Palladium-catalyzed carbonylative synthesis of N-cyanobenzamides from aryl iodides/bromides and cyanamide

Article abstract of DOI:10.1016/j.tetlet.2013.10.040

A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)₆ as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2013.10.040

Tetrahedron Letters 54 (2013) 6912–6915
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed carbonylative synthesis of N-cyanobenzamides
from aryl iodides/bromides and cyanamide q
⇑
Rajendra S. Mane, Patrik Nordeman, Luke R. Odell, Mats Larhed
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2013
Revised 27 September 2013
Accepted 9 October 2013
Available online 17 October 2013
A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available
aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The proto-
col utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate
to good yields.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Aminocarbonylation
Aryl iodides/bromides
Molybdenum hexacarbonyl
N-Cyanobenzamides
Palladium
N-Cyanobenzamides, also known as N-acylcyanamides or N-
cyanocarboxamides, and their derivatives exhibit a diverse range
of biological activities. They have been reported to show excellent
herbicidal1 and fungicidal2,3 properties and have also been uti-
lized as prodrugs of cyanamide.4 N-Acylcyanamides (pKa ꢀ2–4)
are known carboxylic acid bioisosteres5 and have been employed
as the key acidic function in complex hepatitis C virus NS3 prote-
ase inhibitors.6 Although some N-acylcyanamide derivatives can
undergo intermolecular decomposition, N-cyanobenzamides are
found to be stable.7 The valuable two-nitrogen, one-carbon skel-
eton of cyanamide and N-acylcyanamides, makes them versatile
building blocks that can undergo various reactions such as addi-
tion at the cyano group forming acyl ureas and acyl guanidines,
cycloaddition to give acyl tetrazoles, cyclotrimerization, reduc-
tion to primary amines, and metal complex formation.8 N-Cya-
nobenzamides have been employed as versatile synthetic
intermediates in radical cascade reactions9 for the synthesis of
luotonin A, guanidines, quinazolinones, and acylguanidine and
precursors for chloromethylsilane-mediated synthesis of mono-
N-acylguanidines.10
(Scheme 1, path a).4,11 Several additional methods have also been
developed, such as N-cyanation of an amine followed by acylation
(path b)9a or direct N-cyanation of amides to form N-cyanobenza-
mides (path c),9a and derivatives12 and ring-opening rearrange-
ment of 8-methylimidazo[1,5-d][1,2,4]triazin-1(2H)-one (path
d).3b These methods possess a number of drawbacks including
the use of toxic reagents, low functional group tolerance, complex
starting material preparation, and very strict reaction conditions.
Because of their importance, there exists a continuing interest in
the development of new and selective methodologies for the prep-
aration of N-cyanobenzamides.
Since Heck reported the first palladium(0)-catalyzed carbonyl-
ation reaction employing aryl or vinyl halides (or a halide surro-
gate),13
a variety of carbonylation methodologies have been
reported for the synthesis of amides, esters, and ketones.14 The
majority of carbonylation reactions require the use of gaseous
CO, a highly toxic, invisible, flammable, odorless, and tasteless sub-
stance. To overcome this problem, Skrydstrup and co-workers15
developed and explored a connected two chamber system for the
Pd-catalyzed aminocarbonylation of aryl halides using ex situ gen-
eration of CO gas from a CO-releasing source. As a part of our
continuing efforts in this area,16 we have previously reported a pal-
ladium(0)-catalyzed aminocarbonylation of aryl halides using
Mo(CO)6 as a solid CO-releasing reagent in a bridged two-vial
system (Fig. 1)17 for the synthesis of benzamides with primary/sec-
ondary amines, sluggish anilines, and nitro group carrying sub-
strates. This approach was subsequently employed for the novel
synthesis of acyl sulfonimidamides.18 We reasoned that the use
of cyanamide as a nucleophile (Scheme 1), could provide an
Typically, N-acylcyanamides are synthesized by reacting an acid
chloride (or equivalent) with sodium cyanamide in an inert solvent
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
⇑
Corresponding author. Tel.: +46 18 471467; fax: +46 18 4714474.
E-mail address: mats.larhed@orgfam.uu.se (M. Larhed).
