[4+2] Cyclohexane ring formation by a tandem of a free radical alkylation of a non-activated δ-carbon atom and intramolecular carbanion cycloalkylation

Article abstract of DOI:10.1055/s-2004-829115

A [4+2] cyclohexane ring formation was achieved by the combination of free radical and ionic reaction sequences. Free radical alkylation of the remote non-activated δ-carbon atom involves addition of δ-carbon radicals, generated by 1,5-hydrogen transfer in alkoxyl radical intermediates, to the radicophilic olefins, while the polar sequence involves the enolate anions as intermediates which undergo a cycloalkylation reaction. The cyclohexane rings were constructed using diverse acyclic compounds 15 and 18 as well as cyclic alkyl arenesulfenates (e.g., 5, 24, 27) as the precursors of alkoxyl radicals (four-carbon atom fragment) and methyl vinyl ketone or other activated olefins as two-carbon atom fragments. Annulation of the cyclohexane ring was applied for the synthesis of a variety of cyclic systems including monocyclic (17 and 20), fused-rings (e.g. 23, 26, 29) and spirocyclic systems (7).

Full text of DOI:10.1055/s-2004-829115

PAPER
1671
[4+2] Cyclohexane Ring Formation by a Tandem of a Free Radical Alkylation
of a Non-Activated d-Carbon Atom and Intramolecular Carbanion Cyclo-
alkylation
[4+2]
C
yclohexane
o
Ring Form
r
a
tionby
a
a
T
ande
m
R
n
eaction Petrović, Živorad Čeković*
Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 158, 11000 Belgrade, Serbia and Montenegro
E-mail: zcekovich@chem.bg.ac.yu
Received 2 February 2004; revised 1 April 2004
functionalized alkyl chain was introduced at a remote
Abstract: A [4+2] cyclohexane ring formation was achieved by the
combination of free radical and ionic reaction sequences. Free rad-
ical alkylation of the remote non-activated d-carbon atom involves
addition of d-carbon radicals, generated by 1,5-hydrogen transfer in
non-activated carbon atom (Scheme 1, phase 2).3,4 In
these sequential free radical reactions the hydroxy com-
pounds, possessing an electron-withdrawing group at-
alkoxyl radical intermediates, to the radicophilic olefins, while the tached to the 6-position, are obtained. Compounds 2,
polar sequence involves the enolate anions as intermediates which
possessing a suitably disposed procarbanionic carbon
undergo a cycloalkylation reaction. The cyclohexane rings were
atom and leaving group offer the possibility for cyclohex-
constructed using diverse acyclic compounds 15 and 18 as well as
ane ring 1 closure (Scheme 1, step 3).5 This method for the
cyclic alkyl arenesulfenates (e.g., 5, 24, 27) as the precursors of
construction of a cyclohexane rings requires [4+2] carbon
alkoxyl radicals (four-carbon atom fragment) and methyl vinyl ke-
fragments and could be complementary to the Robinson
annulation.6 The four-carbon atom fragment must be a
precursor of the alkoxyl radical generated from the alkyl
arenesulfenates 4, while the two-carbon atom fragment is
preferably an electron-deficient olefinic compound.
tone or other activated olefins as two-carbon atom fragments. An-
nulation of the cyclohexane ring was applied for the synthesis of a
variety of cyclic systems including monocyclic (17 and 20), fused-
rings (e.g. 23, 26, 29) and spirocyclic systems (7).
Key words: annulations, radicals, 1,5-hydrogen transfer, radical
reactions, cycloalkylations, d-alkylations, alkyl arenesulfenates
The cyclohexane ring annulation methodology was veri-
fied using various structurally different four-carbon atom
fragments as precursors of alkoxyl radicals.3a Cycloal-
kylation reactions were applied to the synthesis of a vari-
ety of cyclic compounds including monocyclic, fused-
ring and spirocyclic systems (Scheme 2, Table 1). The
alkyl arenesulfenates, used as precursors of the alkoxyl
radicals, were part of acyclic, monocyclic and polycyclic
systems and methyl vinyl ketone was used as an activated
(radicophilic) olefin.
Reactions and methods for carbocyclic ring construction
are of great importance in organic synthesis. A variety of
cyclization reactions were developed, which may involve
cationic, radical and anionic intermediates, in addition to
pericyclic and metal-catalyzed reactions.1 In addition to
the numerous classical reactions we recently discovered a
new sequence of free radical and carbanionic reactions for
the [4+2] annulation of cyclohexane ring 1, involving a
carbon-carbon bond formation on the remote non-activat-
ed carbon atom (Scheme 1, step 2).2
The method for [4+2] cyclohexane ring annulation was
also successfully used for the construction of spirocyclic
systems. Thus, in the reaction of 3-(cyclohexyl)-propyl-p-
nitrobenzenesulfenate (5, Scheme 2) with tributyltin hy-
dride (TBTH), in the presence of a 10 molar excess of
methyl vinyl ketone, the hydroxy ketone 6 was obtained.
Upon treatment of keto tosylate, derived from ketone 6,
with sodium hydride the cycloalkylation occurred and the
1-spiro[5,5]undec-2-ylethanone (7) was obtained in 36%
overall yield (Scheme 2).
This cyclohexane ring annulation methodology is based
on the recently discovered reaction of the d-carbon radical
3, generated by 1,5-hydrogen transfer in the alkoxyl radi-
cal intermediates (Scheme 1, step 1). It undergoes inter-
molecular addition to activated olefins and thus a
Z
Z
2
3
The alkoxyl radicals 11 were generated from the corre-
sponding alkyl benzene- and p-nitrobenzenesulfenates
(Scheme 3) by reaction with TBTH, and d-alkylation was
carried out in the presence of a 10 molar excess of methyl
vinyl ketone as an activated olefin.2–4,7 The reactions were
performed under irradiation conditions in benzene solu-
tion. Translocation of the radical center from the oxygen
in 11 to the non-activated carbon atom in d-position oc-
curs by 1,5-hydrogen transfer.3a,8 d-Carbon radical 12 un-
dergoes intermolecular addition to methyl vinyl ketone9 to
give the corresponding d-alkylated products 9 containing
OTs
2
1
Z
1
OSAr
OH
4
3
Scheme 1
SYNTHESIS 2004, No. 10, pp 1671–1679
Advanced online publication: 23.06.2004
DOI: 10.1055/s-2004-829115; Art ID: T01304SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4

1672
G. Petrović, Ž. Čeković
PAPER
13 could occur and 8-endo cycloalkylation products could
O-SC6H4NO2-p
H
also be obtained.11
O
i.
+
Thus starting from the primary acyclic alkyl benzene-
sulfenates 15 and 18 the 1,3-substituted cyclohexane de-
rivatives 17 and 20, respectively, were obtained (Table 1).
The described methodology was also applied to the annu-
lation of the fused cyclohexane ring of monocyclic and
polycyclic arenesulfenates such as 21 and 24. Starting
from the 2-(cycloalkyl)-ethyl p-nitrobenzenesulfenates 21
and 24 the corresponding trans-decaline derivative 23 and
adamantane derivative 26 were obtained.
5
O
O
ii. iii.
OH
6
7
i. Bu3SnH, hv, C6H6 (47%)
ii. TsCl, pyridine (80%)
iii. NaH, DME (72%)
Annulation of the cyclohexane ring into the steroid skele-
ton was realized by free radical alkylation of the C-18
angular methyl group of pregnane-20b-O-p-nitrobenzene-
sulfenate derivative 27 by radical addition to methyl vinyl
ketone followed by intramolecular alkylation of the inter-
mediary keto mesylate, prepared from the hydroxy ketone
28. Thus, the ring E was constructed and 18,20-ethano-
pregnane derivative 29 was obtained in 26% overall yield
(Scheme 4).
