Di(benzotriazol-1-yl)methanimine: A new reagent for the synthesis of tri- and tetrasubstituted guanidines

Full text of DOI:10.1021/jo0006526

8080
J . Org. Chem. 2000, 65, 8080-8082
We now describe the use of di(benzotriazol-1-yl)metha-
nimine 1 for the synthesis of tri- and tetrasubstituted
guanidines.
Di(ben zotr ia zol-1-yl)m eth a n im in e: A New
Rea gen t for th e Syn th esis of Tr i- a n d
Tetr a su bstitu ted Gu a n id in es
Resu lts a n d Discu ssion
Alan R. Katritzky,* Boris V. Rogovoy,
Christophe Chassaing,‡ and Vladimir Vvedensky
Starting material 1 was obtained from the reaction of
benzotriazole with cyanogen bromide according to an
already described procedure12 as a mixture of di(1H-
benzotriazol-1-yl)methanimine 1 and 1H-benzotriazol-1-
yl(2H-benzotriazol-2-yl)methanimine 1′ in overall 60-
65% yield. The displacement of the first benzotriazole
moiety was effected by the addition of an amine of choice
to a solution of the mixture of isomers 1+1′ in THF.
Compounds 2a -f were each obtained as pure Bt1 iso-
mers, probably as a consequence of the preferential
displacement of the Bt2 group in the 1′ isomer. Theoreti-
cally, N-monosubstituted carboximidamides can exist in
two tautomeric forms 2a -c and 2′a -c. In CDCl3 solution
we found that the N-phenyl derivative exists solely as
the 2′a tautomer, the N-amyl derivative as the pure 2b
tautomer, and the N-benzyl derivative as a mixture of
2c and 2′c tautomers in approximately equal concentra-
tions, results which conform with those reported previ-
ously.13,14
The synthesis of compounds 2a -f succeeded at room
temperature even for hindered diisopropylamine (com-
pound 2f). The benzotriazole generated as a side product
was easily removed by concentration of the mixture,
dilution with CH2Cl2, and washing with 10% aqueous
Na2CO3. The purification protocol is significantly simpler
than those of the previous methods, which involve the
use of a heavy metal;2,3 furthermore, tedious filtrations
and washing procedures are avoided and the environ-
mentally safe side product benzotriazole can be recycled
into compound 1. This procedure provides 1H-benzotri-
azole-1-carboximidamides 2a -f as pure products without
the need of further purification (Scheme 1). Six diverse
amines gave yields in the range of 68-80% (Table 1).
The fact that compounds 2a -f could be obtained
without contamination by side products resulting from
self-condensation or condensation of a second equivalent
of amine underlines the chemospecificity of the reaction.
Introduction of the first amine into compound 1 evidently
lowers the electrophilicity of the methanimine carbon
sufficiently to prevent further condensation; indeed at-
tempted condensation of 2a -c with a second amine failed
under the above conditions. However, a diverse range of
aromatic and aliphatic primary and secondary amines
in refluxing THF successfully displaced the remaining
benzotriazole group in 2d -f and gave the N,N,N′-tri-
substituted guanidines 3′a ,b,c,e,f,g (this tautomeric form
is preferred in CDCl3 solution) or its N,N,N′,N′-tetrasub-
stituted analogue 3d in fair to good yields (Scheme 1,
Table 2). Repeating the purification protocol used for the
preparation of 2a-f gave the analytically pure guanidines
3a -g. However, it is important that a secondary amine
is utilized at the first stage of the reaction. If the
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received April 27, 2000
In tr od u ction
Polysubstituted guanidine functionality occurs as the
key component for the expression of the biological activity
in numerous natural compounds. The wide range of
biological activities found for guanidines has motivated
the development of many reagents for their preparation.
