Pd/C Catalyzed Carbonylation of Azides in the Presence of Amines

Article abstract of DOI:10.1021/acs.orglett.6b00381

A facile and efficient Pd/C-catalyzed carbonylation of both aliphatic and aromatic azides in the presence of amines is reported. Serving as the widely existed fragments in an array of biological pharmaceuticals, functionalized unsymmetrical ureas were str

Full text of DOI:10.1021/acs.orglett.6b00381

Letter
pubs.acs.org/OrgLett
Pd/C Catalyzed Carbonylation of Azides in the Presence of Amines
Jin Zhao, Zongyang Li, Shuaihu Yan, Shiyang Xu, Ming-An Wang, Bin Fu, and Zhenhua Zhang*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
S
* Supporting Information
ABSTRACT: A facile and efficient Pd/C-catalyzed carbon-
ylation of both aliphatic and aromatic azides in the presence of
amines is reported. Serving as the widely existed fragments in
an array of biological pharmaceuticals, functionalized unsym-
metrical ureas were straightforwardly synthesized by using
readily available and cheap azides with amines under CO
atmosphere, with the extrusion of N2 as the only byproduct. It was found that not only aryl azides but also benzyl and alkyl azides
were suited for this methodology. Another feature of this procedure was the employment of a highly efficient palladium charcoal
catalytic system.
reas are one of the most important bioactive functional
units and synthetic components, specifically alkyl/benzyl
unsymmetrical ureas are widely used in an array of
pharmaceuticals and agrochemicals, such as CCR1 antagonist,1a
PSMA targeting probes,1b and cumyluron1c (Figure 1).
(Scheme 1).11 However, symmetrical urea was usually the
dominate product, which is also the major byproduct in other
U
Scheme 1. General Synthetic Approach Towards Ureas
Figure 1. Selected examples of biological alkyl/benzyl unsymmetrical
ureas.
Furthermore, by serving as hydrogen-bond donors,2 ureas can
also be used as efficient and air-stable organocatalysts3 or ligands
for transition metals.4 Due to their great importance in various
research areas, synthetic approaches toward functionalized ureas
have drawn much attention.
urea formation strategies via transition-metal-catalyzed carbon-
ylation in the presence of amines.
Generally, ureas are synthesized via isocyanate intermediates,
which are commonly generated by phosgenation of arylamines,5
reductive carbonylation of nitroaromatics,6 or Curtius rearrange-
ment.7,8 Unfortunately, either the precursors of these methods
lack environmental friendliness or atomic economy, or the
substrate scope is limited. Recently, studies in urea synthesis have
focused on transition-metal-catalyzed reactions. Buchwald et al.
reported a Pd-catalyzed cross-coupling of aryl chlorides with
sodium cyanate, which represented a practical way to synthesize
unsymmetrical ureas.9 Nonetheless, the application of this
method is limited to aromatic ureas. However, Pd-catalyzed
carbonylation is well established as one of the most important
ways to synthesize compounds bearing carbonyl functionality.10
Pd-catalyzed coupling of amines in the presence of CO and
oxidant provided an alternative strategy to accessing ureas
Transition-metal-catalyzed selective C−N bond formation via
a highly reactive metal−nitrene intermediate has attracted great
attention recently due to its apparent synthetic value for
assembling diverse N-containing functional molecules.12 Com-
pared with those traditional methods responsible for metal−
nitrene generation involving oxidation of amides13 or preacti-
vated nitrene precursors,14 the employment of azide15 as the
substrate has afforded an environmentally friendly and simple
strategy to construct N-containing compounds since it does not
require an external oxidant and generates N2 as the only
byproduct. Transition-metal-catalyzed coupling reaction be-
Received: February 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00381
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tween nitrene and σ-donor/π-acceptor ligand, including
isocyanides16 and CO,17 to introduce nitrogen moiety into
unsaturated systems, has experienced considerable growth
during recent decades. Catalytic carbonylation of nitrene with
amines has become a potential efficient way to synthesize
unsymmetrical ureas. For example, Collman et al. first reported a
palladium mediated carbonylation of arylazide with amines.17a
However, harsh conditions such as high pressure of CO limited
its further development. Jiao et al. reported a PdCl2-catalyzed
carbonylation of arylazides with alcohols to generate carbamates
under a balloon of CO atmosphere very recently.17c Nonetheless,
the method was ineffective for the generation of ureas.
