Copper-catalyzed N-Arylation of 1,1,3,3-Tetramethylguanidine-Phenyl isocyanate adduct

Article abstract of DOI:10.1002/hlca.201300418

The synthesis of a novel class of 3-[bis(dimethylamino)methylidene]-1,1- diarylureas via a Cu-catalyzed multicomponent reaction of phenyl isocyanate (PhNCO), 1,1,3,3-tetramethylguanidine, and aryl halides is described. Copyright

Full text of DOI:10.1002/hlca.201300418

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Helvetica Chimica Acta – Vol. 97 (2014)
Copper-Catalyzed N-Arylation of 1,1,3,3-TetramethylguanidineꢀPhenyl
Isocyanate Adduct
by Issa Yavari* and Manijeh Nematpour
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82883455; e-mail: yavarisa@modares.ac.ir)
The synthesis of a novel class of 3-[bis(dimethylamino)methylidene]-1,1-diarylureas via a Cu-
catalyzed multicomponent reaction of phenyl isocyanate (PhNCO), 1,1,3,3-tetramethylguanidine, and
aryl halides is described.
Introduction. – Ureas play a significant role in organic, bioorganic, medicinal,
supramolecular, and materials chemistry [1][2]. Urea function is common in biological
systems. Substituted ureas have potent inhibiting effects on HIV-1 protease enzyme
[3], as well as anticancer [4][5], anticonvulsive, and sedative-hypnotic activities [6][7].
The standard protocols for the preparation of ureas generally involve the use of toxic
and highly reactive phosgene (COCl2) and its derivatives [8]. Usually, the synthesis of
ureas is achieved through the condensation of amines with isocyanates [9] and
carbamates [10], or oxidative carbonylation of amines with CO in the presence of
transition-metal catalysts [11].
Herein, we report a novel synthesis of 1,1-diaryl-3-[bis(dimethylamino)methyl-
idene]diarylureas 5 via Cu-catalyzed N-arylation of 1-[bis(dimethylamino)methyl-
idene]-3-phenylurea (4; generated in situ by addition of 1,1,3,3-tetramethylguanidine
(3) to phenyl isocyanate (2)) by aryl halides 1 (Scheme).
Results and Discussion. – Initially, PhI (1a), 2, and 3 were selected as model
substrates. Several catalysts such as CuI, CuBr, CuCl, Cu2O, and Cu powder were
tested, with CuI giving the best results. Among several solvents screened, DMF turned
out to be the best. Thus, the optimized reaction conditions used were 10 mol-% of CuI
as the catalyst, 10 mol-% of 1,10-phenanthroline as the ligand, 2.0 mmol of K2CO3 as
the base, 1 mmol of 3, and 1 mmol of 2 in DMF (Table).
Using the optimized conditions described above, various 1,1-diaryl-3-[bis(dime-
thylamino)methylidene]ureas 5 were synthesized by N-arylation of tetramethylguani-
dineꢀphenyl isocyanate adduct 4 with aryl iodides and aryl bromides bearing an
electron-withdrawing substituent. Aryl bromides served as low-yielding substrates
compared to aryl iodides (Scheme).
1
Structures of products 5a – 5h were determined by IR, H- and 13C-NMR, and MS
1
data. The H-NMR spectrum of 5a exhibited two singlets for the Me2N groups (d(H)
2.71 and 2.75), along with characteristic multiplets for the Ph H-atoms. The 13C-NMR
spectrum of 5a exhibits twelve signals in agreement with the proposed structure. The
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 97 (2014)
1133
Scheme
Table. Optimization of Reaction Conditions for the Formation of 5a from Aryl Iodides, Isocyanates, and
1,1,3,3-Tetramethylguanidine
Catalysta)
Solvent
Yield [%]b)
Catalysta)
Solvent
Yield [%]b)
Cu2O
Cu2O
Cu2O
CuCl
CuCl
CuCl
CuIc)
CuI
DMF
41
30
14
52
40
31
80
70
CuI
CuI
CuI
CuBr
CuBr
CuBr
Cu
Toluene
DMSO
THF
40
21
27
58
27
19
–
MeCN
Toluene
DMF
MeCN
Toluene
DMF
DMF
Toluene
DMSO
DMF
MeCN
Cu
Toluene
–
a) 10 mol-% catalyst, unless stated otherwise; 10 mol-% 1,10-phenanthroline. b) Reaction time, 6 h.
c) 5 mol-% catalyst, reaction time, 15 h.
mass spectrum of 5a displayed the molecular-ion peak at m/z 310. The NMR spectra of
5b – 5h were similar to those of 5a, except signals of the substituents.
