The preparation of 1,2,3-trisubstituted guanidines

Article abstract of DOI:10.1002/hlca.200590131

An operationally straightforward and efficient benzotriazole-based method for the guanylation of diverse amines by use of the new reagent classes (bis-benzotriazol-1-yl-methylene)amines 13a-13f and benzotriazole-1- carboxamidines 17a-17i is described. The preparation is described for a variety of both acyclic and cyclic 1,2,3-trisubstituted guanidines in high yields.

Full text of DOI:10.1002/hlca.200590131

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Helvetica Chimica Acta Vol. 88 (2005)
The Preparation of 1,2,3-Trisubstituted Guanidines
by Alan R. Katritzky*, Niveen M. Khashab, and Sergey Bobrov
Center for Heterocyclic Compounds, University of Florida, Department of Chemistry, Gainesville,
Florida 32611-7200, USA (e-mail: Katritzky@chem.ufl.edu)
Submitted to honor the 85th birthday of Rolf Huisgen: inspiring chemist and good friend
An operationally straightforward and efficient benzotriazole-based method for the guanylation of diverse
amines by use of the new reagent classes (bis-benzotriazol-1-yl-methylene)amines 13a 13f and benzotriazole-
1-carboxamidines 17a 17i is described. The preparation is described for a variety of both acyclic and cyclic
1,2,3-trisubstituted guanidines in high yields.
Introduction. A wide variety of structurally diverse molecules that incorporate
guanidine units have been isolated from many microorganisms and higher plants [1].
Guanidines are core features of many therapeutically active compounds [2 7], and
guanidine alkaloids exhibit antiviral, antifungal, and antitumor activities [1]. Thus,
procedures for the preparation of guanidines [8] are of great interest in medicinal
chemistry, and much effort has been directed towards efficient syntheses of these
compounds (see, e.g., [9]).
The synthesis of guanidines 3 is complicated by their high basicity and
nucleophilicity. Many syntheses utilize intermediates with easily removed protective
groups. Common methods for the preparation of guanidines 3 involve attack of an
amine 1 on various activated guanidinylating reagents 2a 2j (Scheme 1). Primary
amines react smoothly and efficiently with these reagents, whereas sterically more
demanding secondary or electronically deactivated aromatic amines face various
difficulties.
Methods for the preparation of guanidines 3 (Scheme 1) include: i) reaction of
various ureas 2a with phosgene then treating the resultant Vilsmeier salt with amines 1
[10]; ii) using triflicguanidines 2b as guanidinylating reagents [11], or iii) guanylpyr-
azole 2c as guanidinylating reagents [12]. Several common routes to 3 involve the
treatment of amines with electrophilic species 2d 2i generated from thioureas: iv)
sulfonic acids 2d derived from N-alkyl-substituted thioureas [13]; v) S-methyl(aryl)-
sulfanylisothioureas 2e [14], in the presence of Hg salts; vi) bis-Boc-isothioureas 2f and
HgCl2 [15 18]; vii) bis-Boc-thioureas 2g and Mukaiyama×s Reagent to form a
carbodiimide subsequently treated with amines [19]; viii) acylthioureas 2h and amines
in the presence of the water-soluble carbodiimide, EDCI (ˆ1-ethyl-3-[3-(dimethyla-
mino)propyl]carbodiimide hydrochloride), [20]; ix) S-methylisothiourea 2i in refluxing
t-BuOH with aryl amines [21][22]; or x) other guanidinylating reagents including 1H-
imidazole-1-carboxamidines 2j [23], and 1,3-diarylthioureas 5 with iminophosphoranes
4 to form trisubstituted guanidines 3 [24].
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
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Scheme 1
Our group introduced benzotriazole-based guanylating reagents: i) 1H-benzotria-
zole-1-carboxamidinium p-toluenesulfonate 6 [25], ii) (1H-benzotriazolyl)carboximi-
doyl chlorides 7 [26], and iii) bis(1H-benzotriazolyl)carboximidamides 8a and 8b
(Scheme 2) [27]. Reagents 6 8 guanylate primary and secondary amines under mild
conditions in high yields (Scheme 2). 1H-Benzotriazole-1-carboxamidinium p-tolu-
Scheme 2

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Helvetica Chimica Acta Vol. 88 (2005)
enesulfonate 6 affords mono- and N,N-disubstituted guanidines (55 86%). Stable,
odorless (1H-benzotriazolyl)carboximidoyl chlorides 7 allow the preparation of
unsymmetric polysubstituted guanidines (45 92%). Bis(1H-benzotriazolyl)carboxi-
midamide 8a enables the synthesis of tri- and tetra-substituted-guanidines from a wide
variety of amines. Bis(1H-benzotriazolyl)carboximidamides 8b are efficient for the
preparation of acylguanidines (48 85%) [28].
To provide for the facile preparation of polysubstituted guanidines (cf. Scheme 3,
and Tables 1 and 3), we have now introduced convenient 1H-benzotriazole-based
guanylation using novel [bis(1H-benzotriazol-1-yl)methylidene]amines 13 and 1H-
benzotriazole-1-carboxamidines 17.
Results and Discussion. [Bis(1H-benzotriazol-1-yl)methylidene]amines 13a 13f
were prepared from bis(1H-benzotriazol-1-yl)methanethione (15) and triphenylphos-
phine imides 14a 14f in toluene at 708 for 3 h and purified by column chromatography
(Scheme 3). Known triphenylphosphine imides 14a 14g were synthesized in quanti-
tative yields from the reaction of the corresponding organic azides with Ph3P in EtOH
at reflux for 2 h [29]. Melting points and spectral data for 14a 14g were identical to
reported values (see the Exper. Part). The structures of novel 13a 13e were supported
1
by their H- and 13C-NMR spectra, and elemental analysis data (see the Exper. Part).
Known 13f was previously been synthesized by a different method [28].
Syntheses of symmetric guanidines 11a 11e from 13a 13e and aliphatic primary
amines were accomplished in high yields on refluxing in toluene for 1 h (Scheme 3 and
Table 1). Compound 11a was prepared earlier [30]; novel 11b 11e were fully
1
characterized on the basis of H- and 13C-NMR spectroscopy, and elemental analysis.
However, we failed to prepare symmetric guanidines corresponding to 11 from 13a
13e and secondary amines; possibly because, with secondary amines, carbodiimide 10
formation [31] by elimination of 1H-benzotriazole from an intermediate analogous to 9
is not possible (Scheme 3).
Table 1. Preparation of Symmetric and Cyclic Trisubstituted Guanidines 11a 11e and 19a 19e
13
R
Product R1
Yield 13
[%]
R
Diamine 18
Product Yield
[%]
13a Ph
11a
Cyclohexyl 79
13b p-Tol
13b p-Tol
NH2(CH2)3NH2
NH2(CH2)2NH2
19a
19b
95
95
96
89
77
13b p-Tol (4-MeÀC6H4) 11b
Bu
i-Pr
83
87
13c 3-CNÀC6H4
13d 4-EtOCOÀC6H4
13e 4-ClÀC6H4
11c
11d
11e
13e 4-ClÀC6H4 (NH2CH2)2CMe2 19c
PhCH(Me) 91
Bn 85
13a Ph
NH2(CH2)3NHMe 19d
NH2(CH2)3NH2 19e
13f PhCO
Reagents 13a and 13b and 13f also successfully guanylated diamines 18 to give
cyclic trisubstituted guanidines 19a 19e in high yields (Scheme 3 and Table 1). The
structures of novel 19a, 19c, and 19d were supported by their 1H- and 13C-NMR spectra,
1
and elemental-analysis data. For known 19b [32] and 19e [33], the H- and 13C-NMR
spectra data are now given, they were previously unreported (see the Exper. Part).
Preparation of intermediates 16a 16h was achieved by a simple one step reaction
of bis(1H-benzotriazol-1-yl)methanethione (15) and appropriate primary amines in
CH2Cl2 at 208 (Scheme 3) [34]. Melting points for known 16a, 16f, and 16h were found

Helvetica Chimica Acta Vol. 88 (2005)
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Helvetica Chimica Acta Vol. 88 (2005)
to be identical to reported values (see the Exper. Part). Novel 16b e, and 16g were
1
characterized by H- and 13C-NMR spectra, and elemental analyses (see the Exper.
