanism, DFT calculations
were performed by using Gaussian 09 programs.9 2-Azidoprop-
1-ene, isocyanomethane, and chlorobis(ethylene)rhodium
dimer were used as model substrates (Figure 1b). Rh(I)
dimer catalyst dissociated to monomeric active catalyst and
coordinated with isonitrile to form active intermediate I, which
coordinated with vinyl azide to generate II. Complex II
showed a Rh−N bond of 2.23 Å and a Rh−C bond of 1.89 Å,
which revealed Rh(I) configuration. Species II released N2 to
produce nitrene intermediate III, which passed through an
exergonic transition state TS-1a of 25.6 kcal/mol. Because the
length of the N−Rh bond was 2.01 Å, it could be regarded as
having a nitrene Rh−N bond character.9a The nitrene moiety
of III subsequently coupled with the isonitrile to form the vinyl
carbodiimide, which coordinated with the Rh center via TS-2a.
Figure 1. (a) Controlled experiments and (b) DFT calculation of the
coupling step.
Finally, ligand exchange generated free vinyl carbodiimide with
a sharp decline of Gibbs energy (ΔG = 21.3 kcal/mol). The
transition state (TS-1c, ΔG = 35.2 kcal/mol) of azirine
formation, which came from vinyl azide directly without Rh
catalyst, was obviously unfavorable as compared to TS-1a. In
addition, the coupling reaction of azide with CO that passed
through a five-membered metallacycle intermediate has been
reported,10 so the reaction via a similar mechanism was also
calculated. The five-membered intermediate IV was generated
by an oxidant addition transition state TS-1b (ΔG = 41.9 kcal/
mol), which had much higher Gibbs energy than TS-1a. In the
structure of species IV, the Rh−N and Rh−C bonds were 1.99
and 2.00 Å, respectively. To produce intermediate V, complex
IV needs to pass through another unfavorable TS-2b (ΔG =
12.8 kcal/mol). These results also supported that the coupling
step should involve a Rh-nitrene intermediate.
After the inspection of vinyl carbodiimide’s formation, which
is unstable in isolation and storage, we further investigated the
construction of azaheterocycles in a tandem process. Using 2.5
mol % [Rh(COD)Cl]2/5 mol % 2,2′-bpy and adding NH4Cl/
NaHCO3 in the second cyclization step, the reaction of vinyl
azide (1a) with t-BuNC (2a) and alkyne (3a) gave
aminopyridine 5a with the best 71% isolated yield.8 Based
on this optimized condition, the substrate scope was studied
(Scheme 3). The reaction showed good substrate generality:
all steric hindrance, electron, and halogen variation of aromatic
rings in the vinyl azides could be successfully introduced,
providing the desired product in moderate to excellent yields
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DOI: 10.1021/acs.orglett.8b03115
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a
a
Scheme 3. Substrate Scope of Cyclization with Alkyne
Scheme 4. Substrate Scope of Cyclization with Benzyne
a
Reaction conditions: 1 (0.30 mmol), 2 (0.30 mmol), 6 (0.15 mmol),
a
Reaction conditions: 1 (0.15 mmol), 2 (0.15 mmol), 3 (0.30 mmol),
[Rh(COD)Cl]2 (2.5 mol %), 2,2′-bpy (5 mol %), NH4Cl (0.15
mmol), NaHCO3 (0.15 mmol), 1,4-dioxane (2 mL), isolated yield,
[Rh(COD)Cl]2 (2.5 mol %), 2,2′-bpy (5 mol %), KF (0.30 mmol),
18-crown-6 (0.30 mmol), 1,4-dioxane (2 mL), isolated yield.
b
n.r. = no reaction. Reaction conditions: 1 (0.30 mmol), 2 (0.30
mmol), 3 (0.15 mmol).
(5a−5j). Benzyl- and alkyl-substituted vinyl azides could also
participate, albeit with relatively low yields (5x−5y).
Investigation of different isonitriles revealed that all alkyl-,
aryl-, and benzyl-substituted isonitriles reacted smoothly to
furnish the corresponding products (5o−5t). In particular, n-
BuNC showed better reactivity than t-BuNC, which provided
up to 80% yield (5k−5n). When 3a was replaced with other
alkynes, the reaction was less efficient (5r−5w), and no
reaction was observed when diphenyl acetylene or 5-decyne
was used.
The tandem cyclization was further extended from alkynes
to benzynes, which afforded aminoisoquinolines as the
product.8 As shown in Scheme 4, the aromatic ring of vinyl
azide bearing an electron-withdrawing group gave a better
result than that with an electron-donating group (7b vs 7c).
