Ruthenium-Catalyzed Urea Synthesis by N-H Activation of Amines

Article abstract of DOI:10.1021/acs.inorgchem.7b00962

Activation of the N-H bond of amines by a ruthenium pincer complex operating via amine-amide metal-ligand cooperation is demonstrated. Catalytic formyl C-H activation of N,N-dimethylformamide (DMF) is observed in situ, which resulted in the formation of CO and dimethylamine. The scope of this new mode of bond activation is extended to the synthesis of urea derivatives from amines using DMF as a carbon monoxide (CO) surrogate. This catalytic protocol allows the synthesis of simple and functionalized urea derivatives with liberation of hydrogen, devoid of any stoichiometric activating reagents, and avoids the direct use of fatal CO. The catalytic carbonylation occurred at low temperature to provide the formamide; a formamide intermediate was isolated. The consecutive addition of different amines provided unsymmetrical urea compounds. The reactions are proposed to proceed via N-H activation of amines followed by CO insertion from DMF and with liberation of dihydrogen.

Full text of DOI:10.1021/acs.inorgchem.7b00962

Article
pubs.acs.org/IC
Ruthenium-Catalyzed Urea Synthesis by N−H Activation of Amines
Varadhan Krishnakumar,† Basujit Chatterjee,† and Chidambaram Gunanathan*
School of Chemical Sciences, National Institute of Science Education and Research, Homi Bhabha National Institute, Bhubaneswar
752 050, India
S
* Supporting Information
ABSTRACT: Activation of the N−H bond of amines by a
ruthenium pincer complex operating via “amine−amide”
metal−ligand cooperation is demonstrated. Catalytic formyl
C−H activation of N,N-dimethylformamide (DMF) is
observed in situ, which resulted in the formation of CO and
dimethylamine. The scope of this new mode of bond
activation is extended to the synthesis of urea derivatives
from amines using DMF as a carbon monoxide (CO)
surrogate. This catalytic protocol allows the synthesis of
simple and functionalized urea derivatives with liberation of
hydrogen, devoid of any stoichiometric activating reagents, and avoids the direct use of fatal CO. The catalytic carbonylation
occurred at low temperature to provide the formamide; a formamide intermediate was isolated. The consecutive addition of
different amines provided unsymmetrical urea compounds. The reactions are proposed to proceed via N−H activation of amines
followed by CO insertion from DMF and with liberation of dihydrogen.
amines using methanol as a CO surrogate, in which methanol
was oxidized to formaldehyde, resulting in coupling with
amines.16 Although direct carbonylation of amines to urea
offers an attractive alternative protocol,17−19 they often suffer
from low yield,17 the requirement of additional and
stoichiometric amounts of oxidant,18 the use of toxic
pressurized CO gas,19 and chromatographic purifications.
Thus, environmentally benign and mild reaction conditions
for urea synthesis still remain a challenge. In a continuation of
our studies on N−H,6 O−D, and Csp−H bond activation
reactions, which resulted in the highly selective deuteration of
amines, amino acids, alcohols, and terminal alkynes using
D2O,20 we report herein facile N−H bond activation by the
ruthenium pincer complex [(PNPPh)RuHCl(CO)] (1; PNP =
bis[2-(diphenylphosphino)ethyl]amine) and its direct catalytic
application to the synthesis of valuable urea derivatives using
N,N′-dimethylformamide (DMF) as a CO alternative (eq 1).