0040-4039/$ - see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.040

R. S. Mane et al. / Tetrahedron Letters 54 (2013) 6912–6915
6913
O
O
20 h led to full conversion of the aryl iodide and the correspond-
ing product was isolated in 83% yield.
NH2CN
Ar
Ar
Cl
(a)
R
O
After the identification of productive reaction conditions
(Table 1, entry 4), we next set about exploring the scope and lim-
itations of the protocol using various aryl iodides (Table 2). In
general meta- and para-substituted aryl iodides afforded good to
excellent yields of the corresponding N-cyanobenzamides. Iodo-
benzene and 4-iodobiphenyl performed well affording the desired
products in excellent yields (88% and 84%, respectively). Notably,
meta-nitroiodobenzene was coupled effectively to yield 80% of
N-cyano-3-nitrobenzamide (4), without traces of the correspond-
ing aniline product.17 The presence of an ortho- substituent
resulted in a slightly lower yield, presumably due to adverse steric
effects (7, 58%). A double aminocarbonylation could also be per-
formed, producing N,N-dicyanoterephthalamide (8) in 78% yield.
In addition, heterocyclic N-cyanothiophene-3-carboxamide (9)
was obtained in good yield (81%). For the para-nitroiodobenzene,
the desired product 10 was obtained in moderate yield (54%) due
to competitive hydrolysis to the corresponding primary acyl
urea.22 Finally, the diacidic, 4-(cyanocarbamoyl) benzoic acid 11
was prepared in moderate yield (64%) from 4-iodobenzoic acid.
Single vial reactions were also performed to examine whether
the two-vial system was essential for the process. These reactions
gave low isolated yields and complex product mixtures were ob-
served, most likely due to Mo-complexes being formed during
the reaction (Table 2). In accordance with previous studies with
amino nucleophiles,17 the use of nitro group containing substrates
yielded <10% of the desired product utilizing the single-vial proto-
col. These results further demonstrate the advantages of the
bridged two-vial system in Mo(CO)6À mediated carbonylations.
Having demonstrated a wide scope for the direct preparation of
N-cyanobenzamides using a range of aryl iodides, we turned our
attention to the analogous aryl bromides. Thus, aryl bromides
and cyanamide were reacted under conditions similar to those
outlined in Table 2. It was found that the optimized conditions em-
ployed for the aryl iodides were also applicable for aryl bromides,
although a higher temperature (85 °C) was required. Using these
conditions, the majority of the aryl bromides provided moderate
to good yields of the desired products. However, less reactive 4-
bromoanisole produced only a moderate yield (46%). Rewardingly,
by changing the Pd catalyst to Pd(dppf)Cl2, the corresponding
product was isolated in an improved 68% yield. For other sub-
strates such as ortho- or meta-nitro, 1,4-dibromo and heteroaryl,
the desired N-cyanobenzamides were obtained in comparable
yields using the two catalysts. In analogy to the results using aryl
iodides, aryl bromides bearing a nitro group at ortho- or para-posi-
tions produced lower yields. Heteroaryl bromides such as 3-bro-
mothiophene and 3-bromobenzo[b]thiophene also furnished
good yields.
R-NH2
BrCN
N
Ar
Cl
(b)
N
O
R
N
N
(c)
O
Ar
Cl
R
BrCN
Present work
Ar
N
H
R-NH2
[Pd]
ArX CO NH2CN
O
R
O
(d)
N
NH
R
N
N
N
R-X
N
N
N
Scheme 1. Synthetic methods for N-cyanobenzamides.
CO
O
CO
CO
O
CO
ArX
[Pd]
Et3N
NH2CN
Mo(CO)6
DBU
O
O
Ar-CO-NH-CN
C1
C2
Figure 1. Schematic representation of the two-vial system.
efficient method for the preparation of N-cyanobenzamides from
readily available aryl halides. Although aryl cyanamides19 are re-
ported, to the best of our knowledge, the synthesis of N-cyanoben-
zamides via an aminocarbonylation approach using cyanamide is
unknown in the literature. Herein, we disclose the first palla-
dium(0)-catalyzed aminocarbonylation protocol for the synthesis
of these valuable compounds utilizing both Mo(CO)6 as a solid
source of CO in a bridged two-vial system and gaseous CO.