In conclusion, we have developed an experimentally simple, Cu-catalyzed CꢀN
bond-formation reaction for the synthesis of 1,1-diaryl-3-[bis(dimethylamino)methyl-
idene]ureas starting from aryl halides, PhNCO, and 1,1,3,3-tetramethylguanidine. The
potential diversity of this type of reaction, and availability of starting materials and
catalysts are the main advantages of this methodology.
Experimental Part
General. All chemicals were obtained commercially and used without further purification. M.p.:
Electrothermal-9100 apparatus. Flash column chromatography (FC): silica gel (SiO2; Merck, 230 – 400

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Helvetica Chimica Acta – Vol. 97 (2014)
mesh). IR Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR spectra: Bruker DRX-
500 Avance instrument (500.1 and 125.7 MHz for 1H and 13C, resp.); in CDCl3; d in ppm rel. to Me4Si as
internal standard, J in Hz. MS: Finnigan-MAT-8430EI-MS mass spectrometer; at 70 eV; in m/z (rel. %).
Elemental analyses: Vario EL III CHNOS elemental analyzer; in %.
General Procedure for Preparation of 5. A mixture of 2 (1 mmol) and 3 (1 mmol) in DMF (2 ml) was
stirred for 30 min. Then, a mixture of aryl halide (1 mmol), CuI (0.1 mmol), 1,10-phenanthroline
(0.1 mmol), and K2CO3 (2.0 mmol) in DMF (3 ml) was slowly added to the first soln. and stirred at 1108
under N2. After completion of the reaction (ca. 6 h; TLC (AcOEt/hexane 1:3) monitoring), the mixture
was diluted with CH2Cl2 (2 ml) and aq. NH4Cl soln. (3 ml), stirred for 30 min, and the layers were
separated. The aq. layer was extracted with CH2Cl2 (3 ꢁ 3 ml), and the combined org. fractions were
dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by FC (hexane/
AcOEt 3 :1) to give the product.
3-[Bis(dimethylamino)methylidene]-1,1-diphenylurea (5a). Yield: 0.25 g (80%). Cream powder.
1
M.p. 119 – 1218. IR (KBr): 2041, 1647, 1549, 1445, 1377, 1179, 1075. H-NMR: 2.71 (s, Me2N); 2.75 (s,
Me2N); 7.06 – 7.12 (m, 5 arom. H); 7.14 – 7.19 (m, 3 arom. H); 7.26 (t, 3J ¼ 7.4, 2 arom. H). 13C-NMR: 42.3
(Me2N); 46.1 (Me2N); 122.3 (C); 124.6 (C); 125.6 (2 CH); 126.2 (2 CH); 127.3 (CH); 127.9 (CH); 128.4
(2 CH); 129.5 (2 CH); 158.4 (C); 162.4 (C). MS: 310 (2, Mþ), 266 (6), 233 (12), 196 (19), 168 (43), 114
(100), 77 (51), 44 (31). Anal. calc. for C18H22N4O (310.18): C 69.65, H 7.14, N 18.05; found: C 69.46, H
7.19, N 18.13.
3-[Bis(dimethylamino)methylidene]-1-(4-methylphenyl)-1-phenylurea (5b). Yield: 0.26 g (81%).
