Synthesis, characterization, and reactivity of N -Acyl chloroformamidines: Useful building blocks for the construction of N-acyl-substituted 1,1-diaminoethylenes, amidines, ureas, and thioureas

Article abstract of DOI:10.1055/s-0032-1316833

The systematic synthesis of a series of N-acyl chloroform-amidines is achieved by reaction of carbodiimides with acid chlorides; the structure of an N-acyl chloroformamidine was confirmed by X-ray diffraction. The reactivity of N-acyl chloroformamidines t

Full text of DOI:10.1055/s-0032-1316833

PAPER
▌347
paper
Synthesis, Characterization, and Reactivity of N-Acyl Chloroformamidines:
Useful Building Blocks for the Construction of N-Acyl-Substituted
1,1-Diaminoethylenes, Amidines, Ureas, and Thioureas
Synthesis and Reactivity of N-Acyl Chloroformamidines
Yang Wang,a Yue Chi,a Fei Zhao,a Wen-Xiong Zhang,*a,b Zhenfeng Xia
a
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University, Beijing 100871, P. R. of China
b
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Fax +86(10)62751708; E-mail: wx_zhang@pku.edu.cn
Received: 23.10.2012; Accepted after revision: 03.12.2012
acyl chloroformamidine for the first time (Scheme 1). In
Abstract: The systematic synthesis of a series of N-acyl chloroform-
this process, the activation of the carbodiimide by an acid
amidines is achieved by reaction of carbodiimides with acid chlo-
chloride changed the course of the reaction. Very recently,
we found that acyl dichlorides, such as oxalyl and malonyl
rides; the structure of an N-acyl chloroformamidine was confirmed
by X-ray diffraction. The reactivity of N-acyl chloroformamidines
towards diethyl malonate, phenylethynyllithium, pentane-2,4-di- chlorides, serve not only as the third component, but also
one, methyl acetoacetate, water, 1,3-dimethylurea, 1,3-dimethyl-
thiourea, and sodium hydrosulfide, resulted in unique protocols for
the synthesis of N-acyl-substituted 1,1-diaminoethylenes, amidines,
under metal-free conditions to provide cyclic dioxoguani-
ureas, and thioureas, respectively. These results show that N-acyl
chloroformamidines have a good ability to accept nucleophilic at-
as the activator of carbodiimides in one-pot sequential re-
action of amines, carbodiimides, and acyl dichlorides
dines.9 Although N-acyl chloroformamidines are poten-
tially very useful, they are rarely involved in organic
synthesis.
tack for the construction of useful N-containing compounds.
Key words: carbodiimide, N-acyl chloroformamidine, 1,1-diami-
As an extension of carbodiimide chemistry,4a,d,8,9,11 we
here report the synthesis of various substituted N-acyl
chloroformamidines by reaction of carbodiimides with
acid chlorides, and subsequent reactions of the N-acyl
chloroformamidines, which provide unique protocols for
the synthesis of different important classes of nitrogen-
containing compounds, such as N-acyl-substituted 1,1-di-
aminoethylenes, amidines, ureas, and thioureas (Scheme
1).10
noethylene, amidine, urea
Carbodiimides (RN=C=NR) have proved, over the last
130 years, to be versatile reagents and they rank as one of
the most important classes of sources of nitrogen in organ-
ic chemistry.1 Their use as condensing agents in the fields
of peptides, nucleotides, and polymeric materials synthe-
sis has remained of particular significance since the start
of carbodiimide chemistry. More systematic studies to-
wards wide applications of carbodiimides in organic syn-
thesis are of more recent origin.2–5 Generally, reactions
initiated with carbodiimide can take place at two classical
reactive sites: the electrophilic carbon center and the un-
saturated C=N bonds. Although the central carbon atom
has a good ability to accept nucleophilic attack, to some
extent, the reactivity is not satisfying when weak nucleo-
philes are utilized. Thus, enhancing the electrophilicity of
the carbodiimide using new activation methods is an im-
portant issue.
O
R1
N
C
N
R2
R2
S
N
R3
previous work
+
O
N
R
R
Li
R3
Cl
R1
+
S8
O
N
O
N
R3
R3
1,1-diamino-
ethylene
R2
R2
O
H
urea
R3
N
C
HN
C
N
R2
CR5R6
O
R1
R1
O
N
C
O
R3
R3
R1
Cl
N-acyl
chloroformamidine
R2
N
R2
amidine
thiourea
N
S
N
C
HN
R1
C
R4
Early attempts to react carbodiimides with acid chloride
were carried out, however, the exact structure of the ad-
duct formed on reaction of an carbodiimide with an acid
chloride was ambiguous.6,7 In 2011, in the course of per-
forming convergent tandem annulation involving terminal
alkynes, sulfur, carbodiimides, and acid chlorides to yield
5-acyl-2-iminothiazolines,8 we identified the intermediate
adduct of the carbodiimide with an acid chloride as an N-
R1
Scheme 1 N-Acyl chloroformamidines as useful building blocks
Various N-acyl chloroformamidines 1 were obtained by
the reaction of carbodiimides with acid chlorides at room
temperature for 48 hours. Summarized in Table 1 are rep-
resentative results for the formation of N-acyl chlorofor-
mamidines 1a–r. Symmetric carbodiimides R1N=C=NR2
(R1 = R2 = i-Pr, Cy, Ph) were examined as suitable nitro-
gen sources in their reactions with acid chlorides. When
an unsymmetrical carbodiimide, N-tert-butyl-N′-ethylcar-
SYNTHESIS 2013, 45, 0347–0354
Advanced online publication: 12.12.2012
DOI: 10.1055/s-0032-1316833; Art ID: SS-2012-H0834-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

348
Y. Wang et al.
PAPER
bodiimide (t-BuN=C=NEt), reacted with 4-chlorobenzoyl These N-acyl chloroformamidines 1a–r were character-
chloride, compound 1q was obtained as the sole regioiso- ized by 1H and 13C NMR, IR, and HRMS. The structure of
mer in 93% yield. Because of the steric hindrance by the 1a was confirmed by single crystal X-ray analysis (Figure
tert-butyl group, the nitrogen atom adjoining the ethyl 1).
group of the carbodiimide is regioselectively attached to
the carbon atom of the carbonyl C=O bond in 1q; N-cyclo-
hexyl-N′-phenylcarbodiimide (CyN=C=NPh) showed
similar, good regioselectivity, providing 1r in quantitative
yield.8 A wide range of aromatic benzoyl chlorides with
both electron-donating and electron-withdrawing groups
furnished the corresponding N-acyl chloroformamidines
1a,b,d–k,p–r in excellent yields. The heteroaromatic acid
chloride, 2-thienylcarbonyl chloride was also an appropri-
ate substrate, giving 1l in 92% yield. Besides, cyclic ali-
phatic acid chlorides, benzoyl chloride and linear aliphatic
acid chlorides also acted as suitable acyl sources to gener-
ate the corresponding products 1c,m–o.
