Mol Divers DOI 10.1007/s11030-015-9601-7
FULL-LENGTH PAPER
A direct access to heptasubstituted biguanides Issa Yavari1 · Manijeh Nematpour1
Received: 29 November 2014 / Accepted: 20 April 2015 © Springer International Publishing Switzerland 2015
Abstract An efficient and experimentally simple coppercatalyzed carbon–nitrogen bond formation for the synthesis of N -arylated biguanides starting from aryl halides, carbodiimides, and 1,1,3,3-tetramethylguanidine is reported. The potential diversity of this type of reaction, easily available starting materials, and commercially available low-cost catalysts are the incremental features of this methodology. Graphical Abstract
Keywords N -Arylation · Carbodiimides · Coppercatalyzed · Biguanides · Tetramethylguanidine
Guanidines are fairly strong bases and their role in biological systems is well documented [9–13]. Structurally diverse molecules that incorporate guanidine moieties have been isolated from plants. Guanidine-containing alkaloids exhibit antiviral, antifungal, and antitumor activities [14,15]. N Arylguanidines have been used as complementary partners of carboxylate and nitro groups in supramolecular chemistry [16]. Complexes containing a guanidine ligand have been reported [17]. The addition reaction between amines and carbodiimides has been extensively studied [18]. Using this strategy, Margetic and co-workers [19] obtained hexasubstituted biguanides from 1,1,3,3-tetramethylguanidine (TMG) and carbodiimides. This work prompted us to describe our results on the direct one-pot synthesis of heptasubstituted biguanides using carbodiimides, TMG, and aryl halides.
Introduction
Results and discussion
The construction of carbon–heteroatom bonds represents a key step in the synthesis of important classes of organic compounds that play a significant role in the material and pharmaceutical industries [1–4]. Several copper-catalyzed coupling reactions have been reported for C(aryl) –N, C(aryl) – O, and C(aryl) –S bond formation [5–8].
Initially, iodobenzene (1a), N ,N -dicyclohexylcarbodiimide (2a), and TMG were selected as the model substrates. Several catalysts such as CuI, CuBr, CuCl, Cu2 O, and copper powder were tested with CuI giving the best results. Among several solvents screened, DMF also provided the best results (Table 1). Thus, the optimized reaction conditions used were 10 mol% of CuI as the catalyst, 10 mol% of 1,10phenanthroline as the ligand, 2.0 mmol of K2 CO3 as the base, 1 mmol of 2a, and 1 mmol of TMG in DMF. Using the optimized conditions described above, various N -arylated biguanides 5 were synthesized from aryl halides 1, carbodiimides 2, and TMG. Aryl bromides served as lowyielding substrates compared to aryl iodides (Table 2). Structures of products 5a–m were assigned by IR, 1 H NMR, 13 C NMR, and mass spectral data. The 1 H NMR spec-
R
N
C
N
NH R
Me2N
i
R = Cy, Pr
NMe2
ArX
CuI (10 mol%) 1,10-phenanthroline (10 mol%) K2CO3 2 eq DMF, reflux, 12 h
NMe2 N
Me2N
N
X = I, Br
Electronic supplementary material The online version of this article (doi:10.1007/s11030-015-9601-7) contains supplementary material, which is available to authorized users.
B 1
Issa Yavari [email protected] Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
R N
R
Ar
123
Mol Divers Table 1 Optimization of reaction conditions for the formation of 5a Entry
Catalysta
1
Cu2 O
DMF
40
2
Cu2 O
MeCN
32
3
Cu2 O
Toluene
16
4
CuCl
DMF
62
5
CuCl
MeCN
51
6
CuCl
Toluene
30
7
CuIc
DMF
80 66
Solvent
Yield
8
CuI
MeCN
9
CuI
Toluene
41
10
CuI
DMSO
31
11
CuI
THF
22
12
CuBr
DMF
65
13
CuBr
Toluene
20
14
CuBr
DMSO
15
15
Cu
DMF
–
16
Cu
Toluene
–
a b c
(%)b
10 mol% catalyst unless stated otherwise; Phen 10 mol% Reaction time = 12 h 5 mol% catalyst; reaction time = 20 h
trum of 5a exhibited two singlets (2.78 and 2.86 ppm) for dimethylamino protons, along with characteristic multiplets for the phenyl group. The 13 C NMR spectrum of 5a exhib-
ited 16 signals in accord with the proposed structure. The mass spectrum of 5a displayed the molecular ion signal at m/z = 397. The NMR spectra of compounds 5b–m are similar to those of 5a, except for the substituents. The synthesis of N -alkylated biguanides 4 through addition of 3 to dialkyl carbodiimides 2, as shown in Table 2, has been discussed previously [9,10]. In addition, 1,10phenanthroline [4] can be used as a unique ligand for the N -arylation of 4 with aryl iodides and aryl bromides (Table 2). When chlorobenzene was subjected to the reaction conditions developed for aryl iodides and bromides, the yield of N -arylation reaction was very low. Thus, our studies are limited to aryl iodides and bromides.
Conclusions In summary, we have developed an efficient and experimentally simple, copper-catalyzed carbon–nitrogen bond formation for the synthesis of N -arylated biguanides starting from aryl halides, carbodiimides, and TMG. The potential diversity of this type of reaction, easily available starting materials, and commercially available low-cost catalysts are the incremental features of this methodology. Direct one-pot synthesis of heptasubstituted biguanides can be considered as an interesting and useful methodology.
Table 2 Copper-catalyzed C–N coupling of aryl halides 1 with carbodiimide-TMG adducts 4
123
Entry
1–5
X
Ar
R
Yield of 5 (%)
1
a
I
Ph
cHex
80
2
b
I
4-Me–C6 H4
cHex
81
3
c
I
4-MeO–C6 H4
cHex
79
4
d
I
4-Br–C6 H4
cHex
75
5
e
I
4-Cl–C6 H4
cHex
73
6
f
I
3-Me–C6 H4
cHex
78
7
g
Br
4-CN–C6 H4
cHex
68
8
h
Br
1-Naphthyl
cHex
69 65
9
i
Br
3-O2 N–C6 H4
cHex
10
j
I
Ph
i-Pr
77
11
k
I
4-Br–C6 H4
i-Pr
72
12
l
I
4-Cl–C6 H4
i-Pr
74
13
m
Br
4-CN–C6 H4
i-Pr
63
Mol Divers
Experimental section
C, 72.50; H, 9.89; N, 17.61 %. Found: C, 72.66; H, 9.97; N, 17.71 %.
