Efficient catalytic Corey-Chaykovsky reactions involving ketone substrates

Article abstract of DOI:10.1002/adsc.201000255

It has been demonstrated for the first time that a sulfide catalyst, utilised at 20 mol% loading, can promote methylene transfer to ketones in the presence of methyl triflate and an organic base. This metal-free methodology is of broad scope-both aliphatic and aromatic ketones (including trifluoromethyl ketones) can be converted to synthetically useful terminal epoxides in excellent yields at room temperature.

Full text of DOI:10.1002/adsc.201000255

UPDATES
DOI: 10.1002/adsc.201000255
Efficient Catalytic Corey–Chaykovsky Reactions Involving
Ketone Substrates
Sarah A. Kavanagh,a Alessandro Piccinini,a and Stephen J. Connona,*
a
Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
Fax : (+353)-167-12826; telephone: (+353)-1-60-81306; e-mail: connons@tcd.ie
Received: April 1, 2010; Revised: July 7, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000255.
Abstract: It has been demonstrated for the first
time that a sulfide catalyst, utilised at 20 mol%
loading, can promote methylene transfer to ketones
in the presence of methyl triflate and an organic
base. This metal-free methodology is of broad
scope – both aliphatic and aromatic ketones (in-
cluding trifluoromethyl ketones) can be converted
to synthetically useful terminal epoxides in excel-
lent yields at room temperature.
chiometric sulfide loadings.[5] For instance, Aggar-
walꢀs[5d] and Goodmanꢀs[5e] benchmark literature pro-
tocols for the asymmetric sulfonium ylide mediated
methylene transfer to benzaldehyde (1) involve the
use of 100–200 mol% of chiral sulfides 3–4 and pro-
duce 2 in ca. 50–60% yield and up to 57% ee
(Scheme 1, A). It is also noteworthy that these proto-
cols involved the use of a modified version of the
classical CC reaction involving a metal-mediated Sim-
mons–Smith type carbenoid transfer.[5e,6]
We recently reported an operationally simple cata-
lytic procedure for metal-free methylene transfer to
Keywords: Corey–Chaykovsky reaction; epoxides;
methylene transfer; organocatalysis; sulfides
Epoxides are among the most valuable synthetic
building blocks available to an organic chemist.
Hence, the synthesis of these spring-loaded electro-
philes in enantiomerically pure form is of great inter-
est.[1] Although there are many distinguished proto-
cols for the synthesis of optically active substituted/
functionalised epoxides,[2] there is a dearth of methods
for the catalytic synthesis of the corresponding un-
functionalised terminal epoxides.
The Corey–Chaykovsky (CC) reaction[3] is a time-
honoured and efficient methodology for the synthesis
of these compounds. Initially this reaction involved
the use of stoichiometric loadings of preformed sul-
f(ox)onium salts (in the presence of base) as the
alkyl-transfer agent, which is naturally undesirable
from an atom-economy perspective.
In a landmark series of studies, Furukawa,[4a] Ag-
garwal[4b–d,g–i,l,n] and others[4e,f,j,k,m] demonstrated that
the (asymmetric) addition of semi-stabilised ylides to
carbonyl compounds is possible using catalytic sulfide
loadings. However, the corresponding asymmetric
methylene transfer (i.e., via a chiral non-stabilised
ylide) has been characterised by moderate yields/
Scheme 1. Protocols for chiral sulfide mediated terminal ep-
enantioselectivities and a requirement for (super)stoi- oxidation.
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Sarah A. Kavanagh et al.
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simple ketones relative to their aldehyde counter-
parts. Initial experimentation in this regard was not
encouraging, for example, we previously reported the
results of a study concerning the influence of hydro-
gen-bond donating catalysts on the CC reaction in a
biphasic solvent system:[10] benzaldehyde (1) could be
converted to 2 in excellent yield in the presence of
catalyst 11, trimethylsulfonium iodide and base. For
the purposes of the current study this reaction was re-
peated using acetophenone (9) as the substrate. The
difference in reaction rate was striking: no conversion
to 10 was observed, even with elevated catalyst load-
ings of 10 mol% (Scheme 3).
