Tandem Michael/Michael reactions mediated by phosphines or aryl thiolates

Article abstract of DOI:10.1016/j.tet.2006.11.064

Tri-n-butyl phosphine was found to effect tandem Michael/Michael cyclisations leading to the formation of cyclopentenes and cyclohexenes in good yields, whilst p-TolSH in conjunction with a catalytic amount of p-TolSNa effected cyclisation to the correspo

Full text of DOI:10.1016/j.tet.2006.11.064

Tetrahedron 63 (2007) 1100–1106
Tandem Michael/Michael reactions mediated
by phosphines or aryl thiolates
a
Paul M. Brown, Nina Kappel, Patrick J. Murphy, Simon J. Coles and Michael B. Hursthouse
a
a,
b
b
*
€
aSchool of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, United Kingdom
bDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom
Received 14 September 2006; revised 9 November 2006; accepted 23 November 2006
Abstract—Tri-n-butyl phosphine was found to effect tandem Michael/Michael cyclisations leading to the formation of cyclopentenes and
cyclohexenes in good yields, whilst p-TolSH in conjunction with a catalytic amount of p-TolSNa effected cyclisation to the corresponding
cyclopentanes and cyclohexanes.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
With the substrates in hand we initially treated them with
a catalytic amount of n-Bu3P (0.2–0.5 equiv) in chloroform
at room temperature to effect cyclisation (Scheme 2, Table 1).
Wewere pleased to find that the phenyl enones 5a and 5b both
underwent cyclisation to give the corresponding cyclo-
pentene 6a and cyclohexene 6b in high yield (entries 1
and 2), however the substrate 5c, which would generate a
cyclohepteneproduct, wasresistant tocyclisationunderthese
conditions even on prolonged reaction and increased temper-
ature (entry 3). Similarly attempted cyclisation of the enoate
substrates 5d and 5e was also unsuccessful, possibly reflect-
ing a low reactivity of enoates towards Michael addition2
(entries 4 and 5). We also investigated the methyl-substituted
enones 5f and 5g and found that they also underwent cyclisa-
tion in good yield (entries 6 and 7) (Scheme 2).
We have previously reported the ability of a range of nucleo-
philes, including secondary amines, thiols and phosphines to
effect a tandem intramolecular Michael/aldol cyclisation of
enones 1 leading to either the adducts 2 or the eliminated
Baylis–Hillman type products 31 (Scheme 1).
O
O
O
OH
OH
(a)
-XH
O
R
R
R
1
X
2
3
n
n
n
Scheme 1. Reagents and conditions: (a) R2NH, R3P, TolSH, n¼1, 2;
R¼Alkyl, Ph, OR; X¼R2N, R3P+, TolS.
We also investigated the development of this reaction and
envisaged that a similar Michael/Michael sequence might
offer a flexible route to cycloalkenes. This observation was
also reported by Roush et al.2 who have reported their studies
on this reaction, which they refer to as a ‘vinylogous Morita–
Baylis–Hillman’ reaction and Krische et al.3 who refer to the
reaction as an intramolecular Rauhut–Currier reaction.4
Cyclisations of this type have been previously reported using
a range of carbanions,5 metal thiolates6 and metal amides7
together with sequences initiated by free radicals.8
O
R
O
O
O
O
O
(a)
(b)
R
R
R
6a-g
n
4
5a-g
n
n
Scheme 2. Reagents and conditions: (a) 2 equiv RCOCH]PPh3, 44–63%
(see Refs. 1 and 7); (b) see Table 1.
We also investigated the enone 8a and enoate 8b in which the
two Michael acceptors are linked by an aromatic ring and
found that these displayed similar reactivity to the previous
examples. We found that the enone substrate 8a cyclised
smoothly to give the isomeric indenes 9a and 9b in excellent
overall yield, whilst enoate 8b was resistant to cyclisation
under these conditions (Scheme 3).
We began out work in this area by embarking on an investi-
gation of the scope of the reaction with regards to the nature
of the electron-withdrawing group on the alkene and the ring
size of the product formed. We thus prepared the bis-enones
5a–f in reasonable yield from the aldehydes 4, by treatment
witha2-foldexcessoftherequisitestabilisedphosphorane.1,9
We investigated the lack of reactivity of the enoate substrates
in more detail and prepared the mixed substrates 12 and 14
from the aldehyde 111c via Wittig reaction. On treatment of
12 with n-Bu3P under standard conditions, we obtained the
Keywords: Tandem reactions; Michael additions; Phosphines.
* Correspondingauthor. E-mailaddresses:paddy@bangor.ac.uk;p.j.murphy@
bangor.ac.uk
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.11.064

P. M. Brown et al. / Tetrahedron 63 (2007) 1100–1106
1101
Table 1
both the enone substrates 5a and 5b underwent cyclisation
to the corresponding carbocycles 17a and 17b in good yield
and as essentially single stereoisomers (entries 1 and 2).
Structural determination was based on the presence of large
trans-diaxial coupling constants for the methine proton at C-
2 of the product 17b (J 10.5, 11 Hz) and corroborating NOE
measurements. Similar reaction of the enoate substrates 5d
and 5e were largely unsuccessful and under all conditions
employed led primarily to the Michael adducts 19d and
19e. However, when we treated the mixed enone/enoate sub-
strate 11 under these conditions, we were pleased to find that
two cyclisation products 17f and 18 were formed in high
overall yield (entry 5), the structure of 18 being determined
by X-ray crystallography10 (Fig. 1).
