Efficient Synthesis of Polysubstituted Acylguanidines and Guanylureas

Article abstract of DOI:10.1021/jo035028i

(Benzotriazol-1-yl)carboximidamides were applied for the preparation of polysubstituted acylguanidines and guanylureas. The reaction sequence utilized mild conditions and gave high yields for final compounds and intermediates. The protocol developed allows for variation of the substituents at all positions of the products.

Full text of DOI:10.1021/jo035028i

Efficien t Syn th esis of P olysu bstitu ted Acylgu a n id in es a n d
Gu a n ylu r ea s
Alan R. Katritzky,* Boris V. Rogovoy, Xiaohong Cai, Nataliya Kirichenko, and
Katherine V. Kovalenko
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received J uly 16, 2003
(Benzotriazol-1-yl)carboximidamides were applied for the preparation of polysubstituted acylguanidines
and guanylureas. The reaction sequence utilized mild conditions and gave high yields for final
compounds and intermediates. The protocol developed allows for variation of the substituents at
all positions of the products.
SCHEME 1
In tr od u ction
Many natural and synthetic guanidines, including
their acyl and carbamoyl derivatives, are of great interest
because of their diverse biological activities.1 Acyl-
guanidines have found applications in the treatment
of osteoporosis,2 cardiac ischemia and reperfusion,3
glaucoma,3c and as initropic drugs,4 antihypertensive
agents,5 Rvâ3 antagonists,6a diuretics,6b and thrombin
inhibitors.7 Their activity toward different receptors has
been studied.8 Acylguanidines have antifungal9 and
plant-protecting10 properties.
Synthetic approaches to acylguanidines (Scheme 1)
include (i) reactions of isocyanide dichlorides11 with
(1) (a) Heys, L.; Moore, C. G.; Murphy, P. J . Chem. Soc. Rev. 2000,
29, 57. (b) Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617. (c) Berlinck,
R. G. S. Nat. Prod. Rep. 1999, 16, 339. (d) Goodman, M.; Zapf, C.; Rew,
Y. Biopolymers 2001, 60, 229.
(2) Carniato, D.; Gadek, T. R.; Gourvest, J .-F.; Knolle, J .; Peyman,
A.; Ruxer, J .-M.; Bodary, S. C. Int. Patent WO 0031046, 2000; Chem.
Abstr. 2000, 133, 4997.
(3) (a) Baumgarth, M.; Beier, N.; Gericke, R. J . Med. Chem. 1997,
40, 2017. (b) Aihara, K.; Hisa, H.; Sato, T.; Yoneyama, F.; Sasamori,
J .; Yamaguchi, F.; Yoneyama, S.; Mizuno, Y.; Takahashi, A.; Nagai,
A.; Kimura, T.; Kogi, K.; Satoh, S. Eur. J . Pharmacol. 2000, 404, 221.
(c) Padmanabhan, S.; Lavin, R. C.; Thakker, P. M.; Guo, J .; Zhang, L.;
Moore, D.; Perlman, M. E.; Kirk, C.; Daly, D.; Burke-Howie, K. J .;
Wolcott, T.; Chari, S.; Berlove, D.; Fischer, J . B.; Holt, W. F.; Durant,
G. J .; McBurney, R. N. Bioorg. Med. Chem. Lett. 2001, 11, 3151.
(4) Buschauer, A. J . Med. Chem. 1989, 32, 1963.
(5) Bream, J . B.; Picard, C. W. Swiss Patent 518910, 1972; Chem.
Abstr. 1972, 77, 61634.
(6) (a) Peyman, A.; Scheunemann, K.-H.; Will, D. W.; Knolle, J .;
Wehner, V.; Breipohl, G.; Stilz, H. U.; Carniato, D.; Ruxer, J .-M.;
Gourvest, J .-F.; Auberval, M.; Doucet, B.; Baron, R.; Gaillard, M.;
Gadek, T. R.; Bodary, S. Bioorg. Med. Chem. Lett. 2001, 11, 2011. (b)
Bicking, J . B.; Mason, J . W.; Woltersdorf, O. W.; J ones, J , H.; Kwong,
S. F.; Robb, C. M.; Cragoe, E. J ., J r. J . Med. Chem. 1965, 8, 638.
(7) (a) Adang, A. E. P.; Lucas, H.; de Man, A. P. A.; Engh, R. A.;
Grootenhuis, P. D. J . Bioorg. Med. Chem. Lett. 1998, 8, 3603. (b)
Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D. J .
