Carbon-carbon bond formation by radical addition-fragmentation reactions of O-alkylated enols

Article abstract of DOI:10.1039/b407215b

α-tert-Butoxystyrene [H₂C = C(OBu^t)Ph] reacts with α-bromocarbonyl or α-bromosulfonyl compounds [R ¹R²C(Br)EWG; EWG = -C(O)X or -S(O₂)X] to bring about replacement of the bromine atom by the phenacyl group and give R ¹R²C(EWG)CH₂C(O)Ph. These reactions take place in refluxing benzene or cyclohexane with dilauroyl peroxide or azobis(isobutyronitrile) as initiator and proceed by a radical-chain mechanism that involves addition of the relatively electrophilic radical R ¹R²(EWG)C* to the styrene. This is followed by β-scission of the derived α-tert-butoxybenzylic adduct radical to give Bu^t*, which then abstracts bromine from the organic halide to complete the chain. α-1-Adamantoxystyrene reacts similarly with R ¹R²C(Br)EWG, at higher temperature in refluxing octane using dα-tert-amyl peroxide as initiator, and gives phenacylation products in generally higher yields than are obtained using α-tert-butoxystyrene. Simple iodoalkanes, which afford relatively nucleophilic alkyl radicals, can also be successfully phenacylated using α-1-adamantoxystyrene. O-Alkyl O-(tert-butyldimethylsilyl) ketene acetals H₂C=C(OR)OTBS, in which R is a secondary or tertiary alkyl group, react in an analogous fashion with organic halides of the type R¹R²C(Br)EWG to give the carboxymethylation products R¹R²C(EWG)CH ²CO²Me, after conversion of the first-formed silyl ester to the corresponding methyl ester. The silyl ketene acetals also undergo radical-chain reactions with electron-poor alkenes to bring about alkylation-carboxymethylation of the latter. For example, phenyl vinyl sulfone reacts with H₂C=C(OBu^t)OTBS to afford Bu ^tCH₂CH(SO₂Ph)CH₂CO₂Me via an initial silyl ester. In a more complex chain reaction, involving rapid ring opening of the cyclopropyldimethylcarbinyl radical, the ketene acetal H ₂C=C(OCMe₂C₃H₅-cyclo)OTBS reacts with two molecules of N-methyl- or N-phenyl-maleimide to bring about [3 + 2] annulation of one molecule of the maleimide, and then to link the bicyclic moiety thus formed to the second molecule of the maleimide via an alkylation-carboxymethylation reaction.

Full text of DOI:10.1039/b407215b

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A R T I C L E
Carbon–carbon bond formation by radical addition–
fragmentation reactions of O-alkylated enols
Yudong Cai, Brian P. Roberts,* Derek A. Tocher† and Sarah A. Barnett‡
Christopher Ingold Laboratories, Department of Chemistry, University College London,
20 Gordon Street, London, UK WC1H 0AJ
Received 12th May 2004, Accepted 8th July 2004
First published as an Advance Article on the web 10th August 2004
-tert-Butoxystyrene [H2CC(OBut)Ph] reacts with -bromocarbonyl or -bromosulfonyl compounds [R1R2C(Br)EWG;
EWG = –C(O)X or –S(O2)X] to bring about replacement of the bromine atom by the phenacyl group and give
R1R2C(EWG)CH2C(O)Ph. These reactions take place in refluxing benzene or cyclohexane with dilauroyl peroxide or
azobis(isobutyronitrile) as initiator and proceed by a radical-chain mechanism that involves addition of the relatively
electrophilic radical R1R2(EWG)C to the styrene. This is followed by -scission of the derived -tert-butoxybenzylic adduct
radical to give But, which then abstracts bromine from the organic halide to complete the chain. -1-Adamantoxystyrene
reacts similarly with R1R2C(Br)EWG, at higher temperature in refluxing octane using di-tert-amyl peroxide as initiator, and
gives phenacylation products in generally higher yields than are obtained using -tert-butoxystyrene. Simple iodoalkanes,
which afford relatively nucleophilic alkyl radicals, can also be successfully phenacylated using -1-adamantoxystyrene.
O-Alkyl O-(tert-butyldimethylsilyl) ketene acetals H2CC(OR)OTBS, in which R is a secondary or tertiary alkyl group,
react in an analogous fashion with organic halides of the type R1R2C(Br)EWG to give the carboxymethylation products
R1R2C(EWG)CH2CO2Me, after conversion of the first-formed silyl ester to the corresponding methyl ester. The silyl ketene
acetals also undergo radical-chain reactions with electron-poor alkenes to bring about alkylation–carboxymethylation of
the latter. For example, phenyl vinyl sulfone reacts with H2CC(OBut)OTBS to afford ButCH2CH(SO2Ph)CH2CO2Me via
an initial silyl ester. In a more complex chain reaction, involving rapid ring opening of the cyclopropyldimethylcarbinyl
radical, the ketene acetal H2CC(OCMe2C3H5-cyclo)OTBS reacts with two molecules of N-methyl- or N-phenyl-maleimide
to bring about [3 + 2] annulation of one molecule of the maleimide, and then to link the bicyclic moiety thus formed to the
second molecule of the maleimide via an alkylation–carboxymethylation reaction.
co-workers6 reported in 1990 that 1,4-dicarbonyl compounds
Introduction
could be prepared by similar radical-chain reactions of stannyl
For a number of years now, a major objective of our research has
enolates with -(phenylselenyl)carbonyl compounds, as illustrated
been the development of synthetically useful radical-chain reac-
in Scheme 1. The mechanism of this type of reaction is generalised
tions that do not require the use of compounds of toxic heavy met-
in Scheme 2, although to ensure efficient chain propagation when
als, notably tin and mercury, as key reagents.1,2 For example, we
R2 is a simple alkyl group it is necessary for the addendum radical
have shown that simple trialkyl- or triaryl-silanes in conjunction
R1 to be relatively electrophilic, a property that is conferred by the
with a thiol catalyst can often provide an effective and ‘greener’
-methoxycarbonyl group in MeO2CCH2 (Scheme 1).
replacement for the triorganotin hydrides that have played such an
More recently, Hosomi and co-workers7 have significantly
important role in the development of many useful radical-chain
expanded the use of stannyl enolates for the formation of
reactions.1,2a,e,f In this situation, the thiol serves as a protic polarity-
carbon–carbon bonds by addition–fragmentation radical-chain re-
reversal catalyst that mediates the abstraction by a nucleophilic
actions. These authors showed that stannyl enolates derived from
carbon radical of the electron-rich hydrogen atom attached to
aromatic ketones are sufficiently reactive towards addition even
silicon.1 We have also demonstrated that amine–borane complexes
of relatively nucleophilic alkyl radicals to allow -ketoalkylation
can fulfil a complementary role as hydridic polarity-reversal
of simple alkyl bromides and iodides to be carried out efficiently
catalysts and thereby promote the abstraction of electron-deficient
(Scheme 2, R1 = alkyl, R2 = aryl, Y = Br or I). Of particular note,
hydrogen by electrophilic radicals.1,2i
it was shown that an effective three-component coupling reaction
Addition of a carbon-centred radical to an unsaturated carbon
could be carried out in the presence of an electron-deficient alkene,
atom in an appropriate acceptor, followed by fragmentation of
as illustrated in Scheme 3 for methyl acrylate. Here the nucleo-
the adduct radical produced, is the key chain propagating event in
philic tert-butyl radical is trapped preferentially by the acrylate,
several important reactions for the construction of carbon–carbon
while the resulting more electrophilic -(methoxycarbonyl)alkyl
bonds. In particular, allylstannanes have been used widely as
radical subsequently adds to the stannyl enolate in preference to
radical acceptors in this context.3,4 Building on an earlier investi-
the acrylate.
gation by Russell and Herold5 of the photo-induced reactions of
While our own work in the area was in progress, Roepel8 reported
O-tributylstannyl enolates with polyhalogenomethanes, Toru and
a means to avoid the use of organotin compounds in this type of
reaction by replacing the stannyl enolate with an O-benzyl enol
in conjunction with an -phenylselenyl-malononitrile or -malonic
ester as the source of an electrophilic carbon-radical addendum (see
Scheme 4, EWG = electron-withdrawing group).
† Correspondence concerning the X-ray crystallography should be directed
to this author.
‡ In part.
Scheme 1
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9
2 5 1 7

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Scheme 2
Scheme 5
However, a major limitation to such use of O-benzyl enols is
the requirement for effective chain propagation by the resonance
stabilised and relatively unreactive benzyl radical. Our ongoing
interest in the -scission of -alkoxyalkyl radicals, with regard
to both mechanistic studies9,10 and applications in synthesis,2d,g
encouraged us to explore the use of O-tert-alkyl enols of the type
1 as radical acceptors for -ketoalkylation of organic halides
according to Scheme 5.11 The initial reasoning behind our approach
was based on the knowledge that tert-alkoxyalkyl radicals undergo
-scission relatively easily9,10 and that, although it is well known
that the C–H bond strength decreases appreciably along the series
Me–H > Et–H > Pri–H > But–H, the corresponding bonds to more
electronegative elements, including bromine and iodine, vary
much less in strength.10–12 For example, the C–I bond dissociation
enthalpies for Me–I, Et–I, Pri–I and But–I are reported to be 239,
236, 234 and 231 kJ mol−1, respectively, while DH(PhCH2–I) is a
lot smaller at 215 kJ mol−1.13 Thus, not only should an adduct radi-
cal of the type 2 undergo ready -scission to give the tertiary alkyl
radical Rt, but the latter should (in contrast to a benzyl radical8)
be relatively easily transformed into the desired addendum radical
R by transfer of an electronegative atom or group, as in the equili-
brium process illustrated by eqn. (1) in Scheme 5.
corresponding O-tert-butyl adduct to give But,18 this propagation
step may not always be critical in determining the overall rate of
the chain reaction, especially at higher temperatures. In the event,
the 1-adamantyl derivative 4 turned out to be beneficially less
reactive in a heterolytic sense than 3 (in particular, more stable
towards hydrolysis), while its use for radical reactions of the type
shown in Scheme 5 often proved advantageous compared with the
corresponding reactions of 3, presumably because of the increased
efficiency of the halogen-atom transfer step.§ The choice of initiator
depended on the temperature at which the reaction was carried out;
azobis(isobutyronitrile) (AIBN) or dilauroyl peroxide (DLP) was
used for reactions in refluxing benzene or cyclohexane and di-tert-
amyl peroxide19 (DTAP) 5 for reactions conducted in refluxing
octane or chlorobenzene.
When -tert-butoxystyrene 3 was heated alone in refluxing
benzene under argon, no change was detected by NMR spectro-
scopy after 3 h. However, in the presence of 5 mol% AIBN or
DLP, similar treatment resulted in the complete conversion of 3 to
neopentyl phenyl ketone 6a, which was isolated in ca. 95% yield.
Under these conditions, 3 undergoes clean radical-chain rearrange-
ment according to the mechanism shown in Scheme 6, resulting in
the formal 1,3-shift of the tert-butyl group.20¶ However, when ethyl
bromoacetate (3 equiv.) was present along with the AIBN, NMR
analysis after removal of the solvent showed complete conversion
of 3 to a mixture of ethyl 4-oxo-4-phenylbutanoate 7a and 6a in the
ratio 70:30. The tert-butyl radical, resulting from the -scission
of the -tert-butoxybenzylic radical of the type 2, now abstracts
bromine from BrCH2CO2Et in competition with its addition to the
We were delighted to discover that O-tert-alkyl enols could
indeed be used successfully for carbon–carbon bond formation as
illustrated in Scheme 5, and a preliminary report of our findings in
this area has appeared already.11 In the present paper we give a fuller
account of this work and describe a number of extensions of the
new methodology, including the reactions of O-alkyl O-silyl ketene
acetals with electron-poor alkenes, some of which have also been
described in a preliminary report.14
Results and discussion
Reactions of -alkoxystyrenes with organic halides
Our work began with an investigation of the radical-chain reactions
of -tert-butoxystyrene15 3 with organic halides that yield relatively
electrophilic carbon-centred radicals in the halogen-atom transfer
step [eqn. (1)] of Scheme 5 (X = Ph). Because of the constraints
imposed by its caged structure, the geometry at the radical centre
in the tertiary 1-adamantyl radical (1-Ad) is more strongly
pyramidal than that in the tert-butyl radical and 1-Ad often
behaves differently from a simple acyclic tertiary alkyl radical.
It is generally more reactive and probably more nucleophilic16
than But and 1-Ad–X bonds are stronger than the corresponding
But–X bonds.17 Therefore, we subsequently explored the use
of -1-adamantoxystyrene 4 for comparison with the tert-butyl
analogue 3. Although -scission of an adduct radical of the type
2 to give 1-Ad is expected to be slower than cleavage of the
§ An alternative approach, also designed to increase the efficiency of
halogen-atom transfer, was described in our preliminary communication.11
This involved using the O-cyclopropyldimethylcarbinyl analogue of 3,
when the tertiary cyclopropyldimethylcarbinyl radical produced in the -
scission step undergoes very rapid ring-opening rearrangement to give a
primary but-3-enyl-type radical, which abstracts halogen more effectively
than the tert-butyl radical.
¶ Under the same conditions, -benzyloxystyrene rearranged only partially
(40%) to give PhCH2CH2C(O)Ph.
Scheme 3
Scheme 4
2 5 1 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9

