Copper-Catalyzed Cascade Substitution/Cyclization of N-Isocyanates: A Synthesis of 1-Aminobenzimidazolones

Article abstract of DOI:10.1021/acs.orglett.6b01686

A copper-catalyzed cascade reaction of in situ generated nitrogen-substituted isocyanates (N-isocyanates) and 2-iodoanilines has been developed. The cascade relies on the base-catalyzed substitution of masked N-isocyanates, followed by Cu(I)-catalyzed cou

Full text of DOI:10.1021/acs.orglett.6b01686

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Cascade Substitution/Cyclization of N‑Isocyanates:
A Synthesis of 1‑Aminobenzimidazolones
Jing An, Howard Alper,* and Andre M. Beauchemin*
́
Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10
Marie-Curie, Ottawa, ON K1N 6N5, Canada
S
* Supporting Information
ABSTRACT: A copper-catalyzed cascade reaction of in situ
generated nitrogen-substituted isocyanates (N-isocyanates) and
2-iodoanilines has been developed. The cascade relies on the
base-catalyzed substitution of masked N-isocyanates, followed
by Cu(I)-catalyzed coupling to afford a variety of 1-amino-
benzimidazolones in moderate to excellent yields. This is the
first example of a transition-metal-catalyzed cascade reaction
involving N-isocyanate intermediates.
Scheme 1. Known Syntheses of 1-Aminobenzimidazolones
he N−N−CO motif is widely present in bioactive
Theterocycles, with over 50 pharmaceuticals and agro-
chemicals incorporating this structural unit.1 In particular, the
4-phenylsemicabazide moiety is associated with remarkable
biological properties.2 For example, pyrifluquinazon3 is a new
insecticide for the control of sucking pests. Selurampanel4 is an
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA)/Kainate receptor antagonist investigated in clinical
trials for the treatment of epilepsy by Novartis. Over the past
decade, much attention has been given to 1-aminobenzimida-
zolones5 which possess both valuable 4-phenylsemicabazide
and benzimidazolone6 skeletons (Figure 1). The compounds
are attractive functional precursors. Compared to normal
containing this motif are often biologically active: examples
isocyanates, the synthetic potential of N-isocyanates is rather
include antitumor7a and anti-inflammatory7b activities.
underdeveloped, mainly due to the tendency of these
amphoteric intermediates to dimerize.9b Recently, our group
successfully implemented alkene aminocarbonylation10 and
several cascade reactions1,11 of masked N-isocyanates12 to
afford diverse nitrogen heterocycles. This reactivity was enabled
by the in situ generation of N-isocyanate intermediates from
carbazates or carbazones. As part of these efforts, we speculated
that masked N-isocyanates could be used as substrates for
different sequences including metal-catalyzed reactions.
Figure 1. Representative bioactive compounds containing the 4-
arylsemicabazide moiety.
Interestingly, while cascade reactions involving isocyanates
are common, metal-catalyzed variants are more scarce.13
Examples using masked/blocked isocyanates are rare and
have not been reported with N-isocyanates. On the other hand,
cascade reactions involving copper catalyzed C−N bond
formation14 have attracted substantial attention because of
their broad applicability and affordability. Therefore, we
became interested in expanding the synthetic utility of N-
isocyanates to copper catalyzed cascade reactions. Herein, we
report the reaction of in situ generated N-isocyanates with 2-
iodoanilines followed by Cu(I) catalyzed intramolecular
Despite their potential applications in drug development,
only limited approaches to 1-aminobenzimidazolones have
been reported in the literature. The most commonly employed
methods include carbonylation of 2-hydrazinylanilines,5 Lewis
acid mediated cyclization of diazenes,8a,b and amination8c of
benzimidazolones (Scheme 1). The conventional strategies
often suffered from multiple synthetic steps, a limited substrate
scope, prefunctionalized starting materials, or required
stoichiometric reagents. Thus, the development of a more
efficient and straightforward approach to 1-aminobenzimidazo-
lones is highly desirable.
For the construction of heterocycles possessing the N−N−
Received: June 10, 2016
CO motif, nitrogen-substituted isocyanates (N-isocyanates)9
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01686
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Organic Letters
Letter
coupling to directly form functionalized 1-aminobenzimidazo-
lones (Scheme 2).
desired product 4aa in 59% yield (entry 5). When the solvent
was changed to MeCN, the yield of 4aa increased to 66%
although some intermediate 3aa still remained even after 48 h
at 100 °C (entry 7). Next, the cascade reaction was conducted
in DMF at 120 °C in order to achieve complete conversion and
the ratio of 1a to 2a was further examined. As expected, when
this ratio was increased to 1:1.5, the desired product 4aa was
obtained in 70% yield (entry 9). A control experiment revealed
that no cyclization product 4aa formed when the CuI catalyst
was omitted (entry 11). To improve the synthetic efficiency,
the reaction of 1a and 2a was also investigated in a one-pot
manner. To our delight, by performing the substitution step in
PhCF3 in the presence of DABCO and then concentrating in
vacuo, followed by addition of CuI, 1,10-phenanthroline and
DMSO gave the desired product 4aa in 86% yield (entry 13).
