Synthesis of some novel chloro-/aryl-substituted-5,5-dimethyl-2-cyclohexenones

Article abstract of DOI:10.1080/00397911.2020.1723108

Two novel structural isomers: the dihalo-5,5-dimethyl-2-cyclohexenones were synthesized. Regioselective Suzuki-Miyaura cross coupling reaction of the isomers with nine different aryl boronic acids afforded eighteen novel compounds: the 2-aryl-3-chloro-5,5-dimethyl-2-cyclohexenones and the 3-aryl-2-chloro-5,5-dimethyl-2-cyclohexenones in 90–95% yields, which were characterized spectroscopically by IR, NMR and MS. The single crystal X-Ray diffraction ORTEP views of four representative compounds unambiguously confirm the formation of substituted cyclohexenones.

Full text of DOI:10.1080/00397911.2020.1723108

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Synthesis of some novel chloro-/aryl-
substituted-5,5-dimethyl-2-cyclohexenones
Jeevan Chakravarthy A. S., Pavan K. P., Venkatesh G. B. & HariPrasad S.
To cite this article: Jeevan Chakravarthy A. S., Pavan K. P., Venkatesh G. B. & HariPrasad S.
(2020): Synthesis of some novel chloro-/aryl-substituted-5,5-dimethyl-2-cyclohexenones, Synthetic
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https://doi.org/10.1080/00397911.2020.1723108
Synthesis of some novel chloro-/aryl-substituted-5,5-
dimethyl-2-cyclohexenones
Jeevan Chakravarthy A. S.a,b, Pavan K. P.c, Venkatesh G. B.d, and HariPrasad S.a
aDepartment of Chemistry, Central College Campus, Bengaluru Central University, Bengaluru, India;
c
bDepartment of Chemistry, Jnana Bharathi Campus, Bangalore University, Bangalore, India; Department
of Post Graduate Studies in Chemistry, SVRM College, Acharya Nagarjuna University, Nagaram, India;
dDepartment of Chemistry, Government Pre-University College, Chickaballapur, India
ABSTRACT
ARTICLE HISTORY
Received 1 October 2019
Two novel structural isomers: the dihalo-5,5-dimethyl-2-cyclohexe-
nones were synthesized. Regioselective Suzuki-Miyaura cross cou-
pling reaction of the isomers with nine different aryl boronic acids
afforded eighteen novel compounds: the 2-aryl-3-chloro-
5,5-dimethyl-2-cyclohexenones and the 3-aryl-2-chloro-5,5-dimethyl-
2-cyclohexenones in 90–95% yields, which were characterized spec-
troscopically by IR, NMR and MS. The single crystal X-Ray diffraction
ORTEP views of four representative compounds unambiguously con-
firm the formation of substituted cyclohexenones.
KEYWORDS
Aryl derivatives; cross
coupling reaction;
halogenated cyclohexe-
nones; single crystal XRD
GRAPHICAL ABSTRACT
Introduction
Being starting materials for the synthesis of a wide range of natural products, substi-
tuted cyclohexenones form an important class of compounds in synthetic organic chem-
istry.[1] Earlier, we have reported the preparation of some substituted
methylcyclohexenones,[2] and their conversion into novel anionic synthons.[3] Based on
these results we are reporting in this communication new methodologies developed for
the synthesis of a wide range of substituted cyclohexenones. To expand the scope and
CONTACT HariPrasad S.
hariprasad@bub.ernet.in
Department of Chemistry, Central College Campus, Bengaluru
Central University, Bengaluru 560001, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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JEEVAN CHAKRAVARTHY A. S. ET AL.
the utility of our work, we were seeking commercially available less expensive com-
pounds to prepare the substrates.[4]
Over the years, our laboratory has been involved in the study of some metal catalyzed
cross-coupling reactions. For examples, (i) Heck-;[5] (ii) Sonagashira-;[6,7] (iii) Suzuki-
Miyaura-;[5,8,9] (iv) Wurtz-Fittig-;[5,6,10] and (v) Buchwald – Hartwig cross-coupling
reactions[11] have been reported from this laboratory. The starting compounds for these
coupling reactions are cyclic vinyl halides/tosylates.[12]
Our earlier studies showed that 1-bromo-2-chlorocycloalkenes form excellent precur-
sors for regioselective transformations. The vicinal olefinic halogens possess differing
carbon-halogen bond strengths, the carbon-chlorine bond strength is 335 kJ molꢀ1
whereas, the carbon-bromine bond strength is 268 kJ molꢀ1 [13]
These results indicated
.
that the bromo- group could be preferentially and regiospecifically replaced under suit-
able reaction conditions.[5,8,11,14]
There are few literature reports for the synthesis of 1,2-vicinal dihalocycloal-
kenes[15–19] and aryl-substituted cycloalkenes/cycloalkenones in short duration of time
and high yields.[20,21] The use of vicinal olefinic 1,2-dibromo- substrates in the Suzuki-
Miyaura cross coupling reactions lead to the formation of the 1,2-diaryl products.
Similar reaction of 1,2-dichloro- substrates lead to the formation of 1-chloro-2-arylcy-
cloalkenes, albeit employing costly catalysts.[22]
Our aim and protocol was preparation of substrates by regiospecific replacement of
only one halogen atom, making use of the differential carbon-halogen bond strengths,
eliminating the competition of substitution of both halogens. This strategy has been
recently and successfully employed by other scientists for aryl systems.[14] In this con-
text 2-bromo-3-chloro- and 3-bromo-2-chloro-5,5-dimethyl-2-cyclohexenones form
excellent precursors in the regioselective Suzuki-Miyaura cross coupling reactions, where
the bromo-group could be selectively replaced.
We now report, for the first instance of time, the synthesis of the novel structural iso-
mers: 2-bromo-3-chloro-5,5-dimethyl-2-cyclohexenone (3a) and 3-bromo-2-chloro-5,5-
dimethyl-2-cyclohexenone (3b) from dimedone, using simple and cost effective reagents.
The Suzuki-Miyaura cross coupling reaction of 3a and 3b with nine different aryl bor-
onic acids: 4a-i afforded a diverse range of novel products: 2-aryl-3-chloro-5,5-
dimethyl-2-cyclohexenones: 5a-i, and 3-aryl-2-chloro-5,5-dimethyl-2-cyclohexenones:
6a-i, by the ipso-substitution at the bromine bearing carbon. The isolated yields of
products were 90–95% (Scheme 1). The novelty of our Suzuki-Miyaura reaction meth-
odology approach is the isolation of compounds 5a-i and 6a-i in high yields.[23]
Results and discussion
During the course of our earlier studies, we have reported the conversion of a wide
range of 2-bromo-1,3-cycloalkanediones to a-bromo-b-chlorocycloalkenones, employing
oxalyl chloride.[24]
Reaction of dimedone (1) with N-halosuccinimide (NBS or NCS), p-TSA in CHCl3
gave the corresponding halogenated compound 2a and 2b respectively. Reaction of 2a
and 2b with oxalyl chloride or oxalyl bromide in THF gave the novel structural isomers:
3a and 3b in 96% and 94% respectively.

