Intercepting the Banert cascade with nucleophilic fluorine: Direct access to α-fluorinated: N H-1,2,3-triazoles

Article abstract of DOI:10.1039/d1cc01179k

The treatment of propargylic azides with silver(i) fluoride in acetonitrile was found to yield α-fluorinated NH-1,2,3-triazoles via the Banert cascade. The reaction was regioselective and the products result from an initial [3,3] rearrangement. The reacti

Full text of DOI:10.1039/d1cc01179k

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Intercepting the Banert cascade with nucleophilic
fluorine: direct access to a-fluorinated
NH-1,2,3-triazoles†
Cite this: DOI: 10.1039/d1cc01179k
Received 4th March 2021,
Accepted 20th April 2021
J. R. Alexander, P. V. Kevorkian and J. J. Topczewski
*
DOI: 10.1039/d1cc01179k
rsc.li/chemcomm
The treatment of propargylic azides with silver(I) fluoride in acetoni- regioisomeric NH-1,2,3-triazoles. Recently, the mechanistic diver-
trile was found to yield a-fluorinated NH-1,2,3-triazoles via the Banert gence of the Banert cascade was investigated (Scheme 1b).24 To our
cascade. The reaction was regioselective and the products result from knowledge, a NH-1,2,3-triazole bearing an a-fluorine atom has not
an initial [3,3] rearrangement. The reaction is demonstrated on 415 yet been reported. We endeavoured to access such mole-
examples with yields ranging from 37% to 86%.
cules utilizing the Banert cascade with a nucleophilic fluoride
source that would allow access to this potentially exciting motif
Triazoles are an important class of nitrogen heterocycles that have (Scheme 1c).
applications in polymer science,1–4 medicinal chemistry,5,6 and
This investigation began by treating propargyl azide 1a with
drug discovery.7–9 Triazoles have also gained recognition as phar- common nucleophilic fluoride sources in acetonitrile (Table 1,
macophores, glycoside mimics, and protease-resistant peptido- entries 1–9). The modestly elevated temperature was used to
mimetics.8,10,11 Likewise, the incorporation of fluorine plays a promote the sigmatropic rearrangement. Due to the high
significant role in drug discovery,12,13 pharmaceutical develop- basicity of fluoride anion in organic media, a competing
ment,14,15 and the agrochemical industry.16,17 In 2019, almost prototropic pathway was conceivable.24 Gratifyingly, AgF pro-
30% of new FDA approved drugs contained at least one fluorine vided the desired product in excellent yield (Table 1, entry 9).
atom.18 It is well accepted that the presence of fluorine enhances With AgF, the regioisomer originating from the prototropic
many pharmacokinetic properties including potency, metabolic rearrangement was not observed. This indicates that the silver
stability, and membrane permeability. Therefore, new synthetic coordinated fluoride anion was not significantly basic under
methods for incorporating a fluorine atom into heterocycles19 are these conditions. All other fluoride sources examined resulted
highly desirable.12,20
Many reactions used to access triazoles rely on azide–alkyne
cycloadditions and predominantly form N-substituted tria-
zoles.21–29 While NH-triazoles may be desirable,30–37 the
hazards of working with HN3 or TMSN3 complicates their
synthesis.38 Hydrazoic acid is highly explosive in neat form
and it is toxic. Therefore, specialised reactors39 or designer
synthons40 are often required. TMS-N3 has shown utility in the
synthesis of NH triazoles.38,41,42 However, in the presence of
water or acid, HN3 can be liberated from the reaction.43
One exciting reaction of azides44–48 that directly affords NH-
triazoles is the Banert cascade of propargylic azides.49–58 This
reaction proceeds via a triazafulvene intermediate that can be
trapped by various N, O, S, or C centred nucleophiles.24,56,59 As
a complicating feature, the Banert cascade can result in
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis,
Minnesota 55455, USA. E-mail: jtopczew@umn.edu
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Scope of the Banert cascade.
d1cc01179k
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Table 1 Reaction optimisation
Entry
Fluoride source
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
CsF
NH4F
NaF
TMAF
DMPU-HF
HF-Et3N
ZnF2
KF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgNO3 + CsF
AgNO3 + KF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
CH2Cl2
PhMe
Et2O
MeOH
EtCN
n.d
n.d
n.d
n.d
n.d
n.d
n.d
n.d
95
9
15
n.d
n.d
n.d
83
9
10
11
12
13
14
15
16
17
18
