Cyanide-Free Synthesis of Air Stable N-Substituted Li and K Cyanamide Salts from Tetrazoles. Applications toward the Synthesis of Primary and Secondary Cyanamides as Precursors to Amidines

Article abstract of DOI:10.1021/acs.orglett.0c03085

A practical two-step synthesis of N,N′-disubstituted cyanamides consists in the low-temperature metalation of N-substituted 5H-tetrazoles that undergo spontaneous cycloreversion at 0 °C releasing dinitrogen, and forming N-metalated cyanamides that can be reacted in situ with a variety of electrophiles. Remarkably, the N-substituted Li and K cyanamides are air stable white solids at room temperature. Addition of lithium organometallics to the N,N′-disubstituted cyanamides provides a new method for accessing N,N′-disubstituted amidines.

Full text of DOI:10.1021/acs.orglett.0c03085

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Letter
Cyanide-Free Synthesis of Air Stable N‑Substituted Li and K
Cyanamide Salts from Tetrazoles. Applications toward the Synthesis
of Primary and Secondary Cyanamides as Precursors to Amidines
Edouard Duchamp and Stephen Hanessian*
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ABSTRACT: A practical two-step synthesis of N,N′-disubstituted cyanamides consists in the low-temperature metalation of N-
substituted 5H-tetrazoles that undergo spontaneous cycloreversion at 0 °C releasing dinitrogen, and forming N-metalated
cyanamides that can be reacted in situ with a variety of electrophiles. Remarkably, the N-substituted Li and K cyanamides are air
stable white solids at room temperature. Addition of lithium organometallics to the N,N′-disubstituted cyanamides provides a new
method for accessing N,N′-disubstituted amidines.
Scheme 1. Synthetic Routes to Cyanamides
yanamides are versatile “value-added” organic nitrogen-
Ccontaining compounds that have been known since they
were first discovered in late 19th century by Cannizzaro.1,2 The
cyanamide molecule NH2CN has been known as an inhibitor
of the enzyme alcohol dehydrogenase, hence its use as a
deterrent to alcohol consumption in some countries.3 The high
polarizability of the cyano group in cyanamides makes them
soft electrophiles, a property that has been exploited in drug
design as covalent inhibitors of cysteine-containing enzymes
such as, among others, cathepsin C4 and Janus kinase 3
(JAK3).5,6 Because of their high N:C ratio, N-substituted
cyanamides have been the mainstay of the agricultural industry
for decades.2 The cyanamide molecule, NH2CN, is endowed
with an ambident electronic character and capable of forming
N salts.2 Calcium cyanamide,7 discovered by Frank and Caro
in 1898, was used as a high-volume fertilizer and for crop
protection for decades.8 The nucleophilic character of calcium
cyanamide was first demonstrated by Vliet in 1924 in its
reaction with alkyl halides under strongly basic conditions in
refluxing aqueous ethanol.9 Ironically, the author was searching
for a practical method for synthesizing secondary amines such
as diallylamine and dibutylamine by hydrolysis of the
corresponding cyanamides. Since then and to date, conven-
tional methods of synthesis of symmetrical N,N′-disubstituted
cyanamides have consisted in the electrophilic cyanation of
amines using cyanogen bromide as exemplified by the von
Braun reaction (Scheme 1A),10 by Cu-mediated cyanation of
amines,11 by variations in the direct alkylation of existing
cyanamide salts,12 and by other methods.13 In a most recent
contribution from the Merck Process group, electrophilic N-
cyanation was achieved by treatment of an N-chloroamine with
zinc(II) cyanide (Scheme 1B).14 One of the major concerns of
these methods of synthesis of cyanamides relying on cyanide-
containing reagents has been the potential hazards of side
products such as HCN and HBr produced during the
cyanation reaction. In spite of its long-standing history, the
direct alkylation of commercially available cyanamide salts
cannot be practically controlled to obtain N-monosubstituted
Received: September 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03085
© XXXX American Chemical Society
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A

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cyanamides.2a,c In an isolated example, Demko and Sharpless
have reported the synthesis of a monoalkylated cyanamide by
displacement of a tosylate with K cyanamide in toluene at 90
°C.15 To the best of our knowledge, a methodology study to
obtain N,N′-differentiated cyanamides without the use of
cyanide-containing reagents has not been reported.
