Pd(II)/Ag(I)-Promoted One-Pot Synthesis of Cyclic Ureas from (Hetero)Aromatic Amines and Isocyanates

Article abstract of DOI:10.1021/acs.orglett.6b03151

A simple and facile one-pot reaction has been developed to afford a diverse range of N,N′-disubstituted benzimidazolones and imidazopyridinones containing two differently substituted N atoms. A cooperative Pd(II)/Ag(I) system promotes the sequential addition/intramolecular C-H amidation reaction of (hetero)aromatic amines and isocyanates, leading to the formation of two C-N bonds. A mechanism involving radical intermediates generated by single-electron transfer (SET) in the presence of a Ag₂CO₃ oxidant and Pd(OAc)₂ Lewis acid is proposed. This protocol offers an operationally easy, simple, and robust approach with the use of readily available starting materials, good functional group tolerance, and high efficiency.

Full text of DOI:10.1021/acs.orglett.6b03151

Letter
pubs.acs.org/OrgLett
Pd(II)/Ag(I)-Promoted One-Pot Synthesis of Cyclic Ureas from
(Hetero)Aromatic Amines and Isocyanates
So Won Youn* and Yi Hyun Kim
Center for New Directions in Organic Synthesis, Department of Chemistry and Institute for Material Design, Hanyang University,
Seoul 04763, Korea
S
* Supporting Information
ABSTRACT: A simple and facile one-pot reaction has been developed to afford a diverse range of N,N′-disubstituted
benzimidazolones and imidazopyridinones containing two differently substituted N atoms. A cooperative Pd(II)/Ag(I) system
promotes the sequential addition/intramolecular C−H amidation reaction of (hetero)aromatic amines and isocyanates, leading
to the formation of two C−N bonds. A mechanism involving radical intermediates generated by single-electron transfer (SET) in
the presence of a Ag2CO3 oxidant and Pd(OAc)2 Lewis acid is proposed. This protocol offers an operationally easy, simple, and
robust approach with the use of readily available starting materials, good functional group tolerance, and high efficiency.
equivalent, inevitably involving protecting group stategies for the
regioselective functionalization of each N atom (Scheme 1, path
a).4 Due to its inefficiency, the use of toxic reagents, and limited
availability of diversely substituted 1,2-diaminobenzenes, alter-
native protocols such as transition-metal-catalyzed inter- (path
b)5 or intramolecular (path c)6 C−Nbond formation using ortho-
haloaniline derivatives have been developed. Obviously, a direct
C−H amidation of N,N′-disubstituted ureas would be a more
efficient route toward this scaffold, obviating the need for
prehalogenation (path d): A handful of experimental studies
under metal-free conditions have been reported.7
enzimidazolones and imidazopyridinones with a benzo- and
Bpyrido-fused cyclic urea framework, respectively, are
versatile building blocks and privileged structural motifs found
in a wide range of pharmaceuticals1 and functional molecules2
(Scheme 1, bottom). In particular, N-arylbenzimidazolones are
known to exhibit a diverse range of biological activities.3
Regioselective synthesis of benzimidazolone derivatives bearing
two different substituents on each nitrogen atom is highly
desirable. Conventional synthesis of such compounds typically
requires the use of 1,2-diaminobenzenes and toxic phosgene or its
Thereareacouple ofexamples ofthedominoprocessinvolving
a reaction between isocyanates8 and amines to form ureas and
ultimately benzimidazolones. Hu et al. reported a PhIO-induced
Hofmann rearrangement of amides for the in situ generation of an
isocyanate moiety which undergoes intramolecular nucleophilic
attack by an ortho amine substituent, leading to benzimidazolones
(path e).9 Very recently, it has been described that a one-pot
reaction of N-aryl-2-nitrosoanilines using CO2 and phosphite for
the synthesis of 1-arylbenzimidazolones involves the intra-
molecular cyclization of an intermediate isocyanate group with
an ortho arylamino group.10 Alper and Beauchemin demonstrated
acascade reaction consistingofthe reactionof insitugenerated N-
isocyanates and 2-iodoanilines followed by Cu(I)-catalyzed
intramolecular coupling (via path c).6d
Scheme 1. Methods for the Synthesis of Unsymmetrical
Benzimidazolones (top) and Selected Bioactive Derivatives
(bottom)
Inspired by these literature reports, we reasoned that new,
carefully chosen oxidative conditions would promote a direct C−
H amidation of in situ generated N,N′-disubstituted ureas from
anilines and isocyanates, leading to N,N′-disubstituted benzimi-
dazolones. Given the diversity of commercially available anilines
Received: October 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03151
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Letter
and isocyanates, the realization of this proposal would provide
another facile route to such compounds and overcome some
drawbacks of the precedents such as the need for often not readily
available starting materials, use of hazardous chemicals, and
requirement of multistep manipulations for the substrate
preparation. As part of our continued interest in the oxidative
cyclizationreaction,11 herein wereportaPd(II)/Ag(I)-promoted
one-pot synthesis of benzimidazolones and imidazopyridinones
containing two differently substituted N atoms from (hetero)-
aromatic amines and isocyanates (path f).
