Simple generalized reaction conditions for the conversion of primary aliphatic amines to surfactant-like guanidine salts with 1H-pyrazole carboxamidine hydrochloride

Article abstract of DOI:10.1080/00397911.2016.1257724

Improved reaction conditions for the electrophilic reaction between a free aliphatic amine and 1H-pyrazole carboxamidine have been discovered. The surfactant-like guanidine salts, which are often hard to work with, were obtained in decent yields with short reaction times, minimal workup, and high level of purity.

Full text of DOI:10.1080/00397911.2016.1257724

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Simple generalized reaction conditions for
the conversion of primary aliphatic amines to
surfactant-like guanidine salts with 1H-pyrazole
carboxamidine hydrochloride
T. A. Bakka & O. R. Gautun
To cite this article: T. A. Bakka & O. R. Gautun (2017) Simple generalized reaction conditions
for the conversion of primary aliphatic amines to surfactant-like guanidine salts with 1H-
pyrazole carboxamidine hydrochloride, Synthetic Communications, 47:2, 169-172, DOI:
10.1080/00397911.2016.1257724
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1257724
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Date: 04 January 2017, At: 08:30

SYNTHETIC COMMUNICATIONS®
2017, VOL. 47, NO. 2, 169–172
http://dx.doi.org/10.1080/00397911.2016.1257724
Simple generalized reaction conditions for the conversion of
primary aliphatic amines to surfactant-like guanidine salts
with 1H-pyrazole carboxamidine hydrochloride
T. A. Bakka and O. R. Gautun
Department of Chemistry, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
ABSTRACT
ARTICLE HISTORY
Received 25 October 2016
Improved reaction conditions for the electrophilic reaction between a
free aliphatic amine and 1H-pyrazole carboxamidine have been
discovered. The surfactant-like guanidine salts, which are often hard
to work with, were obtained in decent yields with short reaction times,
minimal workup, and high level of purity.
KEYWORDS
Guanidine synthesis;
1H-pyrazole carboxamidine;
surfactant synthesis
GRAPHICAL ABSTRACT
Introduction
1H-Pyrazole carboxamidine hydrochloride (1) is a commonly used electrophilic guanyla-
tion reagent for primary amines.[1] This guanylation agent was originally presented by
Bernatowicz et al. in 1992 as a means for guanyl introduction in peptide synthesis, thus
circumventing the use of the sometimes problematic protected arginines.[2] Bernatowicz
reported that 1 showed better reactivity and solubility characteristics than other guanyla-
tion compounds at the time.[3–8] The reaction of 1 with a primary amine is shown in
Scheme 1. A literature search shows that many have employed this method in the synthesis
of a variety of compounds.[9] The most common conditions involve an amine, an organic
(Hünig’s base, or triethyl amine (TEA)) or inorganic base, and 1 in equimolar amounts in a
solvent (most often dimethylformamide, DMF). Removal of base and solvents with high
boiling points may be troublesome in the workup. Thus, many of the procedures reported
employ chromatography and other techniques in the purification step. As guanidines may
be troublesome to work with due to their heavily polar nature, a minimum of workup is
highly preferred.
CONTACT O. R. Gautun
odd.r.gautun@ntnu.no
Department of Chemistry, Norwegian University of Science and
Technology (NTNU), NO-7491 Trondheim, Norway.
1
Supplemental data (experimental procedures for 2a–b and 2d–g, H NMR spectra of previously synthesized compounds,
and full characterization spectra (1H NMR, 13C NMR, and, 2D-techniques) for new compounds.) can be accessed on the
publisher’s website.
© 2017 Taylor & Francis

170
T. A. BAKKA AND O. R. GAUTUN
Scheme 1. Reaction between 1H-pyrazole carboxamidine (1) hydrochloride and a primary aliphatic
amine, leading to formation of the guanylated product 2 and 1H-pyrazole as a by-product.
The reaction conditions presented here renders complete conversion in a matter of
hours, requires minimal workup, and needs no chromatographic purification.
Results and discussion
In our search for simple versatile conversions of amines in order to expand a compound
library of 1,2,3-triazoles for antimicrobial screening, we have found simple and efficient
conditions for converting amines to guanidines utilizing the already reported reagent 1.
We have found that for many amines addition of base does not necessarily decrease reac-
tion time nor substantially increase the yield, as can be seen from Table 1 (entry 2 and 3).
In addition, by running the reactions in acetonitrile at reflux (entry 2 and 3, Table 1) we
achieved rapid full conversion, compared to when using DMF (entry 1, Table 1).
Subjecting the primary amines in Table 2 to the optimal conditions yielded the pure
guanidine salts 2a–g (2e–g >98% in high-performance liquid chromatography, HPLC),
with minimal workup as depicted in the experimental section. The conditions yielding
optimal results are amine and 1 in a 1:0.9–1:0.99 ratio in acetonitrile (3 mL/100 mg amine)
followed by 1–3 h of reflux, leading to complete conversion of 1. These reaction conditions
were easily scalable to a preparative level (>10 g), which in turn was performed to make
13 g of guanidine 2c (93% yield). There have been reported a couple of similar standalone
reactions performed without base in acetonitrile either at room temperature or reflux.[10–12]
However, these examples required a reaction time above 16 h. Also, there have been
reported some reactions with short reaction times (0.5 h) in a volatile solvent (EtOH),
but this was performed under microwave conditions with a base additive.[13]
Table 1. Simplifying the conditions needed for guanylation of lipophilic amines.
Entry
1
Conditions
1 (eq)
1.0
Time (hrs)
18
Yield (%)
a
DIPEA (1 eq), DMF, rt
-
2
3
DIPEA (1 eq), MeCN, reflux
MeCN, reflux
0.9
0.9
3
3
90b
84
aCrude 2:1 SM: product, no final product obtained due to crystallization issues.
bImpure with DIPEA and unindentified byproduct, additional work-up needed.