Cream powder. M.p. 126 – 1288. IR (KBr): 2049, 1591, 1497, 1409, 1303, 1230, 1152, 1021. 1H-NMR: 2.13
(s, Me); 2.67 (s, Me2N); 2.77 (s, Me2N); 6.75 (d, 3J ¼ 7.6, 2 arom. H); 7.05 – 7.13 (m, 5 arom. H); 7.38 (d,
3J ¼ 7.6, 2 arom. H). 13C-NMR: 30.0 (Me); 41.3 (Me2N); 46.2 (Me2N); 122.6 (C); 124.2 (2 CH); 126.1
(2 CH); 127.6 (C); 129.1 (CH); 131.1 (2 CH); 136.1 (2 CH); 137.6 (C); 159.4 (C); 162.3 (C). MS: 324 (3,
Mþ), 247 (3), 233 (21), 210 (17), 142 (31), 114 (100), 91 (71), 77 (50), 44 (31). Anal. calc. for C19H24N4O
(324.20): C 70.34, H 7.46, N 17.27; found: C 70.61, H 7.39, N 17.33.
3-[Bis(dimethylamino)methylidene]-1-(4-bromophenyl)-1-phenylurea (5c). Yield: 0.31 g (79%).
Cream powder. M.p. 133 – 1358. IR (KBr): 2029, 1659, 1597, 1400, 1378, 1271, 1111, 1091. 1H-NMR:
2.61 (s, Me2N); 2.70 (s, Me2N); 6.99 (d, 3J ¼ 7.6, 2 arom. H); 7.11 – 7.19 (m, 5 arom. H); 7.42 (d, 3J ¼ 7.6, 2
arom. H). 13C-NMR: 42.3 (Me2N); 46.5 (Me2N); 122.6 (C); 124.4 (2 CH); 126.0 (2 CH); 127.0 (CH);
129.6 (C); 130.1 (2 CH); 133.0 (C); 138.0 (2 CH); 158.4 (C); 162.8 (C). MS: 388 (2, Mþ), 311 (11), 273
(14), 245 (28), 154 (100), 142 (31), 114 (87), 44 (29). Anal. calc. for C18H21BrN4O (388.29): C 55.54, H
5.44, N 14.39; found: C 55.79, H 5.50, N 14.45.
3-[Bis(dimethylamino)methylidene]-1-(4-chlorophenyl)-1-phenylurea (5d). Yield: 0.26 g (75%).
Cream powder. M.p. 140 – 1438. IR (KBr): 2089, 1640, 1598, 1349, 1228, 1022. 1H-NMR: 2.65 (s,
Me2N); 2.77 (s, Me2N); 7.02 (d, 3J ¼ 7.6, 2 arom. H); 7.16 (d, 3J ¼ 7.3, 2 arom. H); 7.26 – 7.31 (m, 3 arom.
3
H); 7.56 (d, J ¼ 7.6, 2 arom. H). 13C-NMR: 42.0 (Me2N); 46.4 (Me2N); 122.0 (C); 123.0 (2 CH); 124.2
(2 CH); 125.0 (C); 127.9 (CH); 133.0 (2 CH); 138.1 (2 CH); 140.0 (C); 159.4 (C); 162.7 (C). MS: 344 (5,
Mþ), 267 (11), 233 (8), 142 (61), 114 (45), 111 (100), 77 (34), 44 (20). Anal. calc. for C18H21ClN4O
(344.14): C 62.69, H 6.14, N 16.25; found: C 62.96, H 6.16, N 16.34.
3-[Bis(dimethylamino)methylidene]-1-(4-methoxyphenyl)-1-phenylurea (5e). Yield: 0.25 g (73%).
Cream powder. M.p. 143 – 1458. IR (KBr): 2049, 1674, 1540, 1450, 1372, 1277, 1188, 1040. 1H-NMR: 2.80
(s, Me2N); 2.91 (s, Me2N); 3.52 (s, MeO); 7.00 (d, 3J ¼ 7.7, 2 arom. H); 7.11 – 7.19 (m, 5 arom. H); 7.42 (d,
3J ¼ 7.7, 2 arom. H). 13C-NMR: 42.0 (Me2N); 46.7 (Me2N); 55.7 (MeO); 122.3 (C); 124.3 (2 CH); 124.8
(2 CH); 125.5 (2 CH); 127.3 (CH); 129.9 (C); 139.0 (2 CH); 140.0 (C); 157.4 (C); 161.6 (C). MS: 340 (6,
Mþ), 296 (11), 263 (9), 233 (25), 114 (65), 107 (100), 44 (29). Anal. calc. for C19H24N4O2 (340.19): C
67.04, H 7.11, N 16.46; found: C 67.36, H 7.17, N 16.49.
