The sila-Pummerer reaction of γ-silyl substituted cycloalkanoyl sulfoxides: The first examples and a new approach to 3-substituted cycloalk-2-enones

Article abstract of DOI:10.1016/j.tetlet.2014.04.128

The thermal decomposition of 3-(α-trimethylsilyl)alkyl substituted 2-(phenylsulfinyl)cycloalkanones occurs via the γ-sila-Pummerer reaction, affording 3-substituted cycloalk-2-enones and unstable trimethylsilyl benzenesulfenate as an elimination by-product. The starting γ-silyl substituted cycloalkanoyl sulfoxides were obtained through the conjugate addition reaction of nucleophilic reagents to 2-(phenylsulfinyl)cycloalk-2- enones. The tandem conjugate addition/γ-sila-Pummerer reaction investigated here provides a new route to 3-substituted cycloalk-2-enones.

Full text of DOI:10.1016/j.tetlet.2014.04.128

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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The sila-Pummerer reaction of c-silyl substituted cycloalkanoyl
sulfoxides: the first examples and a new approach to 3-substituted
cycloalk-2-enones
⇑
Maciej Mikina, Marian Mikołajczyk
´
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry, Sienkiewicza 112 Str., Łódz 90-363, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The thermal decomposition of 3-(a-trimethylsilyl)alkyl substituted 2-(phenylsulfinyl)cycloalkanones
Received 6 March 2014
Revised 8 April 2014
Accepted 30 April 2014
Available online xxxx
occurs via the
ylsilyl benzenesulfenate as an elimination by-product. The starting
sulfoxides were obtained through the conjugate addition reaction of nucleophilic reagents to 2-(phen-
c-sila-Pummerer reaction, affording 3-substituted cycloalk-2-enones and unstable trimeth-
c
-silyl substituted cycloalkanoyl
ylsulfinyl)cycloalk-2-enones. The tandem conjugate addition/
provides a new route to 3-substituted cycloalk-2-enones.
c
-sila-Pummerer reaction investigated here
Keywords:
Sila-Pummerer reaction
Conjugate addition
Ó 2014 Elsevier Ltd. All rights reserved.
2-(Sulfinyl)cycloalk-2-enones
3-Substituted cycloalk-2-enones
Thermal rearrangement of silyl substituted alkyl sulfoxides
involving the migration of a silyl group from carbon to the sulfinyl
oxygen atom as the first step is now commonly named the
sila-Pummerer reaction. It was discovered by Brook and Anderson
in 1968, who found that (trimethylsilyl)methyl phenyl sulfoxide
(1) rearranges upon heating at 60 °C into (trimethylsilyloxy)methyl
Herein, we disclose our unexpected discovery that c-silyl
substituted cycloalkyl sulfoxides undergo the sila-Pummerer reac-
tion and that, in contrast to b-silylalkyl sulfoxides, there is no com-
petition from b-hydrogen elimination.5 To the best of our
knowledge, there are no reports of the
ment of sulfoxides.
c-sila-Pummerer rearrange-
phenyl sulfide (2).1 The mechanism of the
a
-sila-Pummerer reac-
In an extension of our studies on the synthesis of biologically
tion has attracted considerable attention, and both experimental
and theoretical studies have indicated that it proceeds via unstable
ylide and alkylidene sulfonium ion intermediates (Scheme 1).2,3a
The classical sila-Pummerer rearrangement and its modification
using silyl initiators have found wide applications in organic
synthesis.3
The thermolytic reaction with b-silyl substituted alkyl sulfox-
ides is bidirectional in course, and depends on the substitution pat-
tern of the b-carbon atom (Scheme 2).4 When there is a hydrogen on
the b-carbon atom fast syn-elimination of sulfenic acid is observed
leading to the corresponding olefinic product. Interestingly, the
active compounds (enantiomeric prostaglandin B1 methyl esters,6
8
racemic rosaprostol,7 enantiomeric phytoprostanes B1
) using
3-(dimethoxyphosphorylmethyl)cyclopent-2-enone (3) as a con-
venient building block, we sought to investigate the preparation
and properties of a silicon analogue of 3, where the phosphoryl
group is replaced by a trimethylsilyl group, for example, compound
4. In other words, by employing our multistep synthesis we
wanted to generate an olefinic bond at the C(3)-carbon atom of
the cyclopentenone ring not by the Horner reaction, but by using
4 as a Peterson reaction component. The latter reaction is more
effective than the former and should allow several limitations of
the PO-olefination reaction to be overcome. Taking into account
the synthesis of 3 recently elaborated in our group,9 we anticipated
that 2-(phenylsulfinyl)cyclopent-2-enone (5)10 would be a suitable
substrate for the conjugate addition of a (trimethylsilyl)methyl
carbanion and the corresponding Michael adduct 6 obtained would
give the desired target 4 after thermal elimination of sulfenic acid.
