Synthesis and Claisen rearrangement of bridged bicyclic enol ethers of relevance to the course of ketene s-cis-diene cycloaddition

Article abstract of DOI:10.1039/b611311g

The synthesis is described of a range of 3-alkylidene-2-oxabicyclo[2.2.1] hept-5-ene and 3-alkylidene-2-oxabicyclo[2.2.2]oct-5-ene derivatives; Claisen rearrangement of these substrates either thermally or in the presence of an added Lewis acid results in

Full text of DOI:10.1039/b611311g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and Claisen rearrangement of bridged bicyclic enol ethers of
relevance to the course of ketene s-cis-diene cycloaddition
Jeremy Robertson* and Thomas G. Fowler
Received 4th August 2006, Accepted 5th October 2006
First published as an Advance Article on the web 24th October 2006
DOI: 10.1039/b611311g
The synthesis is described of a range of 3-alkylidene-2-oxabicyclo[2.2.1]hept-5-ene and 3-alkylidene-
2-oxabicyclo[2.2.2]oct-5-ene derivatives; Claisen rearrangement of these substrates either thermally
or in the presence of an added Lewis acid results in the formation of bicyclic cyclobutanones with
generally good conversions. These reactions may be performed in hydroxylic solvents, supporting a
largely non-dissociative pathway for the rearrangement.
Introduction
Theoretical and experimental support for a preferred hetero-
Diels–Alder/Claisen rearrangement pathway1 (Scheme 1) for the
overall [2 + 2]-cycloaddition of diphenylketene and cyclopenta-
diene contributed to a revision of the prevailing view2 of the
mechanism of this classical reaction.3 Examples of this sense of
periselectivity in related cycloadditions had been recorded4 but
the significance of these observations and their potential extent
were perhaps under appreciated. In a later account,5 Yamabe and
Machiguchi noted that the course of ketene–diene cycloadditions
is responsive to the nature of the diene. Thus, the first-formed
products from acyclic dienes—largely s-trans—were reported to
be mixtures of [2alkene + 2alkene] and [4diene + 2carbonyl] cycloadducts
whereas those from cyclic dienes—constrained to be s-cis—were
Scheme 1 Yamabe–Machiguchi mechanism for cyclic diene + ketene
reaction.
reportedly just the [4 + 2] cycloadducts (such as enol ether 1).
of enantiomerically-enriched substrates in a separate account in
which we draw conclusions about the stereospecificity of the
process, under various reaction conditions, and its potential
application in enantioselective synthesis.
The final, stable, products from these reactions were shown to
be overall [4 + 2] and [2 + 2] adducts from acyclic and cyclic
dienes respectively. Ghosez had reported a similar correlation of
product with diene conformation in his study of the cycloadditions
of dimethylketene dimethyliminium tetrafluoroborate; notably,
[4 + 2] alkene–iminium cycloadducts were obtained with either
cyclopentadiene or cyclohexadiene.6
Results and discussion
Following the publication of Yamabe and Machiguchi’s initial
report we sought to address, by experiment,7 some of the questions
raised by their observations: is the formal [3,3]-rearrangement
step an essentially concerted, intramolecular Claisen process, or
is it highly asynchronous or even dissociative, proceeding, in the
latter case, through the free ketene; could we prepare a range of
examples of the bicyclic enol ethers (such as 1) and allow them to
progress to bicyclic cyclobutanones (such as 2) that, for example,
might not be available by formal [2 + 2]-cycloaddition; could we
then prepare these intermediates enriched in one enantiomer as an
alternative access to non-racemic cyclobutanones? In this paper we
describe the results of our efforts to find reliable, flexible methods
for the rational synthesis of the bicyclic enol ethers and detail
the course of Claisen rearrangement of these enol ethers in the
racemic series. We will present the preparation and rearrangement
Because 2-oxabicyclo[2.2.1]heptan-3-one (3, Scheme 2) was
expected8 to be unstable at room temperature, we took the
olefination of the analogous [2.2.2]-lactone 49 as our starting
point. Menger reported10 that Tebbe methylenation of bicyclic
lactones in the [3.3.1] and [3.2.1] series requires special care
and, in our hands, treatment of lactone 4 with freshly-prepared
Tebbe reagent afforded a product of ring-opening, cyclohexenol
derivative 5. Switching to a less Lewis acidic reagent mixture, we
applied Chapleur’s protocol11 to give dichloromethylene bicycle
6 in moderate yield; a slightly higher yield could be obtained
using the anion formed12 by metal–halogen exchange of diethyl
(trichloromethyl)phosphonate but this reaction proved unreliable.
This compound (6) was stable at room temperature but complete
rearrangement (→713) could be achieved in toluene at reflux for
24 h. Clearly, under the traditional conditions for the generation
of dichloroketene (e.g. trichloroacetyl chloride + Zn), and (cyclic)
diene cycloaddition in situ, the so-formed Lewis acid (ZnCl2) is
able to catalyse rearrangement of the putative hetero-Diels–Alder
adduct and that intermediate is simply not seen.
Department of Chemistry, University of Oxford, Chemistry Research Labo-
ratory, Mansfield Road, Oxford, UK OX1 3TA. E-mail: jeremy.robertson@
chem.ox.ac.uk; Tel: +44 (0)1865 275660
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Scheme 4 Synthesis of a bicyclo[3.2.1] substrate. Reagents and conditions:
(i) CHCl3, DBU, 20 ◦C, 16 h (82%); (ii) NPSP, CSA, CH2Cl2, 0 →
20 ◦C (33%; 66% of theoretical); (iii) aq. H2O2, THF, 0 ◦C, 0.5 h (79%);
(iv) t-BuOK, THF, 0 ◦C, 2 h (81%).
Scheme 2 Exploratory studies from lactone 4. Reagents and conditions:
(i) Tebbe reagent, pyridine, THF, PhMe, −48 → 20 ◦C, 1.5 h (72% from 4);
(ii) PPh3, CCl4, THF, reflux, 18 h (35%); (iii) Cl3CPO.(OEt)2, LiCl, BuLi,
THF, −78 → 20 ◦C, 2 h (58%); (iv) PhMe, reflux, 24 h (89%).
