Catalytic Direct Construction of Cyano-tetrazoles

Article abstract of DOI:10.1021/acs.orglett.0c03025

Cyano-tetrazole is the first reported compound that bears four nitrogen atoms in a single five-membered ring. This unique molecular scaffold has long been ignored after its discovery in 1885, mainly attributed to the scarcity of available synthetic methods. Indeed, the most popular approach to tetrazoles (that is the cycloaddition reaction between nitriles and azides) has inevitably excluded the possibility of introducing valuable cyano groups to decorate the final heterocyclic cores. Here, we describe a completely different disconnection strategy to the long time-pursued cyano-tetrazoles via a simple, direct, and practical cycloaddition transformation between readily accessible aryl diazonium salts and diazoacetonitrile. This method provides both regioisomers of disubstituted tetrazoles from the same set of starting materials in a metal cation controlled fashion.

Full text of DOI:10.1021/acs.orglett.0c03025

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Catalytic Direct Construction of Cyano-tetrazoles
Ming-Yang Xiao,∥ Meng-Meng Zheng,∥ Xing Peng, Xiao-Song Xue, Fa-Guang Zhang,* and Jun-An Ma*
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ABSTRACT: Cyano-tetrazole is the first reported compound that bears four nitrogen atoms in a single five-membered ring. This
unique molecular scaffold has long been ignored after its discovery in 1885, mainly attributed to the scarcity of available synthetic
methods. Indeed, the most popular approach to tetrazoles (that is the cycloaddition reaction between nitriles and azides) has
inevitably excluded the possibility of introducing valuable cyano groups to decorate the final heterocyclic cores. Here, we describe a
completely different disconnection strategy to the long time-pursued cyano-tetrazoles via a simple, direct, and practical cycloaddition
transformation between readily accessible aryl diazonium salts and diazoacetonitrile. This method provides both regioisomers of
disubstituted tetrazoles from the same set of starting materials in a metal cation controlled fashion.
eterocyclic compounds play a fundamental and crucial
Hrole in synthetic chemistry, pharmaceuticals, and
materials. Among them, heteroaromatic nitriles have been
recognized as one of the most ubiquitous motifs in drug design
and development, such as pyrrole-nitriles, pyrazole-nitriles,
pyridine-nitriles, and triazole-nitriles.1 Despite the remarkable
achievements, one missing chapter is to merge nitriles with
tetrazoles, a type of unique polynitrogen heterocyclic ring.
Tetrazoles have emerged as privileged cores featuring
increasingly wide applications ranging from medicinal chem-
istry, catalysis, and bioconjugation to energetic materials.2
Arguably, the nitrile-azide (anion or derivatives) cycloaddition
reaction has been established as the most convergent and
commonly used method to access mono- or 1,5-disubstituted
tetrazoles (Scheme 1a1).3 In a similar fashion, the isocyanide-
azide multicomponent coupling (also referred to as the Ugi-
azide reaction) could give access to α-hydroxyl or α-amino 1,5-
disubstituted tetrazoles (Scheme 1a2).4 Although this N1 + N3
logic proved to be powerful, the direct regioselective synthesis
of 2,5-disubstituted tetrazoles remains as an unsolved
challenge. More importantly, as the cyano group is engaged
in the key ring-formation step, the cyano-tetrazoles could not
be easily obtained via the current state of the art method. In
fact, as the first reported compound containing a tetrazole ring
as early as in 1885 by Bladin via N2 + N1 + N1 assembling
(Scheme 1b1),5 cyano-tetrazoles have been long neglected in
the past century, probably due to the lack of practical synthetic
methods. Indeed, most reported examples employed hazardous
cyanogen gas to couple with azide reagents to give
monosubstituted cyano-tetrazoles (Scheme 1b2), which was
initially devised by Passalaqua and co-workers in the early 20th
century.6 Subsequent alkylation of in situ formed tetrazolate
salts could give rise to 1,5-disubstituted cyano-tetrazoles, albeit
often encountered with regioselectivity issues.7 Alternatively,
Zhulin and co-workers disclosed a seminal example of
synthesizing 1,5-disubstituted tetrazole-carbonitriles via the
cycloaddition of cyanogen with phenyl azide under high-
pressure conditions (Scheme 1b3).8 Complementary to these
cyanogen-involving entries, functional group interconversions
on the preformed tetrazole cores have also been utilized to
produce a few 2,5-disubtituted cyano-tetrazoles (Scheme 1b4),
but the lengthy procedures and limited scope still largely
impede the wide applicability.9 Clearly, a conceptually different
approach is greatly needed to overcome the historic challenge
for preparing cyano-tetrazoles, ideally in a regioselective
manner.
