Convenient One-Pot Two-Step Synthesis of Symmetrical and Unsymmetrical Diacyl Ureas, Acyl Urea/Carbamate/Thiocarbamate Derivatives, and Related Compounds

Article abstract of DOI:10.1055/s-0036-1588724

A wide range of chemicals such as amides, hydrazides, amines, alcohols, carbazate, and sulfonate were reacted with acyl isocyanates generated by the reaction of primary amides with oxalyl chloride to give symmetrical and unsymmetrical diacyl urea derivatives, acyl ureas/carbamates/thiocarbamates, and related compounds. This method provides means for convenient one-pot, two-step synthesis of compounds bearing urea, carbamate, and other functional groups from cheap and commercially available starting reagents. It is expected that the results presented in this report will expand the medicinal chemist’s toolbox.

Full text of DOI:10.1055/s-0036-1588724

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–N
paper
A
A. G. Hernandez et al.
Paper
Synthesis
Convenient One-Pot Two-Step Synthesis of Symmetrical and Un-
symmetrical Diacyl Ureas, Acyl Urea/Carbamate/Thiocarbamate
Derivatives, and Related Compounds
Anolan Garcia Hernandez
Gregory M. Grooms
Abir T. El-Alfy1
Jozef Stec*2
Chicago State University, College of Pharmacy, Department of
Pharmaceutical Sciences, 9501 S. King Drive, Chicago, IL
60628, USA
jstec@ketchum.edu
Dedicated to Professor Richard J. Whitby
Received: 19.12.2016
Accepted after revision: 27.01.2017
Published online: 21.02.2017
DOI: 10.1055/s-0036-1588724; Art ID: ss-2016-m0860-op
O
O
O
HO
C
N
NH2
O
NH2
C
NH
H
Amide (1)
Carbamate (2)
Urea (3)
Hydroxyl (4)
Abstract A wide range of chemicals such as amides, hydrazides,
amines, alcohols, carbazate, and sulfonate were reacted with acyl isocy-
anates generated by the reaction of primary amides with oxalyl chloride
to give symmetrical and unsymmetrical diacyl urea derivatives, acyl
ureas/carbamates/thiocarbamates, and related compounds. This meth-
od provides means for convenient one-pot, two-step synthesis of com-
pounds bearing urea, carbamate, and other functional groups from
cheap and commercially available starting reagents. It is expected that
the results presented in this report will expand the medicinal chemist’s
toolbox.
Figure 1 Nonclassical bioisosteres of amide bond: carbamate and urea
groups. Urea is also a bioisostere of the hydroxyl group.
Numerous drug molecules approved for the treatment
of various diseases contain carbamate moiety (Figure 2).5
Rivastigmine (5), for treatment of mild-to-moderate
Alzheimer’s disease (AD) dementia and dementia due to
Parkinson’s disease (PD); the anticonvulsant medication
felbamate (6); the antibiotic linezolid (7); and the anthel-
mintic agents albendazole (8) and mebendazole (9) repre-
sent only few examples of important medications that con-
Key words bioisostere, acyl isocyanates, symmetrical/unsymmetrical
diacyl ureas, acyl ureas, acyl carbamates, acyl thiocarbamates
Carbamate (urethane) 2 and urea 3 functional groups
share similarities in structural, electronic, and biologic
properties with amide (peptide) bond 1 (Figure 1). Both of
these groups are considered to be nonclassical bioisosteres
of amide bond, and in the case of urea – hydroxyl group 4 as
well (Figure 1).3 The overall physicochemical properties of
carbamate and urea linkers are often decisive not only to
the pharmacologic activity but also to the ADME/Tox (ab-
sorption, distribution, metabolism, excretion, and toxicity)
profile of compounds relevant to medicine and agriculture.
Bioisosteric replacement of functional groups is often used
to modulate the druggability of lead candidates by improv-
ing their potency, selectivity, metabolic stability, pharma-
cokinetic properties, and safety profile.4 Accordingly, carba-
mate and urea motifs are broadly utilized in medicinal
chemistry, drug discovery, and development process.
O
O
O
H2N
O
O
NH2
N
N
O
Rivastigmine (Exelon, 5)
Felbamate (Felbatol, 6)
O
N
O
O
O
N
NH
F
Linezolid (Zywox, 7)
O
O
O
H
N
H
N
S
O
O
NH
NH
N
N
Albendazole (Albenza, 8)
Mebendazole (Vermox, 9)
Figure 2 Examples of marketed drugs that contain carbamate moiety
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

B
A. G. Hernandez et al.
Paper
Synthesis
tain a carbamate moiety (Figure 2).5 Additionally, the use of
carbamates in the development of prodrugs cannot be over-
emphasized. Prodrug strategy is frequently employed to in-
crease the bioavailability of drug molecules and to improve
their overall ADME/Tox properties. Representative exam-
ples of carbamate-based prodrugs approved for clinical use
include the beta blocker bambuterol (10) used in the treat-
ment of asthma,5 the antihistamine agent loratadine (12),6
and the anticancer medication capecitabine (14)7 (Figure
3).
peutics and agrochemicals. The antineoplastic agent
sorafenib (19), the anthelmintic drug hetrazan (20), and the
antipsychotic medication cariprazine (21) represent phar-
maceuticals containing urea functionality (Figure 4).9
Cumyluron (22) and tebuthiuron (23) are herbicides that
also possess a urea linker (Figure 4).9
Furthermore, close derivatives of urea group such as hy-
droxyurea (antineoplastic, 24),10 nitrosourea in lomustine
(anticancer, 25),11 sulfonylurea in torsemide (diuretic, 26),12
acylated ureas in pheneturide (anticonvulsant, 27),13
bromisoval (hypnotic and sedative, 28),14 diflubenzuron
(insecticide, 29),15 and lufenuron (insecticide, 30)15b,16 are
decisive to the bioactivity of the aforementioned com-
Basic urea (18) is the end product of protein metabolism
that is excreted in the urine of ureotelic organisms (Figure
4).8 This chemical group is also present in various thera-
Figure 3 Carbamate group employed in the prodrug strategy
O
O
O
O
N
N
N
H
H2N
NH2
N
Cl
N
NH
Urea (18)
Sorafenib (Nexavar, 19)
Diethylcarbamazine
(Hetrazan, 20)
O
N
CF3
H
O
Cl
Cl
O
N
N
O
N
N
N
N
N
N
N
H
H
S
H
H
HN
Cl
Cumyluron (22)
Cariprazine (Vraylar, 21)
Tebuthiuron (23)
Figure 4 Urea motif present in important medications and agrochemicals
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

C
A. G. Hernandez et al.
Paper
Synthesis
O
O
O
NH
N
O
Cl
O O
O
S
N
N
N
N
NH2
HN
N
H
H
HO
H
N
NH2
O
H
Hydroxyurea
(Hydrea, 24)
Lomustine (Gleostine, 25)
Torsemide (Demadex, 26)
Pheneturide (Benuride, 27)
F
F
Cl
Cl
O
O
O
F
O
O
F
O
F
O
F
F
F
F
N
NH2
HN
N
HN
N
Cl
H
H
H
Br
F
Bromisoval (Brovarin, 28)
Diflubenzuron (29)
Lufenuron (30)
Figure 5 Modified urea group installed in drug molecules and agrochemicals
pounds (Figure 5). Ritonavir (31)17 is an approved antiviral
agent that contains both the carbamate and the urea groups
(Figure 6).
ploy various metal and non-metal reagents and raw materi-
als such as carbon monoxide, carbon dioxide, and methanol
(Scheme 4).5,21 Conversion of primary aliphatic amines and
carbon dioxide to urea derivatives in the absence of solvent
and catalyst was also reported.22
O
O
O
H
H
O
O
N
S
N
R1
R2
N
S
R1 NH2
R3
R2
N
N
N
O
R1
R
R
R
N
N
R3
H
H
N
O
O
O
H
O
OH
N
H
Scheme 3 Synthesis of carbamates and ureas from carbonates as the
starting materials
Ritonavir (Norvir, 31)
Figure 6 Structure of ritonavir
O
O
R
R1
R1
A plethora of synthetic protocols provide means for im-
plementation of carbamate or urea functional groups with-
in organic molecules. One of the oldest methods used to ac-
cess carbamates and ureas utilizes the harsh reagent phos-
gene (Scheme 1).18 Commonly adopted methods for
preparation of carbamates and ureas are based on the addi-
tion of alcohols and amines, respectively, to isocyanates
generated in situ or available commercially (Scheme 2).5,19
Newer methods utilize milder and less toxic phosgene sur-
rogates, carbonates, formamides, chloroformates, and other
reagents (Scheme 3).20 Most recent synthetic methods em-
R1
R2
X
X
R1 NH2
i.
R
N
N
R
NH2
N
R2
O
+
CO2
H
ii.
H (R2)
X = halogen
R1
R1 OH
NH
R2
R1 OH
O
R
R1 OH
R
R1
O
+ CO2
NH
R2
R
N3 + CO
R
NH2 + MeOH
N
H
Scheme 4 Exploitation of raw materials in the synthesis of substituted
carbamates and ureas
A simple diacetyl urea (ureide) was first prepared nearly
one and a half centuries ago by condensation of two equiva-
lents of acetamide with phosgene.23 Next, a stepwise ap-
proach to acyl urea, diacyl urea, and acyl carbamate was de-
veloped by reacting ammonia, amide, and alcohol, respec-
tively, with an acyl isocyanate that was generated via
O
O
O
1
R2
R1
i. R1 OH
2
R
NH2
R1
R1
N
R3
O
N
N
Cl
Cl
ii. R2
NH
H
H
R3
Scheme 1 Classic method for preparation of carbamates and ureas
O
Hofmann rearrangement
O
R
NH2
N3
R1 OH
R
R
R1
O
N
H
O
Curtius rearrangement
Lossen rearrangement
R
N C O
R
O
R1
O
R1 NH2
N
H
N
H
OH
R
NH
Scheme 2 Isocyanate-based method for the synthesis of carbamates and ureas
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

