Expedient Diels-Alder assembly of 4-aryl-4-phenylsulfonyl cyclohexanones

Article abstract of DOI:10.1016/j.tetlet.2004.03.031

The efficient preparation of 4-aryl-4-phenylsulfonyl cyclohexanones, containing a quaternary sulfone-bearing carbon centre, is described. Their synthesis proceeds in 38-78% overall yield by way of three steps: (i) sulfinate alkylation; (ii) methylenation;

Full text of DOI:10.1016/j.tetlet.2004.03.031

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3345–3348
Expedient Diels–Alder assembly of 4-aryl-4-phenylsulfonyl
cyclohexanonesq
Jeremy P. Scott,* Deborah C. Hammond, Elizabeth M. Beck, Karel M. J. Brands,
Antony J. Davies, Ulf-H. Dolling and Derek J. Kennedy
Department of Process Research, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon,
Hertfordshire EN11 9BU, UK
Received 28 January 2004; revised 20 February 2004; accepted 8 March 2004
Abstract—The efficient preparation of 4-aryl-4-phenylsulfonyl cyclohexanones, containing a quaternary sulfone-bearing carbon
centre, is described. Their synthesis proceeds in 38–78% overall yield by way of three steps: (i) sulfinate alkylation; (ii) methyl-
enation; and (iii) regioselective Diels–Alder condensation with 2-trimethylsiloxybutadiene. The scope and limitations of the one-pot
Mannich-type methylenation described were examined.
ꢀ 2004 Elsevier Ltd. All rights reserved.
As part of a drug discovery programme, we required an
efficient and scalable synthesis of cyclohexanones with
general structure 1 having a quaternary carbon substi-
tuted with aryl and phenylsulfonyl moieties. An
approach to a related substructure, reliant on a tandem
double Michael–Dieckmann cyclisation followed by
b-decarboxylation, has been documented (Scheme 1).1
We found this chemistry to be unacceptable for the
benzylphenylsulfones 2 of interest to us, with low yields
and attendant poor impurity profiles.2
sulfone 3 with a 2-substituted siloxybutadiene (Scheme
2). Importantly from our perspective, entry to cyclo-
hexanones by 1,4-regioselective [4+2] cycloaddition of
this diene type with electron deficient alkenes has been
documented.3 The utility of 1-aryl-1-phenylsulfonyl
vinyl sulfones 3 in this context has, however, not been
reported.4;5
In this paper we describe the implementation of this
Diels–Alder strategy for the preparation of 4-aryl-4-
phenylsulfonyl cyclohexanones 1 proceeding by way of
three isolated intermediates. The key steps are Mannich-
type methylenation of sulfones 2 to their corresponding
vinyl sulfones 3, followed by thermal Diels–Alder
cycloaddition with 2-trimethylsiloxybutadiene. Acid-
catalysed hydrolysis of the resultant silyl enol ethers
then afforded the desired cyclohexanones 1 in moderate
to excellent overall yields.
We envisaged an alternative Diels–Alder construction of
the cyclohexanone ring by way of the union of a vinyl
O
KOtBu
CO2Et
O O
S
O O
S
Ar
Ph
Ph
CO2Et
Ar
2
O
O O
Construction of ketones 1 began with alkylation of
commercially available benzenesulfinate sodium salt
with benzyl halides 4 to form the requisite methylene
sulfones 2 (Scheme 3). A highly practical procedure was
developed, using DMF or DMSO as solvent, which
n-PrOH
c. HCl
S
Ph
1
Ar
Scheme 1.
Keywords: Cycloadditions; Diels–Alder reactions; Methylenation;
Sulfones.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.031
* Corresponding author. Tel.: +44-0-1992-452614; fax: +44-0-1992-4-
52581; e-mail: jeremy_scott@merck.com
OTMS
OTMS
O O
S
+
1
Ph
Ph
S
Ar
Ar
O O
3
Scheme 2.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.031