One class of reagents achieves guanylation by the addi-
tion of a nucleophilic amine onto a cyanamide,1 or a
carbodiimide.2-6a The carbodiimide is often prepared in
situ from precursors such as oxidized or heavy metal-
coordinated N,N′-dialkylthioureas,2,3 N,N′-diprotected
thioureas,4 N-protected-S-alkyl isothioureas,5 or ami-
noiminosulfonic acid.6b,c A second group of methods is
based on the displacement of a leaving group X from a
reagent of type R2NC(:NR)X, where X can be the benzo-
triazole group of benzotriazole-1-carboxamidinium tos-
ylate,7 the pyrazole moiety of 1H-pyrazole-1-carboxami-
dine,8 or of its N,N′-diprotected derivatives9 or N-triflyl-
amine from N,N′-diprotected triflylguanidines.10 Ad-
ditionally, triurethane-protected guanidines were used
for a Mitsunobu conversion of alcohols into substituted
guanidines.11 These procedures have allowed the syn-
thesis of numerous N-alkyl- and N-aryl-substituted
guanidines. However, the potential diversity of the final
products is limited by the two component nature of the
condensations, along with the frequent need to use
protecting groups. For this reason, we have developed a
new guanylating reagent, which allows access to polysub-
stituted guanidines bearing up to four different groups.
‡ Present address: Intervet GesmbH, Research Pharmaceuticals
Chemistry, Althanstrasse 14, A-1090 Vienna, Austria.
(1) Rowley, G. L.; Greenleaf, A. L.; Kenyon, G. L. J . Am. Chem. Soc.
1971, 93, 5542.
(2) Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841.
(3) Ramadas, K.; J anarthanan, N.; Pritha, R. Synlett 1997, 1053.
(4) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.
(5) Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996,
37, 8711.
(6) (a) Arzeno, H. B.; Bingenheimer, W.; Morgans, D. L., J r. Synth.
Commun. 1990, 20, 3433. (b) Marianoff, C. A.; Stanzione, R. C.;
Plampin, J . N.; Mills, J . E. J . Org. Chem. 1986, 51, 1882. (c) Miller, A.
E.; Bischoff, J . J . Synthesis 1986, 777.
(7) Katritzky, A. R.; Parris, R. L.; Allin, S. M.; Steel, P. J . Synth.
Commun. 1995, 25, 1173.
(8) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J . Org. Chem. 1992,
57, 2497.
(9) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron Lett.
1993, 34, 3389.
(10) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J . Org.
Chem. 1998, 63, 3804.
(12) Thambidurai, S.; J eyasubramanian, K.; Ramalingam, S. K.
Polyhedron 1996, 15, 4011.
(13) Katritzky, A. R.; Brzezinski, J . Z.; Lam, J . N. Rev. Roum. Chim.
1991, 36, 573.
(11) Feichtinger, K.; Sings, H. L.; Baker, T. J .; Matthews, K.;
Goodman, M. J . Org. Chem. 1998, 63, 8432.
(14) Hafelinger, G. The Chemistry of Amidines and Imidates; Patai,
S., Ed.; J ohn Wiley and Sons: London, 1975; p 53.
10.1021/jo0006526 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Notes
J . Org. Chem., Vol. 65, No. 23, 2000 8081
Sch em e 1
2f with amylamine and N-methylaniline gave exclusively
N,N-bis(1-methylethyl)cyanamide as result of the loss of
benzotriazole.
Con clu sion
In summary we have developed the use of di(benzo-
triazolyl)methanimines 1,1′ as a new guanidinylating
reagent for the general synthesis of trisubstituted and
tetrasubstituted guanidines. The sequential condensation
of two amines with 1,1′ is insensitive to electronic and
steric effects allowing the use of a wide diversity of
amines. Previously, good methods were available for the
preparation of mono and disubstituted guanidines.7,8
However, the synthesis of tri- and tetrasubstituted
derivatives usually required the use of oxidizers.3 It is
now possible, with our new method, to obtain nonpro-
tected tri- and tetrasubstituted guanidines in high yields
under neutral and mild conditions using an easy purifi-
cation protocol.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined using a
capillary melting point apparatus equipped with
a digital
thermometer. H and 13C NMR spectra were collected on a 300
MHz NMR spectrometer (300 and 75 MHz, respectively) using
CDCl3 as solvent. Tetrahydrofuran (THF) was distilled under
nitrogen immediately before use from sodium/benzophenone.
Column chromatography was conducted with silica gel grade
230-400 mesh (compounds 2b,f). The chromatographic tech-
nique used was flash chromatography as described by Still15 with
hexanes and ethyl acetate gradients unless otherwise stated.
