Direct conversion of carboxylic acids to various nitrogen-containing compounds in the one-pot exploiting curtius rearrangement

Article abstract of DOI:10.1021/acs.joc.9b01697

Herein we report, a single-pot multistep conversion of inactivated carboxylic acids to various N-containing compounds using a common synthetic methodology. The developed methodology rendered the use of carboxylic acids as a direct surrogate of primary amines, for the synthesis of primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides, and N-formyls, exploiting the Curtius reaction. This approach has a potential to provide a diversified library of N-containing compounds, starting from a single carboxylic acid, based on the selection of the nucleophile.

Full text of DOI:10.1021/acs.joc.9b01697

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Note
Direct Conversion of Carboxylic Acids to Various Nitrogen
Containing Compounds in One-Pot Exploiting Curtius Rearrangement
Arun Kumar, Naveen Kumar, Ritika Sharma, Gaurav Bhargava, and Dinesh Mahajan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01697 • Publication Date (Web): 08 Aug 2019
Downloaded from pubs.acs.org on August 8, 2019
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Page 1 of 13
The Journal of Organic Chemistry
to infuse economic and environmental efficiencies because
Direct Conversion of Carboxylic Acids to Various
Nitrogen Containing Compounds in One-Pot
Exploiting Curtius Rearrangement
1
2
3
4
5
6
7
8
several synthetic transformations and bond-forming steps can
be carried out in a single pot.5 Yamada et al.,6 reported the first
one-pot conversion of inactivated carboxylic acids to
urethanes involving Curtius reaction using DPPA (diphenyl
phosphoric azide). The generation of DPPA needs an
additional step in a different pot involving sodium azide and
diphenyl phosphoryl chloride.7 Recently, Lebel et al.8 reported
one-pot conversion of carboxylic acids employing, either
chloroformate or di-tert-butyl dicarbonate along with sodium
Arun Kumar1, Naveen Kumar1, Ritika Sharma2, Gaurav
Bhargava2 and Dinesh Mahajan1*
1Drug Discovery Research Center, Translational Health
Science and Technology Institute, Faridabad, 121001, India
2Department of Chemical Sciences, I. K. Gujral Punjab
Technical University, Kapurthala, Punjab-144603, India
9
azide as
a
replacement of DPPA. However, these
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methodologies are confined to conversion of carboxylic acids
to corresponding amines, ureas or carbamates only.
RECEIVED DATE (will be automatically inserted after
manuscript is accepted).
Herein, we want to report a direct, multi-step, single pot
conversion of carboxylic acids to corresponding primary
ureas, mixed ureas (secondary/tertiary), O-carbamates, S-
carbamates, acyl ureas, N-formyls and amides exploiting a
single methodology.
R= Aliphatic & (hetro)aromatic
O
O
R
1R
H
N
R2
N
AqNH3
HCOOH
R
OH
2NH
R
Ph2POCl
N
H
NH2
R
R
R1
1
XH;
NaN3
X=O/S
O
Initial optimization efforts were focused on conversion of
benzoic acid to corresponding 1-phenylurea (Table 1). Primary
ureas are not only found to be bioactive molecules but they
also serve as starting materials for molecules of biological and
commercial interests.9 Often, primary ureas are synthesized
from corresponding organic amines and ammonia involving
phosgene, carbamoyl chloride or isocyanates.9 Interestingly,
there is no report for direct conversion of carboxylic acids to
corresponding primary ureas in one pot. This instigated us to
start our optimization efforts for synthesis of 1-phenylurea
(1b), as a model reaction from corresponding benzoic acid (1).
In a typical procedure, benzoic acid was mixed with DPPA
(entry 1, Table 1) at 0°C, using toluene as a solvent. An
equivalent amount of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) was added and reaction was stirred for 30 minutes at
room temperature to facilitate the formation of acyl azide. The
conversion of the acyl azide was monitored as well as
quantified, before heating the reaction to 90°C. Aqueous
ammonium hydroxide was added to this heated solution and
reaction was monitored by TLC and 1H NMR for the
formation of 1-phenylurea as a final product. Use of DPPA as
a reagent of choice provided 32% isolated yield of 1-
phenylurea, albeit corresponding benzoyl azide intermediate
was formed in reasonably good amount (Entry 1, Table 1).
DPPA is a commercial grade reagent which is generally
obtained by vacuum distillation of the crude product obtained
after a reaction of diphenyl phosphoryl chloride with sodium
azide.7 We tried to replace DPPA by in situ use of diphenyl
phosphoryl chloride and sodium azide (entry 2). The reaction
of benzoic acid was repeated and replacement of DPPA was
compensated by in situ addition of diphenyl phosphoryl
chloride, sodium azide (as a solution in dry DMF) and
catalytic amount of DMAP. In new reaction involving sodium
azide, the conversion to corresponding benzoyl azide was less,
however it was pleased to see similar isolated yield for final
product 1b (entry 2 vs entry 1). As clear from data tabulated in
table 1, a quick screening of few other similar reagents
concluded, diphenyl phosphinic chloride (Ph2POCl) as a
reagent of choice for better yields of benzoyl azide as well as
1-phenylurea (entry 3). Decent success in overall conversion
with methanesulfonyl chloride (entry 5) and reaction
feasibility with POCl3 (entry 4) needs special mention as these
two are common reagents in organic chemistry laboratories.
Ammonium chloride or ammonium formate (entry 6 and 7)
were also found to be two other potential sources of ammonia
for the desired conversion. Influenced by the outcome of this
C
6
15 examples
H
15 examples
H
5
CONH
H
COOH
N
H
1
R
R
N
X
2
R
R1
O
H
N
H
N
H
O
5 examples
C6H5
N
R
R1
7 examples
2 Drugs
R
O
O
O
3 examples
7 examples
ABSTRACT: Herein we report, a single pot multi-step
conversion of inactivated carboxylic acids to various N-
containing compounds using
a
common synthetic
methodology. The developed methodology rendered the
use of carboxylic acids as direct surrogate of primary
amines, for the synthesis of primary ureas,
secondary/tertiary ureas, O/S-carbamates, benzoyl ureas,
amides and N-formyls, exploiting Curtius reaction. This
approach has a potential to provide a diversified library of
N-containing compounds starting form a single carboxylic
acid, based on selection of the nucleophile.
Nitrogen containing compounds such as amines, amides,
ureas, acyl ureas, and carbamates are ubiquitous in natural
products, agrochemicals as well as pharmaceutical agents or
molecules of biological and commercial interests. Hence,
synthesis of these various N-containing compounds is an
important objective in organic synthesis. Carboxylic acids are
favorable substrates because of their broad structural diversity,
ease in availability, high stability, low toxicity along with ease
in storage and handling.1 Curtius rearrangement of acyl azides
is a powerful method for construction of a new C-N (sp2C-N
or sp3C-N) bond using azide as a source of nitrogen and
carboxylic acid as source of carbon.2 The conversion of
carboxylic acids to nitrogen containing compounds, avoiding
use of any organic amine as a primary source of nitrogen is
very alluring. In a typical Curtius reaction, an acyl azide is
thermally degraded to rearrange as an isocyanate.3 The acyl
azide is often synthesized in a different pot as a separate step
from a pre-activated carboxylic acid and sodium azide.2-4 The
isocyanate thus formed can be reacted with water, alcohol or
amine as one of the nucleophile to yield corresponding amine,
carbamate or urea as a final product. This makes whole
process multi-pot and practically cumbersome, if one aims for
conversion of carboxylic acids to N-containing compounds.
One pot multi-step conversion provides an effective approach
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quick screening, Ph2POCl and aqueous ammonium hydroxide donating group (3b and 5b). Presence of chemically reactive
1
2
3
4
5
6
7
8
was used in all subsequent reactions for further studies.
phenolic OH (9b and 10b) or labile Boc as a protecting group
(7b) did not interfere with desired conversion and provided
either comparable or better yields to their neutral benzoic acid
(1b) counterparts. The heterocyclic (16b and 17b) as well
aliphatic carboxylic acids (18b and 21b) also afforded good
conversions to their respective primary ureas. The overall
yields of these conversions are appreciable considering the
fact that this process involves four step sequential conversions
of a carboxylic acid to a corresponding primary urea
exploiting sodium azide as a source of nitrogen and aqueous
ammonium hydroxide as a nucleophile in one pot (scheme 1).
