Preparation of β-substituted α-(acetoxymethyl) cyclo hex-2-en-1-ones

Article abstract of DOI:10.1039/a903349a

An effective three-step sequence for the preparation of β-substituted 2-(acetoxymethyl)cyclohex-2-en-1-ones 4, via oxydative allylic transposition of the corresponding allylic alcohols 3, is reported.

Full text of DOI:10.1039/a903349a

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576 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 576^577y
Preparation of b-Substituted
a-(Acetoxymethyl)cyclohex-2-en-1-ones
F. Rezgui and M. M. El Ga|ed*
Laboratoire de Chimie Organique, Faculte des Sciences de Tunis, Campus Universitaire, 1060
Tunis, Tunisia
An effective three-step sequence for the preparation of b-substituted 2-(acetoxymethyl)cyclohex-2-en-1-ones 4,
via oxydative allylic transposition of the corresponding allylic alcohols 3, is reported.
b0-Functionalized cyclohex-2-en-1-ones are useful intermed-
described and could be used for the preparation of various
iates in organic chemistry1
and for biologically active
b0-functionalized-cyclohex-2-en-1-ones.
4
products.5;6 Several methods have been reported7;8 to obtain
these compounds. In connection with our interest in the
functionalization of cyclic a; b-enones, we9 have recently
reported a simple procedure for the preparation of a variety
of 2-(hydroxymethyl)cyclohex-2-en-1-ones from the corre-
sponding a; b-enones. Unfortunately, this method is not
suitable when the starting cyclohex-2-en-1-ones are
b-substituted. In continuation of our previous work, we
report here, an indirect method allowing access to a variety
of 2-(acetoxymethyl)cyclohex-2-en-1-ones 4,10 starting from
1,2-addition of organolithium compounds to enone 1.
An excess of organolithium reagent (2.5 equiv.), reacted
O
HO
R
PCC
OAc
OAc
CH2Cl2
78–87%
R
3a–d
4a–d
Scheme 3
In summary,
a
general preparation of various
2-(acetoxymethyl)cyclohex-2-en-1-ones 4 has been achieved
in a three-step sequence, in fair to good yields. These
acetates are synthetically useful intermediates, via replace-
ment of acetoxy group, for the preparation of allylic amines
and products having biological activities.8;9
at
20 8C with 2-(hydroxymethyl)cyclohex-2-en-1-one 1
in diethyl ether to give regioselectively diols 2a^d, after
hydrolysis in satisfactory yields (Scheme 1).
O
O
O
HO
R
1) RLi, –20˚C
1) MeLi, –20 ˚C (65%)
OH
OAc
OH
OH
2) Ac2O (78%)
3) PCC (83%)
2) Hydrolysis
56–83%
R
5
6
1
2a Me
b Et
Scheme 4
c Ph
d CH2Ph
Scheme 1
Experimental
All reactions progress was monitored by thin-layer
chromatography (TLC) analysis (Merck Kieselgel 60 F254) (eluent:
hexane^ethyl acetate, 1 : 1). All compounds were puri¢ed by
chromatography column (Silica gel 60, 70-230 mesh ASTM). IR
spectra were recorded on Perkin-Elmer model FT PARAGON 1000
PC. 1H NMR (60 or 300 MHz) and 13C NMR (75 MHz) were
recorded on JEOL-CHL 60 or Bruker AC 300 spectrometers using
tetramethylsilane (TMS, d ˆ 0) as internal standard. Mass spectra
were recorded on a Hewlett-Packard instrument (70 eV).
Further monoacetylation of diols 2a^d with acetic
anhydride, in anhydrous pyridine at room temperature,
a¡orded primary acetates 3a^d, in good yields (Scheme 2).
Finally, allylic transposition^oxidation11 of 3a^d with a
suspension of pyridinium chlorochromate (PCC)12;13 in
anhydrous dichloromethane, led to the required
b-substituted a-(acetoxymethyl)cyclohex-2-en-1-ones 4a^d
in good yields (Scheme 3).