Figure 1 ORTEP drawing of 1a with 30% thermal ellipsoids. Hy-
drogen atoms are omitted for clarity. Selected bond lengths [Å]: C4–
Cl1 1.787(4), C4–N1 1.405(4), C4–N2 1.244(4), C2–N2 1.471(5),
C8–N1 1.382(4), C5–N1 1.493(4), C8–O1 1.213(4).
Table 1 Formation of N-Acyl Chloroformamidinesa,b
O
R3
O
N
R2
R1
N
C
N
R2
+
After the successful synthesis and characterization of N-
acyl chloroformamidines, subsequent efforts were used to
examine their reactivity. N-Acyl chloroformamidines
were first used to construct N-acyl-substituted 1,1-diami-
noethylenes. Initially, we expected that treatment of N-
acyl chloroformamidine 1a with diethyl malonate and so-
dium hydride would provide N-acyl amidines 2. However,
the tautomeric N-acyl-substituted 1,1-diaminoethylene 3a
was obtained in 77% yield under these mild reaction con-
ditions (Table 2). Both N-acyl chloroformamidines 1m
and 1q were used in this reaction affording N-acyl-substi-
tuted 1,1-diaminoethylenes 3b and 3c in moderate isolat-
ed yields. To the best of our knowledge, there are no
previous reports of the synthesis of N-acyl-substituted
1,1-diaminoethylenes. From this point of view, research
into the synthesis of different types of 1,1-diaminoethyl-
ene derivatives is still in demand.
THF, r.t., 48 h
R3
Cl
N
C
R1
Cl
1a–r
Product
R1
R2
R3
Yield (%)
1a
1b
1c
1d
1e
1f
i-Pr
i-Pr
i-Pr
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Ph
i-Pr
i-Pr
i-Pr
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Cy
Ph
4-F3CC6H4
Ph
99
99
98
99
96
97
81
92
99
98
82
92
85
85
95
89
93
99
Cy
Ph
4-MeOC6H4
3-MeC6H4
2-MeC6H4
4-PhC6H4
4-ClC6H4
4-F3CC6H4
4-O2NC6H4
2-thienyl
Bn
1g
1h
1i
Table 2 Formation of N-Acyl-Substituted 1,1-Diaminoethylenes
1j
O
R3
1) NaH, THF
0 °C, 15 min
1k
1l
O
H
O
H
N
R2
+
EtO
OEt
2) 0 °C, 1 h
3) r.t., 24 h
N
C
R1
Cl
1
1m
1n
1o
1p
1q
1r
O
O
R3
R3
Pr
R2
COOEt
N
R2
1,3-H shift
N
H
N
C
N
C
COOEt
COOEt
(CH2)5Me
4-F3CC6H4
4-ClC6H4
4-F3CC6H4
R1
R1
H
COOEt
2
3a–c
Product
R1
R2
R3
Yield (%)
t-Bu
Cy
Et
Ph
3a
3b
3c
i-Pr
Cy
i-Pr
Cy
Et
Ph
77
70
66
a Conditions: carbodiimide (1 mmol), acid chloride (1 mmol), THF
Bn
(10 mL).
b Isolated yield.
t-Bu
4-ClC6H4
Synthesis 2013, 45, 347–354
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Reactivity of N-Acyl Chloroformamidines
349
Secondly, N-acyl chloroformamidine 1a was used to syn- two ester-carbonyl groups in 3a–c prefers to tautomerize
thesize an N-acylamidine. When phenylethynyllithium to the more stable 1,1-diaminoethylenes.
was used as the nucleophile in the reaction with 1a, N-acyl
Thirdly, we examined hydrolysis reaction of N-acyl chlo-
propiolamidine 4a was obtained in 87% yield. Interesting-
roformamidine. The reaction of N-acyl chloroformami-
ly, in the presence of a catalytic amount of copper(I) io-
dine 1a with one equivalent of water in tetrahydrofuran at
room temperature for three hours afforded N-acylurea 5 in
quantitative yield. Interestingly, N-acylurea 5 was also
dide and two equivalents of triethylamine, the reaction
between 1a and phenylacetylene in tetrahydrofuran pro-
vided 4a in 79% yield (Scheme 2). Although Xu proposed
obtained by reaction of 1a with 1,3-dimethylurea. The de-
an N-acyliminium salt as the possible intermediate in the
oxygenation of 1,3-dimethylurea provides a potential ap-
copper-catalyzed three-component reaction of carbodi-
plication of N-acyl chloroformamidine (Scheme 3). To
imides, acid chlorides, and alkynes giving propiolami-
date, N-acylureas can be prepared by several methods.12
dines,7 based on our results, we propose that an N-acyl
Our method shows a novel and concise process to synthe-
size this type of useful N-acylurea, since the scope of pre-
chloroformamidine would be a more appropriate interme-
diate. Besides, the nucleophilic addition of pentane-2,4-
vious transformations is often limited by the availability
dione and methyl acetoacetate with 1a led to the forma-
and stability of the required acylation reagents. Finally,
tion of N-acyl amidine derivatives 4b–d in moderate
the reaction between N-acyl chloroformamidine 1a and
yields; N-acyl amidines are seldom utilized in organic
sodium hydrosulfide was conducted; N-acylthiourea 6
synthesis. Our method using N-acyl chloroformamidines
was obtained in 87% yield. Alternatively, 1,3-dimethyl-
as substrates for the synthesis of N-acylamidines could
thiourea reacted with 1a to afford the same N-acylthiourea
provide a highly efficient and straightforward method for
6 in 90% yield (Scheme 3). These results indicated that N-
acyl chloroformamidine has potential as a good desulfur-
the preparation of multisubstituted amidines.
ation reagent. N-Acylthioureas are typically accessible
O
Ph
N
from the reaction of thioureas with anhydrides or the reac-
tion of amines with acyl isothiocyanates.13 However, the
relatively harsh reaction conditions and the use of hazard-
ous isocyanates often make these methods environmental-
ly undesirable. Our method using inexpensive and clean
sodium hydrosulfide is potentially an attractive strategy to
synthesize various substituted N-acylthioureas.