D
A. G. Hernandez et al.
Paper
Synthesis
reaction of acetyl chloride with the explosive mercury(II)
fulminate.23b,24 Modification25 of the initial method by re-
placing phosgene with oxalyl chloride provided diacyl
ureas; however, limitation of this method was observed.23b
Synthesis of symmetrical and unsymmetrical diacyl ureas
by the condensation of monoacyl ureas with acyl chlorides
and sulfuric acid as the catalyst was reported in 1938.23b
The use of oxalyl chloride in generating acyl isocyanates
from primary amides and their subsequent application to
synthesis of acyl ureas, acyl carbamates, and thiocarba-
mates as well as other compounds was extensively investi-
gated by Speziale and Smith.26 Symmetrical diaroyl ureas
can be prepared by the reaction of urea with aromatic acid
esters in the presence of sodium hydride.27 Alternatively,
treatment of urea with excess of acyl chloride in a DMAP–
pyridine solution affords a symmetrical diacyl urea deriva-
tive.28 Dye-induced photooxygenation of imidazolin-2-ones
also was shown to yield diacyl ureas.29 Method for the
preparation of diacyl ureas for use in agriculture from urea
and carboxylic acids was also reported.30 Metal-catalyzed
carbonylation of urea derivatives with aryl halides affords
aroyl ureas.31
O
O
O
R
N
N
R
H
H
35a–p
R = n-alkyl, Ar
O
O
O
O
O
R
NH2
R1
34
NH2
b)
R
N
N
R1
H
H
32
35q–v
R
1 = n-alkyl, Ar,
b)
O
CH=CHPh
O
O
(COCl)2
a)
O
C
N
R
NH2
R
32
H2N
36
NH2
33
O
R
O
O
N
N
NH2
O
b)
H
H
R2
37a,b
R = n-alkyl, Ar
H2N
O
b)
38
O
O
O
R2
R
N
H
N
O
H
R2 = Me, Et
39a,b
Herein we report optimization and scoping studies on
the addition of a wide range of nucleophiles 32, 34, 36, 38,
40, 42, 43, and 45 to acyl isocyanates 33 generated by the
reaction of primary amides 32 with oxalyl chloride
(Scheme 5). This method provides means for convenient
one-pot, two-step synthesis of symmetrical and unsym-
metrical diacyl urea derivatives, acyl ureas/carbamates/
thiocarbamates, and related compounds starting from
cheap and commercially available reagents (Scheme 5). The
obtained compounds are presented in Table 1.
Synthesis of the symmetrical 1,3-diaroyl ureas 35a–o
was efficient and provided the final products in yields rang-
ing from good to excellent (67–92%) (Scheme 5, Table 1).
Exception was the thiobenzamide, which did not provide
the thio analogue of 35a (results not shown).32 Lower yield
for the aliphatic diacyl urea 35p in comparison to aromatic
analogues is consistent with findings reported in the litera-
ture.26b The unsymmetrical acyl ureas 35q–v were obtained
in various yields. The aromatic compounds 35q and 35s
were obtained in very good yields, similarly to the mixed
aromatic-aliphatic counterparts 35u and 35v. For com-
pounds 35s, 35u, and 35v, the acyl isocyanates were gener-
ated from the corresponding benzamides. When the isocya-
nate was generated from nicotinamide (34a) followed by
the addition of benzamide (32a), the crude reaction mix-
ture consisted of several products; thus compound 35s was
neither isolated from that reaction nor the reaction for
symmetrical 1,3-dinicotinoyl urea was successful. The reac-
tion yield for compound 35r was slightly decreased due to
use of only 1.0 equivalent of p-chlorobenzamide. It is note-
worthy that the product 35r is a close analogue of di-
flubenzuron (29). The yield for 35t was compromised by
Scheme 5 Elaboration of acyl isocyanates 33 obtained from primary
amides 32. Reagents and conditions: a) i. 32 (1.0 mmol), anhyd CH2Cl2,
r.t., 5 min, ii. (COCl)2 (3.0 equiv) reflux 2.5–3 h, iii. r.t., in vacuo solvent
evaporation; b) nucleophile 32, 34, 36, or 38 (1.1–1.25 equiv), anhyd
toluene, reflux, 2.5–3 h.
difficult purification. In general, the reaction for unsym-
metrical diacyl ureas was rather capricious, often accompa-
nied by formation of a small amount of the symmetrical
product rendering the need for purification and/or adjust-
ment of equivalents of the nucleophile.
Addition of urea (36) to isocyanates generated from
amides 32a and 32p furnished the expected products 37a
and 37b, respectively (Scheme 5). The reverse reaction was
unsuccessful. Compound 37a was also obtained (87% yield)
when two equivalents of benzoyl isocyanate (33a; R = Ph,
prepared from 32a) were used with respect to one equiva-
lent of urea, thus indicating that the carbamoylation occurs
only at one site of the urea. This result differs from the re-
ported observation relating to the reaction of urea with
equimolar amounts of benzoyl isothiocyanate to provide
the thio analogue of 37a along with small quantities of the
diadduct.33 Attempts of reaction of product 37a with isocy-
anate 33a or benzoyl chloride were ineffective, presumably
due to insolubility of 37a in the reaction solvent (results
not shown). The concept of dicarbamoylation was further
investigated by attempting to generate diisocyanate from
4,5-dichlorophthalamide and further addition of 2 equiva-
lents of benzamide. This reaction failed due to the likely de-
composition of the diisocyanate during in vacuo evapora-
tion of dichloromethane.34 Instead of the desired product,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

E
A. G. Hernandez et al.
Paper
Synthesis
small amount of compound 35a (23%) was isolated from
this reaction. The reverse approach, namely addition of 4,5-
dichlorophthalamide to two equivalents of benzoyl isocya-
nate (33a) also did not occur and the starting material (4,5-
dichlorophthalamide) was isolated (73%). This reaction did
not proceed, likely due to steric hindrance factors. Addition
of succinamide to 2 equivalents of benzoyl isocyanate (33a)
was unproductive, which supported the initial observation
that under the present reaction conditions the dicarbamoy-
lation reaction is apparently ineffective. Conversion of suc-
cinamide to the corresponding diisocyanate was not pur-
sued due to the unsatisfactory results for this reaction re-
ported earlier.34
Table 1 Structural Formulas of the Reaction Substrates and Final Products
No
Starting amide
Nucleophile
Final product
Yield (%)
89
O
O
O
O
O
O
O
O
O
O
O
O
O
1
32a
32a
32b
32c
35a
N
H
N
H
NH2
NH2
NH2
NH2
NH2
NH2
OBn
OBn
OMe
O
O
OBn
OBn
OMe
O
2
3
4
5
6
32b
32c
32d
32e
32f
35b
85
N
H
N
H
OMe
OMe
35c
35d
35e
35f
88
N
H
N
H
O
O
O
O
32d
32e
32f
83a
70b
92
NH2
NH2
N
N
H
H
MeO
NO2
MeO
NO2
MeO
NO2
OMe
O
O
O
O
O
O
O
O
O
NO2
NH2
NH2
N
H
N
H
O
O
O
O2N
NO2
O2N
O2N
N
H
N
NH2
NH2
NH2
NH2
H
O
O
O
N
H
N
H
7
32g
32g
35g
67
O2N
O2N
O2N
NO2
O
O
O
O
O
8
9
32h
32i
32h
32i
35h
35i
83
82
90
93
N
H
N
H
NH2
NH2
O
O
O
O
O
O
O
O
NH2
NH2
N
H
N
H
O
O
10
11
32j
32j
35j
NH2
NH2
N
H
N
H
F
O
F
O
F
O
O
O
F
32k
32k
35k
NH2
NH2
N
H
N
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