3346
J. P. Scott et al. / Tetrahedron Letters 45 (2004) 3345–3348
R2
R2
temperature then afforded the desired vinyl sulfones 3a–
c in moderate overall yields (Table 1, entries 1–3).12
R1
R3
R1
R3
SO2Na
a
X
PhSO2
+
R4
R4
A more practical one-pot procedure was developed for
sulfones 2d–g (Table 1, entries 4–7).13;14 Exposure to
N,N,N0,N0-tetramethylmethylenediamine (TMMD) and
acetic anhydride at elevated temperature in DMF
afforded the vinyl sulfones 3d–g directly in good to
excellent yields (80–91%). The reaction manifold is
illustrated for p-cyanobenzyl phenyl sulfone 2g (Scheme
4). Addition of an initial charge of 1.5 equivof TMMD
and 1.5 equivacetic anhydride to a DMF solution of 2g
afforded a 49:16:35 mixture15 of 2g, the intermediate
dimethylamino adduct 5g and vinyl sulfone 3g after 2 h
at 60 ꢁC. Slow addition of a DMF solution of a further
1.6 equivof acetic anhydride then led to full conversion
to the product 3g. In the case of nitro-substituted sul-
fone 2f, a 71:29 mixture of the dimethylamino interme-
diate 5f and vinyl sulfone 3f was formed after 1 h, with
complete consumption of 2f observed within this time.
This reactivity reflects the enhanced electron with-
drawing nature of a nitro versus a cyano group, with a
predicted lower pKa for 2f versus 2g.16
(90-99%)
R5
R2
R5
2
4
R2
R1
R3
R4
R1
R3
b
PhSO2
Me2N
PhSO2
or c
(64-91%)
R4
R5
R5
5
3
O
TMSO
PhSO2
R5
X = Cl or Br
R1
R2
R1 - R5 = H, F, CN,
F3C or NO2
d (51-90%)
1
R4
R3
Scheme 3. Reagents and conditions: (a) DMSO or DMF, 60 ꢁC; (b)
n-BuLi, THF, )35 ꢁC then (Me2NCH2)I; Ac2O, PhMe, 85 ꢁC; (c)
Me2NCH2NMe2, Ac2O, DMF, 60 ꢁC; (d) o-xylene, 130 ꢁC, HCl, THF,
rt.
A
1H NMR study defined the benefit of adding the
acetic anhydride in two aliquots (Scheme 5). The imin-
ium salt 6 was rapidly and quantitatively formed from
an equimolar mixture of TMMD and acetic anhydride
at 0 ꢁC in d7-DMF. Although this salt was apparently
stable at the reaction temperature (60 ꢁC) for up to 2 h,
addition of further acetic anhydride triggered degrada-
tion over a period of several hours. In the reaction
manifold with methylene sulfones 2d–g, slow addition of
allowed direct crystallisation of sulfones 2a–g in 90–99%
yields (Table 1, entries 1–7).6;7
Conversion of 2 into the corresponding vinyl sulfones 3
was now required.8;9 This was achieved by two proto-
cols, dependent on the nature of the substituents (R1–
R5) pendant to the benzyl moiety of 2. For sulfones 2a–
c, lithiation with n-butyllithium and quenching with
Eschenmoser’s salt afforded the intermediate dimethyl-
amino adducts 5a–c (Scheme 3). Significant amounts (up
to 26%) of unconverted sulfones 2a–c were observed in
this process, likely due to competing proton transfer
from the iminium salt to the lithiated sulfones.10 How-
ever, pH controlled extraction allowed for easy separa-
tion of the tertiary amines 5a–c from the sulfones 2a–c.
Exposure to acetic anhydride in toluene11 at elevated
CN
b
a
PhSO2
Me2N
2g
2g +
3g
3g
+
(89%)
5g
Scheme 4. Reagents and conditions: (a) 1.5 equivMe 2NCH2NMe2,
1.5 equivAc 2O, DMF, 2 h, 60 ꢁC; (b) 1.6 equivAc 2O, DMF, 3 h, 60 ꢁC.
Table 1. Synthesis of 4-aryl-4-phenylsulfonylcyclohexanones 1
O
R2
R2
R1
R3
R4
R1
R3
R4
PhSO2
R5
R1
R2
PhSO2
PhSO2
R5
R5
R4
1
R3
2
3
Entry
Substituents
Sulfone
Yield (%)a
Vinyl sulfone
Yield (%)a
Ketone
Yield (%)a
1
2
3
4
5
6
7
R2–R5 ¼ H; R1 ¼ F
2a
2b
2c
2d
2e
2f
93
90
93
98
99
93
98
3a
3b
3c
3d
3e
3f
64b
66b
68b
82c
80c
91c
89c
1a
1b
1c
1d
1e
1f
64
75
51
72
87
89
90
R1, R2, R4, R5 ¼ H; R3 ¼ F
R2, R3, R4 ¼ H; R1, R5 ¼ F
R2, R3, R5 ¼ H; R1, R4 ¼ F
R1, R2, R4, R5 ¼ H; R3 ¼ CF3
R1, R2, R4, R5 ¼ H; R3 ¼ NO2
R1, R2, R4, R5 ¼ H; R3 ¼ CN
2g
3g
1g
a Yields reported are of compounds isolated by chromatography or crystallisation.
b n-BuLi, THF then (Me2NCH2)I; Ac2O, PhMe.
c Me2NCH2NMe2, Ac2O, DMF.