In this context, we envisioned that the cycloaddition
reaction between cyano-featuring 1,3-dipoles and N−N
dipolarophiles could be the potential candidate to fulfill the
above-mentioned long-standing gap by means of an
unprecedented N2 + N2 strategy. The utilization of
diazoacetonitrile in organic synthesis can be dated back to
1898,10 and the recent renaissance has attracted great attention
since Mykhailiuk’s seminal work.11 For example, Fasan and
Koenigs have achieved olefin cyclopropanation and heterocycle
C−H functionalization reactions with diazoacetonitrile via
metal carbene chemistry, respectively.12 Of particular note is
that feasible dipolarophiles to couple with diazoacetonitrile are
Received: September 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03025
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cycloaddition to 2,5-disubstituted cyano-tetrazoles was first
examined under optimized conditions (2a−2z, left, Scheme 2).
This approach features a remarkable functional group
compatibility including alkyl (2b−2g), alkoxy (2h and 2i),
phenyl (2j), halogens (2k−2q), trifluoromethyl (2s and 2t),
acetyl (2u), ester (2v), and nitro (2w) groups at all positions
of the aromatic ring, thus producing the corresponding
tetrazole-nitriles in 84−97% yields as a single regioisomer in
all cases. Notably, the cycloaddition process demonstrates
excellent reacting selectivity at the NN moiety while being
orthogonal to electron-poor alkenyl motif, as exemplified by
the exclusive formation of 2x in high yield. In addition,
heterocyclic diazonium salts also proved to be viable substrates
and gave rise to 3-thienyl- and 3-quinolyl-derived tetrazole-
nitriles 2y and 2z in yields of 92% and 85%, respectively. Next,
the scope of sodium-mediated cycloaddition to 1,5-disub-
stituted cyano-tetrazoles was also probed (3a−3z, right,
Scheme 2). Again, aryl diazonium salts substituted with
electron-rich or electron-deficient groups, at the para-, meta-,
and ortho-positions on the benzene ring, were equally tolerated
and generated targeted tetrazole-nitriles in practical yields with
moderate regioselectivities. Furthermore, aryl diazonium salt
1x bearing a vinyl ester group also underwent the cycloaddition
selectively at the NN site (3x). Finally, a pair of
heteroaromatic substrates was also efficiently converted to
cycloadducts 3y and 3z, albeit in plain yield with poor
regiocontrol. It should be noted that this metal cation-
controlled switchable transformation constitutes a rare example
of regiodivergent 1,3-dipolar cycloaddition reactions of diazo
compounds.19
Scheme 1. General Synthetic Methods to Tetrazoles and
Cyano-Tetrazoles
Furthermore, the one-pot platform from primary aniline
derivatives to the corresponding tetrazoles is also workable. By
in situ generating aryl diazonium salt in almost quantitative
yield, the silver-catalyzed cycloaddition process would proceed
smoothly to give 2,5-disubstituted cyano-tetrazoles 5 (method
C, Scheme 3a). This facile protocol allows the efficient
preparation of free hydroxyl or carboxylic group-bearing cyano-
tetrazoles from the corresponding anilines in high yields (5a
and 5b). 3-Aminopyridine is also accommodated and delivered
