Direct Catalytic Symmetrical, Unsymmetrical N,N-Dialkylation and Cyclization of Acylhydrazides Using Alcohols

Article abstract of DOI:10.1021/acs.orglett.0c02369

Herein, direct N,N-dialkylation of acylhydrazides using alcohols is reported. This catalytic protocol provides one-pot synthesis of both symmetrical and unsymmetrical N,N-disubstituted acylhydrazides using an assortment of primary and secondary alcohols w

Full text of DOI:10.1021/acs.orglett.0c02369

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Letter
Direct Catalytic Symmetrical, Unsymmetrical N,N-Dialkylation and
Cyclization of Acylhydrazides Using Alcohols
Subramanian Thiyagarajan and Chidambaram Gunanathan*
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ABSTRACT: Herein, direct N,N-dialkylation of acylhydrazides using alcohols is
reported. This catalytic protocol provides one-pot synthesis of both symmetrical and
unsymmetrical N,N-disubstituted acylhydrazides using an assortment of primary and
secondary alcohols with remarkable selectivity and excellent yields. Interestingly, the
use of diols resulted in intermolecular cyclization of acylhydrazides, and such products
are privileged structures in biologically active compounds. Water is the only byproduct,
which makes this catalytic protocol sustainable and environmentally benign.
-Acyl hydrazides are valuable reactive intermediates with
widespread applications in synthesis of pharmaceuticals,
byproducts.15,16 Sustainable alkylation of amines directly from
alcohols is well developed following these two interesting
concepts.15,16 However, currently known methods are largely
limited to monoalkylation of amines.17 One-pot dialkylation of
amines is less developed and also suffers from poor selectivity
due to the competing side reactions.15,16 On the other hand,
selective N-alkylation of acylhydrazides is poorly studied.
Recently, Zhou group reported the selective mono-N-
alkylation of acylhydrazides using racemic alcohols to
enantiomeric amine products.18 However, there is no example
of one-pot N,N-dialkylation of acylhydrazide by alcohols that is
documented. Due to the lack of selectivity and limitations of
the traditional methods for dialkylation reaction and biological
importance of the N,N-disubstituted acylhydrazide products,
development of a green and sustainable process is important
and urgently required.
We recently reported the ruthenium catalyzed regioselective
hydrogenation of epoxides,19 cross-coupling of secondary
alcohols,20 ketazines synthesis directly from secondary
alcohols,21 selective α-alkylation, and α-olefination of nitriles
using alcohols.22 Followed by these recent reports, herein we
describe the Ru-Macho (1) catalyzed N,N-dialkylation and
cyclization of acylhydrazides using alcohols as alkylating
agents. Such a one-pot synthesis of N,N-dialkylacylhydrazides
is a desirable attractive strategy, unknown, and devoid of
lengthy separation and purification procedures of the
intermediate and can save reaction time.
N
polymer materials, and in agricultural chemistry and chemical
industries.1,2 Acylhydrazides analogues possess biological
activities like PGI2 agonists,3 papilloma virus inhibitors,4 D1
dopamine receptor antagonists,5 tuberculostatic,6 antibacteri-
al,7 anticonvulsant,8 and antifungal activities,9 and they are
widely used as precursors for the synthesis of heterocyclic
compounds.2 In particular, the cyclic acylhydrazide products
are highly important in biological applications and synthesis of
drugs (Figure S1).10 Substituted acylhydrazides are conven-
tionally synthesized from the reaction of acyl halides with
substituted hydrazines or reaction of acylhydrazides with
stoichiometric strong bases, followed by addition of toxic alkyl
halides (Scheme 1a).10 Recently, reductive alkylation of
hydrazine derivatives using α-picoline-borane (used in a
stoichiometric amount) to provide alkylated hydrazides has
been reported.11 Copper catalyzed synthesis of N-acyl-N,N-
disubstituted hydrazines using aryl halides via coupling
reaction has also been reported.12,13 These methods suffer
from harsh reaction conditions, use of toxic acyl chlorides and
alkyl or aryl halides, poor yields and produce stoichiometric
amount of undesired byproducts, which curtail the atom
economy of the reactions. Alcohols are sustainable chemical
feedstock for alkylation reactions due to their ready availability,
biorenewability, effective low cost, and environmentally benign
nature.14 Despite these advances, synthesis of N,N-disubsti-
tuted acylhydrazides using alcohols remains unknown. Thus,
direct catalytic N,N-dialkylation of N-acylhydrazides using
alcohols is highly desirable and offers the potential routes to
synthesis of pharmaceutically important hydrazide derivatives
(Scheme 1b).