F
A. G. Hernandez et al.
Paper
Synthesis
Table 1 (continued)
No
Starting amide
Nucleophile
Final product
Yield (%)
85
F
O
F
O
F
O
O
O
F
F
O
F
12
32l
32l
35l
NH2
N
N
H
NH2
H
F
F
O
O
O
O
F3C
F3C
F3C
CF3
13
14
32m
32m
32n
35m
35n
68
91
NH2
NH2
N
H
N
H
O
O
O
O
O
32n
N
N
NH2
NH2
H
H
Cl
Cl
Cl
Cl
O
O
O
O
O
15
16
17
32o
32o
32p
32m
35o
35p
35q
85
60
85
NH2
NH2
N
H
N
H
Ph
Ph
Ph
Ph
O
O
O
O
O
32p
n-C5H11
O2N
N
N
n-C5H11
n-C5H11
NH2
O
n-C5H11
NH2
O
H
H
O
O
O
O2N
F3C
CF3
32f
32l
32a
NH2
NH2
N
N
H
H
F
O
O
F
O
O
O
O
O
18
19
32n
34a
35r
35s
66c
88d
NH2
NH2
N
N
H
H
F
Cl
F
Cl
O
O
O
NH2
N
H
N
H
NH2
NH2
N
N
O
O
O
O
O
O
O
O
O
20
21
22
32a
32a
32d
34b
32p
32p
35t
35u
35v
69e/16f
NH2
N
H
N
H
O
72
NH2
N
H
N
H
n-C5H11
n-C5H11
NH2
O
O
O
O
O
86
NH2
N
N
H
n-C5H11
H
n-C5H11
NH2
MeO
MeO
O
O
O
O
O
23
24
32a
32p
36
36
37a
37b
87g
51f
NH2
N
H
N
NH2
H
H2N
NH2
NH2
O
O
O
O
O
n-C5H11
N
N
NH2
H2N
n-C5H11
NH2
H
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

G
A. G. Hernandez et al.
Paper
Synthesis
Table 1 (continued)
No
Starting amide
Nucleophile
Final product
Yield (%)
59h
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
25
32a
38a
38b
40a
40b
42
39a
NH2
NH2
NH2
NH2
NH2
NH2
N
H
N
H
OMe
H2N
H2N
OMe
O
26
27
28
29
30
31
32
33
32a
32a
32a
32a
32a
32a
39b
41a
41b
41c
44a
44b
55i
N
H
N
H
OEt
O
OEt
O
NH2
88
N
H
N
H
N
N
H
H
O
O
O
89j
NH2
N
H
N
H
N
H
n-C5H11
n-C5H11
N
H
O
O
O
O
83
NH2
N
H
N
H
N
H
O
O
N
H
O
O
NH2
NH
43a
43b
45a
45b
73
S
N
H
N
H
N
H
S
O
O
O
O
90
n-C7H15
S
ONa
NH2
O
N
H
O
S
n-C7H15
O
O
F
F
O
O
NH2
F
F
32q
46a
74k/34f
NH2
N
H
N
H
F
F
O
O
O
60f
NH2
32r
46b
NH2
N
H
N
H
O
O
O
O
O
NH2
O
O
34
32a
45c
46c
78
NH2
N
H
N
H
O
O
O
OH
35
36
37
32a
32a
32a
45d
45e
45f
46d
46e
46f
58
N
H
O
NH2
NH2
NH2
MeO
OMe
O
O
O
O
OMe
MeO
74f
79f
OH
N
H
O
O
OH
N
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

H
A. G. Hernandez et al.
Paper
Synthesis
Table 1 (continued)
No
Starting amide
Nucleophile
Final product
Yield (%)
92
O
O
O
O
O
O
n-C6H13
OH
n-C6H13
38
32a
45g
45h
46g
NH2
NH2
N
H
O
S
n-C6H13
90f
SH
39
32a
n-C6H13
46h
N
H
a 3 mmol scale reaction.
b After purification by crystallization from MeOH.
c 1 equivalent of p-chlorobenzamide (1 equiv) was used. The isolated crude product was still contaminated with ~5% of p-chlorobenzamide as determined by 1H
NMR spectroscopy.
d Isolated crude product contaminated with ~25% of an unknown by-product as determined by 13C NMR spectroscopy.
e Isolated crude product contaminated with cinnamide.
f After purification by flash chromatography.
g 2 mmol scale reaction with 1.0 equivalent of urea being used.
h 2 equivalents of methyl carbamate were used.
i Isolated crude product contaminated with ~20% of an unknown by-product as determined by 1H NMR spectroscopy.
j Contaminated with ~5% of unknown by-product as determined by 1H NMR spectroscopy.
k Isolated crude product contaminated with geranylamine as determined by 1H NMR spectroscopy.
Addition of methyl carbamate (38a) and ethyl carba-
mate (38b) to isocyanate 33a provided products 39a and
39b, respectively, in moderate yields and deteriorated puri-
ty for 39b (Scheme 5, Table 1). Reaction of isocyanate 33a
with hydrazides 40a, and 40b, tert-butyl carbazate (42),
and p-toluenesulfonyl hydrazide 43a provided in good
yields the expected products 41a,b, 41c, and 44a, respec-
tively (Scheme 6). Conversion of benzhydrazide (40a) to its
corresponding isocyanate and subsequent treatment with
benzamide resulted in a mixture of products, two of them
deemed to be the compounds 41a and 48a (entry 27, and
Scheme 7). Of note is the fact that the thio analogue of com-
pound 41a, that is, 1,4-dibenzoylthiosemicarbazide, was
previously obtained via reaction of equimolar amounts of
hydrazine hydrate with benzoyl isothiocyanate.35 An inter-
esting outcome was obtained when benzhydrazide (40a)
and p-toluenesulfonyl hydrazide (43a) were treated with
oxalyl chloride followed by the addition of 40a and 43a, re-
spectively (Scheme 7). In both cases, substitution reaction
occurred to provide the symmetrical products 48a and 48b
in good yields (Scheme 7). However, nucleophilic substitu-
tion reactions that occur in similar manner with oxalyl
chloride are known in the literature.34,36 In contrast, addi-
tion of 40a to 47b provided unidentified mixture of prod-
ucts.
ginine (results not shown). The unsatisfactory outcome of
addition of the amino acids to 33a is especially disappoint-
ing as similar reaction of acyl isothiocyanates with several
amino acids has been reported.37 Reaction of geranyl amine
O
O
H
N
R3
R
N
H
N
H
O
R3 = n-alkyl, Ar
41a,b
O
O
O
O
H2N
a)
tBu
H
H2N
N
H
R3
N
O
N
O
H
R
N
N
tBu
H
H
42
40
O
41c
a)
O
N
O
C
R
O
S
X
R4
33
O
O
O
O
43
R
N
X
S
R4
H
a)
O
Y
R5
44a,b
X = O, NHNH
R4 = n-alkyl, Ar
a)
O
45
O
R5
R
N
Y
H
Sodium 1-heptanesulfonate (43b) readily reacted with
33a to give the final product 44b in excellent yield (Scheme
6). Disappointingly, reactions of benzenesulfonamide with
33a resulted in a mixture of products that was not further
analyzed. Other compounds that were unproductively re-
acted with 33a include benzoic acid, sodium benzoate,
benzhydroxamic acid, dibutyl phosphate, diethyl phosphor-
amidate, and certain amino acids such as L-serine and L-ar-
46a–h
Y = NH, O, S
R
5 = n-alkyl, c-alkyl,
Bn, O-Bn, Ar,
CH2CH=CHPh
Scheme 6 Elaboration of acyl isocyanates 33. Reagents and conditions:
a) nucleophile 40, 42, 43, or 45 (1.1–1.25 equiv), anhyd toluene, reflux,
2.5–3 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