All other reagents were reagent grade and were used without
purification.
1
Di(1H-ben zotr ia zol-1-yl)m eth a n im in e (1) a n d 1H-Ben -
zotr ia zol-1-yl(2H-ben zotr ia zol-2-yl)m eth a n im in e (1′), Mix-
tu r e of Isom er s. Benzotriazole (5.9 g, 0.05 mol) was dissolved
in ethanol (100 mL). To this solution kept at 0 °C was added
cyanogen bromide (2.5 g, 0.025 mol) in acetone (10 mL) followed
by a 10% solution of NaOH (0.025 mol). The white precipitate
was filtered off and washed with ice cold ethanol and recrystal-
lized from benzene to give pure white microneedles, mp 162-
163 °C. Yield 62%. 1H NMR δ 7.44-7.76 (m, 6H), 7.85-7.95 (m,
6H), 8.08 (d, J ) 9.0 Hz, 1H), 8.30-8.39 (m, 8H), 11.77 (s, 2H),
13C NMR δ 110.9, 112.3, 114.0, 120.0, 120.4, 121.2, 125.6, 125.8,
126.6, 127.3, 129.8, 130.7, 131.9, 132.1, 132.2, 140.9, 142.9,
144.9,146.1. Anal. Calcd for C13H9N7: C, 59.31; H, 3.45; N, 37.24.
Found: C, 59.43; H, 3.25; N, 37.27.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr ia z-
ole-1-ca r boxim id a m id es 2. Di(1,2,3-benzotriazol-1-yl)metha-
nimine 1 (2 mmol) was dissolved under an inert atmosphere in
dry THF (20 mL). The appropriate amines (2 mmol, 1 equiv)
were added dropwise, and the resulting mixtures were allowed
to react until complete conversion of 1, as monitored by TLC.
The mixtures were then concentrated under vacuum and dis-
solved in CH2Cl2 (20 mL). The organic layers were washed twice
with aqueous 10% Na2CO3 and dried (MgSO4), and the solvent
was removed under reduced pressure to afford compounds 2, 2′
in analytical purity. For compound 2f heating to 50 °C is
required.
Ta ble 1. P r ep a r a tion of
Ben zotr ia zole-1-ca r boxim id a m id es 2a -f
2
R1
R2
yield (%)
a
b
c
d
e
f
H
H
H
C6H5
n-C5H11
CH2C6H5
80
74
68
71
68
68
-(CH2)4-
-(CH2)2O(CH2)2-
CH(CH3)2 CH(CH3)2
Ta ble 2. P r ep a r a tion of Gu a n id in es 3a -g
reaction yield
3
R1
R2
R3
R4
time (h) (%)
a
b
c
d
e
f
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)4-
C6H5
H
H
H
CH3
H
10
12
12
18
12
17
15
64
74
71
85
68
60
48
4-CH3C6H4
C6H5CH2
C6H5
C6H5
-(CH2)4-
4-CH3OC6H4
H
N-(Ben zyl)ben zotr ia zole-1-ca r boxim id a m id e (2c) a n d
N′-(ben zyl)ben zotr ia zole-1-ca r boxim id a m id e (2′c), m ix-
tu r e of ta u tom er s (1:1): colorless needles, mp 97-98 °C
g
CH(CH3)2 CH(CH3)2 4-CH3OC6H4
H
displacement of the first Bt group is by a primary amine,
the reaction stops at the stage RNHC(:NH)Bt, and it is
difficult to displace the second Bt group.
Tetrasubstituted guanidine 3d was prepared using
extended reaction times in yields comparable to most of
the trisubstituted derivatives. Reaction of 2f with 4-meth-
oxyaniline yielded the desired guanidine 3′g on using an
extended reaction time, but attempted condensations of
1
(hexanes). For 2c: H NMR δ 4.56 (d, J ) 6.2 Hz, 2H), 6.38 (br
s, 1H), 7.13 (br s, 1H), 7.30-7.57 (m, 7H), 8.09 (d, J ) 8.3 Hz,
1H), 8.50 (d, J ) 8.1 Hz, 1H); for 2′c: 1H NMR δ 4.60 (s, 2H),
5.68 (br s, 2H), 7.30-7.57 (m, 7H), 8.08 (d, J ) 8.3 Hz, 1H),
8.53 (d, J ) 8.1 Hz, 1H); 13C NMR (2c + 2′c) δ 45.3, 50.8, 115.4,
119.6, 119.7, 125.0, 125.1, 126.8, 127.2, 127.3, 128.0, 128.5, 128.9,
(15) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8082 J . Org. Chem., Vol. 65, No. 23, 2000
Notes
129.0, 129.2, 129.3, 131.2, 139.9, 146.5, 146.6. Anal. Calcd for
C14H13N5: C, 66.92; H, 5.21; N, 27.87. Found: C, 67.32; H, 5.29;
N, 27.65.
