An improved gem-dimethylcyclopropanation procedure using triisopropyl-sulfoxonium tetrafluoroborate

Article abstract of DOI:10.1055/s-2008-1042761

A new procedure for the cyclopropanation of α,β-unsaturated carbonyl compounds and related systems is described which employs triisopropylsulfoxonium tetrafluoroborate and sodium hydride in dimethylformamide. Using this reagent, a range of α,β-unsaturated ketones (and an ester and a vinyl nitro example) has been converted into the corresponding gem-dimethylcyclopropyl carbonyl compounds; in addition, a preliminary result is described in which an activated alcohol is converted directly into a gem-dimethylcyclopropyl ketone by a one-pot tandem oxidation-cyclopropanation sequence, albeit in low yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042761

LETTER
521
An Improved gem-Dimethylcyclopropanation Procedure Using Triisopropyl-
sulfoxonium Tetrafluoroborate
I
mprove
d
gem-Dimeth
i
ylcyclo
c
propanatio
hn Procedure ael G. Edwards, Richard J. Paxton, David S. Pugh, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 1 December 2007
O
Me
Me
Corey et al.5
Me
Me
Abstract: A new procedure for the cyclopropanation of a,b-unsat-
urated carbonyl compounds and related systems is described which
employs triisopropylsulfoxonium tetrafluoroborate and sodium hy-
dride in dimethylformamide. Using this reagent, a range of a,b-un-
saturated ketones (and an ester and a vinyl nitro example) has been
converted into the corresponding gem-dimethylcyclopropyl carbo-
nyl compounds; in addition, a preliminary result is described in
which an activated alcohol is converted directly into a gem-dimeth-
ylcyclopropyl ketone by a one-pot tandem oxidation–cyclopropana-
tion sequence, albeit in low yield.
BF4
BF4
Ph2S
p-Tol
S
NMe2
1
2
Johnson et al.6
NaH, DMF, 0 °C
tBuLi, THF, –78 °C
Me
Me
I
Ph3P
O2N
Me
Me
3
4
Key words: cyclopropanes, cyclopropanation, tandem oxidation
procedures, sulfoxonium salts, ruthenium tetroxide
Krief et al.7
nBuLi, THF, –78 °C
Ono et al.8
KOtBu, DMSO, r.t.
Figure 1
In recent years there has been a revival of interest in cy-
clopropanation chemistry with the development of effi-
cient carbenoid sources and the application of
organocatalysis to provide several elegant enantioselec-
tive syntheses.1,2 This is a testament to both the prevalence
of the cyclopropane unit in nature1 and the utility of func-
tionalised cyclopropanes as synthetic building blocks.2
Although the parent methylene cyclopropane is present in
numerous natural products, the gem-dimethylcyclopro-
pane group is a more common structural motif.3 There are
numerous procedures available to prepare gem-dimethyl-
cyclopropanes,4 but it is noteworthy that only a limited
number involve isopropyl transfer to electron-deficient
alkenes (Figure 1).5–8 The first such procedure was report-
ed by Corey and Jautelat and utilised diphenylsulfonium
isopropylide (1).5 This reagent efficiently produces gem-
dimethylcyclopropanes from unsaturated esters and
amides but with a,b-unsaturated ketones, epoxide forma-
tion can compete (for example, 3-methyl-2-cyclohex-
enone gives mainly the unsaturated epoxide5a). In
addition, the use of a strong base and low temperatures is
required. In 1973, Johnson’s group disclosed the use of
(dimethylamino)isopropyl-p-tolyloxosulfonium tetraflu-
oroborate (2) for the gem-dimethylcyclopropanation of
trans-1,2-dibenzoylethene and trans-chalcone.6 However
the synthesis of salt 2 was difficult and low-yielding and
the scope of the procedure has not been demonstrated.
More recently, it has been shown that the cyclopropana-
tion of unsaturated esters can be achieved using the iso-
propyl phosphorane 37 and the nitro compound 4,8 but
again the scope of these reagents has not been determined
(e.g. there are no examples of the use with a,b-unsaturated
ketones).