Attempts to generalise this chemistry met with little success,
largely through our inability to identify flexible conditions for
the olefination; however, a Takai olefination14 gave vinyl silane
8 (Fig. 1) in acceptable yield, but subsequent thermolysis gave
slow conversion to a complex product mixture, the reaction
presumably being complicated by desilylation or rearrangement
of the predicted a-(trimethylsilyl)cyclobutanone. A totally dif-
ferent approach was needed and our attention turned to the
selenoetherification15 of cycloalkenyl trichloromethyl carbinols, an
unprecedented16 reaction that would allow flexibility in the order
of formation of the two alkenes (Scheme 3).
Fig. 2 ORTEP representation of bicyclic selenoether 21.18
presumably, cyclisation of the second diastereomer (to give the
endo-isomer) is hampered by crowding in the transition state
between the sterically demanding trichloromethyl group and the
three-carbon bridge. The sequential eliminations, of selenoxide
and then HCl, proceeded without incident and bicyclic enol ether
22 was obtained in good yield. As expected,10 this substrate
required forcing conditions (benzene, 200 ◦C, sealed tube) to
react and decomposition predominated; however, this sequence
had established the viability of the proposal outlined in Scheme 3
and a substrate (23, Scheme 5) was targeted that was tailored to
cyclise preferentially to a bicyclo[2.2.2] system.
Fig. 1
The sequence from carbinol 23 worked well and substrate 25
rearranged cleanly at 80 ◦C to give the formal [2 + 2]-cycloadduct
of dichloroketene and 1,4-dimethylcyclohexa-1,3-diene, 26.19 An-
ticipating an accelerating effect on the [3,3]-rearrangement of a
protic solvent system,20 enol ether 25 was warmed in an NMR
tube in d4-methanol–D2O and, indeed, the reaction was found to
be significantly more rapid, being largely complete within 16 h at
60 ◦C. Importantly, this result strongly supports an intramolecular,
largely non-dissociative, pathway for the rearrangement since any
dichloroketene, formed in a retro-[4 + 2] process, would be rapidly
trapped by the solvent under these conditions.
Scheme 3 Trichloromethyl carbinol cyclisation and double elimination.
This idea was easily tested (Scheme 4) following trichloromethyl
transfer17 to commercially-available aldehyde 20. Of the two
diastereomers formed (16, 1 : 1 ratio) only one cyclised on treat-
ment with NPSP–CSA to afford exo-trichloromethyl selenoether
21 as crystals of suitable quality for X-ray analysis (Fig. 2);18
In the bicyclo[2.2.1] series, cyclisation of trichloromethyl-
carbinol 15 (Scheme 6) proceeded stereoselectively to give the
bicyclic ether 17 as a single diastereomer presumed to be that
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Scheme 5 Synthesis and rearrangement of bicyclo[2.2.2] substrate 25.
Reagents and conditions: (i) methacrolein, ZnCl2, CH2Cl2, 0 → 20 ◦C,
24 h (69%); (ii) LDA, CHCl3, THF, −78 ◦C, 2 h (97%); (iii) NPSP,
CSA, CH2Cl2, 0 → 20 ◦C (89%); (iv) aq. H2O2, THF, 0 ◦C, 0.5 h (90%);
(v) t-BuOK, THF, 0 ◦C, 2 h (quant.); (vi) C6D6, reflux, 27 h (quant.);
(vii) CD3OD, 60 ◦C, 16 h.
Scheme 7 Reagents and conditions: (i) LDA, CH2Br2, THF, −78 ◦C, 0.5 h
(86%); (ii) NPSP, CSA, CH2Cl2, 0 → 20 ◦C (89%); (iii) t-BuOK, THF, 0 →
20 ◦C, 3 h (91%); (iv) Na2CO3·1.5H2O2, aq. THF, 0 → 20 ◦C, 16 h (91%);
(v) C6D6, 100 ◦C, 10 h (27%); (vi) Me2AlCl, CH2Cl2, 0 ◦C, 10 min (72%).
by NOE as indicated). From the exo-situated dibromomethyl
diastereomer, we ascribe this stereoselectivity to E2-elimination
(reacting groups shown in blue) through a transition state deriving
from conformation II (Fig. 3) above conformation I which suffers
from a steric clash between the retained bromine atom and the
proximal bridgehead methyl group (clashing groups shown in
red); from the endo-diastereomer (that is differentiated from the
exo-isomer solely by the location of the PhSe substituent) an
equivalent interaction in conformation III (red groups) slows
down elimination, favouring reaction through conformation IV.
The influence of the bridgehead methyl group here is supported by
the result of double elimination of HBr from substrate 14 (Fig. 1)
in which both olefin diastereomers were obtained in almost equal
proportion.
Scheme 6 Results in the bicyclo[2.2.1] series. Reagents and conditions:
(i) LDA, CHCl3, THF, −98 → −80 ◦C (53%); (ii) NPSP, CSA, CH2Cl2,
reflux, 16 h (81%); (iii) t-BuOK, THF, 0 → 20 ◦C, 4.25 h (67%); (iv) aq.
H2O2, pyridine, THF, 0 → 20 ◦C, 10 h (quant.).
shown. In this case the elimination steps had to be performed in
the order: (1) loss of HCl; (2) selenoxide elimination. When the
selenoxide elimination was attempted first, no isolable products
could be obtained after standard work-up; it is probable that this
2-oxanorbornene system is unstable with respect to cycloreversion
to cyclopentadiene and chloral.21 Under the conditions of the
selenoxide elimination, the expected bicyclic diene (19) was not
obtained, the product immediately rearranging to the cyclobu-
tanone (28)22 in quantitative yield.
Next, we sought a modification to this chemistry that would
allow flexibility in the range of enol ethers that could be generated,
and a series of plausible olefin precursors (9–13, Fig. 1) was
prepared by methods analogous to those used to prepare the
trichloromethyl derivatives.23 Ultimately, none of these proved
useful; for example, whilst nitrile 12 could be deprotonated (with
LDA) and alkylated a- to the cyano group with benzyl bromide,
we were unable to achieve elimination of cyanide and, under basic
conditions, ring-opening was observed instead.
However, selenocyclisation of dibromomethyl adduct 30
(Scheme 7) and consecutive eliminations led to vinyl bromide 32,
which was envisaged as a potential substrate for cross-coupling
chemistry to give a range of substrates for a study of the influence
of electronic effects on the course of the rearrangement step. The
bromide (32) was produced as a single diastereomer (established
Fig. 3 Conformers in the elimination leading to vinyl bromide 32.