(1.0 equiv)
Li
Ph
N
iPr
a)
b)
THF
r.t., 3 h
C
iPr
4a 87%
Ph
(1.2 equiv)
Ph
H
CuI (10 mol%)
Et3N (2.0 equiv)
4a 79%
THF
r.t., 3 h
O
N
Ph
N
iPr
O
N
O
N
H2O
(1.0 equiv)
Ph
O
H
O
NaHS
(1.0 equiv)
O
Ph
R3
C
iPr
iPr
iPr
N
iPr
Cl
1a
THF
r.t., 3 h
HN
iPr
C
THF
r.t., 12 h
(1.0 equiv)
HN
iPr
C
H
O
N
C
c)
O
N
O
S
iPr
Ph
N
1) NaH (1.0 equiv), THF
0 °C to r.t., 10 min
2) 0 °C, 1 h
5: 99%
6: 87%
H
O
iPr
O
S
C
3) r.t., 24 h
4b R3 = Ph, 89%
4c R3 = Cy, 71%
Me
Me
Me
N
Me
O
O
N
N
iPr
Cl
N
Ph
Ph
1a
H
H
H
H
O
O
N
iPr
N
iPr
(1.0 equiv)
(1.0 equiv)
O
Ph
HN
iPr
C
HN
iPr
C
OMe
(1.0 equiv)
THF
r.t., 12 h
THF,
50 °C, 18 h
N
iPr
H
H
O
S
d)
6: 90%
O
5: 63%
N
C
1) NaH (1.0 equiv), THF
0 °C to r.t., 1.5 h
2) 0 °C, 1 h
iPr
H
O
4d 72%
Scheme 3 Formation of N-acylurea and -thiourea
3) r.t., 24 h
OMe
The possible mechanisms for the formation of N-ac-
yl(thio)ureas are shown in Scheme 4. In pathway A, if so-
dium hydrosulfide was used as nucleophile, an N-acyl
thioformamidine intermediate is formed after nucleophil-
ic attack of an ‘SH’ moiety to N-acyl chloroformamidine.
Then the intermediate undergoes intramolecular electron-
pair transformation to give the final product, N-acylthio-
urea. In pathway B, if 1,3-dimethyl(thio)urea is used as
the nucleophile, it could tautomerize to give an ‘EH’ spe-
cies. An N-acyl (thio)formamidine intermediate is formed
after nucleophilic attack of the ‘EH’ moiety to N-acyl
chloroformamidine. Then the intermediate undergoes in-
tramolecular electron-pair transformation and elimination
of carbodiimide to give the final product, N-ac-
yl(thio)urea.
Scheme 2 Formation of N-acylamidines
The amidines 4b–d did not tautomerize to N-acyl-substi-
tuted 1,1-diaminoethylenes. This result was in striking
contrast with that observed for the formation of 3a–c via
tautomerization. Furthermore, we carried out the reaction
of 1a with pentane-2,4-dione or methyl acetoacetate at in-
creased temperatures (up to 80 °C), but the amidines 4b–
d remained the exclusive products; the tautomerization of
4b–d did not occur. This result showed that 4b–d are ther-
modynamically stable. The exact reason whether the am-
idines
tautomerize
to
N-acyl-substituted
1,1-
diaminoethylenes is not clear. This might be due to the
keto-carbonyl group in 4b–d preferring to exist in the enol
form in solution resulting in no tautomerization, however,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 347–354

350
Y. Wang et al.
PAPER
pathway A
tinued for 48 h, and then the mixture was concentrated under vacu-
um to leave virtually quantitative yields of N-acyl
chloroformamidines 1a–r.
O
O
N
O
N
Ph
Ph
Ph
iPr
iPr
iPr
N
SH
– NaCl
N
C
N
C
HN
iPr
C
(Z)-N,N′-Diisopropyl-N-[4-(trifluoromethyl)benzoyl]carba-
mimidic Chloride (1a)
Colorless solid; yield: 334 mg (99%); mp 64.7–65.6 °C.
IR (film): 1668 (C=O), 1564 cm–1 (C=N).
1H NMR (400 MHz, C6D6): δ = 0.64 (d, J = 6.3 Hz, 6 H, CH3), 1.29
(d, J = 6.8 Hz, 6 H, CH3), 3.38–3.44 (m, 1 H, CH), 4.65–4.72 (m, 1
H, CH), 7.22 (d, J = 8.2 Hz, 2 H, CH), 7.44 (d, J = 8.2 Hz, 2 H, CH).
iPr
iPr
S
Cl
S
H
pathway B
E
O
N
O
Ph
Ph
O
iPr
MeHN
NHMe
Ph
N
iPr
N
iPr
N
C
HN
iPr
C
iPr
H
– HCl
N
C
E
E
EH
NMe
iPr
13C NMR (100 MHz, C6D6): δ = 20.0, 21.4, 49.3, 54.6, 124.3 (q,
N
+
C
Cl
MeN
NMe
MeHN
Me
NMe
J
J
C-F = 270.7 Hz), 125.2 (q, JC-F = 3.8 Hz), 128.3, 131.1, 132.1 (q,
C-F = 32.3 Hz), 141.1, 168.6.
E = O and S
Scheme 4 Proposed mechanisms for the formation of N-acylurea
and -thiourea
HRMS: m/z [M + H]+ calcd for C15H19F3N2O: 299.1366; found:
299.1361.
(Z)-N-Benzoyl-N,N′-diisopropylcarbamimidic Chloride (1b)
In summary, a series of N-acyl chloroformamidines are
obtained by reaction of carbodiimides with acid chlorides.
These N-acyl chloroformamidines are highly functional-
ized and potentially useful building blocks. Their subse-
quent reactions with diethyl malonate, phenylethynyl-
lithium, pentane-2,4-dione, methyl acetoacetate, water,
1,3-dimethyl(thio)urea, and sodium hydrosulfide, provid-
ed unique protocols for the synthesis of different classes
of important N-containing compounds, such as N-acyl-
substituted 1,1-diaminoethylenes, amidines, ureas, and
thioureas. These N-acyl derivatives have potentially wide
applications in medicinal chemistry, coordination chemis-
try, and synthetic organic chemistry. The reaction of N-
acyl chloroformamidines with 1,3-dimethyl(thio)urea in-
Colorless oil; yield: 266 mg (99%).