General remarks All purchased solvents and chemicals were of analytical grade and used without further purification. Melting points (uncorrected) and IR spectra of all compounds were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer, respectively. The 1 H and 13 C spectra were obtained with a BRUKER DRX-500 AVANCE instrument using CDCl3 as applied solvent and TMS as internal standard at 500.1 and 125.7 MHz, respectively. The abbreviations used for NMR signals: s = singlet, d = doublet, t = triplet, and m = multiplet. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses for C, H, and N were performed using a Heraeus CHN–O–rapid analyzer. General procedure Preparation of compounds 5. The corresponding carbodiimide 2 (1 mmol) and TMG (1 mmol) were dissolved in DMF (2 mL) and stirred for 30 min. Then, a mixture of aryl halide 1 (1 mmol), CuI (0.1 mmol), 1,10-phenanthroline (0.1 mmol), and potassium carbonate (0.276 g, 2.0 mmol) in DMF (3 mL) was slowly added to the first mixture and stirred at 110 ◦ C, under N2 atmosphere. After completion of the reaction [about 12 h; TLC (AcOEt/hexane 1:3) monitoring], the mixture was diluted with CH2 Cl2 (2 mL) and aqueous NH4 Cl solution (3 mL), stirred for 30 min, and the layers were separated. The aqueous layer was extracted with CH2 Cl2 (3 × 3 mL), the combined organic fractions were dried (Na2 SO4 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel (230–400 mesh; Merck), hexane/AcOEt 3:1] to give desired product. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl]anilino}cyclohexane (5a) Cream powder, m.p.: 149–151 ◦ C; yield: 0.32 g (80 %). IR (KBr) (νmax , cm−1 ): 2059, 1670, 1580, 1455, 1377, 1170, 1075. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.35 (8 H, m, CH2 ), 1.46–1.51 (4 H, m, CH2 ), 1.58–1.64 (4 H, m, CH2 ), 1.87–1.93 (4 H, m, CH2 ), 2.78 (6 H, s, Me2 N), 2.86 (6 H, s, Me2 N), 3.30-3.33 (1 H, m, CH), 3.34–3.37 (1 H, m, CH), 7.02 (2 H, t, 3 J = 7.4 Hz, Ar), 7.25 (1 H, t, 3 J = 7.4 Hz, Ar), 7.61 (2 H, d, 3 J = 7.4 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.7, 24.9, 25.4, 25.6, 28.1, 31.3, 34.7, 36.4, 48.5, 53.2, 127.4, 130.1, 132.0, 137.4, 157.7, 162.4. EIMS: 397 (M+ , 1), 353 (8), 320 (11), 283 (29), 174 (100), 114 (30), 83 (21), 77 (51), 44 (31). Anal. Calc. for C24 H39 N5 (397.32):
1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino}4-methylbenzene (5b) Cream powder, m.p.: 130–133 ◦ C; yield: 0.33 g (81 %). IR (KBr) (νmax , cm−1 ): 2050, 1589, 1492, 1422, 1303, 1230, 1152, 1029. 1 H NMR (500 MHz, CDCl3 ): δH = 1.18–1.34 (8 H, m, CH2 ), 1.45–1.50 (4 H, m, CH2 ), 1.58–1.63 (4 H, m, CH2 ), 1.76–1.79 (4 H, m, CH2 ), 2.21 (3 H, s, Me), 2.76 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.29–3.33 (1 H, m, CH), 3.35–3.38 (1 H, m, CH), 7.11 (2 H, d, 3 J = 7.6 Hz, Ar), 7.43 (2 H, d, 3 J = 7.6 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 21.5 (CH2 ), 23.4 (CH2 ), 24.9 (2 CH2 ), 25.4 (2 CH2 ), 27.9 (2 CH2 ), 28.1, 33.1, 33.9, 36.3, 52.8, 55.9, 123.5, 132.2, 138.9, 139.0, 157.9, 162.4. EIMS: 411 (M+ , 2), 367 (18), 328 (29), 297 (17), 188 (100), 114 (34), 91 (71), 83 (53), 44 (30). Anal. Calcd. for C25 H41 N5 (411.34): C, 72.95; H, 10.04; N, 17.01 %. Found: C, 73.03; H, 10.35; N, 17.21 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino}4-methoxybenzene (5c) Cream powder, m.p.: 133–135 ◦ C; yield: 0.34 g (79 %). IR (KBr) (νmax , cm−1 ): 2024, 1654, 1547, 1401, 1374, 1271, 1111, 1091. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.33 (8 H, m, CH2 ), 1.44–1.48 (4 H, m, CH2 ), 1.56–1.59 (4 H, m, CH2 ), 1.84–1.87 (4 H, m, CH2 ), 2.75 (6 H, s, Me2 N), 2.86 (6 H, s, Me2 N), 3.32–3.35 (1 H, m, CH), 3.39–3.47 (1 H, m, CH), 3.73 (3 H, s, OMe), 6.79 (2 H, d, 3 J = 7.7 Hz, Ar), 7.51 (2 H, d, 3 J = 7.7 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.3, 23.9, 24.8, 25.9, 27.9, 28.2, 35.6, 38.9, 50.5, 51.0, 54.7, 127.5, 132.9, 133.4, 136.5, 159.8, 161.1. EIMS: 427 (M+ , 2), 383 (11), 344 (14), 204 (100), 114 (42), 107 (39), 83 (87), 44 (29). Anal. Calcd. for C25 H41 N5 O (427.33): C, 70.22; H, 9.66; N, 16.38 %. Found: C, 70.32; H, 9.85; N, 16.47 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]4-bromobenzene (5d) Cream powder, m.p.: 138–140 ◦ C; yield: 0.36 g (75 %). IR (KBr) (νmax , cm−1 ): 2089, 1666, 1598, 1439, 1349, 1228, 1011. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.32 (8 H, m, CH2 ), 1.43–1.47 (4 H, m, CH2 ), 1.54–1.58 (4 H, m, CH2 ), 1.82–1.86 (4 H, m, CH2 ), 2.77 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.30–3.35 (1 H, m, CH), 3.38–3.45 (1 H, m, CH), 6.84 (2 H, d, 3 J = 7.8 Hz, Ar), 7.47 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.3, 23.8, 24.9,
123
Mol Divers
25.7, 27.5, 28.1, 35.9, 38.7, 49.0, 55.2, 132.0, 133.2, 136.3, 136.9, 161.4, 164.0. EIMS: 475 (M+ , 5), 392 (18), 361 (10), 252 (100), 154 (45), 114 (37), 83 (33), 44 (29). Anal. Calcd. for C24 H38 BrN5 (475.23): C, 60.50; H, 8.04; N, 16.77 %. Found: C, 60.69; H, 8.20; N, 16.86 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]4-chlorobenzene (5e) Cream powder, m.p.: 143–146 ◦ C; yield: 0.31 g (73 %). IR (KBr) (νmax , cm−1 ): 2048, 1679, 1541, 1453, 1372, 1277, 1188, 1043. 1 H NMR (500 MHz, C DCl3 ): δH = 1.18– 1.30 (8 H, m, CH2 ), 1.42–1.46 (4 H, m, CH2 ), 1.53–1.58 (4 H, m, CH2 ), 1.84–1.89 (4 H, m, CH2 ), 2.79 (6 H, s, Me2 N), 2.85 (6 H, s, Me2 N), 3.31–3.35 (1 H, m, CH), 3.37–3.40 (1 H, m, CH), 7.15 (2 H, d, 3 J = 7.8 Hz, Ar), 7.49 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.9, 24.0, 24.9, 25.4, 27.2, 28.9, 35.3, 38.6, 49.6, 53.5, 122.1, 130.1, 139.0, 140.1, 158.4, 162.3. EIMS: 431 (M+ , 2), 387 (12), 347 (9), 208 (100), 114 (45), 83 (45), 44 (47). Anal. Calcd. for C24 H38 ClN5 (431.28): C, 66.72; H, 8.87; N, 16.21 %. Found: C, 66.81; H, 8.98; N, 16.39 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]3-methylbenzene (5f) Cream powder, m.p.: 119–121 ◦ C; yield: 0.32 g (78 %). IR (KBr) (νmax , cm−1 ): 2044, 1644, 1544, 1416, 1306, 1292, 1169, 1071. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17−1.29 (8 H, m, CH2 ), 1.41–1.45 (4 H, m, CH2 ), 1.57–1.63 (4 H, m, CH2 ), 1.79–1.85 (4 H, m, CH2 ), 2.25 (3 H, s, Me), 2.80 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.34–3.37 (1 H, m, CH), 3.39– 3.46 (1 H, m, CH), 7.32 (1 H, t, 3 J = 7.5 Hz, Ar), 7.51 (1 H, d, 3 J = 7.5 Hz, Ar), 7.62 (1 H, d, 3 J = 7.5 Hz, Ar), 7.72 (1 H, s, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.8, 23.9, 24.6, 25.8, 27.6, 28.8, 29.5, 33.8, 35.0, 49.6, 53.2, 120.4, 123.5, 125.4, 127.9, 130.3, 134.6, 157.4, 162.3. EIMS: 411 (M+ , 1), 328 (6), 297 (19), 188 (100), 114 (76), 91 (64), 77 (25), 44 (55). Anal. Calcd. for C25 H41 N5 (411.34): C, 72.95; H, 10.04; N, 17.01 %. Found: C, 73.00; H, 10.18; N, 17.17 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]4-cyanobenzene (5g) Cream powder, m.p.: 125–127 ◦ C; yield: 0.29 g (68 %). IR (KBr) (νmax , cm−1 ): 2253, 2033, 1610, 1583, 1491, 1366, 1179, 1022. 1 H NMR (500 MHz, CDCl3 ): δH = 1.01−1.21 (7 H, m, CH2 ), 1.23–1.35 (7 H, m, CH2 ), 1.52–1.57 (3 H, m,
123
CH2 ), 1.83–1.89 (3 H, m, CH2 ), 2.78 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.32–3.36 (1 H, m, CH), 3.37–3.42 (1 H, m, CH), 7.45 (2 H, d, 3 J = 7.6 Hz, Ar), 7.73 (2 H, d, 3 J = 7.6 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.1, 24.5, 24.7, 25.3, 27.2, 28.1, 35.9, 38.2, 49.8, 52.9, 115.4, 127.5, 129.2, 135.7, 139.5, 158.4, 162.4. EIMS: 422 (M+ , 2), 378 (13), 339 (18), 320 (22), 199 (100), 114 (53), 83 (71), 77 (54), 44 (30). Anal. Calcd. for C25 H38 N6 (422.32): C, 71.05; H, 9.06; N, 19.89 %. Found: C, 71.19; H, 9.18; N, 19.97 %.