I
A. G. Hernandez et al.
Paper
Synthesis
O
O
O
O
X
X
Cl
N
N
X
NH
X
NH2
N
N
(COCl)2
40a or 43a
H
H
N
N
H
H
H
H
R
a)
b)
R
R
R
40a: X = CO, R = H
43a: X = SO2, R = Me
47a, 47b
48a: X = CO, R = H; 77%
48b: X = SO2, R = Me; 94%
Scheme 7 Reaction of oxalyl chloride with hydrazides 40a and 43a. Reagents and conditions: a) i. 40a or 43a (1.0 mmol), anhyd CH2Cl2, r.t., 5 min,
ii. (COCl)2 (3.0 equiv), reflux 2.5–3 h, iii. r.t., in vacuo solvent evaporation; b) 40a or 43a (1.1 equiv), anhyd toluene, reflux, 2–3 h.
(45a), 2-adamantylamine (45b), and O-benzylhydroxyl-
amine (45c) with the corresponding isocyanates 33q, 33r,
33a gave the final products 46a–c, respectively. The signifi-
cantly lower yield for 46a pertains to difficult purification
of the final product. Addition of various alcohols 45d–g and
a thiol 45h to 33a resulted in a range of benzoyl carbamates
46d–g and benzoyl thiocarbamate (46h), respectively. The
lower yield for 46d is assumed to be associated with the
lower nucleophilicity of phenol (45d) when compared to
the other alcohols 45e–g used in the reaction.
In conclusion, we have reported an optimized synthetic
procedure for the synthesis of a wide range of organic mol-
ecules 35, 37, 39, 41, 44, 46, 48 possessing diacyl urea; acyl
urea, acyl carbamate, acyl thiocarbamate, acyl semicarb-
azide; and other functional groups. Overall, the reaction is
efficient (high yielding) with conversion time of approxi-
mately six hours for both steps and straightforward isola-
tion of the crude materials. The isolated products were vir-
tually pure except for a few cases when crystallization or
automated flash chromatography purification method was
applied. The obtained final products are deemed to share
structural similarities with reported agents possessing an-
tibacterial and antiprotozoal activities.38 Accordingly, the
synthetic protocol is currently utilized in the synthesis of
compounds suitable for biological investigation. It is be-
lieved that the presented results will be of interest to the
broader audience of synthetic organic and medicinal chem-
ists.39
Synthesis of 35, 37, 39, 41, 44, 46, and 48; General Procedure
The appropriate amide 32a–p, benzhydrazide (40a), or p-toluenesul-
fonyl hydrazide (43a) (1.0 mmol, 1.0 equiv) was placed in a Schlenk
Kjeldahl reaction flask and the flask was evacuated/argon re-filled
three times. Subsequently, anhyd CH2Cl2 (25 mL) was added and the
mixture was stirred at r.t. for 10 min before dropwise addition of ox-
alyl chloride (3.0 mmol, 3.0 equiv) followed. The reaction mixture
was then stirred at reflux for 2.5–3.0 h before cooling to r.t. and the
solvent was evaporated in vacuo. Subsequently, the appropriate nuc-
leophile 32, 34, 36, 38, 40, 42, 43, or 45 (1.1–1.25 mmol, 1.1–1.25
equiv) was rapidly added and the flask was evacuated/argon re-filled
before anhyd toluene (12 mL) was added. The reaction mixture was
then stirred at reflux for 2.5–3 h before cooling to r.t. and concentra-
tion to about 1/3 of the initial volume on rotavapor. Hexane was add-
ed to the residue and the obtained precipitate (often sonicated) was
collected by filtration under reduced pressure to yield the crude
product. When necessary, the isolated material was purified either by
crystallization from MeOH or flash chromatography on silica gel with
hexane–EtOAc as the eluent.
N,N′-Carbonyldibenzamide (35a)
Milky-white solid; yield: 240 mg (89%).
1H NMR (400 MHz, DMSO-d6): δ = 11.84 (s, 2 H), 7.97–7.92 (dd, J = 7.4,
1.4 Hz, 4 H), 7.68–7.63 (t, J = 7.4 Hz, 2 H), 7.58–7.52 (t, J = 7.4 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.3 (2 C), 149.5 (C), 133.9 (2 ×
CH), 133.0 (2 C), 129.4 (4 × CH), 128.5 (4 × CH).
HRMS: m/z [M]+ calcd for C15H12N2O3: 268.0848; found: 268.0851.
N,N′-Carbonylbis[2-(benzyloxy)benzamide] (35b)
Off-white solid; yield: 410 mg (85%).
1H NMR (400 MHz, DMSO-d6): δ = 11.53 (s, 2 H), 7.67 (dd, J = 7.8, 1.4
Hz, 2 H), 7.51 (td, J = 7.9, 1.6 Hz, 2 H), 7.45–7.43 (m, 4 H), 7.29–7.21
(m, 8 H), 7.04 (t, J = 7.7 Hz, 2 H), 5.29 (s, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.0 (2 C), 156.6 (2 C), 148.7 (C),
136.8 (2 C), 134.5 (2 C), 131.4 (2 C), 129.0 (4 × CH), 128.5 (2 × CH),
128.0 (4 × CH), 122.6 (2 C), 121.5 (2 × CH), 114.2 (2 × CH), 70.5 (2 ×
CH2).
All reagents were purchased from Sigma-Aldrich and Fisher Scientific.
Anhyd toluene was purchased from Sigma-Aldrich whereas anhyd
CH2Cl2 was obtained by distillation over CaH2. 1H NMR and 13C NMR
spectra were recorded on a Jeol spectrometer at 400 and 100 MHz,
respectively. NMR spectra were reprocessed by ACD/NMR Processor
Academic Edition version 12.01. Standard abbreviations were used for
indicating multiplicity. HRMS experiments were performed on Agi-
lent 6224 Tof-MS instrument with a mixed chemical ionization/posi-
tive electrospray (CI/+ESI) mode. TLC was performed on Merck 60
F254 silica gel plates. Flash chromatography was performed using a
Biotage - Isolera™ system with pre-packed silica gel columns (Biotage
FLSH SNAP CRT SI 10, 25, or 50 grams).
HRMS: m/z [M]+ calcd for C29H24N2O5: 480.1685; found: 480.1691.
N,N′-Carbonylbis(2-methoxybenzamide) (35c)
Grey powder; yield: 288 mg (88%).
1H NMR (400 MHz, DMSO-d6): δ = 11.57 (s, 2 H), 7.78 (dd, J = 7.8, 1.4
Hz, 2 H), 7.56 (td, J = 7.8, 1.8 Hz, 2 H), 7.19 (d, J = 8.2 Hz, 2 H), 7.07 (t,
J = 7.6 Hz, 2 H), 3.93 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.7 (2 C), 157.8 (2 C), 148.8 (C),
134.8 (2 × CH), 131.5 (2 × CH), 121.8 (2 C), 121.4 (2 × CH), 112.9 (2 ×
CH), 56.6 (2 × OCH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