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3
Scheme 1. Synthesis of some novel chloro-/aryl- substituted-5,5-dimethyl-2-cyclohexenones 5a-i
and 6a-i.
The compounds 3a and 3b, were subjected to the Suzuki-Miyaura cross coupling
reaction with nine different aryl boronic acids 4a-i using Pd(dppf)2Cl2 (0.32 mol%)
catalyst, K2CO3 (6.32 m moles), and 5 mL of 1,4-dioxane as solvent, under nitrogen
atmosphere in a 15 mL Sigma Ace pressure tube at 110 ꢁC to isolate the 2-aryl-3-chloro-
5,5-dimethyl-2-cyclohexenones 5a-i; and the 3-aryl-2-chloro-5,5-dimethyl-2-cyclohexe-
nones 6a-i (Scheme 1).
Each coupling reaction was carried out for a minimum of three trials. The optimum
yields of the isolated products were greater than 90% and are given in Table 1. The
compounds were isolated as high boiling liquids/low melting off-white to yellow
Colored solids. Distillation under reduced pressure of 0.01 mm Hg gave tarry material
indicating the decomposition of the compounds. The compounds 5a-i and 6a-i were
finally isolated in pure form using column chromatography or recrystallization from
appropriate solvent and characterized spectroscopically.
X-ray structural analysis
Slow evaporation techniques were employed to isolate good quality crystals in petrol-
eum benzine (60–74 ꢁC) solvent. Among all the compounds which were subjected to
recrystallization, good quality crystals were isolated in the case of: 3a,[24,25] 3b, 3-
chloro-2-napthyl-5,5-dimethyl-2-cyclohexenone (5f) and 2-chloro-3-(30-fluoro-50-meth-
yl)phenyl-5,5-dimethyl-2-cyclohexenone (6d). These compounds were subjected to sin-
gle crystal XRD studies and the ORTEP views are given in Figure 1.
To the best of our knowledge, there are no literature reports for the single crystal
XRD analysis of this class of compounds. Now, first time we are reporting here the sin-
gle crystal XRD data for the representative compounds 3a, 3b, 5f and 6d.
Mechanism
We expect the reaction mechanism for the formation of products 5a-i and 6a-i, to tra-
verse through well established routes earlier reported by scientists for the

