A novel synthetic method for halogenated cyclohexane derivatives from m-xylene

Article abstract of DOI:10.1081/SCC-100108236

The synthesis of halogenated cyclohexane derivatives 7-10 starting from m-xylene is described.

Full text of DOI:10.1081/SCC-100108236

SYNTHETIC COMMUNICATIONS, 31(24), 3851–3858 (2001)
A NOVEL SYNTHETIC METHOD FOR
HALOGENATED CYCLOHEXANE
DERIVATIVES FROM m-XYLENE
S. Krishna Mohan1, and Hari Babu Mereyala2
*
1Department of Chemistry, School of Science,
The University of Tokyo, Bunkyo-ku,
Tokyo 113, Japan
2Organic Chemistry Division III, Indian Institute of
Chemical Technology, Hyderabad 500 007, India
ABSTRACT
The synthesis of halogenated cyclohexane derivatives 7–10
starting from m-xylene is described.
Marine monoterpenes in fact remained unobserved until 1955 when
Faulkner reported1 isolation of polyhalogenated metabolites. Nearly all of
the marine monoterpenes observed to date are halogenated and no halo-
genated monoterpene has been isolated from terrestrial organism. This is
not surprising considering that sea water contains high concentrations of
chloride (1.99 ꢀ 107 mg/L) and bromide (6.8 ꢀ 104 mg/L) ions. Halonium ion
induced cyclization represents a novel ring forming strategy employed by
marine species in their biogenesis contrast to Hþ ion initiated cyclizations.2
Red seaweeds of the families Plocamiaceae and Rhizophyllidaceae or sea
*Corresponding author. E-mail: kmohan_s@yahoo.com
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Copyright & 2001 by Marcel Dekker, Inc.
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Figure 1.
Figure 2.
hares of the genus Aplysia contain acyclic and cyclic monoterpenes.3 Studies
on Plocamium violaceum have resulted in the isolation of monocyclic
monoterpenes belonging to two skeletal classes, violacene-14(I) and viola-
cene-2(II), plocamene-B(III) (Figure 1) along with several other linear
polyhalogenated monoterpenes.
Synthesis of halogenated marine natural products has attracted the
attention of organic chemists due to their very interesting pharmacological
properties. Halomon (IV)5 and isohalomon (V)6 (Figure 2) exhibited high
cytotoxicity against National Cancer Institutes in vitro human tumor cell
line screening panel for brain, renal and colon tumor cell lines. Inspite of
their promising biological activity, synthesis of cyclic and acyclic halogenated
terpenes till date has not been reported. We describe here our efforts that
culminated in the synthesis of halogenated cyclohexane derivatives 7, 8, 9 and
10 related to the naturally occuring polyhalogenated cyclohexane derivatives.
RESULTS AND DISCUSSION
Birch reduction7 of m-xylene 1 gave 1,4-cyclohexadiene derivative 2 in
protons (4H) as multiplet between d 2.3–2.75 and methyl groups (6H) as a
singlet at d 1.70. Epoxidation of 2 with peroxotungstophosphate (PCWP)/
8
H2O2 gave the monoepoxide 3 in 65% yield along with the diepoxide 4 in
17% yield. A similar reaction carried out by use of mCPBA resulted in the

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3853
isolation of 3 and 4 in lower yields due to decomposition of epoxides 3 and 4
1
in the reaction medium. 3 was characterised from H-NMR spectrum from
the appearance of vinylic proton (1H) at d 5.15 as a triplet (J ¼ 6.0 Hz),
epoxy proton (1H) at d 3.05 as a singlet. 3 exhibited a molecular ion peak
Scheme.