presence of
a b-silyl group accelerates this cycloelimination
process. In the absence of a b-hydrogen, thermolysis occurs through
the b-sila-Pummerer reaction involving the elimination of silyl sulf-
enate and the formation of an alkene.
⇑
Corresponding author. Fax: +48 42 680 32 21.
E-mail address: marmikol@cbmm.lodz.pl (M. Mikołajczyk).
http://dx.doi.org/10.1016/j.tetlet.2014.04.128
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mikina, M.; Mikołajczyk, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.128

2
M. Mikina, M. Mikołajczyk / Tetrahedron Letters xxx (2014) xxx–xxx
O
O
Me3SiCH2
S
O
Ph
Me3SiOCH2
S
Ph
O
SPh
(MeO)2PCH(Li)SiMe3
THF, -78 oC to rt
1
2
SiMe3
5
O
P(OMe)2
Me3SiO
OSiMe3
CH2=S–Ph
6b
CH2–S–Ph
CHCl3
reflux, 5 h
Scheme 1.
a-Sila-Pummerer reaction of sulfoxide 1.
O
(Me3Si)2O
O
+
P(OMe)2
PhS(O)SPh
O
R1
H
SPh
7b
(R)
(A)
-PhSOH
-PhSOSi
R1
R
Si
R
Si
Scheme 4. Thermolysis of the 1,4-addition product 6b.
O
R1
R2
Si
R1
SPh
(B)
distillation, the residue was chromatographed to give phenyl
benzenethiosulfinate (33% yield) and 3-(dimethoxyphospho-
ryl)methylcyclopent-2-enone (7b) (35% yield) as the main reaction
product. When decomposition of 6b was performed in a more dilute
chloroform solution, cyclopentenone 7b was isolated in 62% yield.
The formation of the disiloxane and thiosulfinate in the above
reaction indicated clearly that the thermal decomposition of 6b
was not accompanied by the elimination of benzenesulfenic acid,
but occurs in terms of the sila-Pummerer reaction with the elimina-
tion of trimethylsilyl benzenesulfenate. The latter is known to be
very unstable and rearranges into a disiloxane and thiosulfinate
(Eq. 1), as demonstrated by Davis and co-workers.11
R
R2
Scheme 2. Thermolysis of b-silylalkyl sulfoxides: (A) syn-elimination of sulfenic
acid, (B) b-sila-Pummerer reaction.
O
O
O
P(OMe)2
SiMe3
4
3
(Me3Si)2O
With this in mind, the cyclopentenone sulfoxide 5 was added to a
solution of (trimethylsilyl)methylmagnesium chloride in THF at
ꢀ78 °C. The crude 1,4-adduct 6a, isolated by a standard procedure,
was heated at 140 °C under reduced pressure and distilled.
Redistillation of the collected liquid at normal pressure gave two
fractions. The first (bp 84–100 °C) contained virtually pure
hexamethyldisiloxane (ca. 70% yield), while the second (bp 180–
184 °C) was identified as 3-(methyl)cyclopent-2-enone (7a)
obtained in 66% yield (Scheme 3). The desired compound 4 was
not formed.