In the process of optimization, it was found that the
substitution step was promoted by a catalytic amount of base.15
With the optimal reaction conditions in hand, a range of 2-
iodoanilines were first examined (Scheme 3) to explore the
Scheme 2. Reaction Design
The reaction, from a process optimization standpoint,
needed to address challenges which included (1) the propensity
of side reactions because of the somewhat reduced electro-
philicity of amino-isocyanate intermediates and lower nucleo-
philicity of 2-iodoanilines and (2) the compatibility of N-
isocyanate intermediates in the presence of a Cu(I) catalyst.
Based on the optimization15 of the intramolecular coupling
reaction of semicarbazide intermediate 3aa, N,N-disubstituted
carbazate 1a and 2-iodoaniline 2a were chosen as substrates to
test the cascade reaction in the presence of CuI (10 mol %) and
1,10-phenanthroline (20 mol %) (Table 1). However, when the
optimal base for the intramolecular coupling was employed
(K2CO3), the carbazide byproduct16 rather than the desired 1-
aminobenzimidazolone 4aa was obtained (entry 1). By
screening various bases, we were pleased to find that the
utilization of DMAP could suppress the self-condensation of 1a
and the cascade reaction proceeded as envisioned affording the
Scheme 3. Comparison of Efficiency of One-Pot Reaction
ab
,
and Cascade Reaction with 2-Iodoanilines
a
Table 1. Optimization of the Reaction Conditions
temp
ratio
yield
b
entry
base
solvent
DMSO
(°C)
(1a:2a)
(%)
1
2
3
4
5
6
K2CO3
K3PO4
Et3N
100
100
100
100
100
100
100
120
120
120
120
100
100
1:1
trace
trace
trace
trace
59
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
1:1
1:1
i-Pr2NEt
DMAP
DABCO
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DABCO
1:1
1:1
1:1
50
c
7
1:1
66
a
Conditions: Method A: 1a (0.20 mmol), 2 (0.30 mmol), DABCO
(0.60 mmol), PhCF3 (2.0 mL), 100 °C, 12 h; concentrated; add CuI
(0.02 mmol), 1,10-phenanthroline (0.04 mmol), DMSO (2.0 mL);
100 °C, 5 h; Method B: 1a (0.20 mmol), 2 (0.30 mmol), DMAP (0.60
mmol), CuI (0.02 mmol), 1,10-phenanthroline (0.04 mmol), DMF
8
DMF
1:1
66
9
DMF
1:1.5
1:2
70
10
DMF
70
cd
,
11
12
13
DMF
1:1.5
1:1.5
1:1.5
0
b
c
e
e
(2.0 mL), 120 °C, 24 h. Isolated yield. Reaction time: 48 h.
PhCF3/DMSO
PhCF3/DMSO
73
d
Performed in DMSO at 100 °C.
86
a
Conditions: 1a (0.10 mmol), 2a (0.10−0.20 mmol), CuI (0.01
mmol), 1,10-phenanthroline (0.02 mmol), base (0.30 mmol), solvent
substrate scope. As summarized in Scheme 3, the reaction
displayed excellent tolerance for 2-iodoanilines, allowing a
broad range of 1-aminobenzimidazolones to be obtained in
moderate to excellent yields in both one-pot and cascade
reaction conditions (methods A and B, respectively). The
efficiency of the transformation was affected by electronic and
steric effects of the substituents on the 2-iodoanilines. For
b
c
(1.0 mL). Isolated yield. The reaction was stirred at the indicated
d
temperature for 48 h. Without CuI and 1,10-phenanthroline.
e
Conditions: 1a (0.10 mmol), 2a (0.15 mmol), base (0.30 mmol),
PhCF3 (1.0 mL), 100 °C, 24 h, and then concentrated; adding CuI
(0.01 mmol), 1,10-phenanthroline (0.02 mmol), and DMSO (1.0
mL), then stirred at 100 °C for 12 h.
B
DOI: 10.1021/acs.orglett.6b01686
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Organic Letters
Letter
example, 2-iodo-4-methoxyaniline exhibited good reactivity and
produced the corresponding product 4ab in 95% yield (one-pot
reaction) and 77% yield (cascade reaction). In contrast, 2-
iodoanilines with electron-withdrawing groups gave slightly
lower yields (4ac and 4ad). This could be due to the decreased
nucleophilicity of the anilines which allows irreversible
formation of the self-condensation carbazide byproduct. As
shown with substrates bearing methyl groups at different
positions, more sterically hindered substrates such as 2-iodo-6-
methylaniline resulted in a lower product yield (4ag vs 4ae, 4af
and 4ah). Of note, F, Cl, and Br substituents are well tolerated
in this reaction and afforded the corresponding 1-amino-
benzimidazolones (4ai, 4aj, and 4ak) in good yields, thereby
providing the opportunity for subsequent coupling reactions.