MeCN/H2O
MeCN
MeCN
45
94
51
a
Reactions conducted with azide 1a (0.09 mmol) and fluoride source
(0.18 mmol) at 0.1 M in varying solvent at 60 1C. Yield determined from
the quenched reaction mixture against anisonitrile as an internal
standard via calibrated HPLC-UV. All yield values reflect the average
of duplicate trials. Abbreviation n.d. = not detected (less than 5%).
in partially recovered starting material and/or complex mix-
tures.
Scheme 2 Substrate scopea. aIsolated yields are reported. Reactions
conducted with azide (0.5 mmol) and AgF (1.0 mmol) in MeCN (0.1 M) at
60 1C. All yield values reflect the average of duplicate trials. bReaction
performed on 41 mmol scale.
A screen of alternate solvents with AgF did not yield superior
results (Table 1, entries 9–15). Presumably, the solubility of AgF
is minimal in less coordinating solvents and more nucleophilic
solvents may trap the triazafulvene intermediate.56 In MeOH,
the MeOH adduct was exclusively formed (Table 1, entry 14).24
This may be due to the poor solubility of AgF in MeOH The reaction forming product 2b was conducted on a 1 mmol
compared to MeCN,60,61 or due to the weak nucleophilicity of scale, which afforded an identical yield. An ortho chlorine was
solvated fluoride anion.62 Furthermore, when azide 1a was not problematic (2g). Several common functional groups were
treated with AgF in wet MeCN (10% H2O), a mixture of adducts compatible with the conditions including an ester (2h), nitrile
were observed (45% fluorinated, Table 1, entry 16). This (2i) and alkyne (2k) group. The pendent aryl group was not
indicates that while adventitious water may not be problematic, required and could be changed for an alkyl group (2l, 72%
larger quantities are deleterious because water is a competing by NMR analysis, 41% isolated). Lastly both electron rich (2m)
nucleophile. To probe the importance of silver in the reaction, and poor (2n) heterocycles could be incorporated.
propargyl azide 1a was treated with a mixture of AgNO3 and CsF
Several modifications were tolerated on the azide bearing
or KF, which lead to the desired fluorinated triazole product carbon (Scheme 3). The secondary azide was not required and
(Table 1, entries 17 and 18); whereas, treatment with CsF alone primary fluorides 2o–2q could be isolated from a primary azide
(Table 1, entry 1) yielded unreacted or decomposed azide. in acceptable yields. Larger groups could also be incorporated
Cationic silver is known to activate alkynes63 and allenes64,65 into the system (2r–2s). Lastly, a tertiary fluoride product could
to cycloaddition, therefore, it is conceivable that silver activates be isolated (2t).
this system in acetonitrile.66 The results in entry 9 were taken as
optimal.
Other silver salts were examined for reactivity in the
presence of propargyl azide 1a (Scheme 4). The use of AgOAc,
With optimal conditions in hand, the substrate scope of the cleanly gave acetate 3a in high yield. Phenyl ether 3b could be
reaction was examined (Scheme 2). The model substrate 2a was isolated from the use of Ag2CO3 in the presence of base. Water
isolated in acceptable yield. As anticipated, based on the can be used as a simple nucleophile (3c), and the product
mechanism of the initial [3,3] rearrangement, the reaction resulting from elimination was isolated when using AgTFA (3d).
is compatible with electron donating (2b-2c), neutral (2d) Reactions conducted in the absence of silver did not afford
and electron withdrawing (2e–2j) groups on the aromatic ring. comparable yields (see ESI†).
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utilizing CsF and AgNO3 afforded a 57% yield (entry 2). Utiliz-
ing substoichiometric AgNO3 (20 mol%) was detrimental to the
yield (entry 3).
In summary, silver(I) fluoride can intercept the Banert
cascade to deliver a-fluorinated NH-1,2,3-triazoles. The scope
of this process is broad and a range of fluorinated triazoles
could be isolated (415 examples, up to 86% yield). This
reaction expands both the scope of the Banert cascade as well
as access to NH-triazole bioisosteres.
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.
Scheme 3 Modification to Azidea. aIsolated yields are reported. Reactions
conducted with azide (0.5 mmol) and AgF (1.0 mmol) at 0.1 M in MeCN at Conflicts of interest
60 1C. All yield values reflect the average of duplicate trials.
The authors declare no competing financial interest.
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