Scheme 2. Substrate Scope
In 1971, Raap and co-workers reported the decomposition
of 1-methyl-5-lithio tetrazole into nitrogen gas and the
corresponding N-methyl cyanamide at a temperature as low
as −50 °C.16 Related metalated tetrazoles were reacted at −98
°C in TMEDA-THF with electrophiles leading to the 1,5-
disubstituted tetrazoles by Satoh and Marcopoulos.17
The reactivity of such C5-metalated tetrazoles remained
largely unexplored until recently when Wiedemann and co-
workers reported that deprotonation of N-benzyl-5H-tetrazole
with t-BuOK in a mixture of DMAC and THF at −40 °C
resulted in extensive decomposition during the metalation
reaction.18 However, they were able to engage in situ-generated
5-potassio tetrazoles in reactions with aldehydes and ketones
to prepare 1,5-disubstituted tetrazoles. Remarkably, if not
fortuitously, already in 1968, Garber and Brubaker had
reported that treatment of 1-methyltetrazole with n-BuLi at
−78 °C in THF produced a white solid that could be filtered
and analyzed as the 1-methyl-5-lithio tetrazole·THF com-
plex.19 The competing formation of a metalo cyanamide has
been considered as a disadvantage because it can interfere in
subsequent reactions intended for the tetrazole core unit.18 We
surmised that this undesired side reaction can be exploited to
advantage if the cyanamide salts could be isolated because the
only other byproduct is dinitrogen. In that event, such N-
metalo N-substituted cyanamides can be excellent coupling
partners with different electrophiles under extremely mild
conditions, leading to the facile and expedient formation of
various symmetrical and nonsymmetrical N,N′-disubstituted
cyanamides in the same flask, thereby avoiding the use of toxic
cyanide reagents (Scheme 1C).
Further to our interest in the reductive fragmentation
reactions of tetrazoles,20 we became intrigued by the equally
remarkable [3+2] cycloreversion reaction of N-substituted
tetrazoles induced by strong bases leading to the correspond-
ing N-substituted metalo cyanamides that have not been
hitherto isolated as such. Herein, we report our results on the
isolation of air stable N-substituted metalo cyanamides, their
reactivities, and their conversion into diverse N-substituted
cyanamides. We further report a new method for the synthesis
of N,N′-disubstituted amidines from the corresponding N,N′-
disubstituted cyanamides.
In preliminary studies, we used N-allyl tetrazole to establish
reaction parameters with regard to solvent, base, temperature,
and time.21 Thus, using n-BuLi in THF at 0 °C followed by
addition of benzyl bromide led to N-allyl-N′-benzyl cyanamide
1a in 78% yield (NMR). The metalation and in situ alkylation
could also be done using t-BuOK in ether.18,21
We then proceeded to evaluate the scope of the reaction by
varying both the electrophiles and starting tetrazoles. The latter
could be easily obtained by the condensation of a primary
amine with triethylorthoformate and sodium azide in acetic
acid at 80 °C as described by Gaponik and co-workers.22 The
N-substituted tetrazoles could be isolated as crude products
with excellent purity. A variety of symmetrical and nonsym-
metrical N,N′-substituted cyanamides could be prepared in
good to excellent yields by reaction with benzylic halides, as
well as aromatic acyl and sulfonyl halides (Scheme 2).
Arylsulfonyl N-phenyl cyanamides are excellent nontoxic
cyanating agents.23 N-Benzyl-N′-alicyclic cyanamides could
also be obtained in good yields. The poor yield of N-benzyl
adamantyl cyanamide derivative 1t was due to steric reasons
because the fragmentation of the adamantyl tetrazole was
successful, giving 84% of unalkylated N-adamantyl cyanamide
1u.
As mentioned above, we were not aware of any efforts to
isolate the metalo cyanamides in previous studies. Ca
cyanamide decomposes in water and liberates ammonia.24
Therefore, we were pleased that treatment of N-benzyl-5H-
tetrazole 2 with 1.1 equiv of n-BuLi in THF or in ether at 0 °C
for 30 min resulted in the precipitation of the corresponding
N-benzyl Li cyanamide 3a, which was isolated in 66% or 82%
yield, respectively. Remarkably, the white air stable amorphous
solid could be obtained by simple filtration and stored at room
temperature for several months. The corresponding N-
cyclohexyl 3b and N-phenyl 3d lithium salts were also isolated
in the same manner on a 2 g scale (Scheme 3). Using t-BuOK
led to the corresponding K salt of N-cyclohexyl cyanamide 3c.
