Optimisation of the synthesis of guanidines from amines via nitroguanidines using 3,5-dimethyl-N-nitro-1H-pyrazole-1-carboxamidine

Article abstract of DOI:10.1055/s-2004-829130

The synthesis of the useful reagent for the preparation of guanidines, 3,5-dimethyl-N-nitro-1-pyrazole-1-carboxamidine (DMNPC), has been optimised. A detailed protocol for using this reagent for the preparation in pure form of a range of guanidines via nitroguanidines is described. A comparison has been made regarding efficiency between DMNPC and the guanidinylating reagents N,N′-bis-Boc-1-pyrazole-1-carboxamidine (2) and N,N′-bis-Boc- N′-triflylguanidine (3).

Full text of DOI:10.1055/s-2004-829130

PAPER
1655
Optimisation of the Synthesis of Guanidines from Amines via Nitroguanidines
Using 3,5-Dimethyl-N-nitro-1H-pyrazole-1-carboxamidine
1
O
J
ptimisati
o
on of the
S
y
e
nthesis of
G
l
uanidines fro
A
m
A
mines . Castillo-Meléndez,* Bernard T. Golding*
School of Natural Sciences - Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, UK
E-mail: Joel.Castillo@hut.fi; E-mail: B.T.Golding@ncl.ac.uk
Received 10 March 2004; revised 29 March 2004
DMNPC and its related compounds have been shown to
Abstract: The synthesis of the useful reagent for the preparation of
be useful reagents for preparing small libraries of com-
guanidines,
DMNPC), has been optimised. A detailed protocol for using this
reagent for the preparation in pure form of a range of guanidines via of an amino group on solid support.
3,5-dimethyl-N-nitro-1-pyrazole-1-carboxamidine
pounds, through guanidinylation or nitroguanidinylation
(
11,22
Recently, Golding
10
nitroguanidines is described. A comparison has been made regard- et al reported the synthesis of hirudonine using DMNPC
ing efficiency between DMNPC and the guanidinylating reagents
N,N¢-bis-Boc-1-pyrazole-1-carboxamidine (2) and N,N¢-bis-Boc-
N¢-triflylguanidine (3).
(
1). These authors reported a 32% yield for the synthesis
of N-amino-N¢-nitroguanidine (5), an intermediate in the
synthesis of DMNPC (1), which was obtained in a 70%
yield (Scheme 1). For the reaction of DMNPC with
amines a yield range of 80–85% was reported for the ni-
troguanidine products.
Key words: guanidinylation, 3,5-dimethyl-N-nitro-1-pyrazole-1-
carboxamidine, hydrogenolysis, ion exchange chromatography
NNO2
NNO2
Introduction and Background
i
ii
H2N
H2N
NH
NH2
The presence of the guanidine function in natural com-
pounds from many different organisms has promoted
studies regarding the biological function of the guanidine
H2N
4
5
H N
2
NNO2
2
moiety. For this purpose, several methods have been de-
N
veloped to generate the guanidine function, usually by
treating a precursor amine with a suitable reagent selected
Me
N
3
4
1
from carbodiimides, chloroformamidines, pyrazole-1-
Me
5
–11
12
carboxamidines,
cyanamides, aminomethanesulfon-
Scheme 1 Preparation of DMNPC from N-(nitroamino)-guanidine
5). Reagents: i) NH NH –H O. ii) pentane-2,4-dione–HOAc–H O.
ic acids, thioureas,6,7,14–16 triurethanes and triflyl-diure-
1
3
(
2
2
2
2
1
7–21
thanes.
However, some of these reagents are
corrosive, toxic or moisture-sensitive, and the reactions
3
,5–7,14–16
Our aim was to optimise the use of DMNPC for obtaining
guanidines from amines under mild conditions without re-
strictions on the starting material and with difficulties of
purification resolved.1 DMNPC has proven to be an ex-
cellent reagent giving high yields and a very practical syn-
thetic route. An alternative purification method for
guanidinium compounds has been developed. In this re-
search the efficiency and ease of use of DMNPC was
compared with the reagents N,N¢-bis-Boc-1-pyrazole-1-
used may involve high temperatures.
Among the
newer guanidinylating reagents (Figure 1), there are still
limitations relating to the starting material, the preparation
of the guanidinylating reagent and lack of compatibility
with solid-phase synthesis. Most methods encounter diffi-
culties at the purification stage, usually compounded by
the relative high basicity of guanidines.
0,23
NTf
N
NBoc
8
carboxamidine (2) and N,N¢-bis-Boc-N¢-triflylguanidine
N
(3).17 A useful feature of DMNPC is that it does not re-
BocHN
NHBoc
NHBoc
quire inert atmosphere conditions.
2
3
Figure 1 Examples of guanidinylating reagents from the recent li-
terature.
Results and Discussion
3
,5-Dimethyl-N-nitro-1-pyrazole-1-carboxamidine (DM- Preparation of Guanidinylating Reagents
NPC, 1) was originally used for the synthesis of acetyl-
We have found that the yield of N-amino-N¢-nitroguani-
dine (5) from the reaction of hydrazine with N-nitroguani-
dine (4) depends critically on the reaction temperature and
time (Figure 2). The heating speed also played an impor-
tant role in the course of the reaction. This variable was
controlled by using a carousel for parallel synthesis,
spermidines and the marine natural product acarnidine.17
SYNTHESIS 2004, No. 10, pp 1655–1663
x
x.
x
x
.
2
0
0
4
Advanced online publication: 23.06.2004
DOI: 10.1055/s-2004-829130; Art ID: P02704SS
Georg Thieme Verlag Stuttgart · New York
©

1
656
J. A. Castillo-Meléndez, B. T. Golding
PAPER
°
C for 22 minutes, giving a 58% yield. Due to the differ-
ences in the equipment, the heating of the reaction was
slower than in the carousel case. The condensation of 5
with pentane-2,4-dione occurred smoothly to afford
DMNPC. In this step it was possible to improve the yield
by 10–15% to 80% by operating at a higher dilution than
in the reported method. In this way we avoided the forma-
tion of the by-product generated by the condensation of
one molecule of pentane-2,4-dione with two molecules of
10
N-amino-N¢-nitroguanidine.