We found that bromide 32 rearranged inefficiently in d6-benzene
at 100 ◦C, showing merely a 27% conversion to product after 10 h;
prolonged heating led to significant decomposition. However, of
importance to further work in this area, and of relevance to
the more general observation of formal [2 + 2]-cycloadditions,
the rearrangement could be effected cleanly at 0 ◦C with 0.2
equivalents of dimethylaluminium chloride in dichloromethane;
under these conditions the product (33) was obtained as a 3 : 1
diastereomeric mixture at the carbonyl a-centre.
Two modifications to this route were made (Scheme 8): (1) the
route was shortened and more easily effected on a large scale by
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+
relationship using rp with a negative value of the reaction
constant, q.27
Conclusions
This investigation has led to the development of general routes to
functionalised methylene oxabicyclic compounds in the [2.2.1] and
[2.2.2] series, permitting a study of their Claisen rearrangement
under controlled conditions. A substrate in the [2.2.1] series
rearranged spontaneously under the conditions (selenoxide elimi-
nation) used to form it; in the [2.2.2] series, in the absence of an
added Lewis acid, thermolysis is necessary and there is evidence
of competing cycloreversion over a period of hours at 100 ◦C.
Scheme 8 Stille cross-coupling route to a variety of aryl-substituted
cyclobutanones. Reagents and conditions: (i) NBS, CSA, CH2Cl2, 0 →
20 ◦C, 4 h (91%); (ii) t-BuOK, THF, 0 → 20 ◦C, 16 h (96%); (iii) t-BuLi,
THF, Me3SnCl, −78 → 20 ◦C, 1 h then (iv) ArI, PdCl2(PPh3)2, DMF,
60 ◦C, 16 h; (v) C6D6, 100 ◦C (see Table 1).
Experimental
General procedure for selenocyclisation
To a stirred solution of the trichloromethyl- or dibromomethyl-
carbinol (0.15 M in dichloromethane) at 0 ◦C was added
camphorsulfonic acid (CSA, 0.1 equivalents) and N-(phenyl-
seleno)phthalimide (NPSP, 1.25 equivalents). After 30 min, the
cooling bath was removed and stirring continued until TLC
analysis showed complete consumption of the starting carbinol
whereupon the mixture was concentrated in vacuo and purified by
column chromatography.
employing bromoetherification to produce the bicyclic structure
because both alkene functions could then be introduced in a single
step by double elimination (→32); (2) because the vinyl bromide
proved unreactive under conventional Stille-type cross-coupling
conditions, stannyl substrate 35 was targeted, the electron rich
enol ether being better suited as the nucleophilic component in
the coupling chemistry. It proved most convenient to quench the
derived vinyl lithium intermediate 34 with trimethyltin bromide
and to simply concentrate the reaction mixture to give a residue
that was taken directly into DMF for Stille cross-coupling.24 In
this way, we avoided exposure of the somewhat unstable stannane
(35) to aqueous reagents and chromatography, with attendant
gains in overall yield; furthermore, the co-formed LiCl/LiBr
was automatically present in the cross-coupling reaction mixture,
with the beneficial25 result of lowering the temperature needed to
achieve successful cross-coupling.
General procedure for bromine–tin exchange and Stille
cross-coupling
To a stirred solution of bromide 32 (0.1 M in THF) at −78 ◦C was
added tert-butyllithium (2.2 equivalents of a 1.7 M solution in
pentane). After 30 min, trimethyltin chloride (1.2 equivalents of a
1.0 M solution in hexanes) was added and, after a further 10 min,
the mixture was allowed to warm to RT and concentrated in vacuo
[Data for stannane 35: dH (200 MHz, C6D6) 0.46 (9 H, s, Sn(CH3)3),
1.10–1.90 (4 H, m, 2 × CH2) overlays 1.32 (3 H, s) and 1.41 (3 H, s,
A series of electronically-differentiated para-substituted phenyl
derivatives was prepared in this way (Table 1) and their rear-
rangement chemistry studied. Interestingly, we observed a general
inverse correlation of rate of [3,3]-rearrangement with electron de-
ficiency, the most electron rich substrate (36, entry 1) approaching
=
2 × CH3), 4.51 (1 H, s, CHSnMe3), 5.96 (1 H, d, J 8.0) and 6.05
=
(1 H, d, J 8.0, HC CH)]. The residue was re-dissolved in DMF
(to give a 0.3 M solution), treated with the appropriate aryl iodide
(1.0 equivalent) and PdCl2(P◦Ph3)4 (5 mol%), and the resulting
stirred solution heated to 60 C for 16 h. The mixture was then
allowed to cool to RT then stirred with sat. aq. KF (10 mL mmol−1)
for 10 min and extracted with ether (3 × 20 mL mmol−1). The
combined organic extracts were washed successively with sat. aq.
KF (20 mL mmol−1), 2.0 M aq. K2CO3 (2 × 20 mL mmol−1), water
(20 mL mmol−1) and brine (20 mL mmol−1), and were then dried
over Na2SO4, concentrated in vacuo and the product isolated after
column chromatography.
◦
completion26 within 10 h at 100 C whilst rearrangement of the
most electron deficient substrate (40, entry 5) was incomplete after
100 h at this temperature. Epimerisation at the carbonyl a-centre
became pronounced in the slower reactions (e.g. entries 4 and 5).