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JEEVAN CHAKRAVARTHY A. S. ET AL.
Table 1. Chloro-/aryl-substituted-5,5-dimethyl-2-cyclohexenones 5a-i and 6a-i.
2-Aryl-3-chloro-5,5-dimethyl-2-cyclohexenones
3-Aryl-2-chloro-5,5-dimethyl-2-cyclohexenones
Entry
Boronic acids
(Reacꢀon duraꢀon and % yields)
( Reacꢀon duraꢀon and % yields)
1
4a
5a (3 hrs, 92%)
5b (3 hrs, 93%)
6a (2 hrs, 94%)
6b (3 hrs, 95%)
(HO)2
B
2
3
4
4b
F
(HO)2
B
O
F
4c
5c (4 hrs, 91%)
5d (4 hrs, 91%)
6c (2 hrs, 92%)
6d (2 hrs, 92%)
(HO)2
B
4d
F
C6H5
(HO)2
B
5
6
4e
4f
5e (4 hrs, 94%)
5f (3 hrs, 92%)
6e (2 hrs, 95%)
6f (2 hrs, 94% )
(HO)2
B
(HO)2
B
S
7
4g
5g (4 hrs, 90%)
6g (2 hrs, 92%)
(HO)2
B
S
8
9
4h
5h (4 hrs, 91%)
5i (4 hrs, 90%)
6h (4 hrs, 92%)
6i (3 hrs, 91%)
(HO)2
B
4i
Suzuki-Miyaura cross coupling reactions. The oxidative addition of the C-Br bond
of the vinyl halide 3a or 3b to the Pd (0) takes precedence over C-Cl bond, induc-
ing the regioselective formation of products.[14] Our bench-work have also indicated
that the reactions of 3b were faster than 3a and occur in much shorter duration of
time (Table 1). We reason that oxidative addition of C-Br bond of 3b is faster
than 3a, due to steric constraints in the latter. Trans-metallation and reductive elim-
ination of the palladium intermediate yields the novel regioselective products 5a-i
and 6a-i.

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SYNTHETIC COMMUNICATIONSV
5
3a
3b
6d
5f
Figure 1. ORTEP view of compounds 3a, 3b, 5f and 6d.
Experimental section
General procedure for the preparation of 2-bromo-5,5-dimethylcyclohexane-1,3-
dione (2a) and 2-chloro-5,5-dimethylcyclohexane-1,3-dione (2b)
To a solution of dimedone (14 g, 0.1 moles) and p-toluenesulfonic acid (100 mg, 0.58 m
moles) in 100 mL CHCl3, maintained at 0 ꢁC, was added N-halosuccinimide [NBS
(21.35 g, 0.12 moles) or NCS (16.02 g, 0.12 moles)] over a period of 1 hour, followed by
allowing the reaction mixture to attain room temperature. The progress of reaction was
monitored by thin layer chromatography (TLC). After complete disappearance of the
starting material as indicated by thin layer chromatograms using 0.5% methanol/CH2Cl2
as mobile phase, the reaction mixture was quenched with 250 mL of 20% sodium meta-
bisulphite to remove any by-products. The aqueous layer was extracted with CH2Cl2
(3 ꢂ 70 mL), washed with water (3 ꢂ 70 mL), brine solution (2 ꢂ 70 mL) and dried over
anhydrous Na2SO4 crystals. The organic extract was stripped of solvent under vacuum
and the crude compound purified by column chromatography using 60–120 silica gel as
stationary phase and 0.5% methanol/CH2Cl2 as mobile phase to isolate 94% of 2-
bromo-5,5-dimethylcyclohexane-1,3-dione (2a); or 91% of 2-chloro-dimethylcyclohex-
ane-1,3-dione (2b) respectively.
General procedure for the preparation of 2-bromo-3-chloro-5,5-dimethyl-2-
cyclohexenone (3a) and 3-bromo-2-chloro-5,5-dimethyl-2-cyclohexenone (3b)
To a magnetically stirred suspension of 2-bromo-5,5-dimethylcyclohexane-1,3-dione (2a,
2g, 9.1 m moles); or 2-chloro-5,5-dimethylcyclohexane-1,3-dione (2b, 2g, 11.45 m moles)

