Unexpected route for the synthesis of N,N-dialkyl formamidines using phenyl chloroformate and N,N-dialkyl formamides

Article abstract of DOI:10.1016/j.tet.2013.06.026

An unexpected route for the synthesis of N,N-dialkyl formamidines has been reported by the reaction of amines with N,N-dialkyl formamides and phenyl chloroformate.

Full text of DOI:10.1016/j.tet.2013.06.026

Accepted Manuscript
Unexpected route for the synthesis of N,N-dialkyl formamidines using phenyl
chloroformate and N,N-dialkyl formamides
Se Hun Kwak, Young-Dae Gong
PII:
S0040-4020(13)00944-7
10.1016/j.tet.2013.06.026
TET 24502
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 February 2013
Revised Date: 7 June 2013
Accepted Date: 8 June 2013
Please cite this article as: Kwak SH, Gong Y-D, Unexpected route for the synthesis of N,N-dialkyl
formamidines using phenyl chloroformate and N,N-dialkyl formamides, Tetrahedron (2013), doi:
10.1016/j.tet.2013.06.026.
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Unexpected route for the synthesis of N,N-
dialkyl formamidines using phenyl
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chloroformate and N,N-dialkyl formamides.
Se Hun Kwak, Young-Dae Gong*

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1
Tetrahedron
journal homepage: www.elsevier.com
Unexpected route for the synthesis of N,N-dialkyl formamidines using phenyl
chloroformate and N,N-dialkyl formamides.
Se Hun Kwak and Young-Dae Gong
Department of Chemistry, Dongguk-University-Seoul, Pil-dong 3-ga, Jung-gu, Seoul 100715, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
An unexpected route for the synthesis of N,N-dialkyl formamidines has been reported by the
reaction of amines with N,N-dialkylformamides and phenyl chloroformate.
Received in revised form
Accepted
2012 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Formamidine
Phenyl chloroformate
———
Corresponding author. Fax: +82 2 2268 8204; e-mail: ydgong@dongguk.edu

ACCEPTED MANUSCRIPT
2
Tetrahedron
1. Introduction
initially underwent decarboxylation to form the intermediate 4.
The isolation of the intermediate 4 answers the formation of the
formamidines (Scheme 2).
Formamidines are the key intermediates for the construction
of heterocycles1 and functional group transformations.2 They
have also been employed as pharmacological agents,3 protecting
groups for primary amines4, and as a support linker in solid phase
synthesis.5 The use of formamidines as chiral auxiliaries in
asymmetric synthesis6 and as ligand for metal-catalyzed
hydrosilyation and epoxidation has also been reported.7 The
methods for the synthesis of formamidines can largely be divided
into three categories. The first involves the use of N,N-
dialkylformamide dialkylacetals with or without a catalytic
amount of acid. The second involves coupling agents such as
POCl3, P2O5, PCl5, (COCl)2, SOCl2, acid chlorides,
sulfonylchlorides, PyBOP and trifluoroacetic anhydride.8 The last
involves the use of isolated iminium salt like vilsmeier reagent,
which is related to the method reported herein.9 Recently, a new
approach using NaI and TBHP to make N-sulfonyl formamidine
has been reported.10 As a part of our medicinal chemistry
research program we required carbamate 3 for which we
attempted the reaction of phenyl chloroformate with amine 1
(Scheme 1). It was expected that the nucleophilic substitution
would lead to the carbamate. However the product obtained was
confirmed as formamidine 2, strongly suggesting the formation
of a reactive intermediate between N,N-dimethylformamide and
phenyl chloroformate which was reacting with amines (Scheme
2). These findings have not been reported, and have encouraged
us to investigate the formamidine synthesis.
Table 1. Reaction condition screening.a
Base
[equiv.]
R
Time
[min]
Yieldb
[%]
Entry
[equiv.]
1
2
K2CO3 (2.7)
K2CO3(3.0)
-
Ph (2.0)
Ph (2.2)
5
5
5
5
5
5
79
85
86c
84c
12
3
Ph (2.0)
4d
Ph (2.0)
5
6e
-
-
Et (2.0)
p-NitroPh (2.0)
84
a Reaction conditions: DMF (1 ml) and chloroformate were stirred for 5
minutes with base or not before addition of the 6-chloro-2-aminopyraizne
(1 mmol). b isolated yield. c obtained as HCl salt. d DMF (0.5 ml). e DMF
(2 ml).