The ruthenium pincer complex 1 is an efficient catalyst in
oxidative coupling reactions of alcohols and the dehydrogen-
ation and hydrogenation of an assortment of carboxylate
derivatives.21
INTRODUCTION
■
The reactivity of the lone pair of electrons available on the
nitrogen atom dominates the chemistry of amines, resulting in
Lewis acid−base interaction, and thus generally leads to the
formation of Werner types of complexes upon treatment with
transition metals.1 As a result, activation of the N−H bond,
which has enormous potential in catalytic transformation,
remains scarce.2 In contrast, a suitable ligand design resulted in
activation of the N−H bond of amines on the metal center to
provide the “amide”-type ligand. Milstein and co-workers
introduced noninnocent ligand-mediated N−H activation of
amines in which the metal oxidation state remains the same
because of metal−ligand cooperation (MLC).3,4 Although
tremendous strides have been made in various bond activation
and catalytic applications thereof, the chemistry of N−H
activation remains underdeveloped.5 Recently, we demonstra-
ted facile N−H activation of the amine functionality by a
monohydrido-bridged dinuclear ruthenium complex, which
resulted in the selective α-deuteration of amines and amino
acids with excellent catalytic efficiency.6
N,N′-disubstituted urea derivatives have potential applica-
tions as efficient organocatalysts,7 green solvents,8 promising
nonlinear-optical materials,9 and pharmacological compounds
(Figure S1).10−12 Despite notable synthetic advances, the urea
derivatives are, in general, obtained using phosgene and
isocyanates,13 which generates toxic byproducts. The synthesis
of urea compounds using phosgene alternatives requires a
multistep synthesis.14 Catalytic carbonylation reactions have a
profound influence in the chemical synthesis and are known to
employ different compounds as a carbon monoxide (CO)
surrogate.15,16 For example, Kim and Hong recently reported
the ruthenium-catalyzed efficient urea synthesis directly from
2RNH2 + Me2NCHO ⎯⎯⎯c⎯a⎯⎯ta⎯l⎯y⎯s⎯t→⎯ RNHCONHR + H2↑
−HNMMe2
(1)
RESULTS AND DISCUSSION
N−H Activation of Amines. Deprotonation of the
ruthenium pincer complex 1 with a base (KOtBu) in the
■
Received: April 24, 2017
Published: May 30, 2017
© 2017 American Chemical Society
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presence of benzylamine generated complex 3a at room
temperature. When 4-fluorobenzylamine and 4-nitroaniline
were subjected to the reaction under similar conditions,
complexes 3b and 3c were obtained, respectively, as a result
of the facile N−H activation of alkyl- and arylamines.
1, entries 4−6). When 2 mol % catalyst 1 and 10 equiv of DMF
were reacted with benzylamine, N,N′-dibenzylurea was isolated
in 91% yield (Table 1, entry 7). Control experiments with no
catalyst and base (Table 1, entry 8) and in the presence of only
base (Table 1, entry 9) confirmed that the catalyst is essential
for this transformation. Further, we have employed the reactive
catalyst (PNPPh)RuH(H-BH3)(CO) (Ru-Macho-BH)24 used
by Kim and Hong in urea synthesis from methanol and
amine,16 which under neutral conditions failed to produce urea
from amine and DMF (Table 1, entry 10), indicating that this
reaction proceeds via mechanistically different pathways
involving N−H activation of amines.
1
Complexes 3a−3c exhibited characteristic H, 13C, and 31P
NMR signals. Further, the structure of complex 3b was
unequivocally corroborated using single-crystal X-ray analysis
(Scheme 1).22
Scheme 1. N−H Activation by “Amine−Amide” MLC
Operative in Complex 1
Under optimized conditions, an assortment of arylmethyl-
amines was tested for the urea synthesis using catalyst 1 and
DMF (Table 2). Benzylamine with electron-donating groups
Table 2. Synthesis of Arylmethyl- and Arylalkylurea
a
Derivatives
Catalytic Studies. To explore the catalytic application of
N−H activation reactions, direct carbonylation of amines using
DMF was planned. DMF is established as a safe alternative to
toxic CO.23 At the outset, optimization studies were performed
for carbonylation of benzylamine to urea using DMF as a CO
surrogate catalyzed by the ruthenium pincer complex 1, and the
results are summarized in Table 1. Experiments with 0.5 and 1
mol % ruthenium catalyst 1 and benzylamine (1 mmol) and 3−
5 mmol of DMF resulted in poor yields (12−29%) of N,N′-
dibenzylurea (Table 1, entries 1−3). The use of 2 mol %
catalyst 1 with an excess amount of DMF (3−7 equiv) under
open conditions provided enhanced product formation (Table
a
Table 1. Optimization of the Reaction Conditions
a
Amine (1 mmol), catalyst 1 (2 mol %), KOtBu (4 mol %), DMF (10
b
mmol), and xylene (1.5 mL) were heated at 165 °C for 24 h in open
conditions under an argon atmosphere. Yields correspond to isolated
products.