J . Med. Chem. 1998, 32, 228.
amines and (ii) reactions of dimethyl N-acyliminodithio-
carbonates12 with amines, which often form symmetrical
byproducts, (iii) direct acylations of guanidines with
esters,9,13 (iv) treatment of hexamethyl(alkoxymethane)-
triamines with amides,14 (v) reactions of N-chloroamides
with tetramethyl(alkoxymethane)diamines15 to give the
(8) (a) Cheung, A. W.-H.; Danho, W.; Swistok, J .; Qi, L.; Kurylko,
G.; Franco, L.; Yagaloff, K.; Chen, L. Bioorg. Med. Chem. Lett. 2002,
12, 2407. (b) Dixon, R. P.; Geib, S. J .; Hamilton, A. D. J . Am. Chem.
Soc. 1992, 114, 365.
(9) Burmistrov, S. I.; Sukhoruchkin, Yu. V. J . Gen. Chem. USSR
(Engl. Transl.) 1963, 33, 1293.
(11) J ohnson, T. B.; Chernoff, L. H. J . Am. Chem. Soc. 1912, 34,
164.
(12) Augustin, M.; Richter, M.; Salas, S. J . Prakt. Chem. (Leipzig)
1980, 55.
(13) Goerdeler, J .; Mertens, P. Chem. Ber. 1970, 103, 1805.
(14) Kantlehner, W.; Funke, E.; Haug, E.; Speh, P.; Kienitz, L.;
Maier, T. Synthesis 1977, 73 and references therein.
(10) Ernst, G. German Patent DE 19711118, 1972; Chem. Abstr.
1972, 76, 34266.
10.1021/jo035028i CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/25/2003
J . Org. Chem. 2004, 69, 309-313
309

Katritzky et al.
SCHEME 2
corresponding N-acyl-N′,N′,N′′,N′′-tetramethylguanidines,
and (vi) additions to acylcarbodiimides of trimethylstan-
nyl(germanyl or silyl)amines.16 (vii) Reactions of penta-
substituted guanidines with acyl isocyanates or isothio-
cyanates provide tetrasubstituted acylguanidines via the
formation of a four-membered [2 + 2] cycloadduct.17 (viii)
1-Aroylisothioureas have been converted into acylguani-
dines upon reaction with a variety of amines,18 and (xi)
direct conversion of acylthioureas into acylguanidines has
been carried out in the presence of a catalyst (HgCl2,19
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI),
2-chloro-1-methylpyridinium iodide,19b or Bi(NO3)3‚5H2O20).
(x) Acyliminolthiazetidines (formed from the correspond-
ing acylthioureas) afford acylguanidines in moderate to
good yields with amines.21 (xi) The combinatorial solid-
supported preparation of acylguanidines has been devel-
oped with the utilization of solid-supported isothio-
ureas.22,23
We24a-c and others24d have previously reported (ben-
zotriazole-1-yl)carboximidamides 3 to be efficient re-
agents for the synthesis of polysubstituted guanidines in
solution and on solid support.25 Acyl(benzotriazolyl)carbox-
imidamides 5 are also versatile intermediates for the
synthesis of five-26 and six-membered27,24b heterocycles.
We now report the utilization of 5 and synthesis and
utilization of 11 in the efficient preparation of polysub-
stituted acylguanidines and guanylureas, respectively.
TABLE 1. P r ep a r a tion of
N-a cyl(ben zotr ia zole-1-yl)ca r boxim id a m id es 5a -f a n d
Am in oca r bon yl(Ben zotr ia zole-1-yl)ca r boxim id a m id es
11a -d a n d 13a ,b
yield
(%)
entry starting product
R1
-(CH2)5-
i-Pr
i-Pr
R2
R3
Resu lts a n d Discu ssion
1
3a
3b
3b
3c
3c
3c
3c
3d
8a
8b
8c
8c
5a
Ph
78
75
76
(Benzotriazole-1-yl)carboximidamides 3a -d and 8a -c
were prepared by a previously published procedure24a,26a
from di(benzotriazolyl)methanimines 1. The tautomeric
equilibrium of monosubstituted (benzotriazole-1-yl)car-
boximidamides 8a -c in chloroform was discussed previ-
ously,24a and all the present compounds showed spectra
consistent with the discussion in and assignments of our
2
5b
i-Pr
i-Pr
C2H5
Ph
3
5c
4
5d
-(CH2)2O(CH2)2- 4-MeOC6H4 69
5
5e
-(CH2)2O(CH2)2- 2-Furoyl
-(CH2)2O(CH2)2- 4-Cl-C6H4
-(CH2)2O(CH2)2- Ph
64
70
65
80
86
6
5f
7
8
9
10
11
12
13a
13b
11a
11b
11c
11d
Bn
Bn
H
H
Ph
Ph
n-hexyl
Bn
1
4-MeOC6H4 76
previous investigation. Thus, according to both H NMR
and 13C NMR data, aryl substituted compounds 8b ,c
p-tolyl
p-tolyl
H
H
Ph
73
89
4-Cl-C6H4
(15) Bredereck, H.; Simchen, G.; Porkert, H. Chem. Ber. 1970, 103,
245.