O
.
O
N
+
Cl
O
2. Results and discussion
We initially selected 3-aminopyridine and aminopyrazine to
study the optimal conditions. The reaction proceeded well, but
extraction with EtOAc was difficult due to its good solubility in
water. To solve the problem, we used 6-chloro-2-aminopyrazine
as a model substrate since it is well extracted with EtOAc. After
selecting a model compound, we investigated the necessity of
K2CO3 in the methodology and found that K2CO3 was not
necessary for the reacton (Table 1, entries 1-4). Instead, the
reaction required more phenyl chloroformate for completion. In
the absence of the base, the product can be obtained as HCl salt
via simple filtration, which makes the purification much easier.
Two other chloroformates were also screened to compare their
reactivity. Among the chloroformates (Table 1, entries 4 and 5),
p-nitrophenyl chloroformate was found to show similar results to
that of phenylchloroformate, but ethyl chloroformate gave poor
yields. Considering the price of the two aryl chloroformates,
phenyl chloroformate was found to be the reagent of choice for
the reaction.
N+
N+
O
- CO2
Cl-
Cl-
O
O
O
5
4
R
NH2
OH
N
N
R
+
6
Scheme 2.
We started to explore the scope and limitiations of the method
(Table 2). It was found that a greater equivalent of the phenyl
chloroformate has to be used as the nucleophilicity of amines
decreases (Table 2, entries 1-4). In the case of
trihaloaminopyrazine (Table 2, entry 4), the reaction worked well
but the product could not be obtained due to its instability, both
in the protic solvent and in the air. It easily turned back to the
amine. Nitro, methoxy, hydroxy, methyl ester, carboxylic acid
and acetyl-substituted aryls also gave the desired products (Table
2, entries 6-11). When methyl 3-amino-2-thiophenecarboxylate
was tested (Table 2, entry 9), the product was not generated as
salt. So, we employed a silica gel column after aqueous work-up.
However, we failed to obtain the product, because the
formamidine was converted to methyl 3-formamidothiophene-2-
carboxylate in the column. A similar tendency was also reported
when ethyl 2-aminobenzoate was used as a substrate.8a To avoid
the hydrolysis, after extraction, the product was collected as HCl
salt using HCl in diethyl ether. Finally, benzyl amines were
conducted (Table 2, entries 13-15). Since the product was not
precipitated as salt, we had to purify it by column
chromatography.
To study the reaction details, DMF and phenyl chloroformate
were mixed (1:1 molar ratio) and stirred for 5 minutes, and
diluted into CDCl3. The 1H-NMR spectrum indicated the
existence of iminium salt, and that the DMF was completely
consumed. However we were unable to confirm the intermediacy
of either 4 or 5 because bubbles, suspected as CO2 were observed
in the mixture while stirring. A literature survey revealed the
Ph
O
O
O
N
N
2
N
O
N
N
N
NH2
O
Ph
N
N
NH
S
S
S
Cl
O
Cl
Cl
Cl
K2CO3, DMF, r.t
O
1
3
Scheme 1.
isolation of a iminium salt 4, which is used as a chlorinating
agent.11 We also can isolate the intermediate 4 from the described
procedure. It was thus concluded that the intermediate 5 formed

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3
Table 2. Scope of the method.a
Entry
1
product
Time [min]
10
Yieldb [%]
64
Entry
1c
product
Time [min]
5
Yieldb [%]
81
O
7a
7b
N
N
N
N
H
6b
6c
N
N
2c
5
87
2
5
95
N
N
N
N
O
3d
4e
5
6d
6e
6f
20
20
5
71
-
3
7c
10
10
-
N
N
4c
7d
16
N
O
S
O
N
a Reaction conditions: DMF (1 ml) and phenyl chloroformate (2 eq) were
stirred for 5 minutes at rt before addition of the substrates (1 mmol). b
isolated yield. c 3 eq of K2CO3
87
Other N,N-disubstituted amide analogues were tested with 6-
chloro-2-aminopyrazine (Table 4). They were also suitable for
formation of the formamidins. But N,N-dimethylacetamide, N-
methylformamide, NMP and N,N-dimethylbenzamide were
found to be not good for the formation of iminium intermediate
with phenyl chloroformate, giving poor yield or no product.
