A catalytic intramolecular nitrene insertion into a copper(i)-N-heterocyclic carbene bond yielding fused nitrogen heterocycles

Article abstract of DOI:10.1039/c6cc09160a

N-(2-Azidophenyl)azolium salts were easily prepared and reacted with copper(i) under conditions allowing the formation of NHC complexes. Under these conditions, the formation of benzimidazo-fused heterocycles occurred under catalytic, efficient and very mild conditions. This reaction is proposed to proceed via dinitrogen elimination and imido/nitrene-NHC cyclization.

Full text of DOI:10.1039/c6cc09160a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C6CC09160A
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A catalytic intramolecular nitrene insertion into a copper(I)–N-
heterocyclic carbene bond yielding fused nitrogen heterocycles
Kévin Fauché,a Lionel Nauton,a Laurent Jouffret,a Federico Cisnetti,a* Arnaud Gautiera*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-(2-azidophenyl)azolium salts were easily prepared and reacted following the formation of the metal-NHC complex. We
with copper(I) in conditions allowing the formation of NHC demonstrate in this Communication that the latter reactivity
complexes. In these conditions, the formation of benzimidazo- may be harnessed as a highly efficient and catalytic synthetic
fused heterocycles occurred in catalytic, efficient and very mild access to nitrogen-rich fused heterocycles.
conditions. The reaction is proposed to proceed via dinitrogen
elimination and imido/nitrene–NHC cyclization.
N-Heterocyclic Carbenes (NHCs) have become one of the most
powerful tools in synthetic chemistry.1 Chiefly, they play the
role of ancillary ligands allowing the preparation of transition
metal complexes (e.g. Pd,2 Au,3 Cu4…) which have found
plethoric applications in catalysis.5 These complexes are often
stable due to electronic and steric effects. Thus, cases for
which the NHC departs from its archetypical ancillary ligand
role are rarely encountered.6 One of these occurrences was
encountered with a tripodal tris-NHC complex that underwent
an imido insertion into the metal–Ccarbene bond furnishing a
new carbon-nitrogen double bond.7 This bimolecular process is
Scheme 1. Attempted preparation of chelated Cu-(NHC-N3) complexes and C=N
cyclization.
believed to proceed via an azide decomposition to imido with
dinitrogen release through cobalt(III)/cobalt(I) intermediates.
The 1-(2-azidoaryl)imidazolium salt starting materials could be
obtained using several facile well-established synthetic
Other rare cases imply the formation of Ccarbene–nitrogen
bonds from NHC complexes8 or with other types of metal
carbenes, all being stoichiometric.9 In contrast to these
examples, NHC complexes have been used as nitrene insertion
catalysts without any reaction at the NHC center.10
pathways. E.g, the precursor
3 was obtained in gram-scale
with 81% yield using a 3-step synthesis from imidazole and 1-
fluoro-2-nitrobenzene (see ESI for details).13 The formation of
the imidazolium salts 4a,b using benzyl or 2-picolyl chloride
occurs smoothly in excellent yield at 80°C (see ESI). Then, in
order to prepare the metal-NHC complexes, we examined the
reactivity of 4a and 4b with CoCl(PPh3)3 and CuCl in presence
of a 6-fold excess of aqueous ammonia. These conditions were
previously reported for the synthesis of copper(I)-NHC
complexes.14 No reaction were observed with the cobalt
complex but using CuCl, a vigorous gas evolution was observed
with the formation of a precipitate. This proved to be the pure
1H-benzimidazo[1,2-a]imidazole derivative 6a or 6b instead of
Previously, we have reported that azolium salts distally tagged
with azides
1 . We
yielded stable Cu-NHC complexes 2 11
decided to introduce the azide function in close proximity to
the precarbenic center through the preparation of N-(-2-
azidophenyl)imidazolium salts
4
, from azide precursors
3
(Scheme 1). Azolium salts
4
allow in principle to form either
stable bidentate NHC–azide chelates12 or benzimidazo[1,2-
a]imidazoles through NHC-nitrene cyclization. The latter
possibility requires that nitrene decomposition occurs in a step
complexes 5. Compounds 6a,b were isolated in ~95% yield and
aUniversité Clermont Auvergne, CNRS, Sigma Clermont, ICCF, F-63000 Clermont-
Ferrand, France. E-mail: federico.cisnetti@uca.fr, arnaud.gautier@uca.fr
Electronic Supplementary Information (ESI) available: experimental conditions, 1H
and 13C NMR spectra, crystallographic details, DFT data. See
DOI: 10.1039/x0xx00000x
1
were fully characterized by H- and 13C-NMR, IR (lack of the
azide band) spectroscopies, HRMS and CHN elemental
analyses (Scheme 2). The definitive structural proof was
obtained by the X-ray diffraction‡ for 6b, Scheme 2.