(16) (a) Itoh, K.; Matsuda, I.; Ishii, Y. Tetrahedron Lett. 1969, 31,
2675. (b) Matsuda, I.; Itoh, K.; Ishii, Y. J . Organomet. Chem. 1974,
69, 353.
(17) Schaumann, E.; Kausch, E. J ustus Liebigs Ann. Chem. 1978,
1543.
(18) Padmanabhan, S.; Lavin, R. C.; Thakkar, P. M.; Durant, G. J .
Synth. Commun. 2001, 31, 2491.
(19) (a) Cunha, S.; Costa, M. B.; Napolitano, H. B.; Lariucci, C.;
Vencato, I. Tetrahedron 2001, 57, 1671. (b) Zhang, J .; Shi, Y.; Stein,
P.; Atwal, K.; Li, C. Tetrahedron Lett. 2002, 43, 57.
(20) Cunha, S.; de Lima, B. R.; de Souza, A. R. Tetrahedron Lett.
2002, 43, 49.
(21) Okajima, N.; Okada, Y. J . Heterocycl. Chem. 1991, 28, 177.
(22) Dodd, D. S.; Zhao, Y. Tetrahedron Lett. 2001, 42, 1259.
(23) Lin, P.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9789.
(24) (a) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.; Vvedensky,
V. J . Org. Chem. 2000, 65, 8080. (b) Katritzky, A. R.; Rogovoy, B.;
Klein, C.; Insuasty, H.; Vvedensky, V.; Insuasty, B. J . Org. Chem. 2001,
66, 2854. (c) Katritzky, A. R.; Parris, R. L.; Allin, S. M. Synth. Commun.
1995, 25, 1173. (d) Musiol, H.-J .; Moroder, L. Org. Lett. 2001, 3, 3859.
(25) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.; Kovalenko, K.;
Forood, B. J . Comb. Chem. 2002, 4, 290.
(26) (a) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.; Kovalenko,
K.; Steel, P. J .; Markov, V. I.; Forood, B. Synthesis 2001, 897. (b)
Katritzky, A. R.; Vvedensky, V.; Cai, X.; Rogovoy, B. V.; Steel, P. J .
ARKIVOC 2002, vi, 82. (c) Makara, G. M.; Ma, Y.; Margarida, L. Org.
Lett. 2002, 4, 1751. (d) Makara, G. M.; Schell, P.; Hanson, K.; Moccia,
D. Tetrahedron Lett. 2002, 43, 5043.
(R1 ) Ar or HetAr, R2 ) H) exist in chloroform solution
predominantly as the ArNdC(NH2)Bt form. Alkyl sub-
stituted analogue 8a (R1 ) n-hexyl, R2 ) H) exists as a
mixture of both tautomers with C6H13NHC(Bt)dNH
dominating. Acylation of disubstituted (benzotriazole-1-
yl)carboximidamides 3a -d with acid chlorides 4a -e gave
the expected acyl derivatives 5a -f. A similar reaction of
monosubstituted (benzotriazole-1-yl)carboximidamides
8a -c with acid chlorides gave complex reaction mixtures
independent of the substrates used, and no desired
products of type 9 (R2 ) H) were isolated.
Reactions of mono- and disubstituted compounds 3c,d
and 8a -c with isocyanates 10a -c gave the desired
aminocarbonyl(benzotriazole-1-yl)carboximid-
amides 11a -d and 13a ,b in excellent yields (Scheme 2,
Table 1). All compounds 11 and 13 were obtained in the
sole tautomeric form depicted in Scheme 1 due to the
presence of the aminocarbonyl group. A single set of
signals in both the 1H and 13C NMR supports this
1
statement. Thus, H NMR spectrum for N-[1H-benzot-
riazol-1-yl(4-toluidino)methylidene]-N′-phenylurea 11c in
CDCl3 solution showed two singlets for the NH protons
near the carbonyl and tolyl groups at 11.05 and 9.24 ppm,
(27) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.; Hebert, N.;
Forood, B. J . Org. Chem. 2001, 66, 6797.