These qualitative rate effects are consistent with the trends
observed in White’s and Goering’s classic studies in which the
Claisen rearrangements of a variety of para-substituted allyl
phenyl ethers were found to be well described by a Hammett
Table 1 Results for Stille cross-coupling and [3,3]-rearrangement
Entry
ArI
Enol ether (% yield)
Time/h for rearrangement
Cyclobutanone (% yield)
1
2
3
4
5
6
p-MeOC6H4I
p-MeC6H4I
PhI
p-F3CC6H4I
p-O2NC6H4I
2-Iodofuran28
36 (79)
37 (77)
38 (66)
39 (61)
40 (55)
41 (52)
10
16
30
100
100
22
42 (78)
43 (89)
44 (73)
45 (51)
46 (36)
47 (67)
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cis-4-(2-Propenyl)cyclohex-2-en-1-ol (5)29
8,8-Dichlorobicyclo[4.2.0]oct-2-en-7-one (7)13
To a stirred solution of lactone 4 (128 mg, 1.03 mmol) in a mixture
of THF (0.5 mL), toluene (1.5 mL) and pyridine (10 lL) at −48 ◦C
was added dropwise Tebbe reagent (4.1 mL of a 0.5 M solution
in toluene, 2.05 mmol). The mixture was stirred for 30 min then
allowed to warm to RT over 90 min before being re-cooled to
Enol ether 6 (71 mg, 0.37 mmol) was heated under reflux in toluene
(5 mL). After 24 h, the mixture was concentrated in vacuo and the
residue purified by column chromatography (5 : 1 petrol : ethyl
acetate) to afford the product (7) (63 mg, 89%) as an oil. Rf 0.66
(1 : 1 petrol : ethyl acetate); mmax (thin film)/cm−1 2930m, 1801s,
1436w, 1394w, 1343w, 1286w, 1129w, 1094w, 1051w; dH (400 MHz,
CDCl3) 1.65 (1 H, ddt, J 13.6, 10.4, 6.0, COCHCHHꢀ), 2.01–2.22
(3 H, m, COCHCHHꢀCHHꢀ), 3.44–3.49 (1 H, m, CHCCl2), 4.12
(1 H, ddd, J 9.2, 6.0, 3.2, CHCO), 5.87–5.90 and 6.07–6.12 (2 H,
◦
−10 C and quenched with NaOH (0.3 mL of a 4.0 M solution,
1.2 mmol). The mixture was allowed to warm to RT, diluted with
ether, dried over Na2SO4 and concentrated in vacuo. Purification by
column chromatography on basic alumina (ethyl acetate) afforded
the product (5) as an oil (102 mg, 72%). Rf not recorded; mmax
(thin film)/cm−1 3381s, br, 2938s, 1642m, 1451m, 1049m, 891m;
dH (400 MHz, C6D6) 1.55–1.81 (4 H, m, 2 × CH2) overlays 1.71
=
m, HC CH); dC (50 MHz, CDCl3) 18.8, 20.8, 44.2, 53.3, 86.7,
123.0, 132.4, 196.7; m/z (EI+) 192 (4%, M(37Cl35Cl)+), 190 (8), 127
(12), 99 (12), 92 (15), 91 (95), 89 (16), 80 (64), 79 (100).
=
(3 H, s, CH3), 2.56–2.59 (1 H, m, CHC(Me) CH2), 4.07–4.12
=
(1 H, m, CHOH), 4.93 (2 H, s, CH2), 5.73 (1 H, dd, J 10.1, 2.8,
2,2,2-Trichloro-1-(cyclohex-3-enyl)ethanol (16)
=
=
CH CHCHOH) and 5.90 (1 H, app. dt, J 10.1, 3.0, CHCHOH);
dC (100 MHz, C6D6) 21.4, 24.0, 30.4, 43.4, 64.8, 111.5, 131.2, 132.8,
To a stirred solution of 3-cyclohexene-1-carboxaldehyde (20)
(0.59 mL, 5.03 mmol) in chloroform (0.80 mL, 10.1 mmol)
was added dropwise DBU (0.75 mL, 5.03 mmol). Stirring was
continued for a further 16 h before the mixture was diluted with
ethyl acetate (30 mL), washed with hydrochloric acid (10 mL
of a 1 M solution), then dried over MgSO4 and concentrated
in vacuo. Purification by column chromatography (5 : 1 petrol :
ether) gave the product (16) as an oil and a ca. 1 : 1 mixture of
diastereomers (942 mg, 82%) that were not separated. Rf 0.50/0.57
(1 : 1 petrol : ether); mmax (thin film)/cm−1 3436s, br, 2927s, 1665w,
1437m, 1390w, 1329w, 1243w, 1115m, 814s; dH (400 MHz, CDCl3)
1.43–1.54 (1 H, m), 1.71–1.78 (2 H, m), 2.04–2.43 (4 H, m), 2.72–
2.94 (1 H, app. s, OH), 3.93 (0.5 H, dd, J 6.3, 2.9) and 4.05
148.3; m/z (CI+) 138 (78%, MNH4 − H2O), 121 (100, MH+ −
+
H2O); Accurate Mass: Found: 121.1018; C9H13 (MH+ − H2O)
requires 121.1017.
3-Dichloromethylene-2-oxabicyclo[2.2.2]oct-5-ene (6)
Method A. To a stirred solution of lactone 49 (210 mg,
1.69 mmol) and triphenylphosphine (1.78 g, 6.76 mmol) in THF
(30 mL), at reflux, was added over 2 h a solution of carbon
tetrachloride (3.9 mL, 40.6 mmol) in THF (8 mL), via syringe
pump. Reflux was maintained for a further 18 h. The mixture was
then allowed to cool, poured onto a pH 7.5 buffer solution (30 mL)
and extracted with dichloromethane (3 × 30 mL). The combined
organic extracts were washed with sat. aq. NaHCO3, dried over
MgSO4 and concentrated in vacuo. Column chromatography (4 :
1 petrol : ethyl acetate) gave recovered starting material (118 mg,
56%) and the product (6) (114 mg, 35%) as an oil. Rf 0.67 (1 : 1
petrol : ethyl acetate); mmax (thin film)/cm−1 2941m, 1650m, 1614w,
1458w, 1364m, 1345m, 1297m, 1213s, 1173w, 1154w, 1058m,
1028s; dH (400 MHz, CDCl3) 1.41 (1 H, tdd, J 12.0, 4.6, 2.6), 1.51
(1 H, dddd, J 12.8, 12.0, 3.0, 1.8), 1.75 (1 H, dddd, J 12.4, 9.4,
3.0, 2.6) and 2.12 (1 H, dddd, J 12.8, 9.4, 4.6, 3.6, CH2CH2), 3.89
=
(0.5 H, dd, J 6.0, 2.7, CHOH), 5.66–5.73 (2 H, m, HC CH);
dC (50 MHz, CDCl3) 22.1, 25.1, 25.2 (two peaks), 27.2, 31.6,
35.8, 36.3, 85.6, 86.3, 103.8, 104.2, 125.9, 126.1, 126.5, 127.4; m/z
(FI+) 232 (31%, M(37Cl235Cl)+), 230 (98, M(37Cl35Cl2)+), 228 (100,
M(35Cl3)+); Accurate Mass: Found: 227.9872; C8H1135Cl3O (M+)
requires 227.9875.