In light of our recent success in Ag(I)-mediated C−H
amidation11f and considering the beneficial effect of Lewis acids
for the activation of the carbonyl substrate in the Ag-mediated
oxidative cyclization,11c we began our studies on the proposed
reaction using 1a and 2a as the test substrates in the presence of
Ag2CO3 and Pd(OAc)2 as an oxidant and Lewis acid, respectively.
Much to our delight, the desired benzimidazolone 4aa was
obtained in good yield along with a small amount of uncyclized
urea intermediate 3aa (Table 1, entry 1). A variety of other Ag
employing only Ag2CO3 led to the formation of 4aa, albeit in a
much lower yield (entry 12). Thus, although a mechanism
remains elusive atthis juncture, inline withour recentwork,11c we
speculated that this oxidative cyclization might proceed through a
radical mechanism13 facilitated by Pd(OAc)2 as a Lewis acid14 for
the activation of 2a.
To gain further mechanistic insight, this reaction was
performed in the presence of radical scavengers under the
standard reaction conditions. Inclusion of BHT as an additive had
a deleterious effect on the reaction to afford only 3aa, whereas the
addition of TEMPO had only a marginal effect to give 4aa in 72%
yield (eq 1). It cannot be completely ruled out that Ag2CO3 was
Table 1. Optimization Studies
consumed byits direct reaction withBHT, leading toits depletion
and thus shutting down this reaction. However, a similar
observation, no effect with TEMPO but decreased yield of
product with BHT, in radical processes is precedented in the
literature.15 Therefore, these results may suggest a mechanism
involving a radical intermediate during the reaction, although the
correspondingtrappingproductswerenotobservedinbothcases.
Subjectingtheuncyclizedureaintermediate3aatothestandard
reaction conditions resulted in the formation of 4aa in 72% yield
(eq 2). Control experiments employing only either Pd(OAc)2 or
Ag2CO3 gave no or much lower conversion, respectively. These
outcomes suggest that Ag2CO3 is crucial for this transformation
and the presence of Pd(OAc)2 is also required to result in high
reactivity and chemical yields. In addition, the one-pot reaction
proved to be superior to the stepwise reaction with regard to
product yield and efficiency, avoiding the tedious and time-
consuming step by step isolations and purifications of urea
intermediates and reducing the amount of waste.
Subsequently, we set out to explore the scope of this one-pot
domino process. First, we examined the reaction of various N-
methylanilines (1) with phenylisocyanate (2a) (Scheme 2a).
Electron-neutral, moderately electron-rich and -deficient aryl
groups were well tolerated to afford the corresponding
benzimidazolones in good yields. In contrast, strongly electron-
donating and -withdrawing aryl substituents, such as MeO and
NO2, respectively, resulted in moderate yields of the desired
product (e.g., 4ba, 4ea). Thesteric effectof N-substituted anilines
seems to play an important role in this oxidative cyclization:
Transformation of uncyclized urea intermediates to benzimida-
zolones was drastically impeded by the ortho substituents,
resulting in very low conversion (ca. 20%). In the case of meta-
substituted anilines, oxidative cyclization tookplace preferentially
at the sterically less encumbered aryl C−H bond (4fa 46% vs 4fa′
29%). N-Methyl-3-aminopyridine proved to be a suitable
substrate for the formation of the corresponding imidazo-
pyridinones (e.g., 4ha, 4hd, 4hf), while this reaction failed with
2- and 4-aminopyridines.
a
a
entry
catalyst
oxidant
3aa (%)
4aa (%)
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
In(OTf)3
ZnCl2
Ag2CO3
AgOAc
Ag2O
(15)
84
(82)
16
56
−
−
−
−
−
trace
AgNO3
Cu(OAc)2
FeCl3
100
50
(25)
b
7
PhI(OAc)2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
−
trace
−
8
9
68
10
11
12
AlCl3
18
66
CF3CO2H
−
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
35
49
(22)
(24)
(26)
(10)
(14)
(54)
(68)
(67)
(75)
(64)
c
13
d
14
e
15
ef
,
16
a
1
Yields were determined by H NMR using trichloroethylene as an
internal standard. Values in parentheses indicate isolated yields.