Scheme 2
an electron-withdrawing group. Products 9 were isolated
and fully characterized.
In the d-alkylated products the relationship of functional
groups is appropriate for the ionic 6-exo- and 8-endo cy-
cloalkylation, depending of the reaction conditions and
the reagents used.
O
O-SC6H4NO2-p
The hydroxyl group in 9 was converted into the corre-
sponding toluenesulfonate or methanesulfonate esters 13
by reaction with the corresponding sulfonyl chloride in
the presence of pyridine (Scheme 3).10 In the next step, the
keto sulfonate esters 13 were treated under equilibrium-
controlled conditions with sodium hydride in DME thus
furnishing the corresponding more stable enolate anions
14.5 In the presence of a suitably disposed sulfonate leav-
ing group the enolate anions 14 undergo an intramolecular
6-exo alkylation to yield cyclohexane 10 with an exocy-
clic electron-withdrawing group. Under these reaction
conditions the enolate anions 14 undergo exclusively C-
alkylation. We suppose that under kinetic conditions
deprotonation at the terminal position of the keto tosylate
OH
ii. iii.
i.
AcO
27
28
O
O
i. Bu3SnH, hv, C6H6,
ii. TsCl, pyridine
iii. NaH, DME
10 equiv
(27%)
29
Scheme 4
O
O
ii. iii.
O-SAr
i.
OH
8
9
10
ii.
hv
Bu3Sn
O
O
O
H
O
iii.
OH
OTs
OTs
13
12
14
11
O
i. Bu3SnH, hv, C6H6,
ii. TsCl, pyridine
iii. NaH, DME
Scheme 3
Synthesis 2004, No. 10, 1671–1679 © Thieme Stuttgart · New York

PAPER
[4+2] Cyclohexane Ring Formation by a Tandem Reaction
1673
Table 1 Annulation of the Cyclohexane Ring by a Sequence of Free Radical and Carbanionic Reactions Using Methyl Vinyl Ketone as the
Activated Olefin
Alkyl arenesulfenatesa
d-Alkylated products (yields in %)b
Annulated (cyclic) products (yields in %)b,c
O
O
(41%)
(74%)
15
OH
17
16
O
O
(35%)
(76%)d
O-SPh
OH
20
19
18
O
O
O-SC6H4NO2-p
H
H
H
(36%)e
OH
(76%)
21
22
23
26
O
O
O-SC6H4NO2-p
(42%)
OH
(78%)
24
25
a The alkyl benzenesulfenates were purified by distillation under reduced pressure, while the alkyl p-nitrobenzenesulfenates were purified by
dry flash chromatography.
b Yields of isolated products (yields by GC analysis were 10–20% higher).
c The hydroxyl group of the d-alkylated products was converted into the corresponding tosylate or mesylate groups (80–90% yields) and then
the cycloalkylation reaction was carried out under basic conditions (see experimental part).
d Only the cis isomer was obtained.
e The ratio of cis and trans isomers was 1:3.
Cycloalkylation reaction of open-chain or cyclic keto sul-
fonate esters, derived from primary alcohols and possess-
i.
ing appropriately oriented reactive centers, is a favorable
O-SPh
OH
O
reaction (Table 1). However, the modes of cycloalkyla-
tion reactions of cyclic keto sulfonate esters, are very sen-
sitive to the stereoelectronic effects and side reactions can
occur. When the stereochemical relationship of the react-
ing groups is not suitable for the intramolecular substitu-
tion reactions, the sulfonate esters derived from the
secondary hydroxy group rather undergo an elimination
as a side reaction, to give unsaturated products.12
30
31
ii. iii.
O
H
O
H
The importance of the appropriate stereochemistry at the
reactive centers in the cycloalkylation reaction was ob-
served in the annulation of (–)-menthyl benzenesulfenate
30 (Scheme 5). In the reaction with methyl vinyl ketone
the methyl group in position 9 was alkylated and hydroxy
ketone 31 was obtained (the ratio of 6R and 6S is 1:3.5)
which was then converted into the corresponding keto-to-
sylate.13 The enolate anion 31a (Scheme 7) derived from
the keto-tosylate, possessing an equatorial leaving group,
did not undergo a substitution reaction, but rather an elim-
ination reaction to give the unsaturated ketones 32. No
traces of the cycloalkylation product 33 was obtained
(Scheme 5).14
33
32
O
i. Bu3SnH, hv, C6H6,
ii. TsCl, pyridine
iii. NaH, DME
10 equiv (32%)
Scheme 5
In order to carry out the cycloalkylation reaction, the
equatorial hydroxyl group in the d-alkylated product 31
was epimerized to give the axial alcohol 34 via its p-ni-
trobenzoate ester (Scheme 6).15 The enolate anion 35a de-
rived from the corresponding keto-methanesulfonate 35
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1674
G. Petrović, Ž. Čeković
PAPER
with an axial leaving group, has the appropriate stereo-
chemistry for an intramolecular substitution. Thus, cy-
cloalkylation occurs to give the bicyclic product
(tetrahydrokhusitone)13 33 (Schemes 6 and 7). However,
in addition to the bicyclic product 33, the unsaturated ke-
tone 32 was also formed as a product of the elimination re-
action (yields 53% and 34% respectively).14,16 It is well
known that the intramolelcular cycloalkylation reaction is
less favorable when the leaving group (i.e. sulfonate ester
O
H
H
i. ii.
23
OH
O
OH
H
36
22
i. TsCl, pyridine
ii. NaH, DME
Scheme 8
group) is attached to a secondary carbon atom and its tion of cyclohexane rings which require two fragments: an
elimination becomes a serious side reaction.17
activated olefin (Michael acceptor) and a four-carbon
atom chain of type 38 with a proalkoxy radical functional
group, preferably alkyl arenesulfenates (38, X = SPh,
SC6H4NO2-p, Scheme 9). The cyclohexane derivative 37,
formed by applying this methodology, contains only an
exocyclic electron-withdrawing group. The presented
method herein could be complementary to the Robinson
annulation of the cyclohexane ring 39 which requires two
fragments: conjugated and saturated ketones 40 and 41
and two procarbanionic carbon atoms (Scheme 9).6
i. ii.
iii.
iv.
31
33 + 32
OMs
O
OH
O
34
35
i. p-O2NC6H4COOH, Ph3P, DEAD, C6H6, (82%)
ii. KOH, THF, MeOH, H2O, (97%)
iii. MsCl, pyridine, CH2Cl2, (100%)
iv. NaH, DME, (53%)
OX
Scheme 6
Z
Z
+
When the described annulation method was applied to
open-chain non-branched alkyl benzenesulfenates, e.g.
n-octyl benzenesulfenate 18, the cis isomer of 1,3-disub-
stituted cyclohexane derivative 20 was obtained
(Table 1). Formation of the cis isomer is favorable be-
cause the ‘axial’ interaction of the substituents disfavor
the transition state leading to the trans isomer.