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ratio 11:6a was 35:65. At higher temperature in refluxing octane
solvent, in the presence of TMP (0.20 equiv.) with DTAP (0.30
equiv.) as initiator, the ratio 11:6a could be raised to 52:48.
The selectivity for formation of 10 or 11 improved consider-
ably when the O-1-adamantoxy analogue 4 was used in place
of 3. Thus, when an octane solution containing 4, n-butyl iodide
(5 equiv.), DTAP (0.30 equiv.) and TMP (0.20 equiv.) was heated
under reflux for 4 h, the alkoxystyrene was converted to a 90:10
mixture of 10 and 6b from which 10 was isolated in 83% yield by
flash chromatography followed by Kugelrohr distillation. A similar
reaction using s-butyl iodide (3 equiv.) afforded a crude product
containing a 93:7 mixture of 11 and 6b from which pure 11 was
isolated in 86% yield.
In view of the reports by Giese and co-workers21 that -
methoxystyrene 12 undergoes reductive carboxyalkylation when
treated with an -bromo ester and tributyltin hydride [e.g. to give
MeO2CCH2CH2CH(OMe)Ph with methyl bromoacetate], we felt
it was necessary to exclude the mechanism shown in Scheme 7
as a possible alternative pathway to the phenacylation products
observed under our conditions.|| However, when a benzene solution
containing -methoxystyrene, ethyl bromoacetate (3 equiv.), AIBN
(0.05 equiv.) and collidine (0.10 equiv.) was heated under reflux
for 3 h, conditions comparable to those which lead to complete
consumption of -tert-butoxystyrene to afford 7a, there was no
significant reaction of 12 as judged by NMR spectroscopy. There
was also no reaction of -methoxystyrene in a similar experiment
when the -bromo ester was replaced with n-butyl iodide (5 equiv.).
Addition of R to -methoxystyrene 12 should take place at least as
rapidly as its addition to -tert-butoxystyrene 3, to form an adduct
which should abstract halogen as readily as would the O-tert-butyl
analogue 13 (Scheme 7). Hence, if 3 reacted with organic halides
as shown in Scheme 7 under our conditions, we would expect
extensive reaction of -methoxystyrene to take place in the con-
trol experiments, to give either the O-methyl analogue of 14 or its
heterolytic decomposition products. Therefore, we believe that the
mechanism shown in Scheme 5 is followed under our conditions:
in Giese’s21 reactions with -methoxystyrene the intermediate
O-methyl analogue of 13 must be trapped exclusively by the tin
hydride, rather than by the organic halide, to give the reductive
carboxyalkylation product and a stannyl radical that continues the
chain by abstracting halogen from the halide.*
We have also examined briefly the addition–fragmentation
radical-chain reactions of the -1-adamantoxy--methylstyrene
16, prepared as a 66:34 mixture of its E and Z isomers.23 When an
octane solution containing 16 and DTAP (0.20 equiv.) as initiator
was heated under reflux for 4 h, only ca. 30% rearrangement to the
ketone 17 took place, as judged by NMR spectroscopic analysis of
the crude reaction product. The sluggish 1,3-rearrangement of 16,
compared with the corresponding rearrangement of its unmethyl-
ated parent 4 to give 6b, is presumably a result of steric retardation
of the addition of the relatively bulky 1-adamantyl radical to the 
carbon in 16 and, in general, steric effects appear to exert a domi-
nant influence on radical addition to this alkene. Thus, although
benzoylalkylation of EtO2CCH2Br with 16 proceeded smoothly
to give the phenyl ketone 18a in near-quantitative yield, the cor-
responding reaction with EtO2CCMe2Br gave only ca. 10% of
18b, as judged by NMR spectroscopy, and most of the bromo ester
remained unchanged (Table 1, entries 16 and 17). Not only is the
radical EtO2CCMe2 more bulky than EtO2CCH2, but it is also more
nucleophilic and both factors act to slow the rate of its addition to
the electron-rich double bond in 16 to a point where the benzoyl-
alkylation reaction becomes non-viable.
styrene 3. When the latter was added slowly by syringe pump to the
bromoester and AIBN (10 mol%) in refluxing benzene, the product
ratio 7a:6a increased to 95:5. Slow addition of 3 was not necessary
when the bromoacetate was replaced as halogen-atom donor by the
much more reactive ethyl iodoacetate (2 equiv.) and 7a was then
produced in high yield without competitive formation of 6a. For all
radical reactions in the presence of halogen-atom donors, a small
amount of 2,4,6-collidine or 2,2,6,6-tetramethylpiperidine was
also added as a sterically hindered base to suppress acid-catalysed
heterolytic reactions of the -alkoxystyrenes, particularly their
adventitious hydrolysis.
Scheme 6
-1-Adamantoxystyrene 4 underwent a similar radical-chain 1,3-
rearrangement to give the ketone 6b when heated under reflux in
octane containing DTAP initiator (20 mol%) and 6b was isolated
in 91% yield. When ethyl bromoacetate (2 equiv.) and 2,2,6,6-tetra-
methylpiperidine (TMP; 10 mol%) were included in the reaction
mixture, the 1-adamantyl radical was efficiently diverted into
abstracting halogen from the bromo ester and ethyl 4-oxo-4-phenyl-
butanoate 7a was formed in high yield (Table 1, entry 12). Even with
two equivalents of the bromo ester and without syringe pump addi-
tion of the alkoxystyrene, only ca. 5% of the ketone 6b was present
in the crude reaction product (cf. entry 1). Several similar reactions
of the -tert-alkoxystyrenes 3 and 4 with sources of relatively
electrophilic carbon-radical addenda, to afford the phenyl ketones
7–9, were also carried out and the results are collected in Table 1.
In general, although a higher reaction temperature was required,
use of the alkoxystyrene 4 in place of 3 often resulted in improved
yields of the desired phenacylation product, which contained only
small amounts of the easily-separated 1,3-rearrangement product 6b
before purification. For example, the isolated yields of the lactone
8a (entries 9 and 14) and of the camphor derivative 9 (entries 11 and
15) were significantly improved using the procedures based on 4.
Phenyl ketones derived from reactions of the alkoxystyrenes
3 and 4 with sources of relatively nucleophilic radical addenda
proved more difficult to obtain in preference to the styrene-
rearrangement products 6a and 6b, although again -1-adamantoxy-
styrene 4 was significantly more successful than 3 in this type
of reaction. Thus, treatment of 3 with n-butyl iodide (5 equiv.)
in refluxing benzene, containing AIBN (5 mol%) and collidine
(10 mol%), resulted in its complete conversion to a 19:81 mixture
of ketones 10 and 6a after 3 h. Evidently, 3 is preferentially trapping
the tert-butyl radical, rather than the n-butyl radical derived from the
iodide. Slow addition of 3 using a syringe pump only raised the pro-
portion of hexanophenone 10 to 34% and it appears that the equilib-
rium [eqn. (1)] in Scheme 5 lies too far to the left for the reaction to
be useful in the case of a simple primary alkyl iodide. Replacing the
n-butyl iodide with s-butyl iodide (3 equiv.), with all the reagents
present initially, improved the situation such that the product ketone
|| In this mechanism the ion pair 15 might possibly be formed by dissocia-
tive electron transfer to R–Y from the -alkoxybenzyl radical 13, leading
directly to R and Y−.
* The reactions of some organic halides (RHal), including benzyl and n-
butyl bromides, with -methoxystyrene at very high temperatures (<200 °C)
were described briefly in 1940.22 Although PhC(O)CH2R was obtained in
low yield from these reactions, the mechanism by which the ketones were
formed is unclear.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9
2 5 1 9

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Table 1 Reactions of -alkoxystyrenes 3, 4 and 16 with organic halides that afford electrophilic radical addendaa
Entry
Styrene
Halogen donor (equiv.)
Initiator (equiv.)
Solvent
Product (isolated yield)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3b
3
3
3
3
EtO2CCH2Br (3.0)
EtO2CCH2I (2.0)
EtO2CCHMeBr (3.0)
EtO2CCMe2Br (3.0)
(EtO2C)2CHBr (2.0)
(EtO2C)2CMeBr (2.0)
AdC(O)CH2Br (3.0)
PhSO2CH2Br (2.0)
-Bromo--butyrolactone (3.0)
-Bromo--methyl--butyrolactone (3.0)
(1R)-endo-(+)-3-Bromocamphor (3.0)
EtO2CCH2Br (2.0)
AIBN (0.10)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
AIBN (0.05)
DTAP (0.20)
DTAP (0.20)
DTAP (0.20)
DTAP (0.20)
DTAP (0.20)
DTAP (0.20)
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Benzenec
Octanei
7ad (85%)
7a (82%)
7b (86%)
7c (85%)
7d (84%)
7e (91%)
7fe (78%)
7gf (75%)
8a (54%)
8b (55%)
9g (25%)
7a (87%)
7g (84%)
8a (90%)
9g (63%)
18a (95%)
18bj (10%)
3
3
3b
3
3
3
4h
4h
4h
4h
16h
16h
PhSO2CH2Br (2.0)
PhCli
-Bromo--butyrolactone (2.0)
(1R)-endo-(+)-3-Bromocamphor (2.0)
EtO2CCH2Br (2.0)
PhCli
PhCli
Octanei
EtO2CCMe2Br (2.0)
Octanei
a Unless stated otherwise, 2,4,6-collidine (0.10 equiv.) was added to suppress acid-catalysed heterolytic reactions of the styrene and all reagents were present
initially; the reaction time was usually 3 h. b The -tert-butoxystyrene was added by syringe pump over the first 1.5 h. c Bath temp. 90 °C, internal temp. ca.
85 °C. d The crude product contained a 95:5 mixture of 7a and 6a. e The crude product contained an 84:16 mixture of 7f and 6a. f The crude product contained
a 76:24 mixture of 7g and 6a. g The isolated product was a ca. 64:36 mixture of exo and endo isomers. h The collidine was replaced with TMP (0.10 equiv.).
i Bath temp. 140 °C. jAbout 80% of the starting material remained unreacted.
Scheme 7
However, both 19 and 20 reacted smoothly according to Scheme 5
(X = OTBS) with organic bromides that yield relatively electro-
philic addenda. Because the nucleophilic tert-butyl and 1-adamantyl
radicals add particularly slowly to the ketene acetals, there was no
competing formation of their 1,3-rearrangement products, as in
some reactions of the styrenes 3 and 4. The initial products from 19
and 20 were silyl esters of the type 21 but, although these could be
isolated by careful chromatography on Florisil®, because of their
Reactions of O-alkyl O-silyl ketene acetals
(a) Reactions with organic halides. Radical addition to the
O-tert-alkyl O-(tert-butyldimethylsilyl) ketene acetals 19 and 20
(TBS = ButMe2Si) would be expected to be slower than addition to
the -alkoxystyrenes 3 and 4, especially when the addendum radical
is relatively nucleophilic, because the radical-stabilising phenyl
group has been replaced by an electron-donating siloxy group.
relatively high sensitivity to hydrolysis it was more convenient
to convert them first into alkyl esters. This was usually done by
treatment with tetrabutylammonium fluoride (TBAF) and the ap-
propriate alkyl iodide24 or, in some cases, by desilylation with oxalyl
chloride in the presence of catalytic DMF, followed by in situ con-
version of the resulting acid chloride to the ethyl ester by treatment
with ethanol and pyridine.25 The esters 22a–e and 23 were obtained
in this way and the results are summarised in Table 2.
Good isolated yields of the carboxymethylation products
22a–c were obtained from reactions of representative -bromo
esters with the O-tert-butyl ketene acetal 19 (entries 1–3).
Corresponding carboxymethylation of 1-adamantyl bromomethyl
ketone to give 22d was also successful when one equivalent of
the bromo ketone was used in conjunction with TBAF–EtI for
desilylation (entry 4). However, with two equivalents of the bromo
ketone the latter reacted in preference to the ethyl iodide with the
carboxylate derived from the initial silyl ester (see Scheme 8) to
afford the compound 24 in excellent yield (entry 5). In an attempt
to permit the use of excess bromo ketone in order to maximise the
yield of 22d, desilylation was carried out by reaction of the silyl
ester with oxalyl chloride followed by treatment with ethanol and
pyridine. However, rather than giving the normal ester 22d, this
procedure afforded the ‘pseudo ester’26 25, as shown in Scheme 8
(entry 6). The structure of 25 was confirmed by single-crystal X-ray
diffraction. Carboxymethylation of bromomethyl phenyl sulfone to
give 22e was successful using 2 equivalents of the bromide, fol-
lowed by desilylation with TBAF–EtI (entry 7), but with -bromo-
2 5 2 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9