3-[Bis(dimethylamino)methylidene]-1-(3-methylphenyl)-1-phenylurea (5f). Yield: 0.22 g (68%).
Cream powder. M.p. 119 – 1218. IR (KBr): 2027, 1678, 1559, 1411, 1366, 1222, 1177, 1070. 1H-NMR: 2.17
(s, Me); 2.78 (s, Me2N); 2.80 (s, Me2N); 7.22 – 7.25 (m, 2 arom. H); 7.33 (d, 3J ¼ 7.5, 2 arom. H); 7.38 – 7.41
3
3
(m, 3 arom. H); 7.47 (d, J ¼ 7.7, 1 arom. H); 7.56 (d, J ¼ 7.7, 1 arom. H). 13C-NMR: 31.0 (Me); 42.2
(Me2N); 46.4 (Me2N); 122.5 (CH); 123.0 (CH); 124.2 (2 CH); 125.3 (2 CH); 126.0 (CH); 126.9 (C);
128.0 (C); 130.1 (CH); 131.9 (C); 134.9 (CH); 157.4 (C); 162.4 (C). MS: 324 (1, Mþ), 247 (9), 233 (19),

Helvetica Chimica Acta – Vol. 97 (2014)
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142 (23), 114 (100), 91 (44), 77 (25), 44 (45). Anal. calc. for C19H24N4O (324.20): C 70.34, H 7.46, N 17.27;
found: C 70.61, H 7.39, N 17.34.
3-[Bis(dimethylamino)methylidene]-1-(3-nitrophenyl)-1-phenylurea (5g). Yield: 0.24 g (69%). Pale-
yellow powder. M.p. 141 – 1438. IR (KBr): 2039, 1615, 1528, 1459, 1378, 1222, 1191, 1069. 1H-NMR: 2.71
(s, Me2N); 2.80 (s, Me2N); 7.22 – 7.28 (m, 2 arom. H), 7.32 – 7.37 (m, 3 arom. H); 7.42 (d, 3J ¼ 7.5, 2 arom.
H); 7.62 (d, 3J ¼ 7.9, 1 arom. H); 7.71 (d, 3J ¼ 7.9, 1 arom. H). 13C-NMR: 41.7 (Me2N); 44.8 (Me2N); 122.5
(CH); 123.7 (2 CH); 124.1 (2 CH); 125.5 (CH); 126.0 (C); 128.0 (CH); 130.2 (C); 132.7 (CH); 134.4
(CH); 147.7 (C); 158.7 (C); 163.9 (C). MS: 355 (3, Mþ), 278 (9), 233 (15), 213 (22), 122 (100), 114 (41),
44 (52). Anal. calc. for C18H21N5O3 (355.16): C 60.83, H 5.96, N 19.71; found: C 61.09, H 5.88, N 19.79.
3-[Bis(dimethylamino)methylidene]-1-phenyl-1-(thiophen-2-yl)urea (5h). Yield: 0.19 g (60%).
1
Cream powder. M.p. 125 – 1278. IR (KBr): 2038, 1666, 1580, 1481, 1366, 1179, 1082. H-NMR: 2.76 (s,
Me2N); 2.84 (s, Me2N); 6.71 (dd, 3J ¼ 4.6, 4.5, CH); 6.94 (dd, 3J ¼ 4.6, 4J ¼ 2.1, CH); 7.13 (dd, 3J ¼ 4.6, 4J ¼
3
2.1, CH); 7.17 – 7.23 (m, 3 H, Ph); 7.32 (d, J ¼ 7.5, 2 arom. H). 13C-NMR: 41.5 (Me2N); 45.4 (Me2N);
123.3 (C); 124.4 (2 CH); 125.6 (C); 125.9 (2 CH); 126.4 (CH); 127.0 (CH); 127.6 (CH); 131.2 (CH); 158.7
(C); 163.9 (C). MS: 316 (1, Mþ), 239 (17), 233 (26), 202 (29), 142 (35), 114 (23), 83 (100), 77 (54), 44
(33). Anal. calc. for C16H20N4OS (316.14): C 60.73, H 6.37, N 17.71; found: C 60.28, H 6.42, N 17.80.
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Received November 27, 2013