38
37
X = SPh, SC6H4NO2-p, NO
Z = EWG
+
O
O
O
39
40
41
In the annulation of the cyclohexane ring starting from 2-
cyclohexylethyl p-nitrobenzenesulfenate (21) and methyl
vinyl ketone a mixture of cis- and trans-hydroxy ketones
22 was obtained in a ratio of 1:3. The excess of trans iso-
mer is obtained because the addition of the intermediary
cyclohexyl radical (of type 36, Scheme 8) to methyl vinyl
ketone preferentially takes place from the equatorial side
Scheme 9
The solvents and commercial reagents used in all of the experiments
were purified by distillation before use (benzene distilled over CaH2
and CH2Cl2 over P2O5). Purifications and separations of the reaction
to give the trans-diequatorial intermediary hydroxy ke- products were carried out by distillation and preparative column
tone 22,18 which upon cycloalkylation reaction gives the
trans-decaline derivative 23 (Scheme 8 and Table 1).
chromatography using silica gel 100–200 mesh (60 Å) and by dry
flash chromatography using silica gel (60 Å). The reactions were
monitored by TLC using silica gel (TLC 60 Å, plates were visual-
The described annulation methodology consists of a se-
quence of three reactions. It is more convenient to perform
all of the reactions separately, and to isolate the interme-
diary hydroxy ketones as products of the free radical d-
alkylation as well as their tosyl or mesyl derivatives. The
pure keto sulfonate esters must be used in the cycloalkyl-
ation reaction.
ized using ultraviolet light or by H2SO4) or by GC (Varian 3400,
column OV-101 1% on Chromosorb W-AW). Optical rotations
were measured using a Perkin-Elmer 141 MC polarimeter. IR spec-
1
tra were recorded on a Perkin-Elmer 457 grating instrument. H
NMR spectra were recorded in CDCl3 solution (unless otherwise
stated) at 200 MHz, using a Varian Gemini 200 spectrometer. The
chemical shifts (d) are expressed in ppm using TMS as the internal
standard. 13C NMR spectra were measured on the same instrument
at 50 MHz. Mass spectra were performed on a Finningan ITDS 700
instrument.
The sequence of a free radical d-alkylation and enolate an-
ion cycloalkylation offers a new method for the annula-
X
TsO
O
OMs
O
O
33a
35a
31
Scheme 7
Synthesis 2004, No. 10, 1671–1679 © Thieme Stuttgart · New York

PAPER
[4+2] Cyclohexane Ring Formation by a Tandem Reaction
1675
Synthesis of Alkyl Arenesulfenates
Alkyl p-Nitrobenzenesulfenates; General Procedure21
Alkyl Benzenesulfenate; General Procedure3b-3d,6,19
To a solution of starting alcohol (10.5 mmol) and Et3N (2.66 g, 26.4
mmol) in CH2Cl2 (55 mL), cooled to –40 °C under an Ar atmo-
sphere, the solution of p-nitrobenzenesulfenyl chloride (2.2 g, 11.6
mmol) in CH2Cl2 (10 mL) was added drop-wise during 10 min. The
reaction mixture was stirred at –40 °C for 20 min and then allowed
to reach r.t. with stirring for 1.5 h. The mixture was diluted with
CH2Cl2 (200 mL) and washed successively with HCl (30 mL, 2 M),
sat. aq NaHCO3 (30 mL) and H2O (50 mL). The solution was dried
over Na2SO4. The solvent was removed by evaporation and the re-
sidual oil purified by dry flash chromatography on a silica gel col-
umn (toluene). Alkyl p-nitrobenzenesulfenates were obtained in
74–86% yield.
To the solution of starting alcohol (0.02 mol) and Et3N (0.05 mol)
in CH2Cl2 (150 mL), cooled to –78 °C under an Ar atmosphere,
benzenesulfenyl chloride (0.025 mol) was added during 10 min at
–78 °C and left to reach r.t. The mixture was diluted with CH2Cl2
(400 mL) and washed successively with 2 M HCl (50 mL), sat. aq
NaHCO3 (50 mL) and H2O (50 mL). The solution was dried over
Na2SO4. The solvent was removed by evaporation and the residual
oil distilled on a short path under reduced pressure. Solid alkyl ben-
zenesulfenates were purified by dry flash chromatography. Alkyl
benzenesulfenates were obtained in 71–87% yield.
4-Methylpentyl Benzenesulfenate (15)
Yield: 76%; yellow-green oil, bp 80–83 °C/0.02 mmHg.
2-Cyclohexylethyl p-Nitrobenzenesulfenate (21)3b,c
Yield: 82%; red oil.
IR (neat): 3063, 1583, 1477, 1455, 1440, 1387, 1097, 1024, 981,
959, 892, 737, 690 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (d, J = 6.6 Hz, 6 H), 1.15–
1.27 (m, 2 H), 1.52 (hept, J = 6.6 Hz, 1 H), 1.60–1.75 (m, 2 H), 3.78
(t, J = 6.4 Hz, 2 H), 7.15–7.38 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 140.8, 128.8, 126.3, 123.6, 78.8,
34.7, 28.2, 27.7, 22.4.
IR (neat): 1594, 1581, 1515, 1475, 1448, 1424, 1337, 1178, 1111,
1088, 1030, 963, 890, 852, 840, 802, 741 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.85–1.55 (m, 7 H), 1.64 (q,
J = 6.8 Hz, 2 H), 1.59–1.75 (m, 4 H), 3.95 (t, J = 6.8 Hz, 2 H), 7.73
(AA¢BB¢ system, dA = 7.25, dB = 8.21, JAB = 9.0 Hz, JAB¢ = 2.0 Hz,
4 H).
13C NMR (50 MHz, CDCl3): d = 151.7, 144.9, 124.0, 119.6, 77.6,
37.5, 34.05, 30.0, 26.2, 25.9.
Anal. Calcd. for C12H18OS: C, 68.57; H, 8.57; S, 15.23. Found: C,
68.90; H, 8.40; S, 15.02.
3-Cyclohexylpropyl p-Nitrobenzenesulfenate (5)
Yield: 80%; red oil.
Octyl Benzenesulfenate (18)3b,c
Yield: 71%; bp 103–105 °C/0.02 mmHg.
IR (neat): 1594, 1581, 1515, 1475, 1449, 1366, 1337, 1178, 1111,
1088, 1037, 994, 974, 949, 920, 911, 852, 841, 742 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.78–1.09 (m, 2 H), 1.10–1.40 (m,
6 H), 1.60–1.85 (m, 7 H), 3.89 (t, J = 6.8 Hz, 2 H), 7,73 (AA¢BB¢
system, dA = 7.25, dB = 8.21, JAB = 9.0 Hz, JAB¢ = 2.0 Hz, 4 H).
13C NMR (50 MHz, CDCl3): d = 151.8, 145.0, 124.2, 119.7, 79.9,
37.2, 33.1, 27.6, 26.5, 26.2.
IR (neat): 3060, 1583, 1478, 1440, 1378, 1148, 1068, 1024, 968,
894, 737, 690 cm–1.
1H NMR (200 MHz): d = 0.88 (t, J = 6.2 Hz, 3 H), 1.20–1.40 (m, 10
H), 1.58–1.73 (m, 2 H), 3.80 (t, J = 6.6 Hz, 2 H), 7.13–7.40 (m, 5
H).
13C NMR (50 MHz): d = 140.8. 128.9, 126.3, 123.6, 78.6, 31.7,
30.3, 29.1, 25.7, 22.6, 14.0.
2-(1-Adamantyl)ethyl p-Nitrobenzenesulfenate (24)
Yield: 74%; yellow crystals.