310 J . Org. Chem., Vol. 69, No. 2, 2004

Polysubstituted Acylguanidines and Guanylureas
TABLE 2. Syn th esis of N-Acyl Gu a n id in es 7a -o
TABLE 3. Syn th esis of N-Ca r ba m oylgu a n id in es 12a -h
a n d 14a -f
starting
compd
yield
(%)
entry
product
R4
R5
H
starting
entry compd
R4
PhC2H4
4-MeOC6H4
-(CH2)2O(CH2)2-
n-Bu
PhCH2
n-Bu
n-Bu
4-ClC6H4
4-MeOC6H4
n-Bu
4-MeOC6H4
-(CH2)2O(CH2)2-
4-MeOC6H4CH2
R5
product and yield (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5b
5b
5b
5c
5c
5d
5e
5e
5f
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
4-MeOC6H4
-(CH2)2O(CH2)2-
68
78
76
84
51
50
56
70
60
78
84
81
79
70
78
1
2
3
4
5
6
7
8
11a
11a
11b
11b
11c
11c
11d
11d
13a
13a
13b
13b
13b
13b
H
H
12a (51)
12b (67)
12c (85)
12d (87)
12e (60)
Ph
n-Bu
H
H
H
H
H
H
H
H
PhC2H4
PhCH2
i-Bu
4-MeOC6H4CH2
Ph
PhCH2
-(CH2)2O(CH2)2-
PhC2H4
H
H
n-Bu 12f (58)
n-Bu 12g (70)
H
H
H
H
9
12h (57)
14a (0)
14b (43)
14c (0)
14d (0)
14e (35)
14f (31)
10
11
12
13
14
15
9
15a (56)
15b (46)
15a (51)
15d (72)
15e (40)
15b (46)
10
11
12
13
14
H
H
H
p-Tolyl
MeO2CCH(Ph)
-(CH2)4-
H
H
5f
n-Bu
respectively. Similarly, the NH proton of the aminocar-
bonyl group for compound 11a was found at 10.48 ppm;
the NH proton near the n-hexyl moiety overlapped with
some protons of the benzotriazolyl and tolyl moieties in
the region of 7.30-7.64 ppm. All other signals are well
resolved (when no overlapping is present), supporting the
presence of a single tautomeric form.
nyl derivatives. Thus, N-[benzotriazol-1-yl(morpholin-4-
yl)methylene]-4-chlorobenzamide 5f reacted with L-phe-
nylalanine methyl ester hydrochloride in the presence of
triethylamine to afford the corresponding R-guanyl de-
rivative 7n . Because of the strong basicity of the guani-
dine moiety, compound 7n was isolated partially as a
hydrochloride (38%) and partially as hydrate (32%) from
the same reaction mixture. The compositions of both
derivatives were confirmed by combustion analysis and
NMR spectroscopy.
The benzotriazole moiety in compounds 5a -f was
displaced by the action of amines 6a -n in refluxing
tetrahydrofuran (THF) (Scheme 2, Table 2) to form the
desired N-acyl polysubstituted guanidines 7a -o; the
benzotriazole formed as a byproduct was removed from
reaction mixtures by washing with a 10% aqueous
solution of sodium hydroxide. We previously described
reactions of acylated benzotriazolylcarboximidamides 5
with hydrazines for the preparation of 1,2,4-triazole ring
systems.26a In some cases, the concurrent displacement
of benzotriazole or the amino functionality was observed
and 5-amino-1,2,4-triazoles or 5-benzotriazol-1-yl-1,2,4-
triazoles or both were obtained. The amines now used
for the preparation of the acylguanidines are less nu-
cleophilic and, correspondingly, less reactive than hy-
drazines. In most cases, hydrazines displace the benzo-
triazolyl or amino group at room temperature, whereas
displacement of benzotriazole with amines requires
elevated temperature up to reflux in THF for 12-18 h.
The only exception was the reaction of compound 5d with
pyrrolidine. In this case, a symmetrical product was the
major product in a mixture containing the desired
Similarly, N′-substituted and N′,N′-disubstituted N-ami-
nocarbonyl(benzotriazole-1-yl)carboximidamides 11a -d
and 13a ,b were reacted with various amines 6a -n .
