Reaction of 3-Cl/OMe-Substituted 5-Nitrobenzisothiazoles with Hydrazine: Structural and Computational Evidence for Rearrangement Pathways Implicating Intramolecular Formation of Pivotal Meisenheimer Complexes

Article abstract of DOI:10.1021/acs.joc.1c00118

In projected structure-activity relationship studies of the novel diheteroarylamide-based anti-HIV agent 2 (1C8), one objective was to evaluate the influence of incorporating the central amide motif in 2 into a five-membered pyrazolone ring, as found in 3. It was envisaged that compound 3 could be prepared through reaction of 3-hydrazino-5-nitrobenzisothiazole 5 with the methyl ester of 4-chloropyridine-3-carboxylic acid, followed by N-methylation of the pyridine nitrogen. However, the reaction of 3-methoxyl-5-nitrobenzisothiazole with hydrazine resulted in formation of ring-opened hydrazonate product 18. In the corresponding reaction with 3-chloro-5-nitrobenzisothiazole, a different rearrangement product 19 was formed, in which two 2,1-benzisothiazole units are joined by a sulfur bridge. Meisenheimer complex formation, favored by the presence of the 5-nitro substituent on the benzisothiazole ring, was postulated to be a key feature in the formation of these deep-seated rearrangement products. Support for the proposed formation of the pivotal Meisenheimer complexes and their subsequent evolution to the observed products in which the benzisothiazole sulfur atom is either expelled or maintained in the isomeric 2,1-benzisothiazole system was obtained by density function theory calculations.

Full text of DOI:10.1021/acs.joc.1c00118

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Article
Reaction of 3‑Cl/OMe-Substituted 5‑Nitrobenzisothiazoles with
Hydrazine: Structural and Computational Evidence for
Rearrangement Pathways Implicating Intramolecular Formation of
Pivotal Meisenheimer Complexes
Zheng Sonia Lin, Xing Tong, Brian Patrick, Pierre Kennepohl,* and David S. Grierson*
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ABSTRACT: In projected structure−activity relationship studies of the novel diheteroarylamide-based anti-HIV agent 2 (1C8),
one objective was to evaluate the influence of incorporating the central amide motif in 2 into a five-membered pyrazolone ring, as
found in 3. It was envisaged that compound 3 could be prepared through reaction of 3-hydrazino-5-nitrobenzisothiazole 5 with the
methyl ester of 4-chloropyridine-3-carboxylic acid, followed by N-methylation of the pyridine nitrogen. However, the reaction of 3-
methoxyl-5-nitrobenzisothiazole with hydrazine resulted in formation of ring-opened hydrazonate product 18. In the corresponding
reaction with 3-chloro-5-nitrobenzisothiazole, a different rearrangement product 19 was formed, in which two 2,1-benzisothiazole
units are joined by a sulfur bridge. Meisenheimer complex formation, favored by the presence of the 5-nitro substituent on the
benzisothiazole ring, was postulated to be a key feature in the formation of these deep-seated rearrangement products. Support for
the proposed formation of the pivotal Meisenheimer complexes and their subsequent evolution to the observed products in which
the benzisothiazole sulfur atom is either expelled or maintained in the isomeric 2,1-benzisothiazole system was obtained by density
function theory calculations.
3-hydrazino-substituted 5-nitrobenzisothiazole 5 with the
methyl ester of 4-chloropyridine-3-carboxylic acid 4, followed
by N-methylation of the pyridine nitrogen (Figure 1b).
However, the reaction of 3-methoxy- and 3-chloro-5-nitro-
substituted benzisothiazoles 6a and 6b with hydrazine took an
unexpected course, leading to the formation of rearrangement
products 18 and 19, respectively (Figure 3b).
Although markedly different in overall structure, a common
element in both compounds was the extrusion of the sulfur
atom from its attachment at C-8 in the aromatic ring in the
starting benzisothiazole system and introduction of a nitrogen
atom at this same position para to the nitro group on the
aromatic ring in the product structures. To account for this
observation, a mechanism for the formation of rearrangement
INTRODUCTION
■
A compound library synthesis-screening program to identify
noncytotoxic structural mimics of tetracyclic indole compound
1 (IDC16), which similarly block HIV replication through
perturbation of HIV pre-mRNA alternative splicing, led to the
identification of the novel benzisothiazole-based anti-HIV
agent 2 (1C8) (Figure 1a).1 This compound, which remained
active against HIV strains resistant to the drugs used in ART
(antiviral therapy) that target HIV reverse transcriptase,
integrase, and protease, perturbs the function of the host cell
splicing/alternative splicing factor SRSF10 (serine and arginine
rich splicing factor 10).2 In further studies, compound 2 has
been used to determine the involvement of SRSF10 in the
replication of the hepatitis B virus in HBV-infected cells.3 In
SAR studies of 2, one strategy for determining the influence of
the central amide motif in 1C8 and its orientation relative to
the 4-pyridinone carbonyl function on anti-HIV activity was to
incorporate it into a more constrained five-membered
pyrazolone ring, as found in compound 3 (Figure 1b).