The intermediates B, C and D were determined by mass
Table 1. Reaction condition optimization for synthesis of
phenyl urea
1. Reagent (1.1 eq), DBU (1.1 eq),Toluene, 0oC
O
O
2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)
OH
N
H
NH2
3. 90oC; aq. NH4OH (2.0 eq)
1
1b
9
Entry
Reagent
%Yield
acyl
Ammonia
Source
%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yield
azidea
1ba
1
spectrometry, H NMR spectroscopy and/or TLC analysis of
the reaction mixture (see supporting information). Excited by
the success of aqueous ammonium hydroxide as a nucleophile,
we planned to evaluate other N, O and S nucleophiles. The
outcome of this study is summarized in figure 2. The high
isolated yields of corresponding substituted ureas, carbamates
or thio-carbamates with respective N, O and S based
nucleophiles was not surprising owing to historical success of
these nucleophiles in classical Curtius reaction.2 Diverse class
of carboxylic acids such as aromatic, aliphatic or heterocyclic
carboxylic acids gave moderate to high isolated yields of
respective substituted ureas using either aniline (2c to 19c) or
alkyl amine (3d and 3e) as N-nucleophiles. Various alcohols
such as ethanol (3f), isopropanol (3g), tert-butyl alcohol (3h)
and benzyl alcohol (3i) were equally successful as O-
nucleophile using new protocols. Synthesis of corresponding
S-carbamates (3j to 3k) marked the success of thiols as
potential nucleophiles. As noticed before with aqueous
ammonia, the reaction with aniline as a nucleophile also
demonstrated considerable level of functional group tolerance
when attempted in presence of reactive or labile functional
groups (7c, 8c, 13c and 15c). Interestingly, the optimized
conditions also facilitated the use of benzamide as a potential
nucleophile to synthesize corresponding benzoyl ureas (3m,
4m and 19m). However, efforts to exploit primary aliphatic
carboxamides resulted in messy reactions, where we struggle
to isolate corresponding acyl ureas in pure form (not reported).
The successful use of benzamide as a nucleophile encourages
us to exploit carboxylate as a possible nucleophile for this one
pot reaction with an intention to construct a new amide bond
1
2
DPPCl*
DPPCl
75
61
aq. NH4OH
aq. NH4OH
32
32
3
4
5
6
7
Ph2POCl
POCl3
80
34
58
80
80
aq. NH4OH
aq. NH4OH
aq. NH4OH
solid NH4Cl
50
10
35
40
38
CH3SO2Cl
Ph2POCl
Ph2POCl
solid
NH2COONH4
a
*DMAP and NaN3 was not used in this reaction; Isolated
yields are based on independent reaction conversions
The scope of Ph2POCl activated reaction was studied with
various carboxylic acids for the synthesis of corresponding
acyl azides (Figure S1 in supporting information) along with
synthesis of corresponding primary ureas as mentioned in
figure 1. A set of fifteen different carboxylic acids, including
diversely substituted benzoic acid analogs, aliphatic
carboxylic acids as well as heterocyclic carboxylic acids were
evaluated. Most of these carboxylic acids provided
comparable or better yields of corresponding primary ureas in
comparison to benzoic acid. Benzoic acid analogs substituted
with an electron withdrawing group (11b and 12 b) gave poor
conversion unlike analogs substituted with an electron
in
final
product.
Scheme 1: Plausible route for one pot multistep conversion of carboxylic acid to N-containing compounds
O
O
H
N
O
O
Ph
N
D
Ph2POCl
N
P
Nu
NaN3
Nu
Ph
C
N
Ph
O
Ph
O
Ph
Ph
OH
Ph
N
B
E
C
O
Figure 1: Substrates scope of carboxylic acids for mono-substituted urea formation
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1. Ph2POCl (1.1 eq), DBU (1.1 eq),Toluene, 0oC
2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)
O
O
1
2
R
N
NH2
HO
R
OH
H
3. 90oC; aq. NH4OH (2.0 eq)
3
4
5
6
OH
X
O
H3C
NH2
H3CO
NH2
O
BocHN
O
O
O
O
O
N
NH2
N
H
NH2
N
N
NH2
N
H
H
N
H
NH2
N
NH2
H
H
H
9b, 70%
7b, 52%
10b, 50%
5b, X=F, 75%
6b, X=Br, 69%
2b, 56%
1b, 50%
3b, 75%
7
8
9
NC
O
S
O
O
O
O
O
H
O
N
NH2
O
N
H
NH2
N
NH2
N
NH2
N
H
NH2
F3C
N
H
NH2
N
H
NH2
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
O
16b, 58%
22b, 51%
21b,
48%
12b, 25%
17b, 61%
18b, 60%
11b, 25%
Figure 2: Synthetic scope evaluation with other nucleophiles
1. Ph2POCl (1.1 eq), DBU (1.1 eq),Toluene, 0oC
H
O
N
Nu
2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)
R
R
OH
O
3. 90oC; Nucleophile (1 eq)
N-nucelophiles
H
H
N
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
RO
O
H3C
X
BocHN
HO
OHC
5c, X= F, 98%
6c, X=Br, 76%
3c, R=CH3, 98%
4c, R=C2H5, 94%
2c, 93%
8c, 95%
13c, 88%
7c, 98%
R
H
H
H
H
N
H
N
H
N
H
H
H
H
H
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
H3CO
S
O2N
3d, R= H, 70%
3e, R=C2H5, 56%
19c, 68%
18c, 70%
17c, 90%
15c, 62%
16c, 94%
Benzamide-nucleophile
O, S-nucleophiles
H
H
H
N
H
H
H
H
R
H
N
N
S
N
X
N
O
N
N
N
X
O
O
O
O
O
O
O
RO
H3CO
O
H3CO
H3CO
H3CO
3m, R= CH3, 52%
4m, R= C2H5, 46%
19m, 65%
3k, 54%
3f, X= O, 98%
3j, X= S, 56%
3i, X= O, 70%
3l, X= S, 40%
3g, R=H, 70%
3h, R=CH3,65%
Amide moiety is one of the most promiscuous functional
group in natural products as well as synthetic compounds.
Organic chemists have deep admirations to develop new
methods to make amide bond. Historically, amide formation is
one of the most exploited reactions in medicinal and process
chemistry.10 All reported, classical or non-classical methods of
amide bond formations are dependent on the use of
corresponding organic amines for their condensation with
acids.11 We envisaged that a successful use of a carboxylic
acid as a nucleophile in evolved methodology can provide a
new synthetic route for amide bond formation, which will not
be dependent on use of organic amines as substrates. This
contemplation was supported by limited exploitation of
isocyanates for amide bond formation, as reported by Crich et
al.12 We attempted for the use of benzoic acid as a possible
carboxylate nucleophile as mentioned in figure 3, entry 1n. It
was pleased to see the formation of corresponding amide 1n,
when 1 equivalent benzoic acid dissolved in DMF (pre-mixed
with 1 equivalent of DBU) was added to reaction mixture.
This process involving formation of new amide bond,
exploiting benzoic acid as a nucleophile was found equally
efficient when different carboxylic acids (3n, 7n, 13n, 18n and
20n) were used as amine surrogates. The reaction scope was
also evaluated for use of formic acid as potential nucleophile
(entries 1o, 2o, 3o, 4o, 5o and 3p) resulting in the formation of
corresponding N-formyls as final product. In all the cases,
isolated yields of corresponding amides were found to be
moderate to good. The plausible mechanism for this newly
developed amide bond formation reaction is summarized in
scheme 2 involving labile intermediate E1 as an additional
step of scheme 1 mentioned above.12 This newly developed
amide formation reaction appears to be a unique process,
involving one-pot, five step sequential conversions (Scheme 1
and 2) of two inactivated carboxylic acids to corresponding
primary amides, using sodium azide as a source of nitrogen
unlike known traditional methods. Here, one of the carboxylic
acid is being exploited as a direct surrogate of a primary amine
for amide bond formation, which has never been reported
earlier.
