Solid-phase synthesis of N,N′-substituted acylguanidines

Article abstract of DOI:10.1016/S0040-4039(00)02265-6

An efficient method for the solid-phase synthesis of N,N′-substituted acylguanidines is presented. The key-step involves the N-acylation of resin immobilized S-methylisothiourea with a variety of carboxylic acids using PyAOP as the coupling agent. The resulting resin bound N-acyl-derivatives are reacted with a host of amines and the N-acyl,N′-alkyl(aryl)guanidines liberated from the resin upon exposure to TFA.

Full text of DOI:10.1016/S0040-4039(00)02265-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1259–1262
Solid-phase synthesis of N,N%-substituted acylguanidines
Dharmpal S. Dodd* and Yufen Zhao
Early Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton,
NJ 08543-4000, USA
Received 6 November 2000; revised 21 November 2000; accepted 22 November 2000
Abstract—An efficient method for the solid-phase synthesis of N,N%-substituted acylguanidines is presented. The key-step involves
the N-acylation of resin immobilized S-methylisothiourea with a variety of carboxylic acids using PyAOP as the coupling agent.
The resulting resin bound N-acyl-derivatives are reacted with a host of amines and the N-acyl,N%-alkyl(aryl)guanidines liberated
from the resin upon exposure to TFA. © 2001 Published by Elsevier Science Ltd.
Compounds containing the guanidine moiety are
known to elicit a variety of pharmacological responses
and are present in several marketed drugs or drug
candidates.1,2 Acylguanidines are an important class of
these compounds that are currently being evaluated for
the treatment of cardiovascular2a–f and neurological
disorders,2g among others.
resin bound S-methylisothiourea as the masked
guanidine in the synthesis of N-acyl-N%-carbamoyl-
guanidines5b for the preparation of N-acyl,N%-alkyl-
(aryl)guanidines (Scheme 1).
N-Acylation of the resin bound S-methylisothiourea7,8
1 is best carried out with carboxylic acids (2) using
7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium–
hexafluorophosphate (PyAOP) as the coupling agent.
The resin (1), carboxylic acid and PyAOP are mixed in
a reaction vessel, and suspended in 1-methyl-2-pyrro-
lidinone (NMP), and the reaction is initiated by the
addition of diisopropylethylamine (DIPEA). The pro-
gress of the acylation is monitored by reacting a small
sample of the resin from the reaction9a with benzyl-
amine in NMP8 followed by treatment with tri-
fluoroacetic acid (TFA) in dichloromethane to liberate
the N-acyl,N%-benzylguanidines. In general, the reac-
tions are allowed to proceed for 60 h at room tem-
perature.8 For most simple acids, carbodiimide or 2-
isobutoxy - 1 - isobutoxycarbonyl - 1,2 - dihydroquinoline
(IIDQ) mediated acylations were also successful; how-
ever, the reactions were sluggish and in some cases
required double treatments of reagents for complete
Solid-supported organic synthesis has proven to be a
powerful tool in the rapid assembly of small molecules.3
Several methods for the solid-phase synthesis of
guanidines have been reported,4,5 including the prepara-
tion of N-acylguanidines5a and N-acyl-N%-carbamoyl-
guanidines.5b Although, these methods5 are useful for
the generation of smaller focused sets of N-acylguanidi-
nes, they are limiting in that they necessitate the use of
acid chlorides to introduce the N-acyl diversity element.
This imposes restrictions on the library size as well as
the chemical diversity by limiting this input to a small
number of commercially available acid chlorides.6 We
herein describe a protocol for the synthesis of substi-
tuted N-acylguanidines using the much larger pool of
commercially available carboxylic acids6 as the N-acyl
donors. Our strategy utilizes the previously described
1) R1COOH (2),
R2
PyAOP, DIPEA
NMP
NH2
N
O
H
N
H
N
25% TFA
DCM
O
S
O
N
R2
R3
R1
R1
N
H
N
2)
R2
O
NH
O
N
R3
,NMP
R3
(3)
O
1
4
5
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02265-6