entry
catalyst load (mol %)
DMF (equiv)
yield (%)
1
2
3
4
5
6
7
8
0.5
0.5
1.0
2.0
2.0
2.0
2.0
3
5
12
22
29
46
67
74
91
3
provided dialkylurea products in very good yields (Table 2,
4b−4e), while 4-fluorobenzylamine provided the correspond-
ing urea in diminished yield (4f, 76%). The use of 1-
naphthylmethylamine resulted in 92% dinaphthylmethylurea
(Table 2, 4g). Furthermore, reactions of phenethylamine and
its derivatives displayed good reactivity (Table 2, 4k−4n). In
general, benzylamines and alkylamines provided urea products
in good yields. While substitution at the ortho position of
benzylamine was tolerated, substitution at the α-amine
functionality (4h and 4o) and heteroarylmethylamine (2- and
3-picolylamines) delivered urea products in moderate yields (4i
3
5
7
10
10
10
10
c
9
10
Ru-Macho-BH (2.0)
a
Amine (1 mmol), xylene (1.5 mL), and catalyst 1 were heated at 165
°C for 24 h in open conditions under an argon atmosphere. Isolated
b
c
yields. Control experiment in the presence of a base.
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and 4j). However, when aniline was subjected to this catalytic
transformation, N,N′-diphenylurea was obtained only in 2%
yield, implying that nucleophilicity of amines is an essential
requirement for the efficient formation of urea.
Further, linear n-alkyl- and cycloalkylamines were utilized in
the synthesis of N,N′-dialkylurea derivatives. When n-pentyl-
amine was reacted with DMF under optimized conditions,
dipentylurea was obtained in 41% yield, perhaps because of the
lower boiling point (104 °C) of amines. However, when long-
chain amines were reacted, the corresponding urea derivatives
were isolated in excellent yields. Likewise, cyclohexylmethyl-
amine-, morpholine-, and cyclohexenyl-incorporated amines
were subjected to the reaction, which furnished the
corresponding dialkylurea products in good yields (Table 3,
Because formamides can be further used as reagents for the
urea synthesis, this observation revealed the possibility for the
synthesis of unsymmetrical urea derivatives. Thus, upon the
catalytic formation of formamides, different amines were added
to the same reaction mixture and heated at elevated
temperature, which provided the unsymmetrical urea deriva-
tives in good-to-excellent yield (Table 4, 7a−7i).
a
Table 4. Synthesis of Unsymmetrical Urea Derivatives
a
Table 3. Synthesis of N,N′-Dialkylurea Derivatives
a
Amine (1 mmol), 1 (2 mol %), KOtBu (4 mol %), DMF (10 mmol),
and xylene (1.5 mL) were heated at 135 °C for 12 h in open
conditions under an argon atmosphere. Subsequently, a different
amine (1 mmol) was added, and the reaction mixture was heated at
150 °C for 16 h. Yields correspond to isolated products.
When benzylamine was subjected to catalysis using the
isolated complex 3a as the catalyst, N,N′-dibenzylurea was
obtained in 89% yield. Notably, this reaction occurred under
neutral conditions (devoid of KOtBu) to provide results similar
to those of catalyst 1/KOtBu, indicating that the role of the
base in this catalytic process is limited to the generation of
active intermediate 2 from 1 (Scheme 3).
Scheme 3. Catalytic Synthesis of N,N′-Dibenzylurea by N−H
Activation Complex 3a
a
See the footnote of Table 2.
5f−5i). The cyclohexylamine displayed moderate yield (Table
3, 5j), and in the case of the bulkier adamantylamine, the
reaction was sluggish and provided poor yield (Table 3, 5k)
because of steric hindrance. Interestingly, the use of 1,3-
diaminopropane under optimized conditions provided a cyclic
urea (5l).
