Versatile novel syntheses of imidazoles

Article abstract of DOI:10.1021/jo970072h

A novel ring transformation/desulfurization of substituted 2-methyl-1,2,4-thiadiazolium salts 2 provides a versatile entry to imidazoles 3 with a variety of substituents. Simple one-pot procedures combine the preparation of starting 1,2,4-thiadiazolium salts 2 from N-(thiocarbonyl)-N'-methylamidines 1 or 1,2,4-dithiazolium triiodides 6 with the ring transformation/desulfurization to the imidazoles 3. Alternatively, N-(thiocarbonyl)-N'-methylamidines 1 can be transformed to imidazoles 3 or to 1-substituted imidazoles 5 via S-methylation and elimination of methylthiol. In the same manner, a new entry to 4H-imidazoles 8 could be developed.

Full text of DOI:10.1021/jo970072h

3480
J . Org. Chem. 1997, 62, 3480-3487
Ver sa tile Novel Syn th eses of Im id a zoles†
Andreas Rolfs and J u¨rgen Liebscher*
Institut fu¨r Chemie, Humboldt-Universita¨t Berlin, Hessische Strasse 1-2, D-10115 Berlin, Germany
Received J anuary 14, 1997X
A novel ring transformation/desulfurization of substituted 2-methyl-1,2,4-thiadiazolium salts 2
provides a versatile entry to imidazoles 3 with a variety of substituents. Simple one-pot procedures
combine the preparation of starting 1,2,4-thiadiazolium salts 2 from N-(thiocarbonyl)-N′-methyl-
amidines 1 or 1,2,4-dithiazolium triiodides 6 with the ring transformation/desulfurization to the
imidazoles 3. Alternatively, N-(thiocarbonyl)-N′-methylamidines 1 can be transformed to imidazoles
3 or to 1-substituted imidazoles 5 via S-methylation and elimination of methylthiol. In the same
manner, a new entry to 4H-imidazoles 8 could be developed.
Sch em e 1
In tr od u ction
Despite the numerous known syntheses of the imid-
azole ring, it is surprising that special substitution
patterns such as in 2-aryl-5-(N,N-dialkylamino)imid-
azole-4-carboxylates are as yet difficult to synthesize.1
Hence, there is still a need to develop general routes to
this heterocyclic system. Possibilities of constructing the
imidazole skeleton by ring closure of a C-N-C-N-C
precursor have rarely been investigated.1 Thus, base-
catalyzed cyclization of N-cyano-N′-methylamidines with
COO-alkyl, CN, or COPh substituents at the methyl
group affords 4-aminoimidazoles with electron-withdraw-
ing substituents at position 5,2-4 while ring closure of
2-azavinamidinium salts in the presence of sodium amide
gives 4-(dimethylamino)imidazoles.5 Condensed imid-
azoles were obtained by desulfurization of 3-[(acylami-
no)methyl]tetrahydro-1,3-thiazine-2-thiones in the pres-
ence of trifluoroacetanhydride.6 We now report novel and
very versatile routes to imidazoles 3, 5, and 8 starting
from N-(thiocarbonyl)amidines 1 as a C-N-C-N-C
building block or from 1,2,4-dithiazolium salts 6. In two
of these syntheses (methods A and B), a new type of ring
transformation of intermediate 1,2,4-thiadiazolium salts
2 is involved.
Resu lts a n d Discu ssion
The general background of the synthesis of imidazoles
3 was derived from a recently developed efficient access
to pyrroles based on the ring transformation/desulfur-
ization of 2-methyl-1,2-thiazolium salts that could be
obtained by oxidative ring closure of â-aminovinyl thio-
carbonyl compounds.7-9 Extending this concept to the
N-analogous 2-methyl-1,2,4-thiadiazolium salts 2 should
give rise to the formation of imidazoles 3. We therefore
approached the in-situ oxidative cyclization of substituted
N-methyl-N′-(thiocarbonyl)amidines 1 by applying hy-
drogen peroxide in methanol (method A) or iodine in the
presence of triethylamine (method B). The expected
1,2,4-thiadiazolium salts 2 undergo smooth desulfuriza-
tion/ring transformation to imidazoles 3, already in the
reaction mixture in most cases (Scheme 1). High yields
of 3 were obtained with a wide substitution pattern. It
turns out that electron-withdrawing substituents R3 such
as alkoxycarbonyl, cyano, aryl, or hetoaryl are required.
In the case of aminocarbonyl or 4-nitrophenyl substitu-
ents R3 the reaction is slower and intermediate 2-methyl-
1,2,4-thiadiazolium salt 2h (R3 ) CONH2) and the 2H-
1,3,5-thiadiazines 10d (R3 ) 4-NO2C6H4) and 10h (R3 )
CONH2) (see Scheme 3) can be isolated easily. The
transformation of alkoxycarbonyl-substituted compounds
1 (R3 ) COOalkyl) is fast. A corresponding intermediate
2e (R3 ) COOMe) could only be isolated under strongly
acidic conditions (see the Experimental Section). The
thiadiazolium salts 2e and 2h as well as the 2H-1,3,5-
thiadiazines 10d and 10h could be desulfurized and
† Dedicated to Professor Dr. Horst Hartmann on the occasion of his
60th birthday.
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) Ebel, K. Methoden der Organischen Chemie (Houben-Weyl);
Schaumann, E., Ed.; Thieme-Verlag: Stuttgart, New York, 1994; Vol.
E 8c, Part 3, p 1.
(2) Edenhofer, A. Helv. Chim. Acta 1975, 58, 2192.
(3) Gewald, K.; Heinhold, G. Monatsh. Chem. 1976, 107, 1413.
(4) Gompper, R.; Ga¨ng, M.; Saygin, F. Tetrahedron Lett. 1966, 1885.
(5) Gompper, R.; Schneider, C. S. Synthesis 1979, 215.
(6) Holzapfel, C. W.; von Platen, A. E. S. Afr. J . Chem. 1987, 40,
153; Chem. Abstr. 1988, 108, 21788.
(7) Rolfs, A.; Liebscher, J . Angew. Chem., Int. Ed. Engl. 1993, 32,
712.
(8) Rolfs, A.; Brosig, H.; Liebscher, J . J . Prakt. Chem. 1995, 337,
310.
(9) Rolfs, A.; Liebscher, J . J . Chem. Soc., Perkin Trans. 1 1996, in
press.
rearranged to the corresponding imidazoles 3e (R3
)
S0022-3263(97)00072-8 CCC: $14.00 © 1997 American Chemical Society

Versatile Novel Syntheses of Imidazoles
J . Org. Chem., Vol. 62, No. 11, 1997 3481
Ta ble 1. Syn th esis of Im id a zoles 3 a n d 5
yielda (%)/
substrate reagent solvent method
entry product
R1
R2
N(CH2)5
N(CH2CH2)2O
N(CH2CH2)2O
N(CH2CH2)2O
R3
mp (°C) (solvent)
1
2
3
4
5
3a
3b
3c
3d
C6H5
CO2CH3
CO2C2H5
CN
1a
1b
1c
1d
10d
1e
2e
1f
1g
10h
2h
1i
1j
1k
1l
1m
1n
1n
1o
1p
1q
1r
I2/NEt3
I2/NEt3
H2O2
I2/NEt3
NEt3
H2O2
NEt3
H2O2
H2O2
EtOAc
EtOAc
MeOH
EtOH
86/B
91/B
93/A
94/B
92/G
96/A
98/E
94/A
94/A
95/G
82/F
65/B
96/B
73/B
95/A
93/A
94/B
80/C
84/A
88/A
94/B
93/B
90/B
73/D
80/D
58/D
46/D
84/C
87/C
176-177 (MeOH)
4-ClC6H4
4-ClC6H4
4-ClC6H4
212-213 (EtOH/H2O)
251.5 (MeOH)
4-NO2C6H4
308-310 (EtOH)
EtOH
6
7
3e
4-CH3OC6H4
N(CH2CH2)2O
CO2CH3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOAc
MeOH
EtOAc
MeOH
MeOH
EtOH
190-191b (MeOH)
8
9
3f
3g
3h
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
N(CH2CH2)2O
N(CH2CH2)2O
N(CH2CH2)2O
CO2C(CH3)3
CO2Bn
CONH2
163-164 (EtOAc/hexane)
192-193 (EtOH)
247-249 (DMF/Et2O)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
NEt3
KHCO3
I2/NEt3
I2/NEt3
I2/NEt3
H2O2
H2O2
I2/NEt3
CH3I/NEt3 MeOH
H2O2
3i
3j
3k
3l
3m
3n
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
3,4-OCH2OC6H3 N(CH2CH2)2O
4-CF3C6H4
4-BrC6H4
N(CH2CH2)2O
N(CH3)2
N(CH2CH2)2NCH3 CO2CH3
COC6H5
CO2CH3
212-214 (EtOH)
122-122.5 (Et2O/hexane)
153-155 (MeOH)
CO2CH3
CO2CH3
CO2CH3
232-233 (AcOH/H2O)
203-204 (EtOAc/hexane)
213-214.5 (EtOAc/hexane)
N(CH2CH2)2O
N(CH2CH2)2O
3o
3p
3q
3r
3s
3t
3u
3v
3w
5a
5b
3-NO2C6H4
CH3
N(CH2CH2)2O
N(CH2CH2)2O
OC2H5
SC2H5
C6H5
CO2CH3
CO2CH3
CO2CH3
CO2CH3
CO2C2H5
CO2CH3
CO2CH3
CN
MeOH
MeOH
EtOH
EtOH
EtOAc
221-222 (MeCN)
H2O2
142-143c (Et2O)
C6H5
C6H5
C6H5
C6H5
I2/NEt3
I2/NEt3
I2/NEt3
177-179 (CH2Cl2/hexane)
183-184 (EtOAc/hexane)
178-180d,e (EtOAc/hexane)
191-193 (EtOAc/hexane)
182-183f (EtOAc/hexane)
200-201.5 (CHCl3)
1s
C6H5
6a
6b
6b
6c
1x
1y
H2NCH2R3 MeCN
H2NCH2R3 MeCN
H2NCH2R3 MeCN
H2NCH2R3 DMF
CH3I/NEt3 MeOH
CH3I/NEt3 MeOH
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
N(CH2CH2)2O
N(CH2CH2)2O
CO2C2H5
CO2CH3
CO2CH3
208-209 (EtOAc/hexane)
142-143 (MeOH)
106-107 (CH2Cl2/hexane)
a
c
e
f
Yield of purified material. Crystal change at b180-182 °C, 122 °C, d167-169 °C, (lit.18 166-167 °C, lit.19 173-175 °C), 147-148
°C.