Moreover, the sterically demanding 2-iodo-N-methylaniline was
successfully employed and furnished the desired product in
moderate yield (4am). Importantly, the scope could be
extended to incorporate heteroaryl substrates, although the
reaction was less efficient. For instance, when 2-amino-3-
iodopyridine was used, the corresponding heterocycle was
obtained in 50% yield by the one-pot method (4an).
To expand the utility of this strategy, we turned our attention
to other masked N-isocyanates. The aldehyde-derived hydra-
zone 5 showed higher reactivity than hydrazides. The reaction
with substrate 5 proceeded efficiently to produce the
corresponding product in excellent yield, which was followed
by treatment with hydroxylamine to form the 1-amino-
benzimidazolone 7 (eq 1). The masked N-isocyanate 8
The scope of the reaction in terms of carbazates (1) was then
investigated. As shown in Scheme 4, this substitution/
Scheme 4. Comparison of Efficiency of One-Pot Reaction
ab
,
and Cascade Reaction with Carbazates
incorporating a pyrrole unit was also successfully employed in
this reaction sequence, and the functionalized compound 9 was
obtained in 87% yield (one-pot reaction) and 75% yield
(cascade reaction) (eq 2). Furthermore, this cascade protocol
could also be applied to the masked N-isothiocyanate substrate
10 to afford hydrazinylbenzo[d]thiazole 11 in 91% yield, which
possesses a core structure exhibiting promising antioxidant
activity17 (eq 3).18
In order to clarify the mechanism of the coupling step,19
iodo-substitued carbazate 12 was reacted with 2-iodoaniline 2a
under the optimal conditions. As illustrated in Scheme 5, the
Scheme 5. Cascade Substitution/Selective Cyclization
Favored 1-Aminobenzimidazolone
a
Reaction conditions: Method A: 1 (0.20 mmol), 2a (0.30 mmol),
DABCO (0.60 mmol), PhCF3 (2.0 mL), 100 °C, 12 h, then
concentrated; adding CuI (0.02 mmol), 1,10-phenanthroline (0.04
mmol), DMSO (2.0 mL), 100 °C, 5 h; Method B: 1 (0.20 mmol), 2a
(0.30 mmol), DMAP (0.60 mmol), CuI (0.02 mmol), 1,10-
b
phenanthroline (0.04 mmol), DMF (2.0 mL), 120 °C, 24 h. Isolated
yield. The reaction was performed for 12 h.
c
cyclization process was general with respect to structural
variations on the carbazate. When the N-substituent on the
carbazate (1) was benzyl or phenyl, the reaction proceeded
smoothly to provide the products in good yields (4ba and 4ca).
It is noteworthy that the parent N-H carbazate also participated
in this transformation and afforded the corresponding product
in moderate yield (4da). A nitro substituent was tolerated, and
yields of 98% and 78% were obtained for the one-pot and
cascade reactions, respectively (4ga). The electronic nature of
the aryl ring did not have a significant impact on process
efficiency (4ea−4ga), even if electron-withdrawing substituents
appear beneficial, possibly by improving NH acidity.
five-membered 1-aminobenzimidazolone 13 was selectively
formed rather than the six-membered heterocycle 14. When
the reaction time was prolonged, a trace amount of compound
4aa was detected. Therefore, the possibility of a radical pathway
can be excluded and an oxidative addition/reductive elimi-
nation mechanism is proposed for the intramolecular coupling
reaction. The favored six-membered intermediate could
account for the chemoselectivity observed with substrate 12.
Finally, while additional studies are needed to determine the
mechanisms operating under the one-pot and cascade reactions
C
DOI: 10.1021/acs.orglett.6b01686
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Organic Letters
Letter
Curr. Org. Chem. 2011, 15, 1745. (c) Vincent-Rocan, J.-F.;
Beauchemin, A. M. Synthesis, accepted for publication May 31, 2016.
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conditions, the similarity of reactivity trends and reaction
conditions support identical pathways.
In summary, a novel and efficient method for the elaboration
of 1-aminobenzimidazolones through Cu(I)-catalyzed substitu-
tion/cyclization reactions of N-isocyanates has been developed.
To our knowledge, this is the first metal-catalyzed cascade
reaction with masked N-isocyanates. This method features
simple experimental procedures, good functional group
tolerance, and a broad substrate scope. The development of
other metal catalyzed reaction sequences involving N-
isocyanates is underway and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01686.
Additional optimization data, complete experimental
procedures, characterization data, and NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(14) For selected reviews, see: (a) Liu, Y. Y.; Wan, J. P. Org. Biomol.
Chem. 2011, 9, 6873. (b) Sadig, J. E. R.; Willis, M. C. Synthesis 2011,
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For selected examples, see: (d) Liu, X. W.; Fu, H.; Jiang, Y. Y.; Zhao,
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*E-mail: howard.alper@uottawa.ca.
*E-mail: andre.beauchemin@uottawa.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Ottawa, NSERC, CFI, and the
Ontario MRI for generous financial support.
■
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