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3: One-pot conversion of carboxylic acids to amides
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1. Ph2POCl (1.1 eq), DBU (1.1 eq),Toluene, 0oC
2. DMAP (0.1 eq), NaN3(1.1 eq solution in DMF)
H
O
1
2
N
R'
R
R
OH
3. 90oC; RCOOH (1 eq); DBU (1 eq)
O
3
4
5
6
7
H
H
H
N
H
H
H
N
N
N
N
N
O
O
O
O
O
O
OHC
H
H3CO
BocHN
1n, 55%
13n, 53%
20n, 52%
3n, 65%
18n, 60%
7n, 58%
H
N
H
H
H
H
N
8
H
N
N
N
H
H
N
H
CH3
H
9
O
O
O
O
O
O
H3CO
H3C
F
H3CO
C2H5O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2o, 35%
3p, 51%
4o, 37%
5o, 32%
1o, 30%
3o, 52%
Scheme 2: Plausible mechanism for amide bond formation
H
N
H
N
H
N
Nu
Base
-CO2
O
O
O
O
E1
O
Nu = C6H5COO-
1n
E
Scheme 3: Synthesis of Sorafenib and Regorafenib
R
H
H
R
R
I Ph2POCl (1.1eq), DBU (1.1eq), Toluene, 0°C
II DMAP (0.1eq), NaN3 (1.1eq in DMF)
N
N
CF3
Cl
H
H
(CH3)3COK (2.0 eq.), DMF, 2 hrs
K2CO3 (1.0 eq.), 80°C, 6 hrs
N
N
N
CF3
Cl
H
COOH
N
O
O
O
N
H
II 4-chloro-3-(trifluoromethyl)aniline (1eq), 90°C
HO
HO
N
23/24
O
Cl
O
Sorafenib: R=H
Regorafenib: R=F
Rxn scale 1.1 mmol; Yields: 67 % for R=H (23) and 56% for R=F (24)
Rxn scale 7.24 mmol; Yield: 60% for R=H (23)
We also evaluated this methodology for the gram scale
synthesis (scheme 3) of two approved oncology drugs i.e
Sorafenib and Regorafenib. This is a novel synthesis of these
two drugs exploiting the use of 4-hydroxybenzoic acid as a
direct surrogate of 4-aminophenol, which is a required
substrate for all reported synthesis of these two drugs. 13
NMR data with reported literature data and relevant reference
has been provided for same along with new 1H NMR data.
General Procedure for the Synthesis of Acyl Azides (1a-15a):
A solution of 1 mmol carboxylic acid in 5 ml dry toluene was
taken in two neck round bottom flas (rbf) under nitrogen
blanket. Addition of diphenyl phosphinic chloride (210 µL,
1.1 mmol) and DBU (165 µL, 1.1 mmol) was done at 0°C.
After 5 minutes of stirring, a premixed solution of 72 mg (1.1
mmol) NaN3 (12 mg, 0.1 mmol) DMAP in 0.5 ml of DMF was
added to the reaction mixture. After completion of reaction as
monitored by TLC, dilute aqHCl solution (1N, 20mL) was
added and organic layer was extracted with diethyl ether. The
organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure to afford crude product.
The crude product was purified by flash silica gel
chromatography using increasing polarity of ethyl acetate in
hexane (0:100 to 05:95) as eluent to isolate pure products.
In conclusion, we have reinvigorated Curtius rearrangement
and evolved a one-pot direct conversion of carboxylic acids to
various N-containing compounds. This method facilitates the
use of carboxylic acids as direct surrogates of primary amines
employing sodium azide as a source of nitrogen. Both
aliphatic and aromatic carboxylic acids can be transformed to
various nitrogen containing compounds such as primary ureas,
secondary/tertiary ureas, O/S-carbamates, benzoyl ureas,
amides and N-formyls in one-pot using one common reaction
condition just by altering the choice of nucleophile. The
developed methodology is modular in nature, demonstrated
wide product scope as well as high pot economy by providing
moderate to good overall yields for multi-step conversions in
single pot. Ease in availability of carboxylic acids with wide
structural diversity coupled with mild reaction conditions,
inexpensive reagents, functional group tolerance and broad
scope in nitrogen-containing product formation can possibly
make this methodology an important addition to the synthetic
tool box14 of medicinal chemists for easy diversification of a
given carboxylic acid to different N-containing compounds
possessing different physicochemical properties.15
O
N3
Benzoyl azide (1a).16 The title compound was
synthesized from Benzoic acid (122.12 mg, 1.0 mmol) and
Sodium azide (72 mg, 1.1 mmol) according to general
procedure for acyl azide synthesis. Colourless oil (118 mg,
1
80% yield); H-NMR (300 MHz, CDCl3) δ (ppm) 8.01-8.04
(m, 2H), 7.59-7.65 (m, 1H), 7.43-7.49 (m, 2H).
O
EXPERIMENTAL SECTION
N3
1H and 13C NMR spectra were recorded on Bruker 300 MHz
NMR spectrometer using DMSO-d6 /CDCl3 as a solvent.
Chemical shifts are given in ppm with TMS as an internal
reference. J values are given in Hertz. HRMS spectra were
recorded on Bruker micrOTOF Q II Mass spectrometer. All
known compounds are characterized by comparison of new 1H
4-Methylbenzoyl azide (2a).16 The title
H3C
compound was synthesized from p-Toluic acid (136.15 mg,
1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to
general procedure for acyl azide synthesis. Colourless oil (145
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3
4
mg, 90% yield); 1H-NMR (300 MHz, CDCl3) δ (ppm) 7.83 (d,
J = 8.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 2.34 (s, 3H).
O
N3
O
O2N
4-Nitrobenzoyl azide (15a).16 The title
5
6
7
8
N3
compound was synthesized from 4-Nitrobenzoic acid (167.12
mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol)
according to general procedure for acyl azide synthesis.
Yellow solid (77 mg, 40% yield); 1H-NMR (300 MHz, CDCl3)
δ (ppm) 8.30 (d, J = 9.0 Hz, 2H), 8.19-8.22 (m, 2H).
H3CO
4-Methoxybenzoyl azide (3a).16 The title
compound was synthesized from p-Anisic acid (152.15 mg,
1.0 mmol) and Sodium azide (72 mg, 1.1 mmol) according to
general procedure for acyl azide synthesis. White solid (156
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mg, 88% yield); H-NMR (300 MHz, CDCl3) δ (ppm) 7.98
Experimental Details for Scheme 1: A solution of 4-Anisic
acid (1.0 mmol) in 5 ml dry toluene was taken in a two neck
rbf under nitrogen blanket. Addition of diphenyl phosphinic
chloride (210 µL, 1.1 mmol) and DBU (165 µL, 1.1 mmol)
was done at 0°C. Reaction was stirred for 10 minutes and
monitored by TLC. TLC analysis showed consumption of
starting anisic acid and appearance of a new polar spot. An
aliquot was extracted from reaction mixture, diluted with
dichloromethane and washed with sodium bicarbonate
solution. The organic solvent was evaporated by nitrogen
flushing and remaining crude was analyse using 1H NMR
spectroscopy and Mass spectrometry. A peak of M/Z [353.0,
M+H+] was appeared on mass spectrum which correspond to
(dd, J = 6.9 Hz, 2H), 6.92 (dd, J = 6.9 Hz, 2H), 3.87 (s, 3H).
O
N3
4-Fluorobenzoyl azide (5a).16 The title
F
compound was synthesized from 4-Fluorobenzoic acid
(140.11 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol)
according to general procedure for acyl azide synthesis.
Colourless oil (149 mg, 90% yield); 1H-NMR (300 MHz,
CDCl3) δ (ppm) 8.01-8.06 (m, 2H), 7.08-7.14 (m, 2H).
O
1
O
N3
intermediate B. Analysis of H NMR spectrum determine the
presence of mixed anhydride (B) along with some impurity of
phosphinic acid as a by-product. The synthetic procedure for
intermediate C (after addition of sodium azide) has been
discussed (as compound 3a) along with corresponding
analytical data in above experimental section of acyl azides.
Post heating using oil bath fixed at 90°C, formation of
intermediate D i.e. corresponding isocyanate was confirmed
by TLC comparison with authentic sample of 4-
methoxyphenyl isocyanate.
O
N
H
tert-Butyl
(4-
(azidocarbonyl)phenyl)carbamate (7a).17 The title compound
was synthesized from N-Boc-4-aminobenzoic acid (237.25
mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol)
according to general procedure for acyl azide synthesis. Off
white solid (242 mg, 92% yield); 1H-NMR (300 MHz, CDCl3)
δ (ppm) 7.91 (dd, J = 8.7 Hz, 2H), 7.40 (dd, J = 9.0 Hz, 2H),
6.69 (br, 1H), 1.48 (s, 9H).
O
General Procedure for One Pot Conversion of Carboxylic
Acids to Primary Ureas (1b-22b): A solution of 1.0 mmol
carboxylic acid in 5 ml dry toluene was taken in a two neck
rbf under nitrogen blanket. Addition of diphenyl phosphinic
chloride (210 µL, 1.1 mmol) and DBU (165 µL, 1.1 mmol)
was done at 0°C. After 5 minutes of stirring, a premixed
solution of 72 mg (1.1 mmol) NaN3, 12 mg (0.1 mmol) DMAP
in 0.5 ml of DMF was added to the reaction mixture. After
complete consumption of starting material and/or formation of
acyl azide (as monitored by TLC), the reaction mixture was
stirred and heated using silicon oil bath having temperature
fixed at 90°C followed by addition of 2.0 mmol ammonium
hydroxide (28% solution in water). After the completion of
reaction (based on TLC monitoring for consumption of acyl
azide and formation of new spot), reaction mixture was
neutralized with dilute aqHCl solution and extracted with ethyl
acetate. The organic layer was washed with NaHCO3 solution
and dried over anhydrous Na2SO4. Solvent was evaporated
under reduced pressure, resulting crude product was purified
by flash silica gel chromatography using increasing polarity of
ethyl acetate in hexane (20:80 to 40:60) to isolate
corresponding pure primary urea.