product 5c in 84% yield. The applicability of this one-pot
procedure to late-stage functionalization of biologically
interesting compounds proved to be amenable, as demon-
strated by the formation of cyano-tetrazoles 5d−5f with
excellent regioselectivities, which are derived from tocopherol,
pomalidomide, and lenalidomide, respectively. 2,2′-Diamino-
1,1′-binaphthalene (BINAM) was also tolerated and furnished
bi-2-naphthyl tetrazole nitrile 5g in 70% yield. Notably, as a
proof of principle, the promising potential of this method in
regiodivergent synthesis was further showcased by the smooth
preparation of phenylalanine and P2X3 receptor antagonist’s
2,5- and 1,5-disubstituted cyano-tetrazoles 6−9 in practical to
high yields (Scheme 3b).20 For instance, protected 4-
aminophenylalanine 4g was directly transformed to 2-aryl-5-
cyano-tetrazole 6 in 95% yield under silver catalysis conditions
(method C); meanwhile, the 1-aryl-5-cyano-isomer 7 could
also be obtained in decent yields via stepwise diazotization/
method B procedure. For more structurally complex substrate
4i, the diazonium salt was first prepared and then subjected to
standard method A or B to give nitrile analogues 8 or 9,
respectively.
still largely limited to electron-deficient alkynes and alkenes.13
Herein, we report a straightforward cycloaddition process
capable of forming two classes of disubstituted cyano-tetrazoles
from diazoacetonitrile and aryl diazonium salts under mild
conditions (Scheme 1c).14 The synthetic applicability to access
different cyano-tetrazole-decorated pharmacores and non-
canonical amino acids as well as computational mechanistic
studies are also demonstrated.
After extensive screening studies (see Tables S1 and S2), we
identified that the exclusive formation of 2,5-disubstituted
cyano-tetrazoles 2 are achieved by reacting aryl diazonium salt
1 with diazoacetonitrile when adding both silver acetate and
sodium acetate (method A in Scheme 2).15 This reaction
manifold belongs to the recent blossom of silver-enabled
coupling of diazo reagents with aryldiazonium salts from the
research groups of Kamenecka,16a Krasavin,16b and us.17 On
the other hand, 1,5-disubstituted cyano-tetrazoles can also be
obtained as major products when the same set of starting
materials were only treated with sodium acetate in acetonitrile
(method B in Scheme 2).18 It should be mentioned that 1,5-
disubstituted cyano-tetrazole 3a was initially incorrectly
assigned in Bladin’s seminal work, which has been revised to
be 2,5-disubstituted one 2a by Bamberger and De Gruyter.5
Strikingly, both regioisomers of such tetrazole-carbonitriles
have seldom been reported again since then.8,9 In this context,
this protocol allows the regiodivergent preparation of both 1,5-
and 2,5-disubstitued cyano-tetrazoles via [3 + 2] cycloaddition
reactions, thus providing a direct answer to the marked
synthetic challenge. The molecular structures of these cyano-
tetrazoles are determined by X-ray analysis of compounds 2a
and 3a, respectively. Gram-scale experiments to both tetrazoles
turned out to be viable. The substrate scope of silver-catalyzed
To explore the mechanism of this cycloaddition reaction,
density functional theory (DFT) calculations were conducted.