N,N¢-Bis-Boc-1-pyrazole-1-carboxamidine (2)8,24 and
17
N,N¢-bis-Boc-N¢-triflylguanidine (3) were prepared fol-
lowing the reported two-step procedures, which gave 40–
Figure 2 Optimisation of the synthesis of N-amino-N¢-nitroguanidi- 48% and 30–45% overall yields, respectively. In our
ne (5).
hands there is a clear superiority of DMNPC (1) with re-
spect to its preparation (65–70% overall) over the other
reagents.
where the heating speed could be considered constant.
The reactions were quenched by cooling when the entire
solid had been consumed. The optimum conditions were
found to be 55 °C and 15 minutes, which gave a yield of
Reactions of Guanidinylating Reagents with Amines
Several nitroguanidine derivatives were prepared to test
the versatility of DMNPC (1) as a guanidinylating re-
agent. On reaction with DMNPC in MeOH at room tem-
perature for 12 hours, a variety of amines (aliphatic,
5
of up to 60%. Figure 2 shows why the conditions report-
1
0
ed previously (60–65°C, 15 min) gave lower yields of 5
32%).
(
Further optimisation was performed on a 10 gram scale in benzylic and aromatic) gave excellent yields (70–100%)
a round-bottomed flask, the reaction being run at 55–58 of N-alkyl-N¢-nitroguanidines 9–20 (Figure 3), which sep-
_______________________________________________________________
Products
_
______________________________________________________________
NNO2
H
N
HN
9
MeO
N
NH2
16
NNO2
N
HN
NNO2
NH2
10
NH2
O2NN
HN
NH2
1
7
8
H
N
MeO
NH
NNO2
1
1
O2NN
NH2
N
NH2
N
1
N
NH
NNO2
NH2
O
N
1
2
3
O
O
HN
HN
H
N
NNO2
NH2
HN
N
19
20
NNO2
NNO2
HN
1
H2N
H
O NN
2
N
H
N
NH2
14
NH
N
H2N
H
HO
N
15
NNO2
H2N
Figure 3 Examples of nitroguanidines prepared by nitroguanidinylation of amines by the DMNPC method (yields 70–100%).
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

PAPER
Optimisation of the Synthesis of Guanidines from Amines
1657
arated directly from the reaction mixture. The reaction
also proceeded well with morpholine.
H
N
NNO2
In an attempt to improve on the reactivity of DMNPC (1),
we tried to synthesise a more reactive reagent based on the
DMNPC (1) structure, by replacing one of the methyl
groups on the pyrazole ring with a trifluoromethyl group.
However, reaction of N-amino-N¢-nitroguanidine with
i
N
Me
N
H2N
NNO2
Me
N
2
3
Me
N
1
,1,1-trifluoropentane-2,4-dione or 1,1,1,5,5,5-hexafluo-
ii
H
Me
N
NNO2
ropentane-2,4-dione failed to give the necessary trifluo-
romethyl-substituted pyrazoles (Scheme 2).
1
N
Me
N
The structure of 21 and 22 was determined by elemental
1
analysis, H NMR and LC–MS. However, the 22a/22b
Me
2
4
structural isomer could not be unambiguously deter-
mined, although 22b might be favoured because it can be
rationalised as arising from the initial reaction of the ter-
minal nitrogen of the hydrazino function with the more re-
active carbonyl function.
Scheme 3 Alkylation of DMNPC on its amino group. Reagents: i)
bromomethylbenzene–NaH–THF, ii) (2-bromoethyl)benzene–NaH–
THF.
of molecules. Following cleavage of the nitro group from
the intermediate N-alkyl-N¢-nitroguanidines, an initial at-
tempt was made to crystallise the guanidine product as a
hydrochloride salt. When this failed (water-soluble com-
pounds), guanidine purification was achieved using the
Amberlite CGII resin (weak acid) and elution with a hy-
drochloric acid gradient (0.01–1 M). In this way it was
possible to isolate the guanidine compounds as HCl salts,
Heating compounds 21 and 22a/22b at reflux in toluene
with 4-toluenesulfonic acid (p-TsOH) as a catalyst failed
to bring about dehydration.
_____________________________________
Products
_
____________________________________
N
N
NH
2HCl
HN
25
NH
2
Scheme 2 Condensation of nitroguanidine with trifluoromethyl b-
diketones.
H
N
NH
26
2
HCl NH
2
N
N-Alkylation of DMNPC was studied as an alternative
means of elaborating novel nitroamidinyl-pyrazoles. Re-
action of DMNPC with NaH in THF followed by addition
of bromomethylbenzene gave compound 23 in 80% yield.
However, the less reactive alkylating agent 2-bromoethyl-
benzene gave only 20% yield of 24 (Scheme 3). Further
reaction of both 23 and 24 with propylamine in MeOH or
BuOH at reflux failed to give an N,N¢-disubstituted ni-
troguanidine.
NH
O
N
27
NH
2
HCl
H
N
H
N
NH
NH
2
8
9
N
HCl
2
H N
HN
NH
HCl
2
2
MeO
Hydrogenolysis of N-Alkyl-N¢-nitroguanidines to
N-Alkylguanidines
O
HN
HN
For hydrogenolysis of the N-N bond of N-alkyl-N¢-ni-
troguanidines, catalytic transfer hydrogenation with
HOAc and palladium on charcoal in MeOH was used
30
NH
HCl
HN
NH
2
1
0,25
(Figure 4).
HCl HN
NH
NH
2
31
Purification of N-Alkylguanidines
Concerning the purification of guanidines, we aimed to
design a new protocol that can be used with a wide range
Figure 4 Targets synthesised by hydrogenolysis and purified with
CGII Amberlite (yields 80–100%).
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

1
658
J. A. Castillo-Meléndez, B. T. Golding
PAPER
Figure 5 Flow diagram of the guanidinylating methodology.
which were further purified by recrystallisation from agents with 4-methoxybenzylamine and 3-imidazol-1-yl-
i-PrOH or i-PrOH–EtOAc (Figure 5).
propyl amine. In each case the expected product was ob-
tained in high yield and good purity (Figure 6).
8
It has been reported that the main limitation of N,N¢-bis-
Boc-1-pyrazole-1-carboxamidine (2) is in its reaction
with hindered amines, where a decrease in the yield of the
guanidinylation product was found. The original synthesis
Conclusions
1
7
of N,N¢-bis-Boc-N¢-triflylguanidine (3) also reported a
decrease in the yield of reaction with hindered amines.