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Table 2 Reactions of the O-tert-alkyl O-silyl ketene acetals 19 and 20 with organic halides that afford electrophilic radical addendaa
Entry
Silyl ketene acetal
Halogen donor (equiv.)
Solvent
Desilylation methodb
Productc (isolated yield)
1
2
3
4
5
6
7
8
9
19
19
19
19
19
19
19
19
20
20
20
EtO2CCH2Br (2.0)
Cyclohexane
Cyclohexane
Cyclohexane
Benzene
Benzene
Benzene
Benzene
Benzene
Cyclohexane
Cyclohexane
Cyclohexane
A
A
A
A
A
B
A
Bd
A
A
A
22a (83%)
22b (67%)
22c (73%)
22d (83%)
24 (91%)
25 (59%)
22e (84%)
23 (76%)
EtO2CCHMeBr (2.0)
(EtO2C)2CMeBr (1.2)
AdC(O)CH2Br (1.0)
AdC(O)CH2Br (2.0)
AdC(O)CH2Br (2.0)
PhSO2CH2Br (2.0)
-Bromo--butyrolactone (2.0)
EtO2CCH2Br (2.0)
EtO2CCHMeBr (2.0)
AdC(O)CH2Br (1.0)
22a (95%)
22b (77%)
22d (85%)
10
11
a The initiator was DLP (0.05 equiv.) for all reactions and 2,4,6-collidine (0.10 equiv.) was added to suppress acid-catalysed heterolytic reactions of the ketene
acetal. All reagents were present initially and the reaction mixture was heated under reflux, usually for 2.5 h. bA = Addition of methyl or ethyl iodide followed
by treatment with TBAF in THF at 0 °C; B = treatment with oxalyl chloride followed by reaction of the acid chloride with ethanol and pyridine. cAfter conver-
sion of the initially-formed silyl ester to the alkyl ester shown. d Method A afforded a mixture of 23 and the product formed by reaction of the excess -bromo
lactone with the carboxylate (cf. Scheme 8).
a similar way with NMM in refluxing chlorobenzene using DTAP
(0.20 equiv.) as initiator.†† The silyl esters of type 28 produced
initially were converted to the methyl esters 30a and 30b, by treat-
ment with TBAF and methyl iodide, and the trans stereochemistry
of the products (expected on steric grounds) was confirmed by NMR
spectroscopy and by single-crystal X-ray diffraction for the ethyl
ester 31.‡‡ N-Phenylmaleimide (NPM) reacted with 19 in a similar
manner in refluxing benzene to afford the 1-phenylpyrrolidine-2,5-
dione 32 in 71% yield. The results are summarised in Table 3.
-butyrolactone the same procedure afforded a mixture of 23 and
the product corresponding to 24, formed by reaction of the carboxy-
late with the excess of the bromo lactone (cf. Scheme 8). However,
the desired excess of the bromo lactone could be used provided the
desilylation was accomplished with oxalyl chloride, when 23 could
be obtained in good yield (entry 8).
The O-1-adamantyl ketene acetal 20 gave equally good or rather
better results when used in place of 19 for representative carboxy-
methylation reactions under the same conditions (entries 9–11).
Further advantages of 20 over the O-tert-butyl analogue 19 were its
greater thermal stability and lower heterolytic reactivity, especially
its relatively slow hydrolysis.
(b) Reactions with electron-poor alkenes. Simple alkyl
radicals are relatively nucleophilic and do not add readily to electron-
rich alkenes such as 19 and 20, while their addition to electron-poor
alkenes is comparatively rapid.27 Therefore, we reasoned that
O-alkyl O-silyl ketene acetals 26 could react with electron-poor
alkenes to give compounds of the type 28 according to the radical-
chain mechanism generalised in Scheme 9, provided that -scission
of the adduct radical 27 is sufficiently rapid. The O-tert-butyl ketene
acetal 19 reacted as predicted with N-methylmaleimide 29 (NMM,
1.2 equiv.) when heated for 3 h in refluxing benzene containing
DLP (0.05 equiv.) and the O-1-adamantyl analogue 20 reacted in
†† Di-tert-butyl peroxide could also be used as initiator, but the yields were
generally lower than with DTAP.
‡‡ The ethyl ester 31 formed crystals more suitable for X-ray diffraction than
did the methyl ester 30b.
Scheme 8
Scheme 9
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9
2 5 2 1

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Table 3 Reactions of acyclic O-alkyl O-silyl ketene acetals with electron-poor alkenes
Entry
Silyl ketene acetal
Electron-poor alkene (equiv.)
Conditionsa,b
Producte (isolated yield)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
19
20
20
19
33
34
35
20
20
33
20
33
19
19
20
20
33
NMM (1.2)
NMM (1.2)
NMM (1.2)
NPM (1.1)
NMM (1.2)
NMM (1.5)
NMM (1.5)
Dimethyl maleate (1.2)
Dimethyl fumarate (1.2)
Dimethyl fumarate (1.2)
5H-Furan-2-one (1.2)
5H-Furan-2-one (1.5)
Phenyl vinyl sulfone (1.2)
Phenyl vinyl sulfone (0.5)
Phenyl vinyl sulfone (1.2)
Phenyl vinyl sulfone (0.5)
Phenyl vinyl sulfone (0.5)
A
B
B
A
Bc
Bc
Bc
B
B
B
B
B
30a (68%)
30b (66%)
31 (67%)
32 (71%)
30c (70%)
36a + 36b (65%)
37a–d (67%)
38a (70%)
38a (71%)
38b (62%)
41a (61%)
41b (60%)
42a (43%)
42a (89%)
42b (45%)
42b (87%)
42c (80%)
A
Ad
B
Bd
Bd
a The reaction mixture was heated under reflux for 3 h. bA = DLP initiator (0.05 equiv.), benzene solvent, bath temp. 90 °C; B = DTAP initiator (0.20 equiv.),
chlorobenzene solvent, bath temp. 140 °C. c Slow addition of NMM in chlorobenzene during the first 1 h using a syringe pump. dAmount of initiator based
on phenyl vinyl sulfone. eAfter conversion of the initially-formed silyl ester to the alkyl ester shown by treatment with TBAF and methyl or ethyl iodide in
THF at 0 °C.
the pyrrolidinedione ring is cis to the isopropyl group, would be
expected on the basis of steric effects which direct the approach of
NMM to the less hindered face of the intermediate menthyl radi-
cal and place the new substituent in an equatorial site trans to the
isopropyl group. A similar reaction of the O-bornyl ketene acetal 35
with NMM afforded a 41:25:20:14 mixture of all four possible dia-
stereoisomers 37a–d in a total yield of 67%. The major product was
shown by X-ray analysis to be the pyrrolidinedione 37a. The isomer
present originally as 20% of the crude product crystallised particu-
larly well and was shown by X-ray diffraction to have the structure
37b. The remaining two diastereoisomers 37c and 37d could not be
obtained free from the other isomers and their structures could not be
determined unambiguously. The major product 37a arises as a result
of preferential attack by the intermediate 2-bornyl radical from its
less hindered endo face at an Re facial terminus of the CC bond
in NMM and the diastereoselectivity of this radical addition is sig-
nificantly greater than for the corresponding addition of the menthyl
radical to NMM. Preferential addition of NMM to the endo face of
the 2-bornyl radical is in accord with the preferred formation of the
endo-peroxyl radical when dioxygen reacts with the bornyl radical
during autoxidation of the mixture of exo and endo Grignard reagents
derived from bornyl chloride.28 Addition at an Si facial terminus of
NMM leads to 37c and 37d and, assuming preferential attack of the
bornyl radical from its endo face, the crude reaction product would
contain 25% of 37c and 14% of 37d; the spectroscopic assignments
reported in the Experimental section are made on this basis. Future
work on this type of carbon–carbon bond-forming reaction of O-al-
kylated enols should address the general problem of controlling the
diastereoselectivity of radical addition to the electrophilic alkene.
The ketene acetal 20 reacted in a similar fashion with dimethyl
maleate (1.2 equiv.) in refluxing chlorobenzene containing DTAP
initiator and the first-formed monosilyl ester was converted to
the trimethyl ester, which was isolated in 70% yield as a single
diastereoisomer and shown by X-ray crystallography to be the
anti compound 38a. A small amount (ca. 5%) of the syn trimethyl
ester 39a was detected in the crude reaction product and dimethyl
fumarate afforded the same mixture of diastereoisomers in similar
yield.§§ This result implies that addition of the 1-adamantyl radical
to the maleate or to the fumarate gives an adduct radical 40 which
is conformationally equilibrated before it adds to 20. On both steric
and electrostatic grounds, the conformation 40a should be preferred
Despite the fact that an -alkoxyalkyl radical of the type 27
(Scheme 9) will undergo -scission less readily when R is a
secondary alkyl group than when it is tertiary, we were pleased to
find that O-sec-alkyl O-silyl ketene acetals participated successfully
in analogous reactions with NMM in refluxing octane or chloro-
benzene using DTAP as initiator. Initial experiments were carried
out with the O-cyclohexyl ketene acetal 33, but the ketene acetals 34
and 35 behaved similarly and the reaction should be fairly general
for secondary O-alkyl groups; the results are included in Table 3.
The O-cyclohexyl ketene acetal 33 afforded the pyrrolidine-2,5-
dione 30c in 70% isolated yield. The enantiomerically-pure O-(1R)-
menthyl analogue 34 gave a 1:1 mixture of the two diastereoisomeric
adducts 36a and 36b in 65% total yield. The isomer 36a could be
isolated by crystallisation and its structure was confirmed by X-ray
diffraction. The adduct 36b failed to crystallise and could not be
freed from traces of 36a, but examination of its 1H NMR spectrum
leaves not doubt as to the structure. The formation of 36a and 36b,
in preference to the other two possible diastereoisomers in which
§§ The syn isomers 39a and 39b eluted after the anti compounds and were
difficult to obtain free from the latter by column chromatography; they were
also contaminated with the corresponding adduct resulting from trapping of
the ethyl radical (arising from the DTAP initiator). Identification of the syn
isomers was based on comparison of their NMR spectra with those of the
anti forms 38a and 38b.
2 5 2 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9