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl Benzenesulfenate
[(–)-Menthyl benzenesulfenate, (30)]13
22
Yield 87%; bp 108–110 °C/0.07 mmHg; [a]D –256.7 (c = 1,
IR (KBr): 1593, 1577, 1509, 1474, 1448, 1333, 1317, 1253, 1188,
1176, 1109, 1088, 951, 937, 853, 837 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.47–1.68 (m, 12 H), 1.56 (t,
J = 7.4 Hz, 2 H), 1.90–2.00 (m, 3 H), 3.98 (t, J = 7.4 Hz, 2 H), 7.73
(AA¢BB¢ system, dA = 7.25, dB = 8.21, JAB = 9.0 Hz, JAB¢ = 2.0 Hz,
4 H).
CHCl3) of 92% purity of compound (determined by 1H NMR spec-
trum).
IR (neat): 3062, 1583, 1477, 1455, 1440, 1387, 1370, 1345, 1097,
1024, 1004, 981, 959, 914, 851, 778, 738, 690 cm–1.
1H NMR (200 MHz): d = 0.62 (d, J = 7.0 Hz, 3 H), 0.87 (d, J = 7.2
Hz, 3 H), 0.88 (d, J = 7.2 Hz, 3 H), 0.72–1.00 (m, 3 H), 1.20–1.38
(m, 2 H),1.54–1.66 (m, 2 H), 2.18–2.38 (m, 2 H), 3.37 (td, J1 = 10.7
Hz, J2 = 4.4 Hz, 1 H), 7.10–7.40 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 151.8, 146.0, 124.2, 119.7, 76.1,
44.1, 42.5, 38.9, 36.8, 28.4.
Anal. Calcd for C18H23NO3S: C, 64.86; H, 6.90; N, 4.20; S, 9.60.
Found: C, 64.55; H, 7.05; N, 4.08; S, 9.78.
13C NMR (50 MHz): d = 141.3, 128.5, 126.6, 125.4, 87.0, 48.6,
40.9, 34.1, 31.5, 25.1, 22.9, 22.0, 20.9, 15.6.
Methyl (3b,20S)-20-{[(4-nitrophenyl)thio]oxo}pregn-5-ene-3-
carboxylate (27)
Yield: 86%; yellow crystals.
Elemental analysis was not performed because the compound de-
composes with explosion in the Pregl apparatus (determined by 1H
NMR spectrum).
IR (KBr): 1732, 1637, 1593, 1583, 1517, 1747, 1446, 1366, 1350,
1250, 1148, 1112, 1089, 1071, 1039, 866, 853, 837, 738 cm–1.
Alkyl p-Nitrobenzenesulfenates
p-Nitrobenzenesulfenyl Chloride20
1H NMR (200 MHz, CDCl3): d = 0.78 (s, 3 H), 1.04 (s, 3 H), 1.20
(d, J = 6.2 Hz, 3 H), 0.96–1.34 (m, 7 H), 1.39–1.71 (m, 8 H), 1.85–
1.97 (m, 2 H), 2.04 (s, 3 H), 2.07–2.15 (m, 1 H), 2.31–2.35 (m, 2 H),
3.92 (m, 1 H), 4.61 (m, 1 H), 5.38 (d, J = 4.2 Hz, 1 H), 7.75 (AA¢BB¢
system, dA = 7.32, dB = 8.18, JAB = 9.0 Hz, JAB¢ = 2.0 Hz, 4 H).
13C NMR (50 MHz, CDCl3): d = 170.5, 153.4, 144.9, 139.9, 123.9,
122.3, 120.4, 88.0, 73.8, 56.4, 55.9, 49.9, 42.3, 39.3, 38.0, 36.9,
36.5, 31.8, 31.7, 27.7, 25.6, 24.3, 21.4, 20.8, 19.3, 19.0, 12.5.
To a solution of chlorine in CCl4 (14%, 80 mL) cooled to –20 °C, p-
nitrothiophenol (14.0 g, 0.09 mol) was added during 20 min (vigor-
ous reaction). The reaction mixture was stirred for additional 30 min
at –20 °C and 3 h at r.t. The solvent was evaporated and the red re-
sidual oil solidified. The product was dissolved in anhyd Et2O (50
mL), concentrated, and 17.0 g of brown crystalline p-nitrobenzene-
sulfenyl chloride was obtained in 99% yield.
IR (KBr): 2000–1600, 1597, 1576, 1509, 1475, 1398, 1362, 1341,
1317, 1107, 855, 841, 739 cm–1.
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PAPER
Anal. Calcd for C29H39NO5S: C, 67.83; H, 7.60; N, 2.72; S, 6.23.
Found: C, 67.55; H, 7.38; N, 2.80; S, 6.11.
13C NMR (50 MHz, CDCl3): d = 210.0, 63.5, 37.7, 35.6, 33.9, 32.5,
30.4, 29.9, 27.7, 26.9, 26.3, 26.1, 21.4.
Anal. Calcd for C13H24O2: C, 73.58; H, 11.32. Found: C, 73.40, H,
11.48.
Free Radical Alkylation of the Non-Activated d-Carbon Atom;
General Procedure2
A solution of alkyl benzenesulfenates (or p-nitrobenzenesulfenates)
(2.24 mmol), 10 molar equiv of methyl vinyl ketone (1.57 g, 22.4
mmol) and Bu3SnH (0.727 g, 2.5 mmol) in benzene (220 mL) was
irradiated at r.t. by visible light (xenon lamp 250W l > 300 nm or
by UV lamp) for 1 h in an Ar atmosphere. After the reaction was
completed, benzene was evaporated and the residual oil was dis-
solved in Et2O (50 mL) and washed with aq solution of NaF (0.5 g
in 10 mL). The ethereal solution was separated and the aqueous so-
lution extracted with Et2O (2 × 20 mL). The ethereal solutions were
dried (Na2SO4). The ether was evaporated and the reaction products
were separated by chromatography on a silica gel column (ben-
zene–EtOAc, 7:3).
4-[1-(2-Hydroxyethyl)-2-adamantyl]butan-2-one (25)
Yield: 42%; viscous, colorless oil.
IR (neat): 3412, 1713, 1596, 1572, 1518, 1460, 1410, 1356, 1230,
1163, 1058, 916 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.22–1.94 (m, 19 H), 2.14 (s, 3 H),
2.26–2.54 (m, 2 H), 3.70 (t, J = 6.6 Hz, 2 H).
Anal. Calcd for C16H26O2: C, 76.80; H, 10.40. Found: C, 76.62; H,
10.35.
Acetic Acid 17-(1-Hydroxy-ethyl)-10-methyl-13-(4-oxo-pentyl)-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo-
penta[a]phenanthren-3-yl Ester [4-(3b-Acetoxy-20b-hydroxy-5-
pregnen-18-yl)-butan-2-one] (28)
8-Hydroxy-5,5-dimethyloctan-2-one (16)
The compound was obtained as a colorless oil in 41% yield accord-
ing to the described general procedure.
Yield: 27% (from 27); white, crystals.
IR (KBr): 3456, 1732, 1718, 1646, 1596, 1519, 1458, 1374, 1339,
1247, 1156, 1133, 1082, 1032 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 (s, 3 H), 0.85–1.97 (m, 22 H),
1.15 (d, J = 5.8 Hz, 3 H), 2.04 (s, 3 H), 2.14 (s, 3 H), 2.20–2.51 (m,
5 H), 3.64–3.84 (m, 1 H), 4.51–4.68 (m, 1 H), 5.36–5.39 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 209.2, 170.6, 139.7, 122.4, 73.9,
70.2, 59.4, 57.5, 49.8, 44.9, 44.3, 38.0, 36.9, 36.6, 35.8, 31.6, 29.8.