Entry
5
R
n
Methoda
6
Yield (%)
1
2
3
4
5
6
7
5a Ph
5b Ph
5c Ph
5d OMe
5e OMe
5f Me
5g Me
1
2
3
1
2
1
2
0.3 equiv, n-Bu3P, 16 h
0.3 equiv, n-Bu3P, 4 h
6a 80
6b 68
0.3 equiv, n-Bu3P, 21 daysb 6c
0
0
0
0.3 equiv, n-Bu3P, 4 daysc
0.3 equiv, n-Bu3P, 4 daysc
0.2 equiv, n-Bu3P, 5 h
6d
6e
6f 66
6g 58
0.2 equiv, n-Bu3P, 16 h
a
Reactions are performed in chloroform (ca. 1–2 mL per mmol of sub-
strate) at rt.
A further 0.3 equiv of phosphine added after one week and the reaction
refluxed for 16 h.
A further 0.3 equiv of phosphine added after 1 day and the reaction was
refluxed for 16 h.
b
c
cyclohexene 13 as the only product, highlighting the low
reactivity of the enoate to phosphine addition, but confirming
that the enoate is a suitable acceptor for the cyclisation step of
the tandem process. Substrate 14 allowed us to investigate the
relative reactivity of the two enones we have investigated and
not surprisingly we found that a 76:24 mixture of products 15
and 16 were formed in which the product 15 arising from
initial Michael addition to the phenyl substituted enone was
preferred. Repetition of the reaction at 0 ꢀC gave a slightly
improved selectivity for the formation of 15 (Scheme 4).
Following this work, we investigated the thiol-mediated
cyclisation of the substrates 5a,b,d,e and 11 and were dis-
appointed to find that all these substrates were resistant to
cyclisation when treated with p-TolSH at room temperature
or at reflux and only the products 19, resulting from a single
Michael addition of the thiol to the enone, were observed.
We thus employed alternate conditions in which a catalytic
amount of TolSNa was added to the reaction, which was
then heated at reflux in THF. We were pleased to find that
Figure 1. X-ray crystal structure of 18.
O
O
R
R
O
+
CHO
O
R
O
R
(b)
(a)
R
R
CHO
8a,b
9a,b
10a,b
7
O
R = Ph, 9a; 67%, 10a 12%.
R = OMe, 9b, 0%, 10b 0%
Scheme 3. Reagents and conditions: (a) 2 equiv RCOCH]PPh3, 42, 85%; (b) 0.3 equiv n-Bu3P, CHCl3, rt, 16 h.
O
O
O
O
O
(a)
O
(c)
O
OMe
OMe
Ph
H
67%
77%
Ph
Ph
O
11
12
13
(b) 30%
O
O
O
Me
(c)
O
Me
Ph
+
Ph
Me
Ph
14
15
16
Temp
Yield 15:16
rt
66%
66%
76 : 24
88 : 12
0°C
Scheme 4. Reagents and conditions: (a) 1.5 equiv Ph3PCHCO2Me, CH2Cl2, rt, 48 h; (b) 1.5 equiv Ph3PCHCOMe, CH2Cl2, rt, 72 h; (c) 0.3 equiv n-Bu3P,
CHCl3, rt, or 0 ꢀC to rt, 16 h.

1102
P. M. Brown et al. / Tetrahedron 63 (2007) 1100–1106
O
O
R1
n
O
O
R1
n
O
O
O
O
OMe
(a)
R1
R
R
R
+
+
Ph
TolS
TolS
n
TolS
5, 11
17a-f
18
19a-f
Scheme 5. Reagents and conditions: (a) 0.9 equiv TolSH, 0.2 TolSNa, D, THF, 16 h and see Table 2.
The reason for the formation of a mixture of products in this
reaction and the predominance of 18 as the major product is
unclear. A strong possibility is that the reaction is a stepwise
process in which the addition products 19 are formed rapidly
(as appears to be the case from NMR studies) and the cycli-
sation occurs independently as a result of a base-catalysed
enolate formation. It is also possible that the products
formed in the case of the enone substrates 5a/b are equilib-
rium products from a reversible cyclisation step whilst 17f/
18 reflect a non-reversible process due to the lower acidity
of the a-protons of the ester function (Scheme 5). These
reactions do however demonstrate that an enone is required
for an effective cyclisation, a factor that is probably asso-
ciated with the ability to form an enol/enolate under the
conditions employed (Table 2).
in deuterochloroform on either a Bruker AC250 or an
AVANCE500 spectrometer and referenced to residual CHCl3.
IR were recorded as thin films or as chloroform solutions
on a Perkin–Elmer 1600 series instrument. Mass spectra
were recorded on a VG Masslab Model 12/253 spectrometer
using CI (ammonia), EI or ES. All compounds were oils/
gums unless otherwise stated.
2.2. Preparation of bis-enones and enoates
Enones 5a, 5c and 5f were prepared according to the litera-
ture procedures,1,7,11 whilst 5b–e and 5g and were prepared
as follows.
2.2.1. (2E,7E)-1,9-Diphenyl-2,7-nonadiene-1,9-dione
(5b).11,12
Table 2
Ph
O
O
Entry
5
R
R1
n
17 (%)
18 (%)
19 (%)
Ph
1
2
3
4
5
5a
5b
5d
5e
11
Ph
Ph
OMe
OMe
Ph
Ph
Ph
OMe
OMe
OMe
1
2
1
2
2
17a (58)
17b (59)
17d (0)a
17e (0)a
17f (14)
—
—
—
—
56
—
—
67
40
—
2
a
5b
Benzoyltriphenylphosphorane (34.58 g, 91 mmol) was dis-
solved in THF (200 mL) whereupon aqueous glutaric dialde-
hyde solution (25%, 9.8 mL, 26 mmol) was added together
with MgSO4 (ca. 30 g) and the mixture stirred for 2 days.
