Improved dimethylsulfoxonium methylide cyclopropanation procedures, including a tandem oxidation variant

Article abstract of DOI:10.1055/s-2007-967966

A new procedure for the cyclopropanation of α,β-unsaturated carbonyl compounds and related systems is described which employs trimethylsulfoxonium iodide and an organic base in acetonitile to generate dimethylsulfoxonium methylide in situ; in addition, pr

Full text of DOI:10.1055/s-2007-967966

LETTER
633
Improved Dimethylsulfoxonium Methylide Cyclopropanation Procedures,
Including a Tandem Oxidation Variant
I
mprove
d
D
imeth
i
ylsulfo
c
xoniumM
h
a
lopropanati
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on Proce
d
dure
s
J. Paxton, Richard J. K. Taylor*
University of York, Department of Chemistry, Heslington, York, YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
Received 8 November 2006
OH
CO2Et
Me2S
CO2Et
R3
Abstract: A new procedure for the cyclopropanation of a,b-unsat-
O
5
urated carbonyl compounds and related systems is described which
employs trimethylsulfoxonium iodide and an organic base in aceto-
nitile to generate dimethylsulfoxonium methylide in situ; in addi-
tion, preliminary results are described in which activated alcohols
are converted directly into cyclopropyl ketones by a one-pot tandem
oxidation–cyclopropanation sequence.
R1
R3
R1
MnO2, CH2Cl2
4 Å MS
R2
R2
60–100%
Scheme 2
Key words: cyclopropanes, cyclopropanations, tandem oxidation
procedures, one-pot procedures
In order to complement the above methodology, we
wished to explore the use of non-functionalised sulfur
ylides to effect methylene transfer. However, in planning
this aspect of the investigation, we realised the limitations
of the original conditions described by Corey and
Chaykovsky. The use of dimsyl sodium in DMSO at
50 °C is fairly stringent, and although a phase-transfer
variant has been developed, this also requires prolonged
heating in strong base (CH2Cl2, TBAI, 50% aq NaOH,
50 °C, 20 h).4c
Dimethylsulfoxonium methylide (1) has been a mainstay
of organic synthesis as a methylene-transfer reagent
since its development by Corey and Chaykovsky in the
1960s.1–4 The standard method for the preparation of this
sulfurane reagent involves treatment of the commercially
available trimethylsulfoxonium chloride or iodide (2a,b)
with sodium hydride in DMSO,1 although other solvents
(e.g. DMF, THF, dioxane) and bases (e.g. BuLi, t-BuOK)
have been employed.2,4 Dimethylsulfoxonium methylide
(1) has proved particularly valuable for the cyclopropana-
tion of a,b-unsaturated carbonyl compounds and related
systems via a conjugate addition–elimination process; in
the example shown (Scheme 1), chalcone 3a is converted
into 1-benzoyl-2-phenylcyclopropane (4a) in almost
quantitative yield by the use of sulfurane 1.1c
We therefore decided to first investigate simplified proce-
dures for carrying out the cyclopropanation of a,b-unsat-
urated carbonyl compounds and related systems. Initial
studies were carried out using chalcone and trimethyl-
sulfoxonium iodide (2b, Scheme 3). A range of organic
bases were explored to generate the dimethylsulfoxonium
methylide (1) in situ and whilst some were totally ineffec-
tive (DABCO and Et3N, no reaction in MeCN at 60 °C
after 20 h), under the same conditions others gave good to
excellent yields of cyclopropane 4a (DBU, 2.5 h, 75%;
tetramethylguanidine, 19 h, 57%).
Me3S O Cl
2a
NaH
DMSO
O
O
Me3S O I
2b
O
Ph
Ph
Ph
Ph
Me2S
O
1
O
MeCN, 60 °C
3a
4a
6
Ph
Ph
Ph
Ph
DMSO, 50 °C, 1 h
95%
2 equiv MTBD, 2.5 h, 86%
1.3 equiv MTBD, 3 h, 76%
3a
4a
N
Scheme 1
N
N
1.0 equiv MTBD, 3 h, 65%
(+ unreacted 3a)
Me
Recently, we have become interested in the preparation of
functionalised cyclopropanes and have developed a tan-
dem procedure for the one-pot oxidation–cyclopropana-
tion of allylic alcohols using MnO2 in conjunction with
stabilised sulfuranes such as (carbethoxymethylene)di-
methylsulfurane (5) (Scheme 2).5,6
6
0.5 equiv MTBD,
no reaction after 3 h
Scheme 3
However, the best yields were obtained using the com-
mercially available guanidine base 1,3,4,6,7,8-hexa-
hydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine (MTBD,
6)7,8 which produced the cyclopropanated product 4a in
86% yield on treatment in MeCN at 60 °C for 2.5 hours
SYNLETT 2007, No. 4, pp 0633–0637
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967966; Art ID: D33306ST
© Georg Thieme Verlag Stuttgart · New York