N,N¢-Bis-Boc-N¢-triflylguanidine (3) has also been found
to be less effective in reactions with hindered amines than
The reaction between N-nitroguanidine and hydrazine has
been optimised to afford N-amino-N¢-nitroguanidine in up
to 60% yield. As conversion of N-amino-N¢-nitroguani-
dine into 3,5-dimethyl-N-nitro-1-pyra zole-1-carboxami-
dine (DMNPC) by reaction with pentane-2,4-dione gave
ca. 80% yield, this makes DMNPC an attractive reagent
for preparing N-alkylguanidines. The latter were obtained
in high yield by reaction of aliphatic, benzylic and aromat-
2
3
N,N¢-bis-Boc-1-pyrazole-1-carboxamidine (2).
N,N¢-
Bis-Boc-1-pyrazole-1-carboxamidine (2), N,N¢-bis-Boc-
N¢-triflylguanidine (3) and DMNPC (1) were compared
with respect to their effectiveness as guanidinylating re-
Figure 6 Comparative table of guanidinylation reagent templates.
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

PAPER
Optimisation of the Synthesis of Guanidines from Amines
1659
8
,28
ic amines with DMNPC in MeOH (70–100% yield, 12 ex- Synthesis of N,N¢-Di-Boc-1-pyrazole-1-carboxamidine (2);
amples). The problem of guanidine purification has been
Typical Procedure
N-Boc-1-pyrazole-1-carboxamidine (6) (0.50 g, 2.4 mmol) was dis-
solved in anhyd THF (10.0 mL) under a nitrogen atmosphere. The
reaction mixture was cooled to 4 °C and NaH (175 mg, 7.3 mmol)
was added slowly. After the addition of NaH the reaction was stirred
for 30 min and di-tert-butyl-dicarbonate (1.50 g, 6.8 mmol, 1.0 mL)
was added in one portion. The reaction was stirred for 4 h and the
solvent was removed under reduced pressure. The crude product
obtained was purified by normal phase chromatography (eluent: 6%
solved by the use of a weak acid ion exchange resin. The
methodology described is applicable to a wide range of
starting amines and is amenable for library generation.
All chemicals were obtained from Aldrich, Lancaster or Sigma and
were used without purification. Melting points were measured using
1
13
a Stuart Scientific machine. H NMR and C NMR were recorded
1
MeOH–CH Cl ) to give a white solid (446 mg, 1.40 mmol, 60%);
2 2
on Bruker machines at 300 MHz or 500 MHz for H and at 75 or 125
8
MHz for 13C. LC–MS and electron impact (EI) mass spectra were
mp 84–86 °C (lit. mp 84–85 °C).
obtained from an LCMS Micromass/Waters or Micromass Au-
tospec M instrument, respectively. Elemental analyses were carried
out in a Carlo Erba 1106 Elemental Analyser. UV spectra were ob-
tained from a Hitachi U-2001 spectrophotometer. Different num-
bers were assigned to compounds with the same structure as 32, 34
and 33, 35 to differentiate between their experimental and their
spectroscopic data. Previously reported compounds were shown
only with physical properties and LC–MS data.
LC–MS: % purity = 100.
+
+
LC–MS (ESI ): m/z (%) = 311 (60) [MH ].
17
N-N¢-Di-(tert-butoxycarbonyl)guanidine (7); Typical Proce-
dure
1
,4-Dioxane (100 mL) was added to a solution of guanidine hydro-
chloride (4.00 g, 42 mmol) and NaOH (6.72 g, 168 mmol) in water
50 mL) and the resulting mixture was cooled to 0 °C. Di-tert-butyl-
(
dicarbonate (18.28 g, 84 mmol) was added in one portion and the
reaction was allowed to warm to r.t. over 2 h. After stirring for 24 h
the mixture was concentrated in vacuo to one third of its original
volume. The resulting suspension was diluted with water (50 mL)
and extracted with EtOAc. The extract was washed with 10% citric
1
0,26,27
N-Amino-N¢-nitroguanidine (5);
To a stirred solution of nitroguanidine (2.00 g, 19.2 mmol) in water
25 mL) at 55 °C, was added hydrazine hydrate (1.10 g, 21.6 mmol,
.05 mL) dropwise. The temperature was maintained at 55 °C for a
Typical Procedure
(
1
further 15 min with constant stirring. When the entire solid had dis-
solved to give a clear solution, the mixture was cooled rapidly in an
ice bath and concd HCl was added to prevent further reaction. After
standing the mixture overnight at 5 °C, the resultant precipitate was
collected by filtration, washed with cold water and air-dried. The
crude solid was recrystallised from water to give the title compound
as a white solid (1.60 g, 13.4 mmol, 70%); mp 186–187 °C (lit. mp
acid, water and brine (200 mL) and dried with MgSO . The solvent
4
was evaporated and the crude product was purified by normal phase
chromatography on silica (eluent: CH Cl –MeOH, 97:3) to give
2
2
two products 7 and 8, each as a white solid.
N-N¢-Di-(tert-butoxycarbonyl)guanidine (7)
17
Yield: 60%; mp 144–145 °C, (lit. mp 144 °C); R 0.8 (MeOH–
87–188 °C).10
f
1
CH Cl , 6:94).
2
2
LC–MS: % purity = 100.
LC–MS: % purity = 100.
+
+
+
LC–MS (ESI ): m/z (%) = 104 (50) [MH – NH ], 58 (100) [MH –
+
+
2
LC–MS (ESI ): m/z (%) = 260 (50) [MH ].
NH – NO ].
2
2
N-N¢-N¢¢-Tri-(tert-butoxycarbonyl)guanidine (8)
Synthesis of 3,5-Dimethyl-N-nitro-1-pyrazole-1-carboxamidine
16
Yield: 35%; mp 147–148 °C (lit. mp 147–150 °C); R 0.9 (MeOH–
1
0,26,27
f
(
1);
Typical Procedure
CH Cl , 6:97).
2
2
Glacial HOAc (5.4 mL) and pentane-2,4-dione (1.61 mL, 12.6
mmol) were added to N-amino-N¢-nitroguanidine (5) (1.00 g, 8.4
mmol) in boiling water (30.0 mL). The solution was allowed to cool
to r.t., and stirred for 7 h. The resultant white precipitate was col-
lected by filtration. The precipitate was washed with CH Cl . A
LC–MS: % purity = 100.