COOMe), 3d (R3 ) 4-NO2C6H4), and 3h (R3 ) CONH2),
respectively, by treatment with bases (methods E, F, and
G). The transformation of the 1,2,4-thiadiazolium salt
2h to the imidazole 3h could also be effected in a stepwise
manner (method G) via the corresponding 2H-1,3,5-
thiadiazine (10h ) (see the Experimental Section) as an
isolated intermediate. For 2H-1,3,5-thiadiazines 10,
alternative 4H- or 5H-isomers were considered, but 13C
NMR shift of the sp3 ring carbon atom fits best to the
structure 10 if the NMR simulation program (ACD-
CNMR 1.1. and ACD-HNMR 1.0.) is applied to both
possible isomers.
Naturally N,N-disubstituted N′-(thiocarbonyl)amidines
1 (R4 ) methyl) can not be oxidized to 1,2,4-thiadiazolium
salts 2. In order to gain access to 1-substituted imid-
azoles 5, these amidines 1 were S-methylated with
methyl iodide in the presence of triethylamine (method
C). Intermediate N-imidoylisothioimidates 4 would be
expected, but loss of methylthiol afforded imidazoles 5
already in the reaction mixture. The application of
method C to N-monosubstituted (thiocarbonyl)amidines
1 (R4 ) H) gives rise to the same imidazoles 3 similarly
to the oxidative routes (methods A and B) but in
somewhat lower yields. Unlike 1, the bis(ethoxycarbon-
yl)methyl-substituted (thiocarbonyl)amidine 7 lacks a
CH2 group at the N-atom and thus affords the 4H-
imidazole-4,4-dicarboxylate 8 (Scheme 2) when subjected
to the S-alkylation procedure (method C). This example
represents an interesting new synthesis of 4H-imid-
azoles.10 The structure of 8 was proved by X-ray crystal
analysis.29 Sometimes while handling the 4H-imidazole-
4,4-dicarboxylate 8 (e.g., upon longer heating during
recrystallization), partial transformation to the corre-
sponding aromatic 1H-imidazole 3b was observed.
Sch em e 2
Finally, an extremely short synthesis of imidazoles 3
(R1 ) R2 ) aryl) was discovered by reaction of 3,5-diaryl-
1,2,4-dithiazolium triiodides 6 with glycinates or ami-
noacetonitrile (see Table 1, entries 24-27) (method D).
This ring transformation of 1,2,4-dithiazolium salts to
imidazoles 3 comprises nucleophilic ring opening11 to give
(thiocarbonyl)amidines 1 (R4 ) H), oxidation of the
(thiocarbonyl)amidines to 1,2,4-thiadiazolium salts 2 (X-
) I) by the triiodide anion, and conversion of the salts 2
to the imidazoles 3. If the corresponding 1,2,4-dithiazo-
lium perchlorates 16 rather than the triiodides 6 were
reacted with R3CH2NH2 no imidazoles 3 were obtained
but instead N-(thioacyl)amidines 1 (see Scheme 4) due
to the lack of an oxidizing counterion.
Taking into consideration both the known mechanism
of the conversion of â-aminovinyl thiocarbonyl compounds
to pyrroles and the observation of intermediates 2 and
10 in the newly developed synthesis of imidazoles 3, the
following reaction mechanism is proposed for the oxida-
tive transformation of (thiocarbonyl)amidines 1 to imid-
azoles 3 (see Scheme 3). Oxidation of (thiocarbonyl)-
amidines 1 causes ring closure to 1,2,4-thiadiazolium
salts 2 as previously shown for other (thiocarbonyl)-
amidines.12-14 Deprotonation of the NCH2 position of 2
(10) Sammes, M. P.; Katritzky, A. R. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton A. J ., Eds.; Academic Press: New
York, 1983; Vol. 35, p 413ff.
(11) Liebscher, J .; Hartmann, H. Liebigs Ann. Chem. 1977, 1005.
(12) Liebscher, J .; Hartmann, H. Heterocycles 1985, 23, 997.

3482 J . Org. Chem., Vol. 62, No. 11, 1997
Rolfs and Liebscher
Sch em e 3
Sch em e 4
5, and 8 from 1 and 7 demonstrate a considerable
extension of this type of ring synthesis starting from a
C-N-C-N-C precursor.
The starting materials 1 and 7 were obtained by
adopting known procedures, e.g., reaction of amines with
either 3,5-diaryl-1,2,4-dithiazolium salts 16,11 N-(thio-
carbonyl)imidoyl chlorides obtained by O-Cl exchange
from corresponding Ni2+ chelates 14 with thionyl chlo-
ride,20,21 or N-acylthioureas 16 with thiophosgene22 (see
Scheme 4).
Exp er im en ta l Section
Gen er a l Meth od s. All solvents were purchased from
commercial sources and used as received unless otherwise
stated. The reactions and the purities of compounds were
monitored by TLC performed on precoated silica gel plates
with a fluorescent indicator (Merck 60 F254). Merck Kieselgel
60 (0.040-0.063) was used for column chromatography. The
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Bruker AC-300 spectrometer with the solvent
peak as the reference. Elemental analyses were performed
with a Leco CHNS-932 apparatus.
initiates ring opening to N-(thiocarbonyl)-N′-alkylidene-
amidines 9. The latter undergo electrocyclic ring closure
to 2H-1,3,5-thiadiazines 10. Further deprotonation causes
desulfurization under ring contraction via anionic species
11 and 12. Final protonation of the resulting imidazole
anions affords the products 3. Ring contraction by base-
catalyzed desulfurization of 1,3,5-thiadiazines was re-
ported in the 4H-2,4,6-triaryl series.15
Regardless of this multistep character, the one-pot
synthesis of imidazoles 3 from (thiocarbonyl)amidines 1
is a very efficient and novel route to this heterocyclic ring
system. It allows a wide scope of substituents especially
with disubstituted amino, alkoxy, or alkylthio groups for
R2 at position 4. Until now, such substituent patterns
were rarely obtained by ring-closure synthesis5,16 but by
substituent modification (e.g., pharmaceutically active
4-(dialkylamino)imidazole-5-carboxylates were obtained
by reductive alkylation of N-unsubstituted 4-aminoimid-
azole-5-carboxylates17). The syntheses of imidazoles 3,
3,5-Diaryl-1,2,4-dithiazolium triiodides 6,11,23 3,5-diaryl-
1,2,4-dithiazolium perchlorate 16 (R1 ) R2 ) C6H5),11 ben-
zoylthiocarbamic acid O-ethyl ester 15 (R1 ) C6H5, R2
)
OC2H5)24 and benzoyldithiocarbamic acid ethyl ester 15 (R1 )
C6H5, R2 ) SC2H5)25 and Ni2+ chelate 14 (R1 ) C6H5, R2
)
N(CH2)5)20 were prepared according to literature procedures.
P r ep a r a tion of Sta r tin g Ma ter ia ls a n d P r ecu r sor s.
Gen er a l P r oced u r e for th e P r ep a r a tion of N′,N′-Disu b-
stitu ted N-Acylth iou r ea s 15 (Ad op ted fr om Ref 11).
A
stirred solution of acyl chloride (R1COCl) (0.1 mol) and KSCN
(11.7 g, 0.12 mol) in dry MeCN (150 mL) was refluxed (for time
see below). After the mixture was cooled to rt, a solution of
the corresponding amine (0.12 mol) in MeCN (40 mL) was
added dropwise (temperature maintained below 50 °C). The
mixture was stirred for 30 min and poured into an ice/water
mixture (500 mL), again with stirring. The precipitate was
collected and recrystallized from EtOH/H2O. The yields given
were not optimized.
(13) Liebscher; J .; Mitzner, E.; Radics, U.; Klempke, S. Z. Chem.
1985, 25, 363.
(14) Zyabrev, V. S.; Kharchenko, A. V.; Pirozhenko, V. V.; Drach,
B. S. J . Org. Chem. USSR (Engl. Transl.) 1989, 1583.
(15) Giordano, C.; Belli, A. Synthesis 1975, 167.
(16) Brown, T.; Kadir, D.; Mackenzie, G.; Shaw, G. J . Chem. Soc.,
Perkin Trans. 1 1979, 3107.
(17) Heyes, J .; Ward, N. Ger. Offen. 2,142,831, 02 March 1972;
Chem. Abstr. 1972, 76, 153744.
(18) Brackeen, M. F.; Stafford, J . A.; Feldmann, P. L.; Karanewsky,
D. S. Tetrahedron Lett. 1994, 1635.
(19) J ackson, B.; Ma¨rky, M.; Hansen, H.-J .; Schmid, H. Helv. Chim.
Acta 1972, 919.
(20) Beyer, L.; Hoyer, E.; Hennig, H.; Kirmse, R.; Hartmann, H.;
Liebscher, J . J . Prakt. Chem. 1975, 317, 829.
(21) Beyer, L.; Hartung, J . Tetrahedron 1984, 40, 405.
(22) Weber, G.; Hartung, J .; Beyer, L. Tetrahedron Lett. 1988, 29,
3475.
(23) Liebscher, J .; Hartmann, H. Heterocycles 1985, 23, 997.
(24) Loessner, L. J . Prakt. Chem. 1874, 10, 235.
(25) Wheeler, M. J . Am. Chem. Soc. 1901, 23, 292.

Versatile Novel Syntheses of Imidazoles
J . Org. Chem., Vol. 62, No. 11, 1997 3483
1-[N-Ben zoyl(th ioca r ba m oyl)]p ip er id in e [R 1 ) C6H5,
R2 ) N(CH2)5]: 2 h reflux, yield 80%, colorless solid; mp 126-
128 °C (lit.26 mp 122-123 °C).
solution of Et3N (3.1 g, 30 mmol) in THF (20 mmol) was added
dropwise with stirring. The mixture was refluxed and mag-
netically stirred for 2 h. After the mixture was cooled to rt,
Et3NH+Cl- was filtered off and washed with THF (50 mL).
The combined solutions were evaporated to dryness and
crystallized from EtOH/water (50 mL, 9:1).
4-[N-(4-Ch lor oben zoyl)(th iocar bam oyl)]m or ph olin e [R1
) 4-ClC6H4, R2 ) N(CH2CH2)2O]: 40 min reflux, yield 65%,
colorless solid; mp 152-153 °C (lit.26 mp 153-154 °C).
4-[N -(4-Me t h oxyb e n zoyl)(t h ioca r b a m oyl)]m or p h o-
lin e [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O]: 2 h reflux,
yield 74%, colorless solid; mp 136-137 °C (lit.27 mp 134 °C).
N-[(Meth oxyca r bon yl)m eth yl]-N′-[p ip er id in -1-yl(th io-
ca r bon yl)]ben za m id in e (1a ) [R1 ) C6H5, R2 ) N(CH2)5, R3
) CO2CH3, R4 ) H]: colorless solid, yield 66%; mp 111-113
°C; 1H NMR (CDCl3) δ 1.45 (m, 2 H), 1.56 (m, 4 H), 3.64 (m, 2
H), 3.70 (s, 3 H), 4.02 (m, 2 H), 4.11 (d, J ) 4.8 Hz, 2 H), 5.8
(br, 1 H), 7.30-7.45 (m, 5 H); 13C NMR δ 24.3, 25.5, 25.9, 43.9,
48.5, 50.2, 52.3, 127.5, 128.6, 130.7, 133.6, 157 (br), 170.4, 188
(br). Anal. Calcd for C16H21N3O2S: C, 60.16; H, 6.63; N, 13.16;
S, 10.04. Found: C, 60.18; H, 6.68; N, 13.20; S, 10.08.