IR (film): 1643 (C=O), 1580 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 0.74 (d, J = 6.0 Hz, 6 H, CH3), 1.31
(d, J = 6.0 Hz, 6 H, CH3), 3.48–3.56 (m, 1 H, CH), 4.76–4.85 (m, 1
H, CH), 6.95–6.99 (m, 3 H, CH), 7.61–7.65 (m, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 20.2, 21.7, 49.2, 54.6, 128.2, 128.2,
130.4, 131.5, 137.8, 169.96.
HRMS: m/z [M + H]+ calcd for C14H20ClN2O: 267.1207; found:
267.1215.
(Z)-N-(Cyclohexylcarbonyl)-N,N′-diisopropylcarbamimidic
Chloride (1c)
Colorless oil; yield: 267 mg (98%).
IR (film): 1662 (C=O), 1516 cm–1 (C=N).
dicated that N-acyl chloroformamidine is a potential de- 1H NMR (400 MHz, C6D6): δ = 1.03–1.08 (m, 6 H, 2 CH3; 2 H, 1
CH2), 1.13 (d, J = 7.0 Hz, 6 H, CH3), 1.47–1.61 (m, 6 H, CH2),
oxygenation or desulfuration reagent. These results show
that these N-acyl chloroformamidines have a good ability
to accept nucleophilic attack to construct useful N-con-
taining compounds. Studies on the reaction chemistry of
these types of N-acyl compounds in synthetic organic
chemistry are in progress.
1.80–1.84 (m, 2 H, CH2), 2.43–2.48 (m, 1 H, CH), 3.72–3.82 (m, 1
H, CH), 4.49–4.60 (m, 1 H, CH).
13C NMR (75 MHz, C6D6): δ = 20.0, 21.9, 25.8, 25.9, 29.5, 44.4,
47.6, 55.1, 131.0, 173.7.
HRMS: m/z [M + H]+ calcd for C14H26ClN2O: 273.1728; found:
273.1727.
(Z)-N-Benzoyl-N,N′-dicyclohexylcarbamimidic Chloride (1d)
Unless otherwise noted, all starting materials are commercially
available and were used without further purification. Solvents were
purified by an Mbraun SPS-800 Solvent Purification System and
dried over fresh Na chips in a glovebox. C6D6 (all 99+ atom% D)
was obtained from CIL and was dried over fresh Na chips in a
glovebox for NMR analysis. All reactions were carried out under a
dry and O2-free N2 atmosphere in slight positive pressure by using
Schlenk techniques or under a N2 atmosphere in a Mikrouna Super
(1220/750) Glovebox. The N2 in the glovebox was constantly circu-
lated through a Cu/molecular sieve catalyst unit. The O2 and mois-
ture concentrations in the glovebox atmosphere were monitored by
an O2/H2O Combi-Analyzer to ensure both were always below 1
ppm.
Colorless solid; yield: 346 mg (99%); mp 281.2–282.6 °C.
IR (film): 1652 (C=O), 1582 cm–1 (C=N).
1H NMR (400 MHz, C6D6): δ = 0.97–1.21 (m, 8 H, CH2), 1.29–1.49
(m, 6 H, CH2), 1.60–1.65 (m, 2 H, CH2), 1.78–1.97 (m, 4 H, CH2),
3.33–3.40 (m, 1 H, CH), 4.51–4.59 (m, 1 H, CH), 7.00–7.08 (m, 3
H, CH), 7.62–7.64 (m, 2 H, CH).
13C NMR (100 MHz, C6D6): δ = 24.0, 25.8, 25.8, 26.4, 30.9, 31.9,
56.9, 62.0, 128.1, 128.3, 130.5, 131.2, 137.7, 169.7.
HRMS: m/z [M – Cl]+ calcd for C20H27N2O: 311.2118; found:
311.2121.
(Z)-N,N′-Dicyclohexyl-N-(4-methoxybenzoyl)carbamimidic
Chloride (1e)
1H and 13C NMR spectra were recorded on a Jeol JNM-AL300 spec-
trometer (FT, 300 MHz for 1H; 75 MHz for 13C), a Varian Mercury
300 spectrometer (FT, 300 MHz for 1H; 75 MHz for 13C) or a Bruker
ARX400 spectrometer (FT, 400 MHz for 1H; 100 MHz for 13C) at
r.t., unless otherwise noted. IR were recorded on a Thermo Nicolet
Avatar 330 FT-IR spectrophotometer. HRMS were recorded on a
Bruker Apex IV FTMS mass spectrometer using ESI.
Colorless solid; yield: 362 mg (96%); mp 55.2–56.2 °C.
IR (film): 1628 (C=O), 1510 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 1.03–1.35 (m, 10 H, CH2), 1.47–
1.53 (m, 4 H, CH2), 1.62–1.66 (m, 2 H, CH2), 1.92–2.09 (m, 4 H,
CH2), 3.13 (s, 3 H, CH3), 3.47–3.53 (m, 1 H, CH), 4.68–4.79 (m, 1
H, CH), 6.63 (d, J = 9.0 Hz, 2 H, CH), 7.81 (d, J = 9.0 Hz, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 24.1, 25.7, 25.8, 26.4, 31.2, 32.1,
54.7, 57.2, 62.2, 113.6, 130.1, 130.7, 131.5, 162.0, 169.5.
N-Acyl Chloroformamidines 1a–r; General Procedure
In a 25-mL flask containing a stirred soln of carbodiimide (1 mmol)
in THF (10 mL) at r.t., the acid chloride (1 mmol). Stirring was con-
Synthesis 2013, 45, 347–354
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Reactivity of N-Acyl Chloroformamidines
351
HRMS: m/z [M – Cl]+ calcd for C21H29N2O2: 341.2224; found:
341.2225.
CH), 4.48–4.56 (m, 1 H, CH), 7.20 (d, J = 8.2 Hz, 2 H, CH), 7.50
(d, J = 8.2 Hz, 2 H, CH).
13C NMR (100 MHz, C6D6): δ = 23.8, 25.62, 25.70, 26.3, 30.7, 31.7,
57.1, 62.0, 124.4 (q, JC-F = 270.7 Hz), 125.2 (q, JC-F = 3.8 Hz),
128.5, 130.8, 132.1 (q, JC-F = 32.2 Hz), 141.0, 168.5.
HRMS: m/z [M – Cl]+ calcd for C21H26F3N2O: 379.1992; found:
379.1992.
(Z)-N,N′-Dicyclohexyl-N-(3-methylbenzoyl)carbamimidic
Chloride (1f)
Colorless oil; yield: 349 mg (97%).