To gain a better insight into the unexpected course of the above
reaction and to identify all the reaction products, the reaction of
sulfoxide 5 with the lithium salt of dimethyl (trimethylsilyl)meth-
anephosphonate was investigated (Scheme 4). As expected, the cor-
responding 1,4-adduct 6b was formed in the first step, and isolated
in almost quantitative yield. Its 31P NMR spectrum showed eight
resonances at d = 34.7, 35.2, 35.8, 35.9, 36.1, 37.1, 38.8 and 40.7,
as a consequence of the presence of four stereogenic centers in
6b. HRMS confirmed the structure of the adduct [calcd for
ð1Þ
2 Me3SiOSPh
PhS(O)SPh
Most probably, elimination of silyl sulfenate from the 1,-
4-adducts obtained here occurs via a cyclic six-membered transi-
tion state A (or cyclic pentacoordinate silicon anion intermediate
B) (Fig. 1). Cleavage of the carbonAsulfur and siliconAcarbon
bonds in A (or B) resulting in the elimination of unstable silyl
sulfenate is accompanied by formation of the enone system and
a 1,2-proton shift from C-3 to the exocyclic
a-carbon atom. The
question of whether all these elementary steps proceed in a
concerted manner or via ionic or neutral short-lived intermediates
requires further detailed experimental and theoretical studies.
To demonstrate that the c-sila-Pummerer reaction is general in
scope, the 1,4-adducts 6c–f were obtained from the cyclopente-
none sulfoxide 5. Upon heating, they gave the corresponding
3-substituted cyclopentenones 7c–f (Scheme 5). The formation of
C17H28SiPSO5 (M+1) 403.1164; found 403.1153]. Next, adduct 6b
Ph
O Ph
O
S
S
was dissolved in chloroform and refluxed for five hours. After
removal of the solvent and hexamethyldisiloxane (38% yield) by
or
O
O
SiMe3
SiMe3
H
H
R
B
R
A
O
O
O
SPh
O
SPh
Me3SiCH2MgCl
THF, -78 oC to rt
Figure 1. Proposed transition state (A) and pentacoordinate silicon intermediate
(B) for the -sila-Pummerer reaction.
c
CH2SiMe3
5
6a
O
O
O
140 oC
O
SPh
O
SiMe3
R
R
(Me3Si)2O
+
7c
7d
7e
7f
6c
6d
6e
6f
R = Ph
Me
R = Ph2P(O)
R = PhS(O)2
R = EtOC(O)
4
not formed
Scheme 3. Thermolysis of the 1,4-addition product 6a.
Scheme 5. Thermolysis of the 1,4-addition products 6c–f.
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M. Mikina, M. Mikołajczyk / Tetrahedron Letters xxx (2014) xxx–xxx
3
O
O
O
S-phenyl benzenethiosulfinate as by-products. Utilizing the conju-
gate addition of nucleophiles to 2-(sulfinyl)cycloalk-2-enones and
O
O
(MeO)2PCH(Li)SiMe3
SPh
SPh
subsequent
c-sila-Pummerer reaction of the formed 1,4-adducts
SiMe3
n
n
has yielded a new synthetic approach to 3-substituted cycloalk-2-
enones. Further studies on the sila-Pummerer reaction of acyclic
O
9
P(OMe)2
n = 2
8, n = 2
11, n = 3
O
,
12, n = 3
c-silylalkyl sulfoxides are in progress.
O
P(OMe)2
n
Acknowledgment
10
, n = 2
13
, n = 3
This work was financially supported by the Ministry of Science
and Higher Education, Poland.
Scheme 6. Thermolysis of the 1,4-addition products 9 and 12.
Table 1
Synthesis of 3-substituted cycloalk-2-enones from 2-(sulfinyl)cycloalk-2-enones via
Supplementary data
the tandem conjugate addition/
c
-sila-Pummerer reaction
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.
128. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Entry 2-Sulfinyl
1,4-Adduct
3-Substituted
cycloalk-enone/
yield (%)
cycloalk-enone
R
Decomposition
conditions
D
1
2
5
5
6a, R = H
6b, R = (MeO)2
P(O)
Neat, 140 °C
CHCl3, reflux, 5 h
7a, 66
7b, 62
References and notes
3
4
5
6
7
8
5
5
5
5
8
11
6c, R = Ph
Toluene, reflux, 5 h 7c, 43
Benzene, reflux, 5 h 7d, 36
CHCl3, reflux, 22 h 7e, 68
Benzene, reflux, 5 h 7f, 43
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I.; Goldhill, J.; Perry, D. A. J. Chem. Soc., Perkin Trans. 1 1982, 1563–1569.
5. Preliminary results have been presented by one of us (M. Mikina) at the 25th
International Symposium on the Organic Chemistry of Sulfur, Cze˛stochowa,
Poland, June 24–29, 2012.