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and this would be expected to add to 20 from its less shielded face
anti to the bulky adamantyl group,7,29 leading ultimately to the anti
diastereoisomer 38a as the major product.¶¶ A similar reaction of
the O-cyclohexyl ketene acetal 33 with dimethyl fumarate afforded
the anti trimethyl ester 38b as the major product in 62% isolated
yield. About 10% of the syn isomer 39b was detected in the crude
reaction mixture, indicating that the preference for formation of the
anti isomer increases with the bulk of the group R in the radical 40.
On the basis of these results, we reasoned that the O-cyclo-
propyldimethylcarbinyl O-silyl ketene acetal 43 might react with
electron-poor alkenes to bring about [3 + 2] annulation of the
latter, according to the general mechanism shown in Scheme 10
and involving ring opening30 of the cyclopropyldimethylcarbinyl
radical 44 as a key step. Polar effects on the rates of radical addi-
tion reactions27 are of crucial importance in directing the course
of this complex chain process, which results in the formation of
four new C–C bonds. As envisaged, when the ketene acetal 43
was heated for 3 h in refluxing benzene with NMM (2.2 equiv.)
and DLP (0.05 equiv.), an annulated product of the type 45 was
formed and this was isolated as the diastereoisomerically-pure
methyl ester 46. However, under these conditions significant
amounts of by-products analogous to 30 were formed as a result
of trapping by NMM of the undecyl radical (from DLP) and of the
cyclopropyldimethylcarbinyl radical 44; some oligomerisation of
the NMM also appeared to take place. These complications could
be minimised by slow addition over 2 h of the NMM (2.2 equiv.) in
benzene to a refluxing solution of 43 and DLP (0.10 equiv.) in the
same solvent. Now, the crystalline compound 46 could be isolated
in 30% yield and its structure was determined by X-ray diffraction
(see Fig. 1). In the reaction of 43 with NMM, the 5-exo cyclisation
(step A, Scheme 10) preferentially places the exocyclic dimethyl-
carbinyl radical centre in the endo position on the new bicyclic
skeleton, in agreement with previous observations.31 In the next
stage of the propagation cycle (step B, Scheme 10), the addition
of this tertiary alkyl radical to NMM takes place preferentially to
generate a new chiral centre at C-10 with a configuration opposite
(according to the Cahn–Ingold–Prelog rules) from that at C-6
which is separated from it by the dimethylcarbinyl group. Addi-
tion to form a new radical (centred at C-14) in which C-6 and C-10
have the same configuration is predicted by molecular mechanics
calculations to be less favourable thermodynamically, although by
only 4.5 kJ mol−1.32
A corresponding reaction of the ketene acetal 43 with N-phenyl-
maleimide provided the annulation product 47 in a similarly mod-
est isolated yield of 37%. Although the compound 47 did not form
crystals suitable for X-ray diffraction, the close similarity of its 1H
NMR spectrum to that of 46 leaves little doubt as to the structure.
While the yields of 46 and 47 are not high, this type of metal- and
halogen-free reaction is of significant interest in that it involves the
formation, in a single pot from two readily obtained starting mate-
rials, of a cyclopentane ring and four new C–C bonds in a stereo-
controlled manner. In general, the highly functionalised molecules
that result from the alkylation–carboxymethylation and annulation
reactions of electrophilic alkenes described in this paper should be
readily amenable to further elaboration, making the chemistry of
potential use in the construction of complex molecules.
Selected reactions of the silyl ketene acetals with other electro-
philic alkenes, as represented by 5H-furan-2-one and phenyl vinyl
sulfone, were also examined and the results are given in Table 3.
The O-1-adamantyl and O-cyclohexyl silyl ketene acetals reacted
with 5H-furan-2-one in refluxing chlorobenzene in the presence of
DTAP as initiator to give the lactones 41a and 41b, respectively,
in about 60% isolated yield after conversion to the methyl esters
(entries 11 and 12). Phenyl vinyl sulfone afforded very good yields
of the sulfones 42a–c with two equivalents of the ketene acetals 19,
20 and 33, respectively (entries 14, 16 and 17), although the yields
were appreciably lower when the phenyl vinyl sulfone was present
in slight excess (entries 13 and 15).
¶¶ See ref. 7 for a report of related radical-chain reactions between -
(tributylstannyloxy)styrene, an alkyl iodide and dimethyl maleate (cf.
Scheme 3), in which the stereochemistry of the major product was pre-
sumed on similar grounds, but not proven.
Scheme 10
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9
2 5 2 3

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one, phenyl vinyl sulfone, dilauroyl peroxide and di-tert-butyl
peroxide were all obtained from Aldrich and were used as received.
Azobis(isobutyronitrile) was also obtained commercially (Merck/
BDH) and recrystallised from diethyl ether: di-tert-amyl peroxide
was prepared as described by Milas and Surgenor.19 Tetrabutyl-
ammonium fluoride (1 M in tetrahydrofuran) was purchased from
Aldrich and used as received.
-Alkoxystyrenes
-tert-Butoxystyrene 3 was prepared by a modification of the
methods reported by Kostikov et al.15 and Wiberg et al.;20 the final
elimination of HI to produce 3 was accomplished using a method
described by Middleton and Simpkins for a related compound.33
To a mixture of 2-methyl-2-propanol (5.56 g, 0.075 mol), iodine
(12.7 g, 0.05 mol) and mercuric oxide (6.5 g, 0.03 mol) in diethyl
ether (20 mL) was added slowly with stirring a solution of styrene
(5.75 mL, 0.05 mol) in diethyl ether (10 mL). After stirring at room
temperature for 3 h, the mixture was filtered through Celite and the
filter cake was washed with ether. The filtrate was washed with a
solution of potassium iodide with small portions of sodium bisulfite
until the dark colour of iodine was discharged. The ether layer was
separated, washed with water, dried and concentrated under reduced
pressure. The residue was added to a stirred solution of potassium
tert-butoxide (11.2 g, 0.10 mol) in dry THF (50 mL) at room tem-
perature. After stirring at room temperature overnight, the mixture
was diluted with petroleum (100 mL) and filtered through Celite. The
filtrate was concentrated under reduced pressure. The residue was
diluted with ether, washed with water, dried over K2CO3 and con-
centrated under reduced pressure. The residue was purified by distil-
lation under reduced pressure to give -tert-butoxystyrene 3 (6.69 g,
76%) as a colourless oil, bp 48–54 °C/0.05 mm Hg; H 1.42 (9 H, s,
But), 4.57 (1 H, d, J 1.4, CHAHB), 4.96 (1 H, d, J 1.4, CHAHB),
7.26–7.60 (5 H, m, Ph); C 28.6, 78.2, 93.7, 125.7, 128.0 (2 C), 139.1,
156.8. Found: C, 81.8; H, 9.1. C12H16O requires C, 81.8; H, 9.2%.
-1-Adamantoxystyrene 4 was prepared in 60% yield by the
method described above, although the crude product contained ca.
20% -iodostyrene which was removed by Kugelrohr distillation
at 0.05 mm Hg (oven temp. 150 °C) to afford 4 as a colourless oil;
H 1.61 (6 H, brs, Ad), 1.92 (6 H, br d, J 3.0, Ad), 2.14 (3 H, br s,
Ad), 4.70 (1 H, d, J 1.1, CHAHB), 5.09 (1 H, d, J 1.1, CHAHB),
7.27–7.61 (5 H, m, Ph); C 30.9, 36.2, 42.5, 78.0, 98.3, 125.8,
127.9(2), 127.9(4), 139.6, 156.0. Found: C, 84.9; H, 8.9. C18H22O
requires C, 85.0; H, 8.7%.
Fig. 1 Structure of compound 46 as determined by single-crystal X-ray
diffraction.
Experimental
NMR spectra were recorded using a BrukerAVANCE 500 instrument
(500 MHz for 1H, 125.7 MHz for 13C). Unless stated otherwise, the
solvent was CDCl3 and chemical shifts are reported relative to
residual CHCl3 (H = 7.26) or to CDCl3 (C = 77.0 ppm); J values
are quoted in Hz and the use of [multiplet] indicates an apparent
multiplet associated with an observed line spacing. When these were
-Methoxystyrene34 12 was prepared in 79% yield using the
method described above, and -adamantoxy--methylstyrene23 16
were prepared as described in the literature.
O-Alkyl O-(tert-butyldimethylsilyl) ketene acetals
1
not obvious, assignments of the H NMR spectra were made with
The silyl ketene acetals were prepared from the acetate esters
by treatment with lithium diisopropylamide in THF at −78 °C,
followed by quenching of the lithium enolate with tert-butyldi-
methylchlorosilane in the presence of hexamethylphosphoramide
at −78 °C and subsequent warming to room temperature, as
described by Danishefsky et al.;35 the yields ranged from 73 to 90%
and the characteristic properties are given below.
the aid of COSY and NOE techniques; in complex situations where
there are spin systems showing strong coupling the reported J values
will be approximate. Column chromatography and TLC were carried
out using Merck Kieselgel 60 (230–400 mesh) and Kieselgel 60 F254
aluminium-backed pre-coated plates, respectively. Optical rotations
were measured using anAASeries Polaar 2000 polarimeter (Optical
Activity Ltd.) in a 1 dm cell and are given in units of 10−1 deg cm2 g−1.
Infrared (IR) spectra were obtained from liquid films or KBr pellets
using a Shimadzu FTIR-8700 spectrophotometer; wavenumbers
(cm−1) are reported only for strong characteristic bands.
O-tert-Butyl O-(tert-butyldimethylsilyl) ketene acetal 1935
Oil, bp 80–84 °C/15 mm Hg; H 0.19 (6 H, s, SiMe2), 0.93 (9 H,
s, SiBut), 1.35 (9 H, s, OBut), 3.45 (1 H, d, J 1.3, CHAHB), 3.47
(1 H, d, J 1.3, CHAHB); C −4.8, 18.0, 25.7, 28.5, 72.7, 78.0, 157.7.
Found: C, 62.5; H, 11.4. C12H26O2Si requires C, 62.6; H, 11.4%.
All manipulations and reactions of air-sensitive materials were
carried out under an atmosphere of dry argon and all extracts were
dried over anhydrous MgSO4 unless stated otherwise. Petroleum
refers to the fraction of bp 40–60 °C.
O-1-Adamantyl O-(tert-butyldimethylsilyl) ketene acetal 20
Materials
Oil, bp 98–100 °C/0.05 mm Hg; H 0.19 (6 H, s, SiMe2), 0.94 (9 H,
s, But), 1.62 (6 H, m, Ad), 1.92 (6 H, m, Ad), 2.16 (3 H, br s, Ad),
3.51(8) (1 H, d, J 1.1, CHAHB), 3.52(4) (1 H, d, J 1.1, CHAHB);
C −4.8, 18.1, 25.7, 30.9, 36.2, 42.3, 74.6, 77.5, 156.9. Found: C,
69.9; H, 10.6. C18H32O2Si requires C, 70.1; H, 10.5%.
Anhydrous octane and chlorobenzene were obtained commer-
cially (Aldrich); benzene was dried by distillation from sodium
wire and stored under argon. 2,4,6-Trimethylpyridine (collidine),
2,2,6,6-tetramethylpiperidine, N-methylmaleimide, N-phenyl-
maleimide, dimethyl maleate, dimethyl fumarate, 5H-furan-2-
2 5 2 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9