After drying (MgSO4) and filtration, the reaction solvent
was evaporated and the solid mass remaining was triturated
with ether (4ꢁ50 mL). The combined triturates were then
dried (MgSO4), filtered and evaporated. Silica gel chromato-
graphy (40–60% ether in petrol) gave 5b (5.37 g) in 68%
yield. Rf (40–60% ether in petrol) 0.37; dH 1.79 (2H, p,
J 7.5 Hz, CH2), 2.41 (4H, dt, J 6.3, 7.5 Hz, 2ꢁCH2), 6.93
(2H, d, J 15.3, 2ꢁCH), 7.08 (2H, dt, J 15.3, 6.3 Hz, 2ꢁCH),
7.45–7.95 (10H, m, 2ꢁPh); dC 26.6 (CH2), 32.1 (CH2),
126.4 (CH), 128.5 (CH), 132.7 (CH), 137.8 (C), 148.6 (CH),
190.5 (C); nmax 3058, 2933, 1669 (C]O), 1619 (C]C).
a
An inseparable diastereomeric mixture of cyclised products was obtained
in 9% yield.
In conclusion, we have reported that the tandem Michael/
Michael cyclisation of bis-enones is a viable process for
the preparation of five- and six-membered carbocycles, how-
ever it does not appear to be applicable to the synthesis of
larger ring system, a fact also largely apparent in our studies
on tandem Michael/aldol reactions.1 In addition, the use
of bis-enoates in these processes does not appear feasible,
however they are suitable acceptor groups in mixed enone/
enoate substrates. A general order of reactivity towards
addition of phosphines was also established and appears to
be Ph>Me>>>OR.
2.2.2. (2E,6E)-Octa-2,6-dienedioic acid dimethyl ester 5d.
2. Experimental
2.1. General
MeO
O
O
MeO
5d
Column chromatography was carried out on Kieselgel (230–
400 mesh) with the eluant specified. TLC was conducted on
precoated Kieselgel 60 F254 (Art. 5554; Merck) glass plates.
All reactions were conducted in oven-dried apparatus under
an atmosphere of argon. Light petroleum refers to the frac-
tion boiling in the range 35–60 ꢀC. Dichloromethane,
diethyl ether and THF were dried and distilled before use.
Chemical shifts are reported as d values relative to TMS as
Methoxycarbonylmethylenetriphenylphosphorane (40.00 g,
120 mmol) was added to a solution of succinaldehyde
(2.00 g, 23 mmol) dissolved in CH2Cl2 (100 mL) and the
mixture stirred for 18 h. After this time, the solvent was re-
moved in vacuo and the resulting solid extracted with warm
ether (4ꢁ50 mL). The extracts were diluted with hexane
(100 mL) and cooled to ꢂ20 ꢀC overnight. The solution
was then filtered to remove precipitated triphenylphosphine
1
an internal standard. H/13C NMR spectra were recorded

P. M. Brown et al. / Tetrahedron 63 (2007) 1100–1106
1103
oxide and evaporated to give a crude product, which was
purified via column chromatography (30% ether in petrol)
to give 5d (1.42 g) in 31% yield. Rf (30% ether in petrol)
0.18; dH 2.38 (4H, m, 2ꢁCH2), 3.74 (6H, s, 2ꢁOCH3),
5.85 (2H, d, J 15.6 Hz, 2ꢁCH), 6.95 (2H, dt, J 15.6,
6.5 Hz, 2ꢁCH); dC 30.1 (CH2), 51.3 (OCH3), 121.8 (CH),
147.1 (CH), 166.5 (C); nmax 2952, 1720 (C]O), 1658
(C]C); m/z (CI, NH3) 199 (10, MH+) 167 (100, M+);
HRMS (CI, NH3) C10H15O4 ([M+H]+) required 199.0970,
found 199.0968.
dissolved in CH2Cl2 (5 mL) and stirred at rt for 2 days. After
evaporation, silica gel chromatography (30–50% ether/
petrol) gave 8a (0.43 g). Rf (50% ether/petrol) 0.52; dH
7.42–7.64 (8H, m, 8ꢁArH), 7.60 (2H, d, J 15.9 Hz,
2ꢁCH), 7.75 (2H, m, 2ꢁArH), 8.05 (4H, m, 4ꢁArH), 8.21
(2H, d, J 15.9 Hz, 2ꢁCH); dC 126.1 (CH), 128.2 (CH),
128.6 (CH), 130.2 (CH), 133.0 (CH), 135.4 (C), 137.9 (C),
141.7 (CH), 190.1 (C); nmax 3018, 1663 (C]O), 1605,
1447, 928, 754.
2.2.6. (E)-4-[2-((E)-3-Oxo-but-1-enyl)-phenyl]-but-3-en-
2-one 8b.
2.2.3. (2E,7E)-Nona-2,7-dienedioic acid dimethyl ester 5e.
MeO
O
O
O
OMe
OMe
MeO
2
5e
O
8b
This was prepared in an identical manner to 5b using
methoxycarbonylmethylenetriphenylphosphorane (10.00 g,
29.94 mmol) and glutaric dialdehyde (3.96 mL, 1.00 g,
10 mmol). Silica gel chromatography (30% ether in petrol)
gave 5e (0.73 g) in 35% yield. Rf (30% ether/petrol) 0.22;
dH 1.65 (2H, m, CH2), 2.25 (4H, m, 2ꢁCH2), 3.74 (6H, s,
2ꢁOCH3), 5.87 (2H, d, J 16.6 Hz, 2ꢁCH), 6.95 (2H, m,
2ꢁCH); dC 26.8 (CH2), 31.6 (CH2), 51.5 (OCH3), 121.6
(CH), 148.3 (CH), 166.9 (C); nmax 2994, 2950, 2860, 1726
(C]O), 1658 (C]C); m/z (CI, NH3) 213 (5, MH+) 181
(100); HRMS (CI, NH3) C11H17O4 (MH+) required
213.1127, found 213.1124.
o-Phthalicdicarboxaldehyde (0.4 g 3.0 mmol) and methoxy-
carbonylmethylenetriphenylphosphorane (3.00 g, 9.00 mmol)
were dissolved in THF (5 mL) and stirred at rt for 2 days.