4-Ch lor o-N-[(eth oxyca r bon yl)m eth yl]-N′-[m or p h olin o-
N-(4-Meth oxyben zoyl)-N′,N′-d im eth ylth iou r ea [R1
)
4-CH3OC6H4, R2 ) N(CH3)2]: 2 h reflux, yield 51%, colorless
solid; mp 127-128 °C (lit.26 mp 121-122 °C).
1-[N-(4-Meth oxyben zoyl)(th iocar bam oyl)]-4-m eth ylpip-
er a zin e [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH )2NCH3]: 2 h
2
reflux, yield 72%, colorless solid; mp 171-173 °C. Anal. Calcd
for C14H19N3O2S: C, 57.31; H, 6.53; N, 14.33; S, 10.93.
Found: C, 57.29; H, 6.76; N, 14.36; S, 10.90.
4-[N-[3,4-(Meth ylen ed ioxy)ben zoyl](th ioca r ba m oyl)]-
m or p h olin e [R1 ) 3,4-OCH2OC6H4, R2 ) N(CH2CH2)2O]:
1 h reflux, yield 77%, colorless solid; mp 173-174 °C. Anal.
Calcd for C13H14N2O4S: C, 53.05; H, 4.79; N, 9.52; S, 10.89.
Found: C, 53.20; H, 4.48; N, 9.69; S, 10.88.
(th ioca r bon yl)]ben za m id in e (1b) [R1 ) 4-ClC6H4, R2
)
N(CH2CH2)2O, R3 ) CO2C2H5, R4 ) H]: colorless solid, yield
1
50%; mp 140-142 °C; H NMR (CDCl3) δ 1.23 (t, J ) 7.1 Hz,
3 H), 3.56 (m, 2 H), 3.64 (m, 2 H), 3.74 (br, 2 H), 4.07 (br, 2
H), 4.08 (d, J ) 4.7 Hz, 2 H), 4.15 (q, J ) 7.1 Hz, 2 H), 5.8 (br,
1 H), 7.32 (s, 4 H); 13C NMR δ 14.2, 44 (br), 47.8, 49.0, 61.8,
66.3, 66.6, 129.0, 137.1, 131.8 (br), 157 (br), 169.6, 188 (br).
Anal. Calcd for C16H20ClN3O3S: C, 51.96; H, 5.45; N, 11.36;
S, 8.67. Found: C, 51.73; H, 5.65; N, 11.06; S, 8.60.
4-[N-[4-(Tr iflu or om et h yl)b en zoyl](t h ioca r b a m oyl)]-
m or p h olin e [R1 ) 4-CF 3C6H4, R2 ) N(CH2CH2)2O]: 2 h
reflux, yield 63%, colorless solid; mp 167-169 °C. Anal. Calcd
for C13H13F3N2O2S: C, 49.05; H, 4.12; N, 8.80; S, 10.07.
Found: C, 49.04; H, 4.46; N, 8.47; S, 9.83.
Gen er al P r ocedu r e for th e P r epar ation of [Am in o(th io-
ca r bon yl)]a m id in es 1 a n d 7 Sta r tin g fr om Acylth iou r ea s
15 (Ad op ted fr om Ref 22). A solution of SCCl2 (4.85 g, 42
mmol) in dry acetone (15 mL) was added to a stirred solution
of N′,N′-disubstituted N-acylthiourea 15 (40 mmol) in dry
acetone (150 mL). After 15 min of stirring the solvent was
evaporated. The remaining yellow crude product was dis-
solved in dry MeCN (140 mL) and combined with H2NCHR3R4
HCl (40 mmol). A solution of Et3N (8.1 g, 80 mmol) in MeCN
(20 mL) was added dropwise with stirring. After 10 min,
EtOH (20 mL) was added and the solvent of the reaction
mixture removed by rotary evaporation. The residue was
recrystallized by dissolution in hot EtOH (80 mL) and then
by the dropwise addition of water (10 mL) to the hot solution.
After cooling, the product was collected and recrystallized. If
no crystals were formed the solution was poured into water
(250 mL) and extracted three times with EtOAc (about 100
mL). The organic layer was washed with water, dried with
Na2SO4, and then concentrated and purified by chromatogra-
phy (short column, silica gel) using EtOAc/hexane. In most
cases, it was possible to observe traces (but up to 23% for 1i)
of the corresponding imidazole 3 in the reaction mixture. All
substances are colorless solids if not otherwise stated. In some
cases, not all 13C NMR signals appeared or were broad.
4-Ch lor o-N-(cya n om e t h yl)-N′-[m or p h olin o(t h ioca r -
bon yl)]ben za m id in e (1c) [R1 ) 4-ClC6H4, R2 ) N(CH2-
4-[N-(4-Br om oben zoyl)(th iocar bam oyl)]m or ph olin e [R1
) 4-Br C6H4, R2 ) N(CH2CH2)2O]: 2 h reflux, yield 52%,
colorless solid; mp 159-160 °C. Anal. Calcd for C12H13
-
BrN2O2S: C, 43.78; H, 3.98; N, 8.51. Found: C, 43.67; H, 3.83;
N, 8.69.
4-[N-(3-Nitr oben zoyl)(th ioca r ba m oyl)]m or p h olin e [R1
) 3-NO2C6H 4, R 2 ) N(CH 2CH 2)2O]: 40 min reflux, yield
36%, colorless solid; mp 154-155 °C. Anal. Calcd for
C12H13N3O4S: C, 48.80; H, 4.44; N, 14.23; S, 10.86. Found:
C, 48.80; H, 4.12; N, 14.21; S, 10.89.
4-[N-Acetyl(th ioca r ba m oyl)]m or p h olin e [R1 ) CH3, R2
28
) N(CH2CH2)2O]. N-Acetyldithiocarbamic acid ethyl ester
(16.3 g, 0.1 mol) was heated with morpholine (8.7 g, 0.1 mol)
in EtOH (120 mL) for 0.5 h, followed by evaporation of the
solvent. Acetone was added and the product precipitated with
hexane: colorless solid, yield 42%; mp 132-133 °C. Anal.
Calcd for C7H12N2O2S: C, 44.66; H, 6.43; N, 14.88. Found:
C, 44.83; H, 6.41; N, 14.75.
Ni2+-Ch ela tes 14 were prepared according to the literature
procedure.20
R1 ) 4-ClC6H4, R2 ) N(CH2CH2)2O: light brown solid, yield
91%; mp 299 °C dec. Anal. Calcd for C24H24Cl2N4O4S2Ni: C,
46.03; H, 3.86; N, 8.95. Found: C, 45.90; H, 3.81; N, 8.94.
Gen er al P r ocedu r e for th e P r epar ation of [Am in o(th io-
ca r bon yl)]a m id in es 1 (R4 ) H) Sta r tin g fr om Nick el
Ch ela tes 14 (Ad op ted fr om Ref 21). Ni2+ chelate 14 (10
mmol) was suspended in dry CCl4 (60 mL). A solution of SOCl2
(3.14 g, 20 mmol) in CCl4 (10 mL) was added under stirring
over a period of 30 min. The mixture was gently warmed
(about 50 °C) for 30 min. After the mixutre was cooled to rt,
the precipitated NiCl2 was removed by suction filtration and
washed with CCl4 (50 mL). The combined filtrates were evapo-
rated to give the corresponding crude yellow imidoyl chloride,
which was used without further purification [R1 ) C6H5, R2 )
N(CH2)5: yield 67%; R1 ) 4-ClC6H4, R2 ) N(CH2CH2)2O: yield
68%]. The crude product (15 mmol) was suspended in dry THF
1
CH2)2O, R3 ) CN, R4 ) H]: yield 47%; mp 172-174 °C; H
NMR (DMSO-d6) δ 3.62 (m, 4 H), 3.89 (m, 2 H), 3.99 (m, 2 H),
4.29 (s, 2 H), 7.34 (d, J ) 8.5 Hz, 2 H), 7.51 (d, J ) 8.5 Hz, 2
H), 8.57 (s, 1 H); 13C NMR δ 29.8, 47.6, 48.7, 65.7, 65.9, 117.7,
128.5, 129.9, 131.4, 135.4, 156.9, 188.9. Anal. Calcd for
C14H15ClN4OS: C, 52.09; H, 4.68; N, 17.36; S, 9.93; Cl, 10.98.
Found: C, 52.00; H, 4.67; N, 17.17; S, 9.93; Cl; 11.19.
4-Ch lor o-N-[m or ph olin o(th iocar bon yl)]-N′-(4-n itr oben -
zyl)ben za m id in e (1d ) [R 1 ) 4-ClC6H4, R2 ) N(CH2CH2)2O,
R3 ) 4-NO2C6H4, R4 ) H]: yield 53%; mp 154-156 °C; 1H
NMR (CDCl3) δ 3.57 (m, 2 H), 3.70 (m, 2 H), 3.81 (br, 2H),
4.14 (m, 2 H), 4.63 (d, J ) 5.9 Hz, 2 H), 7.31-7.38 (m, 4 H),
7.47 (d, J ) 8.7 Hz, 2 H), 8.18 (d, J ) 8.7 Hz, 2 H). Anal.
Calcd for C19H19ClN4O3S: C, 54.48; H, 4.57; N, 13.38; S, 7.65.
Found: C, 54.36; H, 4.61; N, 13.41; S, 7.63.
(80 mL) and combined with H2NCH2R3‚HCl (15 mmol).
A
(26) Brindley, J . C.; Caldwell, J . M.; Meakins, G. D.; Plackett, S. J .;
Price, S. J . J . Chem. Soc., Perkin Trans. 1 1987, 1153.
(27) Uher, H.; Foltin, J .; Floch, L. Collect. Czech. Chem. Commun.
1981, 46, 11, 2696.
4-Meth oxy-N-[(m eth oxyca r bon yl)m eth yl]-N′-[m or p h o-
lin o(th ioca r bon yl)]ben za m id in e (1e) [R1 ) 4-CH3OC6H4,
R2 ) N(CH2CH2)2O, R3 ) CO2CH3, R4 ) H]: yield 56%; mp
1
153-155 °C; H NMR (CDCl3) δ 3.54 (m, 2 H), 3.64 (m, 2 H),
(28) Chanlarow, N. Chem. Ber. 1882, 15, 1987.
(29) We gratefully acknowledge Dr. Burghard Ziemer from Hum-
boldt-University Berlin for the X-ray structure determination of
compound 8. Full details can be obtained from the Fachinformation-
szentrum Karlsruhe, Gesellschaft fu¨r wissenschaftlich-technische
Information mbH, D-76344 Eggenstein-Leopoldshafen, Germany, on
quoting the full literature citation and the reference number CSD
406621.