SYNTHETIC COMMUNICATIONS®
171
Table 2. Results of exposing amines containing lipophilic groups to the improved reaction condition in
order to synthesize surfactant-like guanidine salts.
2
1 (eq)
0.9
Reflux (hrs)
Yield (%)
2a
2b
2c
2d
2e
3
74
59
0.9
3
0.9
3
93a
70
0.9
3
0.9
1.5
63
2f
0.9
3
70
76
2g
0.98
12
aExperiment performed in multi-gram scale.
It should also be noted that we have used a slight excess of amine in order to ensure
complete conversion of 1, as there sometimes were some uncertainty regarding the purity
of amines synthesized through several previous steps.
The three bottom products given in Table 2 showed a level of purity acceptable for bio-
logical testing, thus making these reaction conditions favorable for compounds intended
for pharmacological testing.
Summary
A simplified protocol for guanylation of primary amines is hereby reported. Seven guani-
dines (2a–g) were prepared, where the synthesis of 2c also was performed on a >10-g scale.
Three of these compounds (2e–g) were subjected to HPLC analysis, giving sufficiently pure
compounds (>95%) for biological testing.
Experimental
General procedure for guanylation of primary aliphatic amines
Amine and 1 (0.9–0.99 eq) was added to MeCN (3 mL/100 mg amine) on a 50- to 100-mg
scale and refluxed for 2–3 h. After complete disappearance of 1 (by TLC w/ 70:30:3 CHCl3/

172
T. A. BAKKA AND O. R. GAUTUN
MeOH/NH4OH) the reaction mixture was cooled down to room temperature. Furthermore,
depending on whether the product precipitated out or not, the following was done:
A) If the product was precipitated by cooling the reaction mixture to room temperature,
the supernatant was removed and the precipitate was washed with MeCN and dried
under reduced pressure.
B) If the product was not precipitated by cooling the reaction mixture to room tempera-
ture, Et2O was added to induce precipitation. The precipitate was then washed with
Et2O and dried under reduced pressure.
Synthesis of 2c
1. General procedure B leads to 2c as a light yellow sticky wax (137 mg, 0.69 mmol, 84%
yield).
2. General procedure B(a) leads to 2c as an off-white solid (13 g, 65 mmol, 93% yield).
1H NMR (400 MHz, d4-MeOH): δ ¼ 7.36–7.22 (m, 5H, Ph-), 3.46 (t, 2H, J ¼ 7.1 Hz,
-NH-CH2-), 2.88 (t, 2H, J ¼ 7.1 Hz, Ph-CH2-) ppm. 13C NMR (100 MHz, d4-MeOH):
=
157.1 (NH-C NH), 137.9 (CH-C-CH), 128.4 (2xCH), 128.3 (2xCH), 126.4 (CH), 42.3
(-CH2-NH-), 34.5 (C-CH2-) ppm. Spectra is highly similar to spectra of the sulfate salt
in D2O reported in a patent by the University of Strathclyde.[14]
Procedure B(a): Preparative scale workup
The reaction mixture was partially evaporated and added to Et2O (200 mL). The ether
phase was decanted and the residual oil was washed with Et2O (3 � 200 mL), before it
was added one last portion of Et2O (200 mL) and left for 48 h. The hard crystalline precipi-
tate was then crushed and stirred with Et2O (3 � 100 mL) for 10 min each time. Decanting
and drying afforded 2c as an off-white solid.
References
[1] Katritzky, A. R.; Rogovoy, B. V. Arkivoc 2005, 4, 49–87.
[2] Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992, 57, 2497–2502.
[3] Davis, T. L. Org. Synth. 1927, 7, 46–49.
[4] Cosand, W. L.; Merrifield, R. B. Proc. Natl. Acad. Sci. U. S. A. 1977, 74, 2771–2775.
[5] Kämpf, A. Ber. Dtsch. Chem. Ges. 1904, 37, 1681–1684.
[6] Arndt, F.; Rosenau, B. Ber. Dtsch. Chem. Ges. 1917, 50, 1248–1261.
[7] Braun, C. E. J. Am. Chem. Soc. 1933, 55, 1280–1284.
[8] Bannard, R. A. B.; Casselman, A. A.; Cockburn, W. F.; Brown, G. M. Can. J. Chem. 1958, 36,
1541–1549.
[9] Reaxys database reaction search, August 2016.
[10] Bennett, C. N. H.; Kurt, D.; Harrison, S. D.; Longo, K. A.; MacDougald, O. A.; Wagman, A. S.
GSK-3 inhibitors, US Patent No. US20050054663, 2005.
[11] Amgen Inc, Aminopyrimidine compounds and methods of use, Patent No/ WO20060661172
A1, 2006.
[12] Nuss, J. M. H.; Stephen, D.; Ring, D. B.; Boyce, R. S.; Johnson, K.; Pfister, K. B.; Ramurthy, S.;
Seely, L.; Wagman, A. S.; Desai, M.; Levine, B. H. Inhibitors of glycogen synthase kinase 3, US
Patent Np. US20020156087 A1, 2002.
[13] Nielsen, M. C.; Larsen, A. F.; Abdikadir, F. H.; Ulven, T. Eur. J. Med. Chem. 2014, 72, 119–126.
[14] Waigh, R. D.; Harvey, A. L.; Mooney, M. H.; Coxon, G. Weight reducing compounds, Patent
No. WO2009087395, 2009.