J
A. G. Hernandez et al.
Paper
Synthesis
HRMS: m/z [M]+ calcd for C17H16N2O5: 328.1059; found: 328.1064.
N,N′-Carbonylbis(3-methylbenzamide) (35j)
White crystalline product; yield: 268 mg (90%).
N,N′-Carbonylbis(4-methoxybenzamide) (35d)
1H NMR (400 MHz, DMSO-d6): δ = 11.79 (s, 2 H), 7.84 (d, J = 8.2 Hz, 4
H), 7.34 (d, J = 8.2 Hz, 4 H), 2.35 (s, 6 H).
White powder; yield: 820 mg (83% on a 3.0 mmol scale).
1H NMR (400 MHz, DMSO-d6): δ = 11.77 (s, 2 H), 7.96–7.91 (m, 4 H),
13C NMR (100 MHz, DMSO-d6): δ = 167.1 (2 C), 149.6 (C), 144.3 (2 C),
7.10–7.05 (m, 4 H), 3.82 (s, 6 H).
130.1 (2 C), 130.0 (4 × CH), 128.6 (4 × CH), 21.6 (2 × CH3).
13C NMR (100 MHz, DMSO-d6): δ = 166.5 (2 C), 163.8 (2 C), 149.7 (C),
HRMS: m/z [M]+ calcd for C17H16N2O3: 296.1161; found: 296.1166.
130.7 (4 × CH), 124.9 (2 C), 114.7 (4 × CH), 56.1 (2 × OCH3).
HRMS: m/z [M + H]+ calcd for C17H17N2O5: 329.1132; found: 329.1131.
N,N′-Carbonylbis(2-fluorobenzamide) (35k)
Milky-white powder; yield: 283 mg (93%).
N,N′-Carbonylbis(2-nitrobenzamide) (35e)
1H NMR (400 MHz, DMSO-d6): δ = 11.57 (s, 2 H), 7.76–7.68 (m, 2 H),
White powder; yield: 250 mg (70%).
7.67–7.57 (m, 2 H), 7.39–7.26 (m, 4 H).
1H NMR (400 MHz, DMSO-d6): δ = 11.29 (s, 2 H), 8.19 (d, J = 7.8 Hz, 2
13C NMR (100 MHz, DMSO-d6): δ = 164.7 (2 C), 159.8 (2 C, d, JC,F
=
H), 7.89–7.84 (m, 2 H), 7.76–7.68 (m, 4 H).
252.1 Hz), 148.8 (C), 135.1 (2 × CH, d, JC,F = 8.6 Hz), 131.1 (2 × CH),
125.4 (2 × CH, d, JC,F = 3.8 Hz), 122.4 (2 C, d, JC,F = 12.5 Hz), 117.0 (2 ×
CH, d, JC,F = 22.1 Hz).
HRMS: m/z [M]+ calcd for C15H10F2N2O3: 304.0659; found: 304.0668.
13C NMR (100 MHz, DMSO-d6): δ = 168.2 (2 C), 149.4 (C), 145.7 (2 C),
135.4 (2 × CH), 132.0 (2 × CH), 131.8 (2 C), 129.1 (2 × CH), 124.8 (2 ×
CH).
HRMS: m/z [M]+ calcd for C15H10N4O7: 358.0549; found: 358.0551.
N,N′-Carbonylbis(2,6-difluorobenzamide) (35l)
N,N′-Carbonylbis(3-nitrobenzamide) (35f)
Off-white powder; yield: 290 mg (85%).
1H NMR (400 MHz, DMSO-d6): δ = 11.39 (s, 2 H), 7.59 (m, 2 H), 7.21 (t,
J = 8.2 Hz, 4 H).
Off-white powder; yield: 330 mg (92%).
1H NMR (400 MHz, DMSO-d6): δ = 11.94 (s, 2 H), 8.71 (br s, 2 H), 8.51–
8.47 (m, 2 H), 8.34 (m, 2 H), 7.86 (t, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.6 (2 C), 159.2 (2 C, d, JC,F
=
13C NMR (100 MHz, DMSO-d6): δ = 165.6 (2 C), 149.2 (C), 148.4 (2 C),
134.7 (2 × CH), 134.6 (2 C), 131.3 (2 × CH), 128.2 (2 × CH), 123.4 (2 ×
CH).
250.1 Hz), 159.1 (2 C, d, JC,F = 250.2 Hz), 148.6 (C), 134.0 (2 × CH, t,
JC,F = 10.6 Hz), 113.8 (2 C, t, JC,F = 20.1 Hz), 112.8 (4 × CH, d, JC,F = 23.0
Hz).
HRMS: m/z [M]+ calcd for C15H8F4N2O3: 340.0471; found: 340.0474.
HRMS: m/z [M]+ calcd for C15H10N4O7: 358.0549; found: 358.0547.
N,N′-Carbonylbis[3-(trifluoromethyl)benzamide] (35m)
N,N′-Carbonylbis(4-nitrobenzamide) (35g)
White solid; yield: 275 mg (68%).
Off-white powder; yield: 240 mg (67%).
1H NMR (400 MHz, DMSO-d6): δ = 11.90 (s, 2 H), 8.24 (br s, 2 H), 8.21
(d, J = 7.8 Hz, 2 H), 8.03 (d, J = 7.8 Hz, 2 H), 7.81 (t, J = 7.8 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6): δ = 11.90 (s, 2 H), 8.37 (d, J = 8.7 Hz, 4
H), 8.13 (d, J = 8.7 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.1 (2 C), 149.3 (C), 134.1 (2 C),
132.6 (2 × CH), 130.8 (2 × CH), 130.3 (2 × CH, d, JC,F = 3.9 Hz), 130.1 (2
13C NMR (100 MHz, DMSO-d6): δ = 166.1 (2 C), 150.6 (2 C), 149.2 (C),
138.6 (2 C), 130.1 (4 × CH), 124.5 (4 × CH).
HRMS: m/z [M]+ calcd for C15H10N4O7: 358.0549; found: 358.0552.
C, q, JC,F = 32.3 Hz), 125.2 (2 × CH, d, JC,F = 3.8 Hz), 124.3 (2 × CH, q, JC,F
=
272.5 Hz).
HRMS: m/z [M]+ calcd for C17H10F6N2O3: 404.0596; found: 404.0598.
N,N′-Carbonylbis(2-methylbenzamide) (35h)
White powder; yield: 245 mg (83%).
1H NMR (400 MHz, DMSO-d6): δ = 11.40 (s, 2 H), 7.52 (d, J = 7.3 Hz, 2
H), 7.41 (t, J = 7.3 Hz, 2 H), 7.31–7.25 (m, 4 H), 2.37 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.8 (2 C), 149.2 (C), 136.9 (2 C),
134.8 (2 C), 131.7 (2 × CH), 131.6 (2 × CH), 128.0 (2 × CH), 126.4 (2 ×
CH), 20.1 (2 × CH3).
N,N′-Carbonylbis(4-chlorobenzamide) (35n)
White crystalline product; yield: 307 mg (91%).
1H NMR (400 MHz, DMSO-d6): δ = 11.80 (s, 2 H), 7.93 (d, J = 8.2 Hz, 4
H), 7.63 (d, J = 8.2 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.4 (2 C), 149.4 (C), 138.8 (2 C),
131.8 (2 C), 130.5 (4 × CH), 129.6 (4 × CH).
HRMS: m/z [M]+ calcd for C17H16N2O3: 296.1161; found: 296.1166.
HRMS: m/z [M]+ calcd for C15H10Cl2N2O3: 336.0068; found: 336.0072.
N,N′-Carbonylbis(3-methylbenzamide) (35i)
N,N′-Carbonylbis([1,1′-biphenyl]-4-carboxamide) (35o)
White crystalline product; yield: 242 mg (82%).
1H NMR (400 MHz, DMSO-d6): δ = 11.78 (s, 2 H), 7.77 (br s, 2 H), 7.73
(d, J = 7.3 Hz, 2H), 7.49–7.40 (m, 4 H), 2.36 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.3 (2 C), 149.5 (C), 138.9 (2 C),
134.5 (2 × CH), 133.0 (2 C), 129.3 (2 × CH), 129.0 (2 × CH), 125.6 (2 ×
CH), 21.4 (2 × CH3).
Milky-white solid; yield: 359 mg (85%).
1H NMR (400 MHz, DMSO-d6): δ = 11.92 (s, 2 H), 8.08–8.04 (m, 4 H),
7.89–7.85 (m, 4 H), 7.76–7.73 (m, 4 H), 7.51–7.46 (m, 4 H), 7.43–7.38
(m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.0 (2 C), 149.6 (C), 145.3 (2 C),
139.2 (2 C), 131.7 (2 C), 129.7 (4 × CH), 129.3 (4 × CH), 129.1 (2 × CH),
127.6 (8 × CH).
HRMS: m/z [M]+ calcd for C17H16N2O3: 296.1161; found: 296.1164.
HRMS: m/z [M]+ calcd for C27H20N2O3: 420.1474; found: 420.1474.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