3.71 (br, 2H), 3.71 (s, 3 H), 3.77 (s, 3 H), 4.10 (m, 4 H), 5.9 (br,
1 H), 6.83-6.87 (m, 2 H), 7.36-7.39 (m, 2 H); 13C NMR δ 44
(br), 47.7, 49.0, 52.4, 55.3, 66.2, 66.6, 114.1, 125.5, 129.3, 158
(br), 161.7, 170.4, 189 (br). Anal. Calcd for C16H21N3O4S: C,
54.68; H, 6.02; N, 11.96; S, 9.12. Found: C, 54.67; H, 6.28; N,
11.92; S, 9.00.

3484 J . Org. Chem., Vol. 62, No. 11, 1997
Rolfs and Liebscher
N -[(t er t -B u t o x y c a r b o n y l)m e t h y l]-4-m e t h o x y -N ′-
[m or ph olin o(th iocar bon yl)]ben zam idin e (1f) [R1 ) 4-CH3-
OC6H4, R2 ) N(CH2CH2)2O, R3 ) CO2C(CH3)3, R4 ) H]:
yield 64% (column chromatography); mp 152 °C; 1H NMR
(CDCl3) δ 1.42 (s, 9 H), 3.54 (m, 2 H), 3.63 (m, 2 H), 3.66 (br,
2 H), 3.76 (s, 3 H), 3.99 (d, J ) 5.2 Hz, 2 H), 4.11 (m, 2 H), 5.8
(br, 1 H), 6.83 (d, J ) 8.6 Hz, 2 H), 7.37 (d, J ) 8.6 Hz, 2 H);
13C NMR δ 28.0, 44.8 (br), 47.6, 48.9, 55.3, 66.3, 66.6, 82.4,
114.0, 125.8, 129.3, 157.5 (br), 161.6, 168.9, 189.5 (br). Anal.
Calcd for C19H27N3O4S: C, 57.99; H, 6.92; N, 10.68; S, 8.15.
Found: C, 58.01; H, 6.86; N, 10.70; S, 8.08.
NMR (CDCl3) δ 3.61 (m, 2 H), 3.67 (m, 2 H), 3.73 (s, 3 H), 3.78
(br, 2 H), 4.10 (m, 4 H), 5.9 (br), 7.52 (d, J ) 8.2 Hz, 2 H), 7.63
(d, J ) 8.2 Hz, 2 H); 13C NMR δ 44 (br), 47.9, 49.0, 52.6, 66.2,
66.6, 124 (q), 125.7 (d, J ) 3.5 Hz), 128.1, 132.5 (q), 137, 170.0.
Anal. Calcd for C16H18F3N3O3S: C, 49.35; H, 4.66; N, 10.79;
S, 8.23. Found: C, 49.08; H, 4.91; N, 10.69; S, 7.93.
4-Br om o-N-[(m et h oxyca r b on yl)m et h yl]-N′-[m or p h o-
lin o(th ioca r bon yl)]ben za m id in e (1n ) [R1 ) 4-Br C6H4, R2
) N(CH2CH2)2O, R3 ) CO2CH3, R4 ) H]: yield 55%; mp 159
1
°C; H NMR (CDCl3) δ 3.56 (m, 2 H), 3.64 (m, 2 H), 3.70 (s, 3
H), 3.73 (br, 2 H), 4.08 (m, 4H), 5.9 (br, 1 H), 7.26 (d, J ) 8.5
Hz, 2 H), 7.48 (d, J ) 8.5 Hz, 2 H); 13C NMR δ 44.1 (br), 47.9,
49.0, 52.6, 66.3, 66.6, 129.2, 132.0, 170.1. Anal. Calcd for
N-[(Ben zyloxyca r b on yl)m et h yl]-4-m et h oxy-N′-[m or -
p h olin o(th ioca r bon yl)]ben za m id in e (1g) [R1 ) 4-CH3-
OC6H4, R2 ) N(CH2CH2)2O, R3 ) CO2Bn , R4 ) H]: yield
71% (column chromatography); mp 123-124 °C; 1H NMR
(CDCl3) δ 2.61(m, 2 H), 3.63 (m, 4 H), 3.76 (s, 3 H), 4.10 (m,
2H), 4.15 (d, J ) 5.3 Hz, 2 H), 5.14 (s, 2 H), 5.9 (br, 1 H), 6.85
(d, J ) 8.7 Hz, 2 H), 7.32 (s, 5 H), 7.37 (d, J ) 8.7 Hz, 2 H);
13C NMR δ 44.3 (br), 47.6, 48.9, 55.3, 66.2, 66.6, 67.2, 114.1,
125.5, 128.3, 128.6, 128.7, 129.3, 135.2, 158 (br), 161.6, 169.8,
190 (br). Anal. Calcd for C22H25N3O4S: C, 61.80; H, 5.90; N,
9.83; S, 7.50. Found: C, 61.60; H, 5.94; N, 9.53; S, 7.25.
N-[(Am in oca r b on yl)m et h yl]-4-m et h oxy-N′-[m or p h o-
lin o(th ioca r bon yl)]ben za m id in e (1h ) [R1 ) 4-CH3OC6H4,
R2 ) N(CH2CH2)2O, R3 ) CONH2, R4 ) H]: yield 42%; mp
C15
H18N3O3S‚1H2O: C, 43.06; H, 4.82; N, 10.05; S, 7.66.
Found: C, 42.91; H, 4.87; N, 10.11; S, 7.77.
N-[(Met h oxyca r b on yl)m et h yl]-N′-[m or p h olin o(t h io-
ca r bon yl)]-3-n itr oben za m id in e (1o) [R1 ) 3-NO2C6H4, R2
) N(CH2CH2)2O, R3 ) CO2CH3, R4 ) H]: yield 57%; mp
1
199-201 °C; H NMR (DMSO-d6) δ 3.59 (m, 2 H), 3.65 (m, 2
H), 3.69 (s, 3 H), 3.74 (m, 2 H), 3.95 (m, 2 H), 4.07 (d, J ) 5.7
Hz, 2 H), 7.76 (m, 2 H), 8.15 (m, 1 H), 8.33 (m, 1 H), 8.74 (br,
1 H); 13C NMR δ 43.4, 47.4, 48.8, 52.1, 65.7, 66.0, 122.7, 125.1,
125.5, 130.2, 134.5, 147.3, 156,4, 170.2, 188.8. Anal. Calcd for
C15H18N4O5S: C, 49.17; H, 4.95; N, 15.30; S, 8.75. Found: C,
49.03; H, 4.65; N, 15.35; S, 8.70.
1
166-168 °C; H NMR (DMSO-d6) δ 3.51 (m, 2 H), 3.57 (m, 2
N-[(Met h oxyca r b on yl)m et h yl]-N′-[m or p h olin o(t h io-
car bon yl)]acetam idin e (1p) [R1 ) CH3, R2 ) N(CH2CH2)2O,
R3 ) CO2CH3, R4 ) H]: yield 40% (column chromatography);
mp 118.5-120 °C; 1H NMR (CDCl3) δ 2.14 (s, 3 H), 3.57 (m, 4
H), 3.67 (s, 3 H), 3.70 (m, 2 H), 3.96 (d, J ) 5.2 Hz, 2 H), 4.15
(m, 2 H), 5.61 (t, br, 1 H); 13C NMR δ 18.1, 43.0, 47.6, 49.2,
52.3, 66.4, 66.6, 157.0, 170.5, 190.3. Anal. Calcd for
C10H17N3O3S: C, 46.31; H, 6.61; N, 16.21. Found: C, 46.55;
H, 6.80; N, 15.91.
H), 3.71 (m, 2 H), 3.78 (s, 3 H), 3.80 (s, 2 H), 3.98 (m, 2 H),
6.96 (d, J ) 8.7 Hz, 2 H), 7.08 (s, 1H), 7.38 (d, J ) 8.7 Hz, 2
H), 7.38 (br, 1 H), 7.96 (br, 1H); 13C NMR δ 44.7, 47.2, 48.5,
55.3, 65.8, 66.0, 113.5, 125.7, 129.7, 157.4, 160.9, 170.9, 188.9.
Anal. Calcd for C15H20N4O3S: C, 53.55; H, 5.99; N, 16.66; S,
9.53. Found: C, 53.35; H, 6.23; N, 16.38; S, 9.49.
N-(Ben zoylm et h yl)-4-m et h oxy-N′-[m or p h olin o(t h io-
ca r bon yl)]ben za m id in e (1i) [R1 ) 4-CH3OC6H4, R2
)
N(CH2CH2)2O, R3 ) COC6H5, R4 ) H]: yield 21%; mp 160-
N-[Eth oxy(th iocar bon yl)]-N′-[(m eth oxycar bon yl)m eth -
1
162 °C; H NMR (CDCl3) δ 3.56 (m, 2 H), 3.68 (m, 2 H), 3.76
yl]ben za m id in e (1q) (R1 ) C6H5, R2 ) OC2H5, R3
)
(m, 2 H), 3.80 (s, 3 H), 4.16 (m, 2 H), 4.89 (d, J ) 4.5 Hz, 2 H),
6.5 (br, 1 H), 6.90 (m, 2 H), 7.44-7.64 (m, 5 H), 7.95 (m, 2 H);
13C NMR δ 47.7, 49.1, 55.4, 66.2, 66.6, 114.1, 125.7, 128.0,
129.0, 129.3, 134.3, 134.4, 158 (br), 161.8, 190 (br), 194.1.
Anal. Calcd for C21H23N3O3S: C, 63.45; H, 5.83; N, 10.57.
Found: C, 63.55; H, 5.79; N, 10.68.
CO2CH3, R4 ) H): yield 27% (column chromatography); mp
1
95-97 °C; H NMR (CDCl3) δ 1.16 (s, br, 3 H), 3.76 (s, 3 H),
4.23 (s, br, 2 H), 4.32 (d, J ) 6.7 Hz, 2 H), 6.07 (s, br, 1 H),
7.35-7.48 (m, 5 H); 13C NMR δ 13.8, 43.9, 52.7, 67.8, 127.7,
128.8, 131.3, 133.0, 160.2, 169.8, 201.3. Anal. Calcd for
C13H16N2O3S: C, 55.69; H, 5.75; N, 10.00; S, 11.44. Found:
C, 55.54; H, 5.70; N, 9.92; S, 11.38.
