One-pot synthesis of N,N′-disubstituted acylguanidines

Article abstract of DOI:10.1016/S0040-4039(01)02071-8

Acylguanidines are isosteres of thioureas (or ureas) and are possible prodrugs of guanidines. A convenient one-pot synthesis of N,N′-disubstituted acylguanidines from primary amides is described.

Full text of DOI:10.1016/S0040-4039(01)02071-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 57–59
One-pot synthesis of N,N%-disubstituted acylguanidines
Jing Zhang, Yan Shi,* Phlip Stein, Karnail Atwal and Chi Li
The Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA
Received 28 September 2001; revised 30 October 2001; accepted 31 October 2001
Abstract—Acylguanidines are isosteres of thioureas (or ureas) and are possible prodrugs of guanidines. A convenient one-pot
synthesis of N,N%-disubstituted acylguanidines from primary amides is described. © 2001 Elsevier Science Ltd. All rights reserved.
We recently required an efficient method for the synthe-
sis of acylguanidines as surrogates of thioureas and
cyanoguanidines. Classically, N,N%-disubstituted acyl-
guanidines are prepared by the reaction of N,N%-disub-
stituted guanidines with various acylating agents.1
However, this procedure usually leads to a mixture of
mono- and multi-acylation products. Alternative meth-
ods involve the stepwise or simultaneous replacement of
both methylthio groups of dimethylthio-N-acyl-
carbonimidate by nucleophilic amines2 or the ring-
opening reaction of 2-acylimino-1,3-thiazetdines.3 All
of these methods require the availability of necessary
starting materials, which are often difficulty to obtain
or involve high temperature and the generation of
noxious mercaptans. More recently, several reports4
have demonstrated that an acylthiourea can be con-
verted to corresponding acylguanidine by the EDCI
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride) coupling reaction with an amine.
Analogous to the synthesis of sulfamoylguanidines5 and
cyanoguanidines,6 we envisioned that the intermediate
acylthiourea anion 2a, generated by the reaction of a
primary amide anion with an isothiocyanate, would
provide a N,N%-disubstituted acylguanidine by the
action of a thiocarbonyl activating reagent and a requi-
site amine (Scheme 1).7 Intermediate 2a (R1=phenyl)
was synthesized from benzamide anion and phenyl
isothiocyanate. The formation of intermediate 2a can
be monitored by LC-MS or TLC analysis, which
showed total conversion of the starting phenyl isothio-
cyanate to 2a in 30 min at 60°C. After cooling to room
temperature, the reaction mixture was treated with
n-butylamine and mercury(II) chloride8 to provide N-
phenyl-N%-n-butyl benzoyl guanidine 3a in 73% yield.
As expected, we also found that EDCI and 2-chloro-1-
methylpyridinium iodide (Mukaiyama’s reagent9) are
also capable of converting intermediate 2a to N-ben-
zoylguanidine 3a in comparable yields (entry a).
In a previous paper,5 we reported two one-pot proce-
dures for the synthesis of N,N%-disubstituted sulfamoyl-
guanidines and sulfonylguanidines from sulfamides and
sulfonamides, respectively. Both routes proceed
efficiently under mild conditions and provide excellent
yields of products. In this report, we disclose the syn-
thesis of acylguanidines from primary amides.
To investigate the scope and limitations of these meth-
ods, we have prepared several additional compounds
from a range of structurally different amides and isoth-
iocyanates. Since all three procedures gave comparable
yields, only method B was utilized to carry out the
additional studies. As shown in Table 1, both alkylacyl-
guanidines (entry b) and benzoylguanidines can be
H
N
H
N
Na
N
H
N
A = HgCl2.
R1
R2
O
1) NaH/DMF
R
R2NH2
B = EDCI, DMAP, Et3N.
C = 2-Chloro-1-methylpyridium
iodide.
R1
N
R
NH2
2)
NCS
R1
A or B or C
O
S
O
R
1
2
3
Scheme 1.
* Corresponding author. Tel.: 609-252-3886; fax: 609-252-6804; e-mail: yan.shi@bms.com
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02071-8

