A Hydrazine Insertion Route to N′-Alkyl Benzohydrazides by an Unexpected Carbon-Carbon Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.9b02657

A serendipitous carbon-carbon bond cleavage in the reaction of benzoyl acrylates, derived from Morita-Baylis-Hillman adducts, with hydrazines delivered new N′,N′-disubstituted benzohydrazides. The reaction features a regioselective formation of two carbon

Full text of DOI:10.1021/acs.orglett.9b02657

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Hydrazine Insertion Route to N′‑Alkyl Benzohydrazides by an
Unexpected Carbon−Carbon Bond Cleavage
Ajit Kumar Jha, Rajkiran Kumari, and Srinivasan Easwar*
Department of Chemistry, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, NH-8, Bandarsindri, Distt.
Ajmer, Rajasthan 305817, India
S
* Supporting Information
ABSTRACT: A serendipitous carbon−carbon bond cleavage in the
reaction of benzoyl acrylates, derived from Morita−Baylis−Hillman
adducts, with hydrazines delivered new N′,N′-disubstituted benzohy-
drazides. The reaction features a regioselective formation of two
carbon−nitrogen bonds and works well with a range of acrylates and
hydrazines. A brief mechanistic investigation alluded to a cyclic
hemiaminal as a plausible intermediate.
he Morita−Baylis−Hillman (MBH) reaction1,2 delivers
anxiety disorders.12 Furthermore, a recent report found both
N′-alkyl and N′-acyl substituted 3-furoic hydrazides to be
promising candidates for antischistosomal activity.13 In
addition to their medicinal value, substituted hydrazides have
also been utilized in the synthesis of 1H-indazolones,14 2-imino
1,3,4-oxadiazolines,15 and N-acylhydrazones that exhibit
promising bioactivity.16,17 Hence, research on the synthesis
of substituted hydrazines and hydrazides has witnessed
continued activity;12,18 new analogs and strategies for their
synthesis would be of interest to the chemical and
pharmaceutical research community.
In the quest of exploring the reactivity of MBH ketones, we
serendipitously observed a reaction that afforded new N′-alkyl
substituted benzohydrazides. We carried out deeper inves-
tigations into the transformation, and the findings of the study
are presented herein.
T
adducts which are multifunctional and can be manipu-
lated in myriad ways.3 One such transformation is the
oxidation of the allylic alcohol,4 which affords the correspond-
ing “MBH ketone”. These 1,1-disubstituted olefins flanked by
two electron-withdrawing groups have attracted considerable
attention owing to their reactivity as Michael acceptors and
their ability to participate in Diels−Alder reactions as a
dienophile as well as heterodiene. Transformations of MBH
ketones have been explored by either generating them in situ5,6
or using the isolated compound.7 The former has been
achieved in two different ways, viz (i) IBX mediated oxidation
of MBH adducts5 and (ii) Knoevenagel condensation of 1,3-
dicarbonyls with formaldehyde,6 followed by trapping the
conjugated olefin in Michael or Diels−Alder fashion. On the
other hand, numerous reports can also be found on
transformations of MBH ketones that have been synthesized
and isolated, albeit not always by oxidation of an MBH
adduct.7 A majority of them pertain to the Diels−Alder
reaction, including an asymmetric version and an application in
natural product synthesis.7a−d Other noteworthy instances
include a [3 + 2] cycloaddition to generate isoxazolines,7e
synthesis of vicinal tricarbonyl compounds by ozonolysis,7f and
access to functionalized 1,4-dicarbonyl compounds by a Stetter
reaction.7g
On the other hand, substituted hydrazides are known to
exhibit interesting biological activity, reflected by their role in