Adapting a known strategy to construct the pyrazolone ring
system,4 we planned to prepare compound 3 by the reaction of
Received: January 30, 2021
Published: April 14, 2021
https://doi.org/10.1021/acs.joc.1c00118
© 2021 American Chemical Society
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to formation of benzonitrile product 10 (note that in cases in
which the S−Nuc bond can be subsequently cleaved,
formation of disulfide 11 is observed).7 Note also that an
additional layer of complexity in the reactivity of benzisothia-
zole 7 with amines (piperazine) has been documented.11
When 7 was heated at 65 °C, ring-opened compound 12 was
formed in high yield, rather than the SNAr product. However,
when heated at a higher temperature (165 °C), the piperazine
nucleophile reacts with the cyano group in 12 to give
presumed intermediate 13, which undergoes ring closure to
give 3-piperazino 14, i.e., the overall product of direct SNAr
substitution.
Reported in only two papers,12,13 the preparation of 3-
hydrazinobenzisothiazole 16 has been achieved by reaction of
3-methoxybenzoisothiazole 15 with excess hydrazine (6 equiv)
in refluxing EtOH for 30 min (Figure 3a). In both cases, the
Figure 1. (a) Structures of 1 (IDC16) and 2 (1C8). (b) Planned
synthesis of 3. Numbers in red (structures 6a and 6b) represent the
numbering system for the benzisothiazole ring.
products 18 and 19 is proposed, the central feature of which is
the formation of a [6,4]-bicyclic Meisenheimer complex as a
pivotal intermediate. Support for this hitherto undocumented
reactivity of the benzisothiazole system is provided by density
functional theory (DFT) calculations.
RESULTS AND DISCUSSION
■
The planned route to analogue 3 of anti-HIV agent 2 (1C8)
was logical in that 3-OMe/Cl benzisothiazoles can react with
amine nucleophiles to give the expected C-3 substitution
products.5−9 However, the adjacency of the N and S atoms in
the five-membered isothiazole ring of this heterocycle is known
to complicate its reactivity,10 making it difficult to predict with
certainty the reaction outcome.
Figure 3. (a) Reaction of 15 with hydrazine and phenyl-
hydrazine.10−12 (b) Conversion of 5-nitrobenzisothiazoles 6a and
6b to rearrangement products 18 and 19, respectively.
Indeed (Figure 2), 3-chloro benzisothiazole 7 can react with
amines by either (a) SNAr-type displacement of the 3-chloro
group to give 3-amino benzisothiazole product 8 or (b) SN2
reaction of the amine at the sulfur atom and cleavage of the
weak S−N bond, leading, after elimination of the Cl− ion in 9,
hydrazine product was isolated by recrystallization from EtOH.
In another study, the reaction of a related 5-acetyl-3-
Figure 2. Competing SNAr and SN2 reaction pathways for the reaction of benzisothiazoles with nucleophiles.
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methoxybenzisothiazole derivative with excess phenylhydrazine
has been shown to be efficient (67% yield).14 In our hands, the
reaction of 15 with phenylhydrazine was also successful, giving
17 as yellow crystals in 57% yield following crystallization from
MeOH/H2O. However, we were unable to detect formation of
compound 16 (R = H) in the reaction of 15 with hydrazine
itself. In this reaction, the only isolatable product was disulfide
11 (72%). In addition, in the corresponding reaction of 5-
nitro-3-methoxybenzisothiazole 6a with hydrazine, neither
hydrazine substitution product 5 nor ring-opened disulfide
product 11 was observed [thin layer chromatography (TLC)
1
and H NMR]. Indeed, in this reaction (Figure 3b), the only
“nonpolar” component detected by TLC (96/4 DCM/
MeOH) and isolated in 76% yield by recrystallization from
MeOH was hydrazonate compound 18 [(Z)-methyl 2-amino-
5-nitrobenzohydrazonate]. The structure of this novel
rearrangement product was confirmed by single-crystal X-ray
diffraction (see the Supporting Information).
Figure 4. Proposed mechanism for the conversion of 6a to 18.