N -[(Dim e t h yla m in o)(t h ioca r b on yl)]-4-m e t h oxy-N ′-
[(m eth oxycar bon yl)m eth yl]ben zam idin e (1j) [R1 ) 4-CH3-
OC6H4, R2 ) N(CH3)2, R3 ) CO2CH3, R4 ) H]: yield 50%;
N-[(Eth ylth io)(th ioca r bon yl)]-N′-[(m eth oxyca r bon yl)-
m eth yl]ben za m id in e (1r ) (R1 ) C6H5, R2 ) SC2H5, R3
)
1
mp 158-160 °C; H NMR (CDCl3) δ 3.14 (s, 3 H), 3.34 (s, 3
CO2CH3, R4 ) H): yield 35% (column chromatography); mp
102-104 °C; 1H NMR (CDCl3) δ 1.24 (t, J ) 7.4 Hz, 3 H), 3.04
(q, J ) 7.4 Hz, 2 H), 3.74 (s, 3 H), 4.20 (br, 2 H), 6.18 (br, 1 H),
7.35-7.53 (m, 5 H); 13C NMR δ 13.4, 31.2, 44.0, 52.6, 128.1,
128.8, 131.4, 156.2, 169.7. Anal. Calcd for C13H16N2O2S2: C,
52.68; H, 5.44; N, 9.45. Found: C, 52.69; H, 5.35; N, 9.38.
H), 3.70 (s, 3 H), 3.76 (s, 3 H), 4.10 (d, J ) 4.4 Hz, 2 H), 6.0
(br, 1 H), 6.83 (d, J ) 8.7 Hz, 2 H), 7.36 (d, J ) 8.7 Hz, 2 H);
13C NMR δ 40.4, 42.7, 44.5, 52.8, 55.7, 114.4, 126.2, 129.6,
161.9, 170.9. Anal. Calcd for C14H19N3O3S: C, 54.35; H, 6.19;
N, 13.58. Found: C, 54.64; H, 6.19; N, 13.52.
4-Meth oxy-N-[(m eth oxyca r bon yl)m eth yl]-N′-[(1-m eth -
ylp ip er a zin -4-yl)(th ioca r bon yl)]ben za m id in e (1k ) [R1
)
)
4-Ch lor o-N-[(m eth oxyca r bon yl)m eth yl]-N-m eth yl-N′-
[m or p h olin o(t h ioca r b on yl)]b en za m id in e (1x) [R 1
)
4-CH3OC6H4, R2 ) N(CH2CH2)2NCH3, R3 ) CO2CH3, R4
4-ClC6H4, R2 ) N(CH2CH2)2O, R3 ) CO2CH3, R4 ) CH3]:
yield 55%; mp 150-152 °C; 13C NMR (CDCl3) δ 39.2, 47.8, 49.1,
51.3, 52.2, 66.2, 66.5, 128.7, 129.4, 130.2, 136.0, 156.9, 169.7,
189.6. Anal. Calcd for C16H20ClN3O3S: C, 51.96; H, 5.45; N,
11.36; S, 8.67; Cl, 9.58. Found: C, 51.88; H, 5.62; N, 11.25; S,
8.46, Cl, 9.73.
H]: colorless oil, yield 51% (column chromatography); crude
product was used without further purification; 1H NMR
(CDCl3) δ 2.26 (s, 3 H), 2.31 (m, 2 H), 2.40 (m, 2 H), 3.72 (s, 3
H), 3.76 (m, 2H), 3.77 (s, 3 H), 4.16 (m, 2 H), 4.12 (d, J ) 5.2
Hz, 2 H), 5.9 (br, 1 H), 6.85 (d, J ) 8.8 Hz, 2 H), 7.37 (d, J )
8.8 Hz, 2 H); 13C NMR δ 44.0, 45.8, 47.0, 48.6, 52.4, 54.5, 54.6,
55.3, 114.0, 125.6, 129.2, 157 (br), 161.6, 170.5, 189 (br).
3,4-(Met h ylen ed ioxy)-N-[(m et h oxyca r b on yl)m et h yl]-
4-Met h oxy-N-[(m et h oxyca r b on yl)m et h yl]-N-m et h yl-
N′-[m or p h olin o(th ioca r bon yl)]ben za m id in e (1y) [R1
)
4-CH3OC6H4, R2 ) N(CH2CH2)2O, R3 ) CO2CH3, R4 ) CH3]:
yield 48%; mp 130-132 °C; 1H NMR (CDCl3) δ 2.92 (s, 3 H),
3.60 (m, 4 H), 3.48 (br, 2 H), 3.69 (s, 3 H), 3.77 (s, 3 H), 4.02
(m, 2 H), 4.16 (s, br, 2 H), 6.85 (d, J ) 8.2 Hz, 2 H), 7.15 (d, J
) 8.2 Hz, 2 H); 13C NMR δ 39.4 (br), 47.7, 49.1, 51.5 (br), 52.1,
55.2, 66.3, 66.6, 113.7, 124.1, 129.6, 160.2, 160.7, 169.9, 190.1.
Anal. Calcd for C17H23N3O4S: C, 55.87; H, 6.34; N, 11.50.
Found: C, 55.74; H, 6.45; N, 11.53.
N′-[m or p h olin o(th ioca r bon yl)]ben za m id in e (1l) [R1
3,4-OCH2OC6H3, R2 ) N(CH2CH2)2O, R3 ) CO2CH3, R4
)
)
H]: yield 46%; mp 191-193 °C; 1H NMR (CDCl3) δ 3.60 (m, 2
H), 3.68 (m, 2 H), 3.73 (s, 3 H), 3.77 (br, 2 H), 4.12 (d, J ) 5.4
Hz, 2 H), 4.15 (m, 2 H), 5.8 (br, 1 H), 5.98 (s, 2 H), 6.78 (d, J
) 8.0 Hz, 1 H), 6.88 (d, J ) 1.7 Hz, 1 H), 6.95 (dd, J ) 8.0, 1.7
Hz, 1 H); 13C NMR δ 44.2, 47.8, 49.0, 52.5, 66.3, 66.6, 101.7,
108.1, 108.5, 122.2, 127.2, 147.9, 149.9, 170.2. Anal. Calcd for
C16H19N3O5S: C, 52.59; H, 5.24; N, 11.50; S, 8.77. Found: C,
52.41; H, 5.38; N, 11.14; S, 8.63.
N-[Bis(eth oxyca r bon yl)m eth yl]-4-ch lor o-N′-[m or p h o-
lin o(th ioca r bon yl)]ben za m id in e (7): yield 55%; mp 137-
1
N-[(Met h oxyca r b on yl)m et h yl]-N′-[m or p h olin o(t h io-
139 °C; H NMR (CDCl3) δ 1.27 (t, J ) 7.2 Hz, 6 H), 3.55 (m,
ca r bon yl)]-4-(tr iflu or om eth yl)ben za m id in e (1m ) [R1
)
2 H), 3.65 (m, 4 H), 4.08 (m, 2 H), 4.23 (m, 4 H), 5.18 (d, J )
6.3 Hz, 1 H), 6.18 (br, 1 H), 7.33-7.39 (m, 4 H); 13C NMR δ
14.0, 48.0, 49.1, 58.6, 62.8, 66.2, 66.5, 129.0, 129.1, 131.0, 137.3,
4-CF 3C6H4, R2 ) N(CH2CH2)2O, R3 ) CO2CH3, R4 ) H]:
yield 72.5% (column chromatography); mp 132-133 °C; 1H

Versatile Novel Syntheses of Imidazoles
J . Org. Chem., Vol. 62, No. 11, 1997 3485
155.5, 166.1, 189.3. Anal. Calcd for C19H24ClN3O5S: C, 51.64;
H, 5.47; N, 9.51; S, 7.26. Found: C, 51.43; H, 5.53; N, 9.51, S,
7.22.
cooling was filtered off by suction, washed first with MeOH
and then with Et2O, and dried: yield 95%; mp 167-170 °C
1
dec; H NMR (DMSO-d6) δ 3.68 (br s, 6 H), 3.79 (s, 3 H) 3.97
(br, 2 H), 5.49 (s, 1 H), 6.92 (d, J ) 8.9 Hz, 2 H), 7.75 (s, 1 H),
7.87 (s, 1 H), 8.17 (d, J ) 8.9 Hz, 2 H); 13C NMR δ 45.8 (br),
46.3 (br), 55.3, 64.6, 65.9, 113.2, 129.6, 129.8, 161.3, 161.4,
162.5, 170.8. Anal. Calcd for C15H18N4O3S: C, 53.87; H, 5.43;
N, 16.76; S, 9.59. Found: C, 53.72; H, 5.31; N, 16.83; S, 9.76.
Syn th esis of Im id a zoles. Gen er a l P r oced u r e for th e
P r ep a r a tion of th e Im id a zoles 3 by Oxid a tion of [Am in o-
(th ioca r bon yl)]a m id in es 1. For yields of pure compounds,
methods, and solvents see Table 1.
Meth od A (H2O2). [Amino(thiocarbonyl)]amidine 1 (10
mmol) was dissolved in MeOH (60 mL) with heating and
stirring. Excess H2O2 (about 15 mmol, 30% aqueous solution)
was added, and the solution was refluxed for 5 min. After
further stirring for 30 min, water (100 mL) was added.
Stirring was continued for a further 30 min. The resulting
precipitate was collected, washed with water, and dried. To
remove the sulfur the product was treated with a short column
(silica gel) and was eluted with hexane. If all sulfur was
removed, the imidazole 3 was eluted with EtOAc or CHCl3/
MeOH mixture.
Meth od B (I2). [Amino(thiocarbonyl)]amidine 1 (10 mmol)
and Et3N (2.55 g, 25 mmol) were dissolved in EtOH (60 mL)
or EtOAc (60 mL) with heating and stirring. A solution of I2
(2.54 g, 10 mmol) in EtOH or EtOAc (about 50 mL) was added.
If EtOAc was used as solvent Et3NH+I- precipitated; this could
be dissolved by addition of 20 mL of EtOH. After 1 h of stirring
at rt, the EtOAc solution was washed with water, dried with
Na2SO4. and purified with silica gel (see Method A). In the
case of EtOH as solvent, water (100 mL) was added and the
precipitate filtered off by suction, washed with water, dried,
and purified by column chromatography (see above). Alter-
natively, the removal of sulfur was possible by dissolving the
product in AcOH. Filtration of the sulfur and addition of water
to the AcOH solution afforded the imidazole 3.
P r ep a r a tion of N-[(Eth oxyca r bon yl)m eth yl]-N′-(th io-
ben zoyl)-4-ben za m id in e (1s) (R1 ) C6H5, R2 ) C6H5, R3
)
CO2C2H5, R4 ) H) Sta r tin g fr om 1,2,4-Dith ia zoliu m Sa lt
16. A solution of Et3N (2.02 g, 20 mmol) in dry MeCN (10
mL) was added dropwise to a stirred solution of 16 (3.55 g, 10
mmol) and ethyl glycinate hydrochloride (1.4 g, 10 mmol) in
dry MeCN (70 mL). After the mixture was stirred for 30 min
and the precipitated sulfur filtered off, water (200 mL) was
added. The mixture was extracted three times with EtOAc.