6
7
6g
6h
5
5
95
79
O
N
N
ꢀ HCl
8
9
6i
6j
5
5
70
90
Table 4.
Reaction of 6-chloro-2-aminopyrazine with various amides.a
Yieldb
[%]
Entry
1c, d
amide
product
Time [min]
O
N
N
N
N
N
Cl
O
N
8a
8b
8c
5
85
10
6k
5
59
ꢀ HCl
N
O
N
Cl
Cl
N
N
N
N
N
N
2c
5
5
81
67
11
12
6l
10
10
60
86
O
O
N
N
N
3c, e
O
6m
O
N
Cl
N
N
N
N
N
N
4
5
8d
8e
20
20
-
N
N
13
14
6n
6o
5
5
50
40
N
N
Cl
O
N
N
N
7
O
N
N
15
6p
10
59
O
f
Cl
N
N
N
NH
F3C
6
7
8f
20
20
-
N
H
a Reaction conditions: DMF (1 ml) and phenyl chloroformate (2 eq) were
stirred for 5 minutes at rt before addition of the amines (1 mmol). b
isolated yield. c phenyl chloroformate (1.5 eq) was used. d 4.5 eq of
phenyl chloroformate. e 7 eq of phenyl chloroformate.
O
Cl
N
N
N
g
8g
-
Ph
N
Ph
N
In addition to aryl and alkyl amines, we have also screened
a Reaction conditions: amide (1 ml) and phenyl chloroformate (2 eq) were
stirred for 10 minutes at rt before addition of 6-chloro-2-aminopyrazine (1
mmol). b isolated yield. c 45 °C. d 3.5 eq of phenyl chloroformate. e 1.5 ml
of 4-formylmorpholine. f No reaction. g decomposition.
phenylhydrazide,
phenylhydrazine,
benzamide
and
phenylsulfonamide (Table 3) to demonstrate further use of the
method. Phenylhydrazide and phenylhydrazine gave good results
but benzamide gave only N-formylbenzamide in 9% yield. The
3. Conclusion
rest
of the unreacted
benzamide was recovered.
In conclusion, we have discovered that phenyl chloroformate
can be used for the synthesis of the formamidines. Mild
conditions, short reaction time and generality verified with
various substrates make this method attractive. Also it is
Phenylsulfonamide was found to be unsuccessful.
Table 3. Expansion of the substrate.a

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4
Tetrahedron
noteworthy that DMF or its derivatives are not good choice as
LC/MS (ESI) m/z 263 [M+H]+; IR (ATR): ν = 2975, 2637, 1692,
1417, 1297, 1163, 1024, 832 cm-1; Anal. Calcd for C7H9BrCl2N4:
C, 28.03; H, 3.02; N, 18.68. Found: C, 28.17; H, 3.01; N, 18.52;
solvent if chloroformates have to be used for the synthesis of the
carbamate.
4.2.5.
N'-(3,5-difluorophenyl)-N,N-dimethylformamidine
1
4. Experimental
4.1. General
hydrochloride (6f). White solid; mp 278-281 °C; H NMR (500
MHz, MeOD) δ 8.74 (s, 1H), 7.15 (m, 2H), 6.93 (tt, J = 9.0, 2.2
Hz, 1H), 3.48 (s, 3H), 3.34 (d, J = 0.6 Hz, 3H); 13C NMR (126
MHz, MeOD) δ 165.05 (dd, JCF = 247.7, 14.6 Hz), 155.44,
141.22 (t, JCF = 13.1 Hz), 104.00 (m), 102.58 (t, JCF = 26.0 Hz),
44.74, 38.00; LC/MS (ESI) m/z 185 [M+H]+; IR (ATR): ν = 3019,
2823, 1695, 1611, 1113, 986 cm-1; Anal. Calcd for C9H11ClF2N2:
C, 48.99; H, 5.03; N, 12.70. Found: C, 49.3; H, 5.1; N, 12.6.;
All reactions were carried out under an air atmosphere. All
commercial reagents and solvents were used as received without
further purification. The reactions were monitored by TLC using
silica gel plates and column chromatography was performed with
Merck silica gel 60 (230-400 mesh). 1H NMR and 13C NMR
spectra were recorded on Bruker AVANCE III 500. Chemical
shift values (δ) are given in parts per million using residual
solvent as internal standard. Mass spectra were obtained on an
Agilent 6400 Triple Quadrupole Mass spectrometer instrument
using ESI. Melting points were measured with a Stuart SMP40
apparatus. IR spectra were recorded on a Smiths IdentifyIR.