Received: July 17, 2020
Borrowing hydrogen methodology and acceptorless dehy-
drogenative coupling reactions are remarkable recent progress
for the construction of new C−C, C−N, and C−O bonds,
which produce molecular hydrogen and water as the only
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© XXXX American Chemical Society
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Scheme 1. Conventional Methods vs Selective Catalytic
N,N-Dialkylation of Acylhydrazides Using Alcohols
Scheme 2. Ruthenium-Catalyzed Symmetrical N,N-
a
Dialkylation of Acylhydrazides Using Alcohols
Optimization studies established that the reaction of
benzohydrazide (0.5 mmol), 1-hexanol (1.1 mmol, 2.2
equiv) in toluene with ruthenium pincer catalyst 1 (2 mol
%) and KOtBu (5 mol %) at 135 °C as the standard
experimental conditions (Table S1). The scope of the different
acylhydrazides using alcohols was examined (Scheme 2).
Reaction of unactivated aliphatic alcohols such as 1-propanol,
1-butanol, 3-methyl-1-butanol, and 1-hexanol with acylhydra-
zides provided the corresponding N,N-dialkyl acylhydrazide
products 2a−2d in excellent yields. The reactions of 5-hexen-
1-ol and a monoterpenoid citronellol with benzohydrazide
resulted in the corresponding N,N-dialkylation products 2e
and 2j in very good yields without affecting both terminal and
internal alkene functionalities. Long-chain linear, branched,
and aryl group embedded aliphatic primary alcohols with
acylhydrazides resulted in the products 2f−2i (Scheme 2).
Further, challenging diethylation and dimethylation reactions
were performed using ethanol and methanol as alkylating
agents. Acylhydrazides bearing different substituents on the
aryl ring were subjected in a catalytic diethylation reaction,
which provided the products in excellent yields (2k−2p).
Interestingly, 4-amino benzohydrazide underwent chemo-
selective acylhydrazide N,N-diethylation without affecting the
aniline amine group (2n, Scheme 2). Furylhydrazide was
amenable to the reaction; however, unexpectedly only
monoethylation occurred to provide 2p, perhaps due to the
involvement of intramolecular hydrogen bonding. Increased
catalyst load (1, 5 mol %) and base KOtBu (50 mol %) with a
prolonged reaction time (48 h) was employed to effect the
dimethylation using methanol. Notably, N,N-dimethylbenzo-
hydrazide 2q was obtained in 93% yield, and this compound is
a
Reaction conditions: acylhydrazide (0.5 mmol, 1 equiv), primary
alcohol (1.1 mmol, 2.2 equiv), toluene (2 mL), catalyst 1 (2 mol %),
and KOtBu (5 mol %) were heated at 135 °C under argon flow for 24
b
h. Reported yields correspond to isolated pure compounds. 10 equiv
c
of ethanol was used. 2 mL of methanol and 5 mol % of catalyst 1 and
50 mol % KOtBu were used and the reaction performed for 48 h.
found to be a pesticide residue in food.2b Other functionalized
benzohydrazides with methanol provided products in good to
excellent yields (2r−2v, Scheme 2).