Additionally, Pd-catalyzed direct carbonylation of alkyl/benzyl
azides has scarcely been reported. In view of the importance of
ureas and our interest in nitrene chemistry, we have paid much
attention to establishing a robust and highly efficient transition-
metal catalyzed synthesis of unsymmetrical ureas via nitrene
intermediates from not only aryl, but also benzyl and alkyl azides.
Furthermore, compared to general homogeneous catalysts,
palladium charcoal has promising opportunities in “green
chemistry” because it can be safely handled, removed, and
recycled from the reaction mixture by simple filtration.18 Thus,
the development of Pd/C catalyzed reactions is highly desirable.
Herein, we report a Pd/C catalyzed carbonylation of benzyl/
alkyl/aryl azides in the presence of amines to generate
unsymmetrical ureas under mild conditions.
DCE, comparable yields were obtained (72% and 73%,
respectively, entry 8 and 9); moderate yield was obtained when
experiment was carried out in CH3CN (67%, entry 10). Finally,
when we changed the reaction temperature to 40 °C, much of 1a
remained unreacted so that the yield decreased to 35% (entry
11). While increasing to 80 °C, the yield also reduced to 73%
because of the expected homocoupling of intermediate
isocyanatobenzene (entry 12).
Having optimized conditions for this cross-coupling trans-
formation, we set out to explore the substrate scope with regard
to different benzyl azides and amines (Scheme 2). To our delight,
Scheme 2. Pd/C-Catalyzed Carbonylation of Benzyl Azides in
a
the Presence of Amines
At the outset of our study, we selected the model reaction
conditions using (azidomethyl)benzene 1a and 4-methoxyani-
line 2a as the substrates to optimize the reaction conditions.
Using Pd/C as the catalyst without any ligand, we detected only
trace amounts of the desired product 3a (Table 1, entry 1). After
exploring the ligand effect, unexpectedly, the phosphorus ligands
influenced the product yields significantly. As a result, the
reaction yield increased up to 91% in the presence of XPhos as
the ligand (entry 6). In further exploration steps, we examined
various solvents. When reactions were carried out in dioxane and
a
Reaction was carried out with 1.0 equiv of 1 (0.4 mmol) and 1.2
equiv of 2 (0.48 mmol). Isolated yield.
not only did benzyl azides bearing an electron-donating group
give excellent results (3c, 3d), but those bearing an electron-
withdrawing group further afforded better yields (3e−3j). The
reactions with the azides bearing substituents at different
positions on the aromatic ring still gave distinguished yields
(3h−3j). Chloride substituent was also well-tolerated on the
aromatic ring (3j). Other aromatics such as naphthalene and
thiophene substituted azides also worked well (3k, 3l). Finally,
the scope of amines was examined. Electron-sufficient
substituents on the aniline ring gave better yield compared
with the electron-deficient ones (91% and 81% for 3a and 3p,
respectively). Sterically hindered secondary alkyl amines also
furnished good yields (3m).
Although we have presented broad substrate generality of
benzyl azides with high level of functional group tolerance,
further application of this Pd-catalyzed reaction still remains
challenging. The installation of aliphatic ureas was also
envisioned to be highly desirable. Because alkyl azides are
much less active than benzyl azides,19 the standard conditions in
Table 1 did not go well in this transformation. However, the
reaction could furnish the desired unsymmetrical alkyl ureas in
acceptable to high yields by properly changing the order of
addition of substrates (for more details, see Supporting
Information). Encouraged by this result, the scope of alkyl
azides was subsequently investigated (Scheme 3). To our delight,
the anticipated products were all obtained in high yields when
secondary alkyl or benzyl amines were used as the nucleophile
(5a−5d). Reactions of aromatic amines bearing either electron-
donating or electron-withdrawing substituents afforded the
desired products in good yields (5e−5h). More importantly,
Table 1. Conditions of Pd-Catalyzed Carbonylation of BnN3
a
1a in the Presence of 4-Methoxyaniline 2a
b
entry
ligand (mol %)
solvent
t (°C)
yield (%)
1
−
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
dioxane
DCE
60
60
60
60
60
60
60
60
60
60
40
80
trace
trace
10
2
PPh3 (10)
3
PCy3HBF4 (10)
DPPP (5)
4
6
5
DPPF (5)
10
6
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
91
c
7
trace
8
72
73
67
35
73
9
10
11
12
MeCN
PhMe
PhMe
a
Reaction was carried out with 1.0 equiv of 1a (0.4 mmol) and 1.2
b
c
equiv of 2a (0.48 mmol). Isolated yield. The reaction was carried out
without Pd/C. DPPP = 1,3-Bis(diphenylphos-phino)propane. DPPF =
1,1′-Bis(diphenylphosphino)ferrocene. XPhos = 2-Dicyclohexylphos-
phino-2′,4′,6′-triisopropylbiphenyl.