Acetanilide was obtained in 88% yield. Using 1.5 equiv of Ag2CO3.
b
c
d
e
f
At 100 °C. Using 2 mol % Pd(OAc)2. Using 2.5 equiv of Ag2CO3.
salts and oxidants were examined (for complete data, see
Supporting Information), and with the exception of AgOAc, all
were not effective for the formation of 4aa, giving only 3aa
(entries2−7). Veryinterestingly, insharpcontrasttotheprevious
report,7a,b the reaction with PhI(OAc)2 afforded neither 3aa nor
4aa; acetanilide was instead obtained presumably as a
consequence of the reaction of 2a with an acetate anion from
PhI(OAc)2 followed by a rearrangement and the concomitant
release of CO2 (entry 7).12
Next, a variety of Lewis and Brønsted acids were examined
(entries 8−11). Pd(OAc)2 proved to be the most effective while
other common Lewis and Brønsted acids could also promote this
reaction to some extent. Decreasing the reaction temperature and
the amount of Pd(OAc)2 or Ag2CO3 significantly reduced the
yield of 4aa (entries 13−16). In addition, a control experiment
Next, we proceeded to investigate the scope of isocyanates (2)
for this reaction (Scheme 2b). A wide range of arylisocyanates
underwent a one-pot reaction smoothly to form the correspond-
B
DOI: 10.1021/acs.orglett.6b03151
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Letter
materialsunderairwithouttheneedforaninertatmosphere:Very
similar product yields could be obtained under both an ambient
and inert atmosphere, thereby obviating any precautionary
measures to rigorously exclude air and moisture from the reaction
mixture.
Scheme 2. Substrate Scope with Isolated Yields
To improve the utility of the products synthesized by this
protocol, removal of N-substituents was performed. Depro-
tection of both Me and CH2CH2CO2Me groups was readily
accomplished to provide 5a and 5b in good to high yields (eq 3).
Scheme 3 outlines a plausible mechanistic proposal for this
reaction. In sharp contrast to the related Pd-catalyzed reactions of
Scheme 3. Proposed Mechanism
a
b
5 mol % Pd(OAc)2. 2 equiv of Ag2CO3.
ing benzimidazolones in good yields regardless of electronic
property and the position of their substituents. Unfortunately,
however, despite extensive experimentations, the reaction with
alkylisocyanates failed to afford the desired benzimidazolones,
leading to only the corresponding N-alkyl-N′-aryl-substituted
urea intermediates.
Benzimidazolones with substitution on both aromatics rings
could be successfully assembled by using diversely substituted N-
methylanilines and arylisocyanates (Scheme 2c). Noteworthy is
the fact that this process can tolerate various functional groups
such as methoxy, halogen, nitro, and ketone groups. This
functional group tolerance should permit further elaboration and
enable greater structural diversity of benzimidazolones and
imidazopyridinones.
aniline derivatives involving a PdII/Pd0 catalytic cycle and ortho
palladation of the anilines,16 our experimental findings suggest
that Pd(OAc)2 acts as a Lewis acid14 and this oxidative cyclization
might proceed through a radical mechanism.11c,f,13 Coordination
of the NCO moiety by Pd(OAc)2 (I/I′) activates phenyl-
isocyanate 2a toward intermolecular nucleophilic attack by the N
atom of N-methylaniline 1a, leading to the uncyclized urea
intermediate 3aa. Activation of urea 3aa by coordination to
Pd(OAc)2 followed by tautomerization of the resulting II
facilitates SET from the so-obtained intermediate III to Ag(I)
to produce IV′ and its resonance structure IV. Subsequently,
further oxidation of radical intermediate V, resulted from the
cyclization of IV, to cationic intermediate VI followed by the
deprotonation forms the desired benzimidazolone product 4aa.
Alternatively, hydrogen abstraction of V to directly give
benzimidazolone 4aa could also be invoked.