1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]naphthalene (5h) Pale yellow powder, m.p.: 151–153 ◦ C; yield: 0.31 g (69 %). IR (KBr) (νmax , cm−1 ): 2049, 1685, 1528, 1459, 1378, 1282, 1191, 1009. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.28 (8 H, m, CH2 ), 1.40–1.45 (4 H, m, CH2 ), 1.52–1.57 (4 H, m, CH2 ), 1.70–1.75 (4 H, m, CH2 ), 2.80 (6 H, s, Me2 N), 2.88 (6 H, s, Me2 N), 3.01–3.14 (1 H, m, CH), 3.20–3.28 (1 H, m, CH), 7.42 (1 H, t, 3 J = 7.4 Hz, Ar), 7.60-7.64 (2 H, m, Ph), 7.79 (1 H, d, 3 J = 7.4 Hz, Ar), 8.19 (1 H, d, 3 J = 7.5 Hz, Ar), 8.28 (1 H, d, 3 J = 7.5 Hz, Ar), 8.39 (1 H, d, 3 J = 7.5 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.9, 24.0, 24.7, 25.2, 29.7, 31.9, 35.9, 36.3, 49.0, 54.9, 122.5, 123.9, 124.2, 129.5, 129.9, 130.1, 134.4, 134.9, 137.2, 137.7, 155.4, 163.9. EIMS: 447 (M+ , 3), 364 (6), 333 (10), 224 (100), 127 (37), 114 (47), 83 (31), 44 (20). Anal. Calcd. for C28 H41 N5 (447.66): C, 75.12; H, 9.23; N, 15.64 %. Found: C, 75.25; H, 9.38; N, 15.77 %.
1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino}3-nitrobenzene (5i) Pale yellow powder, m.p.: 171–173 ◦ C; yield: 0.29 g (65 %). IR (KBr) (νmax , cm−1 ): 2059, 1619, 1520, 1451, 1374, 1222, 1190, 1079. 1 H NMR (500 MHz, CDCl3 ): δH = 1.20−1.33 (8 H, m, CH2 ), 1.40–1.46 (4 H, m, CH2 ), 1.51–1.58 (4 H, m, CH2 ), 1.82–1.88 (4 H, m, CH2 ), 2.78 (6 H, s, Me2 N), 2.89 (6 H, s, Me2 N), 3.32–3.37 (1 H, m, CH), 3.39–3.42 (1 H, m, CH), 7.52 (1 H, t, 3 J = 7.5 Hz, Ar), 7.73 (1 H, d, 3 J = 7.5 Hz, Ar), 7.89 (1 H, d, 3 J = 7.5 Hz, Ar), 7.94 (1 H, s, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.4, 23.5, 24.1, 25.8, 27.3, 28.8, 36.1, 38.0, 49.5, 54.1, 121.9, 129.8, 130.1, 132.9, 136.2, 138.9, 158.8, 162.3. EIMS: 442 (M + , 2), 398 (12), 359 (11), 219 (100), 122 (30), 114 (41), 83 (30), 44 (48). Anal. Calcd. for C24 H38 N6 O2 (442.31): C, 65.13; H, 8.65; N, 18.99 %. Found: C, 65.20; H, 8.78; N, 19.07 %.
Mol Divers
1-[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]benzene (5j) Cream powder, m.p.: 129–131 ◦ C; yield: 0.24 g (77 %). IR (KBr) (νmax , cm−1 ): 2049, 1666, 1581, 1400, 1317, 1174, 1014. 1 H NMR (500 MHz, CDCl3 ): δH = 1.42 (6 H, d, 3 J = 6.8 Hz, Me), 1.53 (6 H, d, 3 J = 6.9 Hz, Me), 2.37 (6 H, s, Me2 N), 2.60 (6 H, s, Me2 N), 3.19–3.23 (1 H, m, CH), 3.50–3.56 (1 H, m, CH), 7.30–7.34 (3 H, m, Ph), 7.47 (2 H, d, 3 J = 7.4 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.1, 25.5, 35.8, 38.9, 48.5, 51.2, 128.7, 129.2, 131.0, 132.5, 158.6, 162.7. EIMS: 317 (M+ , 4), 274 (8), 240 (19), 183 (49), 134 (36), 114 (100), 77 (50), 44 (41). Anal. Calcd. for C18 H31 N5 (317.26): C, 68.10; H, 9.84; N, 22.06 %. Found: C, 68.59; H, 9.99; N, 22.26 %.
1-[[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]4-bromobenzene (5k) Cream powder, m.p.: 157–159 ◦ C; yield: 0.28 g (72 %). IR (KBr) (νmax , cm−1 ): 2044, 1612, 1542, 1488, 1302, 1271, 1118, 1040. 1 H NMR (500 MHz, CDCl3 ): δH = 1.42 (6 H, d, 3 J = 6.8 Hz, Me), 1.49 (6 H, d, 3 J = 6.9 Hz, Me), 2.33 (6 H, s, Me2 N), 2.48 (6 H, s, Me2 N), 3.19–3.24 (1 H, m, CH), 3.50–3.55 (1 H, m, CH), 7.40 (2 H, d, 3 J = 7.8 Hz, Ar), 7.92 (2 H, d, 3 J = 7.8 Hz, Ar).13 C NMR (125.7 MHz, CDCl3 ): δC = 22.0, 25.2, 34.0, 36.8, 46.3, 50.4, 127.5, 130.6, 142.1, 147.2, 158.5, 162.7. EIMS: 395 (M+ , 6), 281 (11), 240 (29), 183 (49), 154 (100), 114 (50), 44 (31). Anal. Calcd. for C18 H30 BrN5 (395.17): C, 54.54; H, 7.63; N, 17.67 %. Found: C, 54.61; H, 7.80; N, 17.89 %.