634
R. J. Paxton, R. J. K. Taylor
LETTER
{hexahydro 2H-pyrimido[1,2-a]pyrimidine (TBD) gave ing by way of chalcone and heterocyclic analogues proved
72% after 2.5 h; polymer-supported TBD gave no reaction to be the best substrates. Thus, a range of 1,3-diaryl allylic
after 24 h}. In terms of solvent, the use of MeCN seemed alcohols underwent one-pot oxidation–cyclopropanation
optimal but others were also successful (DMF, 1.5 h, in good to excellent yields (66–86%, entries 1–6). In
60 °C, 78%; acetone, 24 h, reflux, 69%; CH2Cl2, reflux, addition, four other allylic alcohols also gave the corre-
23 h, 72%). The use of 2 equivalents of MTBD gave the sponding cyclopropyl ketones, albeit in variable yields
highest yields but a lower amount could be employed if (entries 7–10). It is noteworthy that in three cases (entries
longer reaction times were acceptable (Scheme 3). The 1, 4 and 8) the oxidation–cyclopropanation yield com-
Corey and Chaykovsky1c and the PTC procedure4c were mencing from the alcohol was the same or marginally
both reported to give cyclopropane 4a as a cis/trans mix- higher than the corresponding yield of cyclopropanated
ture, and so it is noteworthy that the reactions in Scheme 3 product obtained when commencing directly from the
1
gave only the trans-cyclopropane 4a according to H ketone. Thus, not only will oxidation–cyclopropanation
NMR spectroscopy.
processes be particularly beneficial in cases where the
allylic alcohol, but not the a,b-unsaturated ketone, is com-
mercially available, or when the intermediate carbonyl in-
termediate is ‘difficult’, e.g. volatile, toxic or noxious,
these one-pot process may even be more efficient when
starting from the allylic alcohol.
With the success of the preliminary study shown in
Scheme 3, we went on to explore the scope and limita-
tions of this new cyclopropanation procedure. The results
are collected in Table 1.9,10 As can be seen, chalcone and
a range of heterocyclic analogues underwent efficient
cyclopropanation (entries 1–6). In addition, several other In summary, a new one-pot procedure has been developed
a,b-unsaturated ketones gave the corresponding cyclo- for the cyclopropanation of a,b-unsaturated carbonyl
propanes, albeit in variable yields (entries 7–10), although compounds and related systems which employs trimethyl-
cyclohexenone (entry 11), and substituted derivatives, sulfoxonium iodide (2b) and MTBD (6) to generate di-
could not be cyclopropanated using this procedure. The methylsulfoxonium methylide (1) in situ. In addition,
cyclopropanation of an a,b-unsaturated sulfone was preliminary examples are described in which activated al-
accomplished successfully, however (entry 12).4a
cohols are converted directly into cyclopropyl ketones by
a one-pot tandem oxidation–cyclopropanation sequence.
We are currently optimising and extending this one-pot
cyclopropanation methodology and exploring applica-
tions in target molecule synthesis.
Having developed a successful method for the in situ
generation of dimethylsulfoxonium methylide (1) we
went on to explore the viability of a manganese dioxide
mediated tandem-oxidation process (TOP) in which an
allylic alcohol is oxidised and the intermediate a,b-unsat-
urated carbonyl compound is cyclopropanated in situ. The
preliminary study, summarised in Scheme 4, revealed that
simply by treatment of alcohol 7a with manganese di-
oxide in the presence of trimethylsulfoxonium iodide (2b)
and MTBD (6) in MeCN at 60 °C for 2.5 hours gave an
86% yield of cyclopropyl ketone 4a. This TOP sequence
is advantageous in that it telescopes three processes into a
one-pot operation (alcohol oxidation, sulfurane genera-
tion and cyclopropanation); it is also operationally
straightforward as the work-up consists simply of removal
of MnO2 and other solid by-products by a simple filtration
followed by removal of solvent and chromatography.
Acknowledgment
We are grateful to the EPSRC for support (DTA studentship,
R.J.P.).
References and Notes
(1) (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.
(2) For reviews, see: (a) Trost, B. M.; Melvin, A. S. Sulfur
Ylides: Emerging Synthetic Intermediates; Academic Press:
New York, 1975. (b) Gololobov, Y. G.; Nesmeyanov, A. N.;
Lysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43,
2609. (c) Okazaki, R.; Tokitoh, N. In Encyclopedia of
Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley:
New York, 1995, 2139–2141.
(3) For recent examples, see: (a) Peng, Y.; Yang, J.-H.; Li,
W.-D. Z. Tetrahedron 2006, 62, 1209. (b) Midura, W. H.;
Krysiak, J. A.; Cypryk, M.; Mikolajczyk, M.; Wieczorek, M.
W.; Filipczak, A. D. Eur. J. Org. Chem. 2005, 653.
(c) Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F.; Spiga,
M. Org. Lett. 2005, 7, 4565. (d) Demir, A. S.; Sesenoglu,
O.; Ülkü, D.; Arici, C. Helv. Chim. Acta 2004, 87, 106.
(4) (a) Truce, W. E.; Badiger, V. V. J. Org. Chem. 1964, 29,
3277. (b) Yanovskaya, L. A.; Dombrovsky, V. A.; Chizhov,
O. S.; Zolotarev, B. M.; Subbotin, O. A.; Kucherov, V. F.
Tetrahedron 1972, 28, 1565. (c) Merz, A.; Märkl, G.
Angew. Chem., Int. Ed. Engl. 1973, 12, 845.
MnO2
OH
O
Me3S O I
2b
Ph
Ph
Ph
Ph
6
4a
7a
MeCN, 60 °C, 3.5 h
86% (trans only)
Scheme 4
Having established that the cyclopropanation conditions
are compatible with manganese dioxide, we went on to
explore the scope of the procedure with respect to the
allylic alcohol (Table 2).11 As before, reactions proceed-
Synlett 2007, No. 4, 633–637 © Thieme Stuttgart · New York