Part). Synthesis of 17a 17l was achieved from the reaction of 16a 16h with
triphenylphosphine imides 14a 14g in refluxing toluene for 1 h (Scheme 3 and
Table 2). Novel 1H-benzotriazole-1-carboximidamides 17a 17l were identified by 1H-
and 13C-NMR spectra, and elemental analyses (see the Exper. Part). Attempts to
prepare bis(1H-benzotriazol-1-yl-methylene)amines 17 by the reaction of 16a and 16b
with 14 when R Ts or 4-NO2ÀC6H4 failed, apparently due to the strong electron-
withdrawing nature of these groups (Scheme 3). In addition, our efforts to prepare
analog of 17 from 16b (R1 ˆ i-Pr) also failed to give the corresponding N,N'-substituted
thiourea.
Table 2. Preparation of Guanylating Reagents 17a 17l
Reactants 16 ‡ 14
R1
R
Product 17
Yield [%]
16a ‡ 14a
16a ‡ 14b
16b ‡ 14b
16b ‡ 14e
16c ‡ 14g
16d ‡ 14d
16d ‡ 14g
16e ‡ 14c
16f ‡ 14e
16g ‡ 14b
16h ‡ 14e
16d ‡ 14e
Bn
Bn
i-Pr
i-Pr
Ph
Bu
Bu
Ph
p-Tol
p-Tol
17a
17b
17c
17d
17e
17f
17g
17h
17i
91
96
92
67
80
53
84
95
40
82
93
87
4-ClÀC6H4
Mesityl
4-EtOCOÀC6H4
Mesityl
3-CNÀC6H4
4-ClÀC6H4
p-Tol
Ph(CH2)2
Cyclohexyl
2-Methylbutyl
(Furan-2-yl)methyl
Bu
17j
17k
17l
4-ClÀC6H4
4-ClÀC6H4
Secondary amines (see R2 and R3 for amines in Table 3) underwent efficient
guanylation using reagents 17a, 17b, 17f, 17g, 17h, and 17i in toluene under reflux for
12 h to afford unsymmetric guanidines 12a 12f (Scheme 3 and Table 3). The 1H-
benzotriazole group in 17a 17c, 17e, 17j, and 17k was displaced by primary
alkylamines in refluxing toluene in just 1 h to form unsymmetric guanidines 20a 20f
in high yields (Scheme 3 and Table 3). The 1H-benzotriazole formed as a by-product
was removed by washing with saturated aqueous Na2CO3. Novel compounds 12a 12f
and 20a 20f were fully characterized by 1H- and 13C-NMR spectroscopy, and
elemental analyses. The hydroscopic nature of guanidines 12a 12f and 20a 20f
caused difficulties in obtaining the elemental analyses. For this reason, compounds 12c
and 12d, and 20e and 20f were characterized by elemental analyses of the
corresponding hydrochlorides (see the Exper. Part).
In summary, new routes for the guanylation of a series of structurally varied primary
and secondary amines have been reported. [Bis(1H-benzotriazol-1-yl)methylidene]-
amines 13a 13f and 1H-benzotriazole-1-carboxamidines 17a 17l are stable, crystal-
line guanylating reagents that can be stored at room temperature for many weeks with
no apparent loss of activity. The preparation of reagents of type 13 and 17 is facile and
should find widespread use in the synthesis of guanidines. An attractive feature of this
methodology is that 1H-benzotriazole, which is generated as a by-product, can be easily

Helvetica Chimica Acta Vol. 88 (2005)
1669
Table 3. Preparation of Substituted Unsymmetrical Guanidines 12a 12f and 20a 20f
17
R
R1
R2
R3
Product
Yield [%]
17a
17b
17f
17i
17h
17g
17a
17b
17c
17e
17j
Ph
p-Tol
Bn
Bn
Bu
Cyclohexyl
Ph(CH2)2
Bu
Bn
Bn
i-Pr
i-Pr
À(CH2)2O(CH2)2À
Pr
12a
12b
12c
12d
12e
12f
20a
20b
20c
20d
20e
20f
67
90
96
93
91
93
99
93
71
96
85
91
4-EtOCOÀC6H4
4-ClÀC6H4
3-CNÀC6H4
Mesityl
Ph
p-Tol
p-Tol
Mesityl
p-Tol
4-ClÀC6H4
Pr
ÀCH(Me)(CH2)3CH(Me)À
À(CH2)4À
Et
Bu
Et
Pentyl
PhCH(Me)
i-Pr
Bn
Bu
i-Pr
Ph
2-Methylbutyl
(Furan-2-yl)methyl
17k
--
removed from the reaction mixture by washing with aqueous Na2CO3, followed by
short column chromatography to give the desired guanidines.
Experimental Part
General. M.p.: hot-stage apparatus; uncorrected. NMR Spectra: in CDCl3, or (D6)DMSO with TMS as the
internal standard for 1H- (300 MHz) or a solvent as the internal standard for 13C-NMR (75 MHz). Column
chromatography (CC): on silica gel (200 425 mesh) or on basic alumina (60 325 mesh). Bis(1H)benzotriazol-
1-yl)methanethione (15) was prepared according to a previously reported procedure. M.p. 171 1728, yield 98%,
([35]: M.p. 170 1718, yield 90%).
General Procedure for the Preparation of Compounds 14a 14g [29]. Compounds 14a 14g were prepared
by adding Ph3P to an ethereal solution of the corresponding azide. After the soln. was heated under reflux for
2 h, the solvent was removed under reduced pressure, and the residue was crystallized from abs. EtOH.
(Phenylimino)(triphenyl)phosphorane (14a). White microcrystals from EtOH (100%). M.p. 134 1358
([29]: 133 1348).
[(4-Methylphenyl)imino](triphenyl)phosphorane (14b). Yellow microcrystals from EtOH (99%). M.p.
136 1378 ([29]: 136 1378).
3-[(Triphenyl-l5-phosphanylidene)amino]benzonitrile (14c). White microcrystals from EtOH (96%). M.p.
159 1608 ([29]: 157 158 8).
Ethyl 4-[(Triphenyl-l5-phosphanylidene)amino]benzoate (14d). White microcrystals from EtOH (85%).
M.p. 136 1378 ([36]: 1368).
[(4-Chlorophenyl)imino](triphenyl)phosphorane (14e). White microcrystals from EtOH (71%). M.p.
161 1628 ([29]: 160 1618) [29].
N-(Triphenyl-l5-phosphanylidene)benzamide (14f). White microcrystals from EtOH (98%). M.p. 194
1958 (Lit. M.p. 195 1968) [37 ].
[(2,4,6-Trimethylphenyl)imino(triphenyl)phosphorane (14g). White microcrystals from EtOH (77%). M.p.
146 1478 ([38]: 146 146.58).
General Procedure for the Preparation of Compounds 13a 13f. To a stirred soln. of 15 (0.007mol) in
toluene (12 ml), the appropriate 14a 14f (0.007mol) was added at r.t., and the resulting mixture was heated at
608 for 4 h. Completion of the reaction was monitored by TLC. Then, the mixture was concentrated under
reduced pressure, and the residue purified by gradient CC (AcOEt/hexanes) on silica gel to give 13a 13f.
N-[Bis(1H-benzotriazol-1-yl)methylidene]aniline (13a). White microcrystals from AcOEt/hexanes (76%),
M.p. 155 1568. 1H-NMR (CDCl3): 8.4 (d, J ˆ 8.4, 1 H); 8.21 (d, J ˆ 8.1, 1 H); 8.13 8.12 (m, 1 H); 7 .7 5t,(J ˆ 7.4,
1 H); 7.60 (t, J ˆ 7.7, 1 H); 7.41 7.38 m( , 2 H); 7.20 7.03 (m, 4 H); 6.8 (d, J ˆ 8.2, 2 H). 13C-NMR (CDCl3):
143.4; 130.2; 129.3; 129.2; 126.4; 126.3; 125.0; 121.2; 120.6; 114.3; 110.1. Anal. calc. for C19H13N7: C 67.25, H 3.86,
N 28.89; found: C 67.49, H 4.01, N 28.50.
