Synthesis of 1,2,4-Triazol-3-imines via Selective Stepwise Cycloaddition of Nitrile Imines with Organo-cyanamides

Article abstract of DOI:10.1021/acs.orglett.8b01673

A convenient method for the synthesis of 1,2,4-triazol-3-imines through a selective, formal, 1,3-dipolar cycloaddition of organo-cyanamide ions with nitrile imine dipoles is reported. Hydrolysis of the 1,2,4-triazol-3-imines yields the corresponding 1,2,4-triazol-5-ones. A stepwise mechanism, supported by DFT calculations, is invoked to explain the reaction selectivity.

Full text of DOI:10.1021/acs.orglett.8b01673

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 1,2,4-Triazol-3-imines via Selective Stepwise
Cycloaddition of Nitrile Imines with Organo-cyanamides
Pallavi Sharma,*,†,‡ Shreesha V. Bhat,‡ M. R. Ranga Prabhath,‡ Andrew Molino,† Elisa Nauha,‡
David J. D. Wilson,† and John E. Moses*,†
†La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
‡School of Chemistry, Joseph Banks Laboratory, University of Lincoln, Lincoln, LN6 7DL, U.K.
S
* Supporting Information
ABSTRACT: A convenient method for the synthesis of 1,2,4-
triazol-3-imines through a selective, formal, 1,3-dipolar cyclo-
addition of organo-cyanamide ions with nitrile imine dipoles is
reported. Hydrolysis of the 1,2,4-triazol-3-imines yields the
corresponding 1,2,4-triazol-5-ones. A stepwise mechanism, sup-
ported by DFT calculations, is invoked to explain the reaction
selectivity.
Scheme 1. Synthetic Approaches to 1,2,4-Triazol-3-imines:
(A(i)) Huisgen’s Work with PhNHCN; (A(ii)) Ransom’s
Linear Approach; (B) Present Work Utilizing the Cyanamide
Anion
itrogen-rich heterocycles are an important class of
1
Ncompounds with broad applications and functions.
Nitrogen-containing rings, for example, are prevalent in many
of the most successful medicines developed to date.2 Owing to
their significance and success, nitrogen heterocycles are key
targets for synthesis, and there is a demand for the development
of new methods that allow access to novel and/or under-
developed nitrogen-rich cores.
In the course of our work on the synthesis of “rare” nitrogen-
rich scaffolds,3 the 1,2,4-triazol-3-imine core caught our
attention as an attractive, yet underdeveloped class of nitro-
gen-rich heterocycle with much scope for development. For
example, the 1,2,4-triazol-3-imine core offers a number of
important features that are attractive in drug discovery
applications, including: (i) a densely functionalized heterocyclic
scaffold; (ii) multiple sites to allow fine-tuning of the
physicochemical properties and diversification, with defined
spatial projections; and (iii) physical and thermal stability.4
However, despite these interesting structural features and
potential, the 1,2,4-triazol-3-imine core has been somewhat
overlooked, with very few syntheses or applications reported to
date.
Huisgen and Aufderhaar were the first to describe the
synthesis of a triazol-3-imine (3), in their seminal 1965 report on
nitrile imine dipoles.5 The researchers employed a 1,3-dipolar
cycloaddition of ethoxycarbonyl-N-phenyl-nitrile imine (1)
with phenyl cyanamide (2) in the presence of Et3N, which
gave the 4,5-dihydro triazole cycloadduct 3 in a modest 11%
yield.6 To the best of our knowledge, the synthesis of 3 is the
only reported example of the formal cycloaddition of a nitrile
imine with a cyanamide (Scheme 1A(i)).
A report by Ransom and co-workers in the early 1990s patent
literature7 described the synthesis of the neurotensin antagonist,
1,2,4-triazol-3-imine·HCl salt (6), through the isomerization−
alkylation of amine 5; the latter could be obtained from
aminoguanidines 4, or the corresponding acyl aminoguanidine
(Scheme 1A(ii)).8
Here, we describe the first general and direct method for the
synthesis of 1,2,4-triazol-3-imines by the selective reaction of
organo-cyanamides9 with nitrile imines (Scheme 1B).10
Given our interest in the synthesis of aromatic heterocycles by
1,3-dipolar cycloaddition chemistry,11 we elected to revisit
Received: May 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01673
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 2. Synthesis of 1,2,4-Triazol-3-imine and 1,2,4-Triazol-5-one Cores under Optimized Conditions
a
b
1
13 added after 10 min to the reaction mixture. Calculated from the H NMR of the crude reaction mixture.