LETTER
Improved Dimethylsulfoxonium Methylide Cyclopropanation Procedures
635
Table 1 Cyclopropanation Using Trimethylsulfoxonium Iodide (2b) and MTBD (6) in MeCNa
Entry
1
Substrate
Product
Conditions
Time (h)
2.5
Yield (%)b
O
O
2.0 equiv MTBD
8610
4a
4b
O
O
2
2.0 equiv MTBD
1.5
76
N
N
O
O
O
O
O
O
S
O
S
3
4
2.0 equiv MTBD
2.0 equiv MTBD
2
2
81
75
O
5
6
7
2.0 equiv MTBD
2.0 equiv MTBD
1.3 equiv MTBD
2
2
3
76
83
73
O
O
N
O
O
N
O
O
O
O
O
O
O
O
8
9
1.3 equiv MTBD
1.3 equiv MTBD
1.3 equiv MTBD
2.5
3
23
O
O
25
CO2Me
CO2Me
O
O
O
10
4.5
33c
–
d
11
12
1.2 equiv MTBDd
1.3 equiv MTBD
24
27
–
O2
S
O2
S
72
a Using 1.2 equiv Me3SOI in MeCN at 60 °C unless otherwise stated.
b Isolated yield; >95% trans-isomers by 1H NMR spectroscopy.
c Yield estimated from 1H NMR spectrum as product and SM are inseparable.
d At r.t.; also tried at higher temperatures and in DMF as solvent but without success; no cyclopropanation observed under any conditions.
Synlett 2007, No. 4, 633–637 © Thieme Stuttgart · New York

636
R. J. Paxton, R. J. K. Taylor
LETTER
Table 2 Tandem Oxidation–Cyclopropanation Using MnO2, Trimethylsulfoxonium Iodide (2b) and MTBD (6) in MeCNa
Entry
1
Substrate
Product
Conditions
Time (h)
3.5
Yield (%)b
O
O
OH
2.0 equiv MTBD
86
4a
4b
OH
2
2.0 equiv MTBD
2
6911,12
N
N
OH
OH
OH
O
O
O
S
O
S
3
4
2.0 equiv MTBD
2.0 equiv MTBD
1.5
2
76
77
O
5
6
7
2.0 equiv MTBD
2.0 equiv MTBD
1.3 equiv MTBD
2
2
3
66
71
39
O
O
N
O
O
N
OH
OH
O
O
O
O
O
OH
8
1.3 equiv MTBD
2.5
36
OH
O
CO2Me
9
1.3 equiv MTBD
1.3 equiv MTBD
3
3
23
CO2Me
OH
O
10
28c
a All with 10 equiv MnO2, 1.2 equiv Me3SOI in MeCN at 60 °C.
b Isolated yield; >95% trans-isomers by NMR spectroscopy.
c Yields estimated from 1H NMR spectrum as product and ketone intermediate are inseparable.
(5) (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.
(6) For a recent review of tandem oxidation processes, see:
Taylor, R. J. K.; Reid, M.; Foot, J. S.; Raw, S. A. Acc. Chem.
Res. 2005, 38, 851.
(7) Simoni, D.; Rossi, M.; Rondanin, R.; Mazzali, A.;
Baruchello, R.; Malagutti, C.; Roberti, M.; Invidiata, F. P.
Org. Lett. 2000, 2, 3765.
(8) Blackburn, L.; Pei, C.; Taylor, R. J. K. Synlett 2002, 215.
(9) All known products were characterised by NMR
spectroscopy and comparison of key data with those
published; novel products were fully characterised.
Synlett 2007, No. 4, 633–637 © Thieme Stuttgart · New York