As part of our continuing programme in telescoped pro-
cesses and tandem oxidation processes (TOP),9 we have
recently become interested in developing improved routes
to functionalised cyclopropanes.10,11 First, a tandem pro-
cedure was designed for the one-pot oxidation–cyclopro-
panation of allylic alcohols using MnO2 in conjunction
with stabilised sulfuranes such as (carbethoxymethyl-
ene)dimethylsulfurane.10 We went on to develop an im-
proved procedure for the dimethylsulfoxonium methylide
cyclopropanation of a,b-unsaturated ketones using tri-
methylsulfoxonium iodide and 1,3,4,6,7,8-hexahydro-1-
methyl-2H-pyrimido[1,2-a]pyrimidine (MTBD).11
As an extension for our natural product programme, we
also required a method for the nucleophilic gem-dimeth-
ylcyclopropanation of a,b-unsaturated ketones that would
eliminate competitive epoxide formation (via reaction of
the ketone), proceed under mild reaction conditions, and
be applicable to a range of Michael acceptors. It is well es-
tablished that the ylide derived from treatment of a sulfox-
ium salt with base can undergo nucleophilic
cyclopropanation of a,b-unsaturated alkenes (the Corey–
Chaykovsky reaction) via alkylidene transfer.12 We there-
fore explored the preparation and reactions of a triisopro-
pylsulfoxonium salt. As the S-alkylation of sulfoxides is
successful only in the case of methylation,13 it was neces-
sary to synthesise such a salt by oxidation of the triisopro-
pylsulfonium salt14 (itself derived from diisopropyl
sulfide). Unfortunately, the literature contains few reports
on the oxidation of sulfonium salts to sulfoxonium salts.
The best method, aqueous sodium m-chloroperbenzoate,15
SYNLETT 2008, No. 4, pp 0521–0524
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1042761; Art ID: D39107ST
© Georg Thieme Verlag Stuttgart · New York

522
M. G. Edwards et al.
LETTER
was not useful for this substrate because the oxidation of dimethylsulfoxonium methylide,12 enolisable sub-
could not be driven to completion. We reasoned that the strates can be problematic leading to alternative conden-
use of a more powerful oxidant could overcome the slow sation byproducts and a lower yield (entries 5 and 6).
oxidation of the sterically encumbered sulfonium salt. Ru- Furthermore, the use of cyclohexenone led to only 4% of
thenium tetroxide16 has been applied to the oxidation of the desired product. Presumably, the slower rate of cyclo-
many organic functionalities and, after optimisation of the propanation, due to the steric encumberance of an ylide
classical Sharpless conditions (RuCl3, MeCN–CCl4– bearing three isopropyl groups, renders deprotonation a
H2O),17 we found that with 40 mol% of RuCl3 and 7.5 competitive alternative for the basic ylide.
equivalents of NaIO4, triisopropylsulfoxonium could be
After developing a successful method for cyclopropana-
prepared, after recrystallisation from MeOH–Et2O, in
tion via isopropyl transfer we briefly investigated a one-
76% yield18 (Scheme 1).
pot MnO2 oxidation–cyclopropanation reaction11
(Scheme 3). This procedure produced chalcone in 77%
yield along with a 7% yield of the oxidized/cyclopropan-
ated adduct 6. We are currently optimising these condi-
tions.
RuCl3 (40 mol%)
NaIO4 (7.5 equiv)
S
S
5
MeCN–CCl4–H2O (2:2:3),
r.t., 14 h
O
76%
BF4
BF4
5 (1.2 equiv)
MnO2 (10 equiv)
OH
O
O
+
Ph
Scheme 1
Ph
Ph
Ph
Ph
Ph
MTBD (2.0 equiv)
MeCN, r.t., 24 h
77%
6, 7%
With the sulfoxonium salt in hand, the cyclopropanation
of a,b-unsaturated ketones was explored; the initial exper-
iments were conducted under literature conditions for
dimethylsulfoxonium methylide cyclopropanation (NaH
in DMF).12d We were delighted to observe that, after five
hours at room temperature, the gem-dimethylcyclopro-
pane adduct of chalcone6 was obtained in 91% yield
(Scheme 2). Most notably, only a single diastereomer, the
trans-product, was obtained. Following this success, a
range of a,b-unsaturated ketones was examined as cyclo-
propanation substrates (Table 1).