In light of this result and following the reasoning that
perhaps the -OMe substituent in 5-nitrobenzisothiazole 6a was
not a sufficiently good leaving group to ensure its displacement
on reaction with hydrazine relative to the competing
nucleophilic attack on sulfur, the corresponding reaction of
3-chloro-5-nitrobenzoisothiazole 6b with hydrazine was
studied (Figure 3b). For the reaction in which an excess of
hydrazine (≤6 equiv) was employed, a polar mixture of
multiple inseparable products was produced. However, in
further experiments carried out at room temperature (30 min)
in which less hydrazine was used (≥0.5 equiv) and
diisopropylethylamine (DIPEA) was added as a base, nonpolar
product 19 was isolated after column chromatography in
opportunity would then exist for the NO2 group on the phenyl
ring of 21 to enable an alternate reaction process leading to
formation of nitro group-stabilized bicyclic Meisenheimer
complex 22. In essence, this transformation corresponds to the
first step in an intramolecular SNAr reaction.17,18 Subsequent
loss of NH2NHS− from this Meisenheimer species would then
generate neutral aza-bicyclo-[6,4] compound 23. In these two
steps, migration of the nitrogen atom to the C-8 atom on the
phenyl ring (benzisothiazole numbering) and extrusion of the
sulfur atom are achieved. Although bicyclic compound 23
corresponds to a formally anti-aromatic (4n electron) species
and is inherently highly strained, i.e., reactive, the parent
compound, 7-azabicyclo[4.2.0]octa-1(6),2,4,7-tetraene, miss-
ing the -OMe and -NO2 substituents, is a known compound
with a measurable lifetime.19 In the final steps of the
rearrangement pathway, 1,2-addition of hydrazine to the
“imine” carbon in 23 to generate 24 would set the stage for
participation of the lone pair of electrons on the hydrazine
nitrogen in opening of the strained four-membered (1,2-
dihydroazete) ring and formation of observed product 18.
Although this mechanism is attractive, in that it accounts for
all of the features present in rearrangement product 18, there
was concern about whether formation of Meisenheimer
complex 22 and its evolution to the final product represented
an energetically favorable reaction pathway. To gain support
for this proposed route to 18, the individual steps were
examined using DFT.
In this study, we took account of the susceptibility for the 3-
substituted benzisothiazole system to react with nucleophiles
at the C-3 center or the sulfur atom, and both reaction modes
were examined for the reaction of 6a with hydrazine (Figure
5). For the pathway involving nucleophilic attack of hydrazine
at sulfur and formation of Meisenheimer intermediate 22, two
possibilities were evaluated: the stepwise process in whch ring
opening produces methoxyimidate 21 (P1) and the concerted
process (P2) in which S−N bond cleavage leads to a shift of
the nitrogen atom to give intermediate 22 directly. For the
reaction of hydrazine at C-3 (PC), the reaction was stopped at
the formation of intermediate 25, such that nucleophilic attack
by a second molecule of hydrazine at sulfur could occur prior
to loss of the OMe group, leading via a stepwise process
analogous to P1 to formation of alternate Meisenheimer
complex 27.
1
≤33% yield. Interestingly, from the H and 13C NMR spectra
for this novel product, we determined that it corresponded to
the same compound obtained in a separate experiment in
which 5-nitrobenzisothiazole 6b was reacted with 4-pyridinone
amine 20. In this other experiment, the “dimer-like” structure
of 19, in which two 2,1-benzisothiazole subunits are joined by
a sulfur atom bridge, was confirmed by single-crystal X-ray
diffraction (Supporting Information).
Surprised that in the experiments employing 5-nitro-
benzisothiazoles 6a and 6b as starting materials target 3-
hydrazino-5-nitrobenzisothiazole product 5 was not observed,
we still had to determine how and why novel rearrangement
compounds 18 and 19 were formed. We first considered the
formation of hydrazonate 18. Four features stood out in its
structure that provided clues concerning the mechanism
whereby it was produced. (i) The isothiazole ring was opened.
(ii) The sulfur atom was extruded. (iii) The C-8 sulfur atom
para to the nitro group was replaced by an amino group. (iv)
The intended -OMe leaving group at C-3 was maintained in
the product molecule. This later observation was confirmed by
1
the absence of any OMe → OEt exchange in the H NMR
spectrum of the crude product mixture when the reaction of 6a
with hydrazine was carried out in EtOH as the solvent. Taken
together, these observations suggested that the key step in the
reaction mechanism leading to compound 18 involves ring
opening through attack of hydrazine at the sulfur atom in 6a to
give imidate anion 21 (Figure 4). The fact that intermediate
21, and/or its protonated neutral form, did not spontaneously
eliminate methoxide anion to generate a cyano function, as in
the conversion of chloroimidate 9 to 10 (Figure 2), most
probably stems from its greater stability under both acidic and
basic conditions.15,16 If this factor is taken into account, the
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Figure 6. (a) Reaction coordinate diagram of the first step in P1 and
P2 in the 6a system. The pink area represents an approximation of
where the transition state in the P2 pathway lies. The total Gibbs
energy of all reactants was set as the baseline (0 kcal/mol). Each
plateau represents the total Gibbs energy of all existing compounds
(i.e., reactants, transition state TS, and products) at each stage. (b)
Reaction coordinate diagram of P1 and PC in the 6a reaction system.