LETTER
Improved Dimethylsulfoxonium Methylide Cyclopropanation Procedures
637
(10) Representative Procedure for Cyclopropanation of
a,b-Unsaturated Carbonyl Compounds.
was heated at 60 °C under nitrogen for 2 h. After this time
the reaction mixture was filtered through Celite® and the
residue washed with Et2O. The solvent was removed in
vacuo and the residue was purified by silica column
To a stirred solution of trimethylsulfoxonium iodide (2b,
0.13 g, 0.6 mmol) and MTBD (6, 0.15 g, 1.0 mmol) in
MeCN (4 mL) was added (E)-1,3-chalcone 3a (0.10 g, 0.5
mmol) in MeCN (1 mL). The reaction mixture was heated at
60 °C under nitrogen for 2.5 h. After this time the solvent
was removed in vacuo and the residue purified by silica
column chromatography (PE–EtOAc, 9:1) to afford
cyclopropane 4a (0.095 g, 86%) as a white solid; Rf = 0.38
(PE–EtOAc, 3:1); mp 43–44 °C (lit.13 42.0–43.5 °C), with
spectroscopic data consistent with those reported.14
(11) (E)-1-Phenyl-3-pyridin-2-ylprop-2-en-1-ol was prepared by
NaBH4/CeCl3 reduction of (E)-1-phenyl-3-(pyridin-2-
yl)propenone, see: Bakó, T.; Bakó, P.; Keglevich, G.;
Báthori, N.; Czugler, M.; Tatai, J.; Novák, T.; Parlagh, G.;
Töke, L. Tetrahedron: Asymmetry 2003, 14, 1917.
(12) Representative Procedure for Tandem Oxidation–
Cyclopropanation.
chromatography (PE–EtOAc, 6:1) to afford cyclopropane
4b as a clear oil (0.078 g, 69%); Rf = 0.23 (PE–EtOAc, 3:1).
IR (neat): nmax = 1667, 1504, 1568, 1474 1339, 1222 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.78–1.85 (2 H, m, CHH
and CHH overlapping), 2.73–2.78 (1 H, ddd, J = 4.0, 6.0,
10.0 Hz, CH), 3.29–3.32 (1 H, ddd, J = 4.0, 5.5, 9.0 Hz, CH),
7.93 (1 H, ddd, 1.0, 5.0, 12.0 Hz, ArH), 7.26–7.29 (1 H, m,
ArH), 7.44–7.48 (2 H, m, ArH), 7.54–7.60 (2 H, m, ArH),
8.03–8.05 (2 H, m, ArH), 8.49–8.51 (1 H, m, ArH). 13
C
NMR (100 MHz, CDCl3): d = 19.8 (CH2), 28.4 (CH), 29.9
(CH), 121.4 (CH), 122.8 (CH), 128.3 (CH), 128.5 (CH),
133.0 (CH), 136.2 (CH), 137.7 (C) 149.6 (CH), 159.4 (C),
199.2 (CO). MS (CI): m/z (%) = 224 (100) [MH+], 206 (10),
118 (10), 105 (10). HRMS (CI): m/z calcd for C15H14NO:
224.1075 (2.1 ppm error); found: 224.107078 [MH+].
(13) Yanovskaya, L. A.; Dombrovsky, V. A.; Chizhov, O. S.;
Zolotarev, B. M.; Subbotin, O. A.; Kucherov, V. F.
Tetrahedron 1972, 28, 1565.
To a stirred solution of trimethylsulfoxonium iodide (0.13 g,
0.6 mmol) activated MnO2 (Aldrich 21764-6, 0.44 g, 5.0
mmol) and MTBD (6, 0.15 g, 1.0 mmol) in MeCN (4 mL)
was added (E)-1-phenyl-3-(pyridin-2-yl)prop-2-en-1-ol
(0.10 g, 0.50 mmol) in MeCN (1 mL). The reaction mixture
(14) Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 9159.
Synlett 2007, No. 4, 633–637 © Thieme Stuttgart · New York