58
J. Zhang et al. / Tetrahedron Letters 43 (2002) 57–59
Table 1.
synthesized by these methods. The electron-withdraw-
ing (entry c) and electron-donating (entry d) substitu-
tions on the benzamide are allowed in these reactions,
as is the heterocyclic ring (entry i). Similarly, phenyl
isothiocyanates can tolerate both electron-withdrawing
(entry e) and electron-donating (entry f) substituents.
The yield is lower when 4-nitrophenylisothiocyanate is
used as a starting material; N-n-butyl benzamide is
obtained as a side product. Both hindered amines
(entry g) and anilines (entry h) participate in the reac-
tion to give satisfactory yields.
3. Okajima, N.; Okada, Y. J. Heterocycl. Chem. 1991, 177.
4. (a) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z.
Tetrahedron Lett. 1992, 33, 5833; (b) Schneider, S. E.;
Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E.
V. Tetrahedron 1998, 54, 15063; (c) Doronina, S.; Behr,
J.-P. Tetrahedron Lett. 1998, 39, 547; (d) Josey, J. A.;
Tarlton, C. A.; Payne, C. E. Tetrahedron Lett. 1998, 39,
5899; (e) Wilson, L. J.; Klopfenstein, S. R.; Li, M. Tetra-
hedron Lett. 1999, 40, 3999.
5. Zhang, J.; Shi, Y. Tetrahedron Lett. 2000, 42, 8075.
6. Atwal, K.; Ahmed, S. Z.; O’Reilly, B. C. Tetrahedron Lett.
1989, 30, 7313.
In conclusion, we have developed three one-pot proce-
dures (Methods A, B and C) for the synthesis of
N,N%-disubstituted acylguanidines from primary amides
and isothiocyanates. The reaction proceeds under mild
conditions and provides excellent yields of N,N%-disub-
stituted acylguanidines.
7. Typical procedures. Typical experiment: To a solution of
benzamide (29 mg, 0.24 mmol) in dimethylformamide (0.5
mL) was added sodium hydride (95%, 7.2 mg, 0.31 mmol).
After stirring for 5 min, phenyl isothiocyanate (24 mL, 0.20
mmol) was added via a syringe. The reaction was stirred at
60°C for 30 min, upon which time TLC indicated complete
conversion of phenyl isothiocyanate to 2a. Method A: To
the above mixture was added n-butylamine (24 mL, 0.24
mmol) and mercury(II) chloride (65 mg, 0.24 mmol). After
stirring at room temperature for 10 min, the reaction was
diluted with ethyl acetate (10 mL) and filtered through a
pad of Celite, and the filtrate was concentrated. Purifica-
tion of the residue on a silica gel column gave 43.6 mg of
3a (73% yield). Method B: To the reaction mixture (2a)
was added n-butylamine (24 mL, 0.24 mmol) and EDCI
(46 mg, 0.24 mmol) and a catalytic amount of 4-dimethyl-
aminopyridine. After stirring at room temperature for 3 h,
References
1. (a) Greenhalgh, R.; Bannard, R. A. B. Can. J. Chem. 1961,
39, 1017; (b) Yamamoto, Y.; Kojima, S. In The Chemistry
of Amidines and Imidates; Patai, S.; Rappoport, Z., Eds.;
John Wiley & Sons: New York, 1991; Vol. 2, Chapter 10.
2. (a) Sato, M.; Fukada, N.; Kurauchi, M.; Takashima, T.
Synthesis 1981, 554; (b) Fukuda, N.; Takahashi, Y.;
Hayashi, M. Synthesis 1986, 484.

J. Zhang et al. / Tetrahedron Letters 43 (2002) 57–59
59
the reaction was quenched with water and extracted with
ethyl acetate (3×5 mL). The organic phase was washed
with a saturated sodium chloride aqueous solution and
dried over magnesium sulfate. The solvent was removed to
give a crude product. Purification of the crude product on
a silica gel column with 5–10% MeOH in EtOAc provided
3a (46.5 mg, 78% yield). Method C: To the reaction
mixture (2a) was added n-butylamine (24 mL, 0.24 mmol)
and 2-chloro-1-methylpyridinium iodide (61.3 mg, 0.24
mmol) and triethylamine (33 mL, 0.24 mmol). After stir-
ring at room temperature for 3 h, the reaction was
quenched with water and extracted with ethyl acetate (3×5
mL). The organic phase was washed with saturated
sodium chloride solution, dried over magnesium sulfate
and filtered. The solvent was removed to give the crude
product. Purification of the crude product on a silica gel
column with 5–10% MeOH in EtOAc provided 3a (45.1
mg, 75% yield). Spectral data for 3a: H NMR (CDCl3) l
1
8.07 (d, 2H, J=7.4 Hz), 7.63 (t, 1H, J=7.5 Hz), 7.50 (t,
2H, J=7.5 Hz), 7.45 (t, 2H, J=7.6 Hz), 7.37 (t, 1H,
J=7.0 Hz), 7.30 (d, 2H, J=7.5 Hz), 2.87 (m, 2H), 1.52 (m,
2H), 1.23 (m, 2H), 0.82 (t, 3H, J=7.5 Hz) ppm; 13C NMR
(CDCl3) l 171.26, 163.52, 163.14, 153.57, 135.05, 134.36,
130.89, 129.74, 128.97, 128.85, 127.87, 124.72, 77.32, 77.00,
76.67, 44.98, 30.81, 19.51, 13.26 ppm; HRMS for
C18H21N3O, calcd for (M+H)+: 296.1763, found: 296.1776.
8. Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.
9. (a) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem.
Lett. 1977, 575; (b) Yong, Y. F.; Kowalski, J. A.; Lipton,
M. A. J. Org. Chem. 1997, 62, 1540.
.