The total Gibbs energy of all reactants was set as the baseline (0 kcal/
mol). Each plateau represents the total Gibbs energy of all existing
compounds at each stage.
Figure 5. Three proposed pathways in which hydrazine attacks the S
atom of 6a. The colored arrows represent a thermodynamic change in
the first step for each pathway. Red represents an endergonic process,
while green signifies an exergonic step. The Gibbs energy change is
indicated in parentheses (units of kilocalories per mole).
From the calculated Gibbs energies (ΔG°), the formation of
22 (via P1 or P2) was found to be endergonic (ΔG° = +13.4
kcal/mol). Note, however, that formation of methoxyimidate
21 in the P1 pathway was predicted to be essentially
isoenergetic with 6a (ΔG° = −1.7 kcal/mol). The requisite
transition states for pathways P1 and P2 were explored to
evaluate feasibility. As illustrated in Figure 6a, transition states
for stepwise process P1 were identified and optimized,
connecting 6a ↔ 21 (TS1, 25.8 kcal/mol) and 21 ↔ 22
(TS2, 30.2 kcal/mol). All attempts to resolve an appropriate
transition state for the concerted P2 process invariably
collapsed to structures along the stepwise pathway. We
therefore surmise that either a concerted pathway does not
formally exist or it is higher in energy than the stepwise
pathway. Importantly, however, the stepwise pathway that
allows for the formation of 22 from 6a is well-defined and
energetically accessible. To further validate the feasibility of the
M062X functional, a different functional that explicitly
considers dispersion corrections was used to examine an
exemplary reaction [6a to 22 process (see Figure S10)]. There
were no substantial changes in the results using the LC-ωPBE
functional with dispersion correction.20 The calculated TS
barriers are slightly higher than expected, which implies a
possible pathway catalyzed by both methanol and hydrazine in
such protic media.
For the competing PC pathway, the conversion of 6a to 25
is predicted to be endergonic (ΔG° = +16.0 kcal/mol), while
subsequent conversion to ring-opened intermediate 26 bearing
the three heteroatom substituents on the exocyclic ring carbon
is exergonic (ΔG° = −11.4 kcal/mol) and ring closure to
Meisenheimer complex 27 is endergonic (ΔG° = +6.2 kcal/
mol). These values suggest that this pathway is also kinetically
and thermodynamically feasible and could contribute to the
formation of rearrangement product 18. However, two factors
suggest that its contribution is minimal. First, relative to that of
26, the predicted Gibbs energy for methoxyimidate 21 is
significantly lower (ΔΔG° = −1.7 kcal/mol), indicating that
the P1 pathway is more accessible than the PC route (Figure
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6b). Second, if 26 is formed, the presence of three heteroatoms
on its exocyclic carbon would enable this intermediate to react
via pathways other than that leading to Meisenheimer complex
27 [and, in particular, through loss of the OMe− anion and
formation of imodyl hydrazide 30 (see Figure 9)], a key
intermediate in the formation of rearrangement product 19.
Indeed, formation of 30 from 26 is significantly favored over
conversion to Meisenheimer complex 27 [ΔΔG° = −17.9
kcal/mol (see Figure S8)]. This mode and other reaction
modes open to 26 would not be consistent with the observed
generation of compound 18 from 6a in high (76%) yield.
As further illustrated in the reaction coordinate diagram
(Figure 6b), neutralization of Meisenheimer complex 22
through loss of the NH2NHS− anion and formation of aza-
bicylo intermediate 23 are determined to be highly exergonic
(ΔG° = −49.2 kcal/mol). Similarly, the addition of hydrazine
to the imidate carbon in 23 to give 24 (ΔG° = −18.0 kcal/
mol) and its subsequent collapse to observed product 18 (ΔG°
= −38.3 kcal/mol) were exergonic. These findings strongly
support the idea that the proposed mechanism (Figure 4)
corresponds to the dominant pathway for the conversion of 6a
to rearrangement product 18 upon reaction with hydrazine.
Note, however, that although not anticipated to be generated
to a significant extent, neutralization of Meisenheimer complex
27 was also predicted to be an exergonic process (ΔG° =
−64.6 kcal/mol) producing intermediate 24 directly.
Upon examination of the structure of novel rearrangement
product 19, one feature that immediately stood out is that, as
in compound 18, the nitrogen atom has again migrated to C-8.
This indicated that at some stage in the mechanism leading to
this product a Meisenheimer-type intermediate similar to 22
was generated. In addition, three other distinguishing features
in this molecule relative to 18 stood out: (i) the absence of the
3-chloro atom present in the starting material, (ii) the presence
of the sulfur atom within a 2,1-benzisothiazole ring system, and
(iii) the presence of an additional sulfur atom, which serves as
a link joining two 2,1-benzisothiazole motifs. To connect these
observations together and come up with a plausible mechansim
for the formation of the 2,1-benzisothiazole motifs present in
19, attention was, once again, focused initially on the first step
in which hydrazine reacts with benzisothiazole 6b.