6
JEEVAN CHAKRAVARTHY A. S. ET AL.
was added oxalyl chloride (18.25 m moles); or oxalyl bromide (22.91 m moles) dissolved
individually in 20 mL THF, over a period of 30 minutes, at 0 ꢁC. The reaction mixture
was allowed to attain ambient temperature over a period of two hours. The contents
were then transferred to 100 g of crushed ice and extracted with CHCl3 (2 ꢂ 30 mL).
The combined organic extract was washed with saturated NaHCO3 (2 ꢂ 30 mL), brine
solution (2 ꢂ 30 mL) and dried over anhydrous MgSO4. The organic extract was
stripped of solvent under vacuum to isolate pure compounds 2-bromo-3-chloro-5,5-
dimethyl-2-cyclohexenone (3a) in 96% and 3-bromo-2-chloro-5,5-dimethyl-2-cyclohexe-
none (3b) in 94% yields respectively.
General procedure for the preparation of 2-aryl-3-chloro-5,5-dimethyl-2-
cyclohexenones (5a-i) and 3-aryl-2-chloro-5,5-dimethyl-2-cyclohexenones (6a-i)
A suspension of 2-bromo-3-chloro-5,5-dimethyl-2-cyclohexenone (3a, 0.5 g, 2.11 m
moles); or 3-bromo-2-chloro-5,5-dimethyl-2-cyclohexenone (3 b, 0.5 g, 2.11 m moles),
aryl boronic acid (4a-i, 1.1 m molar equivalent), K2CO3 (0.87 g, 6.32 m moles),
Pd(dppf)2Cl2 catalyst (5 mg, 0.0068 m moles, 0.32 mol%) in 6 mL of 1,4-dioxane was
taken in a 15 mL Sigma-Aldrich ace pressure tube along with a magnetic pellet. The sus-
pension was purged over 5 minutes with nitrogen gas and sealed. The pressure tube was
introduced into a pre-heated oil bath at 110 ꢁC and magnetically stirred for a period of
4 hours. Aliquots indicated the reaction to be completed within the duration of time as
indicated in Table 1. The reaction was allowed to attain ambient temperature, trans-
ferred to a beaker and diluted with ethyl acetate (20 mL). The extract was filtered over a
R
bed of CeliteV. The filtrate was concentrated on a rotary evaporator and the crude prod-
uct was purified by column chromatography using using silica gel (Merck, 60–120
mesh) as the stationary phase and ethyl acetate: petroleum benzine (60–74 ꢁC) as mobile
phase to isolate the compounds 2-aryl-3-chloro-5,5-dimethyl-2-cyclohexenones 5a-i and
3-aryl-2-chloro-5,5-dimethyl-2-cyclohexenones 6a-i in greater than 90% yields. The
novel compounds were characterized by spectral analysis and the yields are reported
in Table 1.
Conclusion
The current work describes an easy protocol for the direct synthesis of chloro-/aryl-sub-
stituted-5,5-dimethyl-2-cyclohexenones in short duration of time and accompanied with
high yields, by the Suzuki-Miyaura cross coupling reaction. The spectroscopic analyses
of all compounds and the single crystal XRD data of four representative compounds
unambiguously confirm the formation of compounds.
Supplementary data associated with this article can be found as a separate word file,
1
which includes: H-NMR, 13C-NMR, FT-IR, Mass spectra of all the novel compounds:
3a, 3b, 5a-i, 6a-i; and crystal data of 3a, 3b, 5f and 6d.
Acknowledgments
The authors thank (1) JCAS for Council of Scientific and Industrial Research (CSIR), Govt. of
India, New Delhi, INDIA; CSIR SRF – File no. 09/039(0119)/2018-EMR-1, dated April 16, 2018.;

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SYNTHETIC COMMUNICATIONSV
7
(2) Bengaluru Central University.; (3) Bangalore University and (4) Dr. B. S. Bandodkar,
Pharmaron Chemical Company, Beijing, China for all help rendered; (5) Suman Bharadwaj,
Christ University, Bangalore.; and (6) Avinash, R., Bangalore; Sreenatha, N. R., Hassan.
Funding
The author JCAS is thankful to Council of Scientific and Industrial Research (CSIR), Govt. of
India, New Delhi, INDIA; CSIR SRF – File no. 09/039(0119)/2018-EMR-1, dated April 16, 2018,
for providing the financial support.
ORCID
HariPrasad S.
http://orcid.org/0000-0001-7157-1538
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crystal data of the compound 3a.