Huisgen’s convergent strategy as a potentially general method
for the synthesis of 1,2,4-triazol-3-imines. We have previously
described how organo-cyanamide anions 9, themselves formed
by fluoride-promoted desulfonylation of N-tosyl N-phenyl
cyanamide (NCTS),12 react with increased reaction rates and
improved yields in the cycloaddition with nitrile oxides to give
oxadiazol-5-imine cores.3 Given this knowledge, we elected to
explore analogous conditions in the reaction with nitrile imines.
Our studies began with the phenylbenzenecarbohydrazonoyl
chloride (13) as the choice of nitrile imine precursor, and NCTS
(14) as the source of the cyanamide anion, using tetrabuty-
lammonium fluoride as the activating agent.3 Under these
conditions, the target triazol-3-imine 17 was isolated in 15%
yield, along with the isomeric N-substituted 1,2,4-triazole-5-
amine13 (18, 11% isolated yield) product [ratio 55:45::17:18
determined by integration of the 1H NMR of the crude reaction
mixture]. The origin of 18 can be attributed to cycloaddition of
the nitrile imine dipole to the nitrile unit of the cyanamide (path
b, Scheme 2). The structures of the isomeric triazole products 17
and 18 were both characterized by extensive spectroscopic
analyses and corroborated by single crystal X-ray crystallography
(Scheme 2). In addition to the triazole products 17 and 18, the
corresponding dimer 1,3,4,6-tetraphenyl-1,4-dihydro-(1,2,4,5)-
tetrazine (19),11 and the N-phenyl cyanamide (2) were formed
as predominant side products.
Optimization studies were next performed to identify
conditions for the selective formation of the target exo-imines
(see Supporting Information (SI), Tables S1, S2, S3). The study
revealed that the rate of cyanamide ion formation was slower
relative to the nitrile imine dipole formation; hence a 10 min
delayed addition of the hydrazonoyl chloride 13 to a prestirred
mixture of 14 and CsF/18-crown-6 (18C6) in acetonitrile at 0
°C was found to be optimum, rendering the target product in an
excellent 89% yield and with impressive selectivity 94:6::17:18
(Scheme 2). The formation of 18 was suppressed by conducting
the reaction at 0 °C, and while additives including Na2SO4 and
molecular sieves improve the ratio of the required imine to
amine products, they result in the predominant formation of the
dimer 19 (see SI, Table S2).
Molecular modeling calculations performed at the M06-2X/
def2-TZVP (SMD, MeCN)//B3LYP-D3(BJ)/6-311++G(d,p)
(SMD, MeCN) level of theory were used to help rationalize the
formation of 17 over 18 (Scheme 2). A representative model
system with phenyl substituents (15, 16; Scheme 2) was utilized
to explore the reaction pathways. Initial adduct formation
between the carbon (C1) of the nitrile imine (15) and either the
amine nitrogen (N1) or nitrile (N2) subunits of the cyanamide
anion (16) via the reaction path a and b, respectively, was
investigated (21 and 22, Figure 1). No transition states for a
concerted one-step cycloaddition were located.
The free energy (ΔG) of product formation for both 17 and
18 is calculated to be favorable overall. The results indicate that
18 is the thermodynamic product because it is more stable than
17 by 35.4 kcal mol−1. The computed energetic barriers reveal
that the initial adduct formation associated with TS1 is both rate
and product determining. The TS1 barrier for path b (22, 25.7
kcal mol−1), to produce 18, is slightly higher than for path a (21,
23.7 kcal mol−1), which yields 17. These calculations support
our experimental observation that the formation of 18 is
inhibited at reduced temperature.
Both reaction pathways exhibit the stable intermediates 23
and 24, although they are not isolated or detected
experimentally. The subsequent barrier for cyclization (TS2;
25 and 26) was found to be readily accessible for both paths a
and b. The formation of 18 proceeds through a higher barrier at
13.8 kcal mol−1 (26), while the barrier for 17 is calculated to be
6.1 kcal mol−1 (25). The difference in energy at TS2 can be
rationalized by steric effects with the phenyl groups of the nitrile
imine and the cyanamide unit producing a steric congestion in
26, which is relieved by the subsequent formation of product 18
B
DOI: 10.1021/acs.orglett.8b01673
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Letter
Scheme 3. Synthesis of 1,2,4-Triazol-3-imines Using
a
Optimized Reaction Conditions
Figure 1. Calculated free energy profile (ΔG, kcal mol−1) for the
formation of 17 and 18 at the M06-2X/def2-TZVP (SMD,
MeCN)//B3LYP-D3(BJ)/6-311++G(d,p) (SMD, MeCN) level of
theory.
through rotation about the exocyclic C−N bond. No such steric
clash is present in transition state 25, which is consistent with the
lower TS2 barrier in path a. Overall, the reaction is predicted to
involve a two-step process and is consistent with experimental
observations with formation of 17 achieved through kinetic
control.