N-[Bis(1H-benzotriazol-1-yl)methylidene]-4-methylaniline (13b). White microcrystals from AcOEt/
hexanes (73%). M.p. 165 1668. 1H-NMR (CDCl3): 8.41 (d, J ˆ 8.2, 1 H); 8.18 (d, J ˆ 8.2, 1 H); 8.14 8.11

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Helvetica Chimica Acta Vol. 88 (2005)
(m, 1 H); 7.7 5 7.7 0m(, 1 H); 7.59 7.54 (m, 1 H); 7.41 7.38 (m, 2 H); 7.13 7.10 (m, 1 H); 6.96 (d, J ˆ 9.0, 2 H);
6.73 (d, J ˆ 9.0, 2 H). 13C-NMR (CDCl3): 146.6; 144.8; 140.7; 136.3; 133.9; 132.4; 131.8; 130.1; 129.8; 129.3;
126.2; 125.0; 121.3; 120.5; 114.2; 110.1; 20.9. Anal. calc. for C20H15N7: C 67.98, H 4.28, N 27.74; found: C 67.81, H,
4.22, N 27.43.
3-{[Bis(1H-benzotriazol-1-yl)methylidene]amino}benzonitrile (13c). Yellow microcrystals from AcOEt/
hexanes (79%). M.p. 205 2068. 1H-NMR (CDCl3): 8.38 (d, J ˆ 8.1, 1 H); 8.22 (d, J ˆ 8.1, 1 H); 8.14 (d, J ˆ 7.6,
1 H); 7.81 7.76 (m, 1 H); 7.63 7.59 (m, 1 H); 7.51 7.45 (m, 2 H); 7.37 (d, J ˆ 7.7, 1 H); 7.30 7.24 m( , 2 H); 7 .10
(d, J ˆ 7.6, 1 H); 6.99 (d, J ˆ 8.1, 1 H). 13C-NMR (CDCl3): 146.8; 144.8; 144.6; 132.5; 131.5; 130.6; 130.2; 129.9;
129.4; 126.7; 125.5; 125.2; 124.9; 120.8; 117.8; 114.2; 113.4; 109.9. Anal. calc. for C20H12N8: C 65.17, H 3.32, N
30.11; found: C 64.71, H 3.20, N 29.83.
Ethyl 4-{[Bis(1H-benzotriazol-1-yl)methylidene]amino}benzoate (13d). Yellow microcrystals from
1
AcOEt/hexanes (53%). M.p. 197 198 8. H-NMR (CDCl3): 8.46 8.36 (m, 1 H); 8.26 8.08 (m, 2 H); 7 .88 d(,
J ˆ 8.5, 2 H); 7.81 7.71 (m, 1 H); 7.62 (br.s, 2 H); 7.43 (br.s, 1 H); 7.12 ( br.s, 1 H); 6.92 (d, J ˆ 8.5, 2 H); 4.31 (q,
J ˆ 7.1, 2 H); 1.35 (t, J ˆ 7.1, 3 H).13C-NMR (CDCl3): 165.7; 147.6; 135.4; 130.8; 130.4; 127.9; 126.6; 125.3; 120.9;
120.7; 114.2; 110.0; 61.0; 14.22. Anal. calc. for C22H17N7O2: C 64.23, H 4.16, N 23.83; found: C 64.12, H 4.11, N
23.88.
[Bis(1H-benzotriazol-1-yl)methylidene](4-chlorophenyl)amine (13e). White microcrystals from AcOEt/
hexanes (58%). M.p. 167 168 8. 1H-NMR (CDCl3): 8.39 (d, J ˆ 8.1, 1 H); 8.20 (d, J ˆ 8.2, 1 H); 8.16 8.13 (m,
1 H); 7.78 7.73 m( , 1 H); 7.62 7.57 (m, 1 H); 7.45 7.42 (m, 2 H); 7.16 7.09 (m, 3 H); 6.7 9 (d, J ˆ 8.7, 2 H).
13C-NMR (CDCl3): 146.7; 144.8; 142.0; 135.0; 131.8; 130.3; 129.6; 129.4; 126.5; 125.2; 122.6; 120.7; 114.2; 110.0.
Anal. calc. for C19H12ClN7: C 61.05, H 3.24, N 26.23; found: C 60.95, H 3.11, N 26.02.
N-[Bis(1H-benzotriazol-1-yl)methylidene]benzamide (13f) [28]. White needles from AcOEt/hexanes
(86%). M.p. 108 1098. 1H-NMR (CDCl3): 8.40 (d, J ˆ 8.2, 1 H); 8.23 8.16 (m, 4 H); 7.74 7.68 (m, 3 H); 7 .61
7.56 (m, 4 H). 13C-NMR (CDCl3): 166.7; 145.7; 133.6; 132.3; 131.7; 131.4; 130.4; 128.4; 126.3; 120.2; 114.8; 109.6.
General Procedure for the Preparation of Compounds 16a 16h. 1-Thiocarbamoyl-1H-benzotriazoles 16a
16h were synthesized by the reaction of compound 15 (2 mmol) and the appropriate primary amine (2 mmol) in
CH2Cl2 at r.t. for 18 h according to the procedure in [34]. M.p. and spectral data were used to characterize
known 16a, 16f, and 16h, and were found to be identical to reported values: 16a: m.p. 108 1098 ([38]: 108
109); 16f: m.p. 728 ([38]: 72 738); 16h: m.p. 1178 ([38]: 117 119 8).
N-Isopropyl-1H-benzotriazole-1-carbothioamide (16b). White powder (95%). M.p. 107.78. 1H-NMR
(CDCl3): 8.84 (d, J ˆ 8.5, 2 H); 8.00 (d, J ˆ 8.2, 1 H); 7.57 7.52 (m, 1 H); 7.41 7.36 (m, 1 H); 4.67( sept., J ˆ
7.0, 1 H); 1.36 (d, J ˆ 6.4, 6 H). 13C-NMR (CDCl3): 173.1; 147.0; 132.4; 130.1; 125.5; 120.1; 116.1; 47.0; 21.5. Anal.
calc. for C10H12N4S: C 54.52, H 5.49, N 25.43; found: C 54.55, H 5.49, N 25.27.
N-Phenyl-1H-benzotriazole-1-carbothioamide (16c). White powder (90%). M.p. 98.58. 1H-NMR (CDCl3):
10.74 (s, 1 H); 8.94 (d, J ˆ 8.5, 1 H); 8.13 (d, J ˆ 8.4, 1 H); 7.77 (d, J ˆ 8.0, 2 H); 7.70 7.65 (m, 1 H); 7.54 7.46 (m,
2 H); 7.38 7.32 (m, 1 H); 7.29 7.20 (m, 1 H). 13C-NMR (CDCl3): 179.7 ; 137.1; 129.5; 129.4; 127.2; 126.9; 125.6;
125.1. Anal. calc. for C13H10N4S: C 63.40, H 3.96, N 18.33; found: C 63.85, H 4.33, N 18.54.
N-Butyl-1H-benzotriazole-1-carbothioamide (16d). White powder (98%). M.p. 92.38. 1H-NMR (CDCl3):
9.10 (br. s, 1 H); 8.92 (d, J ˆ 8.5, 1 H); 8.09 (d, J ˆ 8.2, 1 H); 7.64 (t, J ˆ 7.7, 1 H); 7.47 t(, J ˆ 7.87, 1 H); 3.85 (dd,
J ˆ 12.8, 7.0, 2 H); 1.83 1.75 (m, 2 H); 1.54 1.47( m, 2 H); 1.01 (t, J ˆ 7.3, 3 H).13C-NMR (CDCl3): 174.1; 147.0;
132.4; 130.2; 125.6; 120.2; 116.0; 44.8; 30.1; 20.2; 13.7. Anal. calc. for C H14N4S: C 56.38, H 6.02, N 23.81; found:
11
C 56.74, H 6.40, N 23.47.
N-(2-Phenethyl)-1H-benzotriazole-1-carbothioamide (16e). White powder (93%). M.p. 110.28. 1H-NMR
(CDCl3): 9.18 (s, 1 H); 8.91 (d, J ˆ 8.5, 1 H); 8.07( d, J ˆ 8.2, 1 H); 7.65 7.60 (m, 1 H); 7.48 7.43 (m, 1 H); 7 .36
7.22 (m, 5 H); 4.10 (t, J ˆ 7.1, 2 H); 3.11 (t, J ˆ 7.1, 2 H). 13C-NMR (CDCl3): 174.4; 147.0; 137.8; 132.3; 130.2;
128.8; 128.6; 126.9; 125.6; 120.2; 116.0; 46.1; 34.0. Anal. calc. for C15H14N4S: C 63.80, H 5.00, N 19.84; found: C
63.92, H 4.98, N 19.59.