+
+
LC–MS (ESI ): m/z (%) = 360 (100) [MH ].
2
2
Synthesis of N-N¢-Di-Boc-N¢¢-trifluoromethanesulfonylguani-
dine (3); Typical Procedure
white solid was obtained (1.23 g, 6.72 mmol, 80%); mp 126–127 °C
1
0
(
lit. mp 127–128 °C).
A solution of N,N¢-di-Boc-guanidine (0.78 g, 2.0 mmol) and Et N
3
(
0.28 mL) in anhyd CH Cl (10 mL) was cooled to –78 °C under a
LC–MS: % purity = 100.
2 2
nitrogen atmosphere. Triflic anhydride (0.35 mL, 2.1 mmol) was
added dropwise at a rate such that the reaction temperature did not
exceed –65 °C. After the addition was completed, the mixture was
allowed to warm to r.t. within 4 h. The solution was washed with 2
M sodium bisulfate and water, and dried over anhyd Na SO . After
+
+
LC–MS (ESI ): m/z (%) = 184 (39) [MH ], 137 (49), 95 (68), 81
(
32), 67 (61), 42 (100).
N-Boc-1-pyrazole-1-carboxamidine (6);8,28 Typical Procedure
To a solution of 1-pyrazole-1-carboxamidine nitrate (1.00 g, 6.8
mmol) and DIPEA (1.55 g, 2.0 mL) in CH Cl –DMF (5 mL/5 mL)
was added di-tert-butyl-dicarbonate (2.98 g, 13.6 mmol, 2.12 mL)
in one portion. The mixture was stirred for 2 h at r.t. The solvent was
removed under reduced pressure. The crude product obtained was
purified by normal phase chromatography on silica (eluent: 6%
MeOH–CH Cl ) to give a white solid (1.15 g, 5.5 mmol, 80%); mp
2
4
filtering and removal of the solvent under reduced pressure the
crude product was purified by normal phase chromatography on sil-
ica (eluent: CH Cl ) to give a pale yellow solid (500 mg, 1.4 mmol,
2
2
2
2
17
7
0%); mp 113–114 °C (lit. mp 115 °C).
LC–MS: % purity = 100.
+
+
+
2
2
LC–MS (ESI ): m/z (%) = 414 (100) [M + Na ], 392 (12) [MH ].
8
9
6–97 °C (lit. mp 98–99 °C).
–
–
LC–MS (ESI ): m/z (%) = 390 (M – H) .
LC–MS: % purity = 100.
Preparation of Nitroguanidines by DMNPC Method;10,27 Gen-
eral Procedure
+
+
LC–MS (ESI ): m/z (%) = 211 (100) [MH ].
To an amino compound (5.5 mmol) in MeOH (18 mL) was added
3
,5-dimethyl-N-nitro-1-pyrazole-1-carboxamidine (1) (1.0 g, 5.5
mmol). The mixture was stirred at r.t. for 7–12 h. The mixture was
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

1
660
J. A. Castillo-Meléndez, B. T. Golding
PAPER
filtered and the solid washed with CH Cl . Compound 15 showed
N-Nitro-N¢-[2-(3H-imidazol-4-yl)ethyl]guanidine (14)
2
2
high solubility in MeOH. In this case the MeOH solution was fil-
tered and recovered, evaporated and the product was purified by
normal phase chromatography on silica gel (eluent: 6% MeOH–
CH Cl ).
Yield: 82%; white solid; mp 187–188 °C.
1
H NMR (DMSO-d ): d = 8.6 (br s, 1 H, NH), 7.8 (br s, 2 H, NH ),
6
2
7
.9 (s, 1 H, H-2¢), 6.9 (s, 1 H, H-5¢), 3.4 (m, 2 H, NH-CH ), 2.7 (t,
2
2
2
J = 7.0 Hz, 2 H, Im-CH2).
1
3
C NMR (DMSO-d ): d = 159.9 (C=N), 135.5 (C-2¢), 118.1 (C-4¢
N-Nitro-N¢-(4-methoxy-benzyl)guanidine (9)
6
or C-5¢), 118.3 (C-4¢ or C-5¢), 50.2 (CH -Im), 30.6 (CH -NH).
Yield: 90–100%; white solid; mp 270–272 °C (lit. mp 272–273
2
2
°
C).29
LC–MS: % purity = 100.
+
+
+
LC–MS (ESI ): m/z (%) = 199 (50) [MH ], 153 (75) [MH – NO ].
2
N-Nitro-N¢-(3-imidazol-1-yl-propyl)guanidine (10)
Yield: 90–100%; white solid; mp 173–175 °C.
Anal. Calcd for C H N O : C, 36.36; H, 5.09; N, 42.41. Found: C,
6 10 6 2
1
36.57; H, 5.00; N, 42.35.
H NMR (DMSO-d ): d = 8.5 (s, 1 H, NH), 8.2 (s, 2 H, NH ), 7.70
6
2
(
s, 1 H, H-2¢), 7.30 (s, 1 H, H-5¢), 7.0 (s, 1 H, H-4¢), 4.1 (t, J = 7.0
N-Nitro-N¢-(2-hydroxyethyl)guanidine (15)
Yield: 76%; pale yellow solid; mp 113–114 °C (lit. mp 115 °C).
Hz, 2 H, Im-CH ), 3.2 (m, 2 H, CH NH), 2.0 (m, 2 H, CH CH CH ).
1
2
2
2
2
2
31
3
C NMR (DMSO-d ): d = 159.2 (C=N), 137.8 (C-2¢), 128.4 (C-5¢),
6
LC–MS: % purity = 100.
1
20.1 (C-4¢), 44.1 (C-1), 38.0 (C-3), 29.9 (C-2).
+
+
LC–MS (ESI ): m/z (%) = 147 (20) [MH ].
LC–MS: % purity = 100.
+
+
LC–MS (ESI ): m/z (%) = 213 (83) [MH ].
N-Nitro-N¢-[2-(1H-indol-3-yl)ethyl]guanidine (16)
Yield: 100%; white solid; mp 170–172 °C.
HRMS (EI): m/z calcd for C H N O : 212.1021; found: 212.1012.
7
12
6
2
1
H NMR (DMSO-d ): d = 8.7 (br s, 1 H, NH), 7.8 (br s, 2 H, NH ),
Anal. Calcd for C H N O : C, 39.62; H, 5.70; N, 39.60. Found: C,
9.72; H, 5.81; N, 40.02.