The organic phase was washed with water and dried with
Na2SO4. Chromatography on silica gel with hexane/EtOAc
afforded 1.82 g of the product 1s and 0.4g of the imidazole 3s:
red oil, yield 56% (column chromatography); 13C NMR δ 14.1,
44.9, 62.0, 127.9, 128.1, 128.7, 128.9, 131.6, 131.7, 133.1, 141
(br), 159 (br), 160.3. Anal. Calcd for C18H18N2O2S: C, 66.23;
H, 5.56; N, 8.58. Found: C, 66.21; H, 5.66; N, 8.57.
P r ep a r a t ion of 2-[(Met h oxyca r b on yl)m et h yl]-3-(4-
m eth oxyp h en yl)-5-m or p h olin o-1,2,4-th ia d ia zoliu m P er -
ch lor a te (2e) [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O, R3
) CO2CH3, X ) ClO4-]. H2O2 (1.7 mL, 30% aqueous solution)
was added dropwise with cooling to a solution of the (thiocar-
bonyl)amidine 1e (1.76 g, 5 mmol) in AcOH (30 mL). After 5
min, HClO4 (0.8 g, 5.5 mmol, 70% aqueous solution) was added.
The product was precipitated by dilution with Et2O, filtered
off by suction filtration, washed with Et2O, and recrystallized
from EtOH: colorless crystals; yield 54%; mp 175-177 °C; 1H
NMR (DMSO-d6) δ 3.57 (m, 2 H), 3.71 (s, 3 H), 3.79 (m, 4 H),
3.86 (s, 3 H), 3.97 (m, 2 H), 5.25 (s, 2 H), 7.16 (d, J ) 8.9 Hz,
2 H), 7.74 (d, J ) 8.9 Hz, 2 H); 13C NMR δ 47.8, 51.0, 51.6,
53.2, 55.8, 64.8, 65.2, 115.0, 117.8, 132.0, 163.2, 167.2, 171.1,
176.7. Anal. Calcd for C16H20ClN3O8S: C, 42.72; H, 4.48; N,
9.34; S, 7.13. Found: C, 42.43; H, 4.61; N, 9.42; S, 7.21.
P r ep a r a tion of [(2-Am in oca r bon yl)m eth yl]-3-(4-m eth -
oxyph en yl)-5-m or ph olin o-1,2,4-th iadiazoliu m Iodide (2h )
[R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O, R3 ) CONH2, X )
I-]. A 3.36 g (10 mmol) portion of the (thiocarbonyl)amidine
1h was dissolved in EtOH (100 mL) with stirring and heating.
This was then further combined with a solution of I2 (2.54 g,
10 mmol) in EtOH (70 mL). After 5 min, Et3N (1.01 g, 10
mmol) dissolved in EtOH (10 mL) was added dropwise. During
cooling to rt the product precipitated. It was filtered by
suction, washed first with EtOH and then with Et2O, and
finally dried: colorless solid; yield 3.74 g (81%); mp 176-180
All compounds are colorless solids, if not otherwise stated.
Meth yl 2-P h en yl-5-p ip er id in oim id a zole-4-ca r boxyla te
(3a ) [R1 ) C6H5, R2 ) N(CH2)5, R3 ) CO2CH3]. Method B:
1H NMR (CF3CO2D) δ 1.51 (br, 2 H), 1.71 (br, 4 H), 3.51 (m, 4
H), 3.74 (s, 3 H), 7.19-7.29 (m, 3 H), 7.51 (d, 2 H); 13C NMR
δ 23.8, 26.5, 55.9, 57.7, 113.0, 125.3, 129.6, 132.2, 135.9, 146.3,
149.6, 162.6. Anal. Calcd for C16H19N3O2: C, 67.34; H, 6.71;
N, 14.73. Found: C, 67.32; H, 6.43; N, 14.66.
E t h yl 2-(4-Ch lor op h en yl)-5-m or p h olin oim id a zole-4-
ca r boxyla te (3b) [R1 ) 4-ClC6H4, R2 ) N(CH2CH2)2O, R3
) CO2C2H5]. Method B: 1H NMR (CF3CO2D) δ 1.19 (tr, J )
7.2 Hz, 3 H), 3.45 (m, 4 H), 3.86 (m, 4 H), 4.29 (q, J ) 7.2 Hz,
2 H), 7.31 (d, J ) 8.6 Hz, 2 H), 7.56 (d, J ) 8.6 Hz, 2 H); 13C
NMR δ 15.1, 52.1, 67.0, 68.8, 109.7, 121.2, 131.0, 132.9, 144.3,
145.2, 148.4, 162.5. Anal. Calcd for C16H18ClN3O3: C, 57.23;
H, 5.40; N, 12.52. Found: C, 57.04; H, 5.61; N, 12.34.
2-(4-Ch lor op h en yl)-5-m or p h olin oim id a zole-4-ca r bon i-
tr ile (3c) [R1 ) 4-ClC6H4, R2 ) N(CH2CH2)2O, R3 ) CN].
Method A: 1H NMR (CF3CO2D) δ 4.09 (m, 4 H), 4.43 (m, 4 H),
7.89-7.92 (m, 2 H), 8.06-8.09 (m, 2 H); 13C NMR δ 50.1, 68.2,
86.6, 112.2, 121.0, 130.9, 133.2, 145.0, 146.2, 151.7. Anal.
Calcd for C14H13ClN4O: C, 58.23; H, 4.54; N, 19.41; Cl, 12.28.
Found: C, 58.20; H, 4.58; N, 19.15; Cl, 12.09.
1
°C dec; H NMR (DMSO-d6) δ 3.59 (s, br, 2 H), 3.78 (s, 4 H),
3.86 (s, 3 H), 3.95 (s, 2 H), 4.94 (s, 2 H), 7.19 (d, J ) 8.9 Hz, 2
H), 7.71 (s, 1 H), 7.74 (d, J ) 8.9 Hz, 1 H), 7.91 (s, 1 H); 13C
NMR δ 47.6, 51.4, 52.0, 55.9, 64.9, 65.3, 114.8, 118.5, 132.0,
162.9, 166.7, 170.7, 177.35. Anal. Calcd for C15H19IN4O3S: C,
38.97; H, 4.14; N, 12.12. Found: C, 38.75; H, 4.04; N, 12.41.
P r ep a r a tion of 4-(4-Ch lor op h en yl)-2-(4-n itr op h en yl)-
6-m or p h olin o-2H-1,3,5-th ia d ia zin e (10d ) [R1 ) 4-ClC6H4,
R2 ) N(CH2CH2)2O, R3 ) 4-NO2C6H4]. A solution of I2 (1.27
g, 5 mmol) in EtOH (50 mL) was added to a hot solution of
the (thiocarbonyl)amidine 1d (2.1 g, 5 mmol) in EtOH followed
by the addition of Et3N (0.51 g, 5 mmol) dissolved in EtOH
(10 mL). After the oxidation was complete as confirmed by
TLC, the same quantity of Et3N solution was added and the
resulting solution heated to reflux for 2 min. After cooling,
the precipitate was filtered off, washed with EtOH, and
dried: colorless solid; yield 81.5%; mp 179-181 °C dec; 1H
NMR (CDCl3) δ 3.78 (br s, 6 H), 4.09 (br s, 2 H), 6.02 (s, 1 H),
7.35 (d, J ) 8.6 Hz, 2 H), 7.75 (d, J ) 8.7 Hz, 2 H), 8.16 (d, J
) 8.6 Hz, 2 H), 8.24 (d, J ) 8.7 Hz, 2 H); 13C NMR δ 46 (br),
48 (br), 64.5, 66.5, 123.9, 128.2, 128.8, 129.2, 136.1, 136.7,
147.2, 147.8, 162.4, 163.5. Anal. Calcd for C19H17ClN4O3S: C,
54.74; H, 4.11; N, 13.44; S, 7.69. Found: C, 55.05; H, 4.14; N,
13.30; S, 7.48.
2-(4-Ch lor op h en yl)-4-m or p h olin o-5-(4-n it r op h en yl)-
im id a zole (3d ) [R1 ) 4-ClC6H4, R2 ) N(CH2CH2)2O, R3
)
4-NO2C6H4]. Method B: red solid; 1H NMR (CF3CO2D) δ 3.63
(m, 4 H), 4.38 (m, 4 H), 7.86 (d, J ) 8.6 Hz, 2 H), 8.08 (d, J )
8.6 Hz, 2 H), 8.32 (d, J ) 8.9 Hz, 2 H), 8.69 (d, J ) 8.9 Hz, 2
H); 13C NMR δ 52.5, 69.1, 121.9, 122.0, 127.2, 130.4, 130.5,
133.0, 135.3, 141.3, 143.8, 145.1, 150.4. Anal. Calcd for
C19H17ClN4O3: C, 59.30; H, 4.45; N, 14.56. Found: C, 59.15;
H, 4.41; N, 14.43.
P r ep a r a tion of 2-(Am in oca r bon yl)-4-(4-m eth oxyp h en -
yl)-6-m or p h olin o-2H-1,3,5-th ia d ia zin e (10h ) [R1 ) 4-CH3-
OC6H4, R2 ) N(CH2CH2)2O, R3 ) CONH2]. A 2.31 g (5
mmol) portion of 2h was dissolved in MeOH (60 mL) with
stirring and heating and was combined with a solution of Et3N
(0.51 g, 5 mmol) in MeOH (60 mL). The solid formed during
Meth yl 2-(4-Meth oxyp h en yl)-5-m or p h olin oim id a zole-
4-ca r boxyla te (3e) [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O,
R3 ) CO2CH3]. Method A: 1H NMR (CF3CO2D) δ 3.44 (m, 4
H), 3.70 (s, 3 H), 3.81 (s, 3 H), 3.85 (m, 4 H), 6.89 (d J ) 8.7
Hz, 2 H), 7.60 (d, J ) 8.7 Hz, 2 H); 13C NMR δ 51.5, 55.1,
57.0, 68.3, 108.0, 114.8, 117.5, 131.2, 145.6, 147.9, 162.4, 166.2.

3486 J . Org. Chem., Vol. 62, No. 11, 1997
Rolfs and Liebscher
Anal. Calcd for C16H19N3O4: C, 60.55; H, 6.04; N, 13.24.
Found: C, 60.58; H, 5.95; N, 13.20.
NMR δ 52.3, 55.8, 68.6, 110.0, 125.0, 125.1, 130.5, 134.0, 135.8,
142.9, 148.6, 151.1, 162.4. Anal. Calcd for C15H16N4O5: C,
54.21; H, 4.85; N, 16.86. Found: C, 53.91; H, 4.60; N, 16.91.
Met h yl 2-Met h yl-5-m or p h olin oim id a zole-4-ca r b oxyl-
a te (3p ) [R1 ) CH3, R2 ) N(CH2CH2)2O, R3 ) CO2CH3].
Method A: 1H NMR (CDCl3) δ 2.29 (s, 3 H), 3.39 (m, 4 H),
3.74 (s, 3 H), 3.77 (m, 4 H), 10.0 (br, 1 H); 13C NMR δ 14.4,
49.8, 51.2, 66.8, 104.4, 145.0, 156.3, 159.8. Anal. Calcd for
C10H15N3O3: C, 53.22; H, 6.71; N, 18.66. Found: C, 53.17; H,
6.81; N, 18.80.