Figure 7. Proposed P1−P3 pathways for reaction of hydrazine with
6b. The colored arrows represent thermodynamic changes in the first
step for each pathway. Red represents an endergonic process, while
green signifies an exergonic step. The Gibbs energy change is
indicated in parentheses (units of kilocalories per mole).
In the stepwise SN2 reaction (P1) process, illustrated in
Figure 7, where hydrazine reacts at the sulfur center, it was
expected that ring opening would lead to transient formation
of a 3-chloroimidate species (not shown) that loses a chloride
ion to give stable benzonitrile compound 28. Indeed, this step
was predicted to be highly exergonic (ΔG° = −61.4 kcal/mol).
In the alternate concerted pathway (P2), direct formation of
Meisenheimer complex 29 was predicted to be endergonic
with a ΔG° of +14.0 kcal/mol, a value close to that found for
the corresponding conversion of 6a to 22. However, the
important finding in this study was the prediction that the
competing SNAr pathway (PC) would be even more exergonic
than the formation of nitrile 28. Indeed, the calculated energy
for the SNAr process leading to introduction of the hydrazine
group at C-3 to give compound 5 corresponds to a ΔG° of
−79.9 kcal/mol.
Figure 8. Reaction coordinate diagram of the first step in P1 and PC
reaction modes of 6b with hydrazine. The total Gibbs free energy of
all reactants was set as the baseline (0 kcal/mol). Each plateau
represents the total Gibbs free energy of all existing compounds (i.e.,
reactants and transition state TS) at each stage.
This result showed that the dominant initial step leading to 19
is the transformation that produces the very compound sought
after for the synthesis of the pyrazolone analogue 3 of
compound 1 (1C8). The fact that compound 5 was not
isolated from the experiment in which 6b reacts with hydrazine
pointed to the apparent marked susceptibility of this 5-
nitrobenzisothiazole compound to undergo further reaction
with hydrazine at the isothiazole ring sulfur atom, leading to
ring opening.
Further study to identify the transition states in the P1 and
PC pathways (Figure 8) “confirmed” that, thermodynamically
and kinetically, benzisothiazole 6b would react with hydrazine
preferentially via the SNAr manifold. In fact, it is noteworthy
that neither nitrile 27 nor the disulfide resulting from its
dimerization was detected in the reaction mixture giving 19.
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As illustrated for the formation of suspected precursor 34 to
rearrangement product 19 in Figure 9, ring opening of 5 via a
Figure 10. Reaction coordinate diagram for the conversion of 6b to
pivotal 2,1-benzisothiazole compound 34. The total Gibbs energy of
all reactants was set as the baseline (0 kcal/mol). Each plateau
represents the total Gibbs energy of all existing compounds at each
stage.
process, 5 → 30, is recovered during formation of tricyclic
intermediate 33, Note further that conversion of 34 to sulfur-
bridged dimer 19 would also liberate a molecule of hydrazine
from each benzisothiazole component. Currently, how this
sulfur bridge was introduced remains unclear.
Figure 9. Predicted pathway from 3-hydrazino-5-nitrobenzisothiazole
5 to isomeric 2,1-benzisothiazole intermediate 34. To better compare
the energy of each compound, two states of hydrazine were used
(NH2NH− and NH2NH2). The Gibbs energy change between the
reactant and product in each step is indicated in parentheses (units of
kilocalories per mole). Red represents an endergonic process, while
green signifies an exergonic step.
CONCLUSIONS
■
The isolation of rearrangement product 18, from the reaction
of 5-nitrobenzisothiazole 6a with hydrazine, clearly showed
that the SN2 pathway, involving reaction of hydrazine at the
sulfur atom with ring opening, outcompeted the desired SNAr
displacement reaction. The preferred formation of Meisen-
heimer complex 22 over collapse of derived imidate 21 to a
nitrile function in the subsequent step is considered to be
driven by both the stability of 21 and the stabilization of
complex 22 by the nitro substituent on the aromatic ring. The
DFT calculations support the idea that this is an energetically
feasible transformation. In addition, the calculations predicted
that the ensuing steps in which the Meisenheimer complex
undergoes addition of hydrazine to give reactive azabicyclo
intermediate 24, and ultimately product 18, would be energy-
releasing exergonic steps.