6
2
7
12
6
2
7
7
.5 (d, J = 8.1 Hz, 1 H, H-4, In), 7.3 (d, J = 7.9 Hz, 1 H, H-7, In),
3
.1 (s, 1 H, H-2, In), 7.0 (m, 2 H, H-5, H-6, In), 3.2 (m, 2 H,
CH NH), 2.8 (t, J = 7.0 Hz, 2 H, In-CH ).
N-Nitro-N¢-[2-(pyridin-3-yl)ethyl]guanidine (11)
2
2
Yield: 100%; white solid; mp 198–199 °C.
13
C NMR (DMSO-d ): d = 160.0 (C=N), 137.0 (C-8, In), 128.0
6
1
(C-9, In), 124.0 (C-2, In), 121.7 (C-5), 118.9 (C-6 or C-7 or both),
H NMR (DMSO-d ): d = 8.6 (br s, 1 H, NH), 8.5 (s, 1 H, H-2, py),
6
1
12.0 (C-4), 111.8 (C-3), 42.1 (CH -NH); CH -In was not observed.
8
.4 (d, J = 5.0 Hz, 1 H, H-6, py), 8.0 (br s, 2 H, NH ), 7.7 (d, J = 8.0
2 2
2
Hz, 1 H, H-4, py), 7.4 (dd, J = 5.0, 8.0 Hz, 1 H, H-5, py), 3.4 (m,
J = 7.9 Hz, 2 H, CH ), 2.8 (t, J = 8.0 Hz, 2 H, py-CH ).
LC–MS: % purity = 100.
2
2
+
+
+
LC–MS (ESI ): m/z (%) = 248 (100) [MH ], 202 (5) [MH – NO ].
2
1
3
C NMR (DMSO-d ): d = 160.0 (C=N), 150.6 (C-2, py), 148.3
6
–
–
LC–MS (ESI ): m/z (%) = 246 (100) [M – H] .
Anal. Calcd for C11 : C, 53.43; H, 5.30; N, 28.32. Found: C,
3.58; H, 5.51; N, 28.56.
(
(
C-6, py), 136.9 (C-4, py), 136.0 (C-3, py), 124.0 (C-5, py), 44.0
py-CH ), 40.0 (NH-CH ).
H N O
13 5 2
2
2
5
LC–MS: % purity = 100.
+
+
+
LC–MS (ESI ): m/z (%) = 210 (100) [MH ], 165 (20) [MH – NO ].
2
N-Nitro-N¢-(4-methoxy-phenyl)guanidine (17)
Yield: 100%; pale pink solid; mp 164–165 °C.
Anal. Calcd for C H N O : C, 45.93; H, 5.30; N, 33.48. Found: C,
8
11
5
2
4
5.80; H, 4.97; N, 33.38.
LC–MS: % purity = 100.
+
+
+
LC–MS (ESI ): m/z (%) = 211 (5) [MH ], (100) [MH – NO ].
2
N-Nitromorpholine-4-carboxamidine (12)
Yield: 100%; white solid; mp 186–189 °C (lit. mp 186–188 °C).
3
0
–
–
LC–MS (ESI ): m/z (%) = 209 (20) [M – H] .
1
H NMR (DMSO-d ): d = 8.7 (br s, 2 H, NH ), 3.7 (m, 4 H, 2 ×
6
2
N-Nitro-N¢-(4-imidazol-1-yl-phenyl)guanidine (18)
Yield: 70%; white solid; mp 210 °C (dec).
CH -O), 3.6 (m, 4 H, 2 × CH -N).
1
2
2
3
C NMR (DMSO-d ): d = 158.5 (C=N), 65.5 (C-2, C-6), 44.6
6
1
H NMR (DMSO-d ): d = 8.3 (br s, 2–3 H, NH, NH ), 8.2 (s, 1 H,
6
2
(
C-3, C-5).
H-2¢), 7.7 (s, 1 H, H-5¢), 7.6 (d, J = 9.1 Hz, 2 H, H-2, H-6, Ar), 7.4
(
LC–MS: % purity = 100.
d, J = 9.1 Hz, 2 H, H-3, H-5, Ar), 7.1 (s, 1 H, H-4¢).
+
+
LC–MS (ESI ): m/z (%) = 175 (100) [MH ].
13
C NMR (DMSO-d ): d = 158.6 (C=N), 136.2 (C-2¢), 135.8 (C-4),
6
1
1
34.6 (C-1, Ar), 130.1 (C-4¢), 125.5 (C-3, C-5), 121.7 (C-2, C-6),
18.7 (C-5¢).
Anal. Calcd for C H N O : C, 34.48; H, 5.79; N, 32.17. Found: C,
4.48; H, 5.47; N, 32.06.
5
10
4
3
3
LC–MS: % purity = 100.
N-Nitro-N¢-[2-(2-oxo-imidazolidin-3-yl)ethyl]guanidine (13)
+
+
+
LC–MS (ESI ): m/z (%) = 247 (100) [MH ], 201 (5) [MH – NO ].
2
Yield: 80%; white solid; mp 177–179 °C.
–
–
1
LC–MS (ESI ): m/z (%) = 245 (80) [M – H] .
Anal. Calcd for C10 : C, 48.78; H, 4.09; N, 34.13. Found: C,
48.83; H, 4.13; N, 34.18.
H NMR (DMSO-d ): d = 8.5 (br s, 1 H, NH), 7.9 (br s, 2 H, NH ),
6
2
3
1
.0–3.2 (m, 8 H, 4 × CH2).
H N O
10 6 2
3
C NMR (DMSO-d ): d = 166 (C=O or C=N), 160 (C=O or C=N),
6
4
9.0 (CH ), 45.9 (CH ), 38.1 (CH ); the resonance of one alkyl
2
2
2
N-Nitro-N¢-[3-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)propyl]-
guanidine (19)
Yield: 100%; white solid; mp 212–214 °C.
group was not observed.
LC–MS: % purity = 100.
+
+
LC–MS (ESI ): m/z (%) = 217 (100) [MH ].
1
H NMR (DMSO-d ): d = 8.5 (br s, 1 H NH), 7.9 (br s, 2 H NH ),
6
2
–
–
7.2 (s, 1 H, pyz), 3.1 (m, 2 H, HN-CH ), 2.2 (t, J = 7.1 Hz, 2 H, pyz-
LC–MS (ESI ): m/z (%) = 215 (100) [M – H] .