Initially, we examined the reaction protocol20 previously
developed by us17 using tetrakis(triphenylphosphine)-palla-
dium(0) as the catalyst and Et3N as the base in 1,4-dioxane. Vial
C1 was charged with 0.5 equiv of Mo(CO)6 and vial C2 with 5%
Pd(PPh3)4, 1 equiv of 4-iodoanisole, 2 equiv of cyanamide, 2 equiv
of Et3N as the base, and finally DBU21 was added through the
septum into C1. Heating at 65 °C for 15 h resulted in incomplete
conversion of the aryl iodide, however a promising 68% isolated
yield of N-cyano-4-methoxybenzamide (1) was obtained (Table 1,
entry 1). No significant increase in conversion was found when 1
equiv of Mo(CO)6 was used (70%, entry 2). When 3 equiv of cyan-
amide was used, a slight increase in yield was observed (76%,
entry 3) and finally, extending the reaction time from 15 h to
After demonstrating the effective use of Mo(CO)6 as a solid CO
source for the synthesis of N-cyanobenzamides, we decided to ex-
plore the aminocarbonylation by employing CO gas (molybdenum-
free), with a focus on identifying conditions suitable for larger scale
applications, using a pressurized reactor. With the optimized
conditions defined, carbonylative coupling reactions using various
aryl iodides and aryl bromides produced the corresponding N-cya-
nobenzamides in moderate to good yields as shown in Table 3.
Notably, 4-chloro-N-cyanobenzamide (14) was isolated chemose-
lectively in 78% yield. Furthermore, 4-iodoanisole, iodobenzene
and 1,4-diiodobenzene were coupled effectively with cyanamide,
on a 5 mmol scale, without affecting the reaction outcome.
In summary, we have developed a novel gas-free method for the
synthesis of N-cyanobenzamides via the palladium-catalyzed
aminocarbonylation of aryl halides and cyanamide. This Mo(CO)6-
promoted method displays a broad substrate scope and affords
moderate to excellent yields of the N-cyanobenzamides. In
Table 1
Optimization of the two-vial aminocarbonylation
Entry Time
(h)
Pd(PPh3)4
(mol %)
Mo(CO)6
(equiv)
NH2CN
(equiv)
Yielda
(%)
1
2
3
4
15
15
15
20
5
5
5
5
0.5
1
2
2
3
3
68
70
76
83
1
1
a
Reaction conditions: Vial C1 was loaded with Mo(CO)6. Vial C2 was loaded with
4-iodoanisole (0.5 mmol) and Pd(PPh3)4. 1,4-Dioxane (6 mL, 3 mL in each vial) was
added to vial C1 and to vial C2 were added Et3N (1 mmol) and cyanamide. After
capping, DBU (1.5 mmol) was added to vial C1 which was then sealed and the
double vial was heated at 65 °C for 15–20 h.

6914
R. S. Mane et al. / Tetrahedron Letters 54 (2013) 6912–6915
Applications of this methodology for the synthesis of 11C-labeled
N-cyanobenzamides for PET studies are currently underway in
our laboratory and will be reported in due course.
Table 2
Synthesis of N-cyanobenzamides from aryl iodides and aryl bromides using Mo(CO)6
[Pd]a,b, NH2CN, Et3N
O
[Mo(CO)6, DBU]
X
CN
1,4-dioxane
N
H
Acknowledgements
R
R
65 °C for iodides
85 °C for bromides
20 h
1-12
42-88%
X = I/Br
R = EWG, EDG, NO2
We are thankful to the Swedish Research Council for financial
support. M.L. and R.S.M. are grateful to Erasmus Mundus (EXPERTS
Programme) for Post-doctorate Fellowships.
O
O
O
CN
N
CN
CN
CN
CN
N
H
N
H
H
Supplementary data
O
NC
1
2
3
I = 13%a,c, 83%a
I = 79%a
Br = 69%a
O
I = 88%a
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.040.