1-[[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]4-chlorobenzene (5l) Cream powder, m.p.: 148–150 ◦ C; yield: 0.26 g (74 %). IR (KBr) (νmax , cm−1 ): 2044, 1660, 1578, 1420, 1343, 1238, 1021. 1 H NMR (500 MHz, CDCl3 ): δH = 1.40 (6 H, d, 3 J 6.8 Hz, Me), 1.49 (6 H, d, 3 J 6.9 Hz, Me), 2.29 (6 H, = = s, Me2 N), 2.48 (6 H, s, Me2 N), 3.19–3.26 (1 H, m, CH), 3.60–3.65 (1 H, m, CH), 7.62 (2 H, d, 3 J = 7.8 Hz, Ar), 8.04 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.0, 22.3, 35.5, 38.2, 46.7, 50.1, 127.4, 130.1, 135.7, 144.9, 157.4, 162.8. EIMS: 351 (M+ , 5), 307 (19), 237 (21), 183 (40), 168 (100), 114 (48), 44 (29). Anal. Calcd. for C18 H30 ClN5 (351.22): C, 61.43; H, 8.59; N, 19.90 %. Found: C, 61.69; H, 8.76; N, 20.06 %.
1-[[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]-4-cyanobenzene (5m) Cream powder, m.p.: 121–123 ◦ C; yield: 0.22 g (63 %). IR (KBr) (νmax , cm−1 ): 2256, 2039, 1633, 1501, 1459, 1355, 1257, 1108, 1041. 1 H NMR (500 MHz, CDCl3 ): δH = 1.42 (6 H, d, 3 J = 6.8 Hz, Me), 1.54 (6 H, d, 3 J = 6.9 Hz, Me), 2.71 (6 H, s, Me2 N), 2.80 (6 H, s, Me2 N), 3.18–3.24 (1 H, m, CH), 3.52–3.59 (1 H, m, CH), 7.41 (2 H, d, 3 J = 7.8 Hz, Ar), 7.93 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.0, 22.4, 35.0, 37.9, 49.1, 52.0, 115.6, 127.5, 130.6, 137.4, 141.1, 157.5, 161.0. EIMS: 342 (M+ , 3), 299 (23), 240 (11), 183 (40), 159 (48), 114 (36), 102 (100), 44 (33). Anal. Calcd. for C19 H30 N6 (342.25): C, 66.63; H, 8.83; N, 24.54 %. Found: C, 66.76; H, 8.99; N, 24.69 %.
References 1. Srivastava VP, Yadav DK, Yadav AK, Watal G, Yadav LDS (2013) A copper-catalyzed formamidation of arylboronic acids: direct access to formanilides. Synlett 24:1423–1427. doi:10.1021/ ol200750p 2. Kumar AS, Ramani T, Sreedhar B (2013) Magnetically separable CuFe2 O4 nanoparticles in PEG: a recyclable catalytic system for the amination of aryl iodides. Synlett 24:938–942. doi:10.1055/ s-0032-1316905 3. Yavari I, Nematpour M (2014) Copper-catalyzed N -arylation of 1,1,3,3- tetramethylguanidine-phenyl isocyanate adduct. Helv Chim Acta 97:1132–1135. doi:10.1002/hlca.201300418 4. Yavari I, Ghazanfarpur-Darjani M, Solgi Y, Ahmadian S (2011) Copper(I) iodide catalyzed formation of aryl hydrazides from a mitsunobo reagent and aryl halides. Synlett 12:1745–1747. doi:10. 1055/s-0030-1260802 5. Evano G, Blanchard N, Toumi M (2008) Copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis. Chem Rev 108:3054–3131. doi:10.1021/ cr8002505 6. Monnier F, Taillefer M (2009) Catalytic C–C, C–N, and C–O Ullmann-type coupling reactions. Angew Chem Int Ed 48:6954– 6971. doi:10.1002/anie.200804497 7. Yavari I, Sodagar E, Nematpour M (2014) CuO nanoparticles as effective reusable heterogeneous catalyst for S-arylation reactions. Helv Chim Acta 97:420–425. doi:10.1002/hlca.201300345 8. Xue WJ, Guo YQ, Gao FF, Li HZ, Wu AX (2013) A novel selfsequence reaction network involving a set of six reactions in one pot: the synthesis of substituted benzothiazoles from aromatic ketones and anilines. Org Lett 15:890–893. doi:10.1021/ol400029t 9. Gelbard G, Vieffaure-Joly F (1998) Polynitrogen strong bases: 1new syntheses of biguanides and their catalytic properties in transesterification reactions. Tetrahedron Lett 39:2743–2746. doi:10. 1016/S0040-4039(98)00300-1 10. Katritzky AR, Tala SR, Singh A (2010) Biguanidines, guanylureas and guanylthioureas. Arkivoc viii:76–96 11. Herres-Pawlis S (2009) Aubergewöhnliche donoren und synthetische vielfalt: Guanidine. Nachr Chem 57:20–23. doi:10.1002/nadc. 200960857 12. Bogolubsky AV, Grishchenko A, Pipko SE, Konovets A, Chuprina A, Tolmachev A, Boyko AN, Chekotylo A, Lukin O (2013) A solution-phase parallel synthesis of alkylated guanidines from
123
Mol Divers thioisocyanates and amines. Mol Divers 3:471–477. doi:10.1007/ s11030-013-9444-z 13. Debray J, Bonte S, Lozach O, Meijer L, Demeunynck M (2012) Catalyst-free synthesis of quinazolin-4-ones from (hetero)arylguanidines: application to the synthesis of pyrazolo[4,3f ]quinazolin-9-ones, a new family of DYRK1A inhibitors. Mol Divers 16:659–667. doi:10.1007/s11030-012-9397-7 14. Le VD, Wong CH (2000) Synthesis of 2-substituted polyhydroxytetrahydropyrimidines (N -hydroxy cyclic guanidino-sugars): transition-state mimics of enzymatic glycosidic cleavage. J Org Chem 65:2399–2409. doi:10.1021/jo9915574 15. Reddy NL, Fan W, Magar SS, Perlman ME, Yost E, Zhung L, Berlove D, Fischer JB, Howie KB, Wolcott T, Durant GJ (1998) Design, synthesis, and pharmacological evaluation of conformationally constrained analogues of N , N -diaryl- and N -aryl-N aralkylguanidines as potent inhibitors of neuronal Na+ channels. J Med Chem 41:3041–3068. doi:10.1021/jm980124a
123
16. Berlinck RGS, Burtoloso ACB, Kossuga MH (2008) The chemistry and biology of organic guanidine derivatives. Nat Prod Rep 25:919– 954. doi:10.1039/B507874C 17. Bailey PJ, Pace S (2001) The coordination chemistry of guanidines and guanidinates. Coord Chem Rev 214:91–141. doi:10. 1016/S0010-8545(00)00389-1 18. Williams A, Ibrahim TI (1981) Carbodiimide chemistry: recent advances. Chem Rev 81:589–636. doi:10.1021/cr00046a004 19. Glasovac Z, Troselj P, Jusinski I, Margetic D, Eckert-Maksic M (2013) Synthesis of highly basic hexasubstituted biguanides by environmentally friendly methods. Synlett 24:2540–2544. doi:10. 1055/s-0033-1339876
FULL-LENGTH PAPER
A direct access to heptasubstituted biguanides Issa Yavari1 · Manijeh Nematpour1
Received: 29 November 2014 / Accepted: 20 April 2015 © Springer International Publishing Switzerland 2015
Abstract An efficient and experimentally simple coppercatalyzed carbon–nitrogen bond formation for the synthesis of N -arylated biguanides starting from aryl halides, carbodiimides, and 1,1,3,3-tetramethylguanidine is reported. The potential diversity of this type of reaction, easily available starting materials, and commercially available low-cost catalysts are the incremental features of this methodology. Graphical Abstract
Keywords N -Arylation · Carbodiimides · Coppercatalyzed · Biguanides · Tetramethylguanidine
Guanidines are fairly strong bases and their role in biological systems is well documented [9–13]. Structurally diverse molecules that incorporate guanidine moieties have been isolated from plants. Guanidine-containing alkaloids exhibit antiviral, antifungal, and antitumor activities [14,15]. N Arylguanidines have been used as complementary partners of carboxylate and nitro groups in supramolecular chemistry [16]. Complexes containing a guanidine ligand have been reported [17]. The addition reaction between amines and carbodiimides has been extensively studied [18]. Using this strategy, Margetic and co-workers [19] obtained hexasubstituted biguanides from 1,1,3,3-tetramethylguanidine (TMG) and carbodiimides. This work prompted us to describe our results on the direct one-pot synthesis of heptasubstituted biguanides using carbodiimides, TMG, and aryl halides.