N3
OHC
4-Formylbenzoyl azide (13a). The title
compound was synthesized from 4-Formylbenzoic acid
(150.13 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol)
according to general procedure for acyl azide synthesis.
Yellow solid (105 mg, 60% yield); m.p. 170-175 0C; 1H-NMR
(300 MHz, CDCl3) δ (ppm) 10.10 (s, 1H), 8.18 (d, J = 8.28
Hz, 2H), 7.96 (d, J = 8.25 Hz, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 191.4, 139.9, 130.0, 129.7; HRMS (ESI-TOF) (m/z):
[M+H]+ Calcd for C8H5N3O2H, 176.0460, Mass not found due
to stability reason.
O
N3
H3COC
4-Acetylbenzoyl azide (14a).16 The title
compound was synthesized from 4-Acetylbenzoic acid
(164.16 mg, 1.0 mmol) and Sodium azide (72 mg, 1.1 mmol)
according to general procedure for acyl azide synthesis. White
solid (133 mg, 70% yield); H-NMR (300 MHz, CDCl3) δ
(ppm) 8.08 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.7 Hz, 2H), 2.61
1
General Procedure for the One Pot Direct Conversion to
Substituted Ureas (2c-3e), O/S Carbamates (3f-3i), Benzoyl
Ureas (3m, 4m and 19m), N-formamide and Amides (1n-3p):
A solution of 1.1 mmol carboxylic acid in 5 ml dry toluene
(s, 3H).
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2
3
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5
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8
was taken in a two neck rbf under nitrogen blanket. Addition
Br
O
of diphenyl phosphinic chloride (210 µL, 1.1 mmol) and DBU
(165 µL, 1.1 mmol) was done at 0°C. After 5 minutes of
stirring, a premixed solution of 72 mg (1.1 mmol) NaN3, 12
mg (0.1 mmol) DMAP in 0.5 ml of DMF was added to the
reaction mixture. After the conversion of carboxylic acid into
acyl azide (by TLC monitoring), the reaction mixture was
stirred and heated using silicon oil bath fixed at 90-100°C,
followed by addition of respective nucleophile (1.0 mmol).
Reaction was monitored by TLC and neutralized with dilute
HCl solution followed by extraction with ethyl acetate. The
organic layer was washed with aqNaHCO3 solution and dried
over anhydrous Na2SO4. Solvent was evaporated under
reduced pressure, and the resulting crude product was purified
by flash silica gel chromatography using increasing polarity of
ethyl acetate in hexane (05:95 to 20:80) as eluent to isolate
pure compounds.
N
NH2
1-(4-Bromophenyl)urea (6b).19 The title
H
compound was synthesized from 4-Bromobenzoic acid
(201.02 mg, 1.0 mmol) and Ammonium hydroxide (28 %
solution in water, 186 µL, 2.0 mmol) according to general
procedure for curtius reaction. White crystalline solid (148
mg, 69% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.67
(br, 1H), 7.37 (s, 4H), 5.91 (br, 2H).
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H
O
N
O
O
N
NH2
H
tert-Butyl (4-ureidophenyl)carbamate
(7b). The title compound was synthesized from N-Boc-4-
aminobenzoic acid (237.25 mg, 1.0 mmol) and Ammonium
hydroxide (28 % solution in water, 186 µL, 2.0 mmol)
according to general procedure for curtius reaction. White
O
solid (131 mg, 52% yield); m.p. >150°C H-NMR (300 MHz,
1
N
NH2
DMSO-d6) δ (ppm) 9.10 (br, 1H), 8.36 (br, 1H), 7.22-7.30 (m,
4H), 5.73 (br, 2H), 1.46 (s, 9H) 13C{1H} NMR (75 MHz,
DMSO-d6) δ 156.5, 153.3, 135.5, 133.6, 119.2, 118.7, 28.6;
HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C12H17N3O3Na
274.1168; Found 274.1182.
1-Phenylurea (1b).19 The title compound was
H
synthesized from Benzoic acid (122.12 mg, 1.0 mmol) and
Ammonium hydroxide (28 % solution in water, 186 µL, 2.0
mmol) according to general procedure for Curtius reaction.
White solid (68 mg, 50% yield); 1H-NMR (300 MHz, DMSO-
d6) δ (ppm) 8.49 (br, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.21 (t, J =
7.8 Hz, 2H), 6.88 (t, J = 7.2 Hz, 1H), 5.81 (br, 2H).
O
HO
N
NH2
1-(3-Hydroxyphenyl)urea (9b).19 The
H
H3C
O
title compound was synthesized from 3-Hydroxybenzoic acid
(138.12 mg, 1.0 mmol) and Ammonium hydroxide (28 %
solution in water, 186 µL, 2.0 mmol) according to general
procedure for curtius reaction. Yellow solid (107 mg, 70%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.20 (br, 1H),
8.38 (br, 1H), 6.95-7.04 (m, 2H), 6.68-6.72 (m, 1H), 6.28-6.32
(m, 1H), 5.77 (br, 2H).
N
NH2
1-(p-Tolyl)urea (2b).39 The title
H
compound was synthesized from p-Toluic acid (136.15 mg,
1.0 mmol) and Ammonium hydroxide (28 % solution in water,
186 µL, 2.0 mmol) according to general procedure for curtius
reaction. White crystalline solid (84 mg, 56% yield); 1H-NMR
(300 MHz, DMSO-d6) δ (ppm) 8.38 (br, 1H), 7.26 (d, J = 8.4
Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 5.75 (br, 2H), 2.20 (s, 3H).
OH
O
H3CO
O
N
NH2
1-(2-Hydroxyphenyl)urea (10b).19 The title
H
N
NH2
compound was synthesized from Salicylic acid (138.12 mg,
1.0 mmol) and Ammonium hydroxide (28 % solution in water,
186 µL, 2.0 mmol) according to general procedure for curtius
reaction. White solid (76 mg, 50% yield); 1H-NMR (300 MHz,
DMSO-d6) δ (ppm) 9.91 (br, 1H), 7.99 (br, 1H), 7.83 (dd, J =
7.8 Hz, 1H), 6.70-6.80 (m, 3H), 6.19 (br, 2H).
1-(4-Methoxyphenyl)urea (3b).18 The
H
title compound was synthesized from p-Anisic acid (152.15
mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in
water, 186 µL, 2.0 mmol) according to general procedure for
1
curtius reaction. Off white solid (125 mg, 75% yield); H-
NMR (300 MHz, DMSO-d6) δ (ppm) 8.29 (br, 1H), 7.27 (d, J
= 9.3 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 5.69 (s, 2H), 3.68 (s,
3H).
O
F3C
N
NH2
H
1-(3-(trifluoromethyl)phenyl)urea
F
O
(11b).19 The title compound was synthesized from 3-
(Trifluoromethyl)benzoic acid (190.12 mg, 1.0 mmol) and
Ammonium hydroxide (28 % solution in water, 186 µL, 2.0
mmol) according to general procedure for curtius reaction.
White solid (51 mg, 25% yield); 1H-NMR (300 MHz, DMSO-
d6) δ (ppm) 8.87 (br, 1H), 7.94 (br, 1H), 7.39-7.50 (m, 3H),
7.20 (d, J = 7.5 Hz, 1H), 5.98 (br, 2H).
N
NH2
1-(4-Fluorophenyl)urea (5b).18 The title
H
compound was synthesized from 4-Fluorobenzoic acid(140.11
mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in
water, 186 µL, 2.0 mmol) according to general procedure for
curtius reaction. White crystalline solid (116 mg, 75% yield);
1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.53 (br, 1H), 7.36-
7.41 (m, 2H), 7.01-7.07 (m, 2H), 5.82 (br, 2H).
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O
2
O
3
4
5
6
7
8
9
N
NH2
N
NH2
1-(4-Cyanophenyl)urea (12b).19 The
H
1-(4-isopropylphenyl)urea (22b).19 The
H
title compound was synthesized from 4-Cyanobenzoic acid
(147.13 mg, 1.0 mmol) and Ammonium hydroxide (28 %
solution in water, 186 µL, 2.0 mmol) according to general
procedure for curtius reaction. White solid (41 mg, 25%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.09 (br, 1H),
7.61-7.66 (m, 2H), 7.55-7.58 (m, 2H), 6.11 (br, 2H).
title compound was synthesized from 4-Isopropylbenzoic acid
(164.20 mg, 1.0 mmol) and Ammonium hydroxide (28 %
solution in water, 186 µL, 2.0 mmol) according to general
procedure for curtius reaction. White solid (91 mg, 51%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.37 (br,
1H), 7.28 (d, J = 8.46 Hz, 2H), 7.07 (d, J = 8.46 Hz, 2H), 5.74
(br, 2H), 2.74-2.83 (m, 1H), 1.15 (d, J = 6.9 Hz, 6H).
