Chemical switching in reaction behavior of azine: Synthesis of a novel thienodiazepine derivative

Article abstract of DOI:10.1016/j.tetlet.2021.153043

We previously have reported that an acid-promoted condensation of a hydrazonoester derived from phenylalanine afforded an azine which was converted to a pyrrole through 3 steps: isomerization to dienamine, [3,3]-sigmatropic rearrangement, and cyclization.

Full text of DOI:10.1016/j.tetlet.2021.153043

Tetrahedron Letters 71 (2021) 153043
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemical switching in reaction behavior of azine: Synthesis of a novel
thienodiazepine derivative
Kaoru Ohtake a, Jyunpei Tsuda a, Kazuhiko Takatori b, Shinji Nagumo a, Eiko Yasui a,
⇑
a Department of Chemistry and Life Science, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan
b Meiji Pharmaceutical University, Nishio 2-522-1, Kiyose-shi, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We previously have reported that an acid-promoted condensation of a hydrazonoester derived from
phenylalanine afforded an azine which was converted to a pyrrole through 3 steps: isomerization to dien-
amine, [3,3]-sigmatropic rearrangement, and cyclization. In this study, reaction behavior of the interme-
diate proved to be switched depending on the type of the aromatic ring. Hydrazonoesters derived from
thienylalanines afforded various thienodiazepine derivatives under thermal acidic conditions. A more
reactive thiophene ring is likely to undergo Friedel-Crafts reaction prior to isomerization to dienamine.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 14 February 2021
Revised 23 March 2021
Accepted 25 March 2021
Available online 30 March 2021
Keywords:
Thienodiazepine
Hydrazonoester
a-diazoester
Pyrrole
Friedel-Crafts reaction
Benzodiazepins play an important role in pharmacotherapy for
anxiety and depressive psychosis (Fig. 1). Most of them have a
bicyclic core consisting of benzene and 1,4-diazepine (i.e., 1,4-ben-
zodiazepin), but 2,3-benzodiazepines including tofisopam are also
used as anti-anxiety drugs. Furthermore, a bioisosteric replace-
ment of benzene by thiophene created several anxiolytic thienodi-
azepines represented by etizolam.
Thiophene resembles benzene also in its chemical property.
Although the degree is less than that of benzene, thiophene also
has aromaticity. Therefore, not addition but substitution with var-
ious electrophiles takes place in the ring system. We previously
Hydrazonoesters 1b-c were prepared from thienyl alanines 3b-
c (Scheme 2). Esterification of 3b-c with SOCl2 in MeOH generated
4b-c, which were converted to a-diazoesters 5b-c [3]. Reduction of
5b-c with P(n-Bu)3 gave (E)-hydrazonoesters 1b-c as major prod-
ucts [4]. Furthermore, treatment of 1b with CaCl2 in toluene
resulted in geometric isomerization to afford (Z)-hydrazonoester
1b’ [5]. Other hydrazonoesters 1d-1j having electron-donating or
electron-withdrawing substituents on thiophene rings were syn-
thesized as follows. Upon treatment with LDA and DMF, 6d and
6i were formylated to give 7d and 7i, which were converted into
esters 9d and 9i through Wittig reaction and subsequent hydro-
genation with Pd/C. Esters 9d and 9i were transformed to 1d and
1i by the sequence of benzoylation, diazo transfer reaction [6]
and reduction of the diazo group. In a similar manner, 1e-1h were
synthesized from commercially available aldehydes 7e-h. How-
ever, hydrogenation of conjugated ester 8e-f with bromothio-
phenes was carried out using Wilkinson’s catalyst [7].
With various substrates containing a thienyl group in hand,
dimeric condensation was examined. Treatment of 1b with SOCl2
in methanol under reflux did not give pyrrole 2b but gave a non-
pyrrole product for which the 1H NMR spectrum showed geminally
coupled methylene protons at d 3.76 and 3.61 in CDCl3 (Scheme 3).
These signals suggested the presence of asymmetric center in the
non-pyrrole product. Finally, the product was assigned to be 2,3-
thienodiazepine 10b by X-ray analysis (Fig. 2). Also, (Z)-isomer
1b’ generated 10b in excellent yield.
reported a pyrrole synthesis by dimeric condensation of
zonoester, which was prepared by reduction of -diazoester
(Scheme 1) [1,2]. Thus, two molecules of -hydrazonoester 1a con-
a-hydra-
a
a
dense to form pyrrole diester 2a along with removal of hydrazine
and ammonia upon treatment with SOCl2 in refluxing MeOH. In
this reaction, the phenyl group at the b-position seems to be effec-
tive for obtaining satisfactory yield. We tried the dimeric conden-
sation of a-hydrazonoester containing thiophene in expectation of
its equivalency with benezene but met with unexpected chemical
switching. This paper describes facile formation of thieno-2,3-dia-
zepines by dimeric condensation of
nyl group.
a-hydrazonoester with a thie-
⇑
Corresponding author.
E-mail address: bt13305@ns.kogakuin.ac.jp (E. Yasui).
https://doi.org/10.1016/j.tetlet.2021.153043
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

K. Ohtake, J. Tsuda, K. Takatori et al.
Tetrahedron Letters 71 (2021) 153043
Scheme 3. Dimeric condensation of hydrazonoester of 1b and 1b0.
Fig. 1. Medicinal drugs containing a diazepine structure.
Scheme 1. Dimeric condensation of hydrazonoester of 1a.
Fig. 2. X-ray analysis of 4e (CCDC2056143)
Scheme 2. Synthesis of hydrazonoesters.
Scheme 4. Chemical switching a dimeric condensation.
2