Introduction
Results and discussion
The construction of carbon–heteroatom bonds represents a key step in the synthesis of important classes of organic compounds that play a significant role in the material and pharmaceutical industries [1–4]. Several copper-catalyzed coupling reactions have been reported for C(aryl) –N, C(aryl) – O, and C(aryl) –S bond formation [5–8].
Initially, iodobenzene (1a), N ,N -dicyclohexylcarbodiimide (2a), and TMG were selected as the model substrates. Several catalysts such as CuI, CuBr, CuCl, Cu2 O, and copper powder were tested with CuI giving the best results. Among several solvents screened, DMF also provided the best results (Table 1). Thus, the optimized reaction conditions used were 10 mol% of CuI as the catalyst, 10 mol% of 1,10phenanthroline as the ligand, 2.0 mmol of K2 CO3 as the base, 1 mmol of 2a, and 1 mmol of TMG in DMF. Using the optimized conditions described above, various N -arylated biguanides 5 were synthesized from aryl halides 1, carbodiimides 2, and TMG. Aryl bromides served as lowyielding substrates compared to aryl iodides (Table 2). Structures of products 5a–m were assigned by IR, 1 H NMR, 13 C NMR, and mass spectral data. The 1 H NMR spec-
R
N
C
N
NH R
Me2N
i
R = Cy, Pr
NMe2
ArX
CuI (10 mol%) 1,10-phenanthroline (10 mol%) K2CO3 2 eq DMF, reflux, 12 h
NMe2 N
Me2N
N
X = I, Br
Electronic supplementary material The online version of this article (doi:10.1007/s11030-015-9601-7) contains supplementary material, which is available to authorized users.
B 1
Issa Yavari [email protected] Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
R N
R
Ar
123
Mol Divers Table 1 Optimization of reaction conditions for the formation of 5a Entry
Catalysta
1
Cu2 O
DMF
40
2
Cu2 O
MeCN
32
3
Cu2 O
Toluene
16
4
CuCl
DMF
62
5
CuCl
MeCN
51
6
CuCl
Toluene
30
7
CuIc
DMF
80 66
Solvent
Yield
8
CuI
MeCN
9
CuI
Toluene
41
10
CuI
DMSO
31
11
CuI
THF
22
12
CuBr
DMF
65
13
CuBr
Toluene
20
14
CuBr
DMSO
15
15
Cu
DMF
–
16
Cu
Toluene
–
a b c
(%)b
10 mol% catalyst unless stated otherwise; Phen 10 mol% Reaction time = 12 h 5 mol% catalyst; reaction time = 20 h
trum of 5a exhibited two singlets (2.78 and 2.86 ppm) for dimethylamino protons, along with characteristic multiplets for the phenyl group. The 13 C NMR spectrum of 5a exhib-
ited 16 signals in accord with the proposed structure. The mass spectrum of 5a displayed the molecular ion signal at m/z = 397. The NMR spectra of compounds 5b–m are similar to those of 5a, except for the substituents. The synthesis of N -alkylated biguanides 4 through addition of 3 to dialkyl carbodiimides 2, as shown in Table 2, has been discussed previously [9,10]. In addition, 1,10phenanthroline [4] can be used as a unique ligand for the N -arylation of 4 with aryl iodides and aryl bromides (Table 2). When chlorobenzene was subjected to the reaction conditions developed for aryl iodides and bromides, the yield of N -arylation reaction was very low. Thus, our studies are limited to aryl iodides and bromides.
Conclusions In summary, we have developed an efficient and experimentally simple, copper-catalyzed carbon–nitrogen bond formation for the synthesis of N -arylated biguanides starting from aryl halides, carbodiimides, and TMG. The potential diversity of this type of reaction, easily available starting materials, and commercially available low-cost catalysts are the incremental features of this methodology. Direct one-pot synthesis of heptasubstituted biguanides can be considered as an interesting and useful methodology.
Table 2 Copper-catalyzed C–N coupling of aryl halides 1 with carbodiimide-TMG adducts 4
123
Entry
1–5
X
Ar
R
Yield of 5 (%)
1
a
I
Ph
cHex
80
2
b
I
4-Me–C6 H4
cHex
81
3
c
I
4-MeO–C6 H4
cHex
79
4
d
I
4-Br–C6 H4
cHex
75
5
e
I
4-Cl–C6 H4
cHex
73
6
f
I
3-Me–C6 H4
cHex
78
7
g
Br
4-CN–C6 H4
cHex
68
8
h
Br
1-Naphthyl
cHex
69 65
9
i
Br
3-O2 N–C6 H4
cHex
10
j
I
Ph
i-Pr
77
11
k
I
4-Br–C6 H4
i-Pr
72
12
l
I
4-Cl–C6 H4
i-Pr
74
13
m
Br
4-CN–C6 H4
i-Pr
63
Mol Divers
Experimental section
C, 72.50; H, 9.89; N, 17.61 %. Found: C, 72.66; H, 9.97; N, 17.71 %.
