Organic Letters
Letter
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 NN 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 NN 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.
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
Org. Lett. XXXX, XXX, XXX−XXX