After evaporation, column chromatography (30% ether/
petrol) gave 8b (0.63 g) as a white solid in 85% yield;
mp 46–48 ꢀC, Rf (30% ether/petrol) 0.31; dH 3.83 (6H,
s, 2ꢁOMe), 6.35 (2H, d, J 15.8 Hz, 2ꢁCH), 7.39 (2H,
m, 2ꢁArH), 7.56 (2H, m, 2ꢁArH), 8.03 (2H, d,
J 15.8 Hz, 2ꢁCH); dC 51.7 (OMe), 121.5 (CH), 126.6
(CH), 129.4 (CH), 132.4 (C), 141.5 (CH), 166.8 (C);
nmax 3064, 3022, 2951, 1720 (C]O), 1635 (C]C),
1436; m/z (CI, NH3) 264 (100, M+NH+4); HRMS (CI,
NH3) C14H18NO4 (M+NH+4) required 264.1236, found
264.1235.
2.2.4. (3E,8E)-3,8-Undecadiene-2,10-dione 5g.5b,13
Me
O
O
2.2.7. (2E,7E)-9-Oxo-9-phenyl-nona-2,7-dienoic acid
methyl ester 12.
Me
2
5g
O
This was prepared in an identical manner to 5b using
acetylmethylenetriphenylphosphorane (28.9 g, 91 mmol)
and aqueous glutaric dialdehyde solution (25%, 9.8 mL,
26 mmol). Silica gel chromatography (30–50% ether in
petrol) gave 5g (2.71 g) in 58% yield. Rf (30% ether/petrol)
0.03; dH 1.46 (2H, pentet, J 7.5 Hz, CH2), 2.01 (6H, s,
2ꢁCH3), 2.06 (4H, dt, J 4.2, 7.5 Hz, 2ꢁCH2), 5.85 (2H, d,
J 16.2 Hz, 2ꢁCH), 6.56 (2H, dt, J 16.2, 6.7 Hz, 2ꢁCH);
dC 26.0 (CH2), 26.4 (CH3), 31.3 (CH2), 131.3 (CH), 146.9
(CH), 197.6 (C).
O
OMe
Ph
12
(E)-7-Phenyl-7-oxohept-5-enal1c 11 (1.5 g, 7.4 mmol)
and carbomethoxymethylenetriphenylphosphorane (3.7 g,
11.1 mmol) were dissolved in CH2Cl2 (5 mL) and stirred
at rt for 48 h. After evaporation, column chromatography
(30% ether in petrol) gave 12 (1.28 g) in 67% yield.
Rf (30% ether/petrol) 0.39; dH 1.70 (2H, pentet,
J 7.5 Hz, CH2), 2.33 (2H, dt, J 7.3, 7.0 Hz, CH2), 2.35
(2H, dt, J 7.3, 7.0 Hz, CH2), 3.73 (3H, s, OMe), 5.85
(1H, d, J 15.9 Hz, CH), 6.89 (1H, d, J 15.9 Hz,
CH), 7.00 (2H, m, 2ꢁCH), 7.43–7.94 (5H, m, Ph);
dC 26.5 (CH2), 31.5 (CH2), 32.0 (CH2), 51.5 (OMe),
121.6 (CH), 126.4 (CH), 128.5 (CH), 128.5 (CH), 132.7
(CH), 137.8 (C), 148.4 (C), 148.5 (C), 166.9 (C),
190.6 (C); nmax 3062, 2950, 1672 (C]O), 917; m/z (CI,
NH3) 259 (60%, MH+) 258 (20%, M+); HRMS (CI,
NH3) C16H19O3 (MH+) required 259.1329, found
259.1329.
2.2.5. (E)-3-{2-[(E)-3-Oxo-3-phenyl-1-prophenyl]phenyl}-
1-phenyl-2-propen-1-one 8a.8c
O
Ph
Ph
O
8a
Benzoylmethylenetriphenylphosphorane (2.84 g, 7.47 mmol)
and o-phthalicdicarboxaldehyde (0.4 g, 3.0 mmol) were

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P. M. Brown et al. / Tetrahedron 63 (2007) 1100–1106
2.2.8. Methyl(2E,7E)-9-oxo-9-phenyl-2,7-nonadienoate 14.14
Yield: 68%; Rf (20% ether/petrol) 0.24; dH 1.72 (4H, m,
2ꢁCH2), 2.30 (2H, m, CH2), 2.83 (1H, dd, J 10.6,
14.6 Hz, CHH), 3.44 (1H, dd, J 10.6, 3.1 Hz, CHH), 3.52
(1H, m, CH), 6.66 (1H, t, J 3.5 Hz, CH), 7.44–8.11 (10H,
m, 2ꢁPh); dC 18.1 (CH2), 26.1 (CH2), 26.5 (CH2), 30.4
(CH), 42.5 (CH2), 128.1 (CH), 128.5 (CH), 128.6 (CH),
129.2 (CH), 131.6 (CH), 133.0 (CH), 136.7 (C), 138.8 (C),
141.5 (C), 145.0 (CH), 198.1 (C), 199.7 (C); nmax 3000,
2935, 1675 (C]O), 1641, 1597, 1447, 908; MS (EI): 304
[M]+ (75%); HRMS (EI) C21H20O2 ([M]+) required
304.1463, found 304.1462.