General remarks All purchased solvents and chemicals were of analytical grade and used without further purification. Melting points (uncorrected) and IR spectra of all compounds were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer, respectively. The 1 H and 13 C spectra were obtained with a BRUKER DRX-500 AVANCE instrument using CDCl3 as applied solvent and TMS as internal standard at 500.1 and 125.7 MHz, respectively. The abbreviations used for NMR signals: s = singlet, d = doublet, t = triplet, and m = multiplet. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses for C, H, and N were performed using a Heraeus CHN–O–rapid analyzer. General procedure Preparation of compounds 5. The corresponding carbodiimide 2 (1 mmol) and TMG (1 mmol) were dissolved in DMF (2 mL) and stirred for 30 min. Then, a mixture of aryl halide 1 (1 mmol), CuI (0.1 mmol), 1,10-phenanthroline (0.1 mmol), and potassium carbonate (0.276 g, 2.0 mmol) in DMF (3 mL) was slowly added to the first mixture and stirred at 110 ◦ C, under N2 atmosphere. After completion of the reaction [about 12 h; TLC (AcOEt/hexane 1:3) monitoring], the mixture was diluted with CH2 Cl2 (2 mL) and aqueous NH4 Cl solution (3 mL), stirred for 30 min, and the layers were separated. The aqueous layer was extracted with CH2 Cl2 (3 × 3 mL), the combined organic fractions were dried (Na2 SO4 ) and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel (230–400 mesh; Merck), hexane/AcOEt 3:1] to give desired product. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl]anilino}cyclohexane (5a) Cream powder, m.p.: 149–151 ◦ C; yield: 0.32 g (80 %). IR (KBr) (νmax , cm−1 ): 2059, 1670, 1580, 1455, 1377, 1170, 1075. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.35 (8 H, m, CH2 ), 1.46–1.51 (4 H, m, CH2 ), 1.58–1.64 (4 H, m, CH2 ), 1.87–1.93 (4 H, m, CH2 ), 2.78 (6 H, s, Me2 N), 2.86 (6 H, s, Me2 N), 3.30-3.33 (1 H, m, CH), 3.34–3.37 (1 H, m, CH), 7.02 (2 H, t, 3 J = 7.4 Hz, Ar), 7.25 (1 H, t, 3 J = 7.4 Hz, Ar), 7.61 (2 H, d, 3 J = 7.4 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.7, 24.9, 25.4, 25.6, 28.1, 31.3, 34.7, 36.4, 48.5, 53.2, 127.4, 130.1, 132.0, 137.4, 157.7, 162.4. EIMS: 397 (M+ , 1), 353 (8), 320 (11), 283 (29), 174 (100), 114 (30), 83 (21), 77 (51), 44 (31). Anal. Calc. for C24 H39 N5 (397.32):
1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino}4-methylbenzene (5b) Cream powder, m.p.: 130–133 ◦ C; yield: 0.33 g (81 %). IR (KBr) (νmax , cm−1 ): 2050, 1589, 1492, 1422, 1303, 1230, 1152, 1029. 1 H NMR (500 MHz, CDCl3 ): δH = 1.18–1.34 (8 H, m, CH2 ), 1.45–1.50 (4 H, m, CH2 ), 1.58–1.63 (4 H, m, CH2 ), 1.76–1.79 (4 H, m, CH2 ), 2.21 (3 H, s, Me), 2.76 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.29–3.33 (1 H, m, CH), 3.35–3.38 (1 H, m, CH), 7.11 (2 H, d, 3 J = 7.6 Hz, Ar), 7.43 (2 H, d, 3 J = 7.6 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 21.5 (CH2 ), 23.4 (CH2 ), 24.9 (2 CH2 ), 25.4 (2 CH2 ), 27.9 (2 CH2 ), 28.1, 33.1, 33.9, 36.3, 52.8, 55.9, 123.5, 132.2, 138.9, 139.0, 157.9, 162.4. EIMS: 411 (M+ , 2), 367 (18), 328 (29), 297 (17), 188 (100), 114 (34), 91 (71), 83 (53), 44 (30). Anal. Calcd. for C25 H41 N5 (411.34): C, 72.95; H, 10.04; N, 17.01 %. Found: C, 73.03; H, 10.35; N, 17.21 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino}4-methoxybenzene (5c) Cream powder, m.p.: 133–135 ◦ C; yield: 0.34 g (79 %). IR (KBr) (νmax , cm−1 ): 2024, 1654, 1547, 1401, 1374, 1271, 1111, 1091. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.33 (8 H, m, CH2 ), 1.44–1.48 (4 H, m, CH2 ), 1.56–1.59 (4 H, m, CH2 ), 1.84–1.87 (4 H, m, CH2 ), 2.75 (6 H, s, Me2 N), 2.86 (6 H, s, Me2 N), 3.32–3.35 (1 H, m, CH), 3.39–3.47 (1 H, m, CH), 3.73 (3 H, s, OMe), 6.79 (2 H, d, 3 J = 7.7 Hz, Ar), 7.51 (2 H, d, 3 J = 7.7 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.3, 23.9, 24.8, 25.9, 27.9, 28.2, 35.6, 38.9, 50.5, 51.0, 54.7, 127.5, 132.9, 133.4, 136.5, 159.8, 161.1. EIMS: 427 (M+ , 2), 383 (11), 344 (14), 204 (100), 114 (42), 107 (39), 83 (87), 44 (29). Anal. Calcd. for C25 H41 N5 O (427.33): C, 70.22; H, 9.66; N, 16.38 %. Found: C, 70.32; H, 9.85; N, 16.47 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]4-bromobenzene (5d) Cream powder, m.p.: 138–140 ◦ C; yield: 0.36 g (75 %). IR (KBr) (νmax , cm−1 ): 2089, 1666, 1598, 1439, 1349, 1228, 1011. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.32 (8 H, m, CH2 ), 1.43–1.47 (4 H, m, CH2 ), 1.54–1.58 (4 H, m, CH2 ), 1.82–1.86 (4 H, m, CH2 ), 2.77 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.30–3.35 (1 H, m, CH), 3.38–3.45 (1 H, m, CH), 6.84 (2 H, d, 3 J = 7.8 Hz, Ar), 7.47 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.3, 23.8, 24.9,
123
Mol Divers
25.7, 27.5, 28.1, 35.9, 38.7, 49.0, 55.2, 132.0, 133.2, 136.3, 136.9, 161.4, 164.0. EIMS: 475 (M+ , 5), 392 (18), 361 (10), 252 (100), 154 (45), 114 (37), 83 (33), 44 (29). Anal. Calcd. for C24 H38 BrN5 (475.23): C, 60.50; H, 8.04; N, 16.77 %. Found: C, 60.69; H, 8.20; N, 16.86 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]4-chlorobenzene (5e) Cream powder, m.p.: 143–146 ◦ C; yield: 0.31 g (73 %). IR (KBr) (νmax , cm−1 ): 2048, 1679, 1541, 1453, 1372, 1277, 1188, 1043. 1 H NMR (500 MHz, C DCl3 ): δH = 1.18– 1.30 (8 H, m, CH2 ), 1.42–1.46 (4 H, m, CH2 ), 1.53–1.58 (4 H, m, CH2 ), 1.84–1.89 (4 H, m, CH2 ), 2.79 (6 H, s, Me2 N), 2.85 (6 H, s, Me2 N), 3.31–3.35 (1 H, m, CH), 3.37–3.40 (1 H, m, CH), 7.15 (2 H, d, 3 J = 7.8 Hz, Ar), 7.49 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.9, 24.0, 24.9, 25.4, 27.2, 28.9, 35.3, 38.6, 49.6, 53.5, 122.1, 130.1, 139.0, 140.1, 158.4, 162.3. EIMS: 431 (M+ , 2), 387 (12), 347 (9), 208 (100), 114 (45), 83 (45), 44 (47). Anal. Calcd. for C24 H38 ClN5 (431.28): C, 66.72; H, 8.87; N, 16.21 %. Found: C, 66.81; H, 8.98; N, 16.39 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]3-methylbenzene (5f) Cream powder, m.p.: 119–121 ◦ C; yield: 0.32 g (78 %). IR (KBr) (νmax , cm−1 ): 2044, 1644, 1544, 1416, 1306, 1292, 1169, 1071. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17−1.29 (8 H, m, CH2 ), 1.41–1.45 (4 H, m, CH2 ), 1.57–1.63 (4 H, m, CH2 ), 1.79–1.85 (4 H, m, CH2 ), 2.25 (3 H, s, Me), 2.80 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.34–3.37 (1 H, m, CH), 3.39– 3.46 (1 H, m, CH), 7.32 (1 H, t, 3 J = 7.5 Hz, Ar), 7.51 (1 H, d, 3 J = 7.5 Hz, Ar), 7.62 (1 H, d, 3 J = 7.5 Hz, Ar), 7.72 (1 H, s, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.8, 23.9, 24.6, 25.8, 27.6, 28.8, 29.5, 33.8, 35.0, 49.6, 53.2, 120.4, 123.5, 125.4, 127.9, 130.3, 134.6, 157.4, 162.3. EIMS: 411 (M+ , 1), 328 (6), 297 (19), 188 (100), 114 (76), 91 (64), 77 (25), 44 (55). Anal. Calcd. for C25 H41 N5 (411.34): C, 72.95; H, 10.04; N, 17.01 %. Found: C, 73.00; H, 10.18; N, 17.17 %. 1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]4-cyanobenzene (5g) Cream powder, m.p.: 125–127 ◦ C; yield: 0.29 g (68 %). IR (KBr) (νmax , cm−1 ): 2253, 2033, 1610, 1583, 1491, 1366, 1179, 1022. 1 H NMR (500 MHz, CDCl3 ): δH = 1.01−1.21 (7 H, m, CH2 ), 1.23–1.35 (7 H, m, CH2 ), 1.52–1.57 (3 H, m,
123
CH2 ), 1.83–1.89 (3 H, m, CH2 ), 2.78 (6 H, s, Me2 N), 2.84 (6 H, s, Me2 N), 3.32–3.36 (1 H, m, CH), 3.37–3.42 (1 H, m, CH), 7.45 (2 H, d, 3 J = 7.6 Hz, Ar), 7.73 (2 H, d, 3 J = 7.6 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.1, 24.5, 24.7, 25.3, 27.2, 28.1, 35.9, 38.2, 49.8, 52.9, 115.4, 127.5, 129.2, 135.7, 139.5, 158.4, 162.4. EIMS: 422 (M+ , 2), 378 (13), 339 (18), 320 (22), 199 (100), 114 (53), 83 (71), 77 (54), 44 (30). Anal. Calcd. for C25 H38 N6 (422.32): C, 71.05; H, 9.06; N, 19.89 %. Found: C, 71.19; H, 9.18; N, 19.97 %.