B
DOI: 10.1021/acs.orglett.6b00381
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Pd/C-Catalyzed Carbonylation of Alkyl Azides in
the Presence of Amines
Scheme 4. Pd/C-Catalyzed Carbonylation of Aromatic Azides
in the Presence of Amines
a
a
a
Reaction conditions: 4 (0.4 mmol), PhMe (4 mL) was added and
reacted for 4 h under CO (1 atm), then 2 (0.48 mmol) was added and
reacted for another 8 h. Isolated yield.
a
Reaction was carried out with 1.0 equiv of 6 (0.4 mmol) and 1.2
b
equiv of 2 (0.48 mmol). Isolated yield. When only PhMe was used as
solvent and no nBu4NCl was added, the isolated yield of 7a was 90%,
7e was 81%, 7h was >98%, and 7q was >98%.
various functionalized alkyl azides also gave good reaction yields
(5i−5l).
a
Table 2. Recycling Test
Having successfully surveyed benzyl and aliphatic azides, we
considered expanding the methodology to aryl azides. Owing to
the greater reactivity of aryl azides than others, a better result was
achieved when the reaction was implemented at room
temperature. To our surprise, this cross-coupling reaction
proceeded even in aqueous media. After screening some
additives to “put” this reaction in water, we found the best
conditions eventually: water containing with 5% PhMe and 5%
nBu4NCl. Generally, the transformation of azides with either
electron-donating groups (Me, OMe) or electron-withdrawing
groups (CF3, F, Ac, CO2Me) resulted in good yields (7a−7k)
(Scheme 4). Sterically hindered azides worked just as fine (7l−
7m). In addition, halogen substituents were well-tolerated on the
aromatic ring (7i−7k), thus offering a handle for further
functionalization and cross-coupling chemistry. To explore the
generality of this reaction further, the scope of amines was then
examined. The transformation of different amines with phenyl
azide worked equally well (7n−7r). Both electron-donating and
electron-withdrawing substituents on the aniline aryl ring
afforded the desired products in good yields. Besides, sterically
hindered secondary amines gave good yield (7q, 7r).
b
c
b
c
run
yield (%)
run
yield (%)
1
3
5
94
88
82
2
4
88
86
a
Reaction conditions: 6a (0.4 mmol), 2a (0.48 mmol), XPhos (0.04
mmol), and PhMe (4 mL) were added and reacted for 12 h under CO
b
(1 atm). Reaction products carried out with the same batch of Pd/C.
c
Yield was determined by HPLC analysis.
mixture of Pd/C and XPhos was found to be catalytically
inactive.22,23
On the basis of Pd-nitrene intermediate as stated earlier,17,23,24
a plausible mechanism is proposed in Scheme 5. First, from
organic azide as the substrate, the probable palladium nitrene
species A is formed simultaneously with the release of N2.
Subsequently, the insertion of CO into palladium nitrene species
A occurred to give Pd-coordinated isocyanate B. Finally,
nucleophilic attack of amine at isocyanate C, which is promoted
Since Pd/C could be easily separated from the reaction
mixture by simple filtration, we examined the carbonylation of
phenyl azide 6a in the presence of aniline 2a using recycled Pd/C
catalyst (Table 2). We were pleased that the same batch of 5 mol
% Pd/C was capable of catalyzing at least 5 runs with >80% yield
(the addition of fresh XPhos was necessary).
Scheme 5. Proposed Mechanism
Whether Pd/C in the catalytic cycle works as a heterogeneous
catalyst or undergoes a Pd leaching process is highly
contentious.20 Pd/C-catalyzed Heck/Suzuki−Miyaura reactions
accompanied by a Pd leaching process has been reported, in
which Pd leached into the solution, catalyzed the reaction, and
redeposited on the charcoal at the end of the reaction.21 In this
Pd/C catalytic carbonylation of azides, recycling test in Table 2
gave a much better result compared to the references of a Pd
leaching process. In addition, the filtrate of a preincubated
C
DOI: 10.1021/acs.orglett.6b00381
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Remondini, C.; Caselli, A.; Cenini, S. J. Organomet. Chem. 2005, 690,
4517.
by palladium/phosphine complexes, affords desired unsym-
metrical ureas as the eventual product along with the
regeneration of Pd catalyst.
