Sulphur promoted C(sp3)-C(sp2) cross dehydrogenative cyclisation of acetophenone hydrazones with aldehydes: Efficient synthesis of 3,4,5-trisubstituted 1H-pyrazoles

Article abstract of DOI:10.1039/c4cc08210a

A novel strategy for the cross dehydrogenative coupling (CDC) of acetophenone hydrazones and aldehydes has been developed for the synthesis of highly substituted pyrazoles. This work, for the first time, uses elemental sulfur as a promoter as well as a hydrogen acceptor in effecting the Csp³-Csp² bond formation via C-H activation. This journal is

Full text of DOI:10.1039/c4cc08210a

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Sulphur promoted C(sp3)–C(sp2) cross
dehydrogenative cyclisation of acetophenone
hydrazones with aldehydes: efficient synthesis
of 3,4,5-trisubstituted 1H-pyrazoles†
Cite this:DOI: 10.1039/c4cc08210a
Received 16th October 2014,
Accepted 10th November 2014
Rajeshwer Vanjari, Tirumaleswararao Guntreddi, Saurabh Kumar and
Krishna Nand Singh*
DOI: 10.1039/c4cc08210a
www.rsc.org/chemcomm
A novel strategy for the cross dehydrogenative coupling (CDC) of reactions require transition metal catalysts and oxidants such
acetophenone hydrazones and aldehydes has been developed for as oxygen or peroxides as hydrogen acceptors.
the synthesis of highly substituted pyrazoles. This work, for the first time,
The first CDC approach was reported by Miura and co-workers
uses elemental sulfur as a promoter as well as a hydrogen acceptor in involving the coupling of N,N-dimethylanilines with alkynes.14a Li
effecting the Csp3–Csp2 bond formation via C–H activation.
et al. and others have subsequently enriched this area by expanding
the substrate scope.14–17 An ‘‘iminium ion’’ intermediate is assumed
Pyrazoles constitute an important class of heterocyclic compounds to be formed via amine oxidation by a copper source in the presence
exhibiting a wide range of biological activities such as antibacterial,1 of an oxidant using a single electron transfer (SET) process, which
antiobesity,2 antitumor,3 antileukemic,4 anti-inflammatory,5 subsequently acts as an electrophile for the nucleophilic addition
and analgesic.6 They also act as vital building blocks of many (intermolecular approaches). Ge et al. have successfully applied this
pharmaceuticals and natural products.7 The contemporary strategy to an intramolecular CDC approach using hydrazones as
pyrazole syntheses involve the reaction of hydrazines with potential substrates for the synthesis of pyrazoles.18
1,3-dicarbonyl compounds/unsaturated hydrocarbons,8,9 and
In view of the above and as a part of our interest in C–H
1,3-dipolar cycloaddition of diazoalkanes with alkenes or alkynes,10 activation,19 and development of practical protocols,20 we describe
besides some other strategies.11 Yet, novel, atom economic and herein an unprecedented intramolecular cross dehydrogenative
environmentally benign methodologies, involving readily available cyclisation of acetophenone hydrazones with aldehydes for the
starting materials, are highly desirable.
valuable synthesis of substituted pyrazoles. This work, for the first
The development of advanced and ecologically benevolent time, uses sulphur as a promoter as well as a hydrogen acceptor for
means to achieve C–C and C–X bond formation is of great topical the formation of a C(sp3)–C(sp2) bond via the CDC approach. An
interest. In the present synthesis scenario, the development of illustration of the related reports and the present strategy involving
cross-coupling methods involving unactivated C–H precursors has C–H activation is summarized in Scheme 1.
captured a great deal of attention.12 In this perspective, the direct
The investigation commenced with a model reaction employing
catalytic coupling termed as cross-dehydrogenative coupling acetophenone hydrazone and p-tolualdehyde in the presence of
(CDC) of unfunctionalized C–H bonds has particularly emerged Pd(OAc)2 as a catalyst and t-butyl hydrogen peroxide (TBHP, 70%
as a powerful tool for the synthesis of diverse compounds.13 Most aq.) as an oxidant in t-butanol at 120 1C for 24 h. In conformity with
of the CDC reactions developed so far have been nicely applied for the earlier reports,21 we envisioned the formation of product I via
the formation of C–C (sp–sp, sp–sp2 and sp2–sp2) bonds, but the dehydrogenative coupling of imine–H and aromatic–H (Fig. 1,
formation of a Csp3–C bond via CDC is yet underdeveloped and path A). Surprisingly, but to our utmost delight, unique formation
more challenging.13g Furthermore, most of the explored Csp3–C of pyrazole II (74%, path B) was exclusively observed involving
bond forming reactions are limited to the coupling of C–H bonds intramolecular cross-dehydrogenative cyclisation of Csp3–H with
adjacent to a heteroatom14 and a carbonyl group,15 besides allylic, imine–H under the investigated conditions.
benzylic,16 and alkane C–H bonds.17 Also, many of the CDC
Having observed this distinctive one pot intramolecular
CDC result, the studies were directed towards the optimization
of reaction conditions and the findings are presented in Table 1.
To improve the reaction profile, different parameters such as
catalysts, additives, oxidants and solvents were screened. Out of
the different catalysts tried, only Pd(OAc)2 and Cu(OAc)2 could
