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E. Chainikova et al. / Tetrahedron Letters xxx (2018) xxx–xxx
to oxime 3c (5.17 min) increased. Therefore, it can be concluded
that the signal with RT = 4.90 min corresponded to nitrile oxide 3f.
As seen from Fig. S3a, if the photooxidation of azide 3a was car-
ried out at 20 °C, then oxime 3c and oxadiazol 3h (5.83 and 10.50
min) are practically absent in the reaction mixture, but the
amounts of nitroso compound 3d (9.75 min), nitro compound 3e
(12.52 min), and nitrile 3i (4.27 and 7.85 min) increased; i.e. at
low temperature the probability of the recombination processes
involving nitroso oxides (Scheme 1) increases, and the nitrile oxide
formed as a result of intramolecular transformations of these spe-
cies undergoes photolytic transformations before it has time to
cyclize with oxime formation or to react with acetonitrile. This
conclusion is confirmed by the yields of the products from the pho-
tooxidation of azide 3a measured by HPLC at three temperatures
(Table 1).
Scheme 6. Equilibrium between the conformers of nitroso oxides 2b and 3b and
intermediate nitrile oxide formation upon the photooxidation of azides 2a and 3a.
The Gibbs energies are given in kJ/mol.
We performed the experiment under flash photolysis condi-
tions where an oxygen-saturated acetonitrile solution of azide 3a
was irradiated by a high intensity light pulse of 50 ls duration to
generate triplet nitrenes. The formation of nitroso oxides occurs
in the millisecond range [8] and their lifetime is ꢃ0.005–10 s
depending on the structure and solvent polarity [9]. Therefore,
these reactions proceeded in the dark under the conditions of
our experiment. In the chromatogram of the obtained reaction
mixture (Fig. S4a, see ESI) the signal with RT = 4.90 min which
we assigned to nitrile oxide 3f as well as the signals corresponding
to nitroso compound 3d (9.78 min) and nitro compound 3e (12.57
min) were observed. The product with RT = 10.90 min was 5,50-
diazene-1,2-diylbis(2-methyl-1H-indole) which was formed as a
result of the recombination of triplet nitrenes.
Upon standing this reaction mixture in the dark at room tem-
perature nitrile oxide 3f was converted to oxime 3c (5.13 min)
(Fig. S4b). The formation of other products was not observed (cf.
Fig. S3). Thus, oxadiazol 3h is formed at high temperatures only.
Other products, the signals of which were recorded in the chro-
matogram of the reaction mixture obtained by the steady-state
photolysis of azide 3a in the presence of oxygen, were the result
of secondary photochemical reactions.
To answer a number of questions that arose during the study of
the products for the photooxidation of azides 2a and 3a, we per-
formed a DFT-modeling of the chemical reactions involving the
corresponding nitroso oxides 2b and 3b as well as the nitrile oxides
formed from them. The level of theory used and details of the com-
putational procedures correspond to those described above. The
results of the DFT-calculations for all studied compounds are given
in the ESI. The most important findings are discussed below. The
main question of the theoretical study can be formulated as fol-
lows: why is the composition of the products for the photooxida-
tion of azides 2a and 3a having similar structures different?
The annulated five-membered heterocycle introduces asymme-
try into the conformational states of nitroso oxides 2b and 3b.
There is equilibrium between the four conformers (Scheme 6). In
Scheme 6 the relative Gibbs energies of the conformers and confor-
mational barriers are given. The trans isomers participate in the
recombination reactions or are transformed into the cis isomers.
As seen from Scheme 6, two pathways for ortho-cyclization of
the cis isomers are possible, but only one is realized. The cause of
this effect was studied previously [7b]. It was established that
the preferable direction of the ortho-cyclization of bicyclic ArNOO
leads to partial destruction of the aromatic system and the
Fig. 3. Energy diagram (in terms of Gibbs free energy) for the transformations of
nitrile oxides 2f, 3f into oxadiazols 2h, 3h and oximes 2c, 3c. Gibbs energy levels are
indicated by the solid lines. Calculation conditions: M06L/6-311+G(d,p) + IEFPCM,
MeCN, standard state, 298 K.
(D
G–(TS3) ꢃ 90 kJ/mol), which provides a theoretical justification
for the possibility of this reaction (Fig. 3). In the experiment, during
the photooxidation of azide 3a we observed the formation of nitrile
oxide 3f, its slow transformation to oxime 3c at room temperature,
as well as the formation of its adduct with acetonitrile at high tem-
perature. During the photooxidation of azide 2a the intermediate
formation of nitrile oxide 2f was not observed; oxime 2c was
formed both at high and at room temperature.
The reason for these differences is that the rates of tautomeric
transformations of the indole and indazole rings are very different.
As seen from Fig. 3, the ease of the 2f_3 ? 2j tautomerization of
the indazole results in the efficient transformation of 2j to oxime
2c. The Gibbs activation energies for the transformations 2j ? 2c
and 3j ? 3c are comparable, but the fraction of the reactive tau-
tomer 3j is low in comparison with 2j, which explains the experi-
mentally observed decrease in the reactivity of indole nitrile oxide
3f in the intramolecular cyclization and its involvement in the
reaction with the solvent, especially at high temperature. Indeed,
the free activation energy for the electrophilic cyclization of 3j
(58.7 kJ/mol, TS3 in Fig. 3) is noticeably lower than the value for
formation of
a nitrile oxide containing a second ring with
preservation of aromaticity. In our case it is nitrile oxide 2f (3f)
(Scheme 6).
The nitrile oxides, the relative energies of which are similar,
undergo conformational rotation to
a flat state 2f_3 (3f_3)
(Fig. 3). It was calculated that the [3+2]-cycloaddition of both
nitrile oxides to acetonitrile proceeds with low activation energy
the [3+2]-cycloaddition to acetonitrile (D
G–(TS3) = 89.7 kJ/mol).
Chainikova, Ekaterina