IR (neat): 3443,1715, 1585, 1472, 1417, 1387, 1366, 1299, 1261,
1223, 1164, 1060, 1022, 897, 851, 801, 750, 692 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 (s, 6 H), 1.18-1.27 (m, 2 H),
1.44-1.56 (m, 4 H), 1.85 (br s, 1 H), 2.16 (s, 3 H), 2.35-2.43 (m, 2
H), 3.61 (t, J = 6.4 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 209.8, 63.5, 38.8, 37.4, 35.0, 31.9,
29.8, 27.3, 26.73.
Anal. Calcd for C27H42O4: C, 75.34; H, 9.76. Found: C, 75.48; H,
9.90.
Anal. Calcd for C10H20O2: C, 69.76; H, 11.62. Found: C, 69.95; H,
11.51.
(6R) and (6S)-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]hep-
tan-2-one (31)13
(6R) and (6S)-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-hep-
tan-2-one was obtained [from (–)-menthyl benzenensulfenate 30] in
32% yield (0.2 g) as a yellow-green oil containing a mixture of two
diastereoisomers (6R and 6S) in a ratio of 1:3.5.
5-(3-Hydroxypropyl)nonan-2-one (19)
Yield: 35%; colorless oil.
IR (neat): 3418, 1713, 1456, 1413, 1359, 1308, 1266, 1226, 1166,
1059 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.24–
1.33 (m, 9 H), 1.48–1.64 (m, 4 H), 1.82 (br s, 1 H), 2.15 (s, 3 H),
2.38–2.45 (m, 2 H), 3.63 (t, J = 6.6 Hz, 2 H).
IR (neat): 3420, 1713, 1456, 1411, 1363, 1262, 1226, 1170, 1103,
1080, 1044, 991, 969, 922 cm–1.
13C NMR (50 MHz, CDCl3): d = 209.7 C, (62.9, 40.9) CH2, 36.5
1H NMR (200 MHz): d = 0.80 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 6.4
Hz, 3 H), 0.92 (d, J = 7.0 Hz, 3 H), 0.86–1.71 (m, 9 H), 1.22 (q,
J = 7.8 Hz, 2 H), 1.90–2.06 (m, 2 H), 2.14 (s, 3 H), 2.43 (t, J = 7.4
Hz, 2 H), 3.43 (td, Jaa = 10.0 Hz, Jae = 4.0 Hz, 1 H).
13C NMR (50 MHz): d = 209.5, 70.7, 70.5, 50.3, 48.1, 44.8, 43.8,
43.6, 34.52, 34.3, 31.4, 31.0, 30.2, 29.7, 24.3, 22.8, 22.1, 22.0, 21.8,
17.5, 13.6.
CH3, 32.8 CH2, 29.7 CH, (29.5, 29.1, 28.5, 27. 22.8) CH2, 13.9 CH3.
cis- and trans-4-[2-(2-Hydroxyethyl)cyclohexyl]butan-2-one
(22)
The compound was obtained from the 2-cyclohexylethyl p-ni-
trobenzenesulfenate 21 and the mixture of cis- and trans-hydroxy
ketones 22, with the ratio of 1:3, was isolated as a colorless viscous
oil in 35% yield.
MS (CI, isobutane): m/z (%) = 209 [M+ + 1] (100), 191 [(M+ + 1) –
H2O] (25).
IR (neat): 3417, 1714, 1654, 1596, 1577, 1559, 1447, 1412, 1360,
1272, 1165, 1048 cm–1.
Tosylation (or Mesylation) of Hydroxy Ketones; General Proce-
dure
1H NMR (200 MHz, CDCl3): d = 0.85–1.97 (m, 15 H), 2.15 (s, 3 H),
2.30–2.58 (m, 2 H), 3.57–3.78 (m, 2 H).
To a stirred solution of hydroxy ketones (d-alkylated products) (2.0
mmol) and pyridine (0.47 g, 6.0 mmol) in CH2Cl2 (2 mL), p-tolue-
nesulfonyl chloride (0.76 g, 4.0 mmol) was added at r.t. The reac-
tion was completed after 12 h of stirring at r.t. After standard work
up procedure the crude product was purified by dry flash chroma-
tography (petrolether–acetone, 95:5) to give the pure tosylate.10
13C NMR (50 MHz, CDCl3): d = 209.8, 61.4, 60.8, 41.8, 40.8, 40.6,
38.6, 38.1, 36.3, 35.1, 31.7, 31.3, 29.9, 28.4, 28.2, 27.04, 25.9, 25.9,
23.5, 23.2.
4-[1-(3-Hydroxypropyl)cyclohexyl]butan-2-one (6)
Yield: 47%; viscous, colorless oil.
5,5-Dimethyl-8-p-toluenesulfonyloxyoctan-2-one (from Hy-
droxy Ketone 16)
Following the general procedure this compound is prepared as a
pale yellow oil (87% yield).
IR (neat): 3405, 1713, 1596, 1519, 1459, 1416, 1358, 1339, 1164,
1057, 1018, 964, 918, 852, 822 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.9 (t, J = 7.2 Hz, 2 H), 1.21–1.62
(m, 14 H), 1.93 (br s, 1 H), 2.16 (s, 3 H), 2.29–2.38 (m, 2 H), 3.61
(t, J = 6.4 Hz, 2 H).
IR (neat): 1714, 1599, 1495, 1471, 1358, 1292, 1176, 1098, 1020,
968, 913, 816, 733, 665 cm–1.
Synthesis 2004, No. 10, 1671–1679 © Thieme Stuttgart · New York

PAPER
[4+2] Cyclohexane Ring Formation by a Tandem Reaction
1677
1H NMR (CDCl3, 200 MHz): d = 0.81 (s, 6 H), 1.12–1.21 (m, 2 H),
1.38–1.47 (m, 2 H),1.54–1.65 (m, 2 H), 2.15 (s, 3 H), 2.30–2.38 (m,
2 H), 2.45 (s, 3 H), 4.00 (t, J = 6.4 Hz, 2 H), 7.57 (AA¢BB¢ system,
dA = 7.36, dB = 7.79, JAB = 8.4 Hz, JAB¢ = 1.6 Hz, 4 H).
13C NMR (CDCl3, 50 MHz): d = 209.3, 144.7, 133.0, 129.8, 127.8,
71.2, 38.6, 37.1, 34.8, 31.8, 29.9, 26.5, 23.6, 21.5.
13C NMR (50 MHz, CDCl3): d = 209.2, 144.6, 133.2, 129.8, 127.9,
67.1, 45.6, 42.88, 41.7, 38.7, 38.5, 37.8, 37.4, 14.4, 30.6, 29.9, 29.6,
28.3, 28.0, 21.6, 20.9.
Anal. Calcd for C23H32O4S: C, 68.31; H, 7.92; S, 7.92. Found: C,
68.18; H, 7.95; S, 8.09.
Acetic Acid 17-(1-Methanesulfonyloxy-ethyl)-10-methyl-13-(4-
oxo-pentyl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-3-yl Ester [4-(3b-Acetoxy-20b-
methanesulfonyl-5-pregnen-18-yl)butan-2-one] (from Hydroxy
Ketone 28)
MS (CI, isobutane): m/z (%) = 327 [M+ + 1] (100), 156 [(M+ + 1) –
p-MePhSO3H] (68).
5-(3-p-Toluenesufonyloxypropyl)nonan-2-one (from Hydroxy
Ketone 19)
Yield: 90%.
Yield: 99%; viscous, pale yellow oil.