IR (film): 1640 (C=O), 1531 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 0.97–2.01 (m, 20 H, CH2; 3 H,
CH3), 3.37–3.45 (m, 1 H, CH), 4.56–4.67 (m, 1 H, CH), 6.89–7.01
(m, 2 H, CH), 7.51–7.53 (m, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 20.9, 23.9, 25.6, 25.7, 26.2, 30.9,
31.8, 56.8, 62.0, 125.6, 128.1, 129.2, 131.25, 131.30, 137.69,
137.79, 169.8.
(Z)-N,N′-Dicyclohexyl-N-(4-nitrobenzoyl)carbamimidic
Chloride (1k)
Colorless oil; yield: 320 mg (82%).
IR (film): 1657 (C=O), 1563 (N=O), 1527 (C=N), 1340 cm–1
(N=O).
HRMS: m/z [M – Cl]+ calcd for C21H29N2O: 325.2274; found:
325.2278.
1H NMR (300 MHz, C6D6): δ = 0.97–1.26 (m, 12 H, CH2), 1.35–
1.44 (m, 2 H, CH2), 1.59–1.64 (m, 2 H, CH2), 1.79–1.99 (m, 4 H,
CH2), 3.21–3.33 (m, 1 H, CH), 4.49–4.60 (m, 1 H, CH), 7.37 (d,
J = 9.0 Hz, 2 H, CH), 7.50 (d, J = 9.0 Hz, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 23.8, 25.52, 25.62, 26.2, 30.7, 31.7,
57.1, 62.2, 123.3, 128.8, 130.6, 142.7, 148.9, 167.8.
(Z)-N,N′-Dicyclohexyl-N-(2-methylbenzoyl)carbamimidic
Chloride (1g)
Colorless solid; yield: 290 mg (81%); mp 85.2–85.9 °C.
IR (film): 1629 (C=O), 1534 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 0.95–2.07 (m, 20 H, CH2), 2.47 (s,
3 H, CH3), 3.27–3.33 (m, 1 H, CH), 4.54–4.62 (m, 1 H, CH), 6.87–
7.01 (m, 3 H, CH), 7.33 (d, J = 6.9 Hz, 1 H, CH).
13C NMR (75 MHz, C6D6): δ = 19.7, 24.1, 25.69, 25.80, 26.2, 30.9,
31.84, 56.1, 62.1, 125.2, 127.1, 129.4, 130.42, 130.54, 136.6, 137.6,
169.4.
HRMS: m/z [M – Cl]+ calcd for C20H26N3O3: 356.1969; found:
356.1970.
(Z)-N,N′-Dicyclohexyl-N-(2-thienyl-2-carbonyl)carbamimidic
Chloride (1l)
Colorless oil; yield: 324 mg (92%).
IR (film): 1623 (C=O), 1543 cm–1 (C=N).
HRMS: m/z [M – Cl]+ calcd for C21H29N2O: 325.2274; found:
325.2276.
1H NMR (300 MHz, C6D6): δ = 0.96–1.94 (m, 20 H, CH2), 3.48–
3.58 (m, 1 H, CH), 4.53–4.65 (m, 1 H, CH), 6.57–6.60 (m, 1 H, CH),
6.90 (d, J = 4.8 Hz, 1 H, CH), 7.50 (d, J = 3.9 Hz, 1 H, CH).
13C NMR (75 MHz, C6D6): δ = 24.0, 25.60, 25.63, 26.1, 30.9, 31.8,
57.4, 62.4, 126.9, 130.65, 130.77, 131.0, 139.7, 162.4.
HRMS: m/z [M – Cl]+ calcd for C18H25N2OS: 317.1682; found:
317.1684.
(Z)-N-(Biphenyl-4-ylcarbonyl)-N,N′-dicyclohexylcarbamimid-
ic Chloride (1h)
Colorless solid; yield: 390 mg (92%); mp 64.1–64.1 °C.
IR (film): 1654 (C=O), 1523 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 0.97–1.28 (m, 10 H, CH2), 1.38–
1.42 (m, 4 H, CH2), 1.57–1.65 (m, 2 H, CH2), 1.86–2.05 (m, 4 H,
CH2), 3.36–3.48 (m, 1 H, CH), 4.62–4.72 (m, 1 H, CH), 7.09–7.13
(m, 2 H, CH), 7.17–7.19 (m, 1 H, CH), 7.29–7.33 (m, 4 H, CH), 7.78
(d, J = 9.0 Hz, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 23.8, 25.55, 25.64, 26.2, 30.9, 31.8,
56.9, 62.0, 127.0, 127.4, 128.0, 129.03, 129.07, 131.2, 136.5, 140.5,
143.7, 169.8.
(Z)-N,N′-Dicyclohexyl-N-(2-phenylacetyl)carbamimidic
Chloride (1m)
Colorless oil; yield: 307 mg (85%).
IR (film): 1656 (C=O), 1530 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 1.01–1.37 (m, 8 H, CH2), 1.49–1.76
(m, 10 H, CH2), 2.02–2.05 (m, 2 H, CH2), 3.65–3.86 (m, 1 H, CH;
2 H, CH2), 4.44–4.57 (m, 1 H, CH), 7.17–7.28 (m, 3 H, CH), 7.38
(d, J = 6.0 Hz, 2 H, CH).
HRMS: m/z [M – Cl]+ calcd for C26H31N2O: 387.2425; found:
387.2426.
13C NMR (75 MHz, C6D6): δ = 24.2, 25.75, 25.83, 26.1, 30.9, 32.2,
42.1, 56.2, 62.6, 127.0, 128.5, 129.8, 130.7, 135.3, 168.4.
HRMS: m/z [M – Cl]+ calcd for C21H29N2O: 325.2320; found:
325.2324.
(Z)-N-(4-Chlorobenzoyl)-N,N′-dicyclohexylcarbamimidic
Chloride (1i)
Colorless solid; yield: 380 mg (>99%);mp 81.4–82.1 °C.
IR (film): 1658 (C=O), 1595 cm–1 (C=N).
(Z)-N-Butanoyl-N,N′-dicyclohexylcarbamimidic Chloride (1n)
Colorless oil; yield: 266 mg (85%).
IR (film): 1654 (C=O), 1529 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 0.84 (t, J = 7.5 Hz, 3 H, CH3), 1.04–
1.20 (m, 6 H, CH2), 1.37–1.43 (m, 6 H, CH2), 1.56–1.69 (m, 8 H,
CH2), 1.92–1.95 (m, 2 H, CH2), 2.34 (t, J = 7.5 Hz, 2 H, CH2), 3.53–
3.61 (m, 1 H, CH), 4.34–4.43 (m, 1 H, CH).