In the presence of silver acetate at −30 °C (Scheme 4a, green
B
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a
Scheme 2. Substrate Scope for Synthesis of 1,5- and 2,5-Disubstituted Cyano-tetrazoles
a
General reaction conditions for method A: aryl diazonium salt 1 (0.3 mmol, 1.0 equiv), diazoacetonitrile (2 mL, 0.6 mmol, 0.3 M in CH3CN),
AgOAc (2.6 mg, 5 mol %), and NaOAc (49.2 mg, 200 mol %) in 3 mL of CH3CN were reacted at −30 °C for 12 h. General reaction conditions for
method B: aryl diazonium salt 1 (0.3 mmol, 1.0 equiv), diazoacetonitrile (2 mL, 0.6 mmol, 0.3 M in CH3CN), and NaOAc (49.2 mg, 200 mol %)
in 3 mL of CH3CN was reacted at 0 °C for 12 h. Isolated yields. The regio ratios were determined by 1H NMR analysis of the corresponding crude
mixtures, and the differentiation in regio-isomers were identified by the solely observed 2,5-disubstituted tetrazoles 2 under method A conditions.
Scheme 3. One-Pot Sequence to Cyano-tetrazoles and Synthesis of Cyano-tetrazole-Decorated Noncanonical Amino Acids and
Pharmacores
path), Ag−C(N2)-CN species Int-1Ag is calculated to be
formed and relatively stable by 2.4 kcal/mol compared with
starting diazoacetonitrile.21 The subsequent asynchronous
concerted cycloaddition process could be the rate-determining
step with a barrier of 10.0 kcal/mol relative to Int-1Ag. The
unique role of silver in the stabilization of transition state TS-
C
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Scheme 4. DFT Calculations for the Reaction of Phenyl Diazonium Salt 1a with N2CHCN
2aAg is likely attributed to the beneficial Ag···π interactions.22
All other reaction paths have been calculated to be
unfavorable,23 such as sodium-promoted route to tetrazole
3a involving TS-2bNa requires activation free energy of at least
14.2 kcal/mol (purple path, ΔΔG⧧ = 4.2 kcal/mol relative to
green one), which corresponds to the observed excellent
regioselectivity in a silver-catalyzed cycloaddition system. On
the other hand, when silver salt is absent in the reaction
medium (Scheme 4b), the key cycloaddition event takes place
through a single transition state TS-IIbNa asynchronously with
an overall free energy barrier of 16.4 kcal/mol with respect to
diazoacetonitrile at 0 °C. The moderate regiocontrol in this
scenario is theoretically explained by the relatively small energy
gap between TS-IIaNa and TS-IIbNa (ΔΔG⧧ = 1.4 kcal/mol).23
Further inspection of the two transition states reveals that
there is an attractive C−H···π interaction between the phenyl
moiety and the cyano group (distance = 2.57 Å, see the SI for
the scale of noncovalent interactions), which may lead to the
better stability of TS-IIbNa over TS-IIaNa.24
Despite the fact that 2-phenyltetrazole-5-carbonitrile 2a is
the first reported compound in the history of all tetrazoles, the
study on cyano-tetrazoles has severely lagged behind due to
the lack of available synthetic methods, particularly in the case
of 1,5-disubstituted ones. Here, we develop a cycloaddition
approach from aryl diazonium salts and diazoacetonitrile,
which enables the rapid synthesis of both 1,5- and 2,5-
disubstituted cyano-tetrazoles. We have elucidated the
important aspects of the mechanism and found that the
regioselectivity in such [3 + 2] cycloaddition process is
governed by metal cations. This study fills a century-old gap in
heterocyclic chemistry and the afforded unique cyano-
tetrazoles could have potential implications in organic
synthesis, medicinal chemistry, chemical biology, and materials
science.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03025.