4-exo-Phenylseleno-7-exo-trichloromethyl-6-
oxabicyclo[3.2.1]octane (21)
=
(1 H, app. dq, J 5.4, 2.6, CHC(OR) ), 5.05 (1 H, app. ddt, J 5.2,
Following the general procedure for selenocyclisation, tri-
chloromethyl alcohol 16 (636 mg, 2.77 mmol) gave after column
chromatography (10 : 1 petrol : ether) selenide 21 (352 mg, 33%)
as a yellow solid. [A small sample was crystallised from methanol
by slow evaporation in order to obtain the structure shown in
=
3.6, 1.8, CH(OR)), 6.47–6.54 (2 H, m, HC CH); dC (100 MHz,
CDCl3) 20.0, 25.4, 34.2, 72.1, 93.0, 132.3, 132.6, 150.5; m/z (CI+)
210 (50%, M(37Cl35Cl)NH4 ), 208 (71, M(35Cl2)NH4 ), 192 (34),
190 (59), 176 (28), 174 (100), 162 (31), 155 (30), 140 (81), 127
(50), 121 (46), 91 (83), 80 (52), 55 (95); Accurate Mass: Found:
+
+
◦
Fig. 2.] Mp 128–129 C; Rf 0.60 (2 : 1 petrol : ether); mmax (KBr
208.0294; C8H12NO35Cl2 (MNH4 ) requires: 208.0296.
+
disc)/cm−1 2937s, 1573w, 1474m, 1365w, 1298w, 1194m, 1067s,
1021s, 933m, 876s; dH (400 MHz, CDCl3) 1.67–1.72 (1 H, m,
SeCHCH2CHHꢀ), 1.86–1.91 (2 H, m, SeCHCHHꢀCHHꢀ), 2.06
(1 H, d, J 12.1, CH(OR)CHHꢀ), 2.24–2.34 (1 H, m, SeCHCHHꢀ),
2.46 (1 H, ddd, J 12.1, 7.5, 6.2, CH(OR)CHHꢀ), 2.77 (1 H, app. s,
Cl3CHCH), 3.67–3.69 (1 H, m, SeCH), 4.43 (1 H, s, CHCCl3),
4.70 (1 H, dd, J 6.2, 4.1, CH(OR)), 7.23–7.33 (3 H, m) and 7.48–
7.59 (2 H, m, Ph); dC (100 MHz, CDCl3) 23.7, 27.7, 30.4, 38.9,
43.8, 81.8, 91.9, 100.9, 127.6, 129.3, 129.4, 134.0; m/z (CI+) 385
(M(35Cl380Se)H+, 11%), 355 (12), 353 (56), 351 (100), 349 (45), 347
(13), 317 (34), 315 (65), 157 (32), 123 (30), 94 (32), 93 (36), 91 (35),
81 (83), 78 (74), 58 (29), 45 (28), 44 (37); Found; C 43.74, H 3.93
C14H15Cl3OSe requires C 43.76, H 3.94%.
Method B. To
a stirred solution of (trichloromethyl)-
diethylphosphonate30 (893 mg, 3.5 mmol) and LiCl (135 mg,
3.18 mmol) in THF (10 mL) at −78 ◦C was added dropwise n-
butyllithium (1.98 mL of a 1.6 M solution in hexanes, 3.2 mmol).
After 10 min, a solution of lactone 49 (197 mg, 1.59 mmol) in
THF (5 mL) was added in a slow, dropwise fashion and the mixture
allowed to warm to RT. The reaction mixture was then poured onto
water (20 mL) and extracted with ether (3 × 20 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (10 : 1 petrol : ethyl
acetate) gave recovered starting material (20 mg, 10%) and the
product (6) (174 mg, 58%); spectroscopic data as above.
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7-Trichloromethyl-6-oxabicyclo[3.2.1]oct-3-ene
2,2,2-Trichloro-1-(1,4-dimethylcyclohex-3-enyl)ethanol (23)
To a stirred solution of selenide 21 (143 mg, 0.37 mmol) in
THF (2.5 mL) at 0 ◦C was added dropwise a solution of H2O2
(0.05 mL of a 35% w/v aq. solution) in THF (0.5 mL). After
stirring for 2 h, the mixture was diluted with ether (50 mL),
washed successively with water (20 mL) and brine (20 mL), dried
over MgSO4 and concentrated in vacuo. Purification by column
chromatography (10 : 1 petrol : ether) afforded the title alkene
as an oil (67 mg, 79%). Rf 0.60 (2 : 1 petrol : ether); mmax (thin
film)/cm−1 2966s, 1632w, 1454m, 1434m, 1292m, 1263m, 1121w,
1082s; dH (400 MHz, CDCl3) 1.80 (1 H, d, J 10.9, CH(OR)CHHꢀ),
To a stirred solution of diisopropylamine (0.59 mL, 4.22 mmol) in
THF (5 mL) at 0 ◦C was added dropwise butyllithium (2.6 mL of
a 1.6 M solution in hexanes, 4.22 mmol). Stirring was continued
for 30 min before this solution was added via cannula, in a slow
dropwise fashion, to a stirred solution of aldehyde 29 (530 mg,
3.83 mmol) and chloroform (0.61 mL, 7.67 mmol) in THF (10 mL)
at −78 ◦C. After 2 h the mixture was quenched with hydrochloric
acid (5 mL of a 1 M solution), allowed to warm to RT, poured onto
water (20 mL) and extracted with ether (3 × 20 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (10 : 1 petrol : ether)
afforded the product (23), a mobile oil, as a ca. 1 : 1 mixture of
diastereomers (953 mg, 97%). Rf 0.50 (2 : 1 petrol : ether); mmax (thin
film)/cm−1 3468s, br, 2966s, 1640w, 1446m, 1381, 1288w, 1226w,
1172w, 1058m, 818s; dH (400 MHz, CDCl3) 1.17 and 1.18 (3 H, 2
=
2.19–2.25 (1 H, m, CH CHCHH), 2.35 (1 H, ddd, J 10.9, 5.9, 5.2,
ꢀ
ꢀ
=
CH(OR)CHH ), 2.53 (1 H, ddd, J 18.2, 5.9, 2.4, CH CHCHH ),
2.78–2.82 (1 H, app. s, CHCH(CCl3)), 4.31 (1 H, s, CHCCl3), 4.60
(1 H, app. t, J 5.2, CH(OR)), 5.72–5.79 (1 H, m) and 6.02–6.08
=
(1 H, m, HC CH); dC (100 MHz, CDCl3) 32.9, 35.0, 38.6, 74.3,
=
93.1, 100.3, 128.5, 130.0.