The fact that formation of the 2,1-benzisothiazole
component in sulfur-bridged dimer product 19 during reaction
of 5-nitrobenzisothiazole 6b with hydrazine similarly involved
an SN2-type ring opening in the first step was less obvious. The
DFT calculations provided important insight into this
conundrum, indicating that the SNAr pathway, giving the
desired 3-hydrazino compound 5, would be the more
energetically favored. Not anticipated, however, was the
apparent susceptibility of compound 5 to further reaction
with the amine (hydrazine) nucleophile present in the reaction
medium. Interestingly, ring opening of 5 was seen to enable
formation of a pivotal Meisenheimer complex (cf. 31).
In conclusion, this study revealed new and novel chemistry
of the benzisothiazole system, which is influenced and/or
governed by the presence of the 5-nitro substituent. A
challenge at this juncture will be to identify the reaction
pathway(s) that generates the third or bridging sulfur atom in
product 19 and to find reaction conditions that permit
two-step (P1) process would lead to formation of imodyl
hydrazide 30, which like methoxy imidate 21 would be
expected to be sufficiently stable to enable its conversion to
Meisenheimer complex 31. Consistent with the proposed
formation of Meisenheimer complex 22 from benzisothiazole
6a, the step leading from 5 to 31 is calculated to be endergonic
(ΔG° = +10.7 kcal/mol). At this point, it was anticipated that
the neutralization of Meisenheimer complex 31 must occur in
a way that permitted conservation of the sulfur atom present in
the isomeric 2,1-benzisothiazole components in 19. Indeed, in
contrast to the reactivity of complex 22, which loses the
−SNHNH2 anion to rearomatize the phenyl ring, a [1,3]-
−
migration (or [1,7]-migration of the SNHNH2 motif in 31)
was envisaged to occur giving [4,6]-bicyclo intermediate 32.
Such migrations of sulfur are known,21 and in the case
presented here, this leads to formation of intermediate 32 in an
overall “energy equivalent” process. It is probable that the use
of substoichiometric amounts of hydrazine in the reaction
favors this process. The subsequent steps in the process leading
to 2,1-benzisothiazole 34 would involve ring closure to tricyclic
species 33, and bond reorganization/ring expansion. Both
steps are predicted to be highly exergonic and/or energetically
favorable. The energetics of these steps and the earlier steps are
reflected in the reaction coordinate diagram presented in
Figure 10.
Note that in this mechanism producing intermediate 34 the
molecule of hydrazine consumed during the ring opening
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room temperature for 1 week, upon which crystals were formed and
taken for single-crystal X-ray diffraction experiments.
Melting points (uncorrected for compounds 17−19) were
determined using a Buchi 535 melting point apparatus.
isolation of 3-hydrazino target compound 5, needed for the
synthesis of the constrained analogue of 2.
2,2′-Disulfanediyldibenzonitrile (11).26 Hydrazine monohydrate
(0.24 mL, 3.1 mmol) was added to a stirred solution of 3-
methoxybenzisothiazole 15 (100 mg, 0.6 mmol) in 2 mL of methanol.
The mixture was heated in an oil bath at reflux for 30 min, cooled to
room temperature, and concentrated in vacuo. The light yellow-
colored residue was extracted with DCM/water. The organic layer
was dried over sodium sulfate and concentrated, affording 11 as a
white solid in 72% yield (note that the corresponding experiments
using EtOH as a solvent resulted in the formation of 11 in similar
EXPERIMENTAL SECTION
■
Computational Methods. DFT calculations were performed
using the Gaussian 09 (G09) computational package.22 All geometry
optimizations were performed in G09 using the restricted M06-2X
functional and the DEF2-TZVP basis set.23,24 The LC-ωPBE
functional with dispersion correction was used to validate M062X
results.20 A conductor-like polarizable continuum solvation model
(CPCM) of methanol and an ultrafine integration grid were applied.
All geometries were optimized to a minimum, and frequency
calculations performed at the same level of theory to verify the
absence of imaginary frequencies. Geometry optimization of transition
states employed the quadratic synchronous transit (QST) approach.25
All structures labeled as transition states exhibit one imaginary
frequency. Intrinsic reaction coordinate (IRC) calculations were
carried out to ensure transition states connected the appropriate local
minima23 (see the Supporting Information for the data).
1
yields): H NMR (CDCl3) (identical to that described in ref 23) δ
7.76 (dd, J = 8.3, 0.7 Hz, 2H), 7.63 (dd, J = 7.7, 1.3 Hz, 2H), 7.57 (td,
J = 7.8, 1.3 Hz, 2H), 7.37 (td, J = 7.6, 1.1 Hz, 2H); MS ESI (m/z)
269.1 [M + H]+, 291.0 [M + Na]+.
3-(2-Phenylhydrazinyl)benzo[d]isothiazole (17). Phenylhydrazine
(0.25 mL, 2.5 mmol) and 3-methoxybenzisothiazole 155,14 (82.6 mg,
0.5 mmol) were dissolved in MeOH (1.6 mL), and the mixture was
heated in an oil bath at reflux for 1.5 days under a nitrogen
atmosphere, cooled to room temperature, and concentrated. The
residue was extracted with DCM/water, and the organic layer was
concentrated. Compound 17 was obtained as yellow needles (68.9
mg, 57% yield) by recrystallization from MeOH: mp 134.3−135.6 °C;
Synthetic and Characterization Methods. All reactions were
performed under a nitrogen atmosphere unless otherwise indicated.