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O-Cyclohexyl O-(tert-butyldimethylsilyl) ketene acetal 3336
was cooled in an ice-water bath before the addition of tetrabutyl-
ammonium fluoride (1 M in THF, 2.2 mL) and the mixture was
stirred at 0 °C for 2 h, followed by the addition of saturated aqueous
NH4Cl solution (10 mL). The mixture was extracted with CH2Cl2
(3 × 10 mL), the combined extracts were dried and the solvent was
removed under reduced pressure. The residue was purified by flash
chromatography on silica gel, using petroleum–diethyl ether (4:1)
as eluent, to give the ester 22c (0.379 g, 73%) as a colourless oil.
Oil, bp 60–64 °C/0.06 mm Hg; H 0.18 (6 H, s, SiMe2), 0.93 (9 H,
s, But), 1.28–1.92 (10 H, m, c-Hex), 3.10 (1 H, d, J 2.2, CHAHB),
3.26 (1 H, d, J 2.2, CHAHB), 3.92 (1 H, tt, J 8.9 and 3.7, OCH);
C −4.5, 18.1, 23.7, 25.6, 25.7, 31.3, 61.3, 75.3, 159.7. Found: C,
65.6; H, 11.2. C14H28O2Si requires C, 65.6; H, 11.0%. Contrary to
suggestions in the literature,36 this compound was obtained in an
analytically pure state after simple distillation.
Reactions with electron-poor alkenes
O-(1R)-Menthyl O-(tert-butyldimethylsilyl) ketene acetal 34
O-tert-Butyl O-(tert-butyldimethylsilyl) ketene acetal 19 (0.920 g,
4.0mmol),phenylvinylsulfone(0.336g,2.0mol),dilauroylperoxide
(39.9 mg, 0.10 mmol) and benzene (4 mL) were added to a dry,
argon-filled flask, containing a magnetic stirrer bar and equipped
with a condenser. The flask was then immersed in an oil bath, pre-
heated to 90 °C, and the reaction mixture was stirred at reflux under
argon for 3 h. The solvent was removed by rotary evaporation and
methyl iodide (2.27 g, 16.0 mmol) and dry THF (2 mL) were added
to the residue. The resulting solution was cooled in an ice-water bath
before the addition of tetrabutylammonium fluoride (1 M in THF,
4.4 mL) and the mixture was stirred at 0 °C for 2 h, followed by the
addition of saturated aqueous NH4Cl solution (15 mL). The mixture
was extracted with CH2Cl2 (3 × 15 mL), the combined extracts were
dried and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography on silica gel, using
petroleum–diethyl ether–CH2Cl2 (17:3:5) as eluent, to give the
sulfone 42a (0.532 g, 89%) as a colourless oil.
This compound was prepared starting from (1R)-(−)-menthyl
acetate (Aldrich, 98% ee by GLC). Oil, bp 88–89 °C/0.05 mm Hg,
[]D21 −80.7 (c = 2.2, CHCl3); H 0.17 (3 H, s, SiMe), 0.18 (3 H, s,
SiMe), 0.77 (3 H, d, J 7.0, Me), 0.89 (3 H, d, J 7.0, Me), 0.91 (3 H, d,
J 7.0, Me), 0.81–0.96 (2 H, masked, ring-H), 0.93 (9 H, s, But), 1.01
(1 H, m, ring-H), 1.35 (2 H, m, ring-H), 1.66 (2 H, m, ring-H), 2.13
(1 H, septet of doublets, J 7.0 and 2.7, Me2CH), 2.22 (1 H, m, ring-
H), 3.13 (1 H, d, J 2.2, CHAHB), 3.23 (1 H, d, J 2.2, CHAHB),
3.72 (1 H, [t]d, J 10.6 and 4.1, H-1); C −4.6, −4.5, 16.3, 18.1, 20.8,
22.1, 23.3, 25.6, 25.8, 31.4, 34.5, 39.6, 47.7, 61.1, 76.9, 159.7.
Found: C, 69.0; H, 11.5. C18H36O2Si requires C, 69.2; H, 11.6%.
O-Bornyl O-(tert-butyldimethylsilyl) ketene acetal 3537
This compound was prepared starting from (1S)-(−)-bornyl acetate
(Aldrich, ca. 90% ee by optical rotation). Oil, bp 85–88 °C/0.05 mm
Hg; H 0.19 (3 H, s, SiMe), 0.20 (3 H, s, SiMe), 0.87(6) (3 H, s, Me),
0.87(9) (3 H, s, Me), 0.89 (3 H, s, Me), 0.94 (9 H, s, But), 1.10 (1 H,
dd, J 13.5 and 3.4, ring-H), 1.22 (1 H, m, ring-H), 1.28 (1 H, m, ring-
H), 1.68 (1 H, [t], J 4.6, ring-H), 1.73 (1 H, m, ring-H), 2.02 (1 H,
m, ring-H), 2.23 (1 H, m, ring-H), 2.95 (1 H, d, J 2.1, CHAHB),
3.24 (1 H, d, J 2.1, CHAHB), 4.07 (1 H, m, OCH); C −4.5, −4.4,
13.8, 18.0, 18.9, 19.7, 25.6, 27.0, 27.8, 36.3, 44.9, 47.5, 49.1, 61.6,
82.8, 161.2. Found: C, 69.8; H, 11.1. C18H34O2Si requires C, 69.6;
H, 11.0%.
Characteristic data for reaction products
The ketones 6a38 and 6b39 and the esters 7a40 and 7b41 showed
physical properties and NMR spectroscopic data in agreement with
those reported in the literature. Characteristic data for products that
have not been reported previously, or are inadequately described in
the literature, are given below.
Ethyl 2-methyl-2-phenacylpropanoate 7c. Oil, 85% yield
from 3; H 1.21 (3 H, t, J 7.1, CH2Me), 1.32 (6 H, s, 2 Me), 3.29
(2 H, s, CH2COPh), 4.13 (2 H, q, J 7.1, OCH2), 7.44–7.95 (5 H,
m, Ph); C 14.1, 25.8, 40.1, 48.4, 60.5, 127.9, 128.5, 133.0, 137.1,
177.3, 197.6. Found: C, 71.8; H, 7.6. C14H18O3 requires C, 71.8;
H, 7.7%.
O-Cyclopropyldimethylcarbinyl O-(tert-butyldimethylsilyl)
ketene acetal 43
Oil, bp 90–92 °C/1.0 mm Hg; H 0.19 (6 H, s, SiMe2), 0.38 (4 H, m,
2 ring-CH2), 0.93 (9 H, s, But), 1.11 (1 H, m, ring-CH), 1.25 (6 H, s,
CMe2), 3.47 (1 H, d, J 1.1, CHAHB), 3.52 (1 H, d, J 1.1, CHAHB);
C −4.9, 1.8, 18.0, 21.0, 25.1, 25.7, 73.3, 79.7, 157.6. Found: C,
65.6; H, 10.9. C14H28O2Si requires C, 65.6; H, 11.0%.
Diethyl phenacylmalonate 7d42. Oil, 84% yield from 3; H 1.29
(6 H, t, J 7.1, 2 CH2Me), 3.62 (2 H, d, J 7.1, CH2COPh), 4.06 (1 H, t,
J 7.1, CH), 4.23 (4 H, m, 2 CH2Me), 7.46–8.00 (5 H, m, Ph); C 14.0,
37.8, 47.2, 61.7, 128.1, 128.6, 133.5, 136.0, 169.0, 196.5. Found: C,
64.9; H, 6.4. C15H18O5 requires C, 64.7; H, 6.5%.
Representative procedures
Reactions with organic halides
Example 1. -1-Admantoxystyrene 4 (0.508 g, 2.0 mmol), -
bromo--butyrolactone (0.660 g, 4.0 mmol), di-tert-amyl peroxide
(69.6 mg, 0.40 mmol), 2,2,6,6-tetramethylpiperidine (33.8 l,
0.20 mmol) and dry chlorobenzene (4 mL) were added to a dry,
argon-filled flask, containing a magnetic stirrer bar and equipped
with a condenser. The flask was then immersed in an oil bath, pre-
heated to 140 °C, and the reaction mixture was stirred at reflux
under argon for 3 h. The solvent was removed by rotary evaporation
and the residue was purified by flash chromatography on silica gel,
using petroleum–diethyl ether–CH2Cl2 (3:1:1) as eluent, to give
the lactone 8a (0.368 g, 90%) as a colourless oil, which was recrys-
tallised from hexane–CH2Cl2, mp 73–75 °C.
Diethyl methyl(phenacyl)malonate 7e. Oil, 91% yield from
3; H 1.24 (6 H, t, J 7.1, 2 CH2Me), 1.60 (3 H, s, Me), 3.67 (2 H,
s, CH2COPh), 4.21 (4 H, q, J 7.1, 2 CH2Me), 7.44–7.98 (5 H, m,
Ph); C 13.9, 20.5, 44.2, 51.5, 61.6, 128.0, 128.6, 133.3, 136.6,
171.6, 196.5. Found: C, 65.7; H, 7.1. C16H20O5 requires C, 65.7;
H, 6.9%.
1-Adamantyl-1-phenylbutan-1,4-dione 7f. Mp 85–87 °C, 78%
yield from 3; H 1.71 and 1.76 (6 H, ABq, J 12.2, Ad), 1.89 (6 H, m,
Ad), 2.06 (3 H, br s,Ad), 2.92 (2 H, t, J 6.5, CH2COAd), 3.24 (2 H, t,
J 6.5, CH2COPh), 7.43–7.99 (5 H, m, Ph); C 28.0, 30.3, 32.2, 36.6,
38.4, 46.2, 128.0, 128.5, 133.0, 136.8, 199.0, 214.3. Found: C, 81.1;
H, 8.2. C20H24O2 requires C, 81.0; H, 8.2%.
Example 2. O-tert-Butyl O-(tert-butyldimethylsilyl) ketene
acetal 19 (0.461 g, 2.0 mmol), diethyl 2-bromo-2-methyl malonate
(0.607 g, 2.4 mmol), dilauroyl peroxide (39.9 mg, 0.10 mmol),
2,4,6-collidine (26.4 l, 0.20 mmol) and cyclohexane (4 mL) were
added to a dry, argon-filled flask, containing a magnetic stirrer
bar and equipped with a condenser. The flask was then immersed
in an oil bath, pre-heated to 90 °C, and the reaction mixture was
stirred at reflux under argon for 3 h. The solvent was removed by
rotary evaporation and ethyl iodide (1.25 g, 8.0 mmol) and dry
THF (2 mL) were added to the residue. The resulting solution
3-Benzenesulfonyl-1-phenylpropan-1-one 7g. Mp 92–94 °C,
84% yield from 4; H 3.50 (2 H, m, CH2), 3.57 (2 H, m, CH2),
7.46–7.97 (10 H, m, Ph); C 31.3, 51.0, 128.0, 128.1, 128.8, 129.4,
133.8, 133.9, 135.8, 139.0, 195.4. Found: C, 65.7; H, 5.2. C15H14O3S
requires C, 65.7; H, 5.1%.
Lactone 8a. Mp 73–75 °C, 90% yield from 4; H 1.98 (1 H,
m, OCH2CHAHB), 2.67 (1 H, m, OCH2CHAHB), 3.17 (2 H, m,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9
2 5 2 5