13C NMR (75 MHz, C6D6): δ = 13.9, 18.9, 24.2, 25.76, 25.88, 26.2,
30.9, 32.2, 37.3, 55.6, 62.6, 130.8, 170.1.
1H NMR (300 MHz, C6D6): δ = 0.98–1.18 (m, 8 H, CH2), 1.32–1.45
(m, 6 H, CH2), 1.60–1.64 (m, 2 H, CH2), 1.78–1.97 (m, 4 H, CH2),
3.33–3.39 (m, 1 H, CH), 4.52–4.60 (m, 1 H, CH), 6.97 (d, J = 8.4
Hz, 2 H, CH), 7.46 (d, J = 8.4 Hz, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 24.0, 25.7, 25.8, 26.3, 30.9, 31.9,
57.0, 62.1, 128.5, 129.8, 130.9, 136.0, 136.7, 168.6.
HRMS: m/z [M + H]+ calcd for C20H27Cl2N2O: 381.1491; found:
381.1500.
HRMS: m/z [M + H]+ calcd for C17H30ClN2O: 313.2041; found:
313.2044.
(Z)-N,N′-Dicyclohexyl-N-[4-(trifluoromethyl)benzoyl]carba-
mimidic Chloride (1j)
Colorless solid; yield: 407 mg (98%); mp 96.7–97.4 °C.
IR (film): 1655 (C=O), 1526 cm–1 (C=N).
1H NMR (400 MHz, C6D6): δ = 0.98–1.45 (m, 14 H, CH2), 1.60–
(Z)-N,N′-Dicyclohexyl-N-heptanoylcarbamimidic Chloride (1o)
Colorless oil; yield: 337 mg (95%).
IR (film): 1658 (C=O), 1533 cm–1 (C=N).
1.65 (m, 2 H, CH2), 1.83–1.98 (m, 4 H, CH2), 3.28–3.31 (m, 1 H,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 347–354

352
Y. Wang et al.
PAPER
1H NMR (400 MHz, C6D6): δ = 0.81–0.82 (m, 3 H, CH3), 1.08–1.24
(m, 12 H, CH2), 1.40–1.42 (m, 4 H, CH2), 1.58–1.70 (m, 10 H,
CH2), 1.94–1.96 (m, 2 H, CH2), 2.38–2.41 (m, 2 H, CH2), 3.58–3.62
(m, 1 H, CH), 4.39 (br s, 1 H, CH).
13C NMR (75 MHz, CDCl3, TMS): δ = 13.8, 14.0, 19.7, 20.1, 22.5,
24.7, 44.8, 54.6, 59.8, 60.5, 90.5, 127.8, 128.2, 130.7, 135.3, 159.1,
166.9, 168.94, 169.03.
HRMS: m/z [M + H]+ calcd for C21H31N2O5: 391.2228; found:
391.2229.
13C NMR (100 MHz, C6D6): δ = 14.2, 22.9, 24.2, 25.4, 25.81, 25.92,
26.2, 29.3, 31.0, 32.0, 32.3, 35.5, 55.8, 62.6, 130.9, 170.3.
HRMS: m/z [M + H]+ calcd for C20H36ClN2O: 355.2511; found:
355.2519.
Diethyl 2-[(Cyclohexylamino)(N-cyclohexyl-2-phenylacetami-
do)methylene]malonate (3b)
Colorless oil; yield: 340 mg (70%).
IR (film): 1712 (C=O), 1677 (C=O), 1654 cm–1 (C=C).
(Z)-N,N′-Diphenyl-N-[4-(trifluoromethyl)benzoyl]carbamimid-
ic Chloride (1p)
1H NMR (300 MHz, CDCl3, TMS): δ = 1.21–2.16 (m, 6 H, 2 CH3;
20 H, 10 CH2), 3.49–4.28 (m, 2 H, 2 CH; 6 H, 3 CH2), 7.18–7.35
(m, 5 H, CH), 9.90 (d, J = 9.6 Hz, 1 H, NH).
Colorless oil; yield: 359 mg (89%).
IR (film): 1665 (C=O), 1545 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 6.46–7.13 (m, 12 H, CH), 7.53 (d,
J = 6.0 Hz, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 120.4, 124.2 (q, JC-F = 271.5 Hz),
124.5, 125.65 (q, JC-F = 3.8 Hz), 125.83, 128.4, 129.0, 129.2, 129.8,
132.8 (q, JC-F = 32.5 Hz), 134.7, 138.6, 139.4, 145.5, 169.5.
13C NMR (75 MHz, CDCl3, TMS): δ = 13.8, 14.1, 24.8, 25.47,
25.63, 25.9, 28.9, 30.4, 41.1, 51.3, 59.6, 60.1, 60.6, 92.3, 126.4,
128.0, 129.2, 134.7, 157.1, 166.3, 169.1, 170.0.
HRMS: m/z [M + H]+ calcd for C28H41N2O5: 485.3010; found:
485.3018.
HRMS: m/z [M – Cl]+ calcd for C21H14F3N2O: 367.1134; found:
367.1131.
Diethyl 2-([tert-Butylamino)(4-chloro-N-ethylbenzamido)meth-
ylene]malonate (3c)
Colorless oil; yield: 281 mg (66%).
(Z)-N′-tert-Butyl-N-(4-chlorobenzoyl)-N-ethylcarbamimidic
Chloride (1q)
Colorless solid; yield: 280 mg (93%); mp 44.6–45.5 °C.
IR (film): 1657 (C=O), 1594 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 0.90 (s, 9 H, CH3), 1.08 (t, J = 7.5
Hz, 3 H, CH3), 3.70 (q, J = 7.5 Hz, 2 H, CH2), 6.95 (d, J = 9.0 Hz,
2 H, CH), 7.32 (d, J = 9.0 Hz, 2 H, CH).
13C NMR (75 MHz, C6D6): δ = 12.7, 28.1, 40.9, 56.3, 128.4, 129.7,
132.6, 135.7, 136.5, 169.6.
IR (film): 1711 (C=O), 1675 (C=O), 1654 cm–1 (C=C).
1H NMR (300 MHz, CDCl3, TMS): δ = 1.09–1.40 (m, 18 H, CH3),
3.54–4.20 (m, 6 H, CH2), 7.26–7.35 (m, 2 H, CH), 7.70–7.87 (m, 2
H, CH), 9.01 (br, 1 H, NH).
