Silver Mediated Banert Cascade with Carbon Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.1c01032

The Banert cascade of propargylic azides can be promoted by simple silver salts, and the triazafulvene intermediate can be intercepted by carbon nucleophiles. Various indoles (>25 examples, up to 92% yield) and electron-rich heterocycles were effective. T

Full text of DOI:10.1021/acs.orglett.1c01032

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Letter
Silver Mediated Banert Cascade with Carbon Nucleophiles
Juliana R. Alexander, Paul V. Kevorkian, and Joseph J. Topczewski*
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ABSTRACT: The Banert cascade of propargylic azides can be
promoted by simple silver salts, and the triazafulvene intermediate can
be intercepted by carbon nucleophiles. Various indoles (>25
examples, up to 92% yield) and electron-rich heterocycles were
effective. The Mayr nucleophilicity parameter (N) was found to
correlate to the reaction efficiency, which enabled the formation of
3
2
3
3
Csp −Csp and Csp −Csp bonds under otherwise identical conditions
from structurally dissimilar nucleophiles.
he triazole heterocycle has been widely adopted as a key
Tmolecular building block for a variety of synthetic
applications including in drug discovery,1−4 medicinal
chemistry,5−8 bioconjugation,9,10 and material science.11−13
Triazoles are small, polar, and stable N-heterocycles that can
be used as a peptidomimetic,2,14,15 amide isostere,16,17 N-acetyl
lysine mimic,7,8 or glycosyl surrogate.18−20 NH-triazoles
contain a hydrogen bond donor, more closely resembling
sugars and native amides, relative to N-substituted triazoles.
NH-triazoles can adopt three N−H tautomeric structures,
providing additional flexibility,21 and they have demonstrated
utility in multiple contexts.22−26
Forming NH-triazoles by CuAAC or RuAAC has been
problematic from the standpoint of reactivity and safety.27−29
Thus, we focused on the Banert cascade of propargylic azides
(Figure 1b).30−34 This process commences by either a
sigmatropic or prototropic rearrangement,35 resulting in an
allenyl azide.35,36 The allenyl azide undergoes electrocycliza-
tion37 to form a triazafulvene.38 The triazafulvene will
polymerize or can be intercepted by exogenous nucleophiles,
including alcohols, water, amines, thiols, or azide
anion.30,32,39,40 We were surprised by a lack of well
documented reports utilizing carbon nucleophiles to terminate
the Banert cascade.25,41 Presented herein are silver mediated
conditions enabling the construction of carbon−carbon bonds
α to the newly formed NH-triazole (Figure 1c).
This study began by screening model azide 1a with 2-
methylindole (2a), a representative indole of moderate
nucleophilicity (vide infra). Small quantities of product 3a
were observed upon heating to 60 °C (Table 1, entry 1).
Attempts at optimizing this reaction in the absence of a catalyst
were not fruitful (not shown). Silver salts are known to activate
alkynes42,43 and allenes44,45 to cycloaddition reactions. There-
fore, it was hypothesized that a silver salt may promote the
reaction. The addition of AgNO3 increased the yield of 3a
(entry 2). A silver salt screen (entries 2−5 and Supporting
Information) identified AgOTf as an excellent promoter (entry
Figure 1. Triazole isosterism and the Banert cascade.
4). A solvent screen indicated that nitrile solvents were optimal
(entries 6−9). Decreasing the loading of AgOTf demonstrated
that substoichiometric quantities of silver can catalyze the
reaction (entries 10−12 vs entry 1), but did not further
increase the yield of compound 3a relative to entry 4.
Increasing the silver loading did not increase the yield (entries
13 and 14). Adding more indole 2a improved the yield (entries
Received: March 25, 2021
Published: April 2, 2021
https://doi.org/10.1021/acs.orglett.1c01032
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3227−3230
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a
a
Table 1. Optimization with Indole 2a
Scheme 1. Substrate Scope with Respect to Azide
b
entry
AgX
equiv of AgX equiv 2a
solvent
MeCN
% yield
1
2
3
4
5
6
7
8
−
−
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1.5
2
5
23
50
55
73
47
−
13
28
61
56
60
65
70
70
81
86
77
AgNO3
AgBF4
AgOTf
AgTFA
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
1
1
1
1
1
1
1
DMF
9
CH3CH2CN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14
15
16
17
0.1
0.2
0.5
1.5
2
1
1
1
a
Reactions conducted with azide 1a (0.1 mmol) and 2-methylindole
(2a) at 0.1 M in varying solvent at 60 °C. All yield values reflect the
b
average of duplicate trials. Yield determined using calibrated GC-
FID with naphthalene as an internal standard.
15−17). The conditions in entry 16 were taken as optimal.
Under these conditions, only one triazole regioisomer was
observed, originating from a sigmatropic rearrangement. The
three N−H tautomers are dynamic on the NMR time scale.
The azide scope was investigated (Scheme 1). The model
substrate 3a was isolated in 78% yield. Other azides containing
an aryl group provided similar results (3b−3f). An ortho
substituent did not impact the yield (3g). Various functional
groups were tolerated (3h−3k). The pendent aryl ring was not
required (3l−3m). The reaction also proceeded with primary
(3n−3o), secondary (3p−3q), and tertiary (3r) azides.
The indole scope was investigated (Scheme 2). Indoles with
various substituents worked well (4a−4e). Even potent
withdrawing groups (−NO2) were tolerated (4f). A phenyl
group at C-2 did not affect the reaction (4g). The indole
present in cediranib worked (4h), and N-methylation was
tolerated (4i).
a
Yields are reported for isolated and purified products. Yield values
reflect the average of duplicate trials.
a
Scheme 2. Substrate Scope for Indole
It seemed prudent to expand the nucleophile scope. Since
the product-forming step required nucleophilic attack (Figure
1), the Mayr table of nucleophilicity parameters (N) was
consulted.47 The model nucleophile 2a has an N value of
6.91.48 This is significantly higher than the value for indole (N
= 5.55, 6a, Scheme 3).48 N-Methyl pyrrole (N = 5.85)49 led to
product 6b, and imidazole (N = 11.47)50 afforded product 6c.
Furan (N = 1.33)51 did not afford product. However,
potassium 2-furanyl-trifluoroborate (N value = 5.99)52 did
(6d) as did allyl tributylstannane (N = 5.46, 6e),49 2-
methylallyltributylstannane (N = 7.48, 6f),49 and silyl-ketene
acetal (N = 10.3, 6g).53 Taken together, these data expand the
scope of participating nucleophile well beyond indoles and
provide guidance on which untested nucleophiles would be
likely to participate (N > 5.4).
a
Yields are reported for isolated and purified products. Yield values
reflect the average of duplicate trials.
In conclusion, the Banert cascade can be terminated by a
wide array of carbon nucleophiles. The scope of both the azide
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a
Scheme 3. Scope of Other Nucleophiles and N Parameter
ACKNOWLEDGMENTS
■
This research was supported by the National Institute of
General Medical Sciences of the National Institutes of Health
under Award Number R35GM124718. We also acknowledge
NIH Shared Instrumentation Grant #S10OD011952.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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Experimental procedures and spectral data (PDF)
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Joseph J. Topczewski − Department of Chemistry, University
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Paul V. Kevorkian − Department of Chemistry, University of
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