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CH2COPh), 3.69 (1 H, m, COCH), 4.29 (1 H, ddd, J 10.4, 9.1 and
6.6, OCHAHB), 4.45 (1 H, [t]d, J 8.9 and 2.0, OCHAHB), 7.47–7.99
(5 H, m, Ph); C 29.2, 35.2, 39.4, 66.8, 128.0, 128.7, 133.6, 136.1,
179.1, 197.0. Found: C, 70.5; H, 6.0. C12H12O3 requires C, 70.6;
H, 5.9%.
(lactone), 1732 (ester). Found: C, 55.8; H, 7.1. C8H12O4 requires C,
55.8; H, 7.0%.
Compound 24. Mp 114–116 °C, 91% yield from 19; H 1.68
(12 H, m, Ad), 1.82 (6 H, d, J 2.7, Ad), 1.86 (6 H, d, J 2.7, Ad), 2.04
(6 H, br s, Ad), 2.68 (2 H, t, J 6.6, CH2COAd), 2.82 (2 H, t, J 6.6,
CH2CO2R), 4.86 (2 H, s, OCH2); C 27.6(5), 27.6(9), 27.9, 31.1,
36.4, 36.5, 37.9, 38.3, 45.2, 46.1, 64.6, 172.6, 207.5, 213.7; IR (KBr
disc) 1751 (ester), 1717 (ketone), 1701 (ketone). Found: C, 75.8; H,
8.6. C26H36O4 requires C, 75.7; H, 8.8%.
Lactone 8b. Oil, 55% yield from 3; H 1.39 (3 H, s, Me), 2.15
(1 H, ddd, J 12.7, 7.7 and 3.0, OCH2CHAHB), 2.49 (1 H, d[t],
12.7 and 9.2, OCH2CHAHB), 3.34 and 3.45 (2 H, ABq, J 18.2,
CH2COPh), 4.34 (1 H, [q], J 9.0, OCHAHB), 4.49 (1 H, [t]d, J 9.2
and 3.1, OCHAHB), 7.45–7.96 (5 H, m, Ph); C 23.6, 33.8, 40.0,
45.6, 65.3, 128.0, 128.7, 133.5, 136.5, 181.7, 197.0. Found: C, 71.6;
H, 6.3. C13H14O3 requires C, 71.5; H, 6.5%.
Psuedo ester 25. Mp 98–100 °C (from hexane–CH2Cl2), 59%
yield from 19; H 1.96 (3 H, t, J 6.9, CH2Me), 1.66 (12 H, m, Ad),
1.99 (3 H, br s, Ad), 2.00 (1 H, ddd, J 14.2, 11.3 and 5.4, ring-H),
2.41 (1 H, ddd, J 14.2, 11.4 and 6.6, ring-H), 2.51 (1 H, ddd, J 18.3,
11.4 and 5.4, ring-H), 2.65 (1 H, ddd, J 18.3, 11.3 and 6.6, ring-H),
3.45 (2 H, m, CH2Me); C 15.2, 23.4, 28.0, 29.6, 35.4, 36.9, 40.7,
57.5, 114.8, 176.1; IR (KBr disc) 1760 (lactone). Found: C, 72.7;
H, 9.2. C16H24O3 requires C, 72.7; H, 9.2%. The structure of this
compound was confirmed by X-ray diffraction.
Diones 9a and 9b. These were isolated chromatographically in
63% total yield from 4 as a 64:36 mixture of exo and endo iso-
mers; C (exo + endo) 9.4(5), 9.4(9), 19.3, 19.6, 20.3, 20.4, 21.5,
29.0, 29.2, 31.2, 35.9, 40.7, 45.9, 46.1, 46.6, 46.8, 48.1, 49.0, 57.3,
58.5; (exo) 128.1, 128.6, 133.2, 136.5, 198.1, 221.2; (endo) 128.0,
128.6, 133.2, 136.7, 198.3, 221.1. Found: C, 79.9; H, 8.2. C18H22O2
requires C, 80.0; H, 8.2%.
Reactions of O-alkyl O-silyl ketene acetals with electron-poor
alkenes
exo-Dione 9a. H 0.88 (3 H, s, Me), 0.94 (6 H, s, 2 Me), 1.60
(2 H, m, ring-H), 1.69 (2 H, m, ring-H), 1.96 (1 H, d, J 3.9, bridge-
head-H), 2.68 (1 H, dd, J 9.8 and 2.7, CHCH2COPh), 2.95 (1 H,
dd, J 17.9 and 9.8, CHAHBCOPh), 3.60 (1 H, dd, J 17.9 and 2.7,
CHAHBCOPh), 7.45–7.98 (5 H, m, Ph).
Pyrrolidinedione 30a. Mp 73–75 °C (from hexane–CH2Cl2),
68% yield from 19; H 1.04 (9 H, s, But), 2.36 (1 H, d, J 4.7,
H-3), 2.63 (1 H, dd, J 17.1 and 4.8, CHAHBCO2Me), 2.77 (1 H,
[q], J 4.7, H-4), 2.99 (3 H, s, NMe), 3.03 (1 H, dd, J 17.1 and
4.7, CHAHBCO2Me), 3.67 (3 H, s, OMe); C 24.8, 27.3, 33.7,
35.0, 39.2, 52.0, 54.9, 171.2, 177.6, 178.3; IR (KBr disc) 1763
(imide), 1728 (ester), 1693 (imide). Found: C, 62.9; H, 7.9; N, 5.2.
C12H19NO4 requires C, 62.8; H, 8.1; N, 5.2%.
endo-Dione 9b. H 0.95 (3 H, s, Me), 0.97 (3 H, s, Me), 1.01
(3 H, s, Me), 1.28 (1 H, m, ring-H), 1.44 (1 H, m, ring-H), 1.78
(1 H, m, ring-H), 2.06 (1 H, m, ring-H), 2.30 (1 H, [t], J 4.2, bridge-
head-H), 2.95 (1 H, dd, J 17.9 and 10.0, CHAHBCOPh), 3.12 (1 H,
d[t], J 10.0 and 4.0, CHCH2COPh), 3.46 (1 H, dd, J 17.9 and 3.5,
CHAHBCOPh), 7.45–7.98 (5 H, m, Ph).
Hexanophenone 10 (Aldrich), 3-methyl-1-phenylpentan-1-one43
11 and ethyl 3-methyl-4-oxo-4-phenylbutanoate44 18a showed
spectroscopic data in accord with those of the authentic com-
pounds.
Pyrrolidinedione 30b. Mp 115–117 °C (from hexane–CH2Cl2),
66% yield from 20; H 1.49 (3 H, dd, J 12.0 and 1.8, Ad), 1.64 and
1.71 (6 H, ABq, J 12.3, Ad), 1.83 (3 H, dd, J 12.0 and 1.8, Ad),
2.00 (3 H, br s, Ad), 2.21 (1 H, d, J 4.6, H-3), 2.60 (1 H, dd, J 17.0
and 4.9, CHAHBCO2Me), 2.86 (1 H, [q], J 4.8, H-4), 2.97 (3 H, s,
NMe), 2.99 (1 H, dd, J 17.0 and 4.9, CHAHBCO2Me), 3.66 (3 H,
s, OMe); C 24.7, 28.2, 35.2, 35.8, 36.6, 37.4, 39.5, 52.0, 55.7,
171.2, 177.2, 178.4; IR (KBr disc) 1773 (imide), 1732 (ester),
1697 (imide). Found: C, 67.6; H, 7.9; N, 4.4. C18H25NO4 requires
C, 67.7; H, 7.9; N, 4.4%. The structure of this compound was con-
firmed by X-ray diffraction.
Reactions of O-alkyl O-silyl ketene acetals with organic halides
The products 22a (Aldrich) and 22e45 showed spectroscopic data in
agreement with those of the authentic compounds.
Diethyl 2-methylbutan-1,4-dioate 22b46. Oil, 67% yield from
19; H 1.21 (3 H, d, J 7.2, CHMe), 1.24(8) (3 H, t, J 7.2, CH2Me),
1.25(4) (3 H, t, J 7.2, CH2Me), 2.39 (1 H, dd, J 16.4 and 6.1,
CHAHBCO2Et), 2.72 (1 H, dd, J 16.4 and 8.2, CHAHBCO2Et), 2.89
(1 H, m, CHMe), 4.13 (2 H, q, J 7.2, CH2Me), 4.15 (2 H, q, J 7.2,
CH2CH3); C 14.1, 14.2, 17.0, 35.8, 37.7, 60.5, 60.6, 171.9, 175.3.
Found: C, 57.4; H, 8.7. C9H16O4 requires C, 57.4; H, 8.6%.
Pyrrolidinedione 30c. Mp 76–78 °C (from hexane–CH2Cl2),
70% yield from 33; H 1.00–1.98 (11 H, m, c-Hex), 2.53 (1 H, [t],
J 4.6, H-3), 2.66 (1 H, dd, J 17.0 and 4.6, CHAHBCO2Me), 2.82
(1 H, [q], J 5.1, H-4), 2.93 (1 H, dd, J 17.0 and 5.6, CHAHBCO2Me),
2.99 (3 H, s, NMe), 3.67 (3 H, s, OMe); C 24.8, 25.8(9), 25.9(3),
26.2, 28.4, 30.1, 34.6, 38.6(6), 38.7(0), 50.9, 52.0, 171.2, 178.2,
178.5; IR (KBr disc) 1773 (imide), 1749 (ester), 1699 (imide).
Found: C, 62.8; H, 8.0; N, 5.2. C14H21NO4 requires C, 62.9; H, 7.9;
N, 5.2%.
Ester 22c. Oil, 73% yield from 19; H 1.23 (3 H, t, J 7.1,
CH2Me), 1.25 (6 H, t, J 7.1, 2 CH2Me), 1.53 (3 H, s, Me), 2.92 (2 H,
s, CH2CO2Et), 4.11 (2 H, q, J 7.1, CH2Me), 4.19(2) (2 H, q, J 7.1,
CH2Me), 4.19(4) (2 H, q, J 7.1, CH2Me); C 13.9, 14.1, 20.3, 40.3,
51.6, 60.7, 61.6, 170.3, 171.1. Found: C, 55.4; H, 7.8. C12H20O6
requires C, 55.4; H, 7.7%.
Pyrrolidinedione 31. Mp 141–143 °C (from hexane–CH2Cl2),
67% yield from 20; H 1.23 (3 H, t, J 7.2, CH2Me), 1.49 (3 H, dd,
J 12.0 and 1.8, Ad), 1.64 and 1.71 (6 H, ABq, J 12.3, Ad), 1.84
(3 H, dd, J 12.0 and 1.8, Ad), 2.01 (3 H, br s, Ad), 2.21 (1 H, d, J
4.6, H-3), 2.58 (1 H, dd, J 17.1 and 4.8, CHAHBCO2Et), 2.86 (1 H,
[q], J 4.7, H-4), 2.98 (3 H, s, NMe), 3.02 (1H, dd, J 17.1 and 4.8,
CHAHBCO2Et), 4.11 (2 H, m, CH2Me); C 14.1, 24.7, 28.2, 35.4,
35.8, 36.6, 37.4, 39.4, 55.7, 61.1, 170.7, 177.3, 178.6. Found: C,
68.5; H, 8.3; N, 4.4. C19H27NO4 requires C, 68.4; H, 8.2; N, 4.4%.
Ester 22d. Oil, 83% yield from 19; H 1.24 (3 H, t, J 7.1,
CH2Me), 1.68 and 1.75 (6 H, ABq, J 12.1, Ad), 1.83 (6 H, d, J 2.5,
Ad), 2.04 (3 H, br s, Ad), 2.54 (2 H, t, J 6.5, CH2COAd), 2.76 (2 H,
t, J 6.5, CH2CO2Et), 4.11 (2 H, q, J 7.1, CH2Me); C 14.2, 27.9,
28.0, 31.0, 36.5, 38.3, 46.1, 60.5, 173.1, 213.8; IR (liq. film) 1738
(ester), 1703 (ketone). Found: C, 72.7; H, 9.3. C16H24O3 requires C,
72.7; H, 9.2%.
Pyrrolidinedione 32. Mp 95–97 °C (from hexane–CH2Cl2), 71%
yield from 19; H 1.13 (9 H, s, But), 2.50 (1 H, d, J 4.6, H-3), 2.72
(1 H, dd, J 17.4 and 4.6, CHAHBCO2Me), 2.92 (1 H, [q], J 4.6, H-4),
3.20 (1 H, dd, J 17.4 and 4.6, CHAHBCO2Me), 3.71 (3 H, s, OMe),
7.27–7.48 (5 H, m, Ph); C 27.3, 34.1, 35.3, 39.3, 52.2, 54.9, 126.7,
128.6, 129.1, 132.3, 171.2, 176.7, 177.5. Found: C, 67.3; H, 7.0; N,
4.6. C17H21NO4 requires C, 67.4; H, 7.0; N, 4.7%.
Lactone 23. Oil, 76% yield from 19; H 1.27 (3 H, t, J 7.1,
CH2Me), 2.05 (1 H, m, ring-H), 2.53 (1 H, dd, J 17.0 and 8.7,
CHAHBCO2Et), 2.54 (1 H, m, ring-H), 2.90 (1 H, dd, J 17.0 and 4.0,
CHAHBCO2Et), 2.95 (1 H, m, ring-H), 4.17 (2 H, q, J 7.1, CH2Me),
4.23 (1 H, m, ring-H), 4.40 (1 H, [t]d, J 8.9 and 2.0, ring-H); C
14.1, 28.6, 34.7, 35.9, 61.0, 66.5, 171.2, 178.1; IR (liq. film) 1771
2 5 2 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9