peptidomimetics and other commercial applications.8−10 The
most interesting are the N,N′-diacyl hydrazines, chief among
them N′-tert-butyl substituted benzohydrazides, that have
attracted tremendous interest as growth regulators of
Lepidopteran insects.11 The earliest such report was of
RH5849,11a,b followed by Tebufenozidethe first commercial
nonsteroidal ecdysone agonist,11c and several structural
analogs.11d−g Also, N′-alkyl hydrazide analogs such as
isocarboxazid and iproniazid are classical monoamine oxidase
inhibitors (MAOIs) that have been used for the treatment of
Our group has been evaluating controlled base-mediated
Michael additions of heteroatomic nucleophiles to the highly
reactive MBH ketone. Simultaneously, we were also looking to
connect its two electrophilic ends to dinucleophiles, in typical
fashion involving concomitant Michael addition−condensa-
tion, to construct five-membered heterocycles. In one such
experiment in the midst of these studies, when we treated
MBH ketone 1a with phenylhydrazine (2a) in the presence of
Et3N in THF at room temperature, the major product formed
turned out to be neither a pyrazoline nor the aromatized
pyrazole expected on the above lines; instead, we deciphered it
to be the N′,N′-disubstituted benzohydrazide 3a (Scheme 1)
1
on the basis of two distinct methylenes observed in the H
NMR spectrum, supported by a 13C NMR scan that indicated
the presence of an amide group; additionally, mass
spectrometric analysis revealed an atom economic trans-
formation. X-ray crystal analysis of an analog helped us
Received: August 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02657
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pyrazoline 4 instead of 3a (entry 1). A short survey of solvents
was then carried out for the reaction in the presence of Et3N,
and it was found that CH3CN was the best (entries 2−5).
Lowering the stoichiometry of the base or the hydrazine did
not greatly affect the efficiency of the reaction outcome
(entries 6−10); 10 mol % of Et3N sufficed to deliver a similar
yield of 3a over the same duration (entry 9). Next, a study of
bases was undertaken; organic bases generally produced a
mixture of 3a and 4 (entries 11−14); interestingly, the use of
pyridine as the base as well as solvent afforded pyrazoline 4
Scheme 1. Reaction of 1a with 2a to Generate a
Benzohydrazide
confirm both the structure and the regiochemistry of the
phenylhydrazine insertion (Scheme 2, 3b). Thus, it could be
inferred that N2 of 2a translated to the amide nitrogen,
whereas N1 was linked to the alkyl chain in the product 3a. To
sum up the transformation, two new carbon−nitrogen bonds
are formed in the interaction of phenylhydrazine with the
MBH ketone, whereas the accompanying carbon−carbon bond
cleavage led to the formation of the acyclic benzohydrazide. It
is worth noting that the bond formed in the MBH reaction at
the outset is eventually cleaved in the process. To our
knowledge, this is the first instance of such a carbon−carbon
bond cleavage occurring in a substrate derived from an MBH
reaction. Further, despite the substantial literature on the
synthesis of hydrazines, a one-step access to N-acyl-N′-alkyl
analogs by insertion of a hydrazine does not appear to have
precedent. Lastly, considering the challenges pertaining to N1/
N2 selectivity in hydrazine alkylations,19,20 a prominent feature
of the present transformation is the regioselectivity achieved in
the insertion of phenylhydrazine using a mild organic base.
These interesting features urged us to undertake a detailed
study of the transformation, commencing with the optimiza-
tion of the conditions for the reaction of 1a with 2a (Table 1).