Meth yl 5-Eth oxy-2-ph en ylim idazole-4-car boxylate (3q)
(R1 ) C6H5, R2 ) OC2H5, R3 ) CO2CH3). Method B: 1H NMR
(CF3CO2D) δ 1.68 (m, 3 H), 4.24, 4.25 (2s, 3 H), 4.80 (m, 2 H),
7.74-8.06 (m, 5 H); 13C NMR δ 15.9, 55.8, 76.2, 108.5, 119.1,
129.6, 132.5, 137.0, 144.9, 153.1, 163.0. Anal. Calcd for
C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.29; H,
5.63; N, 11.18.
Meth yl 5-(Eth ylth io)-2-p h en ylim id a zole-4-ca r boxyla te
(3r ) (R1 ) C6H5, R2 ) SC2H5, R3 ) CO2CH3). Method B: 1H
NMR (CF3CO2D) δ 1.54 (t, J ) 7.4 Hz, 3 H), 3.35 (q, J ) 7.4
Hz, 2 H), 4.29 (s, 3 H), 7.77-8.11 (m, 5 H); 13C NMR δ 15.2,
31.2, 55.8, 122.2, 125.4, 129.5, 132.2, 137.0, 139.1, 150.5, 162.5.
Anal. Calcd for C13H14N2O2S: C, 59.52; H, 5.38; N, 10.68; S,
12.22. Found: C, 59.47; H, 5.47; N, 10.66; S, 11.91.
ter t-Bu t yl 2-(4-Met h oxyp h en yl)-5-m or p h olin oim id -
a zole-4-ca r boxyla te (3f) [R1 ) 4-CH3OC6H4, R2 ) N(CH2-
CH2)2O, R3 ) CO2C(CH3)3]. Method A: 1H NMR (CDCl3) δ
1.53 (s, 9 H), 3.48 (m, 4 H), 3.79 (s, 3 H), 3.81 (m, 4 H), 6.90
(d, J ) 8.9 Hz, 2 H), 7.73 (d, J ) 8.9 Hz, 2 H), 9.48 (br, 1 H);
13C NMR δ 28.6, 49.9, 55.3, 66.9, 81.2, 106.9, 114.2, 121.9,
127.2, 144.6, 155.8, 159.4, 160.8. Anal. Calcd for C19H25N3O4:
C, 63.49; H, 7.01; N, 11.69. Found: C, 63.55; H, 7.08; N, 11.71.
Ben zyl 2-(4-Meth oxyp h en yl)-5-m or p h olin oim id a zole-
4-ca r boxyla te (3g) [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O,
R3 ) CO2Bn ]. Method A: 1H NMR (CF3CO2D) δ 3.79 (m, 4
H), 4.02 (m, 4 H), 4.19 (s, 3 H), 5.70 (s, 2 H), 7.39 (d, J ) 8.9
Hz, 2 H), 7.68 (s, 5 H), 8.11 (d, J ) 8.9 Hz, 2 H); 13C NMR δ
52.1, 57.6, 68.6, 72.8, 109.1, 115.3, 118.1, 131.5, 131.8, 132.3,
135.7, 146.4, 148.4, 162.6, 166.8. Anal. Calcd for C22H23N3O4:
C, 67.16; H, 5.89; N, 10.68. Found: C, 67.28; H, 5.88; N, 10.74.
4-Be n zoyl-2-(4-m e t h oxyp h e n yl)-5-m or p h olin oim id -
a zole (3i) [R 1 ) 4-CH 3OC6H 4, R 2 ) N(CH 2CH 2)2O, R 3
)
COC6H5]. Method B: yellow crystals; 1H NMR (CDCl3) δ 3.12
(m, 4 H), 3.45 (m, 4 H), 3.80 (s, 3 H), 6.80 80 (d, J ) 8.8 Hz,
2 H), 7.45-7.54 (m, 3 H), 7.88-7.91 8m, 2 H), 7.99 (d, J ) 8.8
Hz, 2 H), 11.33 (s, 1 H); 13C NMR δ 51.2, 55.3, 66.2, 114.1,
116.6, 121.6, 128.2, 128.5, 128.6, 131.8, 139.2, 148.2, 157.9,
161.1, 183.5. Anal. Calcd for C21H21N3O3: C, 69.40; H, 5.82;
N, 11.57. Found: C, 69.07; H, 5.62; N, 11.49.
Eth yl 2,5-Dip h en ylim id a zole-4-ca r boxyla te (3s) (R1
)
R2 ) C6H5, R3 ) CO2C2H5). Method B: 1H NMR (CF3CO2D)
δ 1.58 (t, J ) 7.2 Hz, 3 H), 4.78 (q, J ) 7.2 Hz, 2 H), 7.83-
8.33 (m, 10 H); 13C NMR δ 14.6, 67.3, 122.1, 122.7, 126.6, 129.8,
131.4, 131.9, 132.7, 134.6, 137.3, 142.9, 149.9, 162.9. Anal.
Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
74.05; H, 5.60; N, 9.56.
Meth yl 5-(Dim eth yla m in o)-2-(4-m eth oxyp h en yl)im id -
a zole-4-ca r boxyla te (3j) [R1 ) 4-CH3OC6H4, R2 ) N(CH3)2,
R3 ) CO2CH3]. Method B: 1H NMR (CDCl3) δ 3.13 (s, 6 H),
3.84 (s, 3 H), 3.85 (s, 3 H), 6.93 (d, J ) 8.9 Hz, 2 H), 7.82 (d,
J ) 8.9 Hz, 2 H), 9.6 (br, 1 H); 13C NMR δ 41.7, 51.1, 55.3,
104.0, 113.7, 121.9, 127.3, 145.4, 157.6, 160.2, 160.8. Anal.
Calcd for C14H17N3O3: C, 61.07; H, 6.22; N, 15.27. Found: C,
60.99; H, 6.14; N, 15.24.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Im id -
a zoles 3 a n d 5 by Meth yla tion of [Am in o(th ioca r bon yl)]-
a m id in es 1. For yields of pure products and methods see
Table 1.
Meth od C. A mixture of [amino(thiocarbonyl)]amidine 1
(10 mmol), EtOH (70 mL), and MeI (1.57 g, 11 mmol) was
gently warmed (about 50 °C) for 15 min. After the addition
of Et3N (1.12 g, 11 mmol), the solution was refluxed for 30
min. After cooling, the solvent was removed under reduced
pressure, and the residue was purified by column chromatog-
raphy using hexane/EtOAc (6:4). All compounds are colorless
solids.
E t h yl 2-(4-Br om op h en yl)-5-m or p h olin oim id a zole-4-
ca r boxyla te (3n ) [R1 ) 4-Br C6H4, R2 ) N(CH2CH2)2O, R3
) CO2CH3]. For spectroscopic data see method B above.
Met h yl 2-(4-ch lor op h en yl)-3-m et h yl-5-m or p h olin o-
im id a zole-4-ca r boxyla te (5x) [R1 ) 4-ClC6H4, R2 ) N(CH2-
CH2)2O, R3 ) CO2CH3]: 1H NMR (CF3CO2D) δ 4.04 (s, 4 H),
4.45 (s, 3 H), 4.52 (s, 3 H), 4.55 (s, 4 H), 7.97-8.11 (m, 4 H);
13C NMR δ 39.0, 52.7, 55.6, 69.0, 112.4, 121.5, 133.0, 133.4,
144.1, 146.6, 149.8, 163.2. Anal. Calcd for C16H18ClN3O3: C,
57.23; H, 5.40; N, 12.52; Cl, 10.56. Found: C, 57.29; H, 5.74;
N, 12.51; Cl, 10.57.
Meth yl 2-(4-Meth oxyp h en yl)-5-(1-m eth ylp ip er a zin -4-
yl)im id a zole-4-ca r boxyla te (3k ) [R1 ) 4-CH3OC6H4, R2
)
N(CH2CH2)2NCH3, R3 ) CO2CH3]. Method B: 1H NMR
(CDCl3) δ 2.30 (s, 3 H), 2.53 (m, 4 H), 3.56 (m, 4 H), 3.80 (s, 6
H), 6.88 (d, J ) 8.9 Hz, 2 H), 7.76 (d, J ) 8.9 Hz, 2 H), 9.68 (br
s, 1 H); 13C NMR δ 46.2, 49.2, 51.3, 55.0, 55.4, 104.7, 114.2,
121.8, 127.4, 145.5, 156.9, 160.0, 160.8. Anal. Calcd for
C17H22N4O3: C, 61,80; H, 6.71; N, 16.96. Found: C, 61.85; H,
6.80; N, 16.84.
Meth yl 2-[3,4-(Meth ylen ed ioxy)p h en yl]-5-m or p h olin o-
im id a zole-4-ca r boxyla te (3l) [R1 ) 3,4-OCH2OC6H3, R2
)
N(CH 2CH 2)2O, R 3
)
CO2CH 3]. Method A: 1H NMR
(CF3CO2D) δ 3.90 (m, 4 H), 4.27 (s, 3 H), 4.32 (m, 4 H), 6.28
(s, 2 H), 7.19 (d, J ) 8.3 Hz, 1 H), 7.51 (d, J ) 1.8 Hz, 1 H),
7.65 (dd, J ) 8.8, 1.7 Hz, 1 H); 13C NMR δ 52.1, 55.7, 68.8,
105.4, 108.6, 109.1, 112.1, 116.2, 126.1, 146.0, 148.4, 152.0,
155.9, 162.9. Anal. Calcd for C16H17N3O5: C, 58.00; H, 5.17;
N, 12.68. Found: C, 58.01; H, 5.17; N, 12.67.
Met h yl 5-Mor p h olin o-2-[4-(t r iflu or om et h yl)p h en yl]-
Meth yl 3-m eth yl-2-(4-m eth oxyp h en yl)-5-m or p h olin o-
im id a zole-4-ca r boxyla te (3m ) [R1 ) 4-CF 3C6H4, R2
)
im id a zole-4-ca r boxyla te (5y) [R1 ) 4-CH3OC6H4, R2
)
N(CH2CH2)2O, R3 ) CO2CH3]. Method A: 1H NMR (CDCl3)
δ 3.54 (m, 4 H), 3.83 (m, 4 H), 3.85 (s, 3 H), 7.66 (d, J ) 8.2
Hz, 2 H), 7.98 (d, J ) 8.2 Hz, 2 H), 9.97 (s br, 1 H); 13C NMR
δ 49.7, 51.6, 66.8, 106.2, 123.8 (q, J ) 272.4 Hz), 125.8 (d, J )
3.6 Hz), 126.0, 131.3 (q, J ) 32.8 Hz), 132.1, 143.6, 156.6,
159.9. Anal. Calcd for C16H16F3N3O3: C, 54.08; H, 4.54; N,
11.83. Found: C, 54.04; H, 4.86; N, 11.85.
N(CH2CH2)2O, R3 ) CO2CH3]: 1H NMR (CDCl3) δ 3.33 (m,
4 H), 3.75 (s, 3 H), 3.79 (m, 4 H), 3.80 (s, 3 H), 3.83 (s, 3 H),
6.93 (d, J ) 8.8 Hz, 2 H), 7.93 (d, J ) 8.8 Hz, 2 H); 13C NMR
δ 35.5, 51.0, 51.1, 55.4, 67.0, 108.9, 114.0, 122.0, 131.0, 149.3,
158.0, 160.6, 160.8. Anal. Calcd for C17H21N3O4: C, 61.61; H,
6.39; N, 12.68. Found: C, 61.61; H, 6.33; N, 12.57.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Im id -
a zoles 3 by Rea ction of th e 1,2,4-Dith ia zoliu m Tr iiod id es
6 w it h Am in es. Met h od D. Dithiazolium triiodide 6 (30
mmol) and H2NCH2R3‚HCl (30 mmol) were dissolved in MeCN
(150 mL). A solution of Et3N (6.06 g, 60 mmol) in MeCN (10
mL) was added dropwise with stirring (exothermic reaction).