Optimization studies, detailed experimental procedures,
characterization data, computational details, and NMR
spectra for new compounds (PDF)
Accession Codes
CCDC 1966132 and 1966135 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Fa-Guang Zhang − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Centre of Chemical
D
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Science & Engineering, Tianjin University, Tianjin 300072,
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Letter
P. Triazoles and tetrazoles: Prime ligands to generate remarkable
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P.R. China; Joint School of National University of Singapore
and Tianjin University, International Campus of Tianjin
University, Binhai New City, Fuzhou 350207, P.R. China;
orcid.org/0000-0002-0251-0456; Email: zhangfg1987@
tju.edu.cn
Jun-An Ma − Department of Chemistry, Tianjin Key Laboratory
of Molecular Optoelectronic Sciences, Frontiers Science Center
for Synthetic Biology (Ministry of Education), and Tianjin
Collaborative Innovation Centre of Chemical Science &
Engineering, Tianjin University, Tianjin 300072, P.R. China;
Joint School of National University of Singapore and Tianjin
University, International Campus of Tianjin University, Binhai
New City, Fuzhou 350207, P.R. China; State Key Laboratory
of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, P.R. China; orcid.org/0000-0002-3902-6799;
Email: majun_an68@tju.edu.cn
́
́
́
̈
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Authors
Ming-Yang Xiao − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Centre of Chemical
Science & Engineering, Tianjin University, Tianjin 300072,
P.R. China; Joint School of National University of Singapore
and Tianjin University, International Campus of Tianjin
University, Binhai New City, Fuzhou 350207, P.R. China
Meng-Meng Zheng − State Key Laboratory of Elemento-
Organic Chemistry, Nankai University, Tianjin 300071, P.R.
China
Xing Peng − Department of Chemistry, Tianjin Key Laboratory
of Molecular Optoelectronic Sciences, Frontiers Science Center
for Synthetic Biology (Ministry of Education), and Tianjin
Collaborative Innovation Centre of Chemical Science &
Engineering, Tianjin University, Tianjin 300072, P.R. China;
Joint School of National University of Singapore and Tianjin
University, International Campus of Tianjin University, Binhai
New City, Fuzhou 350207, P.R. China
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Xiao-Song Xue − State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, P.R. China;
orcid.org/0000-0003-4541-8702
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03025
Author Contributions
∥M.-Y.X. and M.-M.Z. contributed equally.
Notes
(8) Krayushkin, M. M.; Beskopyl’nyi, A. M.; Zlotin, S. G.; Stashina,
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The authors declare no competing financial interest.
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Lead Tetraacetate Oxidation of 1-and 2-Amino-5-phenyl[1,2,3]-
triazolo[4,5-d]-[1,2,3]triazoles; Synthesis of a Fused 1,2,3,4-Tetrazine.
J. Chem. Soc., Perkin Trans. 1 1991, 1, 2045−2048. (c) Jenkins, S. M.;
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ACKNOWLEDGMENTS
■
This work was supported by the National Key Research and
Development Program of China (2019YFA0905100), National
Natural Science Foundation of China (Nos. 21772142,
21901181, and 21961142015), and Tianjin Municipal Science
& Technology Commission (19JCQNJC04700).
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(21) We have performed NMR experiments to explore the formation
silver-diazo intermediate in the reaction. The 1H NMR of
diazoacetonitrile was performed in CD3CN, then AgOAc was
added, and the 1H NMR was performed again. This experiment
clearly showed that the α-proton in diazoacetonitrile disappeared after
being treated with silver salt. Se the SI for details. However, the
possibility of silver salt acting as a Lewis acid could not be fully
excluded, and further studies are ongoing in our lab. For previous
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with phenyldiazonium salt 1a have also been calculated (see the SI for
details). The free energy barriers for the formation of corresponding
tetrazoles are at least 24.0 kcal/mol (CF3CHN2) and 24.4 kcal/mol
(EtO2CCHN2), respectively. In contrast, for the same reaction of
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°C conditions. In addition, the pKa values of the three diazo reagents
in DMSO were calculated to be 12.2 for CNCHN2, 17.1 for
CF3CHN2, and 21.3 for EtO2CCHN2. The gas-phase proton affinities
of the three diazo anions are also calculated: 338.8 kcal/mol for
−C(N2)CN, 347.2 kcal/mol for −C(N2)CF3, and 355.4 kcal/mol for
−C(N2)CO2Et. These data indicate that HC(N2)CN possesses the
highest acidity, which is in good agreement with the experimental
result that diazoacetonitrile exhibits the best reactivity.
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F
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