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Table 1. Optimization of the preparation of 6a.
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DOI: 10.1039/C6CC09160A
Entry
Eq. CuCl
Eq. NH3
Solvent
Conversiona
1
2
1.0
1.0
0.1
0.1
0
6.0
1.0
1.0
0.6
1.0
0
Water
Water
Water
Water
Water
Water
Ethanol
Ethanol
MeCN
DMF
>95%
>95%
93%
3
4
60%
5
0%
6
0.1
0.1
0.01
0.1
0.1
0.1
0.1
0%
7
1.0
1.0
1.0
1.0
1.0
1.0
>95%
62%b
>95%
>95%
>95%
>95%
8
Scheme 2. Preparation of azido substrates and their cyclization; insert: structure of 6b
by X-ray diffraction; selected distances N2-C5 1.361 Å, N3-C5, 1.373 Å, N4-C5, 1.319 Å
9
10
11
12
This synthetic route deserves some literature comparisons. On
the one hand, benzimidazo[1,2-a]imidazoles are recognized as
interesting scaffolds for drug design or optoelectronic
applications. They are accessible via lengthy conventional
multistep organic syntheses.15 Recently, elegant metal-
catalyzed procedures have been developed, but they still need
prolonged reaction times at high temperatures:16 e.g. copper-
catalyzed aerobic oxidative intramolecular C-H amination has
been reported for 9H-benzimidazo[1,2-a]imidazole synthesis
from 2-(1H-imidazol-1-yl)-aniline, but requires 24-55 h in
refluxing m-xylene.16a On the other hand, the azide group is a
well-known precursor for nitrenes whose insertion in C-H
bonds allows the preparation of heterocycles.17 Metal-
catalyzed Csp3-H aminations from azides have been achieved
with exquisite selectivity.18 In the last decade, Csp2-H
aminations have emerged and azides are again among the
preferred precursors.19 Usually, the catalyst is sophisticated
and/or requires a precious metal. In this context, our study
compares well with the rhodium-catalyzed synthesis of
carbolines from aryl azides reported by Driver et al.. His very
efficient and mild protocol requires nevertheless 5 mol-% of
(expensive) [Rh2(esp)2].20 The efficiency of our room
temperature21 conditions and the use of a nonprecious metal
prompted us to perform a detailed study.
DMSO
THF
a reaction duration: 1h bafter 48h
The conditions reported in entry 7 were further modified to
check the influence of metal source and base. The presence of
copper(I) was necessary as other metal salts (10 mol-%, MnCl2,
FeCl2, CoCl2, CoCl(PPh3)3, ZnCl2, NiCl2, NiCl2(dme), PdCl2(PPh3)2,
Pd(PPh3)4, CuCl2) were inefficient to perform the reaction.23
However, other stable copper(I) sources were usable such as
Cu2O, [Cu(MeCN)4](PF6) and the preformed NHC complex
[CuCl(IPr)]14a which give 87%, 92% and 86% conversion,
respectively. Ammonia proved to be an optimal base for this
catalytic reaction as changing the base to Na2CO3, NaOH or
NaOEt gave inferior results (yield reduced to 65% in the first
case due to limited conversion, complete conversion but
extensive degradation in the two latter cases).
First, the effect of ammonia, metal, and solvent were
examined for the formation of 6a (Table 1). The initial
conditions (entry 1) were taken from our previous report on
copper-NHC synthesis and were shown to allow full conversion
of precursors related to 4b to copper complexes within 1 h at
RT.14 Lowering the amount of ammonia doesn’t affect the
conversion (entries 1-2). Importantly, the reaction could be
conducted efficiently within 1 h with substoichiometric CuCl
(10 mol-%, entry 3), keeping the amount of ammonia to 1.0
eq. (entry 4).22 To the best of our knowledge, this is the first
case of a catalyzed imido insertion into a carbene-metal bond.