Br = 0%a,c, 46%a, 68%b
O
Br = 72%a
O
CN
N
H
N
H
N
H
References and notes
CN
NO2
6
4
5
I = <10%a,c, 80%a
I = 84%a
I = 88%a
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Br = 0%a,c, 66%a, 69%b
Br = 77%a
O
Br = 71%a
O
O
CN
CN
CN
N
CN
N
H
N
H
H
N
H
O
NO2
7
NC
S
8
9
O
I = 81%a
I = 58%a
I = <10%a,c, 78%a
Br = 47%a, 55%b
O
Br = 0%a,c, 72%a, 77%b
O
Br = 85%a
O
CN
CN
N
N
H
N
H
H
O2N
HOOC
S
10
11
12
Br = 79%a, 81%b
I = 54%a
Br = 42%a
I = 64%a
Reaction conditions: vial C1 was loaded with Mo(CO)6 (1.0 equiv). The vial C2 was
loaded with aryl halide (0.5 mmol) and [Pd] (5 mol %). 1,4-Dioxane (6 mL, 3 mL in
each vial) was added and to vial C2 were added Et3N (1 mmol) and cyanamide (3.0
equiv). After capping, DBU (1.5 mmol) was added to vial C1 and sealed and the
double vial was heated at 65/85 °C for 20 h.
a
Pd(PPh3)4.
b
Pd(dppf)Cl2.
All reagents were placed in a single vial.
All yields are isolated yields.
c
Table 3
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Synthesis of N-cyanobenzamides from aryl iodides and aryl bromides using CO gas
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CO (2 atm)
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X
CN
1,4-dioxane
N
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R
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65 °C for iodides
85 °C for bromides
18-20 h
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X = I/Br
R = EWG, EDG, NO2
58-85%
3, I = 85%, 84%a
4, I = 73%
a
1
2, I = 76%
, I = 76%, 81%
5, Br = 71%
8, I = 70%, 77%a
9, Br = 79%
10, I = 58%
O
O
CN
CN
N
H
N
H
Cl
13, Br = 69%
14, Br = 78%
Reaction conditions: aryl halide (0.5 mmol), cyanamide (3.0 equiv), Pd(PPh3)4
(5 mol %), Et3N (1 mmol) and CO (2 atm) were reacted in 1,4-dioxane at 65/85 °C for
18–20 h.
a
Reaction conducted on 5 mmol scale.
All yields are isolated yields.
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addition, we have also shown its applicability by using CO gas up
to a 5 mmol scale. To the best of our knowledge, this is the first
reported aminocarbonylative synthesis of N-cyanobenzamides.

R. S. Mane et al. / Tetrahedron Letters 54 (2013) 6912–6915
6915
3793–3799; (e) Nielsen, D. U.; Neumann, K.; Taaning, R.; Lindhardt, A.; Modvig,
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bromides) for 20 h with vigorous stirring. General procedure for the
aminocarbonylation using CO gas: Aryl iodide/bromide (0.5 mmol),
cyanamide (3.0 equiv), Pd(PPh3)4 (5 mol %) and Et3N (1 mmol) were taken up
in 1,4-dioxane (10 mL) and the reaction mixture was placed inside a high
pressure reactor. The reactor was pressurized with CO (2 atm) and heated for
18 h at 65 °C for iodides and 85 °C for bromides. General work-up procedure:
After careful evacuation of excess CO, the crude reaction mixture from C2 was
evaporated to dryness and 10% HCl was added. The residue was extracted with
EtOAc (3 Â 10 mL) and concentrated. Purification by flash column
chromatography eluting with CHCl3/MeOH (9.5/0.5) gave the desired products.
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20. General procedure for the aminocarbonylation using Mo(CO)6 in a two-vial
system (see Fig. 1): Vial (C2) was loaded with aryl iodide/bromide (0.5 mmol),
Pd(PPh3)4 (29 mg, 5 mol %), Et3N (139 lL, 1 mmol) and cyanamide (63 mg,
1.5 mmol). To vial (C1) was added Mo(CO)6 (138 mg, 0.5 mmol) and thereafter
1,4-dioxane (3+3 mL) was added to C1 and C2. The two vials were capped with
22. Formation of the corresponding primary acylurea was observed due to acidic
hydrolysis. See: Xiao, Z.; Yang, M. G.; Tebben, A. G.; Galella, M. A.; Weinstein, D.
S. Tetrahedron Lett. 2010, 51, 5843–5844.
a gas-tight cap and DBU (224
double vial was heated in
l
L, 1.5 mmol) was added to C1. The sealed
a
heat-block (65 °C for iodides and 85 °C for