General Procedure for the Preparation of Diols 2a^d.öThe prep-
aration of 2a from 1 serves to illustrate the general procedure utilized:
a dry four-necked £ask ¢tted with a nitrogen inlet, a mechanical
stirrer, a thermometer and a pressure-equalizing dropping funnel
was charged with methyllithium (1.6 M, 100 mmol, 62.5 mL) in anhy-
drous diethyl ether. Enone 1 (5.04 g; 40 mmol) in anhydrous ether
(50 mL) was added dropwise at 20 8C. The reaction mixture was
stirred at 20 8C for 3 h. The mixture was quenched with saturated
NH4Cl, and the aqueous layer extracted several times with
dichloromethane. The combined organic phases were dried over
MgSO4. Removal of the solvents in vacuo and puri¢cation of the
HO
R
HO
R
Ac2O
OH
OAc
Pyridine
80–95%
2a–d
3a–d
Scheme 2
crude
product
by
chromatography
column
(diethyl
The reaction sequence described above for the prep-
aration of cyclohex-2-en-1-one derivatives 4a^d was success-
fully extended to 2-(hydroxymethyl)-5,5-dimethylcyclohex-
2-en-1-one 5 and allowed access to 2-(acetoxymethyl)-
isophorone 6 in good yield (Scheme 4). To our knowledge,
this polyfunctional synthon has not been previously
ether^dichloromethane, 1 : 1) a¡orded compound 2a, as a yellow oil.
2-(Hydroxymethyl)-1-methylcyclohex-2-en-1-ol 2a: yield ˆ 83%;
viscous oil; IR(CCl4) n=cm 1: 3400, 1670; dH(60 MHz, CCl4) 5.58
(m, 1H), 4.17 (m, 2H), 2.17^1.43 (m, 6H), 1.30 (s, 3H); dC (75 MHz,
CDCl3) 19.5, 23.4, 26.3, 32.3, 64.1, 70.4, 129.4, 136.9; MS (EI)
‡
m/z 79(74), 93(69), 107(100), 123(56), 142(M , 2%).
1-Ethyl-2-(hydroxymethyl)cyclohex-2-en-1-ol 2b: yield ˆ 74%;
solid, mp 48^50 8C; IR (CHCl3) n=cm 1: 3470, 1660; dH(60 MHz,
CCl4) 5.68 (m, 1H), 4.00 (AB, J ˆ 12 Hz, 2H), 2.14±1.40 (m, 8H),
0.80 (t, J ˆ 6 Hz, 3H); dC (75 MHz, CDCl3) 8.2, 18.7, 25.4, 32.0,
34.2, 65.5, 73.0, 129.7, 139.4; MS (EI) m/z 79(61), 93(79), 107(30),
139(M 17, 100%).
* To receive any correspondence.
This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1999 577
2-(Hydroxymethyl)-1-phenylcyclohex-2-en-1-ol 2c: yield ˆ 63%;
solid, mp 150^152 ꢀC; IR (CHCl3) v/cm 1: 3480, 1670, 1600; dH(60
MHz, CDCl3) 7.50^7.17 (m, 5H), 5.98 (m, 1H), 3.93 (m, 2H),
2.46^1.33 (m, 6H); dC(75 MHz, CDCl3) 18.7, 25.3, 40.8, 65.2, 75.2,
125.4, 126.4, 127.8, 129.8, 138.5, 146.8; MS (EI) m=z 77(35), 91(12),
CDCl3) 20.9, 21.4, 21.7, 33.1, 37.4, 57.0, 130.3, 162.8, 171.0, 197.4;
MS (EI) m/z 77(11), 97(7), 112(14), 125(8), 139(M 43, 100), 182(M,
1%).