The requirement of a base for the formation of 3a was revealed
by a reaction in its absence, which resulted exclusively in the
n
exclusively (entry 15). Use of NaH and BuLi as bases proved
futile (entries 16 and 17), whereas the use of Cs2CO3 provided
the only instance of formation of the N-phenyl regioisomer
3a′, alongside the desired 3a (entry 18).21
We then sought to explore the scope of this new method of
generating benzohydrazides by using various MBH ketones in
reactions with the aromatic hydrazines 2a and 2b under the
optimized conditions. The reaction worked well with
substituents of differing electronic character on the aromatic
ring of 1. As shown in Scheme 2, halogen substituents at the
para-position proved favorable in delivering the corresponding
benzohydrazides with excellent efficiency. Reactions of MBH
ketones bearing strong electron-donating (p-OMe) and
electron-withdrawing (p-NO2) substituents proceeded with
comparable efficiency, highlighting the generality of the
process. A fruitful outcome could also be achieved using a
meta-substituted variant as well as a heteroaryl MBH ketone,
resulting in substantial yields of the benzohydrazides 3h and 3i,
respectively. Further, ethyl benzoacrylate analogs participated
in similar fashion to their methyl counterparts and afforded the
benzohydrazides 5a−i in reasonable to high yields. Lastly, the
reaction also worked well using a different hydrazinethe p-
chlorophenyl analog 2b. The efficiency of the reaction using 2b
also remained largely unaffected by the nature of the aromatic
component in 1; benzohydrazides 3j−m and 5j−m (methyl
and ethyl ester derivatives, respectively) could thus be
generated in satisfactory yields.22
a
Table 1. Optimization of Reaction Conditions
To study the reaction using an aliphatic hydrazine, we chose
the tert-butylhydrazine (2c) based on the huge impact of the
N′-tert-butyl substituted hydrazides as insecticides. Gratify-
ingly, the reaction22 proceeded well and a number of N′-tert-
butyl substituted benzohydrazide analogs could be generated
from various MBH ketones (Scheme 3). 4-Halo substituents
proved favorable once again for obtaining good yields of the
hydrazides. The use of the meta-chlorophenyl variant afforded
a crystal of the corresponding benzohydrazide 3r, X-ray
analysis of which confirmed that the aliphatic hydrazine
mirrored the regioselectivity of its aromatic counterparts.
Overall, we were able to access several new N′-tert-butyl
substituted benzohydrazides in moderate yields. Lastly it is
worth mentioning that the reaction also proceeded well using
simple hydrazine and is currently being studied in more detail
for its scope.
After the scope of the reaction was examined, a mechanistic
interpretation of the observations was probed. A plausible
pathway for the reaction is illustrated in Scheme 4. At the
outset, aza-Michael addition of phenylhydrazine (2a) to the
MBH ketone 1a leads to the intermediate I; intramolecular
condensation could then be expected to afford pyrazoline 4 via
the intermediacy of cyclic hemiaminal II. However, in the
presence of Et3N, II perhaps undergoes base catalyzed proton
transfer accompanied by a carbon−carbon bond cleavage,
leading to the formation of 3a. Alternatively, a concerted acyl
b
yield [%]
entry
base [equiv]
solvent
time [h]
3a
4
1
2
3
4
5
6
7
8
9
−
THF
THF
24
17
12
12
12
15
15
15
15
15
15
15
15
15
15
24
1
0
50
10
NEt3 [2.5]
NEt3 [2.5]
NEt3 [2.5]
NEt3 [2.5]
NEt3 [1.5]
NEt3 [1.0]
NEt3 [0.5]
NEt3 [0.1]
65
88
76
80
83
82
83
79
76
71
40
27
63
−
CH3CN
dioxane
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
pyridine
THF
trace
trace
trace
trace
trace
trace
trace
trace
15
28
32
15
54
c
10
NEt3 [0.5]
11
12
13
14
15
16
17
18
pyrrolidine [0.5]
imidazole [0.5]
N-methyl imidazole [0.5]
DMAP [0.5]
d
pyridine
nBuLi [1.2]
−
−
NaH [1.2]
Cs2CO3 [0.5]
THF
CH3CN
−
57
−
e
10
trace
a
Reactions were carried out on 0.5 mmol of 1a using 500 μL of the
solvent at rt. Refers to isolated yield after column chromatographic
purification. 1.2 equiv of 2a was used. Used as a solvent. Refers to
the yield of the mixture of 3a and its regioisomer 3a′.