IR (KBr): 1732, 1715, 1456, 1343, 1246, 1196, 1173, 1033, 971,
944, 908, 855 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86–1.99 (m, 21 H), 1.02 (s, 3 H),
1.47 (d, J = 6.0 Hz, 3 H), 2.04 (s, 3 H), 2.15 (s, 3 H), 2.20–2.50 (m,
5 H), 3.06 (s, 3 H), 4.52–4.68 (m, 1 H), 4.80–4.92 (m, 1 H), 5.36–
5.39 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 209.0, 170.6, 139.8, 122.2, 82.6,
73.8, 57.4, 56.3, 49.8, 44.7, 44.3, 40.0, 38.0, 36.9, 36.5, 35.2, 31.6,
29.8, 27.6, 25.4, 23.3, 21.4, 21.2, 21.0, 19.3, 18.6.
IR (neat): 2000–1600, 1715, 1599, 1456, 1413, 1360, 1307, 1292,
1211, 1189, 1177, 1098, 958, 920, 816, 665 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.87 (t, J = 6.8 Hz, 3 H), 1.18–
1.27 (m, 9 H), 1.40–l.75 (m, 4 H), 2.13 (s, 3 H), 2.33–2.41 (m, 2 H),
2.45 (s, 3 H), 4.01 (t, J = 6.6 Hz, 2 H), 7.57 (AA¢BB¢ system,
dA = 7.35, dB = 7.79, JAB = 8.4 Hz, JAB¢ = 0.6 Hz, 4 H).
13C NMR (CDCl3, 50 MHz): d = 209.1, 144.6, 133.1, 129.8, 127.8,
70.8, 40.7, 36.2, 32.6, 29.8, 28.9, 28.5, 26.9, 25.9, 22.9, 21.5, 13.9.
Anal. Calcd for C19H30O4S: C, 64.40; H, 8.47; S, 9.03. Found: C,
64.18; H, 8.60; S, 8.85.
Epimerization of (1S,2R,4R)-Hydroxy Ketone 31 into
(1S,2S,4R)-Hydroxy Ketone 3415
cis- and trans-4-[2-(2-p-Tolenesulfonyloxyethyl)cyclohexyl]bu-
tan-2-one (from Hydroxy Ketone 22)
Obtained as viscous colorless oil in 92% yield (mixture of cis- and
trans-isomers in a ratio of 1:3).
[(1S,2S,4R)-4-Methyl-2-p-nitrophenylcarbonyloxycyclohex-
yl]heptan-2-one (from Hydroxy Ketone 31)13
To a solution of (6R) and (6S)-[(1S,2R,4R)-2-hydroxy-4-methylcy-
clohexyl]heptan-2-one (31, 0.163 g, 0.72 mmol), PPh3 (1.13 g, 4.31
mmol) and p-nitrobenzoic acid (0.72 g, 4.31 mmol) in benzene (14
mL) was slowly added with stirring diethyl azodicarboxylate (0.75
g, 0.67 ml, 4.31 mmol) at r.t. and in an Ar atmopsphere. Esterifica-
tion was completed during 6 h; silica gel (3 g) was added to the mix-
ture and from the resulting suspension benzene was evaporated. The
residual powder was transferred onto a silica gel column and eluted
with petrolether, petrolether–acetone (95:5), successively. The title
compound was obtained in 82% yield (0.22 g) as an oily mixture of
two diastereoisomers (6R and 6S) in a ratio of 1:3.5.
IR (neat): 1714, 1599, 1450, 1360, 1177, 1098, 1023, 960, 911, 818,
752 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.90–1.42 (m, 9 H), 1.57–1.80 (m,
4 H), 1.85–2.05 (m, 1 H), 2.13 (s, 3 H), 2.25–2.50 (m, 2 H), 2.45 (s,
3 H), 4.02–4.15 (m, 2 H), 7.57 (AA¢BB¢ system, dA = 7.35,
dB = 7.79, JAB = 8.0 Hz, JAB¢ = 1.8 Hz, 4 H).
13C NMR (50 MHz, CDCl3): d = 209.2, 144,7, 133.1, 129.8, 127.9,
69.2, 68.8, 41.5, 40.6, 40.4, 38.0, 37.6, 34.8, 32.2, 31.1, 29.9, 28.39,
28.0, 27.8, 26.7, 25.6, 23.1, 21.6.
IR (neat): 1718, 1609, 1530, 1457, 1411, 1352, 1320, 1273, 1166,
1116, 1104, 1015, 921, 875, 839, 785, 722 cm–1.
1H NMR (200 MHz): d = 0.88 (d, J = 6.4 Hz, 3 H), 0.91 (d, J = 4.8
Hz, 3 H), 0.98–1.89 (m, 12 H), 2.03–2.10 (m, 1 H), 2.07 and 2.12
(s, 3 H), 2.35 (t, J = 7.2 Hz, 2 H), 5.48 (br s, 1 H), 8.26 (AB q,
Anal. Calcd for C19H28O4S: C, 64.77; H, 7.97; S, 9.09. Found: C,
64.56; H, 8.10; S, 9.22.
4-[1-(3-p-Toluenesulfonyloxypropyl)cyclohexyl]-butan-2-one
(from Hydroxy Ketone 6)
Yield: 80%; pale yellow oil.
d
AB = 0.11, JAB = 8.6 Hz, 4 H).
13C NMR (50 MHz): d = 208.9, 164.0, 150.4, 136.3, 130.6, 123.5,
73.3, 72.99, 44.6, 43.8, 39.1, 34.7, 34.2, 34.0, 33.4, 29.8, 26.8, 24.8,
22.0, 20.5, 16.9.
IR (neat): 2000–1600, 1715, 1599, 1496, 1460, 1359, 1308, 1292,
1211, 1189, 1177, 1120, 1098, 1041, 1020, 990, 945, 922, 817, 793,
736, 665 cm–1.
1H NMR (CDCl3, 200 MHz,): d = 1.16–1.25 (m, 6 H), 1.34–1.52
(m, 10 H), 2.14 (s, 3 H), 2.13–2.32 (m, 2 H), 2.45 (s, 3 H), 4.01 (t,
J = 6.2 Hz, 2 H), 7.57 (AA¢BB¢ system, dA = 7.35, dB = 7.79,
JAB = 8.4 Hz, JAB¢ = 0.6 Hz, 4 H).
13C NMR (CDCl3, 50 MHz): d = 209.4, 144.7, 133.1, 129.8, 127.8,
71.4, 37.49, 35.4, 33.9, 32.2, 30.1, 29.9, 26.2, 22.6, 21.5, 21.3.
(6R) and (6S)-[(1S,2S,4R)-2-Hydroxy-4-methyl-cyclohexyl]hep-
tan-2-one (34)13
(6R)- and (6S)-[(1S,2S,4R)-4-Methyl-2-p-nitrophenylcarbonyloxy-
cyclohexyl]heptan-2-one (0.21 g, 0.57 mmol) was dissolved in
MeOH (1.1 mL) and THF (0.25 mL) and then an aq solution of
KOH (0.13 g, 2.3 mmol in 0.2 mL) was added. The mixture was
stirred at r.t. for 30 h. Et2O (150 mL) was added to the reaction mix-
ture and then washed with 2 M HCl (2 mL), sat. aq NaCl (5 mL) and
the resulting solution was dried over Na2SO4. The solvent was evap-
orated and the residual oil was purified by dry flash chromatogra-
phy on silica gel column (petrolether–acetone, 95:5). Isomerized
hydroxy ketone 34 was obtained in 97% yield (0.125 g) as a color-
less oil containing two diastereoisomers (6R and 6S) in the ratio of
1:3.5.