O
O
Me
Ph
14
(E)-7-Phenyl-7-oxohept-5-enal1c 11 (337 mg, 1.4 mmol) and
acetylmethylenetriphenylphosphorane (668 mg, 2.1 mmol)
were dissolved in CH2Cl2 (3 mL) and stirred at rt for
3 days. After evaporation, column chromatography (20%
ether/petrol) gave 14 (107 mg) in 30% yield. Rf (20% ether/
petrol) 0.22; dH 1.63 (2H, pentet, J 7.5 Hz, CH2), 2.16 (3H,
s, CH3), 2.26 (4H, m, 2CH2), 6.01 (1H, d, J 15.9 Hz, CH),
6.72 (1H, dt, J 15.9, 7.0 Hz, CH), 6.83 (1H, d, J 15.3 Hz,
CH), 6.96 (1H, dt, J 15.3, 6.4 Hz, CH), 7.43–7.50 (3H, m,
3ꢁArH), 7.84–7.86 (2H, m, 2ꢁArH); dC 26.4 (CH2), 26.8
(CH3), 31.7 (CH2), 32.0 (CH2), 126.2 (CH), 128.4 (CH),
128.5 (CH), 131.6 (CH), 132.6 (CH), 137.6 (C), 147.1
(CH), 148.4 (CH), 190.3 (C), 198.3 (C); nmax 3000, 2949,
1708 (C]O), 1601, 1450, 754.
2.3.3. 1-(2-Acetyl-2-cyclopenten-1-yl)-acetone 6f.
O
O
Me
Me
6f
Yield: 66%; Rf (40% ether/petrol) 0.16; dH 1.54 (1H, m,
CHH), 2.10 (3H, s, CH3), 2.20 (1H, m, CHH), 2.28 (3H,
s, CH3), 2.50 (2H, m, CH2), 2.96 (1H, dd, J 16.8, 3.4 Hz,
CHH), 3.33 (1H, m, CH), 6.75 (1H, dt, J 1.5, 2.8 Hz, CH);
dC 26.9 (CH2), 29.8 (CH2), 29.9 (CH3), 31.9 (CH3), 39.2
(CH2), 47.5 (CH), 146.0 (C), 196.6 (C), 208.4 (C); nmax
2949, 1721 (C]O), 1673 (C]O) 1627 (C]C); MS (CI)
184 (100%, M+NH+4); HRMS (CI, NH3) C10H18NO2
(M+NH+4) required 184.1338, found 184.1336.
2.3. Cyclisation of bis-enones 5
General method: The required bis-enones 5a–g (100–
200 mg) were dissolved in chloroform (1 mL per mmol of
substrate) and neat n-Bu3P (0.3 equiv) was added via syringe
and the reaction agitated. Further amounts of n-Bu3P were
added if required (see Table 1). After completion of the
reaction, typically 4–16 h for successful reactions (moni-
tored via 1H NMR) the solvent was removed under vacuum
and the cyclised product purified by silica gel chromato-
graphy using an ether/petrol mixture, see specific examples
for Rf values.
2.3.4. 1-(2-Acetyl-cyclohex-2-enyl)-propan-2-one 6g.
O
O
Me
Me
2.3.1. 2-(2-Benzoylcyclopent-2-enyl)-1-phenylethanone 6a.
6g
O
O
Yield: 58%; Rf (30% ether/petrol) 0.19; dH 1.59 (4H, m,
2ꢁCH2), 2.16 (3H, s, CH3), 2.23–2.33 (3H, m, CHH,
CH2), 2.27 (3H, s, CH3), 2.60 (1H, dd, J 15.7, 3.4 Hz,
CHH), 3.15 (1H, m, CH), 6.95 (1H, t, J 4.0 Hz, CH); dC
16.9 (CH2), 25.5 (CH3), 25.9 (CH2), 26.1 (CH2), 27.6
(CH3), 29.7 (CH), 47.4 (CH2), 141.9 (C), 142.6 (CH),
198.7 (C]O), 208.1 (C]O); nmax 2923, 1715 (C]O),
1664 (C]O) 1616 (C]C) 1380; MS (EI) 180 (40%, M+);
HRMS (EI) C11H16O2 (M+) required 180.1150, found
180.1147.
Ph
Ph
6a
Yield: 80%; Rf (20% ether/petrol) 0.19; dH 1.81 (1H, m,
CHH), 2.35 (1H, m, CHH), 2.58 (1H, m, CHH), 2.69 (1H,
m, CHH), 2.84 (1H, dd, J 15.5, 10.4 Hz, CHH), 3.76 (1H,
m, CH), 3.81 (1H, dd, J 15.5, 2.8 Hz, CHH), 6.61 (1H, dt,
J 1.6, 2.6 Hz, CH), 7.46–8.08 (10H, m, 2ꢁPh); dC 29.5
(CH2), 32.6 (CH2), 41.6 (CH), 42.4 (CH2), 128.3 (CH),
132.0 (CH), 133.0 (CH), 136.9 (C), 139.0 (C), 146.1 (C),
148.0 (CH), 194.2 (C), 199.8 (C); nmax 3059, 2917, 1682
(C]O), 1636 (C]C), 1597, 1447, 719; MS (EI) 290 (55%,
M+); HRMS (EI) C20H18O2 (M+) required 290.1307, found
290.1308.
2.3.5. 2-(2-Benzoyl-1H-inden-1-yl)-1-phenyl-1-ethanone
9a and 2-(2-benzoyl-1H-inden-3-yl)-1-phenyl-1-etha-
none 10a.
O
O
2.3.2. 2-(2-Benzoyl-2-cyclohexen-1-yl)-1-phenyl-1-etha-
none 6b.