In summary, we developed a new and straightforward one-pot
reaction for the synthesis of benzo- and pyrido-fused cyclic ureas
containing two differently substituted N atoms. This new
protocol represents an attractive route for an expedient access
to a diverse range of N,N′-disubstituted benzimidazolones and
imidazopyridinones, privileged motifs found in numerous
pharmaceuticals and functional molecules. For example, 4aj is
the key precursor for the synthesis of benzimidazolone-based
FTase inhibitors which show high potency and selectivity
Last, we explored the effect of substituents (R″) on the N atom
(Scheme2d). ThereactionswithN-alkylanilinesandteterahydro-
quinoline uneventfully proceeded to give the corresponding
benzimidazolones; in particular, the latter afforded an interesting
fused tricycle, imidazoquinolinones. Both steric and electronic
properties of R″ exerted a great influence on the reaction: Only
linear alkyl groups were tolerated, while anilines bearing sterically
bulky alkyl, aryl, and electron-withdrawing groups directly
substituted at a N atom as well as free aniline did not undergo
this one-pot oxidative annulation reaction. In addition, when R″ =
Bn, the desired product was obtained in very low yields, probably
resulting from the facile oxidation of the benzylic position. Much
to our delight, however, functional groups (e.g., Ph, CO2Me, CN)
two methylene carbons away from the N atom were well tolerated
(4ja−4la).
From a practical perspective, this newly developed method
offers a user-friendly access to a variety of benzimidazolones and
imidazopyridinones from the readily available, simple starting
C
DOI: 10.1021/acs.orglett.6b03151
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Scheme 1, bottom).1e A cooperative Pd(II)/Ag(I) system
enables two C−N bond formations through the sequential
addition/intramolecular C−H amidation reaction of two types of
readily available, simple starting materials, namely, (hetero)-
aromatic amines and isocyanates. Our experimental findings
suggest that Ag2CO3 and Pd(OAc)2 serve as a one-electron
oxidant and a Lewis acid, respectively, and this one-pot reaction
implicates radical intermediates generated by SET. This opera-
tionally easy and simple one-pot protocol with good functional
group tolerance and high efficiency could be an effective
alternative to the known methods for related transformations.
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Full experimental details and characterization data (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sowony73@hanyang.ac.kr.
ORCID
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Hernandez, K.; Castoldi, L. Org. Biomol. Chem. 2016, 14, 7848. (c) Allen,
A. D.; Tidwell, T. T. Chem. Rev. 2013, 113, 7287. (d) Braunstein, P.;
Nobel, D. Chem. Rev. 1989, 89, 1927.
So Won Youn: 0000-0002-2134-6487
Notes
(9) Liu, P.; Wang, Z.; Hu, X. Eur. J. Org. Chem. 2012, 2012, 1994.
(10) Łukasik, E.; Wrobel, Z. Synthesis 2016, 48, 1159.
́
The authors declare no competing financial interest.
(11) (a) Youn, S. W.; Lee, E. M. Org. Lett. 2016, 18, 5728. (b) Youn, S.
W.; Lee, S. R.; Kim, Y. A.; Kang, D. Y.; Jang, M. J. ChemistrySelect 2016, 1,
5749. (c) Ko, T. Y.; Youn, S. W. Adv. Synth. Catal. 2016, 358, 1934.
(d) Jang, S. S.; Youn, S. W. Org. Biomol. Chem. 2016, 14, 2200. (e) Youn,
S. W.;Lee, S.R. Org. Biomol.Chem. 2015,13,4652. (f)Youn, S.W.;Ko,T.
Y.; Jang, M. J.; Jang, S. S. Adv. Synth. Catal. 2015, 357, 227. (g) Jang, Y. H.;
Youn, S. W. Org. Lett. 2014, 16, 3720. (h) Youn, S. W.; Park, J. H.; Song,
H. S. Org. Biomol. Chem. 2014, 12, 2388. (i) Youn, S. W.; Bihn, J. H.; Kim,
B. S. Org. Lett. 2011, 13, 3738. (j) Park, J. H.; Bhilare, S. V.; Youn, S. W.
Org. Lett. 2011, 13, 2228. (k) Youn, S. W.; Eom, J. I. Org. Lett. 2005, 7,
3355.
ACKNOWLEDGMENTS
■
This work was supported by both the Basic Science Research
Program and Nano·Material Technology Department Program
through the National Research Foundation of Korea (NRF)
funded by the Korea government (MSIP) (Nos.
2 0 1 2 M 3 A 7 B 4 0 4 9 6 4 4 , 2 0 1 4 - 0 1 1 1 6 5 , a n d
2015R1A2A2A01002559). We thank Dr. Ha Jin Lee (Western
Seoul Center, Korea Basic Science Institute) for X-ray crystallo-
graphic analysis.
(12) (a) Blagbrough, I. S.; Mackenzie, N. E.; Ortiz, C.; Scott, A. I.
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DOI: 10.1021/acs.orglett.6b03151
Org. Lett. XXXX, XXX, XXX−XXX