K
A. G. Hernandez et al.
Paper
Synthesis
N,N′-Carbonyldihexanamide (35p)
1H NMR (400 MHz, DMSO-d6): δ = 11.82 (s, 1 H), 11.02 (s, 1 H), 7.85
(dd, J = 7.6, 1.4 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 2 H),
2.46–4.43 (m overlapped with DMSO, 2 H), 1.53 (quint, J = 7.3 Hz, 2
H), 1.29–1.18 (m, 4 H), 0.83 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.5 (C), 165.9 (C), 149.5 (C),
133.8 (CH), 133.2 (C), 129.5 (2 × CH), 128.2 (2 × CH), 36.7 (CH2), 31.1
(CH2), 24.2 (CH2), 22.4 (CH2), 14.3 (CH3).
White powder; yield: 153 mg (60%).
1H NMR (400 MHz, DMSO-d6): δ = 10.83 (s, 2 H), 2.47–2.44 (m over-
lapped with DMSO, 4 H), 1.49 (quint, J = 7.3 Hz, 4 H), 1.29–1.15 (m, 8
H), 0.82 (t, J = 6.9 Hz, 6 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.5 (2 C), 150.0 (C), 36.9 (2 ×
CH2), 31.1 (2 × CH2), 24.1 (2 × CH2), 22.4 (2 × CH2), 14.3 (2 × CH3).
HRMS: m/z [M]+ calcd for C14H18N2O3: 262.1317; found: 262.1324.
HRMS: m/z [M]+ calcd for C13H24N2O3: 256.1787; found: 256.1790.
N-(Hexanoylcarbamoyl)-4-methoxybenzamide (35v)
3-Nitro-N-{[3-(trifluoromethyl)benzoyl]carbamoyl}benzamide
(35q)
White crystalline product; yield: 252 mg (86%).
1H NMR (400 MHz, DMSO-d6): δ = 11.67 (s, 1 H), 11.04 (s, 1 H), 7.84
(d, J = 8.7 Hz, 2 H), 7.06 (d, J = 9.2 Hz, 2 H), 3.80 (s, 3 H), 2.47–2.44 (m
overlapped with DMSO, 2 H), 1.52 (quint, J = 7.3 Hz, 2 H), 1.30–1.20
(m, 4 H), 0.82 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.3 (C), 165.4 (C), 163.7 (C),
149.7 (C), 130.4 (2 × CH), 125.1 (C), 114.8 (2 × CH), 56.1 (CH3), 36.7
(CH2), 31.1 (CH2), 24.2 (CH2), 22.4 (CH2), 14.3 (CH3).
Off-white solid; yield: 325 mg (85%).
1H NMR (400 MHz, DMSO-d6): δ = 11.93 (br s, 2 H), 8.71 (m, 1 H), 8.48
(m, 1 H), 8.34 (m, 1 H), 8.25 (br s, 1 H), 8.22 (d, J = 7.8 Hz, 1 H), 8.04 (d,
J = 7.8 Hz, 1 H), 7.86 (t, J = 8.0 Hz, 1 H), 7.81 (t, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.2 (C), 165.6 (C), 165.5 (C),
149.3 (C), 148.4 (C), 134.7 (CH, q, JC,F = 4.8 Hz), 134.1 (C), 132.6 (CH),
131.3 (CH), 130.8 (CH), 130.3 (CH, d, JC,F = 2.9 Hz), 130.1 (C, q, JC,F
32.3 Hz), 128.2 (CH), 125.3 (CH, d, JC,F = 3.8 Hz), 124.3 (C, q, JC,F = 272.2
=
HRMS: m/z [M]+ calcd for C15H20N2O4: 292.1423; found: 292.1428.
Hz), 123.4 (CH).
N-(Carbamoylcarbamoyl)benzamide (37a)
HRMS: m/z [M]+ calcd for C16H10F3N3O5: 381.0573; found: 381.0567.
White powder; yield: 360 mg (87%).
N-[(4-Chlorobenzoyl)carbamoyl]-2,6-difluorobenzamide (35r)
1H NMR (400 MHz, DMSO-d6): δ = 11.34 (br s, 1 H), 10.25 (s, 1 H), 7.92
(dd, J = 7.6, 1.4 Hz, 2 H), 7.62 (t, J = 7.3 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 2 H),
7.45–7.33 (br s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.6 (C), 153.7 (C), 152.5 (C),
133.8 (CH2), 132.7 (C), 129.2 (2 × CH2), 128.8 (2 × CH2).
White solid; yield: 222 mg (66%).
1H NMR (400 MHz, DMSO-d6): δ = 11.66 (br s, 1 H), 11.41 (br s, 1 H),
7.90 (d, J = 8.2 Hz, 2 H), 7.64–7.57 (m, 1 H), 7.61 (d, J = 8.2 Hz, 2 H),
7.23 (t, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.5 (C), 161.7 (C), 159.2 (2 C, dd,
JC,F = 250.7, 7.2 Hz), 149.0 (C), 138.8 (C), 134.0 (CH, t, JC,F = 10.1 Hz),
131.7 (C), 130.6 (2 × CH), 129.9 (2 × CH), 114.0 (C, t, JC,F = 20.6 Hz),
112.9 (2 × CH, d, JC,F = 23.0 Hz).
HRMS: m/z [M]+ calcd for C9H9N3O3: 207.0644; found: 207.0644.
N-(Carbamoylcarbamoyl)hexanamide (37b)
Off-white solid; yield: 102 mg (51%).
HRMS: m/z [M]+ calcd for C15H9ClF2N2O3: 338.0270; found: 338.0275.
1H NMR (400 MHz, DMSO-d6): δ = 10.84 (s, 1 H), 10.08 (s, 1 H), 7.35 (s,
2 H), 2.33 (t, J = 7.3 Hz, 2 H), 1.48 (quint, J = 7.4 Hz, 2 H), 1.28–1.15 (m,
4 H), 0.82 (t, J = 6.9 Hz, 3 H).
N-(Benzoylcarbamoyl)nicotinamide (35s)
13C NMR (100 MHz, DMSO-d6): δ = 176.5 (C), 153.4 (C), 152.4 (C), 36.4
Off-white solid; yield: 236 mg (88%).
1H NMR (400 MHz, DMSO-d6): δ = 11.86 (br s, 1 H), 11.83 (br s, 1 H),
9.06 (d, J = 1.8 Hz, 1 H), 8.79 (dd, J = 4.8, 1.6 Hz, 1 H), 8.27 (m, 1 H),
7.95–7.92 (m, 2 H), 7.66 (m, 1 H), 7.61–7.53 (m, 3 H).
(CH2), 31.1 (CH2), 24.3 (CH2), 22.3 (CH2), 14.3 (CH3).
HRMS: m/z [M]+ calcd for C8H15N3O3: 201.1113; found: 201.1113.
13C NMR (100 MHz, DMSO-d6): δ = 166.8 (C), 166.7 (C), 154.0 (CH),
149.5 (CH), 149.4 (C), 136.5 (CH), 133.9 (CH), 133.0 (C), 129.5 (2 ×
CH), 129.0 (C), 128.4 (2 × CH), 124.3 (CH).
Methyl (Benzoylcarbamoyl)carbamate (39a)
White solid; yield: 131 mg (59%).
1H NMR (400 MHz, DMSO-d6): δ = 11.29 (s, 1 H), 10.94 (s, 1 H), 7.88
(d, J = 7.8 Hz, 2 H), 7.62 (t, J = 7.3 Hz, 1 H), 7.51 (s, 2 H), 3.68 (s, 3 H).
HRMS: m/z [M]+ calcd for C14H11N3O3: 269.0800; found: 269.0812.
13C NMR (100 MHz, DMSO-d6): δ = 167.3 (C), 153.1 (C), 149.1 (C),
133.8 (C), 132.9 (CH), 129.3 (2 × CH), 128.5 (2 × CH), 53.4 (OCH3).
N-(Cinnamoylcarbamoyl)benzamide (35t)
White solid; yield: 48 mg (16%).
HRMS: m/z [M]+ calcd for C10H10N2O4: 222.0641; found: 222.0646.
1H NMR (400 MHz, DMSO-d6): δ = 12.14 (br s, 1 H), 11.25 (br s, 1 H),
7.89 (d, J = 7.3 Hz, 2 H), 7.79 (d, J = 16.0 Hz, 1 H), 7.68–7.59 (m, 3 H),
7.56 (t, J = 7.6 Hz, 2 H), 7.44 (m, 3 H), 6.92 (d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.8 (C), 165.4 (C), 149.7 (C),
145.5 (CH), 134.4 (C), 133.8 (CH), 133.4 (C), 131.5 (CH), 129.7 (2 ×
CH), 129.6 (2 × CH), 128.9 (2 × CH), 128.1 (2 × CH), 120.0 (CH).
Ethyl (Benzoylcarbamoyl)carbamate (39b)
Off-white solid; yield: 131 mg (55%).
1H NMR (400 MHz, DMSO-d6): δ = 11.29 (s, 1 H), 10.89 (s, 1 H), 7.88
(d, J = 7.3 Hz, 2 H), 7.65–7.60 (m, 1 H), 7.57–7.49 (m, 2 H), 4.14 (q, J =
7.3 Hz, 2 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.4 (C), 152.5 (C), 149.1 (C),
133.8 (CH), 132.9 (CH), 129.3 (2 × CH), 128.5 (2 × CH), 62.3 (OCH2),
14.6 (CH3).
HRMS: m/z [M]+ calcd for C17H14N2O3: 294.1004; found: 294.1013.
N-(Hexanoylcarbamoyl)benzamide (35u)
White crystalline product; yield: 190 mg (72%).
HRMS: m/z [M]+ calcd for C11H12N2O4: 222.0641; found: 222.0646.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