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D. S. Dodd, Y. Zhao / Tetrahedron Letters 42 (2001) 1259–1262
Table 1.
Entry
Puritya,b
Product (5 R2=Bn, R3=H)
R1COOH (2)
O
NH2
N
O
O
OH
N
H
Ph
Ph
(2a)
(2b)
(5a)
(5b)
1
2
>95%
>95%
NH2
N
COOH
N
H
NH2
N
O
O
COOH
COOH
N
H
Ph
Ph
(2c)
(2d)
(5c)
(5d)
3
4
>95%
NH2
N
N
H
c
_
NH2
N
O
O
O
COOH
O
O
N
H
Ph
(2e)
(5e)
5
>95%
O
O
Cl
Cl
NH2
N
O
OH
(2f)
(5f)
6
N
H
>95%
Ph
O
Cl
Cl
aHPLC purity is of the crude material after cleavage determined by evaporative light scattering (ELS); peak
identity based on LC/MS analysis. bCrude yield ranged from 75-85%, as the TFA salt, based on 100% loading
of the p-nitrophenylcarbonate resin. cTrace amount of compound present.
acylation. Furthermore, the purity and yields of the
final products were significantly lower than those with
PyAOP. The acylations are also sensitive to steric hin-
drance. For example, benzoic acid (2b) and 2-methyl-
benzoic acid (2c) both coupled cleanly within 60 h using
PyAOP as the coupling agent, whereas, 2,6-dimethyl-
benzoic acid (2d) gave only a trace amount of the
expected product (see Table 1).
In summary, an efficient route to the solid-phase syn-
thesis of substituted N-acyl,N%-alkyl(aryl)guanidines
using carboxylic acids is presented. This procedure
is mild and general and takes advantage of the
large pool of commercially available carboxylic acids6
to introduce the N-acyl diversity element. It allows
for a high level of flexibility and is amenable for
parallel array or combinatorial synthesis. The resulting
resin bound N-acyl,S-methylisothiourea intermediates
react with ammonia, amines, or anilines to provide
N-acyl,N%-alkyl(aryl)guanidines in high purity and
yield.
The displacement of the thiomethyl group with a vari-
ety of amines appears to be general as shown in Table
2. Ammonia, primary or secondary amines, and aniline
all reacted cleanly at room temperature to give prod-
ucts 5.8,9b This is in contrast to previous
observations4d,5b where the resin-immobilized N-
acylisothioureas failed to react with secondary amines
or anilines in the absence of mercury or silver metal salt
assisted activation, even at elevated temperatures.4d The
final compounds were liberated from the resin by expo-
sure to 25% TFA in dichloromethane.8
Acknowledgements
The authors are grateful to Dr. David B. Rawlins for
helpful suggestions in the preparation of this article.

D. S. Dodd, Y. Zhao / Tetrahedron Letters 42 (2001) 1259–1262
1261
Table 2.
Puritya,b
NH
(5 R1=2,6-dichlorobenzyl)
Entry
(3)
R3
Product
R2
Cl
NH2
O
(5g)
(5h)
NH3
(3a)
1
85%
N
H2N
Cl
Cl
NH2
N
O
(3b)
n-PrNH2
>95%
2
N
H
Cl
Cl
NH2
O
(3c)
(3d)
i-PrNH2
allylNH2
(5i)
(5j)
3
4
>95%
>95%
N
N
H
Cl
Cl
NH2
N
O
N
H
Cl
Cl
NH2
N
O
(CH3)2NH
aniline
(3e)
(3f)
(5k)
(5l)
5
6
>95%
90%
N
Cl
Cl
NH2
N
O
N
H
Cl
aHPLC purity is of the crude material after cleavage and determined by evaporative light scattering (ELS); peak
identity based on LC/MS analysis. bCrude yield ranged from 75-85%, as the TFA salt, based on 100% loading
of the p-nitrophenylcarbonate resin.
References
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6. ACD(Available Chemical Directory); MDL Information
Systems, San Leandro, CA, USA.
7. p-Nitrophenylcarbonate resin was prepared from Wang
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8. Typical procedure: A mixture of p-nitrophenylcarbonate
resin6 (2.5 g, 1.1 mmol/g, 2.75 mmol), S-methylisothiouro-

1262
D. S. Dodd, Y. Zhao / Tetrahedron Letters 42 (2001) 1259–1262
nium sulfate (1.9 g, 6.88 mmol) and Cs2CO3 (9 g, 28
treated with the appropriate amine (3) (0.25 mmol) and
shaken at rt for 48 h (for amine hydrochlorides, 1 mmol of
(i-Pr)2EtN was added to the reaction). The resin (4) was
washed thoroughly with DMF (3×2 mL), THF (4×2 mL),
and CH2Cl2 (4×2 mL) and suspended in 25% TFA/CH2Cl2
(1 mL) and shaken for 1.5 h. The filtrate was collected and
concentrated in vacuo. The purity of the isolated product
5 was established by HPLC using a UV(220 nm) and a
ELS detector.
mmol) was suspended in dry DMF (70 mL). The contents
were shaken vigorously for 48 h at rt. The resin was
washed successively with 10% H2O/DMF (3×50 mL),
DMF (3×30 mL), THF (3×30 mL), and CH2Cl2 (3×30
mL). Resin 1 was dried under high vacuum for 10 h. A
mixture of the resin 1 (0.1 mmol), carboxylic acid (2) (0.3
mmol) and PyAOP (160 mg, 0.3 mmol) was slurried in
NMP (2 mL) and treated dropwise with (i-Pr)2EtN (175
mL, 1 mmol) and gently shaken for 60 h, although the
reactions in most instances are complete within 24–48 h.
The resin was washed using the sequence of solvents
described above and dried under high vacuum. A sample
of the acylated resin (0.05 mmol) in dry NMP (1 mL) was
9. (a) N-acyl,S-methylisothiourea intermediates are sensitive
to TFA cleavage conditions and thus require reaction with
an amine for purity determination; (b) Sluggish reactions
can be heated gently (ꢀ50–60°C) to speed up the aminoly-
sis.
.
.