Mechanistic Considerations and Synthesis of Unsym-
metrical Urea Compounds. To further understand the
mechanistic insight of this useful process, the reaction of
benzylamine with DMF (4 equiv) catalyzed by 1 (0.5 mol %)
was carried out at lower temperature (135 °C), which provided
N-benzylformamide in 78% yield, indicating the involvement of
formamide as a potential intermediate in the synthesis of urea
derivatives (Scheme 2).
Formyl C−H Activation of DMF. The catalytic synthesis
of N,N′-dibenzylurea was performed in closed conditions, and
after 1 h, the gas phase of the reaction mixture was subjected to
gas chromatography (GC) analysis, which allowed us to detect
the in situ formed CO and dihydrogen.25 Further, upon
reaction of the ruthenium pincer complex 1 with a base in
DMF, we observed the formation of complex 8 (31P, 64.28
ppm; IR, 1876 cm−1; Scheme 4). Apparently, complex 8
formed from C−H activation of the formyl functionality of
DMF by the in situ formed unsaturated complex 2 at room
temperature. However, complex 8 remains elusive to complete
characterization, as repeated attempts for its isolation failed.
When crystallization of 8 was attempted directly from the
above reaction mixture, the dichlororuthenium complex 9 was
isolated,24,25 which perhaps resulted from the decomposition of
complex 8.
Scheme 2. Catalytic Synthesis of N-Benzylformamide
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activation of DMF by complex 1 (Scheme 4), leads to
formation of the intermediate 10. The amide-ligated saturated
complex 10 undergoes elimination of the formamide 6 at lower
temperature (135 °C, oil bath temperature) and can regenerate
complex 2 (Scheme 2). At higher temperature (>150 °C), a
second intermolecular nucleophilic attack by amine on a metal-
coordinated amide motif occurs, leading to the formation of
urea and the saturated ruthenium dihydride complex 11,25
which upon liberation of dihydrogen26 regenerates 2 for further
catalysis. Overall, the catalytic carbonylation of amines to urea
derivatives proceeds with the liberation of molecular hydrogen.
Further, to test the applicability of this catalytic method for
the large-scale synthesis of urea derivatives, the reaction of
benzylamine with DMF was performed in a 5 mmol scale,
which produced the N,N′-dibenzylurea in 82% yield (Scheme
6).
Scheme 4. Observed DMF Activation by In Situ Formed
Unsaturated Complex 2
Scheme 6. Large-Scale Synthesis of N,N′-Dibenzylurea
On the basis of the stoichiometric reaction of complex 1 with
different amines in the presence of base (Scheme 1), the
activation of DMF by complex 1 (Scheme 4), and other
experimental observations, a mechanism for the catalytic
carbonylation of amines to urea derivatives is proposed in
Scheme 5. The reaction of complex 1 with a base, KOtBu,
SUMMARY
■
In conclusion, a facile N−H activation of amines is
demonstrated. The C−H bond activation of the formyl
functionality of DMF is observed in situ. These bond
activations are further applied for the development of an
efficient protocol for the synthesis of urea derivatives catalyzed
by the ruthenium catalyst 1. A clean synthetic method using
DMF as an effective surrogate for CO is attained and an
assortment of symmetrical and unsymmetrical urea derivatives
was synthesized by the carbonylation of primary amines.
Operating in open conditions and devoid of any deleterious
side products make this method highly attractive and
advantageous over the related reported procedures for the
synthesis of urea derivatives. As these reactions progress with
the liberation of hydrogen and without the requirement of any
pressure setup, potential applications of this protocol in other
organic transformations are currently being explored.
Scheme 5. Proposed Mechanism for the N−H Activation
and Catalytic Carbonylation of Amines to Urea Using DMF
as a CO Surrogate
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Complexes 3a−3c.
To a screw-cap scintillation vial were added Ru-macho 1 (0.032 mmol,
20 mg), KOtBu (1.1 equiv, 0.035 mmol, 4 mg), and THF (1 mL), and
the resulting mixture was allowed to stir at room temperature for 30
min. To the reddish-brown solution was added dropwise amines (2.2
equiv). The solution was then stirred for 5 min at room temperature.