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KRISHNA MOHAN AND MEREYALA
at Mþ 124. Regioselective nucleophilic opening of the epoxide 3 with
NaCN/DMF at 90ꢁC for 12 h resulted in the isolation of cyanohydrin 5
1
(60% yield) that was characterised by H-NMR spectrum from the appea-
rance of vinylic proton (1H) at d 5.25 (t, J ¼ 6.2 Hz) and IR spectrum from
the nitrile absorption at 2242 cmÀ1 and hydroxyl at 3400 cmÀ1. 5 on reduc-
tion with DIBAL-H at À20ꢁC for 6 h gave the aldehyde 6 which without
purification was immediately reacted with CBr4/TPP9 in dichloromethane at
0ꢁC for 15 min to obtain the dibromo alkene derivative 7 in 40% yield. 7 was
characterised from the appearance of vinylic proton (1H) as a doublet at d
6.25 (J ¼ 12.6 Hz) and cyclic double bond proton (1H) at d 5.32 in the
1H-NMR spectrum. Mass spectrum also indicated the presence of two bro-
mine atoms from the appearance of Mþ at 310.7 on further reaction with
NaOH in PEG-40010 gave the bromoacetylene derivative 8 in 55% yield. 8
was characterised from the 1H-NMR spectrum from the appearance of
double bond proton (1H) at d 5.31 (t, J ¼ 4.8 Hz) and IR spectrum from
the presence of acetylene absorption at 2200 cmÀ1. In order to prepare the
chlorovinylic compound 9, aldehyde 6 was reacted with CrCl2 in
THF/CHCl3 at 65ꢁC to obtain 9 in 55% yield after intensive purification
11
1
by column chromatography and was characterised by the H-NMR spec-
trum from the appearance of chlorovinylic proton (1H) as a multiplet
between d 5.8–6.2 and the vinylic proton (1H) as triplet at d 5.34
(J ¼ 6.5 Hz). 3 on reaction with 2 eq. Br2/CCl4 resulted in the isolation of
tribromo compound 10. 10 was characterised from 1H-NMR from the
appearance of methylene protons (4H) as multiplet between d 2.2–2.7 and
multiplet between d 4.7–4.8 (1H) indicating the presence of secondary
alcohol and molecular ion peak Mþ at 361.
EXPERIMENTAL
1H-NMR spectra were measured with a Varian Gemini (200 MHz)
spectrometer, with tetramethylsilane as internal standard for solutions in
deuteriochloroform. IR spectra were taken with a Nicolet 740 spectrometer.
Mass spectra were taken on Auto spec M. Organic solutions were dried over
anhydrous Na2SO4 and concentrated below 40ꢁC in vacuo.
1,5-Dimethyl-cyclohexa-1,4-diene (2). To liquid ammonia (75 mL) col-
lected by use of Dewar cold finger was added m-xylene (9 g, 84.9 mmol) and
ethanol (12.5 mL). Sodium (5 g, 217.3 mmol) was added during 30 min to the
above reaction mixture and stirred for 2 h. Reaction mixture was quenched
with ammonium chloride (8 g) and contents of the reaction were stirred
for 12 h, chilled water (150 mL) was added and extracted into diethyl-
ether (2 ꢀ 150 mL). Combined etherial solution was dried (Na2SO4) and