N-(2-Methylbutyl)-1H-benzotriazole-1-carbothioamide (16g). White powder (98%). M.p. 968. 1H-NMR
(CDCl3): 9.06 (s, 1 H); 8.91 (d, J ˆ 8.5, 1 H); 8.10 (d, J ˆ 8.2, 1 H); 7.64 (t, J ˆ 7.5, 1 H); 7.47 (t, J ˆ 7.4, 1 H);
1.97 1.93 ( m, 1 H); 1.38 1.26 (m, 2 H); 1.06 (d, J ˆ 6.7, 3 H); 1.01 0.99 (m, 3 H); 0.96 0.86 (m, 2 H).
13C-NMR (CDCl3):174.3; 146.9; 132.2; 130.1; 125.5; 120.0; 115.9; 50.6; 33.8; 27.1; 17.3; 11.1. Anal. calc. for
C12H16N4S: C 58.04, H 6.49, N 22.56; found: C 57.92, H 6.45, N 22.37.
General Procedure for the Preparation of Compounds 11a 11e. To a soln. of 13a 13e (see Table 1;
0.85 mmol) in toluene (10 ml), the amine of choice (2.5 mmol) was added with stirring. The mixture was heated
under reflux until full conversion of starting materials (1 2 h). Upon completion, the solvent was evaporated
under reduced pressure. The crude product was dissolved in CH2Cl2, washed twice with sat. aq. Na2CO3, dried

Helvetica Chimica Acta Vol. 88 (2005)
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(MgSO4), and filtered. The solvent was removed under reduced pressure. The desired guanidines were isolated
by flash CC on basic alumina (first AcOEt to remove impurities and MeOH to elute guanidine) to give 11a
11e.
1,3-Dicyclohexyl-2-phenylguanidine (11a) [30]. Yellow oil (79%). 1H-NMR (CDCl3): 7.24 7.19 (m, 2 H);
7.03 6.98 (m, 3 H); 3.16 3.09 (m, 2 H); 1.91 (s, 2 H); 1.83 1.80 (m, 4 H); 1.61 (br. s, 4 H); 1.48 (br. s, 2 H);
1.23 1.15 (m, 5 H); 1.11 1.05 (m, 5 H). 13C-NMR (CDCl3): 179.6; 153.6; 129.4; 124.2; 122.6; 52.2; 33.2; 25.0;
24.8; 24.7.
1,3-Dibutyl-2-(4-methylphenyl)guanidine (11b). Yellow oil (83%). 1H-NMR (CDCl3): 7.08 (d, J ˆ 8.2, 2 H);
6.95 (d, J ˆ 8.2, 2 H); 3.04 (t, J ˆ 7.0, 4 H); 2.30 (s, 3 H); 1.95 (s, 2 H); 1.51 (quint., J ˆ 7.4, 4 H); 1.26 (sext., J ˆ 7.4,
4 H); 0.84 (t, J ˆ 7.3, 6 H).13C-NMR (CDCl3): 179.2; 155.9; 134.5; 129.9; 122.1; 43.2; 31.3; 20.8; 19.8; 13.5. Anal.
calc. for C16H27N3: C 73.52, H 10.41, N 16.07; found: C 73.28, H 10.39, N 16.38.
2-(3-Cyanophenyl)-1,3-diisopropylguanidine (11c). Yellow oil (87%). 1H-NMR ((D6)DMSO): 8.81 (s,
1 H); 7.94 (s, 1 H); 7 .57 d(d, J ˆ 8.3, 1.0, 1 H); 7.42 (t, J ˆ 8.0, 1 H); 7.31 (d, J ˆ 7.6, 1 H); 6.33 (d, J ˆ 7.4, 1 H); 3.76
(sept., J ˆ 6.7, 2 H); 1.1 (d, J ˆ 6.7, 12 H).13C-NMR ((D6)DMSO): 154.3; 141.5; 130.0; 124.3; 122.1; 119.9; 119.0;
111.4; 41.0; 22.8. Anal. calc. for C14H20N4: C 73.74, H 8.25, N 22.93; found: C 73.89, H 8.30, N 23.54.
Ethyl 4-({Bis[(1-phenylethyl)amino]methylidene}amino)benzoate (11d). Yellow oil (91%). 1H-NMR
(CDCl3): 7.86 7.83 (m, 3 H); 7.34 7.21 (m, 3 H); 7.19 7.15 (m, 3 H); 6.96 6.93 (m, 4 H); 6.80 (d, J ˆ 8.2,
1 H); 4.78 (q, J ˆ 6.4, 1 H); 4.52 (q, J ˆ 6.2, 1 H); 4.30 4.22 (m, 4 H); 1.40 (d, J ˆ 6.7, 2 H); 1.33 1.27 (m, 7 H).
13C-NMR (CDCl3): 166.3; 147.1; 143.4; 143.3; 131.0; 129.0; 128.8; 127.8; 127.5; 125.9; 125.6; 124.6; 122.3; 120.7;
60.7; 52.2; 23.6; 23.1; 14.3. Anal. calc. for C26H29N3O2: C 70.75, H 7.03, N 9.41; found: C 70.27, H 6.80, N 8.95.
1,3-Dibenzyl-2-(4-chlorophenyl)guanidine (11e). Yellow oil (85%). 1H-NMR (CDCl3): 7.24 7.22 (m, 6 H);
7.2 (d, J ˆ 8.6, 2 H); 7.08 7.05 (m, 4 H); 6.81 (d, J ˆ 8.6, 2 H); 4.18 (s, 4 H); 1.80 (s, 2 H). 13C-NMR (CDCl3):
179.8; 154.6; 137.1; 129.4; 129.1; 128.8; 127.7; 127.0; 123.7; 46.5. Anal. calc. for CH20ClN3: C 68.09, H 5.76, N
21
10.21; found: C 68.41, H 5.94, N 10.50.
General Procedure for the Preparation of Compounds 19a 19e. To a soln. of appropriate 13 (see Table 1;
0.70 mmol) in toluene (10 ml), the corresponding diamine 18 (0.7mmol) was added with stirring. The mixture
was heated to reflux and kept at that temp. until the full conversion of starting materials (1 2 h). Upon
completion, the solvent was evaporated under reduced pressure; crude product was dissolved in CH2Cl2, washed
twice with sat. aq. Na2CO3, dried (MgSO4), and filtered. The solvent was removed under reduced pressure.
Desired guanidines were isolated by flash CC on basic alumina (first AcOEt to remove impurities and MeOH to
elute guanidine) to give 19a 19e.
4-Methyl-N-(3,4,5,6-tetrahydro-1H-pyrimidin-2-ylidene)benzenamine (19a). Colorless oil (95%). 1H-NMR
(CDCl3): 7.2 (d, J ˆ 8.2, 2 H); 7.07 (d, J ˆ 8.2, 2 H); 3.37 3.33 ( m, 4 H); 2.32 (s, 3 H); 11.98 (s, 2 H); 1.98 1.93
(m, 2 H). 13C-NMR (CDCl3): 152.7; 136.5; 132.7; 130.5; 125.2; 38.4; 24.2; 20.9; 20.2. Anal. calc. for C11H15N3: C
69.81, H 7.99, N 22.20; found: C 70.01, H 8.25, N 22.27.
N-(Imidazolidin-2-ylidene)-4-methylbenzenamine (19b) [32]. Yellow oil (95%). 1H-NMR (CDCl3): 7.13 (d,
J ˆ 8.2, 2 H); 7.06 (d, J ˆ 8.2, 2 H); 3.66 (s, 4 H); 2.31 (s, 3 H); 1.94 (s, 2 H). 13C-NMR (CDCl3): 159.6; 136.0;
134.1; 130.2; 123.1; 42.9; 20.8.
4-Chloro-N-[3,4,5,6-tetrahydro-5,5-dimethyl-1H-pyrimidin-2-ylidene]aniline (19c). Yellow oil (96%).
1H-NMR (CDCl3): 7.26 (d, J ˆ 8.6, 2 H); 7.08 (d, J ˆ 8.6, 2 H); 2.97( s, 4 H); 1.91 (s, 2 H); 1.02 (s, 6 H).