Scheme 3
Acknowledgment
We are grateful to the EPSRC for studentship support (R. J. P. and
D. S. P.) and Elsevier Science for postdoctoral support (M. G. E.).
References and Notes
(1) See, for example: (a) Donaldson, W. A. Tetrahedron 2001,
57, 8589. (b) Pietruszka, J. Chem. Rev. 2003, 103, 1051.
(2) See, for example: (a) Lebel, H.; Marcoux, J.-F.; Molinaro,
C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
(b) Fedorynski, M. Chem. Rev. 2003, 103, 1099.
(c) Sydnes, L. K. Chem. Rev. 2003, 103, 1133. (d) Reissig,
H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(3) For a recently reported example of a gem-dimethylcyclo-
propane natural product, see: Gao, S.; Liu, H.-Y.; Wang, Y.-
H.; He, H.-P.; Wang, J.-S.; Di Y, T.; Li, C.-S.; Fang, X.;
Hao, X.-J. Org. Lett. 2007, 9, 3453.
(4) For alternative routes to gem-dimethylcyclopropanes, see:
(a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89,
3911. (b) Franck-Neumann, M. Angew. Chem., Int. Ed.
Engl. 1968, 7, 65. (c) Sengmany, S.; Léonel, E.; Paugam, J.
P.; Nédélec, J.-Y. Tetrahedron 2002, 58, 271. (d) Charette,
A. B.; Wilb, N. Synlett 2002, 176; and references cited
therein.
(5) (a) Corey, E. J.; Jautelat, M. J. Am. Chem. Soc. 1967, 89,
3913. (b) Corey, E. J.; Jautelat, M.; Oppolzer, W.
Tetrahedron Lett. 1967, 8, 2325. (c) Tang, C. S. F.;
Rapoport, H. J. Org. Chem. 1973, 38, 2806. (d) For a recent
asymmetric variant, see: Mamai, A.; Madalengoitia, J. S.
Tetrahedron Lett. 2000, 41, 9009.
(6) Johnson, C. R.; Janiga, E. R. J. Am. Chem. Soc. 1973, 95,
7692.
(7) (a) Devos, M. J.; Krief, A. Tetrahedron Lett. 1979, 20,
1515. (b) Krief, A.; Dubois, P. Tetrahedron Lett. 1993, 34,
2691.
O
O
(i-Pr)3S(O)BF4 5 (1.2 equiv)
Ph
Ph
Ph
Ph
NaH (1.2 equiv), DMF, r.t., 5 h
91% (trans only)
6
Scheme 2
The results illustrated in Table 1 indicate that cyclopropa-
nation of a wide range of a,b-unsaturated ketones pro-
ceeds readily in 33–93% yield.19,20 The results
demonstrate a tolerance for both cyclic and acyclic sub-
strates; high yields being obtained in both series. Even in
the cases where moderate yields were obtained, there was
no evidence for any of the epoxide (1,2-addition prod-
ucts). Moreover, in all examples studied, only a single
diastereomer of product, the trans-cyclopropane, was ob-
tained. Most notably, (2E,4E)-1,5-diphenylpenta-2,4-
dien-1-one (entry 3) afforded only the 1,4-mono-addition
product 8 in 85% yield. Electron-poor and electron-rich
a,b-unsaturated ketones both seem to participate reason-
ably well as evidenced by the successful use of both (E)-
1,4-diphenylbut-2-ene-1,4-dione (entry 7) and chromone
(entry 9). Even a terminal vinyl group could be success-
fully cyclopropanated (entry 4). The reaction appears to
tolerate heterocyclic functionality (entry 2) and the use of
(E)-2-nitrostyrene illustrates the use of electron-with-
drawing groups other than carbonyls. In contrast to the use
(8) Ono, N.; Yanai, T.; Hamamoto, I.; Kamimura, A.; Kaji, A.