perform well (entries 1 and 2). Remarkably, addition of a base
Department of Chemistry (Centre of Advanced Study), Faculty of Science,
Banaras Hindu University, Varanasi-221005, India. E-mail: knsingh@bhu.ac.in,
knsinghbhu@yahoo.co.in
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all compounds. CCDC 1027771. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc08210a
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like K2CO3 or DBU either blocked the reaction or diminished the
product yield (entries 3 and 4). Replacement of TBHP by K2S2O8
brought about a modest improvement in the yield (entry 8), but
the use of solvents such as DCE, DMF and DMSO as alternatives
to t-butanol proved to be completely ineffective (entries 5–7). The
reaction employing Pd(OAc)2 without the oxidant also proved to
be worthless (entry 9).
A cognizance of the Willgerodt–Kindler reaction reveals the
formation of an ‘‘enamine’’ intermediate to activate elemental
sulfur, which in turn stimulates the adjoining methyl group.22
Keeping this clue in mind, the formation of an enamine type
intermediate in the presence of S8 in the present investigation
was assumed to cause activation of the sp3 C–H bond. In order
to validate the idea, sulfur powder (S8, mol. wt 32) was used to
test its efficacy as a promoter as well as an oxidant, and to our
aspiration, a considerably enhanced yield of the product was
observed (entry 10). Changing the solvent to 1,4-dioxane in the
presence of S8 without an additive and an oxidant resulted in
further improvement of the yield (85%, entry 12), but the use of
solvents such as DMF and DMSO proved to be ineffective
(entries 14 and 15). Solvent-free conditions as well as the use
of solvents such as toluene, water and chlorobenzene also
promoted the reaction to a good extent (entries 16–19) under
similar conditions. The use of TBHP without the catalyst or the
promoter (entry 11) and the addition of K2CO3 in the presence
of S8 (entry 13) were, however, unsuccessful.
Scheme 1 Related reports and the present strategy.
With the optimized conditions in hand, the generality of the
reaction was examined using diversely substituted acetophenone
hydrazones and various aldehydes to provide the corresponding
3,4,5-trisubstituted 1H-pyrazoles in reasonably high yields. The
outcome is recapitulated in Table 2. The reactions underwent
smoothly with acetophenone hydrazones having different aromatic
substitutions and aldehydes bearing various steric and electronic
properties. Hydrazones bearing heteroaromatic and bicyclic moi-
eties also participated well in the reaction. However, the reaction
required the addition of TFA to achieve adequate conversion to the
products 3as and 3at. The use of an aliphatic aldehyde viz. heptanal
failed to give the product. The structure of a representative product
3ao has been conclusively proved by the X-ray crystal structure
(Fig. 2).23
Fig. 1 Selective sp3 C–H bond cleavage.
Table 1 Optimization of reaction conditionsa
Catalyst/
promoter
Yieldb
(%)
Entry
Additive
Oxidant
Solvent
1
2
3
4
5
6
7
8
Pd(OAc)2
Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
S8
—
S8
S8
S8
—
—
K2CO3
DBU
—
—
—
—
—
—
—
—
K2CO3
—
—
—
—
—
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
—
—
TBHP
—
—
—
t-BuOH
t-BuOH
t-BuOH
t-BuOH
DCE
DMF
DMSO
t-BuOH
t-BuOH
t-BuOH
t-BuOH
1,4-Dioxane
1,4-Dioxane
DMF
74
65
0
30
0
0
0
78
0
82
0
85
0
0
Based on the existing literature22 and isolation of products,
a plausible mechanism is outlined in Fig. 4. It is worthwhile to
mention that the formation of intermediate I (Fig. 3) was
immediately observed during the reaction of acetophenone
hydrazone and p-tolualdehyde, even at room temperature with-
out the addition of S8. The formation of thioamide intermediate
II was, however, not noticed during the entire course of standard
conditions, thereby discarding this pathway.
The formation of an ‘‘enamine’’ type intermediate Ia, ana-
logous to the ‘‘iminium ion’’ reported by Miura and Li, may
therefore be postulated for the reaction. The existence of Ia is
assumed to activate sulfur as in the case of Willgerodt Kindler
reaction to afford Ib, which may eventually lose H2S and
rearrange to give product 3. In order to explore the radical
pathway, some radical trapping experiments were also con-
ducted using BHT and TEMPO as radical scavengers, which did
9
10
11
12
13
14
15
16
17
18
19
S8
S8
S8
S8
—
—
—
—
DMSO
—
Toluene
Water
Chlorobenzene
0
65
59
55
71
S8
—
—
a
Reaction conditions: 1a (0.5 mmol), 2b (1 mmol), catalyst (10 mol%),
oxidant (1 mmol), additive (1 mmol), S8 (1 mmol), solvent (0.75 mL),
b
120 1C, 24 h. Isolated yield.
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Table 2 Reaction scope and versatilitya
Fig. 3 Mechanistic study.
Fig. 4 Proposed mechanism.
explored Csp3–Csp2 bond. The present study comprehends and
demonstrates the innovative dual use of sulfur as a promoter as
well as an oxidant in cross dehydrogenative cyclisation of
acetophenone hydrazones and aldehydes.
We are thankful to the Department of Science and Technology,
Government of India, New Delhi, for providing financial assistance
(Grant No. SR/S1/OC-78/2012). R.V. T.G. and S.K. are thankful to
the CSIR for research fellowships.
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