× s, CH3CCHOH), 1.64 and 1.67 (3 H, 2 × s, CH3C ), 1.82–1.89
(2 H, m), 2.04–2.06 (3 H, m), 2.38 (0.5 H, d, J 16.9) and 2.61 (0.5 H,
d, J 18.0, 3 × CH2), 3.17 (0.5 H, d, J 6.0) and 3.22 (0.5 H, d, J
5.8, OH), 3.93 (0.5 H, d, J 6.0) and 3.95 (0.5 H, d, J 5.8, CHOH),
7-Dichloromethylene-6-oxabicyclo[3.2.1]oct-3-ene (22)
=
5.27–5.30 (1 H, m, CH ); dC (100 MHz, CDCl3) 19.9, 20.3, 20.4,
To a stirred solution of 7-trichloromethyl-6-oxabicyclo[3.2.1]oct-
3-ene (46 mg, 0.20 mmol) in THF (2 mL) at 0 ◦C was added
potassium tert-butoxide (45 mg, 0.40 mmol) in one portion. After
2 h, TLC analysis showed complete consumption of starting
material. The mixture was poured onto water (10 mL) and
extracted with ether (3 × 10 mL). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo to afford the
product (22) as an oil (31 mg, 81%). Rf 0.55 (2 : 1 petrol : ether);
mmax (thin film)/cm−1 2983m, 1664s, 1632w, 1383m, 1192s, 1147s,
1119s, 1013s, 980s; dH (400 MHz, CDCl3) 2.01 (1 H, d, J 10.8) and
2.22 (1 H, app. dt, J 10.8, 5.4, CH(OR)CH2), 2.38–2.53 (2 H, m,
23.2, 26.8, 27.0, 32.0, 32.6, 36.6 (two peaks), 38.9, 39.0, 86.4, 87.1,
103.9 (two peaks), 119.1 (two peaks), 132.1, 132.4; m/z (FI+) 258
(67%, M(37Cl35Cl2)+), 256 (100, M(35Cl3)+); Accurate mass: Found:
256.0179; C10H1535Cl3O (M+) requires 256.0188.
1,4-Dimethyl-3-trichloromethyl-6-phenylseleno-2-
oxabicyclo[2.2.2]octane (24)
Following the general procedure for selenocyclisation, tri-
chloromethyl alcohol 23 (313 mg, 1.22 mmol) gave, after column
chromatography (15 : 1 petrol : ether), selenide 24 (447 mg, 89%)
as an oil and as a ca. 1 : 1 mix of diastereomers. Rf 0.68 (2 : 1
petrol : ether); mmax (thin film)/cm−1 2935s, 1579m, 1477s, 1437s,
1353w, 1201m, 1072s, 1021s; dH (400 MHz, CDCl3) 1.18 (3 H, s,
CH3CCH(OR)), 1.29 (1.5 H, s) and 1.31 (1.5 H, s, CH3C(OR)),
1.40–1.45 (1 H, m), 1.49–1.56 (1 H, m), 1.61–1.75 (1 H, m), 1.78–
1.87 (0.5 H, m), 1.89–1.98 (0.5 H, m), 2.14 (0.5 H, ddd, J 14.0, 12.0,
2.8), 2.25–2.38 (1 H, m) and 3.01 (0.5 H, ddd, J 14.8, 10.8, 3.6, 3 ×
CH2), 3.64 (0.5 H, ddd, J 10.8, 5.6, 2.8) and 3.76 (1 H, ddd, J 10.8,
6.8, 2.8, CHSePh), 4.14 (0.5 H, s) and 4.20 (0.5 H, s, CH(OR)),
7.26–7.34 (3 H, m) and 7.54–7.59 (2 H, m, Ph); dC (100 MHz,
CDCl3) 24.7, 25.0, 25.5, 25.8, 28.7, 29.1, 35.0, 35.1, 37.8, 39.1,
44.6, 45.2, 50.8, 51.0, 75.5, 76.0, 89.7, 90.1, 101.1, 101.2, 127.4,
127.5, 129.2 (two peaks), 130.1, 130.2, 133.8, 133.9; m/z (CI+) 417
(12%, M(37Cl235Cl80Se and 37Cl378Se)H+), 415 (30, M(37Cl35Cl280Se
and 37Cl235Cl78Se)H+), 413 (38, M(35Cl380Se and 37Cl35Cl278Se)H+),
411 (15, M(35Cl378Se)H+), 381 (66), 379 (100), 377 (52), 375 (15),
345 (51), 343 (94), 341 (52), 309 (19); Accurate Mass: Found:
412.9757; C16H20Cl3O80Se requires 412.9745.
=
CH2CH ), 3.35 (1 H, app. s, CHC(CCl2)), 4.76 (1 H, app. t, J 5.4,
=
CH(OR)), 5.81–5.90 (1 H, m) and 6.04–6.11 (1 H, m, HC CH);
dC (100 MHz, CDCl3) 31.3, 35.1, 38.6, 76.3, 95.7, 128.5, 130.2,
157.0.
1,4-Dimethyl-3-cyclohexene-1-carboxaldehyde (29)31
To a rapidly stirred mixture of isoprene (7.5 mL, 75.0 mmol),
ZnCl2 (2.56 g, 18.8 mmol) and hydroquinone (several crystals)
in dichloromethane (75 mL) at 0 ◦C was added dropwise
methacrolein (6.0 mL, 72.5 mmol). After 15 min the cooling
bath was removed and stirring continued for a further 24 h. The
mixture was then diluted with ether (100 mL), washed with sat.
aq. NaHCO3 (75 mL), dried over MgSO4 and the solvent removed
in vacuo. Reduced pressure distillation (86 ◦C @ 24 mmHg (lit.31
70–75 ◦C @ 30 mmHg)) afforded the product (29) as a colourless
oil (6.95 g, 69%, contaminated with ca. 5% of the inseparable
regioisomer); mmax (thin film)/cm−1 2916s, 1728s, 1438s, 1377m,
1017m, 911m; dH (400 MHz, CDCl3) 0.96 (3 H, s, CH3CCHO),
1.43 (1 H, dt, J 13.5, 7.0, CH2CHHꢀCCHO), 1.56 (3 H, d,
1,4-Dimethyl-3-trichloromethyl-2-oxabicyclo[2.2.2]oct-5-ene
ꢀ
=
J 0.9, CH3ꢀC ), 1.68–1.90 (2 H, m, CH2CHH CCHO overlays
=
=
CHCHH ), 1.85–1.89 (2 H, m, CH2C(Me) ), 2.21–2.28 (1 H,
m, CHCHH ), 5.28–5.30 (1 H, m, CH ), 9.39 (1 H, s, CHO); dC
(100 MHz, CDCl3) 20.6, 23.3, 26.8, 28.9, 31.7, 44.2, 118.3, 133.5,
205.9; m/z (CI+) 156 (92%, MNH4 ), 153 (20), 139 (58, MH+),
To a stirred solution of selenide 24 (445 mg, 1.08 mmol) in
THF (7.5 mL) at 0 ◦C was added dropwise a solution of H2O2
(0.16 mL of a 35% w/v aq. solution, 1.62 mmol) in THF (1.6 mL).