4.2.6.
N'-(4-nitrophenyl)-N,N-dimethyl-formamidine
1
hydrochloride (6g). White solid; mp 280-282 °C; H NMR (500
MHz, MeOD) δ 8.87 (s, 1H), 8.34 (d, J = 9.1 Hz, 2H), 7.67 (d, J
= 9.1 Hz, 2H), 3.52 (s, 3H), 3.39 (s, 3H); 13C NMR (126 MHz,
MeOD) δ 154.10, 145.57, 142.69, 125.12, 119.22, 43.52, 36.76;
LC/MS (ESI) m/z 194 [M+H]+; IR (ATR): ν = 2883, 1701, 1597,
1516, 1311, 854, 748 cm-1; Anal. Calcd for C9H12ClN3O2: C,
47.07; H, 5.27; N, 18.3. Found: C, 47.4; H, 5.1; N, 18.0;
4.2. General procedure for the preparation of N,N-dimehtyl
formamidines 6, 7
To the DMF (1 ml) was added dropwise phenyl chloroformate
(2 eq). The mixture was stirred for 5 minutes at room temperature.
Then 6-chloro-2-aminopyrazine (1 mmol) was introduced to the
mixture. After 5 minutes, the solvent (isopropyl alcohol: diethyl
ether, v/v = 1:2) was poured into the mixture. The precipitated
product 6a was filtered off, washed with the solvent and dried.
4.2.7.
N'-(4-methoxyphenyl)-N,N-dimethylformamidine
hydrochloride (6h). Slightly yellow solid; mp 203-205 °C; 1H
NMR (500 MHz, MeOD) δ 8.46 (s, 1H), 7.41 – 7.26 (m, 2H),
7.05 – 6.90 (m, 2H), 3.81 (s, 3H), 3.41 (s, 3H), 3.27 (d, J = 0.6
Hz, 3H); 13C NMR (126 MHz, MeOD) δ 160.10, 155.30, 131.54,
122.76, 116.00, 56.08, 44.16, 37.42; LC/MS (ESI) m/z 179
[M+H]+; IR (ATR): ν = 2970, 2810, 1689, 1507, 1341, 1236,
1019, 794 cm-1; Anal. Calcd for C10H15ClN2O: C, 55.50; H, 7.04;
N, 13.05. Found: C, 55.91; H, 7.02; N, 13.04; HRMS (ESI) m/z
calcd for C10H15N2O [M+H]+ 179.1184, found 179.1178;
4.2.1.
N'-(6-chloropyrazin-2-yl)-N,N-dimethylformamidine
1
hydrochloride (6a). White solid; mp 224-226 °C (decomp.); H
NMR (500 MHz, MeOD) δ 9.09 (t, J = 0.7 Hz, 1H), 8.64 (d, J =
0.6 Hz, 1H), 8.58 (d, J = 0.5 Hz, 1H), 3.57 (d, J = 0.6 Hz, 3H),
3.45 (d, J = 0.8 Hz, 3H); 13C NMR (126 MHz, MeOD) δ 154.11,
148.22, 146.78, 142.47, 134.28, 45.51, 38.90; LC/MS (ESI) m/z
185 [M+H]+; IR (ATR): ν = 3037, 3012, 2689, 1700, 1541, 1383,
1305, 1156, 818 cm-1; Anal. Calcd for C7H10Cl2N4: C, 38.03; H,
4.56; N, 25.34. Found: C, 37.6; H, 4.7; N, 25.1. HRMS (ESI) m/z
calcd for C7H10ClN4 [M+H]+ 184.0594, found 184.0596;
4.2.8.