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S
O
H
H
N
NH2
N
N
1-(Thiophen-3-yl)urea (16b).40 The title
H
O
compound was synthesized from 3-Thiophenecarboxylic acid
(128.14 mg, 1.0 mmol) and Ammonium hydroxide (28 %
solution in water, 186 µL, 2.0 mmol) according to general
procedure for curtius reaction. Off white solid (83 mg, 58%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.76 (br, 1H),
7.35 (dd, J = 5.1 Hz, 1H), 7.13-7.15 (m, 1H), 6.94 (dd, J = 5.1
Hz, 1H), 5.77 (br, 2H).
1-Phenyl-3-(p-tolyl)urea (2c).20 The
H3C
title compound was synthesized from p-Toluic acid (150 mg,
1.1 mmol) and Aniline (92 µL, 1.0 mmol) according to general
procedure for curtius reaction. Off white solid (211 mg, 93%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.54-8.60 (br,
2H), 7.44 (d, J = 7.8 Hz, 2H), 7.24-7.34 (m, 4H), 7.08 (d, J =
8.1 Hz, 2H), 6.96-6.98 (m, 1H), 2.24 (s, 3H).
O
O
H
H
N
N
O
N
NH2
H
1-(Benzo[d][1,3]dioxol-5-yl)urea (17b).
O
H3CO
1-(4-Methoxyphenyl)-3-phenylurea
The title compound was synthesized from Piperonylic acid
(166.13 mg, 1.0 mmol) and Ammonium hydroxide (28 %
solution in water, 186 µL, 2.0 mmol) according to general
procedure for curtius reaction. White solid (110 mg, 61%
(3c).20 The title compound was synthesized from p-Anisic acid
(168 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol) according
to general procedure for curtius reaction. Off white solid (238
mg, 98% yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.56
(br, 1H), 8.45 (br, 1H), 7.43 (dd, J = 8.7 Hz, 2H), 7.35 (dd, J =
6.9 Hz, 2H), 7.23-7.28 (m, 2H), 6.92-6.97 (m, 1H), 6.86 (dd, J
= 6.9 Hz, 2H) 3.71 (s, 3H).
yield); m.p. 165-170ºC; H-NMR (300 MHz, DMSO-d6) δ
1
(ppm) 8.38 (br, 1H), 7.16 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.1
Hz, 1H), 6.60 (dd, J = 8.4 Hz, 1H), 5.92 (s, 2H), 5.74 (br, 2H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 156.5, 147.5, 141.8,
135.5, 110.7, 108.4, 101.0, 100.9; HRMS (ESI-TOF) (m/z):
[M+Na]+ Calcd for C8H8N2O3Na 203.0433; Found 203.0431.
H
H
N
N
O
C2H5O
O
1-(4-Ethoxyphenyl)-3-phenylurea
(4c). The title compound was synthesized from 4-
Ethoxybenzoic acid (183 mg, 1.1 mmol) and Aniline (92 µL,
1.0 mmol) according to general procedure for curtius reaction.
White solid (241 mg, 94% yield); m.p. 165-170°C; H-NMR
(300 MHz, DMSO-d6) δ (ppm) 8.55 (br, 1H), 8.43 (br, 1H),
7.43 (dd, J = 8.7 Hz, 2H), 7.33 (dd, J = 6.9 Hz, 2H), 7.26 (t, J
= 7.8 Hz, 2H), 6.94-6.96 (m, 1H), 6.84 (dd, J = 6.9 Hz, 2H),
3.95-3.98 (m, 2H), 1.30 (m, 3H); 13C{1H} NMR (75 MHz,
DMSO-d6) δ 154.1, 153.2, 140.3, 133.0, 129.2, 122.0, 120.5,
118.5, 115.0, 63.5, 31.1; HRMS (ESI-TOF) (m/z): [M+Na]+
Calcd for C15H16N2O2Na 279.1104; Found 279.1088.
N
NH2
1-Cyclohexylurea (18b).19 The title compound
H
was synthesized from Cyclohexanecarboxylic acid (128.17
mg, 1.0 mmol) and Ammonium hydroxide (28 % solution in
water, 186 µL, 2.0 mmol) according to general procedure for
1
1
curtius reaction. White solid (85 mg, 60% yield); H-NMR
(300 MHz, DMSO-d6) δ (ppm) 5.79-5.81 (br, 1H), 5.27 (br,
1H), 3.23-3.30 (m, 1H), 1.59-1.74 (m, 4H), 1.48-1.53 (m, 1H),
1.02-1.26 (m, 5H).
H
N
NH2
H
H
1-Benzylurea (21b).19 The title compound
O
N
N
was synthesized from Phenylacetic acid (136.15 mg, 1.0
mmol) and Ammonium hydroxide (28 % solution in water,
186 µL, 2.0 mmol) according to general procedure for curtius
reaction. White solid (72 mg, 48% yield); 1H-NMR (300 MHz,
DMSO-d6) δ (ppm) 7.29-7.34 (m, 2H), 7.19-7.26 (m, 3H),
7.38-6.42 (br, 1H), 5.51 (br, 2H), 4.17 (d, J = 6.3 Hz, 2H).
O
F
1-(4-Fluorophenyl)-3-phenylurea
(5c).21 The title compound was synthesized from 4-
Fluorobenzoic acid (154 mg, 1.1 mmol) and Aniline (92 µL,
1.0 mmol) according to general procedure for curtius reaction.
Off white crystalline solid (226 mg, 98% yield); 1H-NMR
(300 MHz, DMSO-d6) δ (ppm) 8.67 (br, 1H), 8.63 (br, 1H),
7.42-7.47 (m, 4H), 7.27 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 8.7 Hz,
2H), 6.96 (t, J = 7.5 Hz, 1H).
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H
H
Nitrobenzoic acid (183.83 mg, 1.1 mmol) and Aniline (92 µL,
N
N
1.0 mmol) according to general procedure for curtius reaction.
1
O
Off white solid (160 mg, 62% yield); H-NMR (300 MHz,
Br
1-(4-Bromophenyl)-3-phenylurea
DMSO-d6) δ (ppm) 9.43 (br, 1H), 8.91 (br, 1H), 8.19 (dd, J =
7.2 Hz, 2H), 7.67-7.71 (m, 2H), 7.47 (dd, J = 8.7 Hz, 2H),
7.28-7.33 (m, 2H), 6.99-7.04 (m, 1H).
(6c).22 The title compound was synthesized from 4-
Bromobenzoic acid (221 mg, 1.1 mmol) and Aniline (92 µL,
1.0 mmol) according to general procedure for curtius reaction.
1
Off white crystalline solid (221 mg, 76% yield); H-NMR
H
H
N
N
(300 MHz, DMSO-d6) δ (ppm) 8.79 (br, 1H), 8.68 (br, 1H),
7.40-7.45 (m, 6H), 7.27 (t, J = 7.8 Hz, 2H), 6.97 ((t, J = 7.5
Hz, 1H).
9
O
S
1-Phenyl-3-(thiophen-3-yl)urea
title compound was synthesized
(16c).
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The
from
3-
Thiophenecarboxylic acid (140.96 mg, 1.1 mmol) and Aniline
(92 µL, 1.0 mmol) according to general procedure for curtius
reaction. White solid (205 mg, 94% yield); m.p. 205-215°C;
1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.91 (br, 1H), 8.61
(br, 1H), 7.42-7.46 (m, 3H), 7.24-7.29 (m, 3H), 7.04 (dd, J =
5.1 Hz, 1H), 6.96-6.98 (m, 1H); 13C{1H} NMR (75 MHz,
DMSO-d6) δ 152.8, 140.2, 137.7, 129.2, 125.0, 122.2, 121.7,
118.6, 106.1; HRMS (ESI-TOF) (m/z): [M+H]+ Calcd for
C11H10N2OSH 219.0592; Found 219.0616.
H
H
N
N
O
HN
O
O
tert-Butyl
(4-(3-
phenylureido)phenyl)carbamate (7c). The title compound was
synthesized from N-Boc-4-aminobenzoic acid (261 mg, 1.1
mmol) and Aniline (92 µL, 1.0 mmol) according to general
procedure for curtius reaction. White solid (321 mg, 98%
yield); m.p. >200ºC; 1H-NMR (300 MHz, DMSO-d6) δ (ppm)
9.17 (br, 1H), 8.56 (br, 1H), 8.49 (br, 1H), 7.43 (dd, J = 8.7
Hz, 2H), 7.23-7.33 (m, 6H), 6.94-6.97 (m, 1H), 1.46 (s, 9H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 153.3, 153.0, 140.2,
134.6, 134.3, 129.2, 122.1, 119.2, 118.5, 79.2, 28.6; HRMS
(ESI-TOF) (m/z): [M+Na]+ Calcd for C18H21N3O3Na
350.1475; Found 350.1446.
