Synthesis of some of new substituted 2-(phenyl)-1,3-dimethyl- and -1,1,3,3-tetramethylguanidines

Article abstract of DOI:10.1080/713744575

A series of new 2-(phenyl)-1,3- and 2-(phenyl)-1,3,3-tetramethylguanidines (a-k) were synthesized by reaction of different substituted aniline and urea derivatives in the presence of phosphorus oxychloride. The yields of products following extraction from

Full text of DOI:10.1080/713744575

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some of New Substituted 2-(Phenyl)-1,3-
dimethyl- and -1,1,3,3-tetramethylguanidines
A. Mobinikhaledi a , N. Forughifar a , S. Mohtasabi a & H. Shalbaf b
a University of Arak , Arak, Iran
b University of Ahvaz , Ahvaz, Iran
Published online: 27 Oct 2010.
To cite this article: A. Mobinikhaledi , N. Forughifar , S. Mohtasabi & H. Shalbaf (2003) Synthesis of Some of New Substituted
2-(Phenyl)-1,3-dimethyl- and -1,1,3,3-tetramethylguanidines, Phosphorus, Sulfur, and Silicon and the Related Elements,
178:10, 2235-2240, DOI: 10.1080/713744575
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Phosphorus, Sulfur, and Silicon, 178:2235–2240, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390234524
SYNTHESIS OF SOME OF NEW SUBSTITUTED
2-(PHENYL)-1,3-DIMETHYL- AND
-1,1,3,3-TETRAMETHYLGUANIDINES
A. Mobinikhaledi,a N. Forughifar,a S. Mohtasabi,a
and H. Shalbaf b
University of Arak, Arak, Irana and University
of Ahvaz, Ahvaz, Iranb
(Received April 15, 2003; accepted May 6, 2003)
A series of new 2-(phenyl)-1,3- and 2-(phenyl)-1,3,3-tetramethyl-
guanidines (a–k) were synthesized by reaction of different substituted
aniline and urea derivatives in the presence of phosphorus oxychloride.
The yields of products following extraction from toluene without further
purification were of the order of 50–70%. We have found that adjusting
of the pH at 8-9 in the work up process increases the yield of products.
IR, 1HNMR, and also mass spectrscopies were used for identification
of these compounds.
Keywords: 1,3-Dimethyurea; dimethylguanidine; guanidine; p-
bromoaniline; phosphorus oxychloride
Guanidines have been found in many natural products and are also
known as critical part of certain biological processes.1 Some of the
guanidines act as antimamalarial agents.2−4 Therefore guanidines
have been subjected to a large variety of structural modifications in
order to obtain derivatives with different properties and applications.
Various synthetic approaches for the synthesis of different guanidines
have been reported in several articles.5−18 Most of these methods,
which are nongeneral processes, are based on using new reagents
for the preparation of protected and unprotected guanidines. A short
review about recent developments in the guanidine chemistry has
been reported by Yet.19
Here, due to versatile biological properties of guanidines, we have
extended the more general synthetic method of Bredereck et al.5 in
order to synthesize some novel guanidines in high yield.
Address correspondence to A. Mobinikhaledi, Department of Chemistry, University
of Arak, Dr. Beheshti Ave., Arak, Iran. E-mail: akbar mobini@yahoo.com
2235

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A. Mobinikhaledi et al.
RESULTS AND DISCUSSION
The new substituted 2-(phenyl)-1,3- and 2-(phenyl)-1,3,3-tetramethyl-
guanidines were synthesized easily by using a modification of
Bredereck’s general method.5 Reaction of 1,3-dimethyurea or tetra-
methylurea with different substituted aniline in the presence of POCl3
under reflux gave compounds 3(a–f) and 3(g–k) respectively. Adjusting
the pH at 8–9 in the work-up process of these reactions is an important
factor, which can transfer the unreacted starting material to the organic
phase. This method is very clean and can be used with different substi-
tuted anilines depending on the group G to prepare various guanidines
(Scheme 1).
Reactions were usually carried out for 7–8 h (Table I). Yields of the
products were in the order of 40–57%; they are summarized in Table I.
1
Based on the H-NMR (500 MHz) spectra these products were of high
purity. The 1H NMR spectra of 3(a–f) show two singlet signals at 2.0–
2.6 and 5.2–5.6 ppm due to the resonance of two CH3 and two NH
groups respectively. The multiplet signal at 6.6–7.2 ppm is assigned to
the resonance of different aryl protons.
1
The H NMR spectra of 3(g–k) are very similar to those of 3(a–f).
Two singlet signals at 2.3–2.80 are due to the resonance of four CH3
groups. The multiplet signal at 6.2–8.0 ppm is assigned to the resonance
of different aryl protons. Compound 3i has two singlet signals at 2.08
and 2.2 ppm attributable to two CH3 groups bonded to the phenyl
ring. Such a resonance can be seen for 3e at 2.0 and 2.2 ppm.
SCHEME 1