The salts were thermally stable and melted with decomposition
at temperatures above 175 °C. Alkylation of these salts with
selected electrophiles led to the same products shown in
Scheme 2. Treatment of the salts with acidified water led to the
corresponding N-monosubstituted cyanamides exemplified by
B
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Scheme 3. Synthesis and Isolation of Cyanamide Salts
Scheme 4. Synthesis of Amidines
compounds 1u−1y. This offers an alternative two-step
cyanide-free method to the Merck protocol14 from readily
available N-substituted tetrazoles toward a variety of function-
alized cyanamides. In addition to N-methyl cyanamide first
reported by Raap,16 N-aryl cyanamides have been proposed as
intermediates in the decomposition of N-aryl tetrazole in
DMSO and NaOH.25
The cyanamide salts could also be used in conventional
SNAr or SN2 displacement reactions with either alkyl bromides
or alkyl tosylates. Reactions took place under remarkably mild
conditions at room temperature in DMSO.21 Reaction of the
salts with terminal epoxides such as styrene oxide led to the
arduously accessible iminooxazolidines.21,26
In spite of the potential electrophilic nature of the cyano
group in N,N′-disubstituted cyanamides, addition of nucleo-
philes has been limited to alcohols and amines requiring acid
catalysis to give the corresponding ureas and guanidines,
respectively.,2a27 Alternatively, strong bases such as amide salts
also lead to tetrasubstituted guanidines. In principle, the
analogous reaction of N,N′-disubstituted cyanamides with
carbon-based nucleophiles should lead to corresponding N,N′-
disubstituted amidines. However, it is expected that the
electrophilicity of the cyano group will decrease due to
electron donation from the N,N′-dialkyl substituents, which
would require highly nucleophilic and strongly basic carbon-
based reagents such as a Grignard reagent or an alkyl lithium to
give the corresponding N,N′-dialkyl amidines (Scheme 4). The
synthesis of N-substituted amidines usually involves indirect
methods such as the reaction of thioamides or imidates with
amines.28 Considering the paramount importance of the
amidine group in a plethora of medicinally important
compounds,28 we wished to explore their synthesis directly
from N,N′-disubstituted cyanamides. Before embarking on
what appeared to be a new method for accessing amidines, we
became aware of a historically important precedent dating to
1916 when Adams and Beebe had reported the reaction of
N,N′-dibenzyl cyanamide with PhMgBr to give the corre-
sponding N,N′-dibenzyl phenyl amidine after a tedious
isolation procedure.29 They stated that amidines are “not
easy substances to work with as most of them are oils or low
melting, very soluble solids. Therefore, only in one case, the
phenyl dibenzyl amidine, have we isolated and purified the free
compound.” Surprisingly, and in spite of the ready availability
of N,N′-disubstituted cyanamides, this apparently simple
synthetic method toward a variety of N-substituted amidines
incorporating the carbon moiety of the organometallic reagent
was hardly paid any attention. In a 1971 report, the addition of
phenyl lithium to N,N-dimethyl cyanamide led to 28% of the
desired N,N-dimethyl phenyl amidine.30 Only recently has the
synthesis of aryl amidines been reported by Larhed and co-
workers using a Pd(II)-catalyzed addition of aryl trifluor-
oborates to principally symmetrical N,N′-disubstituted cyana-
mides.31 The reaction took place in MeOH as the solvent
under microwave conditions and was applicable to cyanamide
itself in some cases.