6d, R = Ph2P(O)
6e, R = PhS(O)2
6f, R = EtOC(O)
9, R = (MeO)2P(O) CHCl3, reflux, 5 h
12, R = (MeO)2
10, 58
13, 59
CHCl3, reflux, 5 h
P(O)
products resulting from the elimination of benzenesulfenic acid
was not observed.
6. Mikołajczyk, M.; Mikina, M.; Jankowiak, A. J. Org. Chem. 2000, 65, 5127–5130.
7. Mikołajczyk, M.; Mikina, M.; Jankowiak, A.; Mphahlele, M. J. Synthesis 2000,
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1771.
Similarly, the adducts 9 and 12, prepared by the addition of
dimethyl lithium(trimethylsilyl)methylphosphonate to cyclohexe-
none sulfoxide 812 and cycloheptenone sulfoxide 11,12 were found
to undergo the c-sila-Pummerer reaction affording the correspond-
ing 3-(dimethoxyphosphoryl)methyl substituted cyclohexenone 10
9. Mikołajczyk, M.; Perlikowska, W. Synthesis 2007, 1225–1229.
and cycloheptenone 13 (Scheme 6).
10. The sulfoxide
5 was obtained according to the procedure described. In:
Monteiro, M. J. J. Org. Chem. 1997, 42, 2324–2326.
11. Davis, F. A.; Rizvi, S. Q. A.; Ardecky, R.; Gosciniak, D. J.; Friedman, A. J.;
Yocklovich, S. G. J. Org. Chem. 1980, 45, 1650–1653.
The results of the c-sila-Pummerer reactions are summarized in
Table 1. All the main products of this reaction, that is, 3-substituted
cycloalk-2-enones 7a–d, 7f, 10, and 13 obtained here, except 7e,13
are known compounds and their spectral properties were identical
to those reported in the literature.14
Finally, from the viewpoint of organic synthesis, it is interesting
to emphasize that the Michael addition of nucleophilic reagents to
12. Both sulfoxides 8 and 11 were prepared according to the procedure described
by Hassner and co-workers: Yechezkel, T.; Ghera, E.; Ostercamp, D.; Hassner, A.
J. Org. Chem. 1995, 60, 5135–5142.
13. Spectral data for 7e: 1H NMR (200 MHz, CDCl3) d = 7.86–7.89 (m, 2H), 7.55–
7.74 (m, 3H), 5.91 (br s, 1H), 4.19 (s, 2H), 2.75–2.79 (m, 2H), 2.41–2.46 (m, 2H);
13C NMR (50 MHz, CDCl3) d = 208.1, 165.4, 138.0, 136.2, 134.4, 129.4, 128.2,
59.6, 35.5, 31.8. MS(EI) 236.1 (M)+; MS FAB 235.1 (Mꢀ1)ꢀ.
14. Spectral properties of known compounds are available: 7a,15 7b,16 7c,17 7d,18
7f,19 10 and 13.16
2-(sulfinyl)cycloalk-2-enones in combination with the
c-sila-
Pummerer reaction of the corresponding formed 1,4-adducts repre-
sents a new synthetic approach to 3-substituted cycloalk-2-enones.
In conclusion, we have described herein the first examples of the
-sila-Pummerer reaction on 3-(a-trimethylsilyl)alkyl substituted
2-(phenylsulfinyl)cycloalkanones. This reaction afforded 3-substi-
15. Kreutzer, A.; Kerres, S.; Ertl, T.; Rücker, H.; Amslinger, S.; Reiser, O. Org. Lett.
2013, 15, 3420–3423.
16. Mikołajczyk, M.; Mikina, M. J. Org. Chem. 1994, 59, 6760–6765.
17. Corbel, B.; Decesare, J. M.; Durst, T. Can. J. Chem. 1978, 56, 505–511.
18. Oehler, E.; Zbiral, E. Synthesis 1991, 357–361.
c
19. Collins, S.; Hong, Y.; Kataoka, M.; Nguyen, T. J. Org. Chem. 1990, 55, 3395–3398.
tuted cycloalk-2-enones together with hexamethyldisiloxane and
Please cite this article in press as: Mikina, M.; Mikołajczyk, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.128