The methyl substituent on the different positions of the
aromatic ring all gave moderate yields (7g−7i), and amino-
isoquinolines from benzyl- and alkyl-substituted vinyl azides
were obtained in 25% and 20% yields (7m−7n). In addition,
alkyl- and benzyl-substituted isonitriles also furnished the
desired products in good yields (7j−7l).
Other common cyclic building blocks were also employed to
construct different azaheterocycles (Figure 2a). Aminopyridine
8 was obtained in 74% yield when vinyl carbodiimide reacted
with an allene. Benzoquinone led to the formation of
aminoisoquinoline-5,8-dione 9 in 65% yield.11 The vinyl
carbodiimide intermediate could also undergo α,α-insertion
reaction with another isonitrile to produce pyrrole-2-imine 10
with 30% yield.
The functional groups of 5a could also been transformed
easily (Figure 2b): (1) The t-Bu group was cleaved to furnish
11 in 97% yield. (2) The ester groups were hydrolyzed to
afford dicarboxylic acid 12 in 86% yield, which could be further
converted to different salts or amides. (3) The ester groups
Figure 2. (a) Rh(I)-catalyzed tandem transformation of vinyl azide.
(b) Functional group transformations of aminopyridine 5a.
were reduced by LiAlH4 to give diol 13 in 95% yield.
Compared to the simple pyridine-2-amine (Φ = 0.6, λem < 380
nm), the above multisubstituted/conjugated aminopyridine
derivatives exhibit either better quantum yield or more diverse
maximum emission wavelength.12 This preliminary fluores-
cence study further shows the potential utility of this new
synthesis method.
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DOI: 10.1021/acs.orglett.8b03115
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Organic Letters
Letter
Taking aminopyridine, for example, the second cyclization
step of the vinyl carbodiimide intermediate has two possible
pathways, direct electrocyclization or Rh(I)-catalyzed oxidative
cyclization/reductive elimination (Figure 3a). In the reaction
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03115.
■
S
Preparation of vinyl azide substrates, general procedure
for Rh-catalyzed reaction of vinyl azides with isonitriles
and alkynes/benzynes, examination of reaction con-
ditions, general procedure for other azaheterocycles and
aminopyridine derivatives, controlled experiments, addi-
tional DFT calculations of the cyclization, spectral data,
and optimized structure and Gibbs energy of DFT
calculation (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangzhh@cau.edu.cn.
ORCID
Zhiyuan Zhang: 0000-0002-2910-1986
Zhenhua Zhang: 0000-0002-6579-1670
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is supported by the National Key Research and
Development program of China (2017YFD0201300) and the
National Natural Science Foundation of China (No.
21672256). Prof. Haixiang Gao of China Agricultural
University is acknowledged for providing computational
resources. We appreciate Dr. Yiyang Liu of University of
Michigan for correcting this manuscript.
Figure 3. (a) Two possible pathways of the second cyclization step.
(b) Controlled experiments.
of isolated vinyl carbodiimide intermediate 4a with alkyne 3a,
the standard Rh(I)-catalyzed condition afforded 5a in 76%
yield, while the catalyst-free condition gave only 49% yield
(Figure 3b). Further detailed controlled experiments and DFT
calculations also suggested that the Rh(I)-catalyzed oxidative
cyclization/reductive elimination mechanism was the domi-
nant pathway. When alkyne was displaced by a more active
benzyne, the effect of Rh catalyst became inapparent. The
Rh(I)-catalyzed conditions and the catalyst-free conditions
gave similar yields. For more details about the mechanism of
study of the cyclization step, see the SI, Parts 6 and 7.
In summary, we developed a Rh(I)-catalyzed coupling
reaction of vinyl azide with isonitrile to form vinyl
carbodiimide, which is an efficient kind of azaheterocycle
building block. We utilized this access to synthesize and
characterize a series of vinyl carbodiimides, which could further
undergo tandem cyclizations with alkynes, benzynes, allenes,
and alkenes etc. to furnish different classes of azaheterocycles,
i.e., aminopyridine, isoquinoline, and pyrroleimine, respec-
tively. Controlled experiments and DFT calculations disclose
that Rh-nitrene is the vital species in the first coupling step,
and Rh(I) catalyst also plays an important role in the
cyclization of alkynes. A preliminary fluorescence study of
aminopyridine and its derivatives further reveals the potential
utility of this method.
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