N'-(2-hydroxyphenyl)-N,N-dimethylformamidine
hydrochloride (6i). Slightly orange solid; mp 155-157 °C; 1H
NMR (500 MHz, MeOD) δ 8.42 (s, 1H), 7.28 (dd, J = 7.9, 1.5 Hz,
1H), 7.19 (ddd, J = 8.2, 7.5, 1.6 Hz, 1H), 6.99 (dd, J = 8.2, 1.3 Hz,
1H), 6.91 (td, J = 7.8, 1.3 Hz, 1H), 3.45 – 3.37 (m, 3H), 3.29 (d, J
= 0.6 Hz, 3H); 13C NMR (126 MHz, MeOD) δ 157.09, 151.45,
129.75, 125.69, 124.85, 121.17, 117.54, 44.20, 37.09; LC/MS
(ESI) m/z 165 [M+H]+; IR (ATR): ν = 3075, 2966, 1689, 1344,
1281, 1131, 748, 681 cm-1; Anal. Calcd for C9H13ClN2O: C,
53.87; H, 6.53; N, 13.96. Found: C, 53.3; H, 6.8; N, 13.9; HRMS
(ESI) m/z calcd for C9H13N2O [M+H]+ 165.1028, found
165.1025;
4.2.2. N,N-dimethyl-N'-(pyridin-3-yl)formamidine (6b). To the
DMF was added dropwise phenyl chloroformate. The mixture
was stirred for 5 minutes in room temperature. Then 3-
aminopyridine was introduced to the mixture. After 5 minutes,
the mixture was basified with K2CO3(aq), extracted with ethyl
acetate and washed with water. The organic layer was dried over
MgSO4, filtered and concentrated. The residue was purified by
column chromatography to give the product. colorless oil; 1H
NMR (500 MHz, CDCl3) δ 8.30 – 8.21 (m, 2H), 7.52 (s, 1H),
7.28 – 7.23 (m, 1H), 7.17 (dd, J = 7.9, 4.8 Hz, 1H), 3.05 (s,
6H).13C NMR (126 MHz, CDCl3) δ 153.80, 147.93, 143.68,
143.16, 128.07, 123.52, 40.30, 34.52; LC/MS (ESI) m/z 150
[M+H]+; IR (ATR): ν = 2921, 2808, 1628, 1573, 1473, 1372,
1266, 1233, 1104, 807, 712 cm-1;
4.2.9. Methyl N'-(thiophen-3-yl)-N,N-dimethylformamidine-2-
carboxylate hydrochloride (6j). To the DMF was added dropwise
phenyl chloroformate. The mixture was stirred for 5 minutes at
room temperature. Then methyl 3-amino-2-thiophenecarboxylate
was introduced to the mixture. After 5 minutes, the mixture was
basified with K2CO3(aq), extracted with ethyl acetate and washed
with water. The organic layer was dried over MgSO4, filtered and
concentrated. The residue was diluted with diethyl ether and HCl
(3 M in diethyl ether) was added. The solution was heated at
35 °C for 10 min. The precipitated product 6j was filtered off,
washed with the solvent (isopropyl alcohol: diethyl ether, v/v =
4.2.3. N,N-dimethyl-N'-(pyrazin-2-yl)formamidine (6c). Slightly
yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.26 (d, J
= 1.4 Hz, 1H), 8.09 (dd, J = 2.7, 1.5 Hz, 1H), 8.05 (d, J = 2.7 Hz,
1H), 3.09 (d, J = 1.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ
158.18, 156.20, 142.14, 141.60, 137.86, 40.97, 34.83; LC/MS
(ESI) m/z 151 [M+H]+; IR (ATR): ν = 3045, 2931, 1614, 1568,
1379, 1099, 1007, 836 cm-1;
1
1:2) and dried. Slightly yellow solid; mp 175-177 °C; H NMR
(500 MHz, MeOD) δ 8.99 (s, 1H), 7.90 (d, J = 5.4 Hz, 1H), 7.49
(d, J = 5.5 Hz, 1H), 3.94 (s, 3H), 3.52 (s, 3H), 3.36 (s, 3H); 13C
NMR (126 MHz, MeOD) δ 165.03, 155.44, 142.70, 134.78,
120.79, 116.49, 53.20, 44.52, 37.17; LC/MS (ESI) m/z 213
[M+H]+; IR (ATR): ν = 3452, 3052, 1671, 1584, 1450, 1279, 787
cm-1; Anal. Calcd for C9H13ClN2O2S: C, 43.46; H, 5.27; N, 11.26.