J. Org. Chem. 1985, 50, 2806.
Synlett 2008, No. 4, 521–524 © Thieme Stuttgart · New York

LETTER
Improved gem-Dimethylcyclopropanation Procedure
523
Table 1 Cyclopropanation Using Triisopropylsulfoxonium Tetrafluoroborate 5 and NaH in DMFa
Entry
1
Substrate
Product
Time (h) Yield (%)b
O
O
5
2
91
71
6
O
O
2
O
N
O
N
7
O
O
3
4
5
6
4
85
53
53
33
8
9
O
O
24
1.5
2
O
O
10
O
O
11
12
O
O
O
O
7
8
23
68
92
O
O
3
O
O
O
O
13
14
15
9
3
95
93
O
O
NO2
NO2
10
17
a Using 1.2 equiv i-Pr3S(O)BF4 in DMF at r.t.
b Isolated yield of chromatographically homogeneous material; >95% trans-isomers by 1H NMR spectroscopy.
Synlett 2008, No. 4, 521–524 © Thieme Stuttgart · New York

524
M. G. Edwards et al.
LETTER
(9) Taylor, R. J. K.; Reid, M.; Foot, J. S.; Raw, S. A. Acc. Chem.
Res. 2005, 38, 851.
water present (60 °C) and the grey solid residue suspended
in acetone (400 mL). The reaction mixture was stirred for a
further 10 min and filtered to remove the residual inorganic
solids. Concentration of the filtrate under reduced pressure
afforded a yellow-orange powder that was recrystallised
from MeOH–Et2O. The crude solid was dissolved in 10 mL
of boiling MeOH and Et2O added until the solution remained
turbid. The mixture was then re-heated until homogeneous
and allowed to cool, to afford the title compound as
(10) (a) Oswald, M. F.; Raw, S. A.; Taylor, R. J. K. Org. Lett.
2004, 6, 3997. (b) Oswald, M. F.; Raw, S. A.; Taylor, R. J.
K. Chem. Commun. 2005, 2253. (c) McAllister, G. D.;
Oswald, M. F.; Paxton, R. J.; Raw, S. A.; Taylor, R. J. K.
Tetrahedron 2006, 62, 6681.
(11) Paxton, R. J.; Taylor, R. J. K. Synlett 2007, 633.
(12) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962,
84, 867. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc.
1962, 84, 3782. (c) Corey, E. J.; Chaykovsky, M. J. Am.
Chem. Soc. 1965, 87, 1353. (d) Yanovskaya, L. A.;
Dombrovsky, V. A.; Chizhov, O. S.; Zolotarev, B. M.;
Subbotin, O. A.; Kucherov, V. F. Tetrahedron 1972, 28,
1565.
colourless plates (5.06 g, 76%); mp 108–109 °C. IR
(acetone): nmax = 3427, 1699, 1642, 1462, 1369, 1235, 1198,
1049 cm–1. 1H NMR (400 MHz, acetone-d6): d = 1.79 (d,
J = 7.0 Hz, 18 H, CH3), 4.73 (sept, J = 7.0 Hz, 3 H, CH). 13
C
F
NMR (100 MHz, acetone-d6): d = 15.7 (CH3), 53.0 (CH). 19
NMR (254 MHz, acetone-d6): d = –151.6. 11B NMR (87
(13) See, for example: (a) Major, R. T.; Hess, H.-J. J. Org. Chem.
1958, 23, 1563. (b) Kobayashi, M.; Kamiyama, K.; Minato,
H.; Oishi, Y.; Takada, Y.; Hattori, Y. Bull Chem. Soc. Jpn.
1972, 45, 3703.
(14) Badet, B.; Julia, M. Tetrahedron Lett. 1979, 20, 1101.
(15) (a) Mori, M.; Takeuchi, H.; Minato, H.; Kobayashi, M.;
Yoshida, M.; Matsuyama, H.; Kamigata, N. Phosphorus,
Sulfur Silicon Relat. Elem. 1990, 47, 157. (b) There is also a
more recent report on the use of RuO2/NaIO4 for the
oxidation of trimethylsulfonium salts: Forrester, J.; Jones, R.