While it was thus obvious that ketones represent a
challenge from an electrophilicity standpoint,[7] the
key question now was whether or not ketones would
be unreactive enough towards ylide 8 under our opti-
ꢀ
mised conditions (Scheme 1) to render C C bond for-
mation (as opposed to sulfide alkylation) the rate-de-
termining step. If this were the case, it would be un-
likely that a practical catalytic procedure would be
possible. However, we envisaged that the homogene-
ous nature of the catalytic methodology (Scheme 1),
which involves the rapid and clean formation of 8 in
Scheme 2. The CC reaction: catalytic cycle.
aldehydes under classical CC conditions using (for the the same phase as the ketone electrophile (thus the
first time) low loadings (20 mol%) of a sulfide cata- concentration of both could be carefully controlled),
lyst 6, which allows the synthesis of 2 in high yield could (at least partially) compensate for the inherent
(Scheme 1, B).[7]
lack of electrophilicity associated with ketone sub-
The key realisation which led to the development strates. To test this hypothesis we applied our catalytic
of a catalytic protocol was that alkylation of the sul- protocol to the epoxidation of a variety of aromatic
fide (i.e., 6!7, Scheme 2) by alkyl electrophiles is ketones (Table 1).
rate-determining. Thus, turnover is facilitated by the
We were delighted to observe that under these con-
use of a powerful alkylating agent such as methyl tri- ditions acetophenone (9) underwent smooth reaction
flate, which leads to the formation of the sulfonium in the presence of catalyst 6 (20 mol%) to furnish ter-
salt 7 in a catalytically feasible time frame, which is minal epoxide 10 in high yield (entry 1). We were
cleanly deprotonated by a phosphazene base to form
ylide 8. Under these conditions 8 reacted rapidly with
aldehydes to furnish a range of epoxides in excellent
yields (Scheme 2).
On completion of this study we realised that for
this methodology to be considered genuinely useful it
must be compatible with ketone substrates. Although
there are numerous reported examples of methylene
transfer to ketones, all of these procedures require
(super)stoichiometric sulfide loadings.[8] For example,
Shibasaki reported a very efficient protocol for the
synthesis of enantioenriched terminal epoxides de-
rived from ketones. This procedure requires a super-
stoichiometric amount of an achiral sulfoxonium
ylide, the observed stereoinduction is derived from a
metal complex catalyst.[9] Given that a catalytic proto-
col for methylene transfer to aldehydes has only re-
cently been reported, the absence of a protocol for
the catalytic (in sulfide) methylene transfer to ketones
is perhaps unsurprising.
An obvious cause of concern in developing such a
process is the greatly reduced electrophilicity of ed epoxidation of 9.
Scheme 3. Urea-catalysed epoxidation of 2 and the attempt-
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Efficient Catalytic Corey–Chaykovsky Reactions Involving Ketone Substrates
Table 1. Catalytic epoxidation of aromatic ketones.
point: despite the relatively hindered nature of the
carbonyl moiety we observed complete conversion to
27 without any trace of the cyclopropanation adduct
being detected. It is also noteworthy that the method-
ology can be utilised in the epoxidation of trifluoro-
methyl ketone 20 (for the first time to the best of our
knowledge) Table 1, entry 9);[11] an interesting build-
ing block in the synthesis of biologically active com-
pounds.[12]
Aliphatic ketones were also susceptible to catalytic
epoxidation under these reaction conditions (Table 2).
Benzylacetone (29, entry 1) proved to be a good sub-
strate in this reaction, producing the corresponding
epoxide 35 in high yield. Cyclohexanone and 4-substi-
tuted cyclohexanone derivatives (30 and 31–32 re-
spectively, entries 2–4) furnished the corresponding
epoxide products 36–38 in excellent yield. Epoxides
derived from long chain aliphatic ethyl (33, entry 5)
and methyl (34, entry 6) ketones could also be pre-
Entry
1
Ketone
Product
X
Yield[a] [%]
85
100
2
3
100
115
89
94[b]
4
5
6
100
100
100
93
89
94
Table 2. Catalytic epoxidation of aliphatic ketones.