Ph
Ph
O
O
O
Ph
Ph
9a
10a
O
Ph
Ph
Bis-enone 8a (84 mg, 0.249 mmol) was dissolved in chloro-
form (1 mL), treated with n-Bu3P (12.2 mL) and stirred at rt
6b

P. M. Brown et al. / Tetrahedron 63 (2007) 1100–1106
1105
for 16 h. After evaporation, silica gel chromatography gave
the title compounds 9a and 10a in a combined yield of 79%
and in a 85:15 ratio.
Keto-ester 14 (0.190 g, 0.78 mmol) was dissolved in chloro-
form (1 mL) at 0 ꢀC and tri-n-butyl phosphine (61 mL,
0.245 mmol) was added. The reaction was agitated for 1 h
and the solvent was evaporated. The crude material was
purified via column chromatography (15% ether in petrol)
to give 15 and 16 (0.126 g) as an inseparable mixture
(88:12) in 66% yield.
Compound 9a: Rf (30% ether/petrol) 0.32; dH 3.20 (1H, dd,
J 17.0, 9.5 Hz, CHH), 4.08 (1H, dd, J 17.0, 3.2 Hz, CHH),
4.71 (1H, ddd, J 9.5, 3.2, 1.6 Hz, CH), 7.33–7.63 (13H, m,
CH, 12ꢁArH), 7.82 (2H, m, 2ꢁArH), 7.99 (2H, m,
2ꢁArH); dC 39.5 (CH2), 45.3 (CH), 124.2 (CH), 124.5
(CH), 127.5 (CH), 128.6 (CH), 132.0 (CH), 133.1 (CH),
136.9 (C), 139.2 (C), 141.6 (C), 144.3 (CH), 147.4 (C),
149.5 (C), 193.0 (C), 198.5 (C); nmax 3066, 2923, 1683
(C]O), 1628 (C]C), 1598, 1447, 908; m/z (CI, NH3)
339 (100% [M+H]+); HRMS (CI, NH3) C24H18O2
([M+H]+) required 339.1385, found 339.1383.
Compound 15 (major): Rf (15% ether/petrol) 0.31; dH (2H,
m, CH2), 2.15 (3H, s, CH3), 2.20 (2H, m, CH2), 2.26
(2H, m, CH2), 2.45 (1H, dd, J 15.9, 9.5 Hz, CHH), 2.69
(1H, dd, J 15.9, 3.5 Hz, CHH), 3.34 (1H, m, CH), 6.55 (1H,
m, ]CH), 7.38–7.65 (5H, m, Ph); dC 18.2 (CH2), 26.0
(CH2), 26.9 (CH2), 29.2 (CH3), 29.9 (CH), 47.4 (CH2),
128.1 (CH), 129.2 (CH), 131.6 (CH), 138.6 (C), 141.2 (C),
144.4 (CH), 197.9 (C), 208.1 (C). Compound 15 (minor):
Rf (15% ether/petrol) 0.31; dH (partial data) 3.46 (1H, m,
CH), 7.00 (1H, m, ]CH); dC 16.8 (CH2), 25.6 (CH3), 26.0
(CH2), 26.2 (CH), 28.8 (CH), 42.6 (CH2), 128.5 (CH),
129.2 (CH), 132.9 (CH), 136.7 (C), 142.3 (C), 143.1 (CH),
199.0 (C), 199.9 (C); nmax 3020 (C–H), 2941 (C–H), 2875
(C–H), 1715 (C]O), 1678 (C]O) 1644 (C]C); m/z (CI,
NH3) 243 (100%, [M+H]+); HRMS (CI, NH3) C16H19O2
([M+H]+) required 243.1385, found 243.1382.
Compound 10a: Rf (30% ether/petrol) 0.24; dH 3.95 (2H, s,
CH2), 4.49 (2H, s, CH2), 7.33–7.63 (10H, m, 10ꢁArH),
7.82 (2H, m, 2ꢁArH), 7.99 (2H, m, 2ꢁArH); dC 37.5
(CH2), 40.8 (CH2), 121.8 (CH), 124.1 (CH), 126.9 (CH),
127.8 (CH), 128.2 (CH), 128.4 (CH), 128.6 (CH), 132.0
(CH), 133.3 (CH), 136.6 (C), 140.1 (C), 141.1 (C), 143.5
(C), 144.4 (C), 146.1 (C), 195.0 (C), 195.8 (C); nmax 3018,
2978, 1684 (C]O), 1634 (C]C), 1521, 1423, 928; m/z
(CI, NH3) 339 (100% [M+H]+); HRMS (CI, NH3)
C24H18O2 ([M+H]+) required 339.1385, found 339.1384.
2.4. Thiolate cyclisation
General method: The required enone/enoate (1–5 mmol) was
dissolved in THF (4 mL per mmol) and 4-methylbenzene-
thiol (0.9 equiv) together with sodium-4-methylbenzene-
thiolate (0.25 equiv) were added. The reaction mixture was
then refluxed for 16 h, cooled, evaporated onto silica gel
(ca. 0.5 g per mmol substrate) and purifed by column chro-
matography (ether/petrol, see specific examples).
2.3.6. (2-Benzoyl-cyclohex-2-enyl)-acetic acid methyl
ester 13.
O
O
OMe
Ph
13
2.4.1. 2-(2-Benzoyl-3-p-tolylsulfanyl-cyclopentyl)-1-
phenyl-ethanone 17a.
Keto-ester 12 (100 mg, 0.39 mmol) was dissolved in chloro-
form (1 mL) at 20 ꢀC and tri-n-butyl phosphine (51 mL,
0.205 mmol) was added. The reaction was agitated for 1 h,
following which the solvent was evaporated and the crude
material was purified via column chromatography (30%
ether in petrol) to give 13 (77 mg) in 77% yield as an oil.