H
H
N
N
O
O
O
1-(Benzo[d][1,3]dioxol-5-yl)-3-
phenylurea (17c).24 The title compound was synthesized from
Piperonylic acid (182.74 mg, 1.1 mmol) and Aniline (92 µL,
1.0 mmol) according to general procedure for curtius reaction.
1
Off white crystalline solid (231 mg, 90% yield); H-NMR
(300 MHz, DMSO-d6) δ (ppm) 8.58 (br, 1H), 8.53 (br, 1H),
7.43 (dd, J = 8.4 Hz, 2H), 7.20-7.29 (m, 3H), 6.93-6.98 (m,
1H), 6.73-6.84 (m, 2H), 5.97 (s, 2H).
H
H
N
N
O
HO
1-(4-Hydroxyphenyl)-3-phenylurea
H
H
(8c).23 The title compound was synthesized from 4-
Hydroxybenzoic acid (152 mg, 1.1 mmol) and Aniline (92 µL,
1.0 mmol) according to general procedure for curtius reaction.
N
N
O
1-Cyclohexyl-3-phenylurea (18c).20 The
title compound was synthesized from Cyclohexanecarboxylic
acid (140.98 mg, 1.1 mmol) and Aniline (92 µL, 1.0 mmol)
according to general procedure for curtius reaction. White
solid (153 mg, 70% yield); 1H-NMR (300 MHz, DMSO-d6) δ
(ppm) 8.33 (br, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.20 (t, J = 7.8
Hz, 2H), 6.87-6.89 (m, 1H), 6.09-6.11 (br, 1H), 3.39-3.47 (m,
1H), 1.77-1.81 (m, 2H), 1.63-1.69 (m, 2H), 1.51-1.55 (m, 1H),
1.36 (m, 5H).
1
Off white solid (217 mg, 95% yield); H-NMR (300 MHz,
DMSO-d6) δ (ppm) 9.05 (br, 1H), 8.50 (br, 1H), 8.29 (br, 1H),
7.42 (dd, J = 8.4 Hz, 2H), 7.19-7.27 (m, 4H), 6.93-6.95 (m,
1H), 6.68 (dd, J = 6.9 Hz, 2H).
H
H
N
N
O
OHC
1-(4-Formylphenyl)-3-phenylurea
H
H
(13c). The title compound was synthesized from 4-
Formylbenzoic acid (165 mg, 1.1 mmol) and Aniline (92 µL,
1.0 mmol) according to general procedure for curtius reaction.
N
N
O
1-Phenyl-3-propylurea (19c).25 The title
1
Brown solid (212 mg, 88% yield); m.p. 140-145ºC; H-NMR
compound was synthesized from Butyric acid (100 µL, 1.1
mmol) and Aniline (92 µL, 1.0 mmol) according to general
procedure for curtius reaction. Yellowish solid (121 mg, 68%
(300 MHz, DMSO-d6) δ (ppm) 9.85 (s, 1H), 9.20 (br, 1H),
8.85 (br, 1H), 7.83 (dd, J = 6.9 Hz, 2H), 7.65-7.68 (m, 2H),
7.47 (dd, J = 8.7 Hz, 2H), 7.30 (t, J = 7.8 Hz, 2H), 6.98-7.03
(m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 191.8, 152.5,
146.1, 139.6, 131.5, 130.5, 129.3, 122.8, 118.9, 118.0; HRMS
(ESI-TOF) (m/z): [M+Na]+ Calcd for C14H12N2O2Na
263.0791; Found 263.0771.
1
yield); H-NMR (300 MHz, CDCl3) δ (ppm) 7.20-7.24 (m,
4H), 6.97-7.01 (m, 1H), 6.86 (br, 1H), 5.15 (br, 1H), 3.08-3.15
(m, 2H), 1.41-1.48 (m, 2H), 0.84-0.87 (m, 3H).
H
H
N
N
H
H
O
N
N
H3CO
1-Ethyl-3-(4-methoxyphenyl)urea
(3d). The title compound was synthesized from p-Anisic acid
(167.36 mg, 1.1 mmol) and Ethylamine hydrochloric salt
(81.55 mg, 1.0 mmol) according to general procedure for
O
O2N
1-(4-Nitrophenyl)-3-phenylurea
(15c).20 The title compound was synthesized from 4-
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curtius reaction. White solid (136 mg, 70% yield); m.p. 125-
130°C; 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 8.16 (br,
1H), 7.26 (dd, J = 6.6 Hz, 2H), 6.79 (dd, J = 6.9 Hz, 2H),
5.93-5.96 (br, 1H), 3.68 (s, 3H), 3.03-3.12 (m, 2H), 1.03 (t, J =
6.9 Hz, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 155.8,
154.3, 134.2, 119.8, 114.3, 55.6, 34.4, 16.0; HRMS (ESI-
TOF) (m/z): [M+H]+ Calcd for C10H14N2O2H 195.1134;
Found 195.1151.
H
N
O
O
H3CO
Benzyl
(4-
methoxyphenyl)carbamate (3i).26 The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and
Benzyl alcohol (100 µL, 1.0 mmol) according to general
procedure for curtius reaction. Off white solid (180 mg, 70%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.57 (br, 1H),
7.35-7.41 (m, 7H), 6.86 (d, J = 9.0 Hz, 2H), 5.12 (s, 2H), 3.70
(s, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 155.2, 153.9,
137.2, 132.5, 128.9, 128.5, 128.4, 120.2, 114.4, 66.0, 55.6.
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10
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28
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34
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36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
N
N
O
H3CO
1,1-Diethyl-3-(4-
methoxyphenyl)urea (3e).31 The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and
Diethylamine (103.45 µL, 1.0 mmol) according to general
procedure for curtius reaction. Colourless oil (124 mg, 56%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 7.99 (br, 1H),
7.34 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 3.70 (s, 3H),
3.27-3.34 (m, 4H), 1.07 (t, J = 6.9 Hz, 6H).
H
N
S
O
H3CO
S-ethyl
(4-
methoxyphenyl)carbamothioate (3j). The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and
Ethanethiol (74 µL, 1.0 mmol) according to general procedure
for Curtius reaction. Brown solid (119 mg, 56% yield); m.p.
H
N
O
O
H3CO
Ethyl (4-methoxyphenyl)carbamate
1
60-65ºC; H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.07 (br,
(3f).26 The title compound was synthesized from p-Anisic acid
(167.36 mg, 1.1 mmol) and Ethanol (58 µL, 1.0 mmol)
according to general procedure for curtius reaction. Brownish
1H), 7.39 (d, J = 9.0 Hz, 2H), 6.84-6.88 (m, 2H), 3.70 (s, 3H),
2.80-2.87 (m, 2H), 1.20-1.25 (m, 4H); 13C{1H} NMR (75
MHz, DMSO-d6) δ 164.8, 155.7, 132.6, 121.1, 120.3, 114.4,
55.6, 23.7, 16.2; HRMS (ESI-TOF) (m/z): [M+H]+ Calcd for
C10H13NO2SH 212.0740; Found 212.0722.
1
oil (192 mg, 98% yield); H-NMR (300 MHz, DMSO-d6) δ
(ppm) 9.37 (br, 1H), 7.34 (d, J = 9 Hz, 2H), 6.84 (d, J = 9.0
Hz, 2H), 4.08-4.10 (m, 2H), 3.70 (s, 3H), 1.22 (m, 3H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 154.15, 154.16,
132.7, 120.2, 114.3, 60.3, 55.5, 15.0.
H
N
S
O
H
H3CO
S-allyl
(4-
N
O
methoxyphenyl)carbamothioate (3k). The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and 2-
Propene-1-thiol (82.56 µL, 1.0 mmol) according to general
procedure for curtius reaction. Brown solid (121 mg, 54%
yield); m.p. 65-70°C; 1H-NMR (300 MHz, DMSO-d6) δ
(ppm) 10.16 (br, 1H), 7.40 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.3
Hz, 2H), 5.75-5.93 (m, 1H), 5.21-5.27 (m, 1H), 5.06-5.10 (m,
1H), 3.71 (s, 3H), 3.55 (d, J = 6.9 Hz, 2H); 13C{1H} NMR
(75 MHz, DMSO-d6) δ 165.2, 156.0, 134.5, 131.8, 121.6,
118.0, 114.5, 55.6, 36.5, 32.0; HRMS (ESI-TOF) (m/z):
[M+Na]+ Calcd for C11H13NO2SNa 246.0559; Found
246.0534.