N-Monosubstituted (benzotriazol-1-yl)carboximidamides
11a -d afforded the desired guanylureas 12a -h (Scheme
2, Table 3). The benzotriazolyl moiety was displaced
under conditions similar to those used for the reaction
of compounds 5a -f with amines: refluxing in THF with
variable reaction times. Completion of the reaction was
determined by thin-layer chromatography (TLC) analysis
from the disappearance of starting material. The pres-
ence of the carbonyl group determines the configuration
1
of the products obtained. According to both the H and
13C NMR, all compounds 12a -h , independently of the
nature of the substituents, were obtained in a single
tautomeric form with the double-bonded CdN nitrogen
bearing the carbonyl group. All well-resolved signals
correspond to a single tautomeric form. The only excep-
tion was for compound 12g (R1 ) p-tolyl, R2 ) H, R3 )
4-Cl-C6H4, R4 ) R5 ) n-Bu), for which two sets of signals
were observed in both the 1H and 13C NMR in the
approximate ratio of 2 to 1. However, it was not possible
to assign signals to the individual tautomeric forms.
1
unsymmetrical acylguanidine as detected by H and 13C
NMR spectroscopy; this mixture could not be separated
because of the close nature of the polarity of the com-
pounds. Reaction of 5d with morpholine gave the desired
N-acyl guanidine 7k in 84% yield. Displacement of amino
functionality was not detected in any other reaction.
Successful displacement of the benzotriazole moiety
from compounds 5a -f does not depend on the nature of
the acyl group. All the acyl-substituted (benzotriazole-
1-yl)carboximidamides gave the desired guanidines 7a -
d ,k -o in good to excellent yields in reactions with
primary and secondary alkylamines, anilines, and R-ami-
no esters. However, hindered N-acyl N′,N′-di(isopropyl)-
carboximidamides 5b,c gave final guanidines 7e-h ,j only
with primary alkylamines. No reaction was observed for
5b,c with morpholine or dibenzylamine.
Reactions of N,N-disubstituted N′-aminocarbonyl(ben-
zotriazol-1-yl)carboximidamides 13a ,b with amines 6a -n
gave the desired guanylureas 14a -f in low yields or not
at all. The major products in the reactions of 13a ,b with
6 are di- and trisubstituted ureas 15a ,b,d ,e as a result
of the nucleophilic attack of an amine on the aminocar-
bonyl group and displacement of the whole (benzotriaz-
olyl)carboximidamide moiety. 1-(Benzotriazol-1-yl-diben-
zylaminomethylene)-3-phenylurea 13b in the reaction
with 4-methoxybenzylamine gave the desired 1-[diben-
zylamino-(4-methoxybenzylamino)methylene]-3-pheny-
lurea 14e in 35% yield along with 1-(4-methoxybenzyl)-
3-phenylurea 15e in 40% yield. Reactions of 13b with
The reaction sequence now developed is suitable for
the conversion of R-amino acids to corresponding R-gua-
J . Org. Chem, Vol. 69, No. 2, 2004 311

Katritzky et al.
11a was recrystallized from chloroform/hexanes; 11b was
purified by gradient column chromatography with ethyl acetate/
hexanes, from 1:9 to 1:3; 11c was purified by gradient column
chromatography with ethyl acetate/hexanes, from 1:20 to 1:1;
11d was used for the subsequent transformations without
additional purification.
p-anisidine and morpholine afforded only the correspond-
ing ureas 15a ,d in 51 and 72% yield, respectively: no
products 14c,d were isolated.
Con clu sion
N-(1H-Ben zotr ia zol-1-yl(h exyla m in o)m eth ylid en e)-N′-
p h en ylu r ea (11a ). White needles were obtained from chlo-
roform/hexanes: mp 121-122 °C. H NMR: δ 0.86 (t, J ) 6.7
We have developed a simple and efficient procedure
for the preparation of acylguanidines 7a -o and guany-
lureas 12a -h . All reaction steps of the sequence are
carried out in mild conditions and provide products in
good to excellent yields. The purification of intermediates
and final products requires in most cases simple washing
with a 10% aqueous solution of sodium hydroxide after
each of two benzotriazole displacement steps and with
water after the acylation step. However, reactions of
13a ,b with amines sometimes give the corresponding
guanylureas 14b,e,f together with substantial amount
of the corresponding simple ureas 15b,e. In other cases
only the urea 15a ,d is formed.