Another feature of the reaction is the potential to achieve
one-pot unsymmetrical N,N-dialkylation of acylhydrazides
using two different alcohols with remarkable selectivity. An
assortment of acylhydrazides was reacted with one equivalent
B
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a
Scheme 3. Ruthenium-Catalyzed Unsymmetrical N,N-Dialkylation of Acylhydrazides Using Alcohols
a
Reaction conditions: acylhydrazide (0.5 mmol, 1 equiv), alcohol (0.55 mmol, 1.1 equiv), toluene (1.5 mL), catalyst 1 (1 mol %), and KOtBu (5
mol %) heated at 135 °C under argon flow for 12 h. After 12 h, different alcohol (0.55 mmol, 1.1 equiv), toluene (1.5 mL), catalyst 1 (1 mol %),
and KOtBu (5 mol %) were added into the reaction mixture and heating continued for another 12 h. Reported yields correspond to isolated pure
b
compounds. 10 equiv of ethanol was used.
of functionalized benzyl and heteroarene embedded primary
alcohols to provide monoalkylation. Subsequently, a different
primary alcohol was introduced in the same reaction, which
provided the unsymmetrical N,N-dialkylation products with
excellent selectivity and yields (3a−3e, Scheme 3). Impres-
sively, the amine group in 4-aminobenzyl alcohol did not
undergo alkylation reaction under this condition, and the
chemoselective second alkylation occurred on monoalkyl
hydrazide-amine functionality to deliver the product 3e in
78% yield. Further, challenging aliphatic alcohols, including
ethanol, was used and the product 3f isolated in excellent yield
(96%). Surprisingly, 4-amino benzohydrazide underwent
selective terminal unsymmetrical N,N-dialkylation without
affecting of aniline amine group (3g and 3h). Such
chemoselective N-alkylation reaction is unknown in the
literature. Interestingly, the secondary alcohols like cyclo-
hexanol and cycloheptanol also underwent selective mono-
alkylation, followed by reaction with primary alcohols and
resulted in unsymmetrical N,N-dialkyl products 3i and 3j in
very good yields (Scheme 3).
Scheme 4. Selective Intermolecular Cyclization of
Acylhydrazides Using Diols
a
Next, a challenging intermolecular cyclization was tested
using acylhydrazides and diols. Surprisingly, reaction of 4-
methyl benzohydrazide, 4-tert-butyl benzohydrazide and 1-
naphthohydrazide with 1,4-butandiol provided cyclized five
membered ring acylhydrazide products 4a, 4b, and 4c in 90%,
86%, and 83% yields, respectively (Scheme 4). Reaction of 1,5-
pentanediol with different benzohydrazide derivatives delivered
six-membered cyclized products in good yields (4d−4g).
Upon employing 1,6-hexanediol, seven-membered cyclization
occurred and the corresponding products 4h and 4i are
isolated in 65% and 70% yields, respectively.
a
Reaction conditions: acylhydrazide (0.5 mmol, 1 equiv), diol (1
mmol, 2 equiv), toluene (2 mL), catalyst 1 (2 mol %), and KOtBu (5
mol %) were heated at 135 °C under argon flow for 24 h. Reported
yields correspond to isolated pure compounds.
Further, experiments that can decipher the mechanistic
insight of N,N-dialkylation of acylhydrazides using alcohols
were designed and demonstrated (Scheme 5). A one-pot-
C
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Scheme 5. Mechanistic Studies for the Selective N,N-
Dialkylation of Acylhydrazides Using Alcohols
Scheme 6. Proposed Mechanism for the Direct N,N-
Dialkylation of Acylhydrazides Using Alcohols
reaction was performed using methyl benzoate and hydrazine
hydrate for 4 h to provide benzohydrazide, and further catalytic
dialkylation was carried out under standard reaction conditions
using 1-hexanol (2.2 equiv). The expected N,N-dialkylation
product 2d was isolated in 93% yield (Scheme 5a). When the
hydrazone intermediate C (see Table S1) was reacted with 1-
hexanol (2.2 equiv) under standard reaction conditions, the
corresponding N,N-dialkylation product 2d was isolated in
83% yield (Scheme 5b). This experiment clearly indicates that
the reaction proceeds via hydrazone intermediate. The
deuterium labeling experiment confirmed the expected
deuterium incorporation at the α-methylene positions of the
alkylation product. Reaction of benzohydrazide with 1-
hexanol-D3 under standard reaction conditions resulted in
the product 5a in 90% yield with 67% deuterium incorporation
at the α-carbon of the dialkylation product indicating the
involvement of the borrowing hydrogen pathway.
cally active intermediate I. Notably, this highly selective
catalysis and +2 oxidation state of metal center in all catalytic
intermediates are facilitated by amine−amide metal−ligand
cooperation.