Rf (30% ether/petrol) 0.3; dH 1.65 (2H, m, CH2), 1.73 (2H,
m, CH2), 1.75 (1H, m, CH), 2.25 (2H, m, CH2), 2.40 (2H,
m, CH2), 3.63 (3H, s, OMe), 6.55 (1H, dt, CH, J 4.0,
1.2 Hz), 7.41–7.67 (5H, m, Ph); dC 18.3 (CH2), 26.0
(CH2), 27.2 (CH2), 30.1 (CH), 37.9 (CH2), 51.5 (Me),
128.0 (CH), 129.3 (CH), 131.6 (C), 138.6 (C), 141.0 (C),
144.2 (CH), 172.9 (C), 197.6 (C); nmax 3024 (C–H), 2934
(C–H), 2864 (C–H), 1732 (C]O), 1644 (C]C); m/z (CI,
NH3) 259 (100%, [M+H]+) 258 (25%, [M]+); HRMS (CI,
NH3) C16H19O3 ([M+H]+) required 259.1329, found
259.1328.
O
Ph
O
Ph
17a
TolS
Compound 17a: 58% yield; Rf (10% ether/petrol) 0.14; dH
1.78 (1H, m, CHH), 1.89 (1H, m, CHH), 2.17 (2H, m,
CH2), 2.29 (3H, s, CH3), 3.02 (1H, m, CH), 3.15 (2H, d, J
7.3 Hz, CH2), 3.65 (1H, t, J 6.0 Hz, CH), 3.87 (1H, m,
CH), 7.01–7.92 (14H, m, 2ꢁPh, 4ꢁArH); dC 21.0 (CH3),
31.5 (CH2), 32.8 (CH2), 39.9 (CH), 44.0 (CH2), 51.9 (CH),
58.3 (CH), 128.0 (CH), 128.5 (CH), 128.5 (CH), 129.7
(CH), 131.3 (C), 132.4 (CH), 133.0 (CH), 133.5 (CH),
133.6 (CH), 136.7 (C), 137.0 (C), 137.3 (C), 198.9 (C),
201.4 (C); nmax 3058, 2922, 1680 (C]O), 1596, 1447; m/z
(CI, NH3): 415 (100%, [M+H]+); HRMS (CI, NH3)
C27H26O2S ([M+H]+) required 415.1732, found 415.1727.
2.3.7. 1-(2-Benzoyl-2-cyclohexen-1-yl)-acetone 15 and 2-
(2-acetyl-2-cyclohexen-1-yl)-1-phenyl-1-ethanone 16.
2.4.2. 2-(2-Benzoyl-3-p-tolylsulfanyl-cyclohexyl)-1-phenyl-
ethanone 17b.
O
O
O
O
Ph
O
O
Me
Ph
Ph
TolS
Ph
Me
17b
15
16

1106
P. M. Brown et al. / Tetrahedron 63 (2007) 1100–1106
Compound 17b: 59% yield; Rf (10% ether/petrol) 0.11; dH
0.98 (1H, m, CHH), 1.12 (1H, m, CHH), 1.37 (1H, m,
CHH), 1.43 (1H, m, CHH), 1.76 (1H, m, CHH), 1.91 (3H, s,
CH3), 2.11 (1H, m, CH), 2.13 (1H, m, CHH), 2.17 (1H, m,
CHH), 2.51 (1H, m, CHH), 2.95 (1H, ddd, J 4.0, 10.5,
12.0 Hz, CH), 3.14 (1H, dd, J 10.5, 10.5 Hz, CH), 7.00–7.69
(14H, m, 2ꢁPh, 4ꢁArH); dC 21.1 (CH3), 25.4 (CH2), 30.9
(CH2), 34.2 (CH2), 39.5 (CH), 43.6 (CH2), 50.8 (CH), 53.9
(CH), 128.1 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH),
129.5 (CH), 130.2 (C), 133.1 (CH), 133.3 (CH), 133.4 (CH),
136.6 (C), 137.5 (C), 139.0 (C), 198.7 (C), 203.9 (C); nmax
3061, 2927, 1676, 1596, 811, 703; m/z (CI, NH3) 429
(100%, [M+H]+); HRMS (CI, NH3) C28H29O2S ([M+H]+) re-
quired 429.1888, found 429.1889.
References and notes
1. (a) Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.;
Nielsen, M.; Williams, H. L.; Walshe, N. D. A. Tetrahedron
Lett. 1997, 38, 8561–8564; (b) Dinon, F.; Richards, E. L.;
Murphy, P. J.; Hibbs, D. E.; Hursthouse, M. B.; Malik,
K. M. A. Tetrahedron Lett. 1999, 40, 3279–3282; (c)
Richards, E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.;
Brown, P. M.; Gelbrich, T.; Hursthouse, M. B. Tetrahedron
2001, 57, 7771–7784.
2. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc.
2002, 124, 2404–2405.
3. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 2402–2403.
4. (a) Rauhut, M. M.; Currier, H. U.S. Patent 3074999, 19630122,
1963, American Cyanamid; (b) McClure, J. D. J. Org. Chem.
1970, 35, 3045–3048.
2.4.3. (2-Benzoyl-3-p-tolylsulfanyl-cyclohexyl)-acetic
acid methyl esters 17f and 18.
5. (a) Saito, S.; Hirohara, Y.; Narahara, O.; Moriwake, T. J. Am.
Chem. Soc. 1989, 111, 4533–4535; (b) Klimko, P. G.;
Singleton, D. A. J. Org. Chem. 1992, 57, 1733–1740; (c)
Cooke, M. P.; Gopal, D. Tetrahedron Lett. 1994, 35, 2837–
2840; (d) Klimko, P. G.; Singleton, D. A. Synthesis 1994,
979–982; (e) Savchenko, A. V.; Montgomery, J. J. Org.