Our method allows the introduction of a variety of
amino group substituents for the preparation of asym-
metrical N-acyl guanidines, which is difficult if not
impossible for the synthesis based on isocyanide dichlo-
rides,11 dimethyl N-acyliminodithiocarbonates,12 hexam-
ethyl(alkoxymethane)triamines,14 or tetramethyl(alkoxy-
methane)diamines;15 moreover, the available diversity of
these reagents is limited. Many previously described
methods16a,b,18-21 impose limits on the number of substi-
tuents in the N-acyl guanidine molecules that can be
prepared, whereas the method presently described allows
the preparation of diversely substituted N-acylguanidines
and N-guanylureas with complete control. Benzotriazole
formed as the only byproduct can be recovered and
recycled.
1
Hz, 3H), 1.24-1.43 (m, 6H), 1.65-1.75 (m, 2H), 3.65-3.68 (m,
2H), 7.09 (t, J ) 7.3 Hz, 1H), 7.30-7.64 (m, 7H), 8.09-8.15
(m, 2H), 10.48 (br s, 1H). 13C NMR: δ 13.8, 22.0, 25.9, 28.5,
30.8, 42.9, 112.7, 118.5, 119.6, 122.1, 125.2, 128.4, 129.1, 131.8,
140.0, 144.9, 146.9, 158.8. Anal. Calcd for C20H24N6O: C, 65.91;
H, 6.64; N, 23.06. Found: C, 65.79; H, 6.63; N, 22.74.
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
13a ,b. Benzotriazole-1-carboximidamide 3 (10 mmol) was
dissolved in dry THF (100 mL), and phenyl isocyanate (1.10
mL, 10 mmol) was added under vigorous stirring. The result-
ing solution was allowed to react for 24 h at room temperature.
After concentration of the reaction mixture, N-aminocarbonyl-
(benzotriazol-1-yl)carboximidamides 13a ,b were obtained and
recrystallized from methanol.
N-[1H-Ben zotr ia zol-1-yl(m or p h olin o)m eth ylid en e]-N′-
p h en ylu r ea (13a ). White prisms were obtained from etha-
nol: mp 158-160 °C (lit.28 158-160 °C). 1H NMR (DMSO-d6):
δ 3.44-3.56 (m, 4H), 3.70-3.81 (m, 4H), 6.90 (t, J ) 7.2 Hz,
1H), 7.16 (t, J ) 7.7 Hz, 2H), 7.35 (d, J ) 8.0 Hz, 2H), 7.51 (t,
J ) 7.6 Hz, 1H), 7.67 (t, J ) 7.6 Hz, 1H), 7.86 (d, J ) 8.2 Hz,
1H), 8.18 (d, J ) 8.3 Hz, 1H), 9.79 (br s, 1H). 13C NMR (DMSO-
d6): δ 46.8, 65.6, 110.8, 118.5, 119.8, 122.2, 125.1, 128.4, 129.4,
132.4, 139.7, 144.5, 145.7, 157.7.
N-[1H-Ben zotr ia zol-1-yl(d iben zyla m in o)m eth ylid en e]-
N′-p h en ylu r ea (13b). White prisms were obtained from
methanol: mp 136-138 °C (lit.28 215-217 °C). 1H NMR
(DMSO-d6): δ 4.67 (s, 4H), 6.89 (t, J ) 7.1 Hz, 1H), 7.14 (t, J
) 7.6 Hz, 2H), 7.22-7.45 (m, 13H), 7.53-7.62 (m, 2H), 8.13
(d, J ) 8.2 Hz, 1H), 10.05 (s, 1H). 13C NMR (DMSO-d6): δ
52.0, 110.1, 118.9, 120.4, 123.2, 124.8, 128.0, 128.1, 128.7,
128.9, 129.3, 132.9, 135.1, 138.4, 145.2, 148.6, 157.3. Anal.
Calcd for C28H24N6O: C, 73.02; H, 5.25; N, 18.25. Found: C,
72.89; H, 5.27; N, 18.24.
Exp er im en ta l Section
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
5a -f. To a stirred solution of 1H-benzotriazol-1-ylcarboximi-
damide (0.011 mol) in chloroform (30 mL), the appropriate acid
chloride (0.011 mol) was added at room temperature followed
by the addition of triethylamine (0.011 mol). The reaction
mixture was allowed to react overnight at room temperature.
Completion of the reaction was monitored by TLC. Upon
completion, the reaction mixture was washed twice with water
and dried over magnesium sulfate, and the solvent was
removed under reduced pressure. The desired N-acyl-1H-
benzotriazol-1-ylcarboimidamides 5a ,c-f were purified by
recrystallization from an appropriate solvent; compound 5b
was purified by gradient column chromatography (ethyl
acetate/hexanes, from 5 to 50% ethyl acetate in 5% steps).