K. Ohtake, J. Tsuda, K. Takatori et al.
Tetrahedron Letters 71 (2021) 153043
The chemical switching between thienodiazepine formation
and pyrrole formation can be explained as follows (Scheme 4).
The first step of both reactions is dimerization of hydrazonoester,
giving enamine B with loss of hydrazine via azine A [8]. The next
step diverges depending on the nucleophilic strength of aromatic
rings in the intermediates. For the phenyl group, further double
bond isomerization takes place to give dienamine C. Subsequently,
diaza-Cope rearrangement of C results in the formation of diimine
D, which is transformed to pyrrole 2a by the sequence of cycliza-
tion and aromatization by removal of ammonia. On the other hand,
for a more reactive thienyl group, Friedel-Crafts (F-C)-type reaction
of B takes place prior to double bond isomerization to form 2,3-
thienodiazepine 10b through an intermediate F.
Table 1 shows dimeric condensation of positional isomer 1c on
thiophene ring and derivatives 1d-1i having electron-donating or
electron-withdrawing substituents on the ring. Dimeric cyclization
of 1c occurred selectively at the 20-position of thiophene to give
thienodiazepine 10c in 86% yield (Entry 1). Compound 1d afforded
thienodiazepine 10d in 44% yield (entry 2). The ester group at the
C5 position did not hinder F-C-type reaction at the C3 position. A
bromide substituent at the C5 position lowered the reactivity of
the F-C-type reaction and the yield of 10e was only 25% (entry
3). On the other hand, the positional isomer 1f yielded thienodi-
azepine 10f (66%) and pyrrole 2f (34%) (entry 4). Compound 1g
having a methyl group at the C5 position favored F-C-type reaction
to give 10g in excellent yield (entry 5). However, a methyl sub-
stituent at the C4 position lowered the yield of thienodiazepine
10h (entry 6). A methoxy substituent directed an azine intermedi-
ate formed by condensation of 1i toward another type of reaction
to give thienopyridine 11i (entry 7). The structure of 11i was
unequivocally determined by X-ray analysis (Fig. 3).
Scheme 5 shows plausible mechanistic pathway for the forma-
tion of 11i. Due to the electron donation from oxygen of the meth-
oxy group, intermediate B most likely undergoes ipso-cyclization
to produce a spiro intermediate G. Then the methoxy thienomethyl
group is removed [9] concomitant with formation of the cyclo-
propane ring to form H. Electron donation from sulfur leads to
cleavage of cyclopropane ring, imine formation, and NAN bond
cleavage. Subsequent cyclization proceeds along with removal of
ammonia to form 11i.
Table 1
Conversion of Hydrazonoesters.
Entry Hydrazonester
1
Products
2
3
4
Fig. 3. X-ray analysis of 11i (CCDC2055983)
5
6
7
1c-1i was refluxed in MeOH with SOCl2.
Scheme 5. Plausible reaction mechanism for thienopyridine 11i.
3

K. Ohtake, J. Tsuda, K. Takatori et al.
Tetrahedron Letters 71 (2021) 153043
Table 2
type reaction to yield a thienodiazepine derivative. Substituents
on the thiophene ring changed the reactivity. Halogen substituents
lowered the reactivity of Friedel-Crafts-type reaction of azine.
Thienodiazepine derivatives were converted to pyrroles at a higher
temperature through a retro Friedel-Crafts reaction. These newly
synthesized compounds are expected to be good lead compounds
for searching for bioactive substances.
Conversion of Thienodiazepine to Pyrrole.
Hydrazonoester
Product
Yield (%)
10b (R = H)
10d (R = CO2Me)
10g (R = Me)
2b (R = H)
2d (R = CO2Me)
11g (R = Me)
32
31
46
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
This study was supported in part by a grant from the Strategic
Research Foundation Grant-aided Project for Private Universities
from the Ministry of Education, Culture, Sport, Science, and Tech-
nology, Japan (MEXT), 2014-2018 (S1411005).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153043.
Scheme 6. Production of thienopyridine 11g.
Finally, conversion of thienodiazepine to pyrrole was examined
(Table 2). Heating of 10b at 160 °C with 10-camphorsulfonic acid
(CSA) in xylene in a sealed tube gave a pyrrole 2b in 32% yield. Also,
10d was converted into pyrrole 2d in moderate yield upon treat-
ment under the same conditions. The transformation commences
with retro Friedel-Crafts reaction of protonated thiophene same
as F that becomes possible at a higher temperature (Scheme 4).
The resulting imine B should be converted into thermodynamically
more stable 2b in the same pathway as the reaction of 1a. On the
other hand, 5-Me thiophene 1g gave a thienopyridine 11g in 46%.
Electrondonating effect of Me group caused elimination of methyl
thienomethyl group [9] to yield intermediate I and subsequent
cyclization gave 11g (Scheme 6).
References
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[8] Azine can’t be isolated as the reaction proceed quickly to yield
thienodiazepines.
In conclusion, we have found that an azine produced from con-
densation of thienyl hydrazonoesters underwent a Friedel-Crafts-
[9] The thiophene derivative produced by elimination has not been isolated.
4