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concentrated to a residue which was distilled at 137ꢁC to obtain the title
compound (5.9 g, 64%).
1H NMR (CDCl3): d 1.7 (s, 6H, 2 ꢀ CH3), 2.3–2.75 (m, 4H, H-3,30 and
H-6,60), 5.38 (br s, 2H, H-2 and H-4). (Found: C, 88.74; H, 11.2. calc. for
C10H12: C, 88.82; H, 11.18%).
1a,3-Dimethyl-1a,2,5,5a-tetrahydrobenzo[b]oxirene (3) and 1a,2a-
dimethyl perhydro oxireno[20,30:4,5]benzo[b]oxirene (4). To a mixture of
PCWP (1.3 g), 30% H2O2 (100 v) (2 mL) in CHCl3 (20 mL) was added
diene 2 (5 g, 46.3 mmol) and stirred for 2 h at room temperature. When
reaction was complete, the reaction mixture was diluted with water
(20 mL) and organic phase was separated. The aqueous phase was extracted
with chloroform (2 ꢀ 50 mL). Combined chloroform phases were dried
(Na2SO4) and concentrated to obtain a residue which was purified by
column chromatography (SiO2, 60–120 mesh) to elute first the monepoxide
3 [hexane : ethyl acetate: (25 : 1), 3.5 g, 65%] as a syrup.
1H NMR (CDCl3): d 1.4 (s, 3H, H-1, CH3), 1.65 (s, 3H, H-3, CH3),
2.10–2.70 (m, 4H, H-2,20 and H-5,50), 3.05 (br s, 1H, H-5a), 5.15 (brs, 2H,
H-4). Ms (m/z): 124. (Found: C, 77.21; H, 9.62. calc. for C8H12O: C, 77.38;
H, 9.74%) followed by diepoxide 4 [hexane : ethyl acetate: (9:1), 1.1 g, 17%]
1
as a syrup. H NMR (CDCl3): d 1.25–1.28 (s, 6H, 2 ꢀ CH3), 2.8–2.9 (m,
2H, H-3,4). (Found: C, 68.42; H, 8.51. calc. for C8H12O2: C, 68.55;
H, 8.63%).
6-Hydroxy-4,6-dimethyl-3-cyclohexene-1-carbonitrile (5). To a solution
of epoxide 3 (3.2 g, 26.2 mmol) in N,N-dimethylformamide (5 mL) was
added sodium cyanide (3.8 g, 78.6 mmol) and the reaction mixture was stir-
red for 12 h at 90ꢁC. Progress of the reaction was monitored by TLC. When
the reaction was complete, the reaction mixture was cooled to room tem-
perature, diluted with water (50 mL) and extracted into diethyl ether
(2 ꢀ 50 mL). Combined etherial layers were washed with water, dried
(Na2SO4) and concentrated to obtained a residue which was purified by
column chromatography [(SiO2, 60–120 mesh; hexane; ethyl acetate: (8:2)]
to obtain the title compound 5 (2.4 g, 60%) as a syrup.
1
IR: 2242 cmÀ1. H NMR (CDCl3): d 1.25 (s, 3H, 6-CH3), 1.65 (s, 3H,
4-CH3), 1.95–2.8 (m, 5H, H-2,20,1,5 and H-50), 4.9 (br s, 1H, OH), 5.25 (br s,
1H, H-3). Ms (m/z): 151. (Found: C, 71.28; H, 8.55; N, 9.19. calc. for
C9H13NO: C, 71.49; H, 8.67; N, 9.26%).
6-(2a,2a-Dibromovinyl)-1,3-dimethyl-3-cyclohexen-1-ol (7). To a solu-
tion of cyanohydrin 5 (3 g, 19.9 mmol) in dry CH2Cl2 (10 mL) was added
diisobutyl aluminium hydride solution in hexane (7.0 g, 24.8 mL, 49.7 mmol)
at À20ꢁC and stirred for 2 h. The reaction mixture was brought to room tem-
perature and stirred for 2 h. Progress of the reaction was monitored by TLC.
When reaction was complete, it was quenched by addition of methanol (3 mL)