2
CH ), 1.6 (m, 2 H, CH ).
2
2
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

PAPER
Optimisation of the Synthesis of Guanidines from Amines
1661
1
3
–
–
C NMR (DMSO-d ): d = 165 (C=O), 160.0 (C=N), 140.0 (C-5,
LC–MS (ESI ): m/z (%) = 128 (90) [M – H] .
6
pyz), 127.0 (C-4, pyz), 103.0 (C-5, pyz), 42.0 (HN-CH ), 26.8
2
(
CH -pyz), 25.7 (HN-CH -CH ).
N-[2-(3H-Imidazol-4-yl)-ethyl]guanidine Dihydrochloride (28)
Yield: 82%; white solid; mp 217–219 °C (lit. mp 222–221 °C).
2 2 2
3
4
LC–MS: % purity = 100.
+
+
LC–MS: % purity = 97%.
LC–MS (ESI ): m/z (%) = 229 (95) [MH ].
+
+
–
–
LC–MS (ESI ): m/z (%) = 154 (100) [MH ].
LC–MS (ESI ): m/z (%) = 227 (70) [M – H] .
Anal. Calcd for C H N O : C, 36.84; H, 5.30; N, 36.83. Found: C,
7
12
6
3
N-(4-Methoxy-phenyl)guanidine Hydrochloride (29)
Yield: 100%; white solid; mp 175 °C (lit. mp 179–180 °C).
3
6.88; H, 5.66; N, 36.74.
35
LC–MS: % purity = 100.
N-Cyclopentyl-N¢-nitroguanidine (20)
Yield: 90%; pale yellow solid; mp 92–93 °C.
+
+
LC–MS (ESI ): m/z (%) = 166 (75) [MH ].
1
H NMR (DMSO-d ): d = 8.4 (br s, 1 H, NH), 8.0 (br s, 1 H, NH ),
6
2
N-[3-(3-Oxo-2,3-dihydro-1H-pyrazol-4-yl)propyl]guanidine
Hydrochloride (30)
Yield: 100%; white solid; mp > 300 °C (dec).
2
1
.6 (m, 1 H, CH), 1.7 (m, 4 H, 2 × CH ), 1.5 (m, 4 H, 2 × CH ).
2
2
3
C NMR (DMSO-d ): d = 159.1 (C=N), 52.4 (C-1), 32.5 (C-2,
6
C-5), 23.6 (C-3, C-4).
1
H NMR (DMSO-d ): d = 8.5 (s, 1 H, NH), 7.2 (s, 1 H, pyz), 3.1 (m,
6
LC–MS: % purity = 80.
2
H, HN-CH ), 2.2 (t, 2 H, pyz-CH ), 1.6 (m, 2 H, CH CH CH ).
2 2 2 2 2
+
+
+
LC–MS (ESI ): m/z (%) = 173 (80) [MH ], 127 (50) [MH – NO ].
13
2
C NMR (DMSO-d ): d = 156.0 (C=N), 141.0 (C-3, pyz), 127.0
6
–
–
(C-5, pyz), 103.4 (C-4, pyz), 42.6 (HN-CH ), 29.7 (CH -pyz), 19.9
LC–MS (ESI ): m/z (%) = 171 (60) [M – H] .
2 2
(HN-CH -CH ).
2 2
Anal. Calcd for C H N O : C, 41.85; H, 7.02; N, 32.54. Found: C,
1.81; H, 7.15; N, 32.36.
6
12
4
2
LC–MS: % purity = 100.
4
+
+
LC–MS (ESI ): m/z (%) = 184 (30) [MH ].
Preparation of Guanidines;10,32 General Procedure
Anal. Calcd for C H N O·HCl: C, 38.27; H, 6.42; N, 31.88. Found:
C, 38.35; H, 6.33; N, 31.90.
7
13
5
The nitroguanidine compound (1 mmol) and 10% Pd/C (50% of the
nitro compound by weight) were added to a flask under nitrogen,
and then a HCOOH–MeOH mixture (0.7 mL/13 mL) was added
slowly. The mixture was stirred at r.t. for 12 h. The catalyst was fil-
tered off using Celite and the filter pad was eluted with hot MeOH
N-Cyclopentyl-N¢-guanidine Hydrochloride (31)
Yield: 100%; white solid; mp 156 °C (lit. mp 142–144 °C).
3
6
(
250 mL). The solvent was evaporated in vacuo to give the guani-
LC–MS: % purity = 100.
dine. TFA or 2 N HCl was added to convert the guanidine into the
guanidinium salt and the solvent was removed in vacuo. The LC–
MS analyses were performed on the guanidines in basic form by us-
+
+
LC–MS (ESI ): m/z (%) = 128 (100) [MH ].
Purification of Guanidinium Compounds Depending on Their
Solubility in Water; General Procedure
ing H O–MeCN–0.1% HCOOH as solvent system.
2
Guanidinium compounds with poor solubility in water were dried
and dissolved in hot i-PrOH. The solution was allowed to cool to r.t.
and EtOAc was added dropwise until the entire solid had crystal-
lised. The solid was filtered and dried to give the guanidinium com-
pound.
N-(3-Imidazol-1-yl-propyl)guanidine Dihydrochloride (25)
Yield: 90–100%; white solid; mp 139–143 °C.
1
H NMR (D O): d = 8.7 (s, 1 H, H-2¢), 7.5 (s, 1 H, H-5¢), 7.4 (s, 1 H,
2
H-4¢), 4.30 (t, 2 H, CH -Im), 3.20 (t, 2 H, CH -NH), 2.04 (m, 2 H,
CH CH CH ).
2
2
2
2
2
Guanidinium compounds soluble were dissolved in water. An ion
exchange column was filled with Amberlite CGII (15 g resin/1 g
compond) and washed with water. A solution containing the guani-
dinium compound was delivered to the column. After elution of all
impurities with water, the guanidinium compound was eluted with
acid solution (HCl) in a range of 0.01–1 M. The purification was
followed by UV spectrophotometry.
1
3
C NMR (D O): d = 155.1 (C=N), 137.4 (C-5¢), 124.7 (C-4¢), 121.9
2
(
C-2¢), 50.1 (CH -Im), 40.3 (CH -NH), 30.0 (CH CH CH ).