NMR δ 20.7, 50.20, 110.1, 120.4, 124.6, 128.0, 128.8, 129.4, 131.9,
132.9, 135.9, 145.0, 145.8, 173.8. Anal. Calcd for C20H23N5O: C,
68.74; H, 6.63; N, 20.04. Found: C, 68.97; H, 6.86; N, 20.20.
N,N-Bis(1-m et h ylet h yl)b en zot r ia zole-1-ca r b oxim id a -
m id e (2f): white needles, mp 86-87 °C; 1H NMR δ 1.38 (d, J )
6.9 Hz, 12H), 3.51-3.61 (m, 2H), 7.43 (t, J ) 7.8 Hz, 1H), 7.56
(t, J ) 7.4 Hz, 1H), 7.72 (d, J ) 8.2 Hz, 1H), 8.10 (d, J ) 8.2 Hz,
1H); 13C NMR δ 20.9, 48.7, 110.9, 120.0, 124.6, 128.6, 132.4,
145.4, 149.3. This compound was characterized as the benzoyl
derivative; see next compound.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acyl Der iva -
tives of 1H-Ben zotr ia zole-1-ca r boxim id a m id es (5d ,f). Ap-
propriate compound 2 (1 equiv) was dissolved in chloroform, and
acyl chloride (1 equiv) was added followed by addition of
triethylamine (1 equiv). The mixture was allowed to react for
2-4 h at ambient temperature. The completion of the reaction
was monitored by TLC. The chloroform solution was then
washed with water to remove triethylamine hydrochloride. The
chloroform layer was separated, dried, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel with ethyl acetate/hexanes: 1/1 as an
eluent.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
3, 3′. Benzotriazole-1-carboximidamides 2 (500 mg, 2 mmol) were
dissolved in dry THF (20 mL) under an argon atmosphere, and
the appropriate amines (2 mmol) were added to the solution.
The resulting mixtures were then refluxed until complete
conversion of 2, as monitored by TLC. After concentration under
reduced pressure, the obtained residues were dissolved in CH2-
Cl2 (20 mL). The organic layers were washed twice with aqueous
5% Na2CO3 and dried (MgSO4), and the solvent was removed
under vacuum to afford guanidines 3 as pure products.
NÅ-P h en yltetr ah ydr o-1H-pyr r ole-1-car boxim idam ide (3′e):
light brown oil; 1H NMR δ 1.82-1.90 (m, 4H), 3.30-3.39 (m,
4H), 3.67 (br s, 2H), 6.66-6.77 (m, 3H), 7.12-7.27 (m, 2H);13
C
NMR δ 25.5, 50.3, 114.9, 117.8, 118.3, 129.1, 146.3. HRMS (EI)
Calcd for C11H16N3 (M + 1): 190.1344. Found: 190.1337.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
HRMS and CHN analysis for compounds 2′a , 2b, 2d , 2e, 3′a ,
3′b, 3c, 3d , 3′f, 3′g, and 5d . This material is available free of
charge via the Internet at http://pubs.acs.org.
N-[1H-Ben zotr iazol-1-yl(diisopr opylam in o)m eth yliden e]-
ben za m id e (5f): white prisms; mp 116-117 °C; 1H NMR δ 1.53
(d, J ) 6.7 Hz, 12H), 3.73-3.80 (m, 2H), 7.32-7.40 (m, 5H),
7.45-7.50 (m, 1H), 7.97-7.99 (m, 2H), 8.05-8.08 (m, 1H); 13C
J O0006526