Found: C, 42.57; H, 5.76; N, 11.27; HRMS (ESI) m/z calcd for
C9H13N2O2S [M+H]+ 213.0698, found 213.0701;
4.2.4.
N'-(5-bromo-6-chloropyrazin-2-yl)-N,N-
dimethylformamidine hydrochloride (6d). White solid; mp 263-
1
266 °C (decomp.); H NMR (500 MHz, MeOD) δ 9.05 (s, 1H),
8.44 (s, 1H), 3.56 (s, 3H), 3.43 (s, 3H); 13C NMR (126 MHz,
MeOD) δ 154.21, 148.70, 145.93, 135.81, 134.05, 45.51, 38.89;

ACCEPTED MANUSCRIPT
5
4.2.10.
N'-(2-acetylphenyl)-N,N-dimethylformamidine
7.03 – 6.86 (m, 3H), 3.35 (s, 3H), 3.19 (s, 3H); 13C NMR (126
1
hydrochloride (6k). White solid; mp 167-169 °C (decomp.); H
NMR (500 MHz, MeOD) δ 9.11 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H),
7.82 – 7.73 (m, 2H), 7.51 – 7.42 (m, 1H), 3.54 (s, 3H), 3.38 (s,
3H), 2.76 (s, 3H); 13C NMR (126 MHz, MeOD) δ 205.26, 154.36,
138.93, 136.63, 134.06, 127.13, 124.59, 118.08, 44.47, 37.37,
28.55; LC/MS (ESI) m/z 191 [M+H]+; IR (ATR): ν = 3374, 2882,
1683, 1630, 1307, 1255, 774 cm-1 Anal. Calcd for C11H15ClN2O:
C, 58.28; H, 6.67; N, 12.36. Found: C, 56.3; H, 7.0; N, 11.8;
HRMS (ESI) m/z calcd for C11H15N2O [M+H]+ 191.1184, found
191.1183;
MHz, MeOD) δ 159.82, 147.06, 128.96, 121.53, 113.44, 42.60,
36.27; LC/MS (ESI) m/z 164 [M+H]+; IR (ATR): ν = 3190, 2977,
2770, 1707, 1486, 770, 753, 703 cm-1; Anal. Calcd for
C9H14ClN3: C, 54.14; H, 7.07; N, 21.04. Found: C, 54.1; H, 7.2;
N, 21.10;
4.2.18.
N,N-dimethyl-N'-(phenylsulfonyl)formamidine
(7d).