J. P. Scott et al. / Tetrahedron Letters 45 (2004) 3345–3348
3347
3. (a) Jung, M. E.; McCombs, C. A. Tetrahedron Lett. 1976,
17, 2935–2938; (b) Jung, M. E.; McCombs, C. A. Org.
Synth. 1978, 58, 163–168; (c) Jung, M. E.; McCombs, C.
A.; Takeda, Y.; Pan, Y.-G. J. Am. Chem. Soc. 1981, 103,
6677–6685.
+
N
Ac2O
DMF
-
decomposition
Ac2O +
1 equiv
Me2N
NMe2
AcO
6
1 equiv
Scheme 5.
4. Diels–Alder reactions of carbonyl conjugated 1,1-disub-
stituted vinyl sulfones with 2-siloxydienes have been
reported: (a) Coltart, D. M.; Danishefsky, S. J. Org. Lett.
2003, 5, 1289–1292; (b) Gomez-Pardo, D.; d’Angelo, J.
Tetrahedron Lett. 1992, 33, 6637; (c) Hirsenkorn, R.;
Schmidt, R. Leibigs Ann. Chem. 1990, 883–899.
5. De Lucchi, O.; Pasquato, L. Tetrahedron 1988, 44, 6755–
6794.
the second acetic anhydride aliquot allows for prefer-
ential conversion of the intermediate dimethylamino
adducts 5d–g to product, whilst reducing degradation of
the iminium salt still present in solution. Addition of the
full amount of acetic anhydride at the reaction outset
invariably led to poor conversion.
6. Jarvis, B. B.; Saukaitis, J. C. J. Am. Chem. Soc. 1973, 95,
7708–7715.
7. All new compounds gave satisfactory NMR, elemental
and/or HRMS analysis.
8. Peterson olefination of an a-silylsulfone with formaldehyde
has been reported for 1-[(phenyl)sulfonyl]ethenylbenzene:
Ager, D. A. J. Chem. Soc., Chem. Commun. 1984, 486–488.
9. Costa, A.; Najera, C.; Sansano, J. M. J. Org. Chem. 2002,
67, 5216–5225.
10. Basicity of sulfone anions in their addition to enolisable
carbonyls has been moderated by CeCl3: Fuchs, P. L.;
Lamothe, M.; Anderson, M. B. Tetrahedron Lett. 1991,
32, 4457–4460.
The scope of the one-pot methylenation with TMMD
and acetic anhydride was found to correlate with the
expected acidity of the methylene sulfones 2a–g.17 No
conversion of monofluorinated sulfones 2a–b, bearing a
2- or 4-substituent on the benzyl moiety, was observed
under these conditions. Whilst 2,5-difluorosubstituted
substrate 2d was consumed in this reaction manifold, the
2,6-difluoro pattern was unreactive, presumably due to
the destabilising electrostatic influence of the proximal
fluorines.
11. A solvent screen of DMF, PhMe and isopropyl acetate for
adduct 5b revealed PhMe to be optimal in terms of
conversion to and purity of 3b.
Diels–Alder reactions of vinyl sulfones 3a–g with com-
mercially available 2-trimethylsiloxybutadiene18 pro-
ceeded thermally in o-xylene as solvent.19;20 Hydrolysis of
the intermediate silyl enol ether was effected with aque-
ous HCl in THF to afford the product cyclohexanones
1a–g in moderate to excellent yields (Table 1, 51–90%).
Reactivity in the cycloaddition mirrored the substituents
attached to the conjugating phenyl ring with conversion
of nitro and cyano substrates 3f and 3g complete within
3 h at 130 ꢁC, whilst substrates 3a–e required extended
reaction times (up to 16 h). An excess of 2-trimethylsil-
oxybutadiene was typically used (2–3 equiv), the surfeit
of which was removed by distillation prior to hydrolysis
of the silyl enol ether intermediate, which minimised
deposition and entrainment of polymeric solids resulting
from degradation of the butadiene. In all cases, only a
single Diels–Alder regioisomer was observed, in accord
with previous observations for this diene class.3c
12. (a) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D.
Tetrahedron Lett. 1977, 19, 1621–1624; (b) Rigby, J. H.;
Wilson, J. Z. J. Am. Chem. Soc. 1984, 109, 8217–8224.
13. (a) Gunda, T. E. Synth. Commun. 1992, 22, 2979–2986; (b)
DeSolms, S. J. J. Org. Chem. 1976, 41, 2650–2651; For a
recent review of the Mannich reaction: (c) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044–1070.
14. Representative procedure: Sulfone 2g (5.2 g, 20.0 mmol)
was dissolved in DMF (56 mL) and N,N,N0,N0-tetra-
methylmethylenediamine (3.1 g, 30.0 mmol) added in one
portion. Ac2O (2.8 mL, 30.0 mmol) was then added and
the mixture was heated at 60 ꢁC for 2.5 h. A solution of
Ac2O (3.0 mL, 32.0 mmol) in DMF (6.2 mL) was then
added via syringe pump over 3 h. The mixture was kept at
60 ꢁC for 0.5 h and then cooled to ambient temperature.
H2O (102 mL) was added dropwise to crystallise the crude
product. Purification by chromatography then afforded 1-
cyano-4-[1-(phenylsulfonyl)ethenyl]benzene 3g in 89%
yield (4.8 g): 1H NMR (400 MHz, CD2Cl2) d 7.61–7.57
(2H, m), 7.52–7.47 (3H, m), 7.40–7.34 (4H, m), 6.60 (1H,
s), 5.98 (1H, s); 13C NMR (100 MHz, CD2Cl2) d 149.6,
138.3, 137.1, 133.8, 132.1, 129.7, 129.2, 128.3, 127.6, 118.1,
113.2; mp 118–120 ꢁC; MS (ES) 292.10 (79, M+Na),
270.05 (100, M+H).
In summary, we have developed an expedient synthesis
of 4-aryl-4-phenylsulfonyl ketones 1 proceeding by way
of three isolated intermediates and in moderate to
excellent overall yields (38–78%). Conditions for the
one-pot conversion of sulfones 2d–g to vinyl sulfones
3d–g were developed and the scope shown to be limited
to those substrates bearing strongly electron withdraw-
ing substituents. Subsequent Diels–Alder condensations
proceeded thermally affording only a single regioiso-
meric product.
15. LC area% ratio at 210 nm determined by reverse phase
HPLC on a Phenomenex Luna 150 · 4.6 mm column.
16. Compare, for example, pKa in DMSO for p-
(NC)C6H4CH3 is 30.8 versus p-(NO2)C6H4CH3 20.4:
Bordwell, F. G.; Algrim, D.; Vanier, N. R. J. Org. Chem.
1977, 42, 1817–1819.
17. PhSO2CH2Ph pKa 23.4 (DMSO): Bordwell, F. G.; Cheng,
J.-P.; Ji, G.-Z.; Satish, A. V.; Zhang, X. J. Am. Chem. Soc.
1991, 113, 9790–9795.
Acknowledgement
We thank Paul Byway for mass spectrometry analysis.
References and notes
18. Purchased from Karl Bucher GmbH, 89637 Waldstetten,
Germany.
19. Lewis acid catalysis with ZnCl2, TiCl4 or BF3ÆOEt2 was
unsuccessful, likely due to degradation of the siloxybuta-
diene and/or poor Lewis basicity of the sulfone oxygen
atoms.
1. Yashimoto, M.; Ishida, N.; Kishida, Y. Chem. Pharm.
Bull. 1972, 20, 2137–2142.
2. Typical overall yields for the two-step process were 20–30%.