4-{2-[1-(2-p-Toluenesulfonylethyl)]-adamantyl}-butan-2-one
(from Hydroxy Ketone 25)
Yield: 79%; viscous, colorless oil.
IR (neat): 1715, 1598, 1495, 1452, 1412, 1361, 1308, 1293, 1189,
1176, 1098, 1020, 958, 841, 816 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.17–1.90 (m, 18 H), 2.13 (s, 3 H),
2.26–2.42 (m, 2 H), 2.45 (s, 3 H), 4.00–4.20 (m, 2 H), 7.57 (AA¢BB¢
system, dA = 7.35, dB = 7.80, JAB = 8.0 Hz, JAB¢ = 1.8 Hz, 4 H).
IR (neat): 3492, 1713, 1531, 1456, 1410, 1363, 1258, 1167, 1129,
1031, 962, 936, 722 cm–1.
Synthesis 2004, No. 10, 1671–1679 © Thieme Stuttgart · New York

1678
G. Petrović, Ž. Čeković
PAPER
1H NMR (200 MHz): d = 0.87 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 7.0
Hz, 3 H), 0.95–1.88 (m, 14 H), 2.14 (s, 3 H), 2.42 (t, J = 7.0 Hz, 2
H), 4.08 (br s, 1 H).
13C NMR (CDCl3, 50 MHz): d = 212.4 (C),51.7 (CH), 37.1 (CH3),
37.0, 34.9, 32.5, 28.9, 28.5 (CH2), 27.9, (CH), 25.6, 22.9 (CH2),
14.1 (CH3).
13C NMR (50 MHz): d = 209.7, 67.8, 45.7, 45.7, 44.0, 43.9, 42.6,
35.0, 33.8, 33.7, 33.5, 33.2, 29.8, 29.6, 25.9, 24.1, 23.8, 22.3, 20.8,
20.7, 17.2, 16.8.
Anal. Calcd for C12H22O: C, 79.12; H, 12.08. Found: C, 78.88; H,
12.25.
1-[(1R,4aS,7R,8a)-4,7-Dimethyldecahydronaphthalen-1-yl]eth-
anone [Tetrahydrokhusitone (33)]13
(6R) and (6S)-[(1S,2S,4R)-2-Methanesulfonyl-4-methylcyclo-
hexyl]heptan-2-one 35 (from Hydroxy Ketone 34)13
Mesylate 35 (30 mg, 0.098 mmol) was dissolved in dimethoxy
ethane (1.5 mL) and then NaH (9.4 mg, 0.39 mmol) was added at
r.t. under an Ar atmosphere. The mixture was stirred and heated to
80 °C during 20 h. After the reaction was complete EtOH (2 mL)
was added to react with the excess of NaH. H2O (2 mL) was added
to the mixture and then extracted with Et2O (3 × 25 mL). The com-
bined ethereal solutions were washed with sat. aq NaCl (10 mL) and
dried over Na2SO4. The solvent was evaporated and the oily residue
purified by preparative TLC chromatography (petrolether–acetone,
97.5:2.5). Tetrahydrokhusitone (33) was obtained (10.9 mg) in 53%
yield as a viscous oil.
To the solution of hydroxy ketone 34 (45 mg, 0.20 mmol) and pyri-
dine (114 mg, 1.4 mmol) in CH2Cl2 (2 mL), cooled to 0 °C, meth-
anesulfonyl chloride (91.3 mg, 0.79 mmol) was added drop-wise
during 3 min. The mixture was stirred for 15 h at r.t. to complete the
reaction. The solvent was evaporated and the residue was dissolved
in Et2O (150 mL), the solution was washed successively with H2O
(10 mL), 1.5 M HCl (2 mL), a sat. aq solution of NaHCO3 (5 mL)
and H2O (10 mL) and dried over Na2SO4. The solvent was removed
by evaporation to give the pure title compound as a viscous oil in
quantitative yield (61 mg). The mesylate was obtained as a mixture
of diastereoisomers (6R and 6S) in a ratio of 1:5.
IR (neat): 1701, 1595, 1453, 1355, 1178, 935 cm–1.
IR (neat): 1714, 1457, 1413, 1348, 1223, 1173, 1085, 1007, 974,
952, 911, 896, 840, 796 cm–1.
1H NMR (200 MHz): d = 0.90 (d, J = 6.6 Hz, 6 H), 0.94–1.82 (m,
13 H), 2.14 (s, 3 H), 2.44 (t, J = 7.0 Hz, 2 H), 3.02 (s, 3 H), 5.11 (br
s, 1 H).
13C NMR (50 MHz): d = 209.3, 81.2, 45.3, 45.0, 43.8, 43.7, 40.0,
39.1, 39.0, 34.3, 33.4, 33.2, 32.9, 29.8, 26.0, 24.0, 23.7, 21.8, 20.5,
20.3, 16.7, 16.5.
1H NMR (200 MHz): d = 0.50–0.67 (m, 1 H), 0.82 (d, J = 6.4 Hz, 3
H), 0.88 (d, J = 6.0 Hz, 3 H), 0.90–1.81 (m, 12 H), 1.96 (dt, J1 = 9.0
Hz, J2 = 3.2 Hz, 1 H), 2.12 (s, 3 H), 2.19 (td, Jaa = 12.8 Hz, Jae = 4.0
Hz, 1 H).
13C NMR (50 MHz): d = 212.7 (C), 58.1 (CH), 47.7 (CH), 43.3
(CH), 40.2 (CH2), 36.8 (CH), 35.13 (CH2), 34.9 (CH2), 32.2 (CH),
30.1 (CH2), 29.7 (CH2), 29.5 (CH3), 22.53 (CH3), 19.7 (CH3).
In addition to tetrahydrokhusitone (33) as a cyclization product
(6R)- and (6S)-[(4R)-4-methylcyclohexen-1-yl]heptan-2-one (32)
was isolated (7 mg, 34% yield) as a colorless oil. This olefinic com-
pound is the product of an elimination reaction and has the same 1H
NMR spectrum as a product obtained in the reaction of the tosylate
derived from 31 with NaH.13
Anal. Calcd for C15H28O4S: C, 59.21; H, 9.21; S, 10.52. Found: C,
59.50; H, 9.45; S, 10.28.
Cycloalkylation of Ketosulfonate Esters; General Procedure22
To a solution of tosylate (or mesylate) from the above experiments
(0.2 mmol) in DME (2.0 mL), NaH (9.6 mg, 0.4 mmol, as a 80%
suspension) was added under an Ar atmosphere and the mixture was
heated to 80 °C during 8 h. After the reaction was complete EtOH
(2 mL) was carefully added followed by H2O (5 mL). The mixture
was extracted with Et2O (3 × 25 mL), the ethereal solution washed
with brine and dried (Na2SO4). The solvent was evaporated and the
oily residue was purified by dry flash chromatography on a silica
gel column (petrolether–acetone, 95:5) to give the cyclic ketone.
cis- and trans-(Decahydronaphthalen-2-yl)ethanone (23)
Obtained by cycloalkylation of the tosylate derived from 22, in 81%
yield as viscous colorless oil.
IR (neat): 1731, 1470, 1441, 1372, 1245, 1103, 1029, 956, 864, 803
cm–1.
