2
Tetrahedron Letters
Table 1. Reactivity of substituted benzenesulfonyl azides
e
entry
BAa
R1
Pb
Timec
Yieldd
Charge of N3
Reactivityf
LUMOg
Eh x 104
1236
1268
1296
860
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
3a
3b
3c
3d
3e
3f
20
20
20
20
17
7
63
46
38
84
95
93
–0.035
–0.038
–0.042
0.005
moderate
moderate
low
–0.0928
–0.0896
–0.0868
–0.1304
–0.1033
–0.1144
4-CH3
4-OCH3
3-NO2
3-CF3
good
0.009
good
1131
1020
3,5-bis-CF3
0.046
very good
[1] = 1.0 M, [2] = 0.5 M. aSubstituted benzenesulfonyl azide. bProduct (sulfonyl amidine derivative). cReaction time (h). dIsolated yield (%).eCharge of the azide
group based on the electron density (total Mulliken population) of the three nitrogen atoms constructing the azide estimated by DFT calculation (RB3LYP/6-
311+G(d,p)). fBased on the isolated yield: low (0–45%), moderate (45–75%), good (75–100%), and very good (75–100% within 10 h). gLUMO energy (hartree).
hEnergy difference (hartree) of the frontier orbitals between LUMO of 1a–f and HOMO of 2a (–0.2164 hartree).
between sulfur and nitrogen to give a linear adduct, followed by
forming an intramolecular nitrogen-carbon bond to afford a
thiatriazoline intermediate (path A). Succeeding retro-[3+2]
cycloaddition furnishes sulfonyl amidine derivatives associated
with N2 gas generation and solid sulfur precipitation. Another
pathway denoted as path B could be anticipated that T* can react
with electron-deficient sulfonyl azides by simultaneous formation
of sulfur-nitrogen and nitrogen-carbon bonds in a single [3+2]
cycloaddition step to give the same thiatriazoline intermediate as
path A.
performed by means of substituted benzenesulfonyl azides 1a–f
and thioacetanilide 2a (Table 1). With the increasing of the
negativity on azide, the isolated yields for 1b and 1c fell down in
comparison to that for 1a (entries 1–3 in Table 1). The electron-
donating groups reduced the charge of N3 accompanied by
raising LUMO energy level to be unstable, giving rise to the low
isolated yields. On the other hand, electron-withdrawing groups
on its phenyl ring seems to improve the reactivity (entries 4–6).
Single functional group-substitution by –NO2 or –CF3 afforded
good isolated yields with somewhat positive N3-charge relative to
the above 1a–c. NO2-substituted 1d has the most stable LUMO
level among the sulfonyl azide compounds in this report. Of
course the narrow HOMO-LUMO gap E is no doubt an
important factor for the reactivity, however, electrophilicity of
the azide group seems to be a dominant factor for the coupling
reaction. Bis-CF3 substitution on the phenyl ring supported this
evaluation, that is, 1f exhibited good reactivity in shorter reaction
time of 7 h with greater azide’s positive-charge in spite of the E
for 1f is larger than that for 1d, indicating the importance of the
electrophilicity so that stepwise, electrostatic-type mechanism of
path A would be preferred rather than the concerted [3+2]
cycloaddition-type path B. To check the reproducibility of the
yields of the coupling reaction, 3a and 3f were synthesized in 3
runs, affording small deviations of the yields within ±5% in both
cases.
To estimate the initial step of the reaction, we conducted
density functional theory (DFT) calculation for benzenesulfonyl
azide 1a and thioacetanilide 2a in the ground state (RB3LYP/6-
311+G(d,p), see Supplementary data in detail).6 Figure 1 displays
the frontier orbitals of the two compounds and their energy
levels. This energy diagram clearly shows that the combination
for the HOMO of thioacetanilide and the LUMO of
benzenesulfonyl azide is energetically more reactive than the
other HOMO-LUMO combination. In the former reactive
combination, the HOMO-localization on sulfur of the thioamide
was visualized as Figure 1 in contrast to almost no orbital phase
on thiocarbonyl-carbon, suggesting that the sulfur would attack
initially to the terminal nitrogen of the azide having the
compatible LUMO phase with the sulfur. Subsequent
intramolecular cyclization of the linear adduct gives
a
thiatriazoline by a nucleophilic attack to thiocarbonyl-carbon
from azide-nitrogen adjacent to the sulfonyl-sulfur. The frontier
orbitals in the less-reactive combination exhibit well-matched
orbital phases between the nitrogen (HOMO) and the
thiocarbonyl-carbon (LUMO). Although the HOMO-LUMO
energy gap is relatively large, the desired nitrogen-carbon linkage
would successively form because the two related atoms are
intramolecularly settled at near position after the generation of
the linear adduct. In addition, thioacetamide and 2-thiopiperidone
have almost the same orbital phases as thioacetanilide in both
HOMO and LUMO (Figure S1), therefore, the estimated reaction
pathway would seem to be extensible to the coupling reaction in
general. These computational examination revealed that the
coupling reaction of thioamides and sulfonyl azides would prefer
to go for the path A in Figure 1 rather than the path B, the
simultaneous two-bonds formation via concerted [3+2]
cycloaddition, which is similar to the reported mechanism for
sulfo-click reaction with electron-deficient azides.3b,c
Next, we anticipated for thioamides that both of the
nucleophilicity on sulfur (–) and the electrophilicity on
thiocarbonyl-carbon (+) would be important for the reactivity
based on the reaction mechanism of path A. In other word, dipole
moment of thioamides would seemingly influence to the
reactivity. Thus, we systematically varied the substituents on the
phenyl ring of thioacetanilide (Table 2). Since each thioamide
derivative shows its dipole moment with different direction, a
decomposed-vector component of the dipole moment along with
the C=S double-bond orientation, DC=S, is brought into for fair
comparison toward the reactivity. Methyl-substituted 2b showed
moderate reactivity with almost the same isolated yield and DC=S
as those for 2a (entry 1,2). By means of the introduction of
MeO– group, 2c exhibited small DC=S of 3.2 debye with low
reactivity in an isolated yield of 37% (entry 3). In contrast, 2f
displayed high DC=S of 5.0 debye with good reactivity in 81%
yield (entry 6). As a consequence, DC=S would be a good
indicator for the reactivity. On the other hand, NO2-tethered 2d
displayed slightly large DC=S but low isolated yield, owing to the
very large E originated from the significant stabilization of
HOMO energy level for 2d by the introduction of a powerful
electron-withdrawing nitro-group (entry 4). The similar tendency
was observed for 2g possessing two electron-withdrawing groups
Based on the above computational estimation, we first
anticipated that electrophilicity of the azide group may play an
important role for the reactivity of the coupling reaction. Thus,
we compared the electrophilicity, the computed charge of N3,
with the experimental reactivity of the coupling reactions