2-(Acetoxymethyl)-3-ethyl-2-cyclohexenone 4b: yield ˆ 87%; oil;
IR (CHCl3) n=cm 1: 1760, 1670, 1630; dH(60 MHz, CDCl3) 4.73
(s, 2H), 2.60^2.00 (m, 8H), 1.97 (s, 3H), 1.10 (t, J ˆ 7 Hz, 3H),
dC(75 MHz, CDCl3) 12.7, 21.0, 22.1, 28.2, 30.4, 37.5, 56.6, 129.4,
167.9, 170.9, 197.7; MS (EI) m/z 79(13), 93(10), 111(15), 125(10),
153(M 43, 100).
‡
105(85), 158(100), 186(23), 204(M , 2%).
1-Benzyl-2-(hydroxymethyl)cyclohex-2-en-1-ol 2d: yield ˆ 56%;
solid, mp 132^134 8C; IR (CHCl3) n=cm 1: 3500, 1610; dH(60 MHz,
CDCl3) 7.20 (s, 5H), 5.70 (m, 1H), 4.26 (AB, J ˆ 12 Hz, 2H), 2.90
(AB, J ˆ 10 Hz, 2H), 2.20±1.37 (m, 6H), dC (75 MHz, CDCl3) 19.1,
25.3, 35.1, 44.8, 65.4, 73.2, 126.5, 128.2, 129.3, 130.6, 136.9, 140.0;
MS (EI) m/z 79(10), 91(100), 129(8), 141(6), 182(12), 200(M 18,
12%).
General Procedure for the Preparation of Acetates 3a^d.öThe
preparation of 3a from 2a serves to illustrate the general procedure
utilized: a mixture of diol 2a (4.69 g, 33 mmol), anhydrous pyridine
(4.5 mL) and acetic anhydride (10 mL, 99 mmol) was stirred at room
temperature for 12 h. The mixture was quenched with water and
extracted with dichloromethane. The combined organic phases were
washed successively with aqueous 1.5 M NaOH and with brine, then
dried and concentrated in vacuo. The puri¢cation of the residue by
chromatography column (eluent: diethyl ether) a¡orded pure 3a.
2-(Acetoxymethyl)-1-methylcyclohex-2-en-1-ol 3a: yield ˆ 95%;
oil; IR (CHCl3) n=cm 1: 3480, 1730, 1670; dH(60 MHz, CDCl3) 5.67
(m, 1H), 4.53 (m, 2H), 2.13^1.90 (m, 2H), 2.00 (s, 3H), 1.80^1.50
(m, 4H), 1.27 (s, 3H); dC(75 MHz, CDCl3) 19.5, 21.4, 25.8, 27.7, 39.4,
65.3, 69.7, 130.2, 137.3, 171.3; MS (EI) m/z 81(71), 96(35), 109(100),
124(29), 169(M 15, 54%).
2-(Acetoxymethyl)-3-phenylcyclohex-2-en-1-one 4c: yield ˆ 85%;
oil; IR (CHCl3) n=cm 1: 1735, 1675, 1620; dH(60 MHz, CDCl3)
7.70^7.17 (m, 5H), 4.56 (s, 2H), 2.90^2.03 (m, 6H), 1.97 (s, 3H);
dC(75 MHz, CDCl3) 20.9, 22.2, 33.2, 37.5, 58.7, 126.8, 128.4, 128.8,
130.5, 139.5, 163.2, 170.5, 197.9; MS (EI) m/z 77(21), 91(20)
184(100), 201(M 43, 75); 245(M ‡ 1, 14%).
2-(Acetoxymethyl)-3-benzylcyclohex-2-en-1-one 4d: yield ˆ 78%;
oil; IR (CHCl3) n=cm 1: 1730, 1675; dH(60 MHz, CDCl3) 7.20 (s, 5H),
4.82 (s, 2H), 3.60 (s, 2H), 2.60^2.20 (m, 4H), 2.60^1.93 (m, 2H), 1.90
(s, 3H); dC(75 MHz, CDCl3) 20.4, 21.5, 30.2, 37.0, 40.2, 56.3, 126.3,
128.2, 128.3, 130.4, 136.8, 163.2, 170.3, 197.1; MS (EI) m/z 77(39),
91(83) 141(79), 167(79), 182(100), 196ꢁM 62, 72%).