We were pleased that the treatment of symmetrical and
nonsymmetrical N,N′-disubstituted cyanamides with Grignard
and organolithium reagents under mild conditions led to the
corresponding amidines, which could also be conveniently
isolated as their amide derivatives (Scheme 4). Thus, the
original Adams and Beebe reaction of N,N′-dibenzyl
cyanamide with PhMgCl led to the corresponding N-acetyl
amidine derivative 4a in 90% overall yield. Simple quenching
of the reaction mixture with HCl in 1,4-dioxane afforded the
unsubstituted NH-amidines. With few exceptions, the yields of
the reactions were good to excellent depending on the source
of the organolithium reagent and the nature of the electrophilic
partner. Grignard reagents failed to add at lower temperatures
as opposed to their lithium counterparts that reacted at −78
°C. The control of the temperature is important as the lithio
amidine intermediates were found to be unstable at room
temperature, leading to the decyanation of starting cyanamide
1h into dibenzylamine. Amidines containing a 2-pyridyl unit
such as 4g are particularly interesting especially as their free
amidines due to their potential coordinating ability.32
In conclusion, we have developed a cyanide-free scalable
method for synthesizing primary and secondary cyanamides
consisting of identical or different N,N′-substituents from N-
substituted 5H-tetrazoles in a one-flask, two-step protocol. In
the presence of n-BuLi or t-BuOK, a wide range of readily
available N-substituted tetrazoles undergo a cycloreversion
reaction releasing dinitrogen under mild conditions. In situ
reaction with a variety of electrophilic reagents leads to the
corresponding N,N′-disubstituted cyanamides.33 The alkali
salts of several N-disubstituted cyanamides can be isolated by
C
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(2) For reviews, see: (a) Nekrasov, D. D. Russ. J. Org. Chem. 2004,
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filtration and are stable to air for more than 4 months at room
temperature without noticeable degradation. These Li and K
salts can be used as soft nucleophiles in SN2-type reactions
with electrophilic reagents, including sulfonyl halides, alkyl
halides, tosylates, and epoxides. The salts can be easily
converted to the corresponding N-monosubstituted primary
cyanamides. The differentially N,N′-disubstituted cyanamides
readily react with Grignard and organolithium reagents to form
known and novel N,N′-substituted amidines, thereby rekin-
dling a literature precedent that has remained untested for 104
years. The cyanamide group can be involved in a plethora of
reactions such as, among others, cycloadditions,2,34 radical
reactions,2,35 and cyclotrimerizations2,30 leading in many
instances to versatile heterocyclic compounds.2,36 The
expedient method of a cyanide-free synthesis of N-mono-
and N,N′-disubstituted cyanamides, combined with an
alternative access to novel amidines, offers a modular protocol
whereby N-substituents can be incorporated voluntarily in
these historically relevant nitrogen-rich carbon compounds.
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ASSOCIATED CONTENT
* Supporting Information
■
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Accession Codes
CCDC 2030376 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
́
Stephen Hanessian − Department of Chemistry, Universite de
́
́
́
Montreal, Montreal, Quebec, Canada H3C 3J7; orcid.org/
0000-0003-3582-6972; Email: stephen.hanessian@
umontreal.ca
Author
(18) (a) Wiedemann, S. H.; Bio, M. M.; Brown, L. M.; Hansen, K.
B.; Langille, N. F. Synlett 2012, 23, 2231−2236. See also:
(b) Schwarz, J. B.; Colbry, N. L.; Zhu, Z.; Nichelson, B.; Barta, N.
S.; Lin, K.; Hudack, R. A.; Gibbons, S. E.; Galatsis, P.; DeOrazio, R. J.;
Manning, D. D.; Vartanian, M. G.; Kinsora, J. J.; Lotarski, S. M.; Li,
Z.; Dickerson, M. R.; El-Kattan, A.; Thorpe, A. J.; Donevan, S. D.;
Taylor, C. P.; Wustrow, D. J. Bioorg. Med. Chem. Lett. 2006, 16,
3559−3563.
́
Edouard Duchamp − Department of Chemistry, Universite de
́
́
́
Montreal, Montreal, Quebec, Canada H3C 3J7
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03085
Notes
The authors declare no competing financial interest.
(19) (a) Garber, L. L.; Brubaker, C. H., Jr. J. Am. Chem. Soc. 1966,
88, 4266−4267. (b) Garber, L. L.; Brubaker, C. H., Jr. J. Am. Chem.
Soc. 1968, 90, 309−312.
ACKNOWLEDGMENTS
■
̂
(20) Duchamp, E.; Deschenes-Simard, B.; Hanessian, S. Org. Lett.
2019, 21, 6593−6596.
The authors acknowledge financial support from NSERC IRC
513339-17 and NSERC Discovery Grant RGPIN/04726-2015.
The authors also thank the staff of Universite de Montreal,
Departement de Chimie: Dr. Thierry Maris for X-ray structure
and the Centre regional de spectrometrie de masse for HRMS
analyses.
(21) See the Supporting Information.
́
́
(22) Gaponik, P. N.; Karavai, V. P.; Grigor’ev, Y. V. Chem.
Heterocycl. Compd. 1985, 21, 1255−1258.
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(24) Auchmoody, L. R.; Wendel, G. W. Effect of calcium cyanamide
on growth and nutrition of plan fed yellow-poplar seedlings. Research
Paper NE-265; U.S. Department of Agriculture, Forest Service,
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