The brownish-yellow solution immediately turned red. The resulting
solution was reduced under vacuum, and the slow addition of cold
hexane (2 mL) provided a yellow precipitate. The solution was
decanted, and the precipitate was washed three times with hexane (1
mL). The precipitate was dried under vacuum for 4 h to afford the
product as a yellow solid.
Ruthenium Benzylamide (3a). Yield: 18.9 mg (87%) as a yellow
solid. IR (C6H6): 3026, 2279 (RuH), 1918, 1603, 1495, 1459, 1221,
1081, 1029, 895, 812, 726, 793 cm−1. 1H NMR (C6D6): δ 7.66 (m, 4H,
ArCH), 7.36 (m, 4H, ArCH), 6.57 (m, 17H, ArCH), 3.35 (br, 1H,
NH), 3.17 (m, 5H, CH2), 2.79 (br, 2H, CH2), 2.49 (t, J = 8 Hz, 1H,
NH), 1.95 (br, 2H, CH2), 1.46 (bs, 2H, CH2), −13.77 (t, J = 16 Hz,
1H, RuH). 31P{1H} NMR (C6D6): δ 61.71 (s).
generates the unsaturated ruthenium(II) intermediate 2.
Formation of the transient intermediate 2 is observed in situ
using 1H (δRu−H −5.85) and 31P NMR (δ 48.45) and
electrospray ionization mass spectrometry analyses (m/z 572
[(M + H)+]). N−H bond activation of the amine functionality
by complex 2 occurs via “amine−amide” MLC4,20 to generate
the intermediate 3 (Scheme 1). The insertion of CO (observed
in the gas phase of the reaction mixture), generated from the
Ruthenium 4-Fluorobenzylamide (3b). Yield: 18.2 mg (75%) as a
yellow solid. IR (C6H6): 3228, 2192 (RuH), 1915, 1610, 1483, 1216,
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1
1176, 1100, 911, 896, 745 cm−1. H NMR (C6D6): δ 6.73 (m, 4H,
ArCH), 6.30 (m, 4H, ArCH), 5.72 (m, 16H, ArCH), 2.25 (br, 1H
NH), 1.53 (br, 1H, NH), 0.98 (br, 1H, CH2), 0.93 (bs, 2H, CH2), 0.88
(bs, 2H, CH2), −13.47 (t, J = 20 Hz, 1H, RuH). 13C NMR: δ 162.42
(quat-C), 159.99 (quat-C), 138.54 (CO), 133.89 (quat-C), 133.81,
133.75, 130.83, 130.78, 130.72, 129.82, 128.82, 128.33, 128.01, 114.30
(CH2), 66.82 (CH2), 24.82 (CH2). 31P{1H} NMR (C6D6): δ 61.93 (s).
Crystal data of 3b: C79H80Cl2F2N4O2P4Ru2, crystal dimensions 0.3 ×
AUTHOR INFORMATION
Corresponding Author
*E-mail: gunanathan@niser.ac.in.
ORCID
■
Chidambaram Gunanathan: 0000-0002-9458-5198
Author Contributions
†V.K. and B.C. contributed equally to this work.
0.15 × 0.12, triclinic with space group P1, a = 13.1153(5) Å, b =
̅
14.6254(5) Å, c = 21.0142(7) Å, α = 83.896(2)°, β = 76.029(2)°, γ =
Notes
67.637(2)°, V = 3617.0(2) Å3, Z = 2, T = 100 K, 2θmax = 30.21, ρcalcd
=
The authors declare no competing financial interest.
1.425 g/cm3, μ(Mo Kα) = 0.635 mm−1, min/max transmission factors
= 0.6892/0.7460, 21358 reflections collected, 18086 unique (R1 =
0.0427), wR2 = 0.0531 (all data). The structure has been deposited at
the CCDC data center and can be retrieved citing CCDC 1526189.
Ruthenium 4-Nitrophenylamide (3c). Yield: 13.6 mg (60%) as a
light-yellow solid. IR (C6H6): 3197, 2194 (RuH), 1893, 1623, 1478,
ACKNOWLEDGMENTS
■
We thank SERB New Delhi (Grants EMR/2016/002517 and
SR/S2/RJN-64/2010), DAE, and NISER for financial support.