The glassware was flame- or oven-dried. All chemicals were purchased
from commercial sources (Aldrich, Alfa Aesar, Oakwood, or TCI
America) unless otherwise indicated. Microwave experiments were
carried out in a Biotage Initiator Robot Eight System. Column
chromatography was performed using silica gel (Silicycle, Siliaflash
F60, 40−60 μm, 230−400 mesh). Thin layer chromatography (TLC)
was performed using EMD Silica gel 60 F254 plates. TLC plates were
visualized using UV light at a wavelength of 254 nm. NMR
experiments were performed on a Bruker Ascend-400 spectrometer
(400 MHz for 1H and 100 MHz for 13C). All spectra were recorded at
room temperature. For NMR spectra, chemical shifts were measured
in parts per million (δ scale). The coupling constants are reported in
hertz. Multiplicities are reported as follows: s, singlet; d, doublet; t,
triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; p,
pentet; m, multiplet; br, broad singlet. For compounds 17 and 19,
high-resolution mass spectrometry (HRMS) was carried out using an
Agilent QTOF G6545B mass spectrometre equipped with electro-
spray ionization. For compound 18, HRMS was was carried out using
a Thermo Scientific Q Exactive Orbitrap High Resolution Mass
Spectrometer. Low-resolution mass spectra were recorded with an AB
Sciex QTRAP 5500-Agilent 1290 instrument.
1
HPLC tR = 4.7 min, 93.37% purity; H NMR (400 MHz, CDCl3) δ
7.89 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.49 (td, J = 7.6,
1.1 Hz, 1H), 7.34 (td, J = 7.6, 1.1 Hz, 1H), 7.24 (s, 1H), 7.2 (t, J = 6.7
Hz, 2H), 7.05 (br, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.86 (t, J = 7.3 Hz,
1H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.6, 152.6, 148.9, 129.4,
128.6, 125.6, 124.4, 122.4, 121.0, 120.5, 113.5, 77.6, 77.24, 76.9; MS
ESI (m/z) 242.1 [M + H]+; HRMS (HESI) m/z calcd for C13H11N3S
241.0674, found 241.0678, [M + H]+ 242.0752.
(Z)-2-Amino-5-nitrobenzohydrazonamide (18). Hydrazine hy-
drate (50−60%, 0.1 mL, 1.5 mmol) was added to a solution of 3-
methoxy-5-nitro-benzisothiazole 6a5 (52.5 mg, 0.25 mmol) in MeOH
(1 mL). The mixture was heated in an oil bath at reflux for 30 min
and then cooled to room temperature. The yellow precipitate formed
was filtered and washed with cold MeOH to give product 18 as yellow
needles (40.3 mg, 76% yield): mp 163.3−164.0 °C; 1H NMR
(DMSO-d6) δ 8.15 (d, J = 2.7 Hz, 1H), 7.92 (dd, J = 9.1, 2.8 Hz, 1H),
7.89 (br, 2H), 6.79 (d, J = 9.1 Hz, 1H), 6.39 (br, 1H), 3.71 (s, 3H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 152.7, 146.4, 135.4, 124.9,
To determine its purity, compound 17 was injected (10 μL) into
an ACQUITY UPLC H-Class system with a PDA detector (Waters,
Milford, MA). The samples were separated on a Waters Acquity BEH-
C18 column (particle size: 1.7 μm inner diameter, 2.1 mm length, 100
mm column) at a flow rate of 0.4 mL min−1. The mobile phase was
composed of solvent A [0.1% trifluoroacetic acid (TFA) in water] and
solvent B (0.1% TFA in methanol). The following gradient was
applied: 95/5 A/B at 0 min, 95/5 A/B at 0.5 min, 25/75 A/B at 1.0
min, 20/80 A/B at 6.0 min, 100/0 A/B at 6.5 min, 95/5 A/B at 7.1
min, and 95/5 A/B at 9.0 min. For compound 19, HPLC was
performed on a Waters Alliance e2695 separations module coupled to
a Waters 2489 UV/vis detector. The column was a reversed phase
C18 Waters Atlantis T3, 100 Å, 5 μm particle size (4.6 mm × 150
mm) instrument, supported by a C18 guard cartridge, and operated in
an oven (40 °C). The column was eluted with the following gradient:
A being TFA in water and B being 90% acetonitrile in water
supplemented with 0.1% TFA, flow rate of 1 mL/min, 95% A from 0
to 3 min, 5% to 100% B from 3 to 18 min, and 100% B from 18 to 21
min. For both compounds 17 and 19, the UV absorbance at 254 nm
was measured. The purity of the compound was measured by
integrating the area under the peaks on the chromatogram.