1
White solid; mp 128-130 °C; H NMR (500 MHz, CDCl3) δ 8.13
(s, 1H), 7.91 – 7.84 (m, 2H), 7.54 – 7.47 (m, 1H), 7.47 – 7.42 (m,
2H), 3.12 (s, 3H), 3.01 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
159.33, 142.52, 131.94, 128.81, 126.56, 41.61, 35.64; LC/MS
(ESI) m/z 213 [M+H]+; IR (ATR): ν = 2930, 1613, 1280, 1145,
1086, 906, 846, 685 cm-1;
4.2.11. N'-(pyridin-2-yl)-N,N-dimethylformamidine-3-carboxylic
acid hydrochloride (6l). White solid; mp 214-216 °C (decomp.);
1H NMR (500 MHz, MeOD) δ 9.47 (s, 1H), 8.61 (dd, J = 4.8, 1.8
Hz, 1H), 8.54 (dd, J = 7.9, 1.8 Hz, 1H), 7.43 (dd, J = 7.9, 4.8 Hz,
1H), 3.58 (s, 3H), 3.41 (d, J = 0.7 Hz, 3H); 13C NMR (126 MHz,
MeOD) δ 168.72, 152.65, 151.53, 149.37, 141.01, 121.39, 112.16,
43.57, 36.49; LC/MS (ESI) m/z 194 [M+H]+; IR (ATR): ν = 3033,
2280, 1826, 1688, 1638, 1210, 778 cm-1; Anal. Calcd for
C9H12ClN3O2: C, 47.07; H, 5.27; N, 18.30. Found: C, 47.04; H,
5.28; N, 18.26;
4.3. General procedure for reaction of 6-chloro-2-
aminopyrazine with amides
To the N,N-diethylformamide (1 ml) was added dropwise
phenyl chloroformate (3.5 eq). The mixture was stirred for 10
minutes at room temperature. Then 6-chloro-2-aminopyrazine (1
mmol) was introduced to the mixture. After 5 minutes at 45 °C,
the mixture was basified with K2CO3(aq), extracted with ethyl
acetate and washed with water. The organic layer was dried over
MgSO4, filtered and concentrated. The residue was purified by
column chromatography to give the product.
4.2.12.
N'-(benzo[d]thiazol-2-yl)-N,N-dimethylformamidine
1
hydrochloride (6m). White solid; mp 197-200 °C; H NMR (500
MHz, MeOD) δ 8.57 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.62 –
7.52 (m, 2H), 7.48 – 7.40 (m, 1H), 3.43 (s, 3H), 3.32 (d, J = 3.4
Hz, 3H); 13C NMR (126 MHz, MeOD) δ 176.00, 162.64, 138.89,
129.44, 126.86, 126.61, 124.24, 115.84, 42.69, 36.93; LC/MS
(ESI) m/z 206 [M+H]+; IR (ATR): ν = 2425, 1637, 1535, 1458,
1394, 1186, 773 cm-1; Anal. Calcd for C10H12ClN3S: C, 49.69; H,
5.00; N, 17.38. Found: C, 49.11; H, 5.01; N, 17.32; HRMS (ESI)
m/z calcd for C10H12N3S[M+H]+ 206.0752, found 206.0755;
4.2.19. N'-(6-chloropyrazin-2-yl)-N,N-diethylformamidine (8a).
1
Slightly yellow oil; H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H),
8.12 (s, 1H), 8.04 (s, 1H), 3.59 (q, J = 7.2 Hz, 2H), 3.40 (q, J =
7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 158.04, 155.89, 146.72, 139.11,
135.72, 46.52, 40.09, 14.93, 12.48; LC/MS (ESI) m/z 213
[M+H]+; IR (ATR): ν = 2975, 2936, 2875, 1605, 1387, 1158,
1115 cm-1;
4.2.13. N'-benzyl-N,N-dimethylformamidine (6n). Slightly yellow
1
oil; H NMR (500 MHz, MeOD) δ 7.52 (s, 1H), 7.29 (m, 2H),
4.2.20.
6-chloro-N-(piperidin-1-ylmethylene)pyrazin-2-amine
1
7.24 (m, 2H), 7.21 (m, 1H), 4.39 (s, 2H), 2.90 (s, 6H); 13C NMR
(126 MHz, MeOD) δ 158.75, 142.90, 129.29, 128.55, 127.64,
59.47, 38.18; LC/MS (ESI) m/z 163 [M+H]+; IR (ATR): ν = 3031,
1658, 1383, 1238, 696 cm-1;
(8b). Slightly yellow solid; mp 71-73 °C; H NMR (500 MHz,
CDCl3) δ 8.49 (s, 1H), 8.12 (s, 1H), 8.04 (s, 1H), 3.73 (m, 2H),
3.44 (m, 2H), 1.67 (m, 6H); 13C NMR (126 MHz, CDCl3) δ
158.03, 155.48, 146.74, 138.98, 135.76, 51.54, 44.02, 26.69,
25.21, 24.51; LC/MS (ESI) m/z 225 [M+H]+; IR (ATR): ν = 3069,
2941, 2855, 1696, 1607, 1353, 1157, 1000, 858 cm-1;