(7) Banthorpe, D. V. Rearrangements involving azido groups. In The
Chemistry of the Azido Group; Patai, S., Ed; Wiley: New York, 1971; pp
397−340.
In summary, we have described a Pd/C-catalyzed carbon-
ylation of azides in the presence of amines. This methodology
provides a facile and efficient approach from simple and cheap
organoazides with amines under atmospheric CO conditions,
obtaining unsymmetrical ureas with good functional group
tolerance. A series of unsymmetrical disubstituted benzyl, alkyl,
and aryl ureas were effectively synthesized using this method.
Further, the palladium charcoal catalyst is advantageous for
industrial applications of this reaction. Further studies of the
mechanistic detail are currently underway.
(8) Another example about the formation of isocyanates from azides,
phosphines and CO , see: Yagodkin, A.; Loschcke, K.; Weisell, J.;
̈
2
Azhayev, A. Tetrahedron 2010, 66, 2210.
(9) Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2012, 134, 11132.
(10) In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons, Inc.: New York, 2002; Chapter VI,
pp 2505−2714.
(11) Guan, Z.-H.; Lei, H.; Chen, M.; Ren, Z.-H.; Bai, Y.; Wang, Y.-Y.
Adv. Synth. Catal. 2012, 354, 489 and references therein..
(12) (a) Brase, S.; Banert, K. Organic Azides: Syntheses and Applications;
̈
ASSOCIATED CONTENT
■
Wiley-VCH: Weinheim, 2010. (b) Brase, S.; Gill, C.; Knepper, K.;
̈
S
Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188. (c) Driver, T. G.
Org. Biomol. Chem. 2010, 8, 3831. (d) Lu, H.; Zhang, X. P. Chem. Soc.
Rev. 2011, 40, 1899. (e) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev.
2011, 40, 1926. (f) Dequirez, G.; Pons, V.; Dauban, P. Angew. Chem., Int.
Ed. 2012, 51, 7384. (g) Daniela, I.; Paolo, Z.; Alessandro, C.; Emma, G.
Chem. Commun. 2014, 50, 11440. (h) Shin, K.; Kim, H.; Chang, S. Acc.
Chem. Res. 2015, 48, 1040.
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00381.
Experimental procedures along with characterization data
and copies of NMR spectra (PDF)
(13) (a) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39,
194. (b) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Acc. Chem. Res. 2012, 45,
911 and references therein..
(14) For selected examples, see: (a) Lebel, H.; Huard, K.; Lectard, S. J.
Am. Chem. Soc. 2005, 127, 14198. (b) Khlebnikov, A. F.; Novikov, M. S.
Tetrahedron 2013, 69, 3363. (c) Bizet, V.; Buglioni, L.; Bolm, C. Angew.
Chem., Int. Ed. 2014, 53, 5639.
(15) When (NC + NO)/NN ≥ 3 (N = number of atoms), azides are safe,
see: Smith, P. A. S. Open-Chain Nitrogen Compounds; Benjamin: New
York, 1966; Vol. 2, p 211.
(16) Zhang, Z.; Li, Z.; Fu, B.; Zhang, Z. Chem. Commun. 2015, 51,
16312.
(17) (a) Collman, J. P.; Kubota, M.; Hosking, J. W. J. Am. Chem. Soc.
1967, 89, 4809. (b) Bennett, R. P.; Hardy, W. B. J. Am. Chem. Soc. 1968,
90, 3295. (c) Ren, L.; Jiao, N. Chem. Commun. 2014, 50, 3706.
(18) (a) Fine Chemicals through Heterogeneous Catalysis; Sheldon, R.
A., van Bekkum, H., Eds.; Wiley-VCH: Weinheim, 2001. (b) Yin, L.;
Liebscher, J. Chem. Rev. 2007, 107, 133. (c) Garrett, C. E.; Prasad, K.
Adv. Synth. Catal. 2004, 346, 889.
(19) Shin, K.; Baek, Y.; Chang, S. Angew. Chem., Int. Ed. 2013, 52, 8031.
(20) (a) Davies, I. W.; Matty, L.; Hughes, D. L.; Reider, P. J. J. Am.