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Pyrrolidinedione 36a. Mp 128–130 °C (from hexane–CH2Cl2),
[]D20 +12.9 (c = 2.0, CHCl3); H 0.65 (1 H, [q], J 11.9, H-6ax), 0.80
(3 H, d, J 6.9, Me), 0.83 (3 H, d, J 6.5, Me), 0.84 (1 H, m, H-4ax),
0.92 (3 H, d, J 6.9, Me), 1.04 (1 H, m, H-2ax), 1.06 (1 H, m, H-3ax),
1.30 (1 H, m, H-6eq), 1.40 (1 H, m, CHMe2), 1.67–1.74 (3 H, com-
plex, H-3eq, H-4eq and H-5ax), 2.15 (1 H, m, H-1ax), 2.58 (1 H,
dd, J 17.3 and 4.8, CHAHBCO2Me), 2.86 (1 H, [q], J 4.9, H-8), 2.96
(1 H, [t], J 4.3, H-7), 3.00 (1 H, dd, J 17.3 and 4.7, CHAHBCO2Me),
3.02 (3 H, s, NMe), 3.69 (3 H, s, OMe); C 15.1, 21.3, 22.5, 23.9,
25.0, 27.2, 32.2, 34.1, 34.8, 35.7, 37.0, 39.2, 43.6, 46.1, 52.1,
171.2, 178.9, 179.7; IR (KBr disc) 1780 (imide), 1725 (ester), 1709
(imide). Found: C, 66.7; H, 9.2; N, 4.4. C18H29NO4 requires C, 66.8;
H, 9.0; N, 4.3%. The structure of this compound was confirmed by
X-ray diffraction.
64.8; H, 8.0. C19H28O6 requires C, 64.8; H, 8.0%. The structure of
this compound was confirmed by X-ray diffraction using crystals
obtained from ethanol.
Trimethyl ester 38b. Oil, 62% yield from 33 and dimethyl
maleate; H 0.95–1.78 (11 H, m, c-Hex), 2.43 (1 H, dd, J 17.1
and 3.1, CHAHBCO2Me), 2.63 (1 H, dd,J 8.3 and 6.6, CHHex-c),
2.79 (1 H, dd, J 17.1 and 11.5, CHAHBCO2Me), 3.27 (1 H, m,
CHCH2CO2Me), 3.64 (3 H, s, Me), 3.67 (3 H, s, Me), 3.71 (3 H,
s, Me); C 26.1, 30.4, 30.6, 32.2, 37.2, 40.5, 51.5, 51.9, 52.1, 52.4,
172.5, 173.1, 174.1. Found: C, 60.0; H, 8.0. C15H24O6 requires C,
60.0; H, 8.1%.
Trimethyl ester 39a. Oil; H 1.57–1.75 (12 H, m, Ad), 1.98 (3 H,
br s, Ad), 2.28 (1 H, d,J 3.5, CHAd), 2.60 (1 H, dd, J 16.7 and 4.7,
CHAHBCO2Me), 2.92 (1 H, dd, J 16.7 and 10.3, CHAHBCO2Me),
3.27 (1 H, m, CHCH2CO2Me), 3.64 (3 H, s, Me), 3.67 (3 H, s, Me),
3.68 (3 H, s, Me).
Pyrrolidinedione 36b. Oil; H (part spectrum only) 0.68 (3 H, d,
J 6.9, Me), 0.84 (3 H, d, J 6.5, Me), 0.92 (3 H, d, J 6.9, Me), 1.98
(1 H, m, H-1ax), 2.96 (3 H, s, NMe), 3.68 (3 H, s, OMe); C 15.0,
21.4, 22.5, 24.2, 24.7, 26.6, 32.8, 34.6, 34.8, 36.6, 41.2, 41.7, 43.5,
46.0, 52.1, 171.3, 177.6, 178.5.
Trimethyl ester 39b. Oil; H 0.95–1.87 (11 H, m, c-Hex), 2.56
(1 H, dd, J 8.0 and 6.0, CHHex-c), 2.61 (1 H, dd, J 16.8 and 4.7,
CHAHBCO2Me), 2.73 (1 H, dd, J 16.8 and 9.1, CHAHBCO2Me), 3.29
(1 H, m, CHCH2CO2Me), 3.67 (3 H, s, Me), 3.69(0) (3 H, s, Me),
3.69(4) (3 H, s, Me).
Pyrrolidinedione 37a. Mp 93–95 °C (from hexane–CH2Cl2),
19
[]D +2.8 (c = 2.1, CHCl3); H 0.74 (1 H, dd, J 12.7 and 5.6, H-
3A), 0.86(4) (3 H, s, Me), 0.86(8) (3 H, s, Me), 0.87(2) (3 H, s, Me),
1.08 (1 H, m, H-6A), 1.42–1.46 (2 H, complex, H-5A and H-6B),
1.64 (1 H, [t], J 4.5, H-4), 1.78 (1 H, m, H-5B), 1.92 (1 H, m, H-
3B), 2.26 (1 H, m, H-2), 2.61 (1 H, dd, J 5.6 and 3.7, H-8), 2.73
(1 H, dd, J 17.0 and 5.1, CHAHBCO2Me), 2.82 (1 H, [q], J 4.4, H-9),
2.99 (3 H, s, NMe), 3.03 (1 H, dd, J 17.0 and 4.8, CHAHBCO2Me),
3.67 (3 H, s, OMe); C 14.4, 18.5, 19.3, 25.1, 28.5, 29.4, 32.2,
35.3, 41.1, 44.2, 46.1, 46.4, 48.5, 49.6, 52.1, 171.1, 178.8, 179.6;
IR (KBr disc) 1767 (imide), 1730 (ester), 1701 (imide). Found:
C, 67.3; H, 8.6; N, 4.4. C18H27NO4 requires C, 67.3; H, 8.5; N,
4.4%. The structure of this compound was confirmed by X-ray
diffraction.
Lactone 41a. Oil, 61% yield from 20; H 1.46 and 1.52 (6 H,
Abq, J 12.0, Ad), 1.63 and 1.73 (6 H, Abq, J 12.0, Ad), 2.01 (3 H,
br s, Ad), 2.06 (1 H, [q], J 7.9, CHAd), 2.69 (1 H, dd, J 16.7 and
4.8, CHAHBCO2Me), 2.80 (1 H, m, CHCH2CO2Me), 2.87 (1 H, dd,
J 16.7 and 5.3, CHAHBCO2Me), 3.71 (3 H, s, Me), 4.20 (1 H, dd,
J 9.3 and 7.0, OCHAHB), 4.31 (1 H, [t], J 9.0, OCHAHB); C 28.1,
33.9, 35.7, 36.1, 36.8, 39.4, 50.2, 52.0, 66.9, 171.5, 178.9; IR (liq.
film) 1774 (lactone), 1740 (ester). Found: C, 69.8; H, 8.4. C17H24O4
requires C, 69.8; H, 8.3%.
Lactone 41b. Oil, 60% yield from 33; H 0.82–1.77 (11 H, m,
c-Hex), 2.24 (1 H, [quintet], J 8.4, CHHex-c), 2.69–2.81 (3 H,
CH2CO2Me and CHCH2CO2Me), 3.70 (3 H, s, Me), 3.97 (1 H, [t],
J 8.9, OCHAHB), 4.39 (1 H, [t], J 8.9, OCHAHB); C 25.9, 26.0, 26.1,
29.6, 31.0, 34.4, 39.5, 40.6, 45.6, 52.0, 69.9, 171.5, 178.5; IR (liq.
film) 1771 (lactone), 1738 (ester). Found: C, 64.9; H, 8.4. C13H20O4
requires C, 65.0; H, 8.4%.
Pyrrolidinedione 37b. Mp 160–162 °C (from hexane–CH2Cl2),
[]D22 +72.7 (c = 2.0, CHCl3); H (C6D6 solvent) 0.57 (3 H, s, Me-
1), 0.65 (3 H, s, Me-7anti), 0.84 (3 H, s, Me-7syn), 0.83 (1 H,
m, H-6A), 0.99 (1 H, m, H-5A), 1.30 (1 H, m, H-6B), 1.54–1.59
(2 H, complex, H-4 and H-5B), 2.18–2.22 (2 H, complex, H–3A
and H–3B), 2.42–2.47 (2 H, complex, H-9 and CHAHBCO2Me),
2.50 (1 H, m, H-8), 2.68 (1 H, m, H-2), 2.77 (1 H, [dd], J 18.4 and
5.6, CHAHBCO2Me), 2.84 (3 H, s, NMe), 3.16 (3 H, s, OMe); C
(CDCl3 solvent) 14.2, 20.0, 20.5, 24.9, 27.1, 33.7, 35.0, 39.9, 44.8,
45.6, 48.0, 48.1, 48.3, 51.8, 52.1, 170.9, 178.5, 178.7; IR (KBr
disc) 1771 (imide), 1744 (ester), 1699 (imide). Peak separation in
Sulfone 42a. Oil, 89% yield from 19; H 0.83 (9 H, s, But), 1.33
(1 H, dd, J 14.7 and 8.3, CHAHBBut), 1.98 (1 H, dd, J 14.7 and 1.4,
CHAHBBut), 2.54 (1 H, dd, J 17.5 and 2.7, CHAHBCO2Me), 2.97
(1 H, dd, J 17.5 and 9.1, CHAHBCO2Me), 3.57 (3 H, s, Me), 3.69
(1 H, [br t], J 8.5, CHSO2Ph), 7.55–7.92 (5 H, m, Ph); C 29.1, 31.0,
35.8, 41.1, 52.1, 57.9, 129.1, 129.3, 133.8, 137.3, 170.7; IR (liq.
film) 1740 (ester), 1306 (sulfone), 1148 (sulfone). Found: C, 60.2;
H, 7.5. C15H22O4S requires C, 60.4; H, 7.4%.
1
the H NMR spectrum was better in C6D6 solvent than in CDCl3.
Found: C, 67.3; H, 8.6; N, 4.4. C18H27NO4 requires C, 67.3; H, 8.5;
N, 4.4%. The structure of this compound was confirmed by X-ray
diffraction.
Pyrrolidinedione 37c. H (part spectrum only) 0.77 (3 H, s, Me),
0.84 (3 H, s, Me), 1.11 (3 H, s, Me), 2.70 (1 H, dd, J 17.5 and 5.0,
CHAHBCO2Me), 2.98 (3 H, s, NMe), 3.16 (1 H, dd, J 17.5 and 4.0,
CHAHBCO2Me), 3.66 (3 H, s, OMe).
Sulfone 42b. Oil, 87% yield from 20; H 1.20 (1 H, dd, J 14.8
and 8.3, CHAHBAd), 1.30 and 1.43 (6 H, Abq, J 12.0, Ad), 1.56
and 1.65 (6 H, Abq, J 12.2, Ad), 1.81 (1 H, dd, J 14.8 and 1.0,
CHAHBAd), 1.91 (3 H, br s, Ad), 2.51 (1 H, dd, J 17.4 and 2.7,
CHAHBCO2Me), 2.93 (1 H, dd, J 17.4 and 9.3, CHAHBCO2Me),
3.57 (3 H, s, Me), 3.75 (1 H, [br t], J 8.4, CHSO2Ph), 7.54–7.91
(5 H, m, Ph); C 28.3, 32.7, 36.1, 36.6, 41.9(0), 41.9(4), 52.1,
56.1, 129.0, 129.3, 133.8, 137.3, 170.7; IR (liq. film) 1739 (ester),
1306 (sulfone), 1148 (sulfone). Found: C, 67.0; H, 7.6. C21H28O4S
requires C, 67.0; H, 7.5%.
Pyrrolidinedione 37d. H (part spectrum only) 0.85 (3 H, s,
Me), 0.86 (3 H, s, Me), 0.87 (3 H, s, Me), 2.61 (1 H, dd, J 10.3
and 4.5, H-8), 3.00 (3 H, s, NMe), 3.06 (1 H, dd, J 17.1 and 4.3,
CHAHBCO2Me), 3.68 (3 H, s, OMe).
Trimethyl ester 38a. Mp 87–89 °C (from hexane–CH2Cl2 or
from ethanol), 70% yield from 20 and dimethyl maleate; H 1.53
(3 H, d, J 12.0, Ad), 1.62 and 1.69 (6 H, Abq, J 12.0, Ad), 1.75 (3 H,
d, J 12.0, Ad), 1.98 (3 H, br s, Ad), 2.55 (1 H, dd, J 16.8 and 3.3,
CHAHBCO2Me), 2.56 (1 H, d,J 5.9, CHAd), 2.71 (1 H, dd, J 16.8
and 11.0, CHAHBCO2Me), 3.25 (1 H, m, CHCH2CO2Me), 3.64 (3 H,
s, Me), 3.66 (3 H, s, Me), 3.71 (3 H, s, Me); C 28.5, 35.0, 35.5, 36.7,
38.3, 39.8, 51.1, 51.8, 52.2, 57.1, 172.3, 172.6, 174.9. Found: C,
Sulfone 42c. Oil, 80% yield from 33; H 0.83–1.64 (11 H, m, c-
Hex), 1.38 (1 H, ddd, J 14.3, 9.1 and 5.4, CHAHBHex-c), 1.78 (1 H,
ddd, J 14.3, 8.8 and 4.5, CHAHBHex-c), 2.46 (1 H, dd, J 16.8 and
5.9, CHAHBCO2Me), 2.87 (1 H, dd, J 16.8 and 6.7, CHAHBCO2Me),
3.61 (3 H, s, Me), 3.70 (1 H, m, CHSO2Ph), 7.55–7.90 (5 H, m,
Ph); C 25.8, 26.0, 26.2, 32.1, 33.6, 33.7, 34.7, 35.8, 52.2, 58.6,
129.0(6), 129.1(4), 133.8, 137.3, 170.8; IR (liq. film) 1742 (ester),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 5 1 7 – 2 5 2 9
2 5 2 7