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KRISHNA MOHAN AND MEREYALA
and 5% aqueous HCl (30 mL), stirred for an additional 45 min and
extracted into dichloromethane (2 ꢀ 50 mL). The aqueous layer was sepa-
rated and once again extracted into dichloromethane (2 ꢀ 25 mL). Com-
bined dichloromethane layers were dried (Na2SO4) and concentrated to
obtain aldehyde 6 which without further purification was utilised for further
reaction.
To a solution of carbon tetrabromide (9.8 g, 29.4 mmol) in dichloro-
methane (20 mL), triphenylphosphine (15.3 g, 58.8 mmol) was added por-
tionwise under N2 atmosphere at 0ꢁC and stirred for 1 h. A solution of
6 (1 g, 6.6 mmol) in dichloromethane (5 mL) was added dropwise over
30 min and was further stirred for 15 min at 0ꢁC. Progress of the reaction
was monitored by TLC. When the reaction was complete it was filtered,
residue washed with hexane (20 mL) and filtrate was concentrated to
obtain a residue which was purified by column chromatography [(SiO2,
60–120 mesh; hexane : ethyl acetate: (11:1)] to obtain the title compound 7
(0.8 g, 40%) as a syrup.
1H NMR (CDCl3): d 1.25 (s, 3H, CH3), 1.65 (s, 3H, CH3), 2.05–2.7 (m,
5H, H-2,20,5,50 and H-6), 5.32 (br s, 1H, H-4), 6.25 (d, 1H, J ¼ 12.6 Hz,
H-1a). Ms (m/z): 310. (Found: C, 38.69; H, 4.48. calc. for C10H14Br2O : C,
38.74; H, 4.55%).
6-(2a-Bromo-1a-ethynyl)-1,3-dimethyl-3-cyclohexene-1-ol (8). A mix-
ture of polyethylene glycol (PEG-400) (4 mL) and 10 N sodium hydroxide
(3 mL) was stirred for 30 min at room temperature. 7 (100 mg, 0.3 mmol)
was dissolved in polyethylene glycol-400 (1 mL) and added dropwise to the
above reaction mixture and stirred at room temperature for 12 h. Progress of
the reaction was monitored by TLC. When the reaction was complete,
chilled water (4 mL) was added to the reaction mixture and extracted into
diethyl ether (2 ꢀ 50 mL). Aqueous layer was extracted into diethyl ether
(2 ꢀ 25 mL) and combined etherial layers were washed with water, dried
(Na2SO4) and concentrated to obtain the title compound 8 (40 mg, 55%)
as a syrup.
IR: 2200 cmÀ1. 1H NMR (CDCl3): d 1.3 (s, 3H, CH3), 1.7 (s, 3H, CH3),
2.1–2.7 (m, 5H, H-2,20,5,50 and H-6), 5.31 (br s, 1H, H-4). (Found: C, 52.39;
H, 5.68. calc. for C10H13BrO: C, 52.42; H, 5.71%).
6-[2a-Chloro-(E )-1a-ethenyl]-1,3-dimethyl-3-cyclohexen-1-ol (9). To a
mixture of anhydrous chromium(II) chloride (0.45 g, 3.6 mmol) suspended
in dry THF (5 mL) under argon atmosphere a solution of aldehyde 6
(0.1 g, 0.6 mmol) in chloroform (1 mL) and THF (4 mL) was added drop-
wise at 0ꢁC and the resulted suspension was heated to 65ꢁC for 2 h. Progress
of the reaction was monitored by TLC. When the reaction was complete,
the reaction mixture was poured into water (5 mL) extracted into
dichloromethane (2 ꢀ 25 mL). Organic phase was separated, dried (Na2SO4)

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and concentrated to obtain a residue which was purified by column
chromatography [(SiO2, 60–120 mesh; hexane : ethyl acetate: (45:2)] to
obtain the title compound 9 (60 mg, 55%) as a syrup.
1H NMR (CDCl3): d 1.5 (s, 3H, CH3), 1.72 (s, 3H, CH3), 1.95–2.5 (m,
5H, H-2,20,5,50 and H-6), 5.34 (br s, 1H, J ¼ 6.5 Hz, H-4), 5.8–6.2 (m, 2H,
H-1a and H-2a). Ms (m/z): 151. (Found: C, 64.29; H, 7.93. calc. for
C10H15ClO: C, 64.34; H, 8.09%).
2,4,5-Tribromo-2,4-dimethyl-1-cyclohexanol (10). To a solution of the
mono-epoxide 3 (250 g, 2.0 mmol) in carbon tetrachloride (1 mL) was added
bromine (0.96 g, 6.0 mmol) in CCl4 (5 mL) at 0ꢁC. The reaction mixture was
stirred at room temperature for 30 min. Progress of the reaction was moni-
tored by TLC. When the reaction was complete, the reaction mixture was
diluted with water (10 mL) and extracted into dichloromethane (2 ꢀ 50 mL).
Combined dichloromethane layers were washed with water, dried (Na2SO4)
and concentrated to obtain a residue which was purified by column chro-
matography [SiO2, 60–120 mesh; hexane : ethyl acetate: (25 : 0.5)] to obtain
the title compound 10 (0.28 g, 38%) as a syrup.
1H NMR (CDCl3): d 2.05, 2.1 (2s, 6H, 2 ꢀ CH3), 2.2–2.6 (m, 4H,
H-3,30,6 and H-60), 4.5–4.6 (m, 1H, H-5), 4.7–4.8 (m, 1H, H-1). Ms (m/z):
361. (Found: C, 26.24; H, 3.47. calc. for C8H13Br3O: C, 26.33; H, 3.58%).
ACKNOWLEDGMENT
SKM thanks CSIR, New Delhi for the financial assistance.
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Received in the Netherlands February 9, 2001

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