We thank Prof. S. Muthusamy and Dr. J. V. Yeldho for their
kind help in the preparation of this manuscript. V.K. thanks
SERB for the National Postdoctoral Fellowship. B.C. thanks
UGC for a research fellowship. C.G. is a Ramanujan Fellow.
1216, 1173, 1156, 941, 887, 746 cm−1. H NMR (C6D6): δ 8.12 (m,
1
4H, ArCH), 8.01 (m, 4H, ArCH), 7.77 (m, 4H, ArCH), 7.48 (m, 4H,
ArCH), 6.99 (m, 8H, ArCH), 3.59 (m, 3H, CH2 and NH), 3.36 (s, 1H,
NH), 3.28 (br, 2H, CH2), 2.36 (br, 2H, CH2), 2.21 (br, 2H, CH2),
−11.97 (t, J = 16 Hz, 1H, RuH). 13C NMR: δ 147.11 (quat-C), 133.88
(quat-C), 133.81 (CO), 130.72, 129.92, 128.87, 128.32, 127.82,
126.82, 124.42, 124.35, 66.82 (CH2), 24.82 (CH2). 31P{1H} NMR
(C6D6): δ 58.53 (s).
DEDICATION
■
Dedicated to Prof. David Milstein on the occasion of his 70th
birthday, with our very best wishes.
General Procedure for the Synthesis of Symmetrical Urea
Derivatives. To an oven-dried Schlenk tube were added catalyst 1 (2
mol %, 0.019 mmol, 12 mg), KOtBu (4 mol %, 0.039 mmol, 4.4 mg),
and xylene (1.5 mL), and the reaction mixture was stirred for 10 min
at room temperature. After that, amine (1 mmol) and DMF (10
mmol) were added to the reaction mixture, and the Schlenk tube was
fitted with a condenser. The Schlenk tube was immediately immersed
in a preheated oil bath at 165 °C and heated for 24 h with stirring.
Upon completion, the reaction mixture was allowed to cool at room
temperature. Hexane (5 mL) was added to the reaction mixture, and
the precipitated urea derivative was further washed with hexane (3
mL). The solid obtained was dried under vacuum.
General Procedure for the Synthesis of Unsymmetrical Urea
Derivatives. To an oven-dried Schlenk tube were added catalyst 1 (2
mol %, 0.019 mmol, 12 mg), KOtBu (4 mol %, 0.039 mmol, 4.4 mg),
and xylene (1.5 mL), and the reaction mixture was stirred for 10 min
at room temperature. After that, amine (1 mmol) and DMF (10
mmol) were added to the above reaction mixture, and the Schlenk
tube was fitted with a condenser under an argon atmosphere. The
Schlenk tube was immediately immersed in a preheated oil bath at 135
°C and heated for 12 h with stirring. Further, a different amine (1
mmol) was added to the reaction mixture and heated to 150 °C for 16
h. Upon completion, the reaction mixture was allowed to cool at room
temperature. Hexane (5 mL) was added to the reaction mixture, and
the precipitated urea derivative was further washed with hexane (3
mL). The solid obtained was dried under vacuum.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.7b00962.
General experimental procedures and spectral data of
complexes and urea compounds (PDF)
Accession Codes
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Hydrogen Activation Oxidative Addition of Ammonia to Iridium(I).
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C. R. Activation of Amide Nitrogen-Hydrogen Bonds by Iron and
Ruthenium Phosphine Complexes. J. Am. Chem. Soc. 1990, 112,
1628−1629. (c) Kanzelberger, M.; Zhang, X.; Emge, T. J.; Goldman,
CCDC 1526189 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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7283
DOI: 10.1021/acs.inorgchem.7b00962
Inorg. Chem. 2017, 56, 7278−7284

Inorganic Chemistry
Article
(26) Transfer hydrogenation products such as (dimethylamino)
1
methanol were not observed in the H NMR and GC analyses of the
reaction mixtures.
7284
DOI: 10.1021/acs.inorgchem.7b00962
Inorg. Chem. 2017, 56, 7278−7284