Negative controls (entries 5 and 6) show that copper and
ammonia are necessary for the reaction. Various solvent such
as ethanol, acetonitrile, DMF, DMSO and THF (entries 7, 9-12)
could be used instead of water. A lower metal loading caused
reduced yield despite long reaction times (entry 8).
Scheme 3. Cyclization through silver transmetalation. Insert: structure of the dimer of 7
by X-ray diffraction; selected structural parameters Ag-C: 2.089 Å, Ag-Cl: 2.403 Å,
Ag…Cl: 2.793 Å, C-Ag-Cl: 163.5 °, Ag-Cl...Ag: 90.15°.
As an alternative to the ammonia protocol, we also considered
the silver to metal transmetallation.24 Indeed, the reaction of
4a with silver(I) oxide afforded
7 (Scheme 3) without any gas
evolution.25 Subsequently, 10 mol-% of copper(I) were added:
to our delight, a gas evolution was observed and compound 6a
could be isolated in quantitative yield. Using 10 mol-% of
CoCl(PPh3)3, 6a was identified in the crude mixture
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accompanied by an iminophosphorane imidazolium resulting the imidazolium’s27 which slows down the formatiVoienwoArftitchleeOnCliune-
DOI: 10.1039/C6CC09160A
from a Staudinger reaction (~80/20 by HPLC-HRMS). While the NHC complex intermediate.
cyclization by the Ag2O route could be performed in one-pot
conditions, the intermediate silver-NHC complex
7 could be
isolated and fully characterized. In the solid state, the
structure shows a well-known Ag2(µ-Cl)2 diamond core arising
from Ag…Cl-Ag interaction with usual bond lengths and angles
and no interaction between Ag and N3. Interestingly,
7 could
also undergo cyclization in rather inefficient conditions (ESI).
All these observations, as well as mechanistic precedents,
strongly support the involvement of a metal imido-NHC
intermediate.
The cyclization reaction using copper(I)/ammonia protocol was
applied to other representative azolium salts with good yields
(Scheme 4) and most of the products were obtained as
analytically pure materials after simple extraction. Besides
Scheme 5. Cyclization of a 1,2,3-triazolium salt.
A proposed mechanism is sketched in Scheme 6. The CuI-NHC
complex
5 is formed either by direct metalation in the
presence of ammonia or by transmetalation from a silver
precursor (step I). Copper chelation to azide and extrusion of
dinitrogen (step II) forms the complex
formally a copper(III) center chelated by both imido and
carbene donors. This intermediate is expected to undergo a
carbene-nitrene reductive cyclization to compound
with copper(I) chloride regeneration. This can be explained by
the electrophilic nature of the imido donor which inserts into
the copper-NHC bond. Compared to previous reports of
stoichiometric transformations,7,8 the catalytic nature of the
process is facilitated by the ease of formation of the copper-
NHC complex using either protocol and the intramolecular
nature of the reaction.
8, which includes
6a,b the method tolerates the presence of alkyl substitutions
on the benzimidazole ring (6c) as well as an electron-
withdrawing group (trifluoromethyl, 6d). The reaction also
applied to a benzimidazolium salt to yield 6e16c and to N-alkyl
substituted products (6f,g) as well. The cyclization was not
restricted to the imidazolium salts but also applied in the same
6 (step III)
conditions
to
1,2,4-triazolium
salts
leading
to
benzo[4,5]imidazo[1,2-b]-1,2,4-triazole 6h,i in good yields.26
However, the cyclization of a N-(2-azidobenzyl)-imidazolium
(4j, ESI) failed (after several days at 90°C the starting material
was recovered unchanged).
Scheme 6. Postulated catalytic reaction mechanism
To support the proposed mechanism, we examined the
energetic profile of steps II and III by DFT calculations for
model compounds 1-(2-azidophenyl)-4-methyl imidazolium
Scheme 4.. Isolated yields for the cyclization products.