2 2 2 2 2
+
+
EI–MS: m/z (%) = 168 (20) [MH ], 151 (55) [MH – NH ].
3
Anal. Calcd for C H N ·2HCl: C, 35.01; H, 6.30; N, 29.16. Found:
7
13
5
C, 35.15; H, 6.28; N, 29.60.
N-(2-Pyridin-3-yl-ethyl)guanidine Dihydrochloride (26)
Yield: 100%; cream-colored solid; mp 88–92 °C.
Preparation of the Compounds 32 and 33 using N,N¢-Di-Boc-1-
23
pyrazole-1-carboxamidine (2); General Procedure
1
To an amino compound (5.5 mmol) in THF (18 mL) was added
N,N¢-di-Boc-1-pyrazole-1-carboxamidine (9) (1.7 g, 5.5 mmol).
The mixture was stirred at r.t. for 24 h. Compound 32 was isolated
by the work up of the reaction mixture by washing with 2 M sodium
bisulfate, 10% NaHCO and brine. After drying with Na SO and
H NMR (D O): d = 8.55 (s, 1 H, H-2, py), 8.40 (d, J = 4.9 Hz, 1 H,
2
H-6, py), 8.25 (d, J = 8.0 Hz, 1 H, H-4, py), 7.90 (t, J = 7.9 Hz, 1 H,
H-5 py), 3.25 (t, J = 7.0 Hz, 2 H, CH ), 2.95 (t, J = 7.0 Hz, 2 H, CH ).
2
2
1
3
C NMR (D O): d = 157.3 (C=N), 145.1 (C-2, py), 143.4 (C-6, py),
2
3
2
4
1
3
40.0 (C-4, py), 138.2 (C-3, py), 127.8 (C-5, py), 41.9 (NH-CH2),
2.4 (py-CH2).
filtering, the solvent was removed under reduced pressure. Com-
pound 33 was isolated without work up due to its solubility in water.
The solvent was evaporated and the product characterised without
purification.
LC–MS: % purity = 90.
+
+
LC–MS (ESI ): m/z (%) = 165 (100) [MH ].
Anal. Calcd for C H N H O·2HCl: C, 37.66; H, 6.32; N, 21.96.
Found: C, 37.55; H, 6.53; N, 21.75.
8
12
4
2
N,N¢-Di-Boc-N¢¢-(4-methoxybenzyl)guanidine (32)
Yield: 95%; white solid; mp 113 °C (lit. mp 110.5–111.5 °C).
28
LC–MS: % purity = 93.
Morpholine-4-carboxamidine Hydrochloride (27)
Yield: 100%; white solid; mp 138–139 °C (lit. mp 138 °C).
3
3
+
+
+
LC–MS (ESI ): m/z (%) = 380 (20) [MH ], 402 (10) [M + Na ].
LC–MS: % purity = 100.
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

1
662
J. A. Castillo-Meléndez, B. T. Golding
PAPER
N,N¢-Di-Boc-N¢¢-[3-(imidazol-1-yl)-propyl]guanidine (33)
Yield: 70%; white solid; mp 113–114 °C.
3-Methyl-5-trifluoromethyl-N-nitro-1-pyrazole-1-carboxami-
dine (22)37
1
Yield: 85%; white solid; mp 120–121 °C.
H NMR (DMSO-d ): d = 8.3 (br s, 1 H, NH), 7.6 (s, 1 H, H-2¢), 7.2
6
1
(
3
s, 1 H, H-5¢), 7.1 (s, 1 H, H-4¢), 4.0 (t, J = 7.0 Hz, 2 H, Im-CH2),
H NMR (DMSO-d ): d = 9.0 (br s, 2 H, NH ), 8.2 (br s, 1 H, OH),
6
2
.2 (m, 2 H, CH -NH), 1.7 (m, 2 H, CH CH CH ), 1.4 (s, 9 H, 3 ×
3.9 (d, J = 19.4 Hz, 1 H, CHH), 3.4 (d, J = 19.4 Hz, 1 H, CHH), 2.3
2
2
2
2
CH ), 1.3 (s, 9 H, 3 × CH ).
1
(s, 3 H, CH3).
3
3
3
C NMR (DMSO-d ): d = 163.3 (C=O), 155.7 (C=N or C=O),
LC–MS: % purity = 70.
6
1
(
(
52.2 (C=N or C=O), 137.6 (C-2¢), 128.6 (C-5¢), 119.6 (C-4¢), 83.1
t-Bu-C), 78.4 (t-Bu-C), 43.9 (CH -Im), 34.6 (CH -NH), 30.5
+
+
LC–MS (ESI ): m/z (%) = 256 (70) [MH ].
2
2
–
–
LC–MS (ESI ): m/z (%) = 254 (100) [M – H] .
CH CH CH ), 28.3 (3 × CH , Boc), 27.9 (3 × CH , Boc).
2
2
2
3
3
Anal. Calcd for C H F N O : C, 28.24; H, 3.16; N, 27.45. Found:
C, 28.36; H, 3.10; N, 27.75.
LC–MS: % purity = 91.
6
8
3
5
3
+
+
LC–MS (ESI ): m/z (%) = 368 (80) [MH ].
N-Nitro-N¢-benzyl-3,5-dimethyl-pyrazole-1-carboxamidine
Preparation of the Compounds 34 and 35 using N,N¢-Di-Boc-
(
23) and N-Nitro-N¢-phenethyl-3,5-dimethyl-pyrazole-1-car-
1
7
N¢¢-trifluoromethanesulfonylguanidine (3); General Proce-
boxamidine (24); General Procedure
dure
A mixture of NaH (5.83 mmol) and THF (20 mL) was stirred at r.t.
After 5 min DMNPC (1) (0.49 g, 2.7 mmol) was added, the stirring
continue for 10 min and the phenyl alkyl bromide (4.1 mmol) was
added. The reaction was heated at reflux for 7 h. The reaction was
quenched by addition of glacial HOAc dropwise to the cooled (10–
A solution of an amino compound (5.5 mmol) and Et N (1.0 mL) in
3
CH Cl (2 mL) was added to a solution of N,N¢-di-Boc-N¢¢-trifluo-
2
2
romethane sulfonylguanidine (3) (1.98 g, 5.5 mmol) in CH Cl (1
2
2
mL). The mixture was stirred at r.t. overnight. Compound 34 was
isolated by the work up of the reaction mixture by washing with 2
1
5 °C) mixture. Saturated NaHCO was added slowly and the mix-
3
M sodium bisulfate, 10% NaHCO and brine. After drying with
3
ture was stirred for 15 min. The resulting solution was extracted
with CH Cl . The organic layer was washed with brine, dried
Na SO and filtering, the solvent was removed under reduced pres-
2
4
2
2
sure. Compound 35 was isolated without work up due to its solubil-
ity in water. The solvent was evaporated and the product
characterised without purification.