1H NMR (200 MHz, CDCl3): d = 0.82–1.94 (m, 16 H), 2.13 (s, 3 H),
2.39 (tt, Jaa = 11.8 Hz, Jae = 3.4 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 212.6, 51.7, 42.6, 42.4, 35.5, 33.8,
1-(3,3-Dimethylcyclohexyl)ethanone (17)
Ketone 17 was obtained as colorless oil according to the described
procedure (yield 74%).
IR (neat): 1748, 1462, 1378, 1268, 1164, 779 cm–1.
33.6, 33.0, 28.3, 27.9, 26.5.
Anal. Calcd for C12H20O: C, 80.00; H, 11.11. Found: C, 79.77; H,
11.28.
1H NMR (CDCl3, 200 MHz): d = 0.92 (s, 3 H), 0.94 (s, 3 H), 1.02–
l.71 (m, 7 H), 1.80–1.94 (m, 1 H), 2.14 (s, 3 H), 2.50 (tt, Jaa = 12.4
Hz, Jae = 3.6 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): d = 212.6 (C), 47.7 (CH), 41.0, 38.5
(CH2), 33.1 (CH3), 30.5 (C), 28.2 (CH2), 27.9, 24.4 (CH3), 21.5
(CH2).
1-Spiro[5.5]undec-2-ylethanone (7)
Following the described procedure bicyclic ketone 7 was obtained
in 77% yield as a colorless oil.
IR (neat): 1709, 1451, 1372, 1354, 1270, 1236, 1189, 1164, 964,
903, 843 cm–1.
1H NMR (CDCl3, 200 MHz): d = 0.89–1.90 (m, 18 H), 2.13 (s, 3 H),
2.50 (tt, Jaa = 12.2 Hz, Jae = 3.4 Hz, 1 H).
MS (CI, isobutane): m/z (%) = 155 [M + 1] (100).
13C NMR (CDCl3, 50 MHz): d = 212.8 (C), 46.7 (CH), 41.8 (CH3),
38.7, 35.8 (CH2), 32.6 (C), 32.1, 28.7 (CH2), 27.9, 26.8, 21.5, 20.7
(CH2).
cis-1-(3-Butylcyclohexyl)ethanone (20)
Following the described procedure compound 20 was obtained in
76% yield as a colorless oil.
IR (neat) : 1712, 1448, 1353, 1259, 1296, 1175, 968 cm–1.
MS (CI, isobutane): m/z (%) = 195 [M + 1] (100).
1H NMR (CDCl3, 200 MHz): d = 0.78–1.01 (m, 3 H), 1.17–1.39 (m,
1-Acetyl-cyclohexyl[3,4:2,1]adamantane (26)
Yield: 78%; viscous, colorless oil.
10 H), 1.68–1.96 (m, 5 H), 2.14 (s, 3 H), 2.34 (tt, Jaa = 12.0 Hz,
Jae = 3.2 Hz, 1 H).
IR (neat): 1709, 1456, 1352, 1313, 1274, 1238, 1200, 1158, 1106,
962, 906, 746 cm–1.
Synthesis 2004, No. 10, 1671–1679 © Thieme Stuttgart · New York

PAPER
[4+2] Cyclohexane Ring Formation by a Tandem Reaction
1679
1H NMR (200 MHz, CDCl3): d = 0.82–2.12 (m, 20 H), 2.15 (s, 3 H),
2.38 (tt, Jaa = 11.8 Hz, Jae = 3.8 Hz, 1 H).
(7) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. J. Chem.
Soc., Chem. Commun. 1989, 1202.
(8) (a) Mihailović, M. L. J.; Čeković, Ž. Synthesis 1970, 20.
(b) Kalvoda, J.; Heusler, K. Synthesis 1971, 501.
(c) Barton, D. H. R. Pure Appl. Chem. 1968, 16, 1.
(d) Majetich, G.; Wheles, K. Tetrahedron 1995, 51, 7095.
(e) Feray, L.; Kuznetsov, N.; Renaud, P. In Radicals in
Organic Synthesis, Vol. 2; Renaud, P.; Sibi, M., Eds.; Wiley-
VCH: Weinheim, 2001, Chap. 36, 246–277.
(9) (a) Giese, B. Angew. Chem., Int. Ed. Engl. 1983, 22, 753.
(b) Giese, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 553.
(c) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon Press: Oxford, 1988.
(d) Curran, D. P. Synthesis 1988, 417. (e) Curran, D. P.
Synthesis 1988, 489.
(10) (a) Kabalka, G. W.; Varma, M.; Varma, R. S. J. Org. Chem.
1986, 51, 2386. (b) Ikeda, N.; Takahashi, M.; Uchino, T.;
Ohno, K.; Tamura, Z.; Kido, M. J. Org. Chem. 1983, 48,
4241.
(11) House, H. O.; Sayer, T. S. B.; Zau, C.-C. J. Org. Chem.
1978, 43, 2153.
(12) (a) Saunders, W. H. Jr.; Cockerill, A. F. Mechanisms of
Elimination Reactions; Wiley-Interscience: New York,
1973. (b) Coates, R. M.; Sowerby, R. L. J. Am. Chem. Soc.
1971, 93, 1027.
(13) Petrović, G.; Čeković, Ž. J. Serb. Chem. Soc. 2003, 68, 313.
(14) Hughes, E. D.; Ingold, C. K.; Rose, J. B. J. Chem. Soc. 1953,
3839.
(15) Martin, F. S.; Dodge, A. J. Tetrahedron Lett. 1991, 26, 3017.
(16) Beltreme, P.; Ceccon, A.; Winstein, S. J. Am. Chem. Soc.
1972, 94, 2315.
(17) Dhar, M. L.; Hughes, E. D.; Ingold, C. K. J. Chem. Soc.
1948, 2058.
13C NMR (50 MHz, CDCl3): d = 212.5, 52.3, 46.9, 46.7, 39.6, 39.2,
38.2, 35.2, 33.6, 31.1, 29.7, 29.3, 29.2, 28.6, 28.1, 23.3.
Anal. Calcd for C16H24O: C, 82.75, H, 10.34. Found: C, 82.70, H,
10.25.
1-(10-Hydroxy-4,12a-dimethyl-eicosahydro-indeno[1,7a-
a]phenanthren-3-yl)-ethanone [1-(18,20-Ethano-3b-hydroxy-5-
pregnen-22-yl)ethanone] (29)
Yield: 95%; white crystals.
IR (KBr): 3431, 1694, 1638, 1441, 1362, 1298, 1243, 1106, 1066,
1009, 956 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.79 (d, J = 6.8 Hz, 3 H), 0.88–
1.14 (m, 5 H), 1.00 (s, 3 H), 1.24–1.67 (m, 15 H), 2.14 (s, 3 H),
1.80–2.40 (m, 7 H), 3.44–3.62 (m, 1 H), 5.33–5.36 (m, 1 H).
13C NMR (50 MHZ, CDCl3): d = 213.5 (C), 140.9 (C), 121.6 (CH),
71.7 (CH), 56.9 (CH), 53.4 (CH), 52.1 (CH), 50.5 (CH), 42.2 (CH2),
41.9 (C), 37.2 (CH2), 36.6 (C), 33.0 (CH2), 31.9 (CH2), 31.6 (CH2),
31.3 (CH), 31.2 (CH), 29.3 (CH3), 25.1 (CH2), 23.5 (CH2), 21.9
(CH2), 21.7 (CH2), 20.4 (CH2), 19.5 (CH3), 17.9 (CH3).
Anal. Calcd for C27H40O3: C, 78.64; H, 9.70. Found: C, 78.34, H,
9.84.
References
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Synthesis 2004, No. 10, 1671–1679 © Thieme Stuttgart · New York