13C NMR (75 MHz, CDCl3, TMS): δ = 12.3, 14.0, 27.9, 30.6, 38.1,
47.2, 56.1, 60.5, 93.7, 128.0, 128.3, 130.5, 134.0, 160.1, 167.2,
168.4, 168.8.
HRMS: m/z [M + H]+ calcd for C21H30ClN2O5: 425.1838; found:
425.1841.
HRMS: m/z [M – Cl]+ calcd for C14H18ClN2O: 265.1120; found:
265.1123.
(E)-N-Isopropyl-N-[1-(isopropylimino)-3-phenylprop-2-
ynyl]benzamide (4a)
(Z)-N′-Cyclohexyl-N-phenyl-N-[4-(trifluoromethyl)benzo-
yl]carbamimidic Chloride (1r)
Colorless solid; yield: 408 mg (99%); mp 73.6–74.3 °C.
IR (film): 1678 (C=O), 1596 cm–1 (C=N).
1H NMR (300 MHz, C6D6): δ = 1.00–1.35 (m, 10 H, CH2), 3.41 (br
s, 1 H, CH), 6.91–7.12 (m, 5 H, CH), 7.23 (d, J = 7.2 Hz, 2 H, CH),
7.53 (d, J = 7.8 Hz, 2 H, CH).
Method A: In a 25-mL flask containing N-acyl chloroformamidine
(1 mmol) in THF (10 mL) at r.t., phenylethynyllithium (1.0 mmol)
was added. After 3 h, the solvent was evaporated from the mixture
under vacuum. The residue was purified by chromatography to give
N-acylamidine 4a (289 mg, 87%).
Method B: In a 25-mL flask containing N-acyl chloroformamidine
(1 mmol) in THF (10 mL) at r.t., Et3N (2.0 mmol), CuI (0.1 mmol),
and alkyne (1.2 mmol) were added. After 3 h, the reaction was
quenched with H2O at r.t. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were washed successively
with brine. The solvent was removed under reduced pressure and
the residue was purified by chromatography to give N-acylamidine
4a (263 mg, 79%).
13C NMR (75 MHz, C6D6): δ = 23.8, 25.6, 31.8, 61.6, 124.3 (q,
J
C-F = 270.7 Hz), 125.4 (q, JC-F = 3.7 Hz), 127.3, 128.1, 128.8,
129.6, 131.0, 132.5 (q, JC-F = 32.1 Hz), 138.5, 139.9, 169.2.
HRMS: m/z [M + H]+ calcd for C21H21ClF3N2O: 409.1289; found:
409.1300.
N-Acyl-Substituted 1,1-Diaminoethylenes 3a–c; General Proce-
dure
Colorless solid; mp 65.9–66.7 °C.
IR (film): 2203 (C≡C), 1662 (C=O), 1593 cm–1 (C=N).
In a 25-mL flask, NaH (60% dispersion, 1 mmol) in THF (5 mL)
was cooled to 0 °C. Diethyl malonate (1 mmol) was added to the
stirred mixture and after 15 min at 0 °C, N-acyl chloroformamidine
(1 mmol) in THF (5 mL) was added dropwise. The resulting soln
was stirred for 1 h at 0 °C and 24 h at r.t. The soln was concentrated
under vacuum. The residue was purified by chromatography to give
N-acyl-substituted 1,1-diaminoethylene 3a–c.
1H NMR (400 MHz, CDCl3, TMS): δ = 0.94 (d, J = 6.2 Hz, 6 H,
CH3), 1.47 (d, J = 6.8 Hz, 6 H, CH3), 3.83–3.92 (m, 1 H, CH), 4.87–
4.97 (m, 1 H, CH), 7.29–7.41 (m, 8 H, CH), 7.53–7.55 (m, 2 H, CH).
13C NMR (100 MHz, CDCl3, TMS): δ = 20.7, 22.5, 48.3, 54.3, 81.0,
95.7, 120.7, 127.89, 128.01, 128.5, 129.78, 129.92, 132.0, 138.0,
140.2, 170.7.
Diethyl 2-[(Isopropylamino)(N-isopropylbenzamido)meth-
ylene]malonate (3a)
Colorless solid; yield: 300 mg (77%); mp 98.7–99.5 °C.
HRMS: m/z [M + H]+ calcd for C22H25N2O: 333.1961; found:
333.1963.
N-Acylamidines 4b,c; General Procedure
IR (film): 3629 (N–H), 1719 (C=O), 1677 (C=O), 1653 cm–1 (C=C).
A 25-mL flask containing NaH (60% dispersion, 1 mmol) and THF
(5 mL) was cooled to 0 °C. Pentane-2,4-dione (1 mmol) was added
to the stirred mixture and it was allowed to warm to r.t. The mixture
was stirred for 10 min, and then N-acyl chloroformamidine (1
mmol) in THF (5 mL) was added dropwise. The resulting soln was
stirred for 1 h at 0 °C and 24 h at r.t. The soln was concentrated un-
1H NMR (300 MHz, CDCl3, TMS): δ = 1.18–1.46 (m, 18 H, CH3),
3.51–3.66 (m, 1 H, CH), 4.08–4.29 (m, 1 H, CH; 4 H, 2 CH2), 7.31–
7.43 (m, 3 H, CH), 7.92 (d, J = 7.2 Hz, 2 H, CH), 9.40 (d, J = 9.4
Hz, 1 H, NH).
Synthesis 2013, 45, 347–354
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Reactivity of N-Acyl Chloroformamidines
353
der vacuum. The residue was purified by chromatography to give
N-acylamidines 4b and 4c.
13C NMR (100 MHz, CDCl3, TMS): δ = 20.7, 22.1, 42.6, 50.0,
126.3, 128.5, 130.5, 137.1, 154.0, 172.1.
HRMS: m/z [M + Na]+ calcd for C14H20N2NaO2: 271.1417; found:
271.1420.
(E)-N-[2-Acetyl-1-(isopropylimino)-3-oxobutyl]-N-isopropyl-
benzamide (4b)
Colorless oil; yield: 294 mg (89%).
N-Isopropyl-N-(isopropylcarbamothioyl)benzamide (6)
To a 25-mL flask containing N-acyl chloroformamidine (1 mmol)
in THF (10 mL) at r.t., NaHS (1 mmol) or 1,3-dimethylthiourea (1
mmol) was added with stirring. After 12 h, the solvent was evapo-
rated from the mixture under vacuum. The residue was purified by
chromatography to give N-acyl thiourea 6 (NaHS: 230 mg, 87%;
1,3-dimethylthiourea: 238 mg, 90%) as a colorless solid; mp 148.5–
149.4 °C.