1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino]naphthalene (5h) Pale yellow powder, m.p.: 151–153 ◦ C; yield: 0.31 g (69 %). IR (KBr) (νmax , cm−1 ): 2049, 1685, 1528, 1459, 1378, 1282, 1191, 1009. 1 H NMR (500 MHz, CDCl3 ): δH = 1.17–1.28 (8 H, m, CH2 ), 1.40–1.45 (4 H, m, CH2 ), 1.52–1.57 (4 H, m, CH2 ), 1.70–1.75 (4 H, m, CH2 ), 2.80 (6 H, s, Me2 N), 2.88 (6 H, s, Me2 N), 3.01–3.14 (1 H, m, CH), 3.20–3.28 (1 H, m, CH), 7.42 (1 H, t, 3 J = 7.4 Hz, Ar), 7.60-7.64 (2 H, m, Ph), 7.79 (1 H, d, 3 J = 7.4 Hz, Ar), 8.19 (1 H, d, 3 J = 7.5 Hz, Ar), 8.28 (1 H, d, 3 J = 7.5 Hz, Ar), 8.39 (1 H, d, 3 J = 7.5 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 23.9, 24.0, 24.7, 25.2, 29.7, 31.9, 35.9, 36.3, 49.0, 54.9, 122.5, 123.9, 124.2, 129.5, 129.9, 130.1, 134.4, 134.9, 137.2, 137.7, 155.4, 163.9. EIMS: 447 (M+ , 3), 364 (6), 333 (10), 224 (100), 127 (37), 114 (47), 83 (31), 44 (20). Anal. Calcd. for C28 H41 N5 (447.66): C, 75.12; H, 9.23; N, 15.64 %. Found: C, 75.25; H, 9.38; N, 15.77 %.
1-{[{[Bis(dimethylamino)methylene]amino} (cyclohexylimino)methyl](cyclohexyl)amino}3-nitrobenzene (5i) Pale yellow powder, m.p.: 171–173 ◦ C; yield: 0.29 g (65 %). IR (KBr) (νmax , cm−1 ): 2059, 1619, 1520, 1451, 1374, 1222, 1190, 1079. 1 H NMR (500 MHz, CDCl3 ): δH = 1.20−1.33 (8 H, m, CH2 ), 1.40–1.46 (4 H, m, CH2 ), 1.51–1.58 (4 H, m, CH2 ), 1.82–1.88 (4 H, m, CH2 ), 2.78 (6 H, s, Me2 N), 2.89 (6 H, s, Me2 N), 3.32–3.37 (1 H, m, CH), 3.39–3.42 (1 H, m, CH), 7.52 (1 H, t, 3 J = 7.5 Hz, Ar), 7.73 (1 H, d, 3 J = 7.5 Hz, Ar), 7.89 (1 H, d, 3 J = 7.5 Hz, Ar), 7.94 (1 H, s, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.4, 23.5, 24.1, 25.8, 27.3, 28.8, 36.1, 38.0, 49.5, 54.1, 121.9, 129.8, 130.1, 132.9, 136.2, 138.9, 158.8, 162.3. EIMS: 442 (M + , 2), 398 (12), 359 (11), 219 (100), 122 (30), 114 (41), 83 (30), 44 (48). Anal. Calcd. for C24 H38 N6 O2 (442.31): C, 65.13; H, 8.65; N, 18.99 %. Found: C, 65.20; H, 8.78; N, 19.07 %.
Mol Divers
1-[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]benzene (5j) Cream powder, m.p.: 129–131 ◦ C; yield: 0.24 g (77 %). IR (KBr) (νmax , cm−1 ): 2049, 1666, 1581, 1400, 1317, 1174, 1014. 1 H NMR (500 MHz, CDCl3 ): δH = 1.42 (6 H, d, 3 J = 6.8 Hz, Me), 1.53 (6 H, d, 3 J = 6.9 Hz, Me), 2.37 (6 H, s, Me2 N), 2.60 (6 H, s, Me2 N), 3.19–3.23 (1 H, m, CH), 3.50–3.56 (1 H, m, CH), 7.30–7.34 (3 H, m, Ph), 7.47 (2 H, d, 3 J = 7.4 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.1, 25.5, 35.8, 38.9, 48.5, 51.2, 128.7, 129.2, 131.0, 132.5, 158.6, 162.7. EIMS: 317 (M+ , 4), 274 (8), 240 (19), 183 (49), 134 (36), 114 (100), 77 (50), 44 (41). Anal. Calcd. for C18 H31 N5 (317.26): C, 68.10; H, 9.84; N, 22.06 %. Found: C, 68.59; H, 9.99; N, 22.26 %.
1-[[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]4-bromobenzene (5k) Cream powder, m.p.: 157–159 ◦ C; yield: 0.28 g (72 %). IR (KBr) (νmax , cm−1 ): 2044, 1612, 1542, 1488, 1302, 1271, 1118, 1040. 1 H NMR (500 MHz, CDCl3 ): δH = 1.42 (6 H, d, 3 J = 6.8 Hz, Me), 1.49 (6 H, d, 3 J = 6.9 Hz, Me), 2.33 (6 H, s, Me2 N), 2.48 (6 H, s, Me2 N), 3.19–3.24 (1 H, m, CH), 3.50–3.55 (1 H, m, CH), 7.40 (2 H, d, 3 J = 7.8 Hz, Ar), 7.92 (2 H, d, 3 J = 7.8 Hz, Ar).13 C NMR (125.7 MHz, CDCl3 ): δC = 22.0, 25.2, 34.0, 36.8, 46.3, 50.4, 127.5, 130.6, 142.1, 147.2, 158.5, 162.7. EIMS: 395 (M+ , 6), 281 (11), 240 (29), 183 (49), 154 (100), 114 (50), 44 (31). Anal. Calcd. for C18 H30 BrN5 (395.17): C, 54.54; H, 7.63; N, 17.67 %. Found: C, 54.61; H, 7.80; N, 17.89 %.