13C-NMR (CDCl3): 152.0; 134.1; 132.2; 130.1; 126.3; 50.1; 27.2; 24.1. Anal. calc. for C H16ClN3: C 60.63, H 6.78,
12
N, 17.68; found: C 60.78, H 6.55, N 17.77.
N-[3,4,5,6-Tetrahydro-1-methyl-1H-pyrimidin-2-ylidene]benzenamine (19d). Yellow oil (89%). 1H-NMR
(CDCl3): 7.31 7.26 (m, 2 H); 7.08 7.03 (m, 1 H); 7 .00 (d, J ˆ 7.8, 2 H); 3.42 3.33 (m, 4 H); 2.75 (s, 3 H); 2.11
2.03 (m, 2 H); 1.99 (s, 1 H). 13C-NMR (CDCl3): 154.4; 139.9; 129.4; 123.7; 121.1; 48.5; 39.6; 38.5; 21.8. Anal. calc.
for C11H15N3: C 69.81, H 7.99, N 22.20; found: C 69.98, H 7.75, N 22.57.
N-(3,4,5,6-Tetrahydro-1H-pyrimidin-2-ylidene)benzamide (19e) [33]. White microcrystals from AcOEt/
hexanes (77%). M.p. 132 1338. 1H-NMR (CDCl3): 7.80 (d, J ˆ 7.1, 2 H); 7.41 7.32 (m, 5 H); 3.41 3.49 (m,
4 H); 1.78 1.62 (m, 2 H). 13C-NMR (CDCl3): 183.3; 168.2; 134.2; 131.5; 128.5; 127.0; 36.2; 29.8.
General Procedure for the Preparation of Compounds 17a 17l. To a stirred soln. of 16a 16h (0.01 mol) in
toluene (12 ml), the corresponding 14 (0.01 mol; see Table 2) was added at room temperature and the resulting
mixture was heated at 1108 for 1 h. Completion of the reaction was monitored by TLC. Upon completion, the
reaction mixture was concentrated under reduced pressure and residue purified by gradient CC (AcOEt/
hexanes) on silica gel to give 17a 17l.
N-Benzyl-N'-phenyl-1H-benzotriazole-1-carboximidamide (17a). White microcrystals from AcOEt/
hexanes (91%). M.p. 129 1308. 1H-NMR (CDCl3): 8.14 (br. s, 1 H); 8.06 (d, J ˆ 8.2, 1 H); 7.51 7.46 (m,

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Helvetica Chimica Acta Vol. 88 (2005)
1 H); 7.42 7.37 (m, 1 H); 7.32 7.22 (m, 7H); 7.03 6.94 ( m, 3 H); 6.53 (br. s, 1 H); 4.31 (s, 2 H). 13C-NMR
(CDCl3): 146.5; 141.0; 137.4; 131.6; 129.0; 128.9; 128.7 ; 127.8; 127.5; 125.0; 122.9; 121.6; 119.8; 114.5; 47.8. Anal.
calc. for C20H17N5: C 73.37, H 5.23, N 21.39; found: C 73.78, H 5.25, N 21.27.
N-Benzyl-N'-(4-methylphenyl)-1H-benzotriazole-1-carboximidamide (17b). Yellow oil (96%). 1H-NMR
(CDCl3): 8.06 (d, J ˆ 8.1, 1 H); 7.51 7.46 (m, 1 H); 7.42 7.37 (m, 1 H); 7.33 7.24 (m, 6 H); 7 .05 (d, J ˆ 7.1, 2 H);
6.86 (d, J ˆ 7.1, 2 H); 6.45 (br.s, 1 H); 4.31 (s, 2 H); 2.30 (s, 3 H). 13C-NMR (CDCl3): 143.9; 137.5; 134.6; 132.3;
131.7; 129.5; 129.2; 129.0; 128.7; 127.7; 127.5; 125.0; 121.4; 119.7; 115.3; 47.9; 20.8. Anal. calc. for C 21H19N5: C
73.88, H 5.61, N 19.90; found: C 73.83, H 5.96, N 19.85.
N-Isopropyl-N'-(4-methylphenyl)-1H-benzotriazole-1-carboximidamide (17c). Yellow oil (92%). 1H-NMR
(CDCl3): 7.97 (d, J ˆ 8.2, 1 H); 7.67 7.60 (m, 1 H); 7.45 7.28 (m, 2 H); 7.00 (d, J ˆ 7.0, 2 H); 6.82 (d, J ˆ 7.0,
2 H); 5.82 (br. s, 1 H); 3.61 (br. s, 1 H); 2.22 (s, 3 H); 1.08 (d, J ˆ 6.2, 6 H). 13C-NMR (CDCl3): 144.3; 132.3;
132.1; 131.7; 129.5; 128.8; 128.5; 128.4; 124.8; 121.1; 119.6; 44.5; 23.0; 20.8. Anal. calc. for C17H19N5: C 69.60, H
6.53, N 23.87; found: C 69.40, H 6.38, N 23.62.
N'-(4-Chlorophenyl)-N-isopropyl-1H-benzotriazole-1-carboximidamide (17d). Yellow oil (67%). 1H-NMR
(CDCl3): 8.06 (d, J ˆ 8.2, 2 H); 7.51 7.46 (m, 1 H); 7.42 7.37 (m, 1 H); 7.20 (d, J ˆ 8.2, 2 H); 6.90 (d, J ˆ 8.0,
2 H); 6.02 (br. s, 1 H); 3.69 (br. s, 1 H); 1.19 (d, J ˆ 6.3, 6 H). 13C-NMR (CDCl3): 146.3; 145.6; 141.3; 131.5;
129.0; 128.9; 127.8; 125.0; 122.6; 119.8; 114.1; 44.6; 22.8. Anal. calc. for C H16ClN5: C 61.24, H 5.14, N 22.32;
16
found: C 61.43, H 5.11, N 21.95.
N-Phenyl-N'-(2,4,6-trimethylphenyl)-benzotriazole-1-carboximidamide (17e). Yellow microcrystals from
AcOEt/hexanes (80%). M.p. 140 1418. 1H-NMR (CDCl3): 8.42 8.40 (m, 1 H); 8.10 (d, J ˆ 8.4, 1 H); 7.87 (br.s,
1 H); 7.59 7.54 (m, 1 H); 7.48 7.43 (m, 1 H); 7.02 6.85 (m, 3 H); 6.76 6.70 (m, 2 H); 6.66 (s, 1 H); 6.59 (s,
1 H); 2.23 (s, 3 H); 2.15 (s, 6 H). 13C-NMR (CDCl3): 135.0; 132.3; 132.2; 131.5; 129.2; 128.7; 128.5; 128.4; 128.2;
127.7; 125.1; 123.1; 122.3; 120.5; 119.8; 20.6; 18.4 (2C). Anal. calc. for C H21N5: C 74.34, H 5.95, N 19.70; found:
22
C 74.15, H 6.03, N 19.44.
Ethyl 4-{[(1H-benzotriazol-1-yl)(butylamino)methylidene]amino}benzoate (17f). Yellow oil (53%).
1H-NMR (CDCl3): 8.00 (d, J ˆ 8.2, 1 H); 7.96 (d, J ˆ 8.2, 1 H); 7.87 (d, J ˆ 8.4, 2 H); 7.42 7.37 (m, 1 H);
7.33 7.28 (m, 1 H); 6.91 (d, J ˆ 8.2, 2 H); 6.40 6.30 (m, 1 H); 4.25 (q, J ˆ 7.1, 2 H); 3.00 (q, J ˆ 6.3, 2 H); 1.44
(quint., J ˆ 7.3, 2 H); 1.29 (t, J ˆ 7.1, 3 H); 1.23 (sext., J ˆ 7.5, 2 H); 0.77 (t, J ˆ 7.3, 3 H). 13C-NMR (CDCl3):
166.4; 151.5; 146.3; 141.3; 131.4; 130.4; 129.1; 125.0; 124.4; 121.3; 119.7; 114.2; 60.6; 43.4; 31.5; 19.6; 14.2; 13.5.
Anal. calc. for C20H23N5O2: C 65.73, H 6.34, N 19.16; found: C 65.63, H 6.77, N 18.90.
N-Butyl-N'-(2,4,6-trimethylphenyl)-1H-benzotriazole-1-carboximidamide (17g). Yellow oil (84%).