123.2, 114.6, 111.8, 56.5; HRMS (HESI) m/z calcd for C8H10N4O3
[M + H]+ 211.0826, found 211.0810. The structure of compound 18
was confirmed by single-crystal X-ray diffraction (see the Supporting
Information).
Synthesis of Bis(5-nitrobenzo[c]isothiazol-3-yl)sulfane (19).
From the Reaction between Hydrazine and 6b. Hydrazine
monohydrate (0.5 equiv) (10 μL) was added to a solution containing
diisopropylethylamine (DIPEA, 1.0 equiv, 0.09 mL) and 3-chloro-5-
nitro-benzisothiazole 6b27 (107.3 mg, 0.5 mmol) in anhydrous EtOH
(1.6 mL). The mixture was stirred at room temperature for 30 min,
and then the resulting dark purple mixture was concentrated and silica
gel column chromatographed using hexane/ethyl acetate (100/0 to
85/15) as the eluant. Compound 19 is obtained as a yellow solid
(20.5 mg, 31.5% yield): mp 203.0−204.1 °C; HPLC tR = 18.8 min,
1
95.05% purity; H NMR (chloroform-d) δ 8.86 (s, 2H), 8.30 (d, J =
9.7 Hz, 2H), 7.95 (d, J = 9.6 Hz, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 163.0, 157.4, 146.2, 133.6, 124.3, 123.3, 117.8; HRMS
(HESI) m/z calcd for C14H6N4O4S3 389.9551, found 389.9550, [M +
H]+ 390.9624.
From the Reaction between 20 and 6b. A mixture of 2028 (51.7
mg, 0.42 mmol) and 3-chloro-5-nitrobenzisothiazole 6b (74.5 mg,
0.35 mmol) in acetonitrile (1.5 mL) was heated at 125 °C for 2.5 h
under microwave conditions. The resulting dark purple mixture was
concentrated and silica gel column chromatographed using hexane/
ethyl acetate (100/0 to 85/15) as the eluant. Compound 19 is
obtained as a yellow solid (16.0 mg, 35% yield). The structure of 19
Single-crystal X-ray diffraction experiments were carried out using a
Bruker APEX II area detector diffractometer. Crystals of compound
18 were prepared from recrystallization in MeOH. Crystals of
compound 19 were obtained by using the vapor diffusion method. A
small test tube containing a solution of 19 in EtOAc was placed within
a larger sealed glass tube containing hexane. The sample was left at
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Article
has been confirmed by single-crystal X-ray diffraction (see the
Supporting Information).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00118.
1H and 13C{1H} NMR spectra of compounds 11 and
17−19, UPLC/HPLC data for compounds 17 and 19,
HRMS spectra of compounds 17−19, single-crystal
diffraction data for compounds 18 and 19, and DFT
calculations for the formation of 18 and 19 (PDF)
Accession Codes
CCDC 2055628 and 2055694 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
David S. Grierson − Faculty of Pharmaceutical Sciences, The
University of British Columbia, Vancouver, British Columbia
V6T 1Z3, Canada; orcid.org/0000-0002-4745-4240;
Phone: +1 604 8273353; Email: dgrierso@mail.ubc.ca
Pierre Kennepohl − Department of Chemistry, The University
of British Columbia, Vancouver, British Columbia V6T 1Z1,
Canada; Department of Chemistry, University of Calgary,
Calgary, Alberta T2N 1N4, Canada; Phone: +1 403
2208138; Email: Pierre.kennepohl@ucalgary.ca
Authors
Zheng Sonia Lin − Faculty of Pharmaceutical Sciences, The
University of British Columbia, Vancouver, British Columbia
V6T 1Z3, Canada
Xing Tong − Department of Chemistry, The University of
British Columbia, Vancouver, British Columbia V6T 1Z1,
Canada; Department of Chemistry, University of Calgary,
Calgary, Alberta T2N 1N4, Canada
Brian Patrick − Department of Chemistry, The University of
British Columbia, Vancouver, British Columbia V6T 1Z1,
Canada; orcid.org/0000-0002-2921-8439
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00118
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by grants from the
Canadian Institutes of Health Research (CIHR) and NSERC
(Discovery): NSERC Discovery Grant 2016-05453 and CIHR
Doctoral Scholarship 293029. The authors thank Dr. Yun Ling
and Ms. Jane Ju from the UBC Mass Spectrometry Centre for
performing the HRMS analyses of compounds 17 and 19. The
authors also thank Ms. Anne Nguyen for performing the
UPLC analysis of compound 17 and Mr. Lennart Bohrmann
for performing the HPLC analysis of compound 19.
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