N-(1H-Ben zotr ia zol-1-yl(p ip er id in o)m eth ylid en e)ben -
za m id e (5a ). White microcrystals were obtained from ethyl
Gen er a l P r oced u r e for th e P r ep a r a tion of Gu a n id in es
7a -o. To a solution of N-acyl-1H-benzotriazol-1-ylcarboximi-
damide 5a -f (3.0 mmol) in THF (25 mL), the amine of choice
(3.0 mmol) was added with stirring. The reaction mixture was
heated to reflux and kept at that temperature until the full
conversion of starting materials (TLC control). Upon comple-
tion, the solvent was evaporated under reduced pressure; crude
product was dissolved in chloroform, washed twice with
saturated aqueous sodium carbonate, dried over magnesium
sulfate, and filtered. The solvent was removed under reduced
pressure. Desired guanidines were isolated by column chro-
matography (first ethyl acetate to remove impurities and
methanol to elute guanidine) with additional recrystallization
from ethyl acetate where applicable.
N -[(4-Me t h o x y a n ilin o )(p ip e r id in o )m e t h y lid e n e ]-
ben za m id e (7a ). Microcrystals were isolated as a carbonate
salt: mp 77-79 °C. 1H NMR: δ 1.58 (s, 6H), 3.48-3.50 (m,
4H), 3.78 (s, 3H), 6.84 (d, J ) 8.9 Hz, 2H), 7.02 (d, J ) 8.9 Hz,
2H), 7.38-7.46 (m, 3H), 8.24 (d, J ) 6.6 Hz, 2H), 11.74 (br s,
1H). 13C NMR: δ 24.3, 25.5, 47.8, 55.4, 114.5, 123.0, 127.8,
129.0, 131.1, 133.0, 138.5, 156.4, 160.0, 176.5. Anal. Calcd for
1
acetate: mp 148-149 °C. H NMR: δ 1.80 (br s, 6H), 3.56-
3.59 (m, 4H), 7.36-7.41 (m, 3H), 7.45-7.52 (m, 3H), 8.04-
8.09 (m, 3H). 13C NMR: δ 24.0, 25.7, 48.9, 110.9, 120.3, 124.9,
128.0, 129.2, 129.5, 132.1, 132.7, 135.7, 145.5, 147.3, 174.9.
Anal. Calcd for C19H19N5O: C, 68.45; H, 5.74; N, 21.01.
Found: C, 68.10; H, 5.55; N, 21.01.
C
21H25N3O5: N, 10.52. Found: N, 10.83.
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
11a -d . To a solution of (benzotriazole-1-yl)carboximidamide
(0.01 mol) in chloroform (10 mL) was added aryl isocyanate
(0.01 mol) at room temperature with stirring. The reaction
mixture was allowed to react at room temperature overnight.
Completion of the reaction was monitored by TLC. Upon
completion, the solvent was evaporated under reduced pres-
sure, and the pure desired aminocarbonyl(benzotriazole-1-yl)-
carboximidamides 11a -d were obtained after purification:
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Gu a n yl-
u r ea s 12a -h . To a stirred solution of N-aminocarbonyl-1H-
benzotriazol-1-ylcarboximidamides 11a -d (0.54 mmol) in THF
(10 mL) was added the amine of choice at room temperature.
The reaction mixture was heated to reflux and allowed to react
(28) Katritzky, A. R.; Cai, X.; Vvedensky, V. Y.; Rogovoy, B. V.;
Forood, B.; Hebert, N. Heterocycles 2002, 57, 1799.
312 J . Org. Chem., Vol. 69, No. 2, 2004

Polysubstituted Acylguanidines and Guanylureas
at this temperature overnight. Completion of the reaction was
monitored by TLC. Upon completion, the solvent was evapo-
rated and the obtained residue was dissolved in chloroform.
The solution was washed twice with 10% aqueous NaOH and
dried over magnesium sulfate, and the solvent was evaporated
under reduced pressure. Desired guanylureas 12a -h were
obtained after purification by column chromatography: 12a
ethyl acetate/hexanes, 3:1 (silica gel); 12b chloroform (basic
alumina, 50-200 µm, Acros); 12c gradient elution with ethyl
acetate/hexanes, from 1:1 to pure ethyl acetate (silica gel); 12d
gradient elution with chloroform/methanol, from 1:1 to 5:1
(silica gel); 12e chloroform/ethyl acetate, 20:1 (silica gel); 12f
gradient elution with ethyl acetate/hexanes, from 1:19 to 1:1
(basic alumina, 50-200 µm, Acros); 12g gradient elution with
ethyl acetate/hexanes, from 1:19 to 1:4 (silica gel); 12h gradient
elution with ethyl acetate/hexanes from 1:19 to 1:3 (silica gel).
