Highly efficient methods for the one-pot synthesis of β-substituted enones

Article abstract of DOI:10.1039/b512177a

A new mild and practically convenient one-pot procedure for the direct β-substitution of enones, developed using a conjugate addition-oxidation strategy with a full range of copper based reagents and N-tert- butylphenylsulfinimidoyl chloride, was analyzed. To start the investigation reaction of a simple Gilman cuprate, lithium di-n-butylcuprate, with cyclohex-2-enone was performed. The desired one-pot transformation was found to be achievable, albeit in a low 39% yield. The application of a series of individual organocuprate reagents was also investigated. It was observed that the technique provided good to excellent yields of β-substituted enones from all of the unsaturated starting materials employed.

Full text of DOI:10.1039/b512177a

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Highly efficient methods for the one-pot synthesis of b-substituted enones
William J. Kerr,* Colin M. Pearson and Graeme J. Thurston
Received 30th August 2005, Accepted 3rd November 2005
First published as an Advance Article on the web 25th November 2005
DOI: 10.1039/b512177a
A mild and practically-convenient one-pot procedure for the
direct b-substitution of enones has been developed using a
conjugate addition–oxidation strategy with a full range of
copper-based reagents and N-tert-butylphenylsulfinimidoyl
chloride; alkyl- and aryl-substituted enones are delivered in
good to excellent yields.
b-Functionalised enones are of elevated importance in organic
chemistry and have wide preparative utility in transformations
such as Michael addition processes and Diels–Alder reactions.
Having stated this, synthetic methods for the production of
this moiety are somewhat limited. Although effective preparative
Scheme 1
strategies exist, in general, most techniques involve multistage
processes, harsh reaction conditions, or the use of expensive
that, following conjugate addition of an organocuprate to an
a,b-unsaturated enone, N-tert-butylphenylsulfinimidoyl chloride
(1) could be applied as an electrophilic quench to generate b-
substituted enones directly from unsubstituted enones in a one-
pot, two-step procedure. Accordingly, this strategy was embarked
upon. However, following completion of our studies and during
the preparation of our manuscript for publication, Matsuo and
Aizawa divulged their findings using a very similar approach.10
Based on this, we now communicate the preparative outcomes
from our endeavours in this area, whilst highlighting the differ-
ences and potentially wider practical utility of our techniques over
the recently published procedures.
Based on the utility and synthetic complementarity of the range
of known organocuprate reagents and protocols,11 we felt that any
procedure that was developed as part of this programme should be
compatible with as wide a spectrum of the available copper-based
methods as possible. Nonetheless, to initiate our studies in this
area, we investigated the reaction of a simple Gilman cuprate,12
lithium di-n-butylcuprate, with cyclohex-2-enone, followed by
application of 1 as the electrophilic quench. As shown in Table 1,
Entry 1, using 2.5 equivalents of N-tert-butylphenylsulfinimidoyl
chloride (1), the desired one-pot transformation was found to
be achievable, albeit in a rather low 39% yield. In order to
optimise the efficiency of this process, the number of equivalents
of 1 was progressively increased. Gratifyingly, an improved yield
was obtained following each increase in the quantity of the
sulfinimidoyl chloride employed. Indeed, using 5 equivalents of
1 produced a good yield of 82% of the desired b-substituted enone
product (Table 1, Entry 4). Importantly, at this stage, we felt that
to enhance the reactivity of the intermediate enolate ion, formed
following conjugate addition, tuning of the polarity of the reaction
medium could be beneficial. Accordingly, the oxidant 1 was added
in the more polar THF. When this practical amendment was made,
the two-step, one-pot addition–oxidative quench was achieved in
an excellent and near quantitative 98% yield (Table 1, Entry 5).
Consequently, following this brief programme of optimisation, by
transition metals. In this regard, perhaps the most widely used
method for the formation of b-substituted enones is based on the
conjugate addition of an alkyl or aryl cuprate to an enone, followed
by the introduction of a selenyl species to provide an a-arylselenyl
ketone, which can then be oxidised and eliminated.1 Despite the
efficacy of this strategy, the toxicity and two-step nature of the
process somewhat detract from its synthetic utility. The analogous
technique with a substituted sulfide2 also has severe limitations
with regard to functional group compatibility, given the relatively
harsh reaction conditions required for the oxidation/elimination.
Another applicable method for enone functionalisation is the use
of b-halo enones which, following 1,4-addition, readily eliminate
to generate the substituted enone product.3 Although valuable, the
difficulty in accessing b-halo enones and the formation of disub-
stituted by-products, limit the utility of this methodology severely.
More recently, Nicolaou4 and co-workers have reported on the
use of IBX to generate b-substituted enones in an efficient manner,
from b-substituted trimethylsilyl enol ethers, themselves generated
by conjugate addition to enones. Although this methodology is
very mild and efficient, it again involves a multistep process.