IR (film): 1686 (C=O), 1647 (C=O), 1601 cm–1 (C=N).
1H NMR (400 MHz, CDCl3, TMS): δ = 1.04 (d, J = 5.6 Hz, 6 H,
CH3), 1.43 (d, J = 5.6 Hz, 6 H, CH3), 2.07 (s, 3 H, CH3), 2.10 (s, 3
H, CH3), 4.16–4.24 (m, 1 H, CH), 4.56–4.64 (m, 1 H, CH), 5.37 (s,
1 H, CH), 7.38–7.42 (m, 2 H, CH), 7.50–7.53 (m, 1 H, CH), 7.63–
7.64 (m, 2 H, CH).
13C NMR (100 MHz, CDCl3, TMS): δ = 20.2, 20.5, 21.2, 31.8, 50.3,
51.5, 125.9, 128.0, 128.2, 131.5, 136.3, 150.1, 154.7, 170.2, 197.0.
IR (film): 3245 (N–H), 1525 (C=N), 1221 cm–1 (C=S).
1H NMR (400 MHz, CDCl3, TMS): δ = 0.74 (d, J = 6.6 Hz, 6 H,
CH3), 1.48 (d, J = 6.9 Hz, 6 H, CH3), 4.10–4.18 (m, 1 H, CH), 4.94–
5.04 (m, 1 H, CH), 7.16 (br s, 1 H, NH), 7.28–7.45 (m, 3 H, CH),
7.70 (d, J = 7.3 Hz, 2 H, CH).
13C NMR (100 MHz, CDCl3, TMS): δ = 20.16, 20.24, 48.0, 51.2,
127.1, 128.2, 130.8, 136.6, 169.2, 183.8.
HRMS: m/z [M + Na]+ calcd for C19H26N2NaO3: 353.1836; found:
353.1834.
(E)-N-[2-Acetyl-1-(isopropylimino)-3-oxobutyl]-N-isopropylcy-
clohexanecarboxamide (4c)
Colorless oil; yield: 239 mg (71%).
IR (film): 1704 (C=O), 1665 (C=O), 1637 cm–1 (C=N).
1H NMR (300 MHz, CDCl3, TMS): δ = 1.10–1.43 (m, 16 H, 4 CH3,
2 CH2), 1.66–1.81 (m, 6 H, 3CH2), 2.07–2.33 (m, 7 H, 2 CH3, 1
CH), 3.51–3.58 (m, 1 H, CH), 4.28–4.42 (m, 1 H, CH), 5.75 (s, 1 H,
CH).
HRMS: m/z [M + Na]+ calcd for C14H20N2NaOS: 287.1189; found:
287.1191.
Acknowledgment
13C NMR (75 MHz, CDCl3, TMS): δ = 19.5, 20.2, 20.7, 22.8, 23.7,
25.31, 28.8, 30.2, 30.9, 42.6, 48.5, 49.8, 117.1, 144.8, 158.2, 175.1,
195.6.
This work was supported by the ‘973’ program from National Basic
Research Program of China (2011CB808601), and the Natural Sci-
ence Foundation of China.
HRMS: m/z [M + Na]+ calcd for C19H32N2NaO3: 359.2305; found:
359.2309.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are spectroscopic data (1H and 13C NMR spectra for new com-
Methyl (E)-2-(N-Benzoyl-N,N′-diisopropylcarbamimidoyl)-3-
oxobutanoate (4d)
A 25-mL flask containing NaH (60% dispersion, 1 mmol) and THF
(5 mL) was cooled to 0 °C. Methyl acetoacetate (1 mmol) was add-
ed to the stirred mixture and the mixture was allowed to warm to r.t.
and stirred for 1.5 h; N-acyl chloroformamidine (1 mmol) in THF (5
mL) was added dropwise. The resulting soln was stirred for 1 h at 0
°C and 24 h at r.t. The soln was concentrated under vacuum. The
residue was purified by chromatography to give N-acylamidine 4d
as a colorless oil; yield: 250 mg (72%).
pounds and X-ray data for compound 3a).SnuIpofoprimnitgrSatnoIufimgp
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References
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IR (film): 1730 (C≡C), 1689 (C=O), 1656 cm–1 (C=O, C=N).
1H NMR (400 MHz, CDCl3, TMS): δ = 0.27 (br, 3 H, CH3), 0.97
(br, 3 H, CH3), 1.48 (br, 6 H, CH3), 2.01 (s, 3 H, CH3), 3.35 (br s, 1
H, CH), 3.70 (s, 3 H, CH3), 4.61 (br s, 1 H, CH), 5.43 (s, 1 H, CH),
7.33–7.43 (m, 3 H, CH), 7.79–7.81 (m, 2 H, CH).
13C NMR (75 MHz, CDCl3, TMS): δ = 19.9, 20.6, 21.6, 23.4, 49.2,
49.4, 50.7, 107.1, 127.92, 128.01, 130.9, 135.2, 143.9, 160.8, 164.0,
169.4.
HRMS: m/z [M + Na]+ calcd for C19H26N2NaO4: 369.1785; found:
369.1782.
N-Isopropyl-N-(isopropylcarbamoyl)benzamide (5)
To a 25-mL flask containing N-acyl chloroformamidine (1 mmol)
in THF (10 mL) at r.t., H2O (1 mmol) or 1,3-dimethylurea (1 mmol)
was added with stirring. After 3 h at r.t. (for H2O) or 18 h at 50 °C
(for 1,3-dimethylurea), the solvent was evaporated from the mixture
under vacuum. The residue was purified by chromatography to give
N-acyl urea 5 (H2O: 248 mg, 99%; 1,3-dimethylthiourea: 156 mg,
63%) as a colorless solid; mp 106.4–107.1 °C.
IR (film): 3303 (N–H), 1685 (C=O), 1633 (C=O) cm–1.
1H NMR (400 MHz, CDCl3, TMS): δ = 0.96 (d, J = 6.6 Hz, 6 H,
CH3), 1.42 (d, J = 6.8 Hz, 6 H, CH3), 3.76–3.87 (m, 1 H, CH), 4.38–
4.48 (m, 1 H, CH), 6.69 (br s, 1 H, NH), 7.39–7.52 (m, 5 H, CH).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 347–354

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Y. Wang et al.
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Synthesis 2013, 45, 347–354
© Georg Thieme Verlag Stuttgart · New York