L
A. G. Hernandez et al.
Paper
Synthesis
N,2-Dibenzoylhydrazine-1-carboxamide (41a)
1H NMR (400 MHz, DMSO-d6): δ = 10.81 (s, 1 H), 8.22 (t, J = 5.3 Hz, 1
H), 7.50–7.36 (m, 2 H), 5.18 (t, J = 6.6 Hz, 1 H), 5.03 (t, J = 6.9 Hz, 1 H),
3.76 (t, J = 6.2 Hz, 2 H), 2.04–1.92 (m, 4 H), 1.61–1.59 (m, 6 H), 1.52 (s,
3 H).
13C NMR (100 MHz, DMSO-d6): δ = 164.4 (C), 152.9 (C), 152.6 (C, ddd,
JC,F = 252.1, 9.6, 2.9 Hz), 149.0 (C, ddd, JC,F = 254.6, 10.5, 3.4 Hz), 139.4
(C, dt, JC,F = 250.2, 15.6 Hz), 138.5 (C), 131.5 (C), 125.3 (CH, dd, J = 8.6,
3.8 Hz), 124.4 (CH), 121.5 (C, overlapped d, JC,F = 2.9 Hz), 121.4 (CH),
113.5 (CH, dd, JC,F = 17.7, 3.4 Hz), 39.4 (CH2), 37.5 (CH2), 26.4 (CH2),
26.0 (CH3), 18.1 (CH3), 16.5 (CH3).
Pale yellow powder; yield: 248 mg (88%).
1H NMR (400 MHz, DMSO-d6): δ = 11.07 (s, 1 H), 10.62 (d, J = 1.4 Hz, 1
H), 10.13 (d, J = 1.4 Hz, 1 H), 7.97 (d, J = 7.3 Hz, 2 H), 7.87 (dd, J = 7.6,
1.4 Hz, 2 H), 7.62 (t, J = 7.3 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.52–7.46
(m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.6 (C), 166.0 (C), 154.3 (C),
133.6 (CH), 132.7 (2 C), 132.5 (CH), 129.1 (2 × CH), 129.0 (2 × CH),
128.8 (2 × CH), 128.1 (2 × CH).
HRMS: m/z [M]+ calcd for C15H13N3O3: 283.0957; found: 283.0961.
HRMS: m/z [M]+ calcd for C18H21F3N2O2: 354.1555; found: 354.1557.
N-Benzoyl-2-hexanoylhydrazine-1-carboxamide (41b)
N-[(Adamantan-2-yl)carbamoyl]adamantane-1-carboxamide
(46b)
White crystalline product; yield: 246 mg (89%).
1H NMR (400 MHz, DMSO-d6): δ = 10.98 (s, 1 H), 10.04 (d, J = 2.3 Hz, 1
H), 10.00 (d, J = 1.8 Hz, 1 H), 7.93 (d, J = 7.3 Hz, 2 H), 7.60 (t, J = 7.5 Hz,
1 H), 7.48 (t, J = 7.5 Hz, 2 H), 2.10 (t, J = 7.3 Hz, 2 H), 1.49 (quint, J = 7.2
Hz, 2 H), 1.29–1.16 (m, 4 H), 0.82 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.5 (C), 168.5 (C), 153.7 (C),
133.5 (CH), 132.7 (C), 129.1 (2 × CH), 128.8 (2 × CH), 33.5 (CH2), 31.3
(CH2), 25.2 (CH2), 22.4 (CH2), 14.4 (CH3).
White powder; yield: 212 mg (60%).
1H NMR (400 MHz, CDCl3): δ = 9.05 (s, J = 7.8 Hz, 1 H), 8.19 (s, 1 H),
3.99 (d, J = 8.2 Hz, 1 H), 2.06 (br s, 3 H), 1.93–1.82 (m, 16 H), 1.76–1.60
(m, 10 H).
13C NMR (100 MHz, CDCl3): δ = 179.8 (C), 153.2 (C), 54.1 (CH), 41.9
(C), 38.6 (3 × CH2), 37.6 (CH2), 37.1 (2 × CH2), 36.3 (3 × CH2), 32.2 (2 ×
CH), 32.0 (2 × CH), 28.0 (3 × CH), 27.3 (CH), 27.2 (CH).
HRMS: m/z [M]+ calcd for C14H19N3O3: 277.1426; found: 277.1422.
HRMS: m/z [M]+ calcd for C22H32N2O2: 356.2464; found: 356.2459.
tert-Butyl 2-(Benzoylcarbamoyl)hydrazine-1-carboxylate (41c)
N-[(Benzyloxy)carbamoyl]benzamide (46c)
White powder; yield: 231 mg (83%).
White powder; yield: 210 mg (78%).
1H NMR (400 MHz, DMSO-d6): δ = 10.91 (s, 1 H), 9.72 (s, 1 H), 8.97 (s,
1 H), 7.92 (d, J = 7.8 Hz, 2 H), 7.60 (t, J = 7.3 Hz, 1 H), 7.48 (t, J = 7.6 Hz,
2 H), 1.38 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.5 (C), 155.8 (C), 154.7 (C),
133.5 (CH), 132.7 (C), 129.1 (2 × CH), 128.8 (2 × CH), 80.0 (C), 28.6 (3 ×
CH3).
1H NMR (400 MHz, DMSO-d6): δ = 10.99 (s, 1 H), 10.84 (s, 1 H), 7.89
(d, J = 7.3 Hz, 2 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 2 H),
7.43–7.29 (m, 5 H), 4.87 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.8 (C), 153.8 (C), 136.3 (C),
133.4 (CH), 132.6 (C), 129.4 (2 × CH), 129.0 (2 × CH), 128.9 (3 × CH),
128.8 (2 × CH), 77.9 (CH2).
HRMS: m/z [M]+ calcd for C13H17N3O4: 279.1219; found: 279.1225.
HRMS: m/z [M]+ calcd for C15H14N2O3: 270.1004; found: 270.1008.
N-Benzoyl-2-tosylhydrazine-1-carboxamide (44a)
Phenyl Benzoylcarbamate (46d)
White powder; yield: 242 mg (73%).
Off-white solid; yield: 140 mg (58%).
1H NMR (400 MHz, DMSO-d6): δ = 10.93 (s, 1 H), 9.92 (s, 2 H), 7.87 (d,
J = 7.3 Hz, 2 H), 7.70 (d, J = 8.2 Hz, 2 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.48–
7.44 (m, 2 H), 7.37 (d, J = 8.2 Hz, 2 H), 2.35 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.6 (C), 153.6 (C), 144.3 (C),
135.9 (C), 133.7 (CH), 132.3 (C), 130.2 (2 × CH), 129.1 (2 × CH), 128.8
(2 × CH), 128.2 (2 × CH), 21.6 (CH3).
1H NMR (400 MHz, DMSO-d6): δ = 11.47 (s, 1 H), 7.92 (dd, J = 7.3, 1.4
Hz, 2 H), 7.61 (tt, J = 7.6, 1.4 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.45–7.40
(m, 2 H), 7.29–7.19 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.5 (C), 150.5 (C), 150.4 (C),
135.5 (C), 133.4 (CH), 130.1 (2 × CH), 129.0 (4 × CH), 126.5 (CH), 122.4
(2 × CH).
HRMS: m/z [M]+ calcd for C15H15N3O4S: 333.0783; found: 333.0787.
HRMS: m/z [M]+ calcd for C14H11NO3: 241.0739; found: 241.0743.
Benzoylcarbamic Heptane-1-sulfonic Anhydride (44b)
2,3-Dimethoxybenzyl Benzoylcarbamate (46e)
White solid; yield: 293 mg (90%).
White solid; yield: 233 mg (74%).
1H NMR (400 MHz, DMSO-d6): δ = 11.84 (s, 1 H), 7.94 (dd, J = 8.5, 1.1
Hz, 2 H), 7.65 (m, 1 H), 7.57–7.53 (m, 2 H), 2.33–2.29 (m, 2 H), 1.52–
1.45 (m, 2 H), 1.25–1.19 (m, 8 H), 0.81 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.3 (C), 149.5 (C), 133.9 (CH),
133.0 (C), 129.4 (2 × CH), 128.5 (2 × CH), 52.1 (SO2CH2), 31.7 (CH2),
29.1 (CH2), 28.9 (CH2), 25.7 (CH2), 22.6 (CH2), 14.5 (CH3).
1H NMR (400 MHz, DMSO-d6): δ = 11.02 (s, 1 H), 7.84–7.81 (m, 2 H),
7.56 (tt, J = 7.4, 1.4 Hz, 1 H), 7.46–7.43 (m, 2 H), 7.08–6.98 (m, 3 H),
5.15 (s, 2 H), 3.78 (s, 3 H), 3.74 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.4 (C), 152.9 (C), 152.0 (C),
147.4 (C), 133.7 (C), 133.1 (CH), 129.8 (C), 128.9 (4 × CH), 124.5 (CH),
121.9 (CH), 113.8 (CH), 62.5 (CH2), 60.9 (OCH3), 56.3 (OCH3).
HRMS: m/z [M]+ calcd for C15H21NO5S: 327.1140; found: 327.1138.
HRMS: m/z [M]+ calcd for C17H17NO5: 315.1107; found: 315.1108.
(E)-N-[(3,7-Dimethylocta-2,6-dien-1-yl)carbamoyl]-2,3,4-trifluo-
robenzamide (46a)
Cinnamyl Benzoylcarbamate (46f)
Off-white solid; yield: 224 mg (79%).
White solid; yield: 122 mg (34%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