4.2.14. N'-(4-methoxybenzyl)-N,N-dimethylformamidine (6o).
1
Slightly yellow oil; H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H),
7.19 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 4.39 (s, 2H),
3.77 (s, 3H), 2.89 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 158.43,
155.69, 133.96, 128.76, 113.82, 58.19, 55.37, 37.54; LC/MS
(ESI) m/z 193 [M+H]+; IR (ATR): ν = 2933, 2836, 1646, 1510,
1242, 1059, 816 cm-1;
4.2.21. 6-chloro-N-(morpholinomethylene)pyrazin-2-amine (8c).
Slightly yellow solid; mp 121-123 °C; 1H NMR (500 MHz,
CDCl3) δ 8.52 (s, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 3.82 (m, 2H),
3.75 (m, 4H), 3.51 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
157.33, 155.43, 146.79, 139.01, 136.64, 67.15, 66.35, 50.04,
43.70; LC/MS (ESI) m/z 227 [M+H]+; IR (ATR): ν = 2980, 2911,
2867, 1609, 1389, 1348, 1162, 1104, 1006, 848 cm-1;
4.2.15. N'-(4-(trifluoromethyl)benzyl)- N,N-dimethylformamidine
(6p). Slightly yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J
= 8.1 Hz, 2H), 7.37 (m, 3H), 4.49 (s, 2H), 2.89 (s, J = 19.9 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 156.17, 146.57, 128.55 (q, J
4.2.22.
6-chloro-N-(1-methylpyrrolidin-2-ylidene)pyrazin-2-
1
amine (8e). Slightly yellow oil; H NMR (500 MHz, CDCl3) δ
8.11 (s, 1H), 8.00 (s, 1H), 3.45 (t, J = 7.1 Hz, 2H), 3.06 (s, 3H),
2.94 (t, J = 7.9 Hz, 2H), 2.06 (dt, J = 15.2, 7.6 Hz, 2H); 13C NMR
(126 MHz, CDCl3) δ 167.47, 158.76, 146.37, 139.50, 134.69,
51.38, 31.80, 29.69, 19.88; LC/MS (ESI) m/z 211 [M+H]+; IR
(ATR): ν = 2925, 2870, 2175, 1590, 1469, 1379, 1288, 1158,
1001, 921 cm-1;
= 32.2 Hz), 127.67, 125.11 (q, JCF = 3.8 Hz), 124.43 (q, JCF
=
271.7 Hz), 59.08, 37.77; LC/MS (ESI) m/z 231 [M+H]+; IR
(ATR): ν = 2871, 1648, 1321, 1108, 1065, 1017, 819 cm-1;
4.2.16. N'-benzoyl-N,N-dimethylformohydrazonamide (7a). the
procedure is same with 6c. Slightly yellow solid; mp 171-173 °C;
1H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H), 7.90 (s, 1H), 7.79 –
7.73 (m, 2H), 7.46 – 7.41 (m, 1H), 7.40 – 7.33 (m, 2H), 2.86 (s,
6H); 13C NMR (126 MHz, CDCl3) δ 180.30, 164.84, 157.95,
134.53, 131.12, 128.60, 126.97, 37.92; LC/MS (ESI) m/z 192
[M+H]+; IR (ATR): ν = 3216, 3064, 2905, 1603, 1572, 1355,
1110, 902, 694 cm-1;
Acknowledgments
This research was supported by grants from the National
Research Foundation of Korea (2010-0004128) funded by the
Ministry of Education, Science and Technology, and was funded
by the Ministry of Knowledge Economy, Korea.
4.2.17.
N,N-dimethyl-N'-phenylformohydrazonamide
hydrochloride (7b). Slightly yellow solid; mp 201-203 °C; 1H
NMR (500 MHz, MeOD) δ 8.32 (s, 1H), 7.28 (t, J = 7.1 Hz, 2H),
Supplementary data

ACCEPTED MANUSCRIPT
6
Tetrahedron
Copies of the 1H NMR and 13C NMR spectra of the
compounds.
References and notes
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12