1H-NMR (CDCl3): 8.40 (d, J ˆ 8.3, 1 H); 8.02 (d, J ˆ 8.2, 1 H); 7.48 7.43 (m, 1 H); 7.38 7.33 (m, 1 H); 6.78
(s, 2 H); 6.28 (br. s, 1 H); 2.78 (q, J ˆ 6.7, 2 H); 2.20 (s, 3 H); 2.11 (s, 6 H); 1.34 (quint., J ˆ 7.1, 2 H); 1.16 (sext.,
J ˆ 7.1, 2 H); 0.73 (t, J ˆ 7.3, 3 H).13C-NMR (CDCl3): 146.7; 141.8; 139.5; 131.9; 131.7; 128.9; 128.2; 128.1; 124.9;
119.6; 115.5; 42.2; 32.1; 20.7; 19.7; 18.6 (2C); 13.4. Anal. calc. for C20H25N5: C 71.61, H 7.51, N 20.53; found: C
71.90, H 7.80, N 20.19.
N'-(3-Cyanophenyl)-N-(2-phenylethyl)-1H-benzotriazole-1-carboximidamide (17h). Yellow oil (95%).
1H-NMR (CDCl3): 8.02 (d, J ˆ 8.2, 1 H); 7.91 (br. s, 1 H); 7.50 7.45 (m, 1 H); 7.41 7.36 (m, 1 H); 7.32 7.24
(m, 5 H); 7.21 7.20 (m, 1 H); 7.12 7.10 (m, 3 H); 6.47(br. s, 1 H); 3.45 3.43 (m, 2 H); 2.87( t, J ˆ 7.0, 2 H).
13C-NMR (CDCl3): 147.7; 146.1; 141.8; 137.5; 131.2; 129.6; 129.1; 128.6; 128.6; 126.7; 126.1; 126.0; 125.0; 124.8;
119.8; 118.6; 113.6; 112.6; 44.6; 35.6. Anal. calc. for C22H18N6: C 71.61, H 5.35, N 23.04; found: C 71.22, H 5.07, N
23.12.
N'-(4-Chlorophenyl)-N-cyclohexyl-1H-benzotriazole-1-carboximidamide (17i). Yellow oil (40%).
1H-NMR (CDCl3): 8.06 (d, J ˆ 8.2, 2 H); 7.52 7.47 (m, 1 H); 7.42 7.37 (m, 1 H); 7 .22 d(, J ˆ 8.2, 2 H); 6.90
(d, J ˆ 8.0, 2 H); 6.09 (br. s, 1 H); 3.30 (br. s, 1 H); 1.94 1.92 (m, 2 H); 1.74 1.66 (m, 2 H); 1.52 (br. s, 1 H);
1.32 1.09 (m, 5 H) . 13C-NMR (CDCl3): 146.4; 145.7; 141.2; 131.6; 129.0; 128.9; 127.8; 125.0; 122.6; 119.8; 114.2;
51.3; 33.0; 25.3; 24.4. Anal. calc. for C19H20ClN5: C 63.13, H 5.70, N 18.79; found: C 62.70, H 5.65, N 18.91.
N-(2-Methylbutyl)-N'-(4-methylphenyl)-1H-benzotriazole-1-carboximidamide (17j). Yellow oil (82%).
1H-NMR (CDCl3): 8.06 (d, J ˆ 8.2, 1 H); 7.51 7.46 (m, 1 H); 7.42 7.37 (m, 1 H); 7 .07 d,( J ˆ 7.1, 2 H); 6.89
(br. s, 2 H); 6.22 (br. s, 1 H); 3.08 2.90 (m, 2 H); 2.30 (s, 3 H); 1.62 1.45 (m, 1 H); 1.36 1.30 (m, 1 H); 1.17
1.08 (m, 1 H); 0.88 (d, J ˆ 6.7, 3 H); 0.81 (t, J ˆ 7.4, 3 H). 13C-NMR (CDCl3): 144.2; 141.6; 132.0; 131.7; 129.4;
128.9; 126.1; 124.9; 121.3; 119.6; 117.9; 49.2; 35.1; 26.7; 20.8; 17.0; 11.0. Anal. calc. for C H23N5: C 71.00, H 7.21, N
19
21.79; found: C 71.15, H 7.45, N 21.65.
N'-(4-Chlorophenyl)-N-[(furan-2-yl)methyl]-1H-benzotriazole-1-carboximidamide (17k). Yellow oil
(93%). 1H-NMR (CDCl3): 8.00 (d, J ˆ 8.2, 2 H); 7.50 7.40 (m, 1 H); 7.35 7.30 (m, 1 H); 7.27 (d, J ˆ 1.0,
1 H); 7.14 (d, J ˆ 8.2, 2 H); 6.81 (d, J ˆ 8.0, 2 H); 6.45 (s, 1 H); 6.23 6.21 (m, 1 H); 6.11 (s, 1 H); 4.26 (s, 2 H).

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13C-NMR (CDCl3): 150.1; 145.0; 142.6; 141.2; 131.5; 129.2; 129.0; 128.7; 128.2; 125.1; 122.8; 120.0; 119.9; 110.4;
108.0; 40.8 Anal. calc. for C18H14ClN5O: C 61.45, H 4.01, N 18.91; found: C 61.10, H 3.89, N 18.50.
N-Butyl-N'-(4-chlorophenyl)-1H-benzotriazole-1-carboximidamide (17l). Yellow oil (87%). 1H-NMR
(CDCl3): 7.98 (d, J ˆ 8.2, 1 H); 7.44 7.39 (m, 1 H); 7.34 7.25 (m, 1 H); 7.13 (d, J ˆ 8.3, 2 H); 6.82 (d, J ˆ 8.1,
2 H); 6.17( s, 1 H); 3.03 (br. s, 2 H); 1.51 1.41 (m, 2 H); 1.28 1.18 (m, 2 H); 0.79 (t, J ˆ 7.3, 3 H). 13C-NMR
(CDCl3): 146.4; 145.6; 141.7; 131.5; 129.1; 128.8; 128.8; 127.7; 125.0; 122.8; 119.8; 43.5; 31.7; 19.7; 13.6. Anal. calc.
for C17H18ClN5: C 62.29, H 5.53, N 21.36; found: C 62.69, H 5.59, N 20.98.
General Procedure for the Preparation of Compounds 12a 12f. To a stirred soln. of appropriate 17 (see
Table 3 for R and R1; 1.6 mmol) in toluene (10 ml) was added the secondary amine (see Table 3 for R2 and R3)
of choice (1.6 mmol) at r.t. The reaction mixture was heated under reflux overnight. Completion of the reaction
was monitored by TLC. Upon completion, the solvent was evaporated, and the residue was dissolved in CH2Cl2.
The soln. was washed twice with sat. aq. Na2CO3 and dried (MgSO4), and the solvent was evaporated under
reduced pressure. The desired guanidines 12a 12f were purified by flash CC on basic alumina (first AcOEt to
remove impurities and the MeOH to elute the guanidine).
3-Benzyl-1,1-diisopropyl-2-phenylguanidine (12a). Yellow oil (67%). 1H-NMR (CDCl3): 7.22 7.08 (m,
8 H); 6.89 6.85 (m, 2 H); 4.07( s, 2 H); 3.77 (sept., J ˆ 6.8, 2 H); 1.89 (s, 2 H); 1.12 (d, J ˆ 6.9, 12 H). 13C-NMR
(CDCl3): 151.3; 150.0; 139.1; 129.3; 128.7; 127.4; 127.3; 123.5; 121.6; 46.0; 41.6; 31.8; 19.9. Anal. calc. for
C20H27N3: N 13.58; found: N 13.73.
N-Benzyl-N'-(4-methylphenyl)-4-morpholinecarboximidamide (12b). Yellow oil (93%). 1H-NMR
(CDCl3): 7.26 7.16 (m, 3 H); 7.13 7.10 (m, 2 H); 6.91 (d, J ˆ 8.1, 2 H); 6.76 (br. s, 1 H); 6.52 (d, J ˆ 8.1,
2 H); 4.11 (s, 2 H); 3.67 3.64 ( m, 4 H); 3.19 3.16 (m, 4 H); 2.17( s, 3 H). 13C-NMR (CDCl3): 156.0; 151.2;
146.5; 138.8; 131.2; 129.8; 129.7; 128.6; 127.4; 127.3; 122.0; 66.7; 66.4; 49.3; 48.3; 46.9; 20.6; 0.9. Anal. calc. for
C19H23N3O: C 73.76, H 7.49, N 13.58; found: C 73.36, H 7.76, N 13.26.