In 2000, Mukaiyama and co-workers reported on the use of the
versatile reagent, N-tert-butylphenylsulfinimidoyl chloride (1),5
as an oxidant which mediated the oxidation (dehydrogenation)
of a series of organic compounds.6,7 In particular, this reagent
can be employed in the oxidation of alcohols, amines, and
hydroxylamines,7 and in the dehydrogenation of ketones to enones
under very mild, low temperature conditions.6b,8 In attempts to fur-
ther widen the applicability of this sulfinimidoyl species, and given
the commercial availability9 and relative ease of preparation of 1 on
a large scale,5b we believed that this reagent could be strategically
utilised in a novel fashion to directly access b-substituted enones.
More specifically and as illustrated in Scheme 1, we envisaged
WestCHEM, Department of Pure and Applied Chemistry, University of
Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK G1 1XL. E-
mail: w.kerr@strath.ac.uk; Fax: +44 141 548 4246; Tel: +44 141 548 2959
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Table 1 Optimisation of the one-pot b-substitution of cyclohex-2-enone
with a simple Gilman cuprate
Matsuo and Aizawa, who found that use of a simple Gilman
cuprate, followed by the addition of 1 in ether (cf . in THF within
our optimised system), only produced a low yield of the desired
substituted enone product from cyclohex-2-enone (Me2CuLi,
3 equiv. 1; 27% yield).10
Following these successful initial optimisation studies, the
generality and applicability of our developed method with alter-
native a,b-unsaturated substrates was investigated using a Gilman
cuprate.† As Table 2 illustrates, this technique provides good to
excellent yields of b-substituted enones from all of the unsaturated
starting materials employed. In this regard, enones of varied ring
size (5–7) were applied without difficulty. Furthermore, a six-
membered ring substrate with a sterically demanding t-butyl group
present in the 4-position also reacted very efficiently (Table 2,
Entry 4). In addition, this method is not restricted to cyclic
substrates, as can be seen from Entry 5, with a good 83% yield
being obtained from the acyclic substrate shown. Again, this shows
some advantages over the recently published protocols, where the
optimised conditions (with higher-order cuprates) delivered only
low to moderate yields of substituted acyclic enones.10
Entry
Solventa
1 (equiv.)
Yield (%)b
1
2
3
4
5
Et2O
Et2O
Et2O
Et2O
THF
2.5
3.2
4.4
5.0
5.0
39
59
67
82
98
a Solvent used for the addition of 1. b Isolated yield.
employing readily prepared and handled simple cuprate reagents,
followed by sulfinimidoyl chloride (1), a practically-convenient
protocol had been established for the direct preparation of b-
substituted enones from the equivalent unsubstituted starting
materials. Importantly, this outcome contrasts with the work of
Having demonstrated the use of various a,b-unsaturated sub-
strates, our attention turned to the delivery of alternative suitable
lithium dialkylcuprates. Gratifyingly, the introduction of alterna-
tive alkyl groups was readily achieved, again in excellent yields.
As illustrated in Table 3, delivery of methyl and n-octyl groups
provided the product enones in 86 and 80% yield, respectively, with
Table 2 One-pot b-substitution of a range of enones with a simple
Gilman cuprate
Table 3 One-pot b-substitution of cyclohex-2-enone with alkyl and
aryl units of simple Gilman cuprates
Entry
1
Substrate
Product
Yield (%)a
98
Entry
1
Product
Yield (%)a
98
2
80
2
3
4
86
80
84
3
4
95
90
5b
83c
a Isolated yield. b Initial reaction performed at −20 ◦C. c Z : E 87 : 1313
4 8 | Org. Biomol. Chem., 2006, 4, 47–50
a Isolated yield.
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Table 5 One-pot b-substitution of cyclohex-2-enone using more econom-
ical copper-based reagents with only one transferring unit.
the efficiency of the former process contrasting with the 27% yield
obtained with the same cuprate reagent and 1 under the recently
published conditions.10 In addition and pleasingly, the conjugate
delivery of a phenyl group was also highly effective (Table 3, Entry
4) demonstrating that this methodology is not solely limited to the
introduction of alkyl groups.
Having established successful protocols with pre-formed
Gilman reagents, we then further expanded our study and initiated
investigations into alternative copper-mediated methods for 1,4-
attack on enones. In this regard, we firstly turned to copper
iodide-catalysed conjugate additions with Grignard reagents.14 As
shown in Table 4, the delivery of b-functionalised enones was,
again, possible using this method, with primary, secondary, and
tertiary alkyl groups all being delivered successfully. Whilst these
copper-catalysed Grignard processes were marginally less efficient
than the methods described above, good yields (73–74%) of the
functionalised enones were still obtained using this practically-
convenient protocol.