b
c
d
e
B
DOI: 10.1021/acs.orglett.9b02657
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Organic Letters
Letter
a
Scheme 2. Benzohydrazides from the Reaction of 1 with Aryl Hydrazines
a
b
Yields refer to isolated yields after column chromatographic purification. Reactions were carried out using 0.5 equiv of Et3N in 500 μL of
c
d
CH3CN. 2b was prepared and used as a hydrochloride. Reactions were carried out using 3.5 equiv of Et3N and 50 μL of H2O in 500 μL of
CH3CN.
a
Scheme 3. Benzohydrazides from the Reaction of 1 with tert-Butylhydrazine (2c)
a
b
c
Yields refer to isolated yields after column chromatographic purification. Used as a hydrochloride. Reactions were carried out on 0.5 mmol of 1
using 3.5 equiv of Et3N, 500 μL of CH3CN, and 50 μL of H2O.
transfer occurring on I to directly deliver 3a may also be
considered.23 To gain insight into the pathway, we set up the
reaction of 1a with 2a monitored by 1H NMR spectroscopy.24
After 15 min in the absence of Et3N, the 1H NMR spectrum of
the crude reaction mixture showed complete consumption of
1a and formation of pyrazoline 4 (signals at δ 4.07, 4.35, and
4.48 ppm); no characteristic peaks of 3a were observed at this
stage. In contrast, the H NMR spectrum recorded 15 min
after the addition of Et3N showed the appearance of a singlet at
δ 3.63 and two triplets at δ 2.77 and 3.97, indicating the
1
C
DOI: 10.1021/acs.orglett.9b02657
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Plausible Mechanistic Pathway for the Reaction of 1a with 2a Leading to the Formation of 3a
formation of 3a. The intensity of the peaks corresponding to
3a increased with time, accompanied by a gradual disappear-
ance of the signals corresponding to pyrazoline 4.25 The study
supports the pathway illustrated in Scheme 4, in which one
may imagine the intermediate II to be in a dynamic
equilibrium with both 4 and 3a; the former has a dominant
presence in the initial stages of the reaction, whereas the
acyclic hydrazide manifests as the eventual major product after
addition of the base. A control experiment was also performed
to attempt the conversion of isolated pyrazoline 4 to 3a using
H2O/Et3N; however it did not prove successful, perhaps
suggestive of the origin of hemiaminal II and the dynamic
nature of the equilibrium in the parent reaction. The study also
suggests that the reaction does not proceed through a
concerted acyl transfer mechanism, but rather an addition−
elimination sequence. It is worth noting that the loss of a
carbon−carbon bond in the process prevails over the
formation of a heterocycle with a propensity for aromatization.
In summary, new N′,N′-disubstituted benzohydrazides were
synthesized by the reaction of MBH ketones with aryl/alkyl
hydrazines in the presence of triethyl amine. The reaction
features a regioselective insertion of the hydrazine into the
benzoyl acrylate skeleton. A brief mechanistic study indicated
the involvement of a cyclic hemiaminal intermediate that
preferentially breaks down to the acyclic amide by a general
base mediated proton transfer.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: easwar.srinivasan@curaj.ac.in.
ORCID
Srinivasan Easwar: 0000-0002-7352-0897
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Sushil Kumar (NCL Pune) and T.
Vijayakanth (IISER Pune) for assistance in solving the crystal
structures. The authors acknowledge funding received from
CSIR and SERB, India in the form of research grants (CSIR
Grant Ref. No.: 02(0316)/17/EMR-II; SERB Grant Ref. No.:
EMR/2017/005350). The authors thank DST-FIST for a
research grant to the Department of Chemistry (Grant Ref.
No.: SR/FST/CSI-257/2014 (C)) and Central University of
Rajasthan for support.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
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glett.9b02657.
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Accession Codes
CCDC 1905374 and 1905377 contain the supplementary
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