Ethyl 4-{[(Butylamino)(dipropylamino)methylidene]amino}benzoate (12c). Yellow oil (96%). 1H-NMR
(CDCl3): 7.83 (d, J ˆ 8.5, 2 H); 6.76 (d, J ˆ 8.5, 2 H); 4.26 (q, J ˆ 7.1, 2 H); 3.08 (t, J ˆ 7.4, 4 H); 2.89 (t, J ˆ 7.0,
2 H); 1.55 1.48 (m, 4 H); 1.40 1.28 (m, 5 H); 1.22 1.17( m, 2 H); 0.82 (t, J ˆ 7.3, 6 H); 0.79 (t, J ˆ 7.2, 3 H).
13C-NMR (CDCl3): 166.9; 156.1; 130.9; 130.8; 129.7; 121.0; 60.4; 50.8; 44.5; 32.1; 21.4; 19.9; 14.4; 13.7; 11.4; 1.0.
Anal. calc. for C20H33N3O2 ¥ HCl: C 62.96, H 9.33, N 10.14; found: C 63.24, H 9.75, N 9.91.
N'-(4-Chlorophenyl)-N-cyclohexyl-3,4,5,6-tetrahydro-2,6-dimethyl-2H-pyridine-2-carboximidamide (12d).
Yellow oil (93%). 1H-NMR ((D6)DMSO) 7.41 (d, J ˆ 8.9, 2 H); 7.24 (d, J ˆ 8.9, 2 H); 6.30 (d, J ˆ 7.8, 1 H);
3.51 3.45 (m, 1 H); 3.02 2.97( m, 2 H); 1.80 1.64 (m, 7H); 1.55 1.42 ( m, 2 H); 1.33 1.10 (m, 3 H).
13C-NMR ((D6)DMSO) 154.3; 139.7; 128.4; 124.1; 118.8; 52.2; 47.49; 32.9; 30.1; 25.2; 24.3; 22.4; 19.4. Anal. calc.
for C20H30ClN3 ¥ HCl: N 10.93; found: N 11.13.
N'-(3-Cyanophenyl)-N-(2-phenylethyl)pyrrolidine-1-carboximidamide (12e). Yellow oil (91%). 1H-NMR
(CDCl3): 7.32 7.21 (m, 4 H); 7 .2 (d, J ˆ 6.9, 2 H); 7.1 (d, J ˆ 7.6, 1 H); 7.03 7.00 (m, 2 H); 4.95 (br. s, 1 H); 3.39
3.31 (m, 2 H); 3.16 3.11 (m, 4 H); 2.82 2.78 (m, 2 H); 1.83 1.79 (m, 4 H). 13C-NMR (CDCl3): 153.0; 138.5;
132.0; 129.5; 128.7; 128.6; 126.6; 126.5; 124.6; 123.2; 119.5; 112.3; 48.0; 44.7; 36.0; 25.3. Anal. calc. for C20H22N4:
C 75.44, H 6.96, N 17.59; found: C 75.62, H 7.19, N 17.28.
3-Butyl-1,1-diethyl-2-(2,4,6-trimethylphenyl)guanidine (12f). Yellow oil (93%). 1H-NMR (CDCl3): 6.73 (s,
2 H); 3.19 (q, J ˆ 7.0, 4 H); 2.83 (t, J ˆ 7.0, 2 H); 2.15 2.12 (m, 5 H); 1.97 (s, 6 H); 1.09 (t, J ˆ 7.0, 6 H); 1.26 1.17
(m, 2 H); 0.75 (t, J ˆ 7.0, 3 H). 13C-NMR (CDCl3): 154.9; 130.6; 129.6; 129.0; 128.6; 44.5; 42.6; 32.9; 20.7; 19.8;
18.3; 13.7; 12.8. Anal. calc. for C18H31N3: C 74.69, H 10.79, N, 14.32; found: C 74.68, H 10.91, N 13.88.
General Procedure for the Preparation of Compounds 20a 20f. To a soln. of the appropriate 17 (see Table 3
for R and R1; 2.2 mmol) in toluene (10 ml), the amine (see Table 3 for R2; 2.2 mmol) was added with stirring.
The reaction mixture was heated under reflux until full conversion of starting materials (TLC control). Upon
completion, the solvent was evaporated under reduced pressure; the crude product was dissolved in CH2Cl2,
washed twice with sat. aq. Na2CO3, dried (MgSO4), and filtered. The solvent was removed under reduced
pressure. The desired guanidines were isolated by flash CC on basic alumina (first AcOEt to remove impurities
and MeOH to elute guanidine) to give 20a 20f.
1-Benzyl-3-butyl-2-phenylguanidine (20a). Yellow oil (99%). 1H-NMR (CDCl3): 7.27 7.26 (m, 4 H); 7.21
7.16 (m, 3 H); 6.89 6.83 (m, 3 H); 4.30 (s, 2 H); 3.86 (br. s, 1 H); 3.03 (t, J ˆ 7.0, 2 H); 1.34 (quint., J ˆ 7.2, 2 H);
1.16 (sext., J ˆ 7.2, 2 H); 0.79 (t, J ˆ 7.3, 3 H). 13C-NMR (CDCl3): 151.3; 150.0; 139.1; 129.3; 128.7; 127.4; 127.3;
123.6; 121.6; 46.03; 41.6; 31.8; 19.9; 13.7. Anal. calc. for C H23N3: C 76.43, H 8.95, N 14.93; found: C 75.84, H
18
8.50, N 14.76.
1-Benzyl-3-pentyl-2-(4-methylphenyl)guanidine (two tautomers; 20b). Yellow oil (93%). 1H-NMR
(CDCl3): 7.26 7.17 (m, 5 H); 7 .00 d(, J ˆ 8.0, 2 H); 6.81 (d, J ˆ 8.2, 2 H); 4.29 (s, 2 H); 2.90 (t, J ˆ 6.9, 2 H);

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Helvetica Chimica Acta Vol. 88 (2005)
2.29 (s, 3 H); 1.96 (s, 3 H) 1.44 1.34 (m, 2 H); 1.26 1.10 (m, 3 H); 1.05 0.87( m, 1 H); 0.84 0.74 (m, 4 H).
13C-NMR (CDCl3): 179.3; 155.6; 155.4; 137.5; 133.7 ; 133.7; 129.7 ; 128.5; 128.5; 127.4; 127.0; 127.0; 122.1; 48.8;
46.1; 43.1; 34.6; 28.8; 28.5; 26.5; 24.4; 22.0; 20.6; 16.7; 13.7; 10.8. Anal. calc. for C20H27N3: C 77.63, H 8.79, N
13.58; found: C 77.58, H 8.43, N 13.61.
1-Isopropyl-2-(4-methylphenyl)-3-(1-phenylethyl)guanidine (20c). Yellow oil (71%). 1H-NMR (CDCl3):
7.38 7.21 (m, 5 H); 7.09 7.06 (m, 2 H); 6.7 9 (d, J ˆ 7.8, 2 H); 4.62 4.60 (m, 1 H); 3.76 (br. s, 1 H); 2.30 (s, 3 H);
1.39 1.37( m, 3 H); 1.08 (d, J ˆ 6.3, 3 H); 0.90 (d, J ˆ 6.3, 3 H). 13C-NMR (CDCl3): 151.3; 144.5; 129.9; 128.8;
128.6; 127.4; 125.7; 125.6; 123.2;51.8; 43.0; 23.8; 23.3; 22.8; 20.8. Anal. calc. for C H25N3: C 77.85, H 8.61, N
19
13.54; found: C 77.63, H 8.44, N 13.10.
1-Isopropyl-2-mesityl-3-phenylguanidine (20d). Yellow oil (96%). 1H-NMR (CDCl3): 7.27 7.19 (m, 3 H);
7.06 6.99 (m, 3 H); 6.81 (s, 1 H); 3.74 (br. s, 1 H); 2.19 (s, 3 H); 2.16 (s, 6 H); 1.93 (s, 1 H); 1.00 (d, J ˆ 6.6, 6 H).
13C-NMR (CDCl3): 151.1; 138.9; 129.5; 129.3; 128.8; 124;7; 123.9; 123.4; 114.9; 43.7; 23.0; 20.8; 18.1. Anal. calc.
for C19H25N3: C 77.85, H 8.61, N 13.54; found: C 77.70, H 8.46, N 13.09.