New Substituted 2-(Phenyl)-1,3-dimethyl- and -1,1,3,3-tetramethylguanidines 2237
TABLE I Reaction Time and Yields
on the Formation of Guanidines
Entry
Reaction time (h)
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
7
8
8
7
7
8
8
8
7
7
7
40
55
45
43
49
48
42
40
49
46
57
3j
3k
In the IR spectra of compounds 3(g–k) the absence of the absorption
at 3200–3400 cm−1, the characteristic absorption of the NH2 group
of the starting material, is good evidence of the expected reactions.
Additional evidence for the structure of the compounds was obtained
from mass spectra. The molecular ion peak of the compounds could be
seen clearly.
EXPERIMENTAL
Melting points were determined with an electrothermal digital melt-
ing point apparatus. IR spectra were recorded on a Galaxy series FT-
IR 5000 spectrophotometer by using KBr pellets. HNMR spectra were
recorded on Bruker 400 and 500 MHz spectrometers, using Me4Si
(TMS) as an internal standard. Mass spectra were measured with an EI
(70 eV) + Q1MSLMR up LP spectrometer. Reaction courses and product
mixtures were monitored by thin layer chromatography.
General Procedure for Preparation
1,3-Dimethyurea or tetra-methylurea (0.01 mmol) in dry toluene (50 ml)
was stirred for 5 min. This solution was treated dropwise with a solution
of phosphorus oxychloride (0.15 mmol) in 20 ml of dry toluene. The
reaction mixture was stirred at room temperature for 10 h and then a
solution of the appropriate substituted aniline (0.015 mmol) was added.
The reaction mixture was refluxed for 7–8 h and the oily substance
separated by a separator funnel. The residue was then dissolved in
water and the pH adjusted to 8–9 with adding 2 N NaOH solution.