Stirring was continued for 4 h before the mixture was diluted
with ether (50 mL), washed with water (2 × 20 mL), dried over
MgSO4 and concentrated in vacuo. Column chromatography (20 : 1
ꢀ
=
=
+
138 (97), 123 (41), 110 (23), 109 (85), 95 (100), 94 (34), 91 (22), 81
(29), 58 (30), 50 (26), 44 (50).
4312 | Org. Biomol. Chem., 2006, 4, 4307–4318
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petrol : ether) gave the title alkene as an oil and as a ca. 1 : 1 mixture
of diastereomers (249 mg, 90%). Rf 0.66 (2 : 1 petrol : ether); mmax
(thin film)/cm−1 2934s, 1464m, 1380m, 1210w, 1116w, 1051s; dH
(400 MHz, CDCl3) 1.11 (0.5 H, dddd, J 12.8, 12.0, 5.8, 1.3) and
1.27 (0.5 H, td, J 12.0, 5.4, MeC(OR)CH2CHHꢀ), 1.38–1.49 (1 H,
m, MeC(OR)CHHꢀ) overlays 1.45 (2 × 1.5 H, 2 × s), 1.46 (1.5 H, s)
and 1.47 (1.5 H, s, 2 × CH3), 1.61–1.68 (0.5 H, m), 1.88 (0.5 H, ddd,
J 12.8, 9.2, 5.4), 2.01 (0.5 H, ddd, J 13.2, 9.4, 5.8) and 2.40 (0.5 H,
ddd, J 12.8, 9.4, 2.0, MeC(OR)CHHꢀCHHꢀ), 3.77 (0.5 H, d, J
1.0) and 4.15 (0.5 H, d, J 1.3, CHCCl3), 6.06 (0.5 H, d, J 9.0) and
16 h whereupon 1H NMR analysis recorded ca. 90% conversion.
dH (200 MHz, 4 : 1 CD3OD : D2O) key peaks only, sample not
=
purified: 1.50 (3 H, s, CH3CCO), 1.86 (3 H, s, CH3C ), 3.22–3.30
=
(1 H, m, CHCCl2), 5.15–5.22 (1 H, m, CH ).
2,2,2-Trichloro-1-(3-cyclopentenyl)ethanol (15)
To a stirred solution of diisopropylamine (0.68 mL, 4.88 mmol) in
THF (10 mL) at 0 ◦C was added dropwise butyllithium (2.77 mL of
a 1.6 M solution in hexanes, 4.43 mmol) and stirring continued for
30 min before cooling to −98 ◦C and slow addition of chloroform
(0.39 mL, 4.88 mmol). After 15 min a solution of 3-cyclopentene-1-
carboxaldehyde32 (213 mg, 2.22 mmol) in THF (5 mL) was added
and the mixture allowed to warm to −80 ◦C before quenching
with hydrochloric acid (5 mL of a 1 M aqueous solution). The
mixture was then allowed to warm to RT, poured onto water
(20 mL) and extracted with ether (3 × 20 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (10 : 1 petrol : ether) gave
the product (15) as an oil (254 mg, 53%). Rf 0.45 (2 : 1 petrol :
ether); mmax (thin film)/cm−1 3460brs, 2946s, 1614w, 1450w, 1380w,
1347w, 1120w, 1049w; dH (400 MHz, CDCl3) 2.30–2.48 (2 H, m,
2 × CHHꢀ), 2.57–2.64 (2 H, m, 2 × CHHꢀ), 2.99 (1 H, app. quind,
J 8.8, 4.0, CHCHOH), 3.21 (1 H, d, J 5.6, OH), 4.18 (1 H, dd,
=
6.16–6.21 (1.5 H, m, HC CH); dC (100 MHz, CDCl3) 22.9, 23.6,
23.7, 23.8, 26.6, 32.9 (two peaks), 35.0, 38.8, 40.0, 72.6, 72.9, 88.5,
90.1, 100.6, 101.0, 135.3, 136.0, 136.7, 142.4; m/z (CI+) 259 (27%,
M(37Cl235Cl)H+), 257 (84, M(37Cl35Cl2)H+), 255 (88, M(35Cl3)H+),
202 (25), 187 (34), 185 (100), 151 (80), 111 (80), 109 (80), 107 (31),
91 (20); Accurate Mass: Found: 255.0114; C10H1435Cl3O (MH+)
requires 255.0110.
3-Dichloromethylene-1,4-dimethyl-2-oxabicyclo[2.2.2]oct-5-ene
(25)
To
a stirred solution of 1,4-dimethyl-3-trichloromethyl-2-
oxabicyclo[2.2.2]oct-5-ene (185 mg, 0.72 mmol) in THF (7.5 mL)
at 0 ◦C was added in one portion potassium tert-butoxide (326 mg,
2.90 mmol). After stirring for 15 min, the cooling bath was
removed and stirring continued for 8 h whereupon TLC analysis
showed complete consumption of starting material. The mixture
was poured onto water (20 mL) and extracted with ether (3 ×
20 mL). The combined organic extracts were dried over MgSO4
and concentrated in vacuo to afford the enol ether (25), as an oil
(158 mg, 100%) that required no further purification. Rf 0.54 (2 : 1
petrol : ether); mmax (thin film)/cm−1 2936s, 1613m, 1460m, 1383m,
1223m, 1100s, 1062m, 995s; dH (400 MHz, CDCl3) 1.31 (1 H, td, J
=
J 5.6, 4.0, CHOH), 5.61–5.72 (2 H, m, CH CH); dC (100 MHz,
CDCl3) 33.1, 36.6, 39.9, 84.6, 104.0, 129.4, 130.1; m/z (FI+) 218
(31%, M(37Cl235Cl)+), 216 (100), 214 (90); Accurate mass: Found:
213.9716; C7H935Cl3O (M+) requires: 213.9719.