Similarly, the 1,2,3-triazolium 4k stayed unchanged at room and 1-(2-azidophenyl)-4-methylbenzimidazolium (Table S5).
temperature for several hours. However, increasing the The calculations show that dinitrogen generation forming the
temperature to 80°C and extending time to 3 days allowed a carbene-imido complex and reductive elimination of copper
clean conversion to a benzo[4,5]imidazo[1,2-c]-1,2,3-triazol-2- (step II-III, Scheme 6) are both exergonic and that the higher
ium specie (Scheme 5).26b To avoid anion scrambling issues, 6k transition state energy (step II) is only ~10 kcal mol-1. In the
was also obtained using copper(I) oxide as the metal source (in intermediates of type
8, the complex is favorably organized for
somewhat less efficient conditions: 4 days, 90°C, 20 mol-% reductive elimination with Nnitrene-Cu-Ccarbene angles < 90°,
Cu2O). We also tested the silver oxide/catalytic CuCl procedure which is in line with a low TS energy (1-5 kcal mol-1). The
(scheme 3) and found that the reaction took place in few reactivity could be explained by the weak N-N2 and the strong
minutes, once the formation of the silver complex was
NN bonds, and by the extended conjugation in the final
complete. The lower reactivity of 4k could be explained by the product.
lower acidity of the 1,2,3-triazolium proton in comparison to
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13 A. J. Blake, B. A. J. Clark, H. McNab, and C. C. Sommerville, J.
In conclusion, we have reported a novel synthetic method
based on a cyclization reaction leading to the formation of
polycyclic nitrogen-rich compounds. This process is believed to
occur through reductive elimination from copper(III) in a
View Article Online
Chem. Soc. Perkin Trans. 1, 1997, 1605.
DOI: 10.1039/C6CC09160A
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Gibard, H. Ibrahim, A. Gautier and F. Cisnetti,
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Lorbach, A. Eichhorn, F. Cisnetti and A. Steffen, Chem.
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chelated
carbene-copper-nitrene
intermediate.
This
constitutes the first catalytic and synthetically efficient
occurrence of this type of cyclization with N-heterocyclic
carbenes not acting as spectator ligands but as reactive
partners. This against-the-rules reactivity of NHC ligands may
open new horizons in synthesis by redirecting the extensive
literature reports for the preparation of azolium salts to the
preparation of diversified heterocyclic scaffolds.28
15 L. M. Werbel and M. L. Zamora,. J. Heterocycl. Chem. 1965, 2,
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‡ CCDC 1491878 and 1529895 contains the supplementary
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5
21 Thermal generation of a nitrene from an azide giving
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Khan and V. L. T. Ribeiro, Pak. J. Sci. Ind. Res., 2000, 43, 168.
See also ref 13 for flash vacuum pyrolysis.
22 A pH change consistent with the conversion of NH3 to NH4Cl
was observed although the actual values were not fully
reproducible due to their sensitivity to trace amounts of
basic or acid impurities in the reactants.
23 The metal-NHC complexes with the elements considered
here are not formed while attempting to apply the
metalation conditions described in reference 14 with N-
mesityl-N’-2-picolylimidazolium salts.
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yielded ~10% conversion to the same species.
26 Previous reports on benzo[4,5]imidazo[1,2-c]-1,2,3-triazol-2-
ium species: (a) V. V. Kuz’menko, T. A. Kuz’menko, A. F.
Pozharskii, V. N. Doron’kin, N. L. Chikina and S. S.
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8
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metal-nitrene angle
 180°.
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12 Metal-chelating azides are known in the literature, but no
example of copper(I)-NHC complex containing a bidentate
azidocarbene ligand has been reported: (a) M. Barz, E.
Herdtweck and W. R. Thiel, Angew. Chem. Int. Ed. Engl.,
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Uttamapinant, S. Tangpeerachaikul, S. Grecian, S. Clarke, U.
Singh, P. Slade, K. R. Gee and A. Y. Ting, Angew. Chem. Int.
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, 5852; e) V. Bevilacqua, M. King, M.
Chaumontet, M. Nothisen, S. Gabillet, D. Buisson, C. Puente,
A. Wagner and F. Taran, Angew. Chem. Int. Ed., 2014, 53
5872.
,
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