N-[(Hexyla m in o)(p h en eth yla m in o)m eth ylen e]-N′-p h e-
n ylu r ea (12a ) White prisms were obtained from methanol:
mp 90-92 °C. Broadening of signals and some doubling of
signals are observed that are due to restricted rotation. Spectra
appear as described. 1H NMR: δ 0.67-0.87 (m, 3H), 1.20-
1.39 (m, 6H), 1.41-1.52 (m, 2H), 2.70-2.91 (m, 2H), 2.90-
3.20 (m, 2H), 3.30-3.52 (m, 2H), 4.20 (br s, 1H), 6.95 (t, J )
7.4 Hz, 1H), 7.10-7.36 (m, 7H), 7.45 (d, J ) 7.7 Hz, 2H), 9.39
(br s, 1H). 13C NMR: δ 14.0, 22.4, 26.5, 29.0, 31.3, 35.8, 41.0,
42.2, 118.7, 121.7, 121.8, 126.6, 128.6, 128.7, 138.4, 140.0,
158.9, 163.5. Anal. Calcd for C22H30N4O3: C, 72.10; H, 8.63;
N, 15.29. Found: C, 72.22; H, 8.63; N, 15.35.
N-[(Bu tyla m in o)(m or p h olin o)m eth ylid en e]-N′-p h en yl-
u r ea (14b). White prisms were obtained from methanol
(43%): mp 108-110 °C. H NMR: δ 0.98 (t, J ) 7.3 Hz, 3H),
1.38-1.51 (m, 2H), 1.59-1.70 (m, 2H), 3.18-3.25 (m, 2H), 3.41
(t, J ) 4.7 Hz, 4H), 3.78 (t, J ) 4.6 Hz, 4H), 7.04 (t, J ) 7.3
Hz, 1H), 7.12 (br s, 1H), 7.28-7.34 (m, 2H), 7.49 (d, J ) 7.8
Hz, 2H), 9.05 (br s, 1H). 13C NMR: δ 13.6, 19.9, 32.5, 45.4,
47.8, 66.5, 118.8, 122.3, 128.7, 139.6, 162.9, 164.7. Anal. Calcd
for C16H24N4O2: C, 63.13; H, 7.95; N, 18.41. Found: C, 63.43;
H, 8.12; N, 18.66.
1
N-(4-Meth oxyph en yl)-N′-ph en ylu r ea (15a). White prisms
were obtained from methanol: mp 199-201 °C (lit.29 196-
1
197 °C). H NMR (DMSO-d6): δ 3.71 (s, 3H), 6.87 (d, J ) 9.0
Hz, 2H), 6.95 (t, J ) 7.3 Hz, 1H), 7.27 (t, J ) 7.8 Hz, 2H), 7.37
(d, J ) 8.9 Hz, 2H), 7.46 (d, J ) 7.8 Hz, 2H), 8.47 (br s, 1H),
8.58 (br s, 1H). 13C NMR (DMSO-d6): δ 55.1, 114.0, 118.1,
120.0, 121.6, 128.7, 132.7, 139.9, 152.7, 154.5.
Su ppor tin g In for m ation Available: Descriptions of NMR
data, elemental analysis (CHN) or high-resolution mass
spectrometry (HRMS), and physical properties for compounds
5b-f, 7b-o, 11b-d , 12b-h , 14e,f, and 15b,d ,e. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035028I
(29) Etter, M. C.; Urban˜czyk-Lipkowska, Z.; Zia-Ebrahimi, M.;
Panunto, T. W. J . Am. Chem. Soc. 1990, 112, 8415.
(30) Scheerder, J .; Engbersen, J . F. J .; Casnati, A.; Ungaro, R.;
Reinhoudt, D. N. J . Org. Chem. 1995, 60, 6448.
(31) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J . Org. Chem. 1997,
62, 4155.
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
14b,e,f a n d 15a ,b,d ,e. Compounds 14b,e,f and 15a ,b,d ,e were
prepared starting from 13a ,b according to the procedure for
the preparation of compounds 12a -h .
(32) Corrie, J . E. T.; Kirby, G. W.; Sharma, R. P. J . Chem. Soc.,
Perkin Trans. 1 1982, 7, 1571.
J . Org. Chem, Vol. 69, No. 2, 2004 313