O
H3CO
Isopropyl
(4-
methoxyphenyl)carbamate (3g).27 The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and 2-
Propanol (77 µL, 1.0 mmol) according to general procedure
1
for curtius reaction. Yellowish oil (147 mg, 70% yield); H-
NMR (300 MHz, DMSO-d6) δ (ppm) 9.31 (br, 1H), 7.34 (d, J
= 9.0 Hz, 2H), 6.83 (dd, J = 6.6 Hz, 2H), 4.81-4.90 (m, 1H),
3.69 (s, 3H), 1.23 (d, J = 6.3 Hz, 6H); 13C{1H} NMR (75
MHz, DMSO-d6) δ 155.0, 153.7, 132.8, 120.1, 114.3, 67.5,
55.6, 22.4.
H
H
N
S
N
O
O
O
H3CO
S-benzyl
(4-
H3CO
tert-Butyl
(4-
methoxyphenyl)carbamothioate (3l). The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and
Benzyl mercaptan (117.39 µL, 1.0 mmol) according to general
procedure for curtius reaction. Yellowish crystalline solid (110
methoxyphenyl)carbamate (3h).28 The title compound was
synthesized from p-Anisic acid (167.36 mg, 1.1 mmol) and
Tert-butanol (96 µL, 1.0 mmol) according to general
procedure for curtius reaction. Colourless oil (145 mg, 65%
yield); 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 9.10 (br, 1H),
7.34 (d, J = 8.7 Hz, 2H), 6.82 (dd, J = 6.9 Hz, 2H), 3.69 (s,
3H), 1.46 (s, 9H); 13C{1H} NMR (75 MHz, DMSO-d6) δ
154.9, 153.4, 133.0, 120.1, 114.2, 79.1, 55.5, 28.6.
1
mg, 40% yield); m.p. 40-45ºC H-NMR (300 MHz, DMSO-
d6) δ (ppm) 7.90 (dd, J = 6.9 Hz, 2H), 7.27-7.39 (m, 5H), 7.07
(d, J = 9.0 Hz, 2H), 4.30 (s, 2H), 3.84 (s, 3H); 13C{1H} NMR
(75 MHz, DMSO-d6) δ 189.2, 164.2, 138.2, 129.6, 129.3,
129.0, 127.6, 114.7, 56.1, 32.7; HRMS (ESI-TOF) (m/z): [M-
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2
3
CH3+Na]+ Calcd for C14H12NO2SNa 281.0481; Found
281.0519.
H
N
O
4
5
6
7
8
9
H3CO
H
H
N-(4-methoxyphenyl)benzamide
N
N
(3n).29 The title compound was synthesized from p-Anisic acid
(167.36 mg, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0
mmol) according to general procedure for curtius reaction.
O
O
H3CO
N-((4-
methoxyphenyl)carbamoyl)benzamide (3m).38 The title
compound was synthesized from p-Anisic acid (167.36 mg,
1.1 mmol) and Benzamide (121.14 mg, 1.0 mmol) according
to general procedure for curtius reaction. White solid (141 mg,
1
White crystalline solid (148 mg, 65% yield); H-NMR (300
MHz, DMSO-d6) δ (ppm) 10.12 (br, 1H), 7.94 (d, J = 6.6 Hz,
2H), 7.67 (d, J = 9.0 Hz, 2H), 7.49-7.58 (m, 3H), 6.92 (d, J =
9.0 Hz, 2H), 3.74 (s, 3H).
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
52% yield); H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.97
(br, 1H), 10.67 (br, 1H), 8.004-8.033 (m, 2H), 7.63-7.65 (m,
1H), 7.48-7.56 (m, 4H), 6.93 (dd, J = 6.9 Hz, 2H), 3.74 (s,
3H).
H
N
O
HN
H
H
O
O
N
N
O
O
tert-Butyl
(4-
C2H5O
N-((4-
benzamidophenyl)carbamate (7n).34 The title compound was
synthesized from N-Boc-4-aminobenzoic acid (261 mg, 1.1
mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to
general procedure for curtius reaction. White solid (181 mg,
58% yield); H-NMR (300 MHz, DMSO-d6) δ (ppm) 10.14
(br, 1H), 9.30 (br, 1H), 7.92-7.95 (m, 2H), 7.64 (d, J = 9.0 Hz,
2H), 7.52-7.58 (m, 3H), 7.41 (d, J = 9.0 Hz, 2H), 1.48 (s, 9H).
ethoxyphenyl)carbamoyl)benzamide (4m). The title compound
was synthesized from 4-Ethoxybenzoic acid (182.79 mg, 1.1
mmol) and Benzamide (121.14 mg, 1.0 mmol) according to
general procedure for curtius reaction. Off white solid (131
mg, 46% yield); m.p. 150-155°C; 1H-NMR (300 MHz,
DMSO-d6) δ (ppm) 10.99 (br, 1H), 10.68 (br, 1H), 8.02 (d, J
= 9.0 Hz, 2H), 7.47-7.66 (m, 5H), 6.92 (d, J = 9.0 Hz, 2H),
3.98-4.05 (q, J = 13.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 169.1, 155.4, 151.6,
133.4, 132.8, 130.9, 129.0, 128.7, 122.0, 115.0, 63.6, 15.1;
HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for C16H16N2O3Na,
307.1053; Found 307.1029.
1
H
N
O
N-(4-formylphenyl)benzamide (13n).35
OHC
The title compound was synthesized from 4-Formylbenzoic
acid (165.14 mg, 1.1 mmol) Benzoic acid (122.12 mg, 1.0
mmol) according to general procedure for curtius reaction. Off
white solid (120 mg, 53% yield); 1H-NMR (300 MHz, DMSO-
d6) δ (ppm) 10.45 (br, 1H), 10.11 (br, 1H), 8.13 (d, J = 8.4 Hz,
2H), 8.05 (d, J = 8.7 Hz, 2H), 7.77-7.80 (m, 2H), 7.37 (t, J =
7.8 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H).
H
H
N
N
O
O
N-(propylcarbamoyl)benzamide (19m).
The title compound was synthesized from Butyric acid (100
µL, 1.1 mmol) and Benzamide (121.14 mg, 1.0 mmol)
according to general procedure for curtius reaction. Off white
solid (134 mg, 65% yield); m.p. 60-65ºC; 1H-NMR (300 MHz,
DMSO-d6) δ (ppm) 10.66 (br, 1H), 8.66-8.70 (br, 1H), 7.94-
7.97 (m, 2H), 7.59-7.64 (m, 1H), 7.48-7.53 (m, 2H), 3.16-3.23
(m, 2H), 1.49-1.56 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H); 13C{1H}
NMR (75 MHz, DMSO-d6) δ 168.7, 153.9, 133.1, 133.0,
128.9, 128.5, 41.2, 22.9, 11.7; HRMS (ESI-TOF) (m/z):
H
N
O
N-cyclohexylbenzamide (18n).36 The title
compound was synthesized from Cyclohexanecarboxylic acid
(140.98 mg, 1.1 mmol) and Benzoic acid (122.12 mg, 1.0
mmol) according to general procedure for curtius reaction.
White solid (122 mg, 60% yield); 1H-NMR (300 MHz, CDCl3)
δ (ppm) 7.73 (dd, J = 8.1 Hz, 2H), 7.37-7.47 (m, 3H), 5.94 (br,
1H), 3.98 (m, 1H), 1.99-2.04 (m, 2H), 1.70-1.77 (m, 4H),
1.35-1.45 (m, 2H), 1.17-1.28 (m, 3H).
[M+Na]+ Calcd for C11H14N2O2Na
229.0968.
229.0953; Found
H
N
O
N-phenylbenzamide (1n).30 The title
compound was synthesized from Benzoic acid (134.33 mg, 1.1
mmol) and Benzoic acid (122.12 mg, 1.0 mmol) according to
general procedure for curtius reaction. White crystalline solid
(109 mg, 55% yield); 1H-NMR (300 MHz, DMSO-d6) δ
(ppm) 10.25 (br, 1H), 7.95 (dd, J = 8.1 Hz, 2H), 7.78 (dd, J =
8.7 Hz, 2H), 7.50-7.60 (m, 3H), 7.36 (t, J = 7.8 Hz, 2H), 7.08-
7.13 (m, 1H).
H
N
N-ethylbenzamide (20n).37 The title compound
was synthesized from Propionic acid (82 µL, 1.1 mmol) and
Benzoic acid (122.12 mg, 1.0 mmol) according to general
procedure for curtius reaction. White solid (78 mg, 52%
yield); H-NMR (300 MHz, CDCl3) δ (ppm) 8.05-8.08 (m,
2H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 4.36-
4.43 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).