2238
A. Mobinikhaledi et al.
The resulting solution was washed several times with 20 ml portions
of toluene. The pH was adjusted to about 14 by adding 2 N NaOH and
extracted several times-with 20 ml portions of toluene. Evaporation of
toluene on a rotary evaporator afforded the desired compound.
2-(4-Bromophenyl)-1,3-dimethylguanidine (3a)
m.p. 145–147◦C. IR (KBr): υ = 3225 (NH), 2900–3050 (CH arom
and aliph), 1520–1620 (C C and C N conjugated), 1055 (C N) cm−1
.
1HNMR (DMSO-d6): δ = 6.6–7.2 (m, 4Harom), 5.4 (s, 2H, 2-NH), 2.6 (s,
6H, 2-CH3) MS: (m/z %) = 242 (M+, 98%), 241 (100%), 183 (84%), 170
(21%), 89 (37%).
2-(2-Chlorophenyl)-1,3-dimethylguanidine (3b)
m.p. 130–132◦C. IR (KBr): υ = 3245 (NH), 2900–3050 (CH arom
and aliph), 1520–1620 (C C and C N conjugated), 1153 (C N) cm−1
.
1HNMR (DMSO-d6): δ = 6.7–7.2 (m, 4Harom), 5.2 (s, 2H, 2-NH), 2.6 (s,
6H, 2-CH3).
2-(2,4,5-Trichlorophenyl)-1,3-dimethylguanidine (3c)
m.p. 162–164◦C. IR (KBr): υ = 3240 (NH), 2900–3045 (CH arom
and aliph), 1520–1620 (C C and C N conjugated), 1150 (C N) cm−1
.
1HNMR (CD3OD): δ = 7.5 (s, 1Harom), 6.9 (s, 1Harom), 5.6 (s, 2H, 2-
NH), 2.6 (s, 6H, 2-CH3) MS: (m/z %) = 266 (M+, 66%), 264 (80%), 236
(68%), 234 (80%), 194 (73%), 159 (40%), 123 (49%), 83 (45%).
2-(3,4-Dichlorophenyl)-1,3-dimethylguanidine (3d)
m.p. 111–113◦C. IR (KBr): υ = 3267 (NH), 2850–3050 (CH arom and
aliph), 1500–1630 (C C and C N conjugated), 830 (C-Cl) cm−1. 1HNMR
(DMSO-d6): δ = 6.6–7.2 (m, 3 Harom), 5.5 (s, 2H, 2-NH), 2.6 (s, 6H, 2-
CH3). MS: (m/z %) = 232 (M+, 37%), 230 (100%), 202 (42%), 160 (76%),
71 (41%), 57 (52%).
2-(2,4-Dimethylphenyl)-1,3-dimethylguanidine (3e)
m.p. 95–97◦C. IR (KBr): υ = 3225 (NH), 2900–3100 (CH arom and
aliph), 1520–1650 (C C and C N conjugated), 1147 (C N) cm−1
.
1HNMR (CD3OD): δ = 6.6–6.9 (m, 3Harom), 2.7 (s, 6H, 2N-CH3), 2.2
(s, 3H, CH3), 2.0 (s, 3H, CH3). MS: (m/z %) = 199 (M+, 100%), 176
(86%), 159 (24%), 105 (6%), 90 (6%).
2-Phenyl-1,3-dimethylguanidine (3f)
m.p. 112–114◦C. IR (KBr): υ = 3265 (NH), 2900–3100 (CH arom
and aliph), 1500–1650 (C C and C N conjugated), 1149 (C N) cm−1
.
1HNMR (CD3OD): δ = 6.6–7.2 (m, 5Harom), 2.7 (s, 6H, 2N-CH3). MS:

New Substituted 2-(Phenyl)-1,3-dimethyl- and -1,1,3,3-tetramethylguanidines 2239
(m/z %) = 163 (M+, 97%), 148 (15%), 133 (54%), 106 (100%), 91 (19%),
77 (6%).
2-(4-Nitrophenyl)-tetramethylguanidine (3g)
m.p. 83–85◦C. IR (KBr): υ = 2900–3050 (CH arom and aliph), 1480–
1550 (C C and C N conjugated), 1103 (C N), 1280–1320 (NO2) cm−1
1HNMR (CD3OD): δ = 6.6–8.0 (m, 4Harom), 2.8 (s, 12H, 4-N-CH3).
.
2-(3-Nitrophenyl)-tetramethylguanidine (3h)
m.p. 233–235◦C. IR (KBr): υ = 2850–3100 (CH arom and aliph),
1500–1600 (C C and C N conjugated), 1146 (C N), 1348 (NO2) cm−1
1HNMR (CD3OD): δ = 2.5 (s, 12H, 4-N-CH3), 6.5–6.7 (m, 4Harom).
.
2-(2,4-Dimethylphenyl)-tetramethylguanidine (3i)
m.p. 228–230◦C. IR (KBr): υ = 2900–3100 (CH arom and aliph),
1500–1700 (C C and C N conjugated), 1138 (C N). 1HNMR (CD3OD):
δ = 6.4–6.9 (m, 3Harom), 2.6 (s, 12H, 4-NCH3), 2.2 (s, 3H, CH3), 2.08
(s, 3H, CH3).
2-(4-Bromophenyl)-tetramethylguanidine (3j)
m.p. 170–172◦C. IR (KBr): υ = 2900–3100 (CH arom and aliph),
1500–1580 (C C and C N conjugated), 1141 (C N), 642 (C-Br).
1HNMR (CDCl3): δ = 6.5–7.7 (m, 4Harom), 2.8 (s, 12H, 4-NCH3).
2-Phenyl-tetramethylguanidine (3k)
m.p. 257–258◦C. IR (KBr): υ = 2850–3100 (CH arom and aliph),
1500–1600 (C C and C N conjugated), 1146 (C N). 1HNMR (CDCl3):
δ = 6.2–6.9 (m, 5Harom), 2.3 (s, 12H, 4-NCH3).
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