1-Benzyl-3-(2-methylbutyl)-2-(4-methylphenyl)guanidine (20e). Yellow oil (85%). 1H-NMR (CDCl3):
7.36 7.25 (m, 5 H); 7.06 (d, J ˆ 8.1, 2 H); 6.91 (d, J ˆ 8.1, 2 H); 4.30 (s, 2 H); 2.85 (dd, J ˆ 3.0, 6.0, 1 H); 2.71 (dd,
J ˆ 13.0, 7.1, 1 H); 2.28 (s, 3 H); 1.99 (s, 2 H); 1.52 1.40 (m, 1 H); 1.23 1.18 (m, 1 H); 1.03 0.96 (m, 1 H); 0.74
(d, J ˆ 7.4, 3 H); 0.73 (d, J ˆ 7.4, 3 H). 13C-NMR (CDCl3): 156.3; 137.0; 134.8; 130.0; 129.0; 128.0; 127.1; 124.9;
122.5; 49.4; 46.7; 34.8; 26.6; 20.8; 16.9; 11.0. Anal. calc. for C20H27N3 ¥ HCl: N 12.15; found: N 11.78.
1
1-Butyl-2-(4-chlorophenyl)-3-(2-furylmethyl)guanidine (20f). Yellow oil (91%). H-NMR (CDCl3): 7.38
7.37 (m, 1 H); 7.23 (d, J ˆ 8.5, 2 H); 6.89 (d, J ˆ 8.5, 2 H); 6.34 6.33 (m, 1 H); 6.28 6.27( m, 1 H); 4.42 (s, 2 H);
3.15 (t, J ˆ 7.1, 2 H); 1.52 1.44 (m, 2 H); 1.34 1.26 (m, 2 H); 0.85 (t, J ˆ 7.3, 3 H). 13C-NMR (CDCl3): 152.5;
151.2; 142.4; 129.5; 129.4; 124.7; 124.0; 110.5; 107.8; 42.3; 39.4; 31.5; 19.9; 13.7. Anal. calc. for C16H20ClN3O ¥ HCl:
C 56.15, H 6.18, N 12.28; found: C 56.28, H 6.20, N 12.36.
REFERENCES
[1] R. G. S. Berlinck, Nat. Prod. Rep. 1999, 16, 339; L. Heys, C. G. Moore, P. J. Murphy, J. Chem. Soc. Rev. 2000,
29, 57.
[2] O. E. Levy, J. E. Semple, M. L. Lim, J. Reiner, W. E. Rote, E. Dempsey, B. M. Richard, E. Zhang, A.
Tulinsky, W. C. Ripka, R. F. Nutt, J. Med. Chem. 1996, 39, 4527; M. J. Rynkiewicz, B. A. Seaton, Biochem. J.
1996, 35, 16174.
[3] I. J. McAlpine, R. W. Armstrong, Tetrahedron Lett. 2000, 41, 1849.
[4] V. D. Le, C. H. Wong, J. Org. Chem. 2000, 65, 2399.
[5] C. G. Silva, E. Parolo, E. L. Streck, M. Wajner, C. M. D. Wannmacher, A. T Wyse, Brain Res. 1999, 838, 7 8.
[6] N. L. Reddy, W. Fan, S. S. Magar, M. E. Perlman, E. Yost, L. Zhung, D. Berlove, J. B. Fischer, K. B. Howie,
T. Wolcott, G. J. Durant, J. Med. Chem. 1998, 41, 3298.
[7] P. W. Smith, S. L. Sollis, P. D. Howes, P. C. Cherry, I. D. Starkey, K. N. Cobley, H. Weston, J. Scicinski, A.
Merritt, A. Whittington, P. Wyatt, N. Taylor, D. Green, R. Bethell, S. Madar, R. J. Fenton, P. J. Morley, T.
Pateman, A. Beresford, J. Med. Chem. 1998, 41, 787.
[8] A. R. Katritzky, B. Rogovoy, Arkivoc 2005, Part iv, 49.
[9] K. Wermann, M. Walther, E. Anders, Arkivoc 2002, 24; T. Genski, G. Macdonald, X. Wei, N. Lewis, R. J. K.
Taylor, Arkivoc 2000, 266.
[10] D. H. R. Barton, J. D. Elliott, S. D. Gero, J. Chem. Soc., Perkin Trans. 1. 1982, 2085.
[11] K. Feichtinger, C. Zapf, H. L. Sings, M. Goodman, J. Org. Chem. 1998, 63, 3804.
[12] M. S. Bernatowicz, Y. Wu, G. R. Matsueda, Tetrahedron Lett. 1993, 34, 3389.
[13] C. A. Maryanoff, R. C. Stanzione, J. N. Plampin, J. E. Mills, J. Org. Chem. 1986, 51, 1882.
[14] D. R. Kent, W. L. Cody, A. M. Doherty, Tetrahedron Lett. 1996, 37, 8711.
[15] Z. X. Guo, A. N. Cammidge, D. C. Horwell, Synth. Commun. 2000, 30, 2933.
[16] K. S. Kim, L. Qian, Tetrahedron Lett. 1993, 34, 7677.
[17] C. Levallet, J. Lerpiniere, S. Y. Ko, Tetrahedron Lett. 1997, 53, 5251.
[18] E. J. Iwanowicz, M. A. Poss, J. Lin, Synth. Commun. 1993, 23, 1443.
[19] Y. F. Yong, J. A. Kowalski, M. A. Lipton, J. Org. Chem. 1997, 62, 1540.
[20] M. A. Poss, E. Iwanowicz, J. A. Reid. J. Lin, Z. Gu, Tetrahedron Lett. 1992, 33, 5933.
[21] C. R. Rasmussen, F. J. Villani, L. E. Weaner, B. E. Reynolds, A. R. Hood, L. R. Hecker, S. O. Nortey, A.
Hanslin, M. J. Costanzo, E. T. Powell, A. J. Molinari, Synthesis 1988, 23, 456.

Helvetica Chimica Acta Vol. 88 (2005)
1675
[22] C. R. Rasmussen, F. J. Villani, B. E. Reynolds, J. N. Plampin, A. R. Hood, L. R. Hecker, S. O. Nortey, A.
Hanslin, M. J. Costanzo, R. M. Howse, A. J. Molinari, Synthesis 1988, 23, 460.
[23] Y. Q. Wu, S. K. Hamilton, D. E. Wilkinson, G. S. Hamilton, J Org. Chem. 2002, 67, 7553.
[24] P. Molina, M. Alajarin, J. Saez, Synth. Commun. 1983, 13, 67 .
[25] A. R. Katritzky, R. L. Parris, S. M. Allin, Synth. Commun. 1995, 25, 1173.
[26] A. R. Katritzky, B. Rogovoy, C. Klein, H. Insuasty, V. Vvedensky, B. Insuasty, J. Org. Chem. 2001, 66, 2854.
[27] A. R. Katritzky, B. V. Rogovoy, V. Vvedensky, J Org. Chem. 2000, 65, 8080.
[28] A. R. Katritzky, B. V. Rogovoy, X. Cai, N. Kirichenko, K. V. Kovalenko, J. Org. Chem. 2004, 69, 309.
[29] A. W. Johnson, S. C. K. Wong, Can. J. Chem. 1966, 44, 2793.
[30] D. F. Gavin, W. J. Schnabel, E. Kober, M. Roninson, J. Org. Chem. 1967, 32, 2511.
[31] M. Mikolajczyk, P. Kielbasinski, Tetrahedron 2000, 37, 233.
[32] A. Trani, E. Bellasio, J. Heterocycl. Chem. 1974, 11, 257.
[33] J. Burkhardt, K. Hamann, Chem. Ber. 1967, 100, 2569.
[34] A. R. Katritzky, S. Ledoux, R. M. Witek, S. K. Nair, J. Org. Chem. 2004, 69, 2976.
[35] C. Larsen, K. Steliou, D. N. Harpp, J. Org. Chem. 1978, 43, 337.
[36] E. M. Briggs, Synthesis 1980, 295.
[37] P. Laszlo, Tetrahedron Lett. 1984, 25, 4651.
[38] V. N. Fetyukhin, Zh. Obshch. Khim. 1983, 53, 1763.
Received March 1, 2005