O
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H
H
N
H
N
CH3
O
O
N-phenylformamide (1o).33b The title compound
H3CO
N-(4-methoxyphenyl)acetamide
was synthesized from Benzoic acid (134.33 mg, 1.1 mmol)
and Formic acid (38 µL, 1.0 mmol) according to general
procedure for curtius reaction. Brownish solid (36 mg, 30%
(3p).32 The title compound was synthesized from p-Anisic acid
(167.36 mg, 1.1 mmol) and acetic acid (57 µL, 1.0 mmol)
according to general procedure for curtius reaction. Off white
solid (85 mg, 51% yield); H-NMR (300 MHz, DMSO-d6) δ
(ppm) 9.77 (br, 1H), 7.47 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0
1
yield); H-NMR (300 MHz, CDCl3, mixture of two rotamers)
1
δ (ppm) 8.62 (d, J = 11.43 Hz, 1H), 8.32 (d, J = 1.14 Hz, 1H),
7.46-7.48b (br, 1H), 7.47 (d, J = 7.71 Hz, 2H), 7.25-7.32 (m,
4H), 7.00-7.15 (m, 5H).
Hz, 2H), 3.71 (s, 3H), 2.00 (s, 3H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
H
H
F
F
H
N
N
N
H
O
O
HO
Cl
1-(4-Chloro-3-
H3C
N-p-tolylformamide (2o).33a The title
(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (23).41 The
title compound was synthesized from 4-Hydroxybenzoic acid
compound was synthesized from p-Toulic acid (150 mg, 1.1
mmol) and Formic acid (38 µL, 1.0 mmol) according to
general procedure for curtius reaction. White solid (47 mg,
35% yield); 1H-NMR (300 MHz, CDCl3, mixture of two
rotamers) δ (ppm) 8.55 (d, J = 11.46 Hz, 1H), 8.26 (d, J =
1.59 Hz, 1H), 7.46 (br, 1H), 7.34 (d, J = 8.37 Hz, 2H), 7.06 (t,
J = 8.41 Hz, 4H), 6.91 (d, J = 8.31 Hz, 2H), 2.25/2.24(2s,
6H).
(151.93
mg,
1.1
mmol)
and
4-Chloro-3-
(trifluoromethyl)aniline (195.57 mg, 1.0 mmol) according to
general procedure for curtius reaction. White solid (222 mg,
67% yield); m.p. 210-215°C; 1H-NMR (300 MHz, DMSO-
d6) δ (ppm) 9.13 (br, 1H), 9.03 (br, 1H), 8.49 (br, 1H), 8.09 (s,
1H), 7.60 (d, J = 3.3 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 6.69
(d, J = 8.7 Hz, 2H).
H
N
H
F
F
H
H
F
F
N
N
O
H3CO
N-(4-methoxyphenyl)formamide (3o).33a
O
HO
Cl
1-(4-Chloro-3-
The title compound was synthesized from p-Anisic acid
(167.36 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol)
according to general procedure for curtius reaction. Colourless
(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea
(24). The title compound was synthesized from 2-Fluoro-4-
Hydroxybenzoic acid (262.26 mg, 1.68 mmol) and 4-Chloro-
3-(trifluoromethyl)aniline (300 mg, 1.53 mmol) according to
general procedure for curtius reaction. Off white solid (300
mg, 56% yield); m.p. 195-200ºC; 1H-NMR (300 MHz,
DMSO-d6) δ (ppm) 9.68 (br, 1H), 9.32 (br, 1H), 8.26 (br, 1H),
8.11 (s, 1H), 7.58-7.64 (m, 3H), 6.56-6.66 (m, 2H); 13C{1H}
NMR (75 MHz, DMSO-d6) δ 155.0, 154.8, 139.9, 132.4,
127.3, 125.0, 123.2, 118.1, 117.9, 116.9, 116.9, 111.4, 103.2,
102.9; HRMS (ESI-TOF) (m/z): [M+Na]+ Calcd for
C14H9ClF4N2O2Na 371.0186; Found 371.0170.
1
oil (79 mg, 52% yield); H-NMR (300 MHz, CDCl3, mixture
of two rotamers) δ (ppm) 8.48 (d, J = 11.6 Hz, 1H), 8.32 (s,
1H), 7.43 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 6.84-
6.90 (m, 4H), 3.78/3.79 (2s, 6H).
H
N
H
O
C2H5O
N-(4-ethoxyphenyl)formamide (4o).33a
The title compound was synthesized from 4-Ethoxybenzoic
acid (183 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol)
according to general procedure for curtius reaction. White
solid (61 mg, 37% yield); 1H-NMR (300 MHz, CDCl3,
mixture of two rotamers) δ (ppm) 8.49 (d, J = 11.52 Hz, 1H),
8.30 (d, J = 1.59 Hz, 1H), 8.07-8.10 ( br, 1H), 7.42 (d, J =
8.94 Hz, 2H+1NH), 7.01 (d, J = 8.85 Hz, 2H),6.85 (t, J = 8.41
Hz, 4H), 3.96-4.04 (m, 4H), 1.38-1.43 (m, 6H).
F
H
H
F
F
N
N
N
H
N
O
O
Cl
O
4-(4-(3-(4-chloro-3-
(trifluoromethyl)phenyl)ureido)phenoxy)-N-
methylpicolinamide (Sorafenib).42 The title compound was
synthesized from O-alkylation of compound 8 q (300 mg
0.907 mmol) with 4-chloro-N-methylpicolinamide (86 mg,
H
N
H
1
0.503 mmol). Off white solid (210 mg, 50% yield); H-NMR
O
N-(4-fluorophenyl)formamide (5o).33b The
F
(300 MHz, DMSO-d6) δ (ppm) 9.49 (br, 1H), 9.24 (br, 1H),
8.83 (d, J = 6.0 Hz, 1H), 8.51 (d, J = 6.0 Hz, 1H), 8.11 (s, 1H),
7.58-7.64 (m, 4H), 7.43 (d, J = 3.0 Hz, 1H), 7.17 (dd, J = 9.0
Hz, 3H).
title compound was synthesized from 4-Fluorobenzoic acid
(154.12 mg, 1.1 mmol) and Formic acid (38 µL, 1.0 mmol)
according to general procedure for curtius reaction. White
solid (32 mg, 32% yield); 1H-NMR (300 MHz, CDCl3) δ
(ppm) 8.58 (d, J = 11.4 Hz, 1H), 8.38 (d, J = 1.32 Hz, 1H),
7.88 (br, 1H), 7.50-7.55 (m, 2H), 7.02-7.10 (m, 6H).
ASSOCIATED CONTENT
Supporting Information Figure S1 to S4 and analytical spectral
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116, 12029-12122. (b) Pattabiraman, V. R.; Bode, J. W. Rethinking
data of all reported compounds is available as supporting
information
amide bond synthesis. Nature. 2011, 480, 471-479. (c) Valeur, E.;
Bradley, M. Amide bond formation: beyond the myth of coupling
reagents. Chem. Soc. Rev. 2009, 38, 606-631. (d) Lanigan, R. M.;
Sheppard, T. D. Recent Developments in Amide Synthesis: Direct
Amidation of Carboxylic Acids and Transamidation Reactions.
Eur. J. Org. Chem. 2013, 2013, 7453-7465.
AUTHOR INFORMATION
Corresponding Author
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(12) Sasaki, K.; Crich, D. Facile Amide Bond Formation from
Email:dinesh.mahajan@thsti.res.in; chemidinesh@gmail.com.
ACKNOWLEDGMENT
Carboxylic Acids and Isocyanates. Org. Lett. 2011, 13, 2256-2259.
(13) (a) Raoul, J. L.; Kudo, M.; Finn, R. S; Edeline, J.; Reig, M.; Galle,
P. R. Systemic therapy for intermediate and advanced
hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat.
Rev. 2018, 68, 16-24. (b) Finn, R. S. Review of Regorafenib for the
Authors acknowledged the support of THSTI for lab facility.
AK and NK acknowledge the support of DBT-BIRAC for
research fellowship under BIRAC CRS scheme,
BT/CRS0200/CRS -10/16. Authors also acknowledge the
support of GNDU Amritsar, for HRMS analysis and kind
facilitation by Prof Palwinder Singh for same.
Treatment of Hepatocellular Carcinoma. Gastroenterology
&
Hepatology. 2017, 13, 492-495. (c) Bankston, D.; Dumas, J.;
Natero, R.; Riedl, B.; Monahan, M. K.; Sibley, R. A Scaleable
Synthesis of BAY 43-9006:ꢀ A Potent Raf Kinase Inhibitor for the
Treatment of Cancer. Org. Proc. Res. Dev. 2002, 6, 777-781
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