It is widely recognised that the requirement for two equivalents
of the nucleophilic component within dialkyl- or diarylcuprates
lowers their overall effectiveness as reagents in organic synthesis,
especially if the transferring alkyl or aryl unit is synthetically valu-
able. Despite the general effectiveness of the protocols developed
here, the cuprates (and the copper-catalysed Grignard processes)
employed, in conjunction with the sulfinimidoyl chloride 1, do
require excesses of the nucleophilic agent. Based on this, we pro-
ceeded to investigate a number of alternative and potentially more
preparatively economical organocuprate reagents, where only one
equivalent of the transferring unit is employed. In this regard,
use of a mono-organocuprate in dimethyl sulfide15 proceeded
Entry
Reagent
Solventa
Yield (%)b
1
2
3
n-BuCu.SMe2
n-BuCu
n-Bu(2-thienyl)Cu(CN)Li2
Et2O
Et2O
THF
74
77
76
a Solvent used for the addition of the copper reagent. b Isolated yield.
effectively to deliver a 74% yield of the desired b-substituted enone
product (Table 5, Entry 1). Indeed, as shown by Entry 2 in Table 5,
for the delivery of such a simple alkyl group in our addition–
oxidation procedure, the sulfide additive was not required. Finally
in this series, the popular thienylcuprates developed by Lipshutz,16
in which the 2-thienyl group is used as a non-transferable ligand
within mixed higher-order cyanocuprates, were applied to our
system with 1. Pleasingly, this also proved highly effective and
produced a very good 76% yield of the desired enone product
(Table 5, Entry 3). Interestingly, Matsuo and Aizawa have reported
that, when using their established techniques, with ether as solvent
for both the cuprate and sulfinimidoyl chloride, use of Lipshutz-
type higher-order cuprates bearing either a 2-thienyl or an N-
imidazolyl group only gave very low to moderate yields of the a,b-
unsaturated ketone product. In contrast and to complement the
methods reported here, this previously published study shows how
higher order dialkyl (or diaryl) cyanocuprates can be employed
successfully in this addition–oxidation process, albeit with excesses
of the transferring unit being required.10
Table 4 One-pot b-substitution of cyclohex-2-enone using copper-
catalysed Grignard processes‡
In summary, we have developed a mild and practically-
convenient one-pot conjugate addition–oxidation protocol, to
directly produce b-substituted enones in a highly efficient manner.
This methodology has proven to be effective with both cyclic
and acyclic enones. Furthermore, the application of a series
of individual organocuprate reagents has also been success-
fully demonstrated, to install primary, secondary, and tertiary
alkyl units, as well as aryl moieties. Given all of these features,
coupled with the ease of preparation and commercial availability
of the oxidant, and linked with the simple experimental procedures
developed, we feel that these techniques will be of value to the
wider scientific community.
We thank the EPSRC for funding (G.J.T.), the C. K. Marr Trust
for a Postgraduate Scholarship (C.M.P.), Pfizer Global Research
and Development, Sandwich for generous funding of our research,
and the EPSRC Mass Spectrometry Service, University of Wales,
Swansea for analyses.
Entry
1
Product
Yield (%)a
74
2
3
74
73b
Notes and references
† Representative experimental procedure: to a slurry of CuI (229 mg, 1.2
mmol) in Et2O (10 ml) cooled to −78 ◦C, was added n-BuLi (2.5 M, 0.96 ml,
2.4 mmol) dropwise. After stirring for 1 h, cyclohexanone (96.1 mg, 1
mmol) in Et2O (2 ml) was carefully added. After stirring for a further
a Isolated yield. b Only reacted at −20 ◦C for 1 h prior to quench with 1.
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1 h, N-tert-butylphenylsulfinimidoyl chloride (1) (1077 mg, 5 mmol) was
added rapidly as a solution in THF (3 ml). The reaction was then allowed
to slowly warm to room temperature and stirring was continued for 16 h.
The reaction was then quenched with 2 M HCl (30 ml) and extracted
with EtOAc (3 × 20 ml). The combined organics were then washed
with brine (30 ml) and dried over MgSO4. The crude residue was then
carefully purified by silica chromatography eluting with ether–petroleum
ether mixtures. The product, 3-n-butylcyclohex-2-en-1-one was obtained as
a pale yellow oil (150 mg, 98%), with analysis identical to that described in
recent and practically-utilisable preparation, see: (b) J. Matsuo, D. Iida,
K. Tatani and T. Mukaiyama, Bull. Chem. Soc. Jpn., 2002, 75, 223–234.
6 (a) T. Mukaiyama, J. Matsuo and M. Yanagisawa, Chem. Lett., 2000,
1072–1073; (b) T. Mukaiyama, J. Matsuo and H. Kitagawa, Chem.
Lett., 2000, 1250–1251.
7 For reviews, see: (a) T. Mukaiyama, Angew. Chem., Int. Ed., 2004, 43,
5590–5614; (b) J. Matsuo, J. Synth. Org. Chem., Jpn., 2004, 62, 574–583.
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the literature;17 IR (liq. film) 1670 (C O), 1624 (C C) cm−1; dH (400 MHz,
CDCl3): 5.87 (s, 1H), 2.34–2.37 (m, 2H), 2.27–2.30 (m, 2H), 2.17–2.23 (m,
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‡ A solution of the Grignard reagent in ether was added over 15 min to an
ether solution of CuI and enone at −20 ◦C and stirring was continued for
2 h; the reaction mixture was then cooled to −78 ◦C and a solution of 1
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