Chem. Soc. 2001, 123, 10139. (b) Widegren, J. A.; Finke, R. G. J. Mol.
Catal. A: Chem. 2003, 198, 317.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangzhh@cau.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is supported by the National Natural Science
Foundation of China (No. 21302219), Chinese Universities
Scientific Fund (2016QC040), the National S&T Pillar Program
of China (2015BAK45B01), and the Beijing National Laboratory
of Molecular Sciences (BNLMS).
REFERENCES
■
(1) (a) Santella, J. B.; Gardner, D. S.; Duncia, J. V.; Wu, H.; Dhar, M.;
Cavallaro, C.; Tebben, A. J.; Carter, P. H.; Barrish, J. C.; Yarde, M.;
Briceno, S. W.; Cvijic, M. E.; Grafstrom, R. R.; Liu, R.; Patel, S. R.;
Watson, A. J.; Yang, G.; Rose, A. V.; Vickery, R. D.; Caceres-Cortes, J.;
Caporuscio, C.; Camac, D. M.; Khan, J. A.; An, Y.; Foster, W. R.; Davies,
P.; Hynes, J. J. Med. Chem. 2014, 57, 7550. (b) Harada, N.; Kimura, H.;
Ono, M.; Saji, H. J. Med. Chem. 2013, 56, 7890. (c) Guan, A.; Liu, C.;
Yang, X.; Dekeyser, M. Chem. Rev. 2014, 114, 7079.
(2) Bordwell, F. G.; Algrim, D. J.; Harrelson, J. A., Jr. J. Am. Chem. Soc.
1988, 110, 5903.
(3) For selected examples, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713. (b) Fisher, T. J.; Mattson, A. E. Org. Lett. 2014, 16,
5316.
(21) (a) Heidenreich, R.-G.; Krauter, J. G. E.; Pietsch, J.; Koheler, K. J.
̈
Mol. Catal. A: Chem. 2002, 182−183, 499. (b) Simeone, J. P.; Sowa, J. R.,
Jr Tetrahedron 2007, 63, 12646.
(22) The mixture of Pd/C (21 mg, 0.02 mmol) and XPhos (19 mg,
0.04 mmol) was vigorously stirred in PhMe for 4 h at rt. Then the
mixture was filtered though a 0.45 μm filter, and the colorless filtrate was
used for a reaction of phenyl azide 6a (53 mg, 0.4 mmol) with aniline 2a
(59 mg, 0.48 mmol) under CO atmosphere. After 24 h, HPLC analysis
showed that the yield of urea 7a was < 10%.
(4) For selected examples, see: (a) Gamez, P.; Dunjic, B.; Lemaire, M.
J. Org. Chem. 1996, 61, 5196. (b) Lucas, R. L.; Zart, M. K.; Murkerjee, J.;
Sorrell, T. N.; Powell, D. R.; Borovik, A. S. J. Am. Chem. Soc. 2006, 128,
15476. (c) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D.
J. J. Am. Chem. Soc. 2009, 131, 9140.
(23) For additional mechanism study, see Supporting Information.
́
(24) (a) Besenyei, G.; Parkanyi, L.; Foch, I.; Simandi, L. I.; Kalman, A.
Chem. Commun. 1997, 12, 1143. (b) Broere, D. L. J.; Bruin, B.; Reek, J.
N. H.; Lutz, M.; Dechert, S. J. Am. Chem. Soc. 2014, 136, 11574.
(5) For phosgene, see: Slocombe, R. J.; Hardy, E. E.; Saunders, J. H.;
Jenkins, R. L. J. Am. Chem. Soc. 1950, 72, 1888. For triphosgene, see:
Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894. For
carbonyldiimidazole, see: Batey, R. A.; Santhakumar, V.; Yoshina-Ishii,
C.; Taylor, S. D. Tetrahedron Lett. 1998, 39, 6267.
(6) For a review, see: Paul, F. Coord. Chem. Rev. 2000, 203, 269. For
examples, see: (a) Dieck, H. A.; Laine, R. M.; Heck, R. F. J. Org. Chem.
1975, 40, 2819. (b) Kim, K. D.; Lee, S. M.; Cho, N. S.; Oh, J. S.; Lee, C.
W.; Lee, J. S. J. Mol. Catal. 1992, 75, L1. (c) Gasperini, M.; Ragaini, F.;
D
DOI: 10.1021/acs.orglett.6b00381
Org. Lett. XXXX, XXX, XXX−XXX