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J. P. Scott et al. / Tetrahedron Letters 45 (2004) 3345–3348
20. Representative procedure: Vinyl sulfone 3g (2.0 g,
7.4 mmol) was heated with 2-trimethylsiloxybutadiene
(2.1 g, 14.9 mmol) in o-xylene (4.0 mL) at 130 ꢁC for 3 h.
The reaction mixture was then allowed to cool to ambient
temperature, diluted with o-xylene (20 mL) and evapo-
rated in vacuo. The residue was taken up in THF (30 mL)
and 2 M HCl (20 mL) added. After 1.0 h at rt, the mixture
was filtered through a layer of Whatman Glass Fibre,
then extracted with CH2Cl2. Evaporation in vacuo
followed by chromatography then afforded 4-(4-cyano-
phenyl)-4-(phenylsulfonyl)cyclohexanone 1g in 90%
yield (2.3 g): 1H NMR (400 MHz, d6-DMSO) d 7.75–
7.72 (2H, m), 7.64–7.59 (1H, m), 7.52–7.46 (2H, m),
7.45–7.38 (2H, m), 7.24–7.20 (2H, m), 2.80–2.72 (2H, m),
2.40–2.30 (2H, m), 2.21–2.14 (2H, m), 1.99–1.88 (2H, m);
13C NMR (100 MHz, d6-DMSO) d 207.6, 137.2, 135.0,
134.3, 132.6, 131.3, 130.4, 129.5, 118.9, 112.1, 68.9, 36.9,
28.2; mp 221 ꢁC (decomp.); HRMS (CI) calcd for
C19H21N2O3S (M+NH4) requires 357.1273; found
357.1265.