2-(Acetoxymethyl)-3,5,5-trimethylcyclohex-2-en-1-one 6: yield ˆ
83%; oil; IR (CHCl3) n=cm 1: 1730, 1670, 1640; dH(60 MHz, CDCl3)
4.70 (s, 2H), 2.33^2.17 (m, 4H), 2.00 (s, 3H), 1.95 (s, 3H); 1.00 (s,
6H); dC(75 MHz, CDCl3) 20.7, 21.3, 28.0, 32.5, 46.9, 50.6, 56.7, 129.0,
159.9, 170.8, 197.5 (Found: C, 68.7; H, 8.5. C12H18O3 requires C,
68.57; H, 8.57%).
2-(Acetoxymethyl)-1-ethylcyclohex-2-en-1-ol 3b: yield ˆ 80%; oil;
IR (CHCl3) n=cm 1: 3480, 1730; dH(60 MHz, CDCl3) 5.73 (m, 1H),
4.50 (m, 2H), 2.20^1.90 (m, 2H), 2.00 (s, 3H), 1.80^1.46 (m, 6H), 1.83
(t, J ˆ 7 Hz, 3H); dC(75 MHz, CDCl3) 8.3, 18.7, 21.1, 25.6, 32.0, 34.3,
65.0, 71.7, 131.1, 136.4, 170.9; MS (EI) m/z 81(46), 109(100), 127(7),
169(M 29; 38%).
Received, 27th April 1999, Accepted, 8th June 1999
Paper E/9/03349A
2-(Acetoxymethyl)-1-phenylcyclohex-2-en-1-ol 3c: yield ˆ 83%;
oil; IR (CHCl3) n=cm 1: 3480, 1735, 1670; dH(60 MHz, CDCl3)
7.50^7.10 (m, 5H), 6.03 (m, 1H), 4.40 (AB, J ˆ 13 Hz, 2H), 2.40^1.80
(m, 6H), 1.77 (s, 3H); dC(75 MHz, CDCl3) 18.3, 20.4, 25.2, 40.4, 65.2,
73.9, 125.5, 126.4, 127.6, 131.2, 135.7, 146.1, 171.0; MS (EI) m/z
References
1
2
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‡
77(33), 91(11), 105(88), 158(100), 168(20), 186(25), 246(M , 2%).
2-(Acetoxymethyl)-1-benzylcyclohex-2-en-1-ol 3d: yield ˆ 86%;
oil; IR (CHCl3) n=cm 1: 3500, 1760, 1660, 1610; dH(60 MHz, CDCl3)
7.13 (s, 5H), 5.73 (m, 1H), 4.58 (s, 2H), 2.83 (AB, J ˆ 14 Hz, 2H),
2.13^1.93 (m, 2H), 2.00 (s, 3H), 1.83^1.67 (m, 4H); dC(75 MHz,
CDCl3) 18.8, 20.9, 25.2, 35.1, 44.8, 64.4, 71.6, 126.2, 127.9, 130.4,
136.87, 136.90, 170.8; MS (EI) m/z 81(45), 91(36), 109(100),
169(M 91, 60%).
General Procedure for the Preparation of Enones 4a^d.öThe prep-
aration of 4a from 3a serves to illustrate the general procedure
utilized: to a suspension of PCC (3.23 g, 15 mmol) in anhydrous di-
chloromethane (20 mL) was added rapidly at 0 8C, 3a (1.84 g,
10 mmol) dichloromethane (20 mL). The mixture was stirred at room
temperature for 5 h. After evaporation of the solvent, the mixture
was £ash-chromatographed over silica gel using diethyl ether as eluent
to give 4a as a yellow oil.
3
4
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2-(Acetoxymethyl)-3-methylcyclohex-2-en-1-one 4a: yield ˆ 85%;
oil; IR (CHCl3) n=cm 1: 1760, 1670, 1635; dH(60 MHz, CDCl3) 4.63
(s, 2H), 2.57^2.07 (m, 6H), 2.0 (s, 3H), 1.93 (s, 3H), dC(75 MHz,
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