(
MgSO ) and concentrated in vacuo. The crude product was puri-
4
fied by normal phase chromatography (elution with 6% MeOH–
CH Cl ) to give compound 23 and 24 in 80% and 20% yields re-
2
2
spectively.
N,N¢-Di-Boc-N¢¢-(4-methoxybenzyl)guanidine (34)
2
8
Yield: 100%; white solid; mp 112 °C (lit. mp 110.5–111.5 °C).
NMR data was similar to that for compound 32.
LC–MS: % purity = 100%.
N-Benzyl-3,5-dimethyl-N¢-nitropyrazole-1-carboxamidine (23)
Yield: 80%; pale yellow oil.
1
H NMR (DMSO-d ): d = 11.9 (br s, 1 H, NH), 7.2 (m, 3 H, Ar), 6.9
6
+
+
+
(m, 2 H, Ar), 5.6 (s, 1 H, pyz-H), 5.0 (s, 2 H, CH ), 2.0 (s, 3 H, CH ),
2
3
LC–MS (ESI ): m/z (%) = 380 (30) [MH ], 402 (5) [M + Na ].
1
.9 (s, 3 H, CH3).
1
3
N,N¢-Di-Boc-N¢¢-[3-(imidazol-1-yl)-propyl]guanidine (35)
C NMR (DMSO-d ): d = 150.0 (C=N), 138.5 (pyz, C-5), 138.2
6
Yield: 80%; white solid; mp 113–114 °C.
(pyz, C-3), 128.8 (C-1, Ar), 128.6 (C-2, C-6, Ar), 126.3 (C-3, C-5,
Ar), 104.3 (pyz, C-4), 45.8 (CH ), 13.3 (pyz, C-5, CH ), 10.4 (pyz,
C-3, CH3).
2
3
NMR data was similar to that for compound 33.
LC–MS: % purity = 98.
LC–MS: % purity = 100.
+
+
LC–MS (ESI ): m/z (%) = 368 (100) [MH ].
+
+
+
LC–MS (ESI ): m/z (%) = 274 (100) [MH ], 228 (80) [MH – NO ].
2
Synthesis of 3,5-Di-trifluoromethyl-N-nitro-1-pyrazole-1-car-
boxamidine (21) and 3-Methyl-5-trifluoromethyl-N-nitro-1-
HRMS (EI): m/z calcd for C H N O : 273.1222; found: 273.1220.
1
3
15
5
2
1
0,27,32,37
pyrazole-1-carboxamidine (22);
General Procedure
3,5-Dimethyl-N-phenethyl-N¢-nitropyrazole-1-carboxamidine
(24)
Yield: 20%; pale yellow oil.
Glacial HOAc (5.39 mL) and either 1,1,1,5,5,5-hexafluoroacetyl
acetone (12.6 mmol) or 1,1,1-trifluoro-2,4-pentanedione were add-
ed to nitroaminoguanidine (5) (1.00 g, 8.41 mmol) in boiling water
1
H NMR (CDCl ): d = 12.5 (br s, 1 H, NH), 7.1 (m, 3 H, Ar), 7.0 (m,
3
(
30 mL). The solution was allowed to cool to r.t., and stirred for 7
2
H, Ar), 5.6 (s, 1 H, pyz-H), 4.0 (t, J = 7.2 Hz, 2 H, NH-CH ), 2.9
2
h. The resultant white precipitate was collected by filtration. The
precipitate was dissolved in CH Cl and filtered. The solvent was
(
t, J = 7.2 Hz, 2 H, Ar-CH ), 2.2 (s, 3 H, CH ), 1.7 (s, 3 H, CH ).
2 3 3
2
2
1
3
C NMR (DMSO-d ): d = 147.0 (C=N), 138.8 (pyz, C-3 or C-5),
removed under reduced pressure to give white solids (3.12 g, 10.1
mmol, 80%) of 21 and (2.73 g, 10.7 mmol, 85%) of 22.
6
1
1
38.2 (pyz, C-3 or C-5), 128.7 (C-1, Ar), 128.6 (C-2, C-6, Ar),
26.3 (C-3, C-5, Ar), 104.3 (pyz, C-4j), 49.8 (NH-CH ), 36.8
2
(
Ar-CH ), 13.3 (pyz, C-5, CH ), 10.4 (pyz, C-3, CH ).
3
(
,5-Di-trifluoromethyl-N-nitro-1-pyrazole-1-carboxamidine
2
3
3
21)37
LC–MS: % purity = 100.
Yield: 80%; white solid; mp 197–198 °C.
+
+
+
LC–MS (ESI ): m/z (%) = 288 (80) [MH ], 241 (100) [MH – NO ].
2
1
H NMR (DMSO-d ): d = 9.6 (br s, 1 H, OH), 8.40 (br, 1 H, NHH),
6
HRMS (EI): m/z calcd for C H N O : 288.1461; found: 288.1468.
1
4
18
5
2
7
.7 (s, 1 H, NHH), 3.9 (d, J = 19.4 Hz, 1 H, CHH), 3.6 (d, J = 19.4
Hz, 1 H, CHH).
LC–MS: % purity = 60.
Acknowledgment
–
–
LC–MS (ESI ): m/z (%) = 308 (80) [M – H] .
We would like to express our sincere thanks to Professor Ari Koski-
nen for his help in verifying the optimisation data and OSI Pharma-
ceuticals (Oxford, UK), FONACIT (National Foundation of
Anal. Calcd for C H F N O ·H O: C, 22.03; H, 2.16; N, 21.41.
6
5
6
5
3
2
Found: C, 21.98; H, 2.00; N, 21.51.
Synthesis 2004, No. 10, 1655–1663 © Thieme Stuttgart · New York

PAPER
Optimisation of the Synthesis of Guanidines from Amines
1663
Science, Technology and Innovation) and Newcastle University for
funding of this project.
(18) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. X.
Tetrahedron Lett. 1992, 33, 5933.
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