1-[[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]4-chlorobenzene (5l) Cream powder, m.p.: 148–150 ◦ C; yield: 0.26 g (74 %). IR (KBr) (νmax , cm−1 ): 2044, 1660, 1578, 1420, 1343, 1238, 1021. 1 H NMR (500 MHz, CDCl3 ): δH = 1.40 (6 H, d, 3 J 6.8 Hz, Me), 1.49 (6 H, d, 3 J 6.9 Hz, Me), 2.29 (6 H, = = s, Me2 N), 2.48 (6 H, s, Me2 N), 3.19–3.26 (1 H, m, CH), 3.60–3.65 (1 H, m, CH), 7.62 (2 H, d, 3 J = 7.8 Hz, Ar), 8.04 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.0, 22.3, 35.5, 38.2, 46.7, 50.1, 127.4, 130.1, 135.7, 144.9, 157.4, 162.8. EIMS: 351 (M+ , 5), 307 (19), 237 (21), 183 (40), 168 (100), 114 (48), 44 (29). Anal. Calcd. for C18 H30 ClN5 (351.22): C, 61.43; H, 8.59; N, 19.90 %. Found: C, 61.69; H, 8.76; N, 20.06 %.
1-[[{[Bis(dimethylamino)methylene]amino} (isopropylimino)methyl](isopropyl)amino]-4-cyanobenzene (5m) Cream powder, m.p.: 121–123 ◦ C; yield: 0.22 g (63 %). IR (KBr) (νmax , cm−1 ): 2256, 2039, 1633, 1501, 1459, 1355, 1257, 1108, 1041. 1 H NMR (500 MHz, CDCl3 ): δH = 1.42 (6 H, d, 3 J = 6.8 Hz, Me), 1.54 (6 H, d, 3 J = 6.9 Hz, Me), 2.71 (6 H, s, Me2 N), 2.80 (6 H, s, Me2 N), 3.18–3.24 (1 H, m, CH), 3.52–3.59 (1 H, m, CH), 7.41 (2 H, d, 3 J = 7.8 Hz, Ar), 7.93 (2 H, d, 3 J = 7.8 Hz, Ar). 13 C NMR (125.7 MHz, CDCl3 ): δC = 22.0, 22.4, 35.0, 37.9, 49.1, 52.0, 115.6, 127.5, 130.6, 137.4, 141.1, 157.5, 161.0. EIMS: 342 (M+ , 3), 299 (23), 240 (11), 183 (40), 159 (48), 114 (36), 102 (100), 44 (33). Anal. Calcd. for C19 H30 N6 (342.25): C, 66.63; H, 8.83; N, 24.54 %. Found: C, 66.76; H, 8.99; N, 24.69 %.
References 1. Srivastava VP, Yadav DK, Yadav AK, Watal G, Yadav LDS (2013) A copper-catalyzed formamidation of arylboronic acids: direct access to formanilides. Synlett 24:1423–1427. doi:10.1021/ ol200750p 2. Kumar AS, Ramani T, Sreedhar B (2013) Magnetically separable CuFe2 O4 nanoparticles in PEG: a recyclable catalytic system for the amination of aryl iodides. Synlett 24:938–942. doi:10.1055/ s-0032-1316905 3. Yavari I, Nematpour M (2014) Copper-catalyzed N -arylation of 1,1,3,3- tetramethylguanidine-phenyl isocyanate adduct. Helv Chim Acta 97:1132–1135. doi:10.1002/hlca.201300418 4. Yavari I, Ghazanfarpur-Darjani M, Solgi Y, Ahmadian S (2011) Copper(I) iodide catalyzed formation of aryl hydrazides from a mitsunobo reagent and aryl halides. Synlett 12:1745–1747. doi:10. 1055/s-0030-1260802 5. Evano G, Blanchard N, Toumi M (2008) Copper-mediated coupling reactions and their applications in natural products and designed biomolecules synthesis. Chem Rev 108:3054–3131. doi:10.1021/ cr8002505 6. Monnier F, Taillefer M (2009) Catalytic C–C, C–N, and C–O Ullmann-type coupling reactions. Angew Chem Int Ed 48:6954– 6971. doi:10.1002/anie.200804497 7. Yavari I, Sodagar E, Nematpour M (2014) CuO nanoparticles as effective reusable heterogeneous catalyst for S-arylation reactions. Helv Chim Acta 97:420–425. doi:10.1002/hlca.201300345 8. Xue WJ, Guo YQ, Gao FF, Li HZ, Wu AX (2013) A novel selfsequence reaction network involving a set of six reactions in one pot: the synthesis of substituted benzothiazoles from aromatic ketones and anilines. Org Lett 15:890–893. doi:10.1021/ol400029t 9. Gelbard G, Vieffaure-Joly F (1998) Polynitrogen strong bases: 1new syntheses of biguanides and their catalytic properties in transesterification reactions. Tetrahedron Lett 39:2743–2746. doi:10. 1016/S0040-4039(98)00300-1 10. Katritzky AR, Tala SR, Singh A (2010) Biguanidines, guanylureas and guanylthioureas. Arkivoc viii:76–96 11. Herres-Pawlis S (2009) Aubergewöhnliche donoren und synthetische vielfalt: Guanidine. Nachr Chem 57:20–23. doi:10.1002/nadc. 200960857 12. Bogolubsky AV, Grishchenko A, Pipko SE, Konovets A, Chuprina A, Tolmachev A, Boyko AN, Chekotylo A, Lukin O (2013) A solution-phase parallel synthesis of alkylated guanidines from
123
Mol Divers thioisocyanates and amines. Mol Divers 3:471–477. doi:10.1007/ s11030-013-9444-z 13. Debray J, Bonte S, Lozach O, Meijer L, Demeunynck M (2012) Catalyst-free synthesis of quinazolin-4-ones from (hetero)arylguanidines: application to the synthesis of pyrazolo[4,3f ]quinazolin-9-ones, a new family of DYRK1A inhibitors. Mol Divers 16:659–667. doi:10.1007/s11030-012-9397-7 14. Le VD, Wong CH (2000) Synthesis of 2-substituted polyhydroxytetrahydropyrimidines (N -hydroxy cyclic guanidino-sugars): transition-state mimics of enzymatic glycosidic cleavage. J Org Chem 65:2399–2409. doi:10.1021/jo9915574 15. Reddy NL, Fan W, Magar SS, Perlman ME, Yost E, Zhung L, Berlove D, Fischer JB, Howie KB, Wolcott T, Durant GJ (1998) Design, synthesis, and pharmacological evaluation of conformationally constrained analogues of N , N -diaryl- and N -aryl-N aralkylguanidines as potent inhibitors of neuronal Na+ channels. J Med Chem 41:3041–3068. doi:10.1021/jm980124a
123
16. Berlinck RGS, Burtoloso ACB, Kossuga MH (2008) The chemistry and biology of organic guanidine derivatives. Nat Prod Rep 25:919– 954. doi:10.1039/B507874C 17. Bailey PJ, Pace S (2001) The coordination chemistry of guanidines and guanidinates. Coord Chem Rev 214:91–141. doi:10. 1016/S0010-8545(00)00389-1 18. Williams A, Ibrahim TI (1981) Carbodiimide chemistry: recent advances. Chem Rev 81:589–636. doi:10.1021/cr00046a004 19. Glasovac Z, Troselj P, Jusinski I, Margetic D, Eckert-Maksic M (2013) Synthesis of highly basic hexasubstituted biguanides by environmentally friendly methods. Synlett 24:2540–2544. doi:10. 1055/s-0033-1339876