View Article Online
1308 (sulfone), 1148 (sulfone). Found: C, 62.8; H, 7.5. C17H24O4S
requires C, 62.9; H, 7.5%.
217 parameters gave R = 0.0521 (Rw = 0.1255) for 4058 indepen-
dent reflections [I > 2(I)] and R = 0.0694 (Rw = 0.1363) for all
3215 independent reflections for  in the range 1.95 to 28.30°. The
final electron density map was featureless with the largest peak
0.366 e Å−3.
Annulation product 46. Mp 182–184 °C (from hexane–
CH2Cl2), 30% yield from 43; H 0.85 (3 H, s, CMe), 0.89 (3 H,
s, CMe), 1.21 (1 H, m, H–7A), 1.72 (1 H, m, H–7B), 1.85 (1 H,
m, H–8A), 2.23 (1 H, dd, J 13.0 and 6.1, H–8B), 2.78 (1 H, dd,
J 17.0 and 5.2, CHAHBCO2Me), 2.82 (1 H, [q], J 4.6, H-14), 2.87
(1 H, m, H-6), 2.96 (3 H, s, NMe), 3.01 (3 H, s, NMe), 3.13 (1 H,
dd, J 17.0 and 3.6, CHAHBCO2Me), 3.23 (1 H, [t], J 8.7, H-1),
3.56 (1 H, [t], J 8.4, H-5), 3.72 (3 H, s, OMe), 4.09 (1 H, d, J 4.9,
H-10); C 20.1, 24.4, 24.8, 25.1, 25.3, 28.4, 34.4, 36.8, 38.9, 45.3,
45.7, 50.3, 52.0, 53.2, 171.6, 178.6, 178.7, 180.1, 180.2; IR (KBr
disc) 1767 (imide), 1736 (ester), 1695 (br, imide). Found: C, 60.3;
H, 6.9; N, 7.3. C19H26N2O6 requires C, 60.3; H, 6.9; N, 7.4%. The
structure of this compound was confirmed by X-ray diffraction and
is shown in Fig. 1.
Crystal data for the pyrrolidinedione 36a. Data collected
at 293 K. C18H29NO4, M = 323.42, orthorhombic, space group
P212121, a = 8.1750(15), b = 10.6612(19), c = 20.842(4) Å,
U = 1816.5(6) Å3, Z = 4, F(000) = 704, Dc = 1.183 g cm−3, (Mo-
K) = 0.083 mm−1, colourless crystal 0.48 × 0.45 × 0.37 mm3. Full
matrix least-squares refinement on 209 parameters gave R = 0.0474
(Rw = 0.1281) for 4055 independent reflections [I > 2(I)] and
R = 0.0494 (Rw = 0.1301) for all 4242 independent reflections for
 in the range 1.95 to 28.34°. The final electron density map was
featureless with the largest peak 0.202 e Å−3.
Crystal data for the pyrrolidinedione 37a. Data collected at
150 K. C18H27NO4, M = 321.41, orthorhombic, space group C2221,
a = 8.2843(8), b = 10.1695(9), c = 41.757(4) Å, U = 3517.9(6) Å3,
Z = 8, F(000) = 1392, Dc = 1.214 g cm−3, (Mo-K) = 0.085 mm−1,
colourless crystal 0.50 × 0.42 × 0.03 mm3. Full matrix least-squares
refinement on 208 parameters gave R = 0.0879 (Rw = 0.2223)
for 3685 independent reflections [I > 2(I)] and R = 0.0976
(Rw = 0.2304) for all 4212 independent reflections for  in the range
1.95 to 28.26°. The final electron density map was featureless with
the largest peak 0.742 e Å−3.
Annulation product 47. Mp 168–170 °C (from methanol),
37% yield from 43; H 1.01 (3 H, s, CMe), 1.07 (3 H, s, CMe),
1.43 (1 H, m, H–7A), 1.82 (1 H, m, H–7B), 1.93 (1 H, m, H–8A),
2.35 (1 H, dd, J 13.1 and 6.1, H–8B), 2.83 (1 H, dd, J 17.5 and 4.6,
CHAHBCO2Me), 2.94–3.00 (2 H, complex, H-6 and H-14), 3.19
(1 H, dd, J 17.5 and 4.2, CHAHBCO2Me), 3.37 (1 H, [t], J 8.7, H-1),
3.67 (3 H, s, OMe), 3.80 (1 H, [t], J 8.4, H-5), 4.24 (1 H, d, J 4.8,
H-10), 7.21–7.49 (10 H, m, 2 Ph); C 20.2, 24.5, 25.5, 28.9, 34.8,
37.3, 39.0, 45.4, 45.7, 50.5, 52.0, 53.6, 126.6, 126.7, 128.6, 128.7,
129.1, 129.2, 132.1, 132.2, 171.6, 177.7, 177.8, 179.1, 179.2; IR
(KBr disc) 1773 (imide), 1729 (ester), 1700 (br, imide). Found: C,
69.1; H, 6.0; N, 5.6. C29H30N2O6 requires C, 69.3; H, 6.0; N, 5.6%.
Crystal data for the pyrrolidinedione 37b. Data collected at
293 K. C18H27NO4, M = 321.41, orthorhombic, space group P212121,
a = 6.9054(5), b = 9.2827(7), c = 27.029(2) Å, U = 1732.6(2) Å3,
Z = 4, F(000) = 696, Dc = 1.232 g cm−3, (Mo-K) = 0.086 mm−1,
colourless crystal 0.48 × 0.16 × 0.08 mm3. Full matrix least-squares
refinement on 208 parameters gave R = 0.0588 (Rw = 0.1452)
for 3589 independent reflections [I > 2(I)] and R = 0.0672
(Rw = 0.1513) for all 4169 independent reflections for  in the range
1.51 to 28.30°. The final electron density map was featureless with
the largest peak 0.245 e Å−3.
X-Ray crystallography|| ||
Single crystals were mounted on glass fibres and all geometric and
intensity data were collected from these samples using a Bruker
SMART APEX CCD diffractometer, in conjunction with graphite-
monochromated Mo-K radiation ( = 0.71073 Å). Data reduction
and integration were carried out with Bruker SAINT+ software47
and absorption corrections were applied using the program
SADABS.48 Structures were solved by direct methods and
developed using alternating cycles of least-squares refinement and
difference-Fourier synthesis. All non-hydrogen atoms were refined
anisotropically. Hydrogen atoms were placed in calculated positions
and their thermal parameters linked to those of the atoms to which
they were attached (riding model). Structure solution and refine-
ment used the SHELXTL PLUS V6.12 program package.49
Crystal data for the trimethyl ester 38a. Data collected at
150 K. C19H28O6, M = 352.41, orthorhombic, space group Pbca, a =
16.5381(12), b = 11.3348(8), c = 19.0816(14) Å, U = 3577.0(4) Å3,
Z = 8, F(000) = 1520, Dc = 1.309 g cm−3, (Mo-K) = 0.096 mm−1,
colourless crystal 0.38 × 0.08 × 0.06 mm3. Full matrix least-squares
refinement on 226 parameters gave R = 0.0802 (Rw = 0.1464)
for 3387 independent reflections [I > 2(I)] and R = 0.1112
(Rw = 0.1589) for all 4396 independent reflections for  in the range
2.13 to 28.31°. The final electron density map was featureless with
the largest peak 0.342 e Å−3.
Crystal data for the pseudo ester 25. Data collected at
150 K. C16H24O3, M = 264.35, monoclinic, space group P21/c,
a = 12.9963(15), b = 15.2812(17), c = 15.4858(17) Å,  =
113.494(2)°, U = 2820.5(5) Å3, Z = 8, F(000) = 1152, Dc =
1.245 g cm−3, (Mo-K) = 0.084 mm−1, colourless crystal
0.48 × 0.46 × 0.38 mm3. Full matrix least-squares refinement on
353 parameters gave R = 0.0572 (Rw = 0.1588) for 5697 indepen-
dent reflections [I > 2(I)] and R = 0.0634 (Rw = 0.1661) for all
6578 independent reflections for  in the range 1.71 to 28.32°. The
terminal carbon atom of the ethyl group is disordered over two sites
with 50% occupancy; the hydrogen atoms are omitted from the dis-
ordered model. The final electron density map was featureless with
the largest peak 0.475 e Å−3.
Crystal data for the annulation product 46. Data collected at
150 K. C19H26N2O6, M = 378.42, orthorhombic, space group Pbca,
a = 18.717(3), b = 10.0246(14), c = 19.808(3)Å, U = 3716.6(10)Å3,
Z = 8, F(000) = 1616, Dc = 1.353 g cm−3, (Mo-K) = 0.101 mm−1,
colourless crystal 0.60 × 0.45 × 0.09 mm3. Full matrix least-squares
refinement on 249 parameters gave R = 0.0629 (Rw = 0.1335)
for 4548 independent reflections [I > 2(I)] and R = 0.0748
(Rw = 0.1391) for all 3899 independent reflections for  in the range
2.06 to 28.30°. The final electron density map was featureless with
the largest peak 0.44 e Å−3. The structure is shown in Fig. 1.
Crystal data for the pyrrolidinedione 30b. Data collected
at 150 K. C19H27NO4, M = 333.42, monoclinic, space group
P21/c, a = 6.7197(6), b = 20.8230(17), c = 12.2379(10) Å,
 = 98.890(2), U = 1691.8(2) Å3, Z = 4, F(000) = 720, Dc =
Acknowledgements
We are grateful to Dr A. E. Aliev for his help in assigning a num-
ber of 1H NMR spectra. Support for this work from the EPSRC is
acknowledged.
1.309
g
cm−3, (Mo-K) = 0.091 mm−1, colourless crystal
0.36 × 0.12 × 0.08 mm3. Full matrix least-squares refinement on
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