M
A. G. Hernandez et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 11.03 (s, 1 H), 7.84 (m, 2 H), 7.57
(tt, J = 7.6, 1.4 Hz, 1 H), 7.49–7.41 (m, 4 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.24
(tt, J = 7.3, 2.3 Hz, 1 H), 6.74 (d, J = 16.0 Hz, 1 H) 6.39 (dt, J = 15.9, 6.0
Hz, 1 H), 4.78 (dd, J = 6.2, 1.2 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 166.4 (C), 152.0 (C), 136.4 (C),
134.0 (CH), 133.8 (C), 133.1 (CH), 129.3 (2 × CH), 128.9 (2 × CH), 128.9
(2 × CH), 128.6 (CH), 127.0 (2 × CH), 124.1 (CH), 65.8 (CH2).
References
(1) Current address: University of South Carolina, S. o. M. G., Green-
ville, SC 29605, USA.
(2) Current address: Marshall B. Ketchum University, C. o. P.,
Department of Pharmaceutical Sciences, 2575 Yorba Linda
Blvd., Fullerton, CA 82831, USA. Phone: +1 7148725711;
jstec@ketchum.edu.
(3) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
(4) Silverman, R. B.; Holladay, M. W. The Organic Chemistry of Drug
Design and Drug Action; Academic Press: San Diego, 2014, 62.
(5) Ghosh, A. K.; Brindisi, M. J. Med. Chem. 2015, 58, 2895.
(6) Simplício, A. L.; Clancy, J. M.; Gilmer, J. F. Molecules 2008, 13,
519.
HRMS: m/z [M]+ calcd for C17H15NO3: 281.1052; found: 281.1056.
Hexyl Benzoylcarbamate (46g)
White solid; yield: 229 mg (92%).
1H NMR (400 MHz, CDCl3): δ = 8.11 (br s, 1 H), 7.86–7.78 (m, 2 H),
7.57 (tt, J = 7.6, 1.6 Hz, 1 H), 7.49–7.44 (m, 2 H), 4.21 (t, J = 6.9 Hz, 2 H),
1.71–1.64 (m, 2 H), 1.40–1.23 (m, 6 H), 0.87 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.9 (C), 151.2 (C), 133.1 (C), 133.1
(CH), 129.0 (2 × CH), 127.7 (2 × CH), 66.7 (OCH2), 31.5 (CH2), 28.6
(CH2), 25.5 (CH2), 22.6 (CH2), 14.1 (CH3).
(7) Blum, J. L. Oncologist 2001, 6, 56.
(8) Tymoczko, J. L.; Berg, J. M.; Stryer, L. Biochemistry: A Short
Course; W. H. Freeman and Company: New York, 2015, 526.
(9) Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Granat, D. S.;
Pipko, S. E.; Konovets, A. I.; Doroschuk, R.; Tolmachev, A. ACS
Comb. Sci. 2014, 16, 303.
HRMS: m/z [M]+ calcd for C14H19NO3: 249.1365; found: 249.1366.
(10) Roche, V. F. In Foye’s Principles of Medicinal Chemistry; Lemke, T.
L.; Williams, D. A.; Roche, V. F.; Zito, S. W., Eds.; Walters Kluwer
Health/Lippincott Williams & Wilkins: Baltimore, 2013, 1243.
(11) (a) Ishikawa, S.; Mochizuki, M. Genes Environ. 2007, 29, 1.
(b) Roche, V. F. In Foye’s Principles of Medicinal Chemistry;
Lemke, T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W., Eds.;
Walters Kluwer Health/Lippincott Williams & Wilkins: Balti-
more, 2013, 1215.
(12) Harvison, P. J.; Rankin, G. O. In Foye’s Principles of Medicinal
Chemistry; Lemke, T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W.,
Eds.; Walters Kluwer Health/Lippincott Williams & Wilkins:
Baltimore, 2013, 740.
S-Hexyl Benzoylcarbamothioate (46h)
White solid; yield: 238 mg (90%).
1H NMR (400 MHz, DMSO-d6): δ = 11.68 (s, 1 H), 7.88 (dd, J = 8.5, 1.1
Hz, 2 H), 7.59 (m, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 2.79 (t, J = 7.3 Hz, 2 H),
1.52 (quint, J = 7.3 Hz, 2 H), 1.35–1.23 (m, 6 H), 0.82 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 170.6 (C), 166.8 (C), 133.5 (CH),
132.7 (C), 129.1 (2 × CH), 128.8 (2 × CH), 31.3 (CH2), 29.3 (CH2), 29.2
(CH2), 28.5 (CH2), 22.5 (CH2), 14.5 (CH3).
HRMS: m/z [M]+ calcd for C14H19NO2S: 265.1136; found: 265.1127.
(13) Gallagher, B. B. In Anticonvulsants; Vida, J., Ed.; Academic Press:
New York, 1977, 42.
(14) Saam, E. US Patent 914518A, 1909.
(15) (a) Diflubenzuron. WHO Specifications and Evaluations for
Public Health Pesticides; 2006; http://www.who.int/whopes/
quality/diflubenzuron_eval_march_2006.pdf. (b) Pete, U. D.;
Zade, C. M.; Bhosale, J. D.; Tupe, S. G.; Chaudhary, P. M.;
Dikundwar, A. G.; Bendre, R. S. Bioorg. Med. Chem. Lett. 2012, 22,
5550.
N′1,N′2-Dibenzoyloxalohydrazide (48a)
Pale yellow solid; yield: 251 mg (77%).
1H NMR (400 MHz, DMSO-d6): δ = 10.82 (s, 2 H), 10.49 (s, 2 H), 7.86
(dd, J = 7.7, 1.8 Hz, 4 H), 7.57 (t, J = 7.3 Hz, 2 H), 7.49 (t, J = 7.6 Hz, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.7 (2 C), 159.1 (2 C), 132.7 (2 C),
132.5 (2 × CH), 129.1 (4 × CH), 128.0 (4 × CH).
HRMS: m/z [M]+ calcd for C16H14N4O4: 326.1015; found: 326.1010.
(16) Lufenuron. FAO Specifications and Evaluations for Agricultural
Pesticides; 2008; http://www.fao.org/fileadmin/templates/
agphome/documents/Pests_Pesticides/Specs/Lufenuron08.pdf.
(17) Woster, P. M. In Foye’s Principles of Medicinal Chemistry; Lemke,
T. L.; Williams, D. A.; Roche, V. F.; Zito, S. W., Eds.; Walters
Kluwer Health/Lippincott Williams & Wilkins: Baltimore, 2013,
1298.
(18) (a) Babad, H.; Zeiler, A. G. Chem. Rev. 1973, 73, 75. (b) Bigi, F.;
Maggia, R.; Sartori, G. Green Chem. 2000, 2, 140. (c) Kreye, O.;
Mutlua, H.; Meier, M. A. R. Green Chem. 2013, 15, 1431.
(19) (a) Dubé, P.; Nathel, N. F.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org.
Lett. 2009, 11, 5622. (b) El Dine, T. M.; Chapron, S.; Duclos, M.-
C.; Duguet, N.; Popowycz, F.; Lemaire, M. Eur. J. Org. Chem. 2013,
5445.
(20) (a) Zadeh, E. H. G.; Abo-Dya, N. E.; Sotuyo, A. C.; Ghiviriga, I.;
Hall, C. D. Tetrahedron Lett. 2013, 54, 5467. (b) Spyropoulos, C.;
Kokotos, C. G. J. Org. Chem. 2014, 79, 4477. (c) Han, C.; Porco, J.
A. Jr. Org. Lett. 2007, 9, 1517.
(21) (a) Yoshida, M.; Hara, N.; Okuyama, S. Chem. Commun. 2000,
151. (b) Kim, S. H.; Hong, S. H. Org. Lett. 2016, 18, 212. (c) Sun,
D.-L.; Ye, J.-H.; Fang, Y.-X.; Chao, Z.-S. Ind. Eng. Chem. Res. 2016,
N′1,N′2-Bis[(4-methylphenyl)sulfonyl]ethanedihydrazide (48b)
Milky-white solid; yield: 400 mg (94%).
1H NMR (400 MHz, DMSO-d6): δ = 10.82 (d, J = 2.8 Hz, 2 H), 9.90 (d, J =
3.2 Hz, 2 H), 7.60 (d, J = 8.2 Hz, 4 H), 7.32 (d, J = 7.8 Hz, 4 H), 2.34 (s, 6
H).
13C NMR (100 MHz, DMSO-d6): δ = 158.6 (2 C), 143.9 (2 C), 136.8 (2 C),
129.9 (4 × CH), 128.1 (4 × CH), 21.6 (2 × CH3).
HRMS: m/z [M]+ calcd for C16H18N4O6S2: 426.0668; found: 426.0673.
Acknowledgment
All authors acknowledge CSU COP (summer research training for AGH
and GMG) and CSU CTRE (Seed Grant) for generous financial
support of this project. The unlimited access to the NMR facility (JEOL
400) in the Department of Chemistry at CSU is acknowledged. Sarah
Cramer is acknowledged for the assistance with analyzing the NMR
spectra.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

N
A. G. Hernandez et al.
Paper
Synthesis
55, 64. (d) Shi, F.; Deng, Y.; SiMa, T.; Peng, J.; Gu, Y.; Qiao, B.
Angew. Chem. Int. Ed. 2003, 42, 3257. (e) Díaz, D. J.; Darko, A. K.;
McElwee-White, L. Eur. J. Org. Chem. 2007, 4453.
(27) Wolfe, J. F.; Trimitsis, G. B. Can. J. Chem. 1969, 47, 2097.
(28) Kanji Kubo, K.; Moriy, A. Chem. Lett. 2005, 34, 1250.
(29) Chawla, H. M.; Pathak, M. Tetrahedron 1990, 46, 1331.
(30) Dean, F. W. US Patent 6448440 B1, 2004.
(31) Bjerglund, K.; Lindhardt, A. T.; Skrydstrup, T. J. Org. Chem. 2012,
77, 3793.
(22) Wu, C.; Cheng, H.; Liu, R.; Wang, Q.; Hao, Y.; Yua, Y.; Zhao, F.
Green Chem. 2010, 12, 1811.
(23) (a) Schmidt, E. J. Prakt. Chem. 1872, 5, 63. (b) Stoughton, R. W.;
Diacylureas, I. J. Org. Chem. 1938, 2, 514.
(32) Cohen, V. I. J. Org. Chem. 1974, 39, 3043.
(24) (a) Scholl, R. Ber. Dtsch. Chem. Ges. 1890, 23, 3516. (b) Meyer, V.;
Jacobson, P. Lehrbuch der Organischen Chemie: Allgemeiner Theil;
Veit & Comp: Leipzig, 1893, 1013–1014. (c) Bayer & Co. German
Patent 286 760, 1913; Chem. Abstr. 1916, 10, 1579
(25) Bornwater, J. T. Rec. Trav. Chim. Pays-Bas 1912, 31, 105.
(26) (a) Speziale, A. J.; Smith, L. R. J. Org. Chem. 1962, 27, 3742.
(b) Speziale, A. J.; Smith, L. R.; Fedder, J. E. J. Org. Chem. 1965, 30,
4306. (c) Speziale, A. J.; Smith, L. R. US Patent 3213135, 1965.
(d) Speziale, A. J.; Smith, L. R. Org. Synth. 1966, 46, 16.
(e) Speziale, A. J.; Smith, L. R. J. Org. Chem. 1963, 28, 1805.
(f) Speziale, A. J.; Smith, L. R.; Fedder, J. E. J. Org. Chem. 1965, 30,
4303. (g) Smith, L. R.; Speziale, A. J.; Fedder, J. E. J. Org. Chem.
1969, 34, 633.
(33) Basyouni, M. N.; El-Khamry, A.-M. Bull. Chem. Soc. Jpn. 1979, 52,
3728.
(34) Otohiko, T.; Tadashi, I.; Masashi, T. Tetrahedron 1968, 24, 2583.
(35) (a) Hoggarth, E. J. Chem. Soc. 1949, 1160. (b) Durant, G. J.
J. Chem. Soc. C 1967, 92.
(36) (a) Nenitzescu, C. D.; Necsoiu, I.; Zalman, M. Comun. Acad. Rep.
Populare Romine 1958, 8, 659; Chem. Abstr. 1959, 53, 17092.
(b) McDonald, R. J. Org. Chem. 1959, 24, 1580.
(37) Elmore, D. T.; Ogle, J. R. J. Chem. Soc. 1958, 1141.
(38) Stec, J.; Huang, Q.; Pieroni, M.; Kaiser, M.; Fomovska, A.; Mui, E.;
Witola, W.; Bettis, S.; McLeod, R.; Brun, R.; Kozikowski, A. P.
J. Med. Chem. 2012, 55, 3088.
(39) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N