V. H.; Preston, P. N.; Simpson, E. S. C. J. Chem. Soc.,
Perkin Trans. 1 1995, 2289.
(16) Martín, V. S.; Palazón, J. M.; Rodríguez, C. M.; Nevill, C.
R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L., Ed.; John Wiley: New York, 2004.
(17) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936.
MHz, acetone-d6): d = –1.9. ESI-MS: m/z (%) = 177 (100)
[M+]. HRMS–FAB: m/z calcd for C9H21OS: 177.1308 (0.4
ppm error); found: 177.1308 [M+]. Anal. Calcd for
C9H21BF4OS: C, 40.93; H, 8.01. Found: C, 40.76; H, 7.85.
(19) All known products were characterised by NMR
spectroscopy and comparison of key data with those
published; novel products were fully characterised.
(20) Representative Procedure for Cyclopropanation of a,b-
Unsaturated Carbonyl Compounds (Table 1, Entry 1)
A 25 mL round-bottomed flask with stirrer bar was charged
with NaH (60% dispersion in mineral oil, 23 mg, 0.57 mmol,
1.2 equiv), sealed with a rubber septum and purged with
argon. The flask was maintained under argon and anhyd
DMF (4 mL) was added. The vigorously stirred suspension
was cooled to 0 °C, the septum briefly removed and
triisopropylsulfoxonium tetrafluoroborate (152 mg, 0.57
mmol, 1.2 equiv) added in a single portion. The mixture was
stirred for 5 min before the addition of a solution of (E)-
chalcone (100 mg, 0.48 mmol) in DMF (1 mL) dropwise by
cannula. The cooling bath was removed and the brown-
coloured solution allowed to stir at r.t. until the reaction was
deemed to be complete by TLC (5 h). The reaction was
quenched by the addition of sat. aq NH4Cl (5 mL), diluted
with H2O (20 mL) and extracted with Et2O (3 × 15 mL). The
combined organic extracts were dried (Na2SO4) and the
solvent removed in vacuo. The residue was purified by
column chromatography (PE–Et2O, 19:1 ) to afford trans-
(2,2-dimethyl-3-phenylcyclopropyl)-phenylmethanone (6)
as a cream-coloured solid (109 mg, 91%); mp 63–64 °C.
Rf = 0.29 (PE–Et2O, 19:1). 1H NMR (400 MHz, CDCl3):
d = 1.12 (s, 3 H, CH3), 1.27 (s, 3 H, CH3), 2.91 (d, J = 6.0
Hz, 1 H, CH), 3.12 (d, J = 6.0 Hz, 1 H, CH), 7.20–7.24 (m,
3 H, ArH), 7.28–7.32 (m, 2 H, ArH), 7.49–7.53 (m, 2 H,
ArH), 7.57–7.61 (m, 1 H, ArH),7.99–8.02 (m, 2 H, ArH).
Data consistent with those reported in the literature.6
(18) Preparation of Triisopropylsulfoxonium
Tetrafluoroborate
A 250 mL round-bottomed flask with stirrer bar was charged
with triisopropylsulfonium tetrafluoroborate14 (6.20 g, 25.0
mmol, 1.0 equiv), and then MeCN (36 mL), CCl4 (36 mL),
and H2O (54 mL) were added via syringe. The resulting
biphasic solution was stirred vigorously and ruthenium(III)
chloride (2.07 g, 10.0 mmol, 0.40 equiv) added in a single
portion. The mixture was stirred for 10 min and then NaIO4
(40.10 g, 187.5 mmol, 7.5 equiv) was added in 5 portions
over ca. 5 min to the brown-coloured solution. The flask was
loosely stoppered with a cork and the mixture vigorously
stirred overnight at r.t. (14 h). The resulting grey-brown
heterogeneous suspension was filtered through a Celite® pad
(3 cm × 70 mm Ø) and washed with H2O (400 mL). The
yellow filtrate was stirred vigorously and MeOH (50 mL)
added to quench the residual RuO4. The green suspension
was concentrated under reduced pressure to remove the
Synlett 2008, No. 4, 521–524 © Thieme Stuttgart · New York

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