After further stirring for 15 min, the same quantity of Et3N
solution was added again. Stirring was continued for 30 min.
Precipitated sulfur was filtered off, and the filtrate was poured
into water. After extraction with EtOAc (three times with 100
mL), the combined organic phases were washed with water
and dried with Na2SO4. The solvent was removed under
reduced pressure and the residue purified by column chroma-
tography using hexane/EtOAc.
Meth yl 2-(4-Br om op h en yl)-5-m or p h olin oim id a zole-4-
ca r boxyla te (3n ) [R1 ) 4-Br C6H4, R2 ) N(CH2CH2)2O, R3
) CO2CH3]. Method B: 1H NMR (DMSO-d6) δ 3.37 (m, 4 H),
3.71 (m, 4 H), 3.78 (s, 3 H), 7.65 (d, J ) 8.6 Hz, 2 H), 8.04 (d,
J ) 8.6 HZ, 2 H), 12.71 (s, 1 H); 13C NMR δ 49.6, 51.2, 66.2,
105 (br), 122.8, 128.4, 128.7, 131.8, 143 (br), 156 (br), 159.5.
Anal. Calcd for C15H16BrN3O3: C, 49.19; H, 4.40; N, 11.48; Br,
21.82. Found: C, 49.15; H, 4.27; N, 11.50; Br, 21.72.
Met h yl 5-Mor p h olin o-2-(3-n it r op h en yl)im id a zole-4-
ca r boxyla te (3o) [R 1 ) 3-NO2C6H4, R2 ) N(CH2CH2)2O, R3
) CO2CH3]. Method A: 1H NMR (CF3CO2D) δ 4.16 (m, 4 H),
4.49 (s, 3 H), 4.54 (m, 4 H), 8.26 (t, J ) 8.2 Hz, 1 H), 8.74 (d,
J ) 7.9 Hz, 1 H), 8.94 (d, J ) 8.4 Hz, 1 H), 9.27 (s, 1 H); 13C

Versatile Novel Syntheses of Imidazoles
J . Org. Chem., Vol. 62, No. 11, 1997 3487
Meth yl 2,5-d ip h en ylim id a zole-4-ca r boxyla te (3t) (R1
)
(50 mL) was added to a solution of the 1,2,4-thiadiazolium salt
2h (4.61 g, 10 mmol) in MeOH (50 mL). The mixture was
refluxed for 15 min. After cooling, the product precipitated.
This material was filtered off, dried, and purified by column
chromatography with CHCl3, affording 2.47 g of colorless
crystals: 1H NMR (DMSO-d6) δ 3.03 (m, 4 H), 3.73 (m, 4 H),
3.78 (s, 3 H), 6.97 (d, J ) 8.9 Hz, 2 H), 8.87 (br, 2 H), 7.99 (d,
J ) 8.6 Hz, 2 H), 12.58 (s, 1 H); 13C NMR δ 51.8, 55.3, 66.4,
114.1, 114.4, 122.5, 127.4, 144.1, 152.4, 159.8, 161.1. Anal.
Calcd for C15H18N4O3: C, 59.59; H, 6.00; N, 18.53. Found: C,
59.36; H, 6.26; N, 18.25.
R2 ) C6H5, R3 ) CO2CH3): 1H NMR (CDCl3) δ 3.78 (s, 3 H),
7.33-7.90 (m, 10 H), 10.56 (br, 1 H); 13C NMR (CF3CO2D) δ
55.4, 121.0, 122.1, 125.9, 129.2, 130.9, 131.2, 132.0, 134.0,
136.6, 142.4, 149.3, 162.6. Anal. Calcd for C17H14N2O2: C,
73.36; H, 5.07; N, 10.07. Found: C, 73.31; H, 5.06; N, 10.10.
Meth yl 2,5-bis(4-m eth oxyp h en yl)im id a zole-4-ca r box-
yla te (3u ) (R1 ) R2 ) 4-CH3OC6H4, R3 ) CO2CH3): 1H NMR
(DMF-d7) δ 3.81 (s, 3 H), 3.86 (s, 3 H), 3.87 (s, 3 H), 7.03 (d, J
) 8.9 Hz, 2 H), 7.09 (d, J ) 8.9 Hz, 2 H), 7.99 (d, J ) 8.8 Hz,
2 H), 8.23 (d, J ) 8.8 Hz, 2 H); 13C NMR (DMF-d7) δ 51.4,
55.6, 55.7, 113.8, 114.8, 122 (br), 123.3, 125.6, 128.4, 131.3,
145 (br), 148.0, 140.4, 161.3. Anal. Calcd for C19H18N2O4: C,
67.45; H, 5.36; N, 8.28. Found: C, 67.59; H, 5.39; N, 8.48.
2,5-Bis(4-m eth oxyp h en yl)im id a zole-4-ca r bon itr ile (3v)
(R1 ) R2 ) 4-CH3OC6H4, R3 ) CN): 1H NMR (CDCl3) δ 3.83
(s, 3 H), 3.84 (s, 3 H), 7.08 (d, J ) 8.9 Hz, 2 H), 7.14 (d, J )
8.9 Hz, 2 H), 7.83 (d, J ) 8.9 Hz, 2 H), 7.98 (d, J ) 8.9 Hz, 2
H); IR (cm-1) 2250. Anal. Calcd for C18H15N3O2: C, 70.80; H,
4.95; N, 13.77. Found: C, 70.90; H, 4.96; N, 13.76.
P r ep a r a tion of Im id a zoles 3 by Ba sic Tr ea tm en t of th e
1,3,5-Th ia d ia zin es 10. For yields see Table 1.
Meth od G. Et3N (0.51 g, 5 mmol) was added to a suspen-
sion of 1,3,5-thiadiazine 10 (5 mmol) in EtOH (50 mL). After
2 h of reflux, the solvent was removed under reduced pressure
and the residue purified by column chromatography.
2-(4-Ch lor oph en yl)-4-m or ph olin o-5-(4-n itr oph en yl)im id-
a zole (3d ) [R 1 ) 4-ClC6H 4, R 2 ) N(CH 2CH 2)2O, R 3
4-NO2C6H4]. For spectroscopic data see method B.
)
Eth yl 2,5-bis(4-ch lor op h en yl)im id a zole-4-ca r boxyla te
(3w ) (R1 ) R2 ) 4-ClC6H4, R3 ) CO2C2H5): 1H NMR (CDCl3)
δ 1.33 (t, J ) 7.1 Hz, 3 H), 4.34 (q, J ) 7.1 Hz, 2 H), 7.32-
7.50 (m, 4 H), 7.85-7.96 (m, 4 H); 13C NMR (CF3CO2D) δ 14.6,
67.4, 121.0, 122.4, 124.8, 131.1, 131.7, 133.0, 133.2, 141.6,
141.7, 144.7, 148.9, 162.5. Anal. Calcd for C18H14Cl2N2O2: C,
59.85; H, 3.91; N, 7.76; Cl, 19.63. Found: C, 59.64; H, 3.92;
N, 7.81; S, 19.91.
P r ep a r a t ion of Im id a zoles 3 b y Ba sic Tr ea t m en t of
1,2,4-Th ia d ia zoliu m Sa lts 2. Meth yl 2-(4-Meth oxyp h en -
yl)-5-m or ph olin oim idazole-4-car boxylate (3e) [R1 ) 4-CH3-
OC6H4, R2 ) N(CH2CH2)2O, R3 ) CO2CH3]. Meth od E. A
solution of the thiadiazolium salt 2e (2.25 g, 5 mmol) and Et3N
(0.5 g, 5 mmol) in MeOH (50 mL) was refluxed for 2 min. After
cooling, the solvent was removed under reduced pressure and
the residue purified by column chromatography with hexane/
EtOAc. This afforded 1.55 g of the colorless product (spectro-
scopic data see method A above).
2-(4-Meth oxyph en yl)-5-m or ph olin oim idazole-4-car box-
a m id e (3h ) [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O, R3
CONH2]. For spectroscopic data see method F.
)
P r ep a r a tion of Dieth yl 2-(4-Ch lor op h en yl)-5-m or p h o-
lin o-4H-im id a zole-4,4-d ica r boxyla te (8) via Meth yla tion
of [Am in o(th ioca r bon yl)]a m id in e 7. A mixture of [ami-
no(thiocarbonyl)]amidine 7 (2.21 g, 5 mmol), EtOH (70 mL),
and MeI (0.78 g, 5.5 mmol) was gently warmed (about 50 °C)
for 15 min. Et3N (0.56 g, 5.5 mmol) was added and the mixture
refluxed for 30 min. After cooling, the solvent was reduced to
30 mL. Crystallization in a refrigerator (-20 °C) afforded 1.78
g (87%) of the product: colorless crystals; mp 107.5-108 °C;
1H NMR (CDCl3) δ 1.26 (t, J ) 7.1 Hz, 6 H), 3.67 (br s, 2 H),
3.77 (br s, 4 H), 3.96 (br s, 2 H), 4.25, 4.26 (2 q, J ) 7.1 Hz, 4
H), 7.35 (d, J ) 8.6 Hz, 2 H), 8.13 (d, J ) 8.6 HZ, 2 H); 13C
NMR δ 13.9, 48.0, 49.6, 63.1, 66.4, 66.7, 88.3, 128.4, 130.4,
130.5, 137.5, 164.8, 177.4, 178.3. Anal. Calcd for
C19H22ClN3O5: C, 55.95; H, 5.44; N, 10.31. Found: C, 56.08;
H, 5.79; N, 10.32.
2-(4-Meth oxyph en yl)-5-m or ph olin oim idazole-4-car box-
a m id e (3h ) [R1 ) 4-CH3OC6H4, R2 ) N(CH2CH2)2O, R3
)
CONH2]. Meth od F . A saturated aqueous KHCO3 solution
J O970072H