In conclusion, we have successfully demonstrated an
unprecedented ruthenium(II) catalyzed efficient and direct
coupling of acylhydrazides and alcohols to N,N-dialkylacylhy-
drazides. The reactions require only a catalytic amount of base.
Both symmetrical and unsymmetrical N,N-dialkylation of
acylhydrazides using alcohols is achieved in a one-pot
synthesis. Expediently, various functionalities such as olefins,
halides, amines, and heteroaromatic groups were tolerated in
this catalytic protocol. Remarkably, chemoselective N,N-
dialkylation of acylhydrazides over the amine functionality is
also developed. Synthetically challenging diethylation and
dimethylation were attained using ethanol and methanol,
respectively, as alkylating agents. Interestingly, using diols, the
formation of five, six, and seven-membered heterocyclic
acylhydrazides were obtained, which are analogous to various
drugs and biologically active molecules. This catalytic method
also performed on direct N,N-dialkylation from corresponding
ester under one-pot tandem reaction conditions. Mechanistic
studies indicated that the reaction undergoes via hydrazone
intermediate and follows the borrowing hydrogen pathway.
This N,N-dialkylation strategy can inspire the development of
new C−N bond formation reactions and sustainable trans-
formations.
Based on the previous reports19−23 and preliminary
mechanistic studies, a plausible mechanism is proposed for
the N,N-dialkylation of acylhydrazides using alcohols (Scheme
6). Catalyst 1 reacts with base leading to dehydrohalogenation
and formation of active coordinatively unsaturated intermedi-
ate I (which is previously observed by us in mass spectrometry
analysis).23b,24 Intermediate I reacts with alcohol by O−H
bond activation resulting in an alkoxo-coordinated ruthenium
intermediate II or II′ as already established.23d Perhaps, β-
hydride elimination reaction from alkoxide ligands may result
in formation of carbonyl intermediate and provide the
ruthenium complex III. A base catalyzed condensation reaction
between in situ formed carbonyl intermediate (aldehyde or
ketone) with N-acylhydrazide generates a hydrazone inter-
mediate (see Table S1 and Scheme 5b). In situ formed
hydrazone undergoes hydrogenation by ruthenium dihydride
intermediate III to provide monoalkyl acylhydrazide and
regenerates the catalytically active intermediate I. Further, the
second condensation of monoalkyl acylhydrazide with in situ
formed aldehyde intermediate occurs to provide iminium
intermediate IV (which can also be in equilibrium with
intermediate V under the basic condition). Hydrogenation of
iminium intermediate IV by ruthenium dihydride III results in
N,N-dialkylacylhydrazide product and regenerates the catalyti-
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02369.
Experimental procedures, spectral data, and copies of 1H
and 13C NMR spectra of the products (PDF)
D
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AUTHOR INFORMATION
■
Corresponding Author
Chidambaram Gunanathan − School of Chemical Sciences,
National Institute of Science Education and Research (NISER),
HBNI, Bhubaneswar 752050, India; orcid.org/0000-0002-
9458-5198; Email: gunanathan@niser.ac.in
Author
Subramanian Thiyagarajan − School of Chemical Sciences,
National Institute of Science Education and Research (NISER),
HBNI, Bhubaneswar 752050, India; orcid.org/0000-
0002-0735-5686
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02369
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank SERB New Delhi (Grant EMR/2016/002517),
DAE, and NISER for financial support. S.T. thanks UGC for a
research fellowship.
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DEDICATION
■
Dedicated to Prof. Srinivasan Natarajan on the occasion of his
60th birthday, with our best wishes.
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