Chem. 1996, 61, 1562–1563; (f) Montgomery, J.; Oblinger,
E.; Savchenko, A. V. J. Am. Chem. Soc. 1997, 49, 4911–
4920.
6. (a) Voigt, K.; Lansky, A.; Noltemeyer, M.; de Meijere, A.
Liebigs Ann. 1996, 899–911; (b) Erguden, J.-K.; Moore,
H. W. Org. Lett. 1999, 1, 375–377; (c) Chavan, S. P.;
Subbarao, Y. T.; Chittiboyina, A. G.; Sivappa, R.; Suresh,
C. G. Tetrahedron: Asymmetry 2001, 12, 1101–1103.
7. (a) Uyehara, T.; Shida, N.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1989, 753–754; (b) Uyehara, T.; Shida, N.;
Yamamoto, Y. J. Org. Chem. 1992, 57, 3139–3145; (c) Shida,
N.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1992, 57,
5049–5051; (d) Urones, J. G.; Garrido, N. M.; Diez, D.;
Dominguez, S. H.; Davies, S. G. Tetrahedron: Asymmetry
O
O
OMe
Ph
TolS
17f
Compound 17f (minor): 14% yield; Rf (30% ether/petrol)
0.3; dH 0.75 (1H, m, CHH), 1.00 (2H, m, CH2), 1.37 (2H,
m, CH2), 1.61 (1H, m, CHH), 1.70 (1H, m, CHH), 1.76
(1H, m, CHH), 1.85 (3H, s, CH3), 1.86 (1H, m, CH), 2.87
(1H, ddd, J 11.3, 11.3, 3.8 Hz, CH), 3.02 (1H, dd, J 11.3,
10.4 Hz, CH), 3.10 (3H, s, CH3), 7.00–7.50 (9H, m, Ph,
4ꢁArH); dC 20.5 (CH2), 24.4 (CH3), 31.5 (CH2), 33.8
(CH2), 38.5 (CH2), 38.8 (CH3), 50.4 (CH), 51.0 (CH), 52.6
(CH), 128.3 (CH), 128.6 (CH), 128.8 (CH), 131.2 (C),
132.7 (CH), 134.3 (C), 136.4 (C), 171.0 (C), 203.0 (C);
nmax 3022, 2934, 2857, 1726 (C]O), 1674 (C]O); m/z
(ES): 383 (100%, [M+H]+); HRMS (ES) C23H27O3S
([M+H]+) required 383.1681, found 383.1679.
ꢀ
1997, 8, 2683–2685; (e) Urones, J. G.; Garrido, N. M.; Dıez,
O
D.; Dominguez, S. H.; Davies, S. G. Tetrahedron: Asymmetry
1999, 10, 1637–1641; (f) Bull, S. D.; Davies, S. G.; Smith,
A. D. J. Chem. Soc., Perkin Trans. 1 2001, 2931–2938.
O
OMe
Ph
TolS
ꢀ
ꢀ
8. (a) Renaud, R. N.; Stephens, C. J.; Berube, D. Can. J. Chem.
1982, 60, 1687–1691; (b) Boger, D. L.; Mathvink, R. J.
J. Am. Chem. Soc. 1990, 112, 4003–4008; (c) Suwa, T.;
Nishino, K.; Miyatake, M.; Shibata, I.; Baba, A. Tetrahedron
Lett. 2000, 41, 3403–3406.
18
Compound 18 (major): 55% yield; Rf (30% ether/petrol)
0.40; mp 56–58 ꢀC; dH 1.18 (2H, m, CH2), 1.25 (2H, m,
CH2), 1.53 (2H, m, CH2), 1.95 (3H, s, CH3), 1.98 (2H,
m, CH2), 2.32 (1H, m, CH), 3.04 (1H, m, CH), 3.10 (3H,
s, CH3), 3.32 (1H, dd, J 6.0, 4.7 Hz, CH), (9H, m, Ph,
4ꢁArH); dC 20.8 (CH2), 21.2 (CH3), 28.8 (CH2), 29.3
(CH2), 32.1 (CH), 35.8 (CH2), 46.9 (CH), 48.8 (CH), 51.4
(Me), 128.2 (CH), 128.6 (CH), 129.8 (CH), 129.9 (C),
130.3 (C), 133.0 (CH), 133.2 (C), 135.0 (CH), 173.1 (C),
200.8 (C); nmax 3058, 2938, 2870, 1726; m/z (ES) 383
(100%, [M+H]+); HRMS (CI, NH3) C23H27O3S ([M+H]+)
required 383.1681, found 383.1683.
9. (a) Murphy, P. J.; Williams, H. L.; Hibbs, D. E.; Hursthouse,
M. B.; Malik, K. M. A. Tetrahedron 1996, 52, 8315–8332;
(b) Black, G. P.; Murphy, P. J.; Walshe, N. D. A. Tetrahedron
1998, 54, 9481–9488.
10. Cambridge Crystallographic Data Centre deposition number
CCDC 615910. Formula: C23H26O3S: Unit cell parameters:
a 7.22450(10), b 24.0470(3), c 11.75190(10), b 92.2160(10),
space group P21/c.
11. Hon, Y.-S.; Chu, K.-P.; Hong, P.-C.; Lu, L. Synth. Commun.
1992, 22, 429–443.
12. Montgomery, J.; Savchenko, A. V.; Zhao, Y. J. Org. Chem.
1995, 60, 5699–5701.
Acknowledgements
13. Enholm, E. J.; Kinter, K. S. J. Am. Chem. Soc. 1991, 113,
7784–7785.
14. Felton, G. A. N.; Bauld, N. L. Tetrahedron 2004, 60, 10999–
11010.
Thanks are given to the EPSRC for a studentship to PMB
(GR/M50584), the Erasmus Scheme (NK) and to the EPSRC
Mass Spectrometry Centre at Swansea.