Entry
1
Ketone
Product
X
Yield[a] [%]
89
7
8
100
110
100
92
88
85
100
2
3
144
118
95
9
93[b]
[a]
Isolated yield.
[b]
1
Determined by H NMR spectroscopy using an internal
standard due to product decomposition during column
chromatography.
4
5
118
94
next interested in evaluating the performance of a
range of ketones of variable steric and electronic
characteristics in the catalytic CC reaction. The cata-
lytic procedure proved robust – epoxide products 21–
28 could be synthesised in excellent isolated yield
using catalytic sulfide loadings in each case. Electron-
rich substrates 13 and 14 (entries 2 and 3, respective-
ly), in addition to activated ketones 15–18 (entries 4–
7), afforded epoxide yields ranging between 89 and
93%.
136
118
83[c]
90
6
[a]
Isolated yield.
dr (O-ax:O-eq)=40:60.
Determined by H NMR spectroscopy using an internal
standard.
[b]
[c]
Chalcone[1d] (19) (Table 1, entry 8) represented an
interesting substrate from a chemoselectivity stand-
1
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Sarah A. Kavanagh et al.
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additions of methyl triflate and P2 base were repeated in
this fashion an additional four times at 25 min intervals. The
remaining methyl triflate (6.4 mL, 0.06 mmol) and P2 base
(2.0M in THF, 28 mL, 0.06 mmol) were then added. After
pared without difficulty. Undesired aldol-derived side
products were not detected in any of these reactions.
In summary, it has been shown, for the first time,
that ketones can be converted to terminal epoxides
via a CC reaction involving methylene transfer in the
presence of substoichiometric loadings of a sulfide
catalyst. The method is of broad scope: a diverse
array of aromatic (including hindered, activated and
deactivated analogues) and aliphatic aldehydes are
amenable to epoxidation. Product yields are invaria-
bly high-excellent using a convenient, room tempera-
ture protocol. It should now be possible to develop
chiral sulfide catalysts capable of promoting efficient
asymmetric variants of this reaction. Studies along
these lines are underway in our laboratory.
1
25 min the reaction was analysed by H NMR spectroscopy.
After purification of the crude material by flash chromatog-
raphy (7:3 hexane/CH2Cl2) the product 35 was obtained as a
pale yellow liquid; yield: 81.9 mg (89%). 1H NMR
(400 MHz, CDCl3): d=7.30–7.26 (m, 2H), 7.21–7.18 (m,
3H), 2.76–2.68 (m, 2H), 2.61–2.58 (m, 2H), 1.97–1.80 (m,
2H), 1.38 (s, 3H); 13C NMR (100 MHz, CDCl3): d=141.6,
128.5, 128.3, 126.0, 56.7, 54.0, 38.6, 31.5, 21.1; HR-MS-CI:
m/z=163.1123 [M+H+], calcd. for C11H15O: 163.1123
Acknowledgements
This material is based upon work supported by Science
Foundation Ireland.
Experimental Section
Representative Procedure for the Catalytic
Methylene Transfer to 17 using Sulfide 6
References
A 5-mL round-bottomed flask containing a stirring bar was
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spectroscopy. After purification of the crude material by
flash chromatography (8:2 hexane/CH2Cl2) the product 25
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1H NMR (400 MHz, CDCl3): d=7.32 (s, 4H), 2.99 (d, 1H,
J=5.5 Hz), 2.77 (d, 1H, J=5.5 Hz), 1.72 (s, 3H);13C NMR
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Representative Procedure for the Catalytic
Methylene Transfer to 29 using Sulfide 6
A 5-mL round-bottomed flask containing a stirring bar was
charged with catalyst 6 (10 mL, 0.11 mmol), fitted with a
septum and flushed with argon. CH2Cl2 (1.80 mL, 0.32M)
was added via syringe followed by styrene (65 mL,
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added followed by 4-phenyl-2-butanone (29) (85 mL,
0.57 mmol). The first aliquot of methyl triflate (11.6 mL,
0.10 mmol) was added and the resulting solution was al-
lowed to stir at room temperature for 25 min. The first ali-
quot of P2 base was then added (2.0M in THF, 51 mL,
0.10 mmol) and allowed to stir for 25 min. The consecutive
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