With the optimized conditions in hand, the scope of the
reaction was explored with a range of substituted hydrazonoyl
chlorides (both at R1 and R2). Both hydrazonoyl chlorides
bearing electron-donating (EDG) and/or electron-withdrawing
(EWG) aryl groups on R1 were well tolerated, with products
isolated in 76−86% yields (27−30, Scheme 3).
Introducing an EDG on R2 had a profound effect on the
reaction outcome; for example, p-methoxy substituents on the
aryl group gave excellent yields (32, 83%). This is consistent
with the findings of Qing Lin et al. on the role of electron-
donating groups on R2 in increasing the HOMO energy of the
dipole.14 Furthermore, the sterically hindered nitrile imines gave
the target imines in moderate yields (31, 44%).
The reaction of 4-fluoro substituted cyanamide with the
model substrate 13 afforded 33 in only 44% yield, whereas the
corresponding p-methoxy substituted cyanamides yielded
cyclized product in moderate yields (34, 61%). Furthermore,
the reaction of 4-fluoro substituted cyanamides with an electron-
rich nitrile imine (R2 = EDG) yielded the imine product with
much improved yields (36, 78%). The same was true when a
combination of electron-rich cyanamide was reacted with
electron-poor nitrile imine (R2 = EWG) (35, 71%). Heterocyclic
hydrazonoyl chlorides, such as thiophene and pyridine, were
also well tolerated, giving 37 and 38 in 85% and 70% yields,
respectively. Other hydrazonoyl chlorides such as cyclopropyl,
alkyl esters, and an NH-Boc protected substrate gave good
product yields (3, 39−43, 58−82%). Noteworthy is the
formation of compound 3 in 82% yield, which compares
favorably to the 11% yield first reported by Huisgen [Scheme
1A(i) vs Scheme 3].
a
Ten min delayed addition of 8 (total reaction time 20 min).
Isolated yield of 3, 17, 27−43; see SI for detailed information.
b
Having successfully achieved the synthesis of a variety of
triazol-imines, we next investigated their direct conversion into
1,2,4-triazol-5-ones (20). Triazol-5-ones are important hetero-
cyclic cores with a broad spectrum of biological activities15 (e.g.,
Ganetepsib 44 (Scheme 4)16 is a small-molecule heat shock
protein 90 (Hsp90) inhibitor that is being developed to treat
multiple solid tumor and hematologic cancers).
Treating 17 with sodium nitrite and sodium acetate in 50%
acetic acid gave the desired product 20 in good yield (76%).5b
The structure of product 20 was confirmed by spectroscopic
analyses and unambiguously corroborated by single crystal X-ray
crystallography. A number of other triazol-5-one products were
subsequently synthesized in good to excellent yields following
the same method (Scheme 4).
In conclusion, we have developed a robust one-pot method
for the selective synthesis of 1,2,4-triazol-3-imine heterocyclic
cores from nitrile imines and cyanamide ions in excellent yields.
High-level DFT calculations support a two-step mechanistic
pathway, with the target imine product produced under kinetic
control. The imine products were further converted to 1,2,4-
C
DOI: 10.1021/acs.orglett.8b01673
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Organic Letters
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a
Scheme 4. Synthesis of 1,2,4-Triazol-5-one
ACKNOWLEDGMENTS
■
P.S. thanks the EPSRC (EP/N00969X/1) for research funding.
We thank the University of Lincoln for a PhD studentship
(S.V.B.). We thank La Trobe University, NCI and Intersect for
computing resources. J.E.M. thanks the ARC for a Future
Fellowship (FT170100156).
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bridge Crystallographic Data Centre, 12 Union Road, Cam-
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: p.sharma@latrobe.edu.au.
*E-mail: j.moses@latrobe.edu.au.
ORCID
Pallavi Sharma: 0000-0001-5226-7864
Andrew Molino: 0000-0002-0954-9054
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b01673
Org. Lett. XXXX, XXX, XXX−XXX