6-Phenylseleno-3-trichloromethyl-2-oxabicyclo[2.2.1]heptane (17)
To a stirred solution of trichloromethyl alcohol 15 (152 mg,
0.71 mmol) and CSA (16 mg, 0.07 mmol) in dichloromethane
(10 mL) at reflux was added over 2 h a solution of NPSP (426 mg,
1.41 mmol) in dichloromethane (5 mL). Reflux was maintained
for a further 14 h before the mixture was concentrated in vacuo.
Purification by column chromatography (15 : 1 petrol : ether) gave
the product (17) as a solid (215 mg, 81%). Rf 0.63 (2 : 1 petrol :
ether); mp 94–95 ◦C; mmax (KBr disc)/cm−1 2886m, 1442m, 1277m,
1151m, 1067m, 1044m, 896s, 808s, 705s; dH (400 MHz, CDCl3) 1.62
(1 H, ddd, J 13.2, 5.6, 3.8, CHHꢀCHSe), 1.78 (1 H, dd, J 11.2, 3.0,
apical-CHHꢀ), 2.09 (1 H, ddd, J 13.2, 8.2, 2.4, CHHꢀCHSe), 2.45
(1 H, app. dquin, J 11.2, 2.4, apical-CHHꢀ), 2.93 (1 H, d, J 3.8,
CH(CCl3)CH), 3.50 (1 H, ddd, J 8.2, 5.6, 2.4, CHSe), 4.00 (1 H, s,
CHSeCH(OR)), 4.49 (1 H, d, J 3.0, CHCCl3), 7.31–7.34 (3 H, m)
and 7.52–7.55 (2 H, m, Ph); dC (100 MHz, CDCl3) 31.9, 36.6, 41.1,
41.5, 82.5, 91.5, 99.4, 127.6, 129.3, 129.8, 133.2; m/z (CI+) 375
(30%, M(37Cl378Se and 37Cl235Cl80Se)H+), 373 (82, M(37Cl235Cl78Se
and 37Cl35Cl280Se)H+), 371 (98, M(37Cl35Cl278Se and 35Cl380Se)H+),
369 (46, M(35Cl378Se)H+), 339 (65), 337 (100), 335 (50), 303 (290),
301 (67), 299 (32), 109 (27), 78 (68), 67 (34); Accurate mass: Found:
370.9280; C13H14Cl3O80Se (MH+) requires: 370.9275.
11.6, 4.8, MeC(OR)CH2CHHꢀ), 1.56 (1 H, ddd, J 12.6, 11.6, 3.2,
ꢀ
=
MeC(OR)CHH ) overlays 1.57 (3 H, s, CH3CC(OR) ), 1.67 (3 H,
s, CH3CO), 1.76–1.82 (1 H, m, MeC(OR)CH2CHHꢀ), 1.92 (1 H,
ddd, J 12.6, 9.6. 4.8, MeC(OR)CHHꢀ), 6.11 (1 H, d, J 7.8) and
=
6.24 (1 H, d, J 7.8, HC CH); dC (100 MHz, CDCl3) 23.1, 23.4,
32.2, 33.6, 40.7, 76.8, 95.1, 135.9, 138.0, 152.5; m/z (CI+) 219
(11%, M(35Cl2)H+), 151 (100), 109 (74), 108 (52); Accurate Mass:
Found: 219.0347; C10H1335Cl2O (MH+) requires: 219.0343.
8,8-Dichloro-3,6-dimethylbicyclo[4.2.0]oct-2-en-7-one (26)19
Method A. An NMR sample of enol ether 25 (28 mg,
0.13 mmol) in d6-benzene (0.5 mL) was heated under reflux for
27 h whereupon analysis by 1H NMR spectroscopy showed clean
and complete conversion to cyclobutanone 26. Rf 0.52 (2 : 1 petrol :
ether); mmax (thin film)/cm−1 2931m, 1802s, 1446m, 870w, 804m; dH
(400 MHz, C6D6) 1.09 (1 H, ddd, J 12.8, 7.2, 4.4, CHHꢀC(Me)CO),
1.14 (3 H, s, CH3CCO), 1.35–1.49 (1 H, m, CHHꢀC(Me)CO), 1.57–
ꢀ
=
=
1.58 (1 H, m, C(Me)CHH ) overlays (3 H, s, CH3C ), 1.79 (1 H,
ꢀ
=
ddd, J 13.4, 7.0, 5.2, C(Me)CHH ), 2.93 (1 H, d, J 1.9, CHCCl2),
5.44 (1 H, d, J 1.9, CH ); dC (100 MHz, C6D6) 21.2, 23.4, 26.3,
29.2, 54.1, 58.3, 87.9, 117.3, 140.1, 201.1; m/z (CI+) 221 (62%,
M(37Cl35Cl)H+), 219 (100, M(35Cl2)H+), 168 (27), 151 (22), 141
(25), 108 (22).
=
3-Dichloromethylene-6-phenylseleno-2-oxabicyclo[2.2.1]heptane
(27)
To a stirred solution of bicycle 17 (319 mg, 0.86 mmol) in THF
(9 mL) at 0 ◦C was added potassium tert-butoxide (386 mg,
3.44 mmol). After 15 min, the cooling bath was removed and
stirring continued a further 4 h whereupon the mixture was poured
Method B. An NMR sample of enol ether 25 (21 mg,
0.10 mmol) in 4 : 1 CD3OD : D2O (0.5 mL) was heated to 60 ◦C for
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onto NaHCO3 (20 mL of a sat. aq. solution) and extracted with
ether (3 × 20 mL). The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo. Purification by column
chromatography (10 : 1 petrol : ether + 1% triethylamine) afforded
the product (27) (192 mg, 67%) as a yellow oil; Rf 0.67 (2 : 1
petrol : ether); mmax (thin film)/cm−1 2959m, 1675s, 1578m, 1476s,
1438s, 1317s, 1271m, 1179s, 1100s, 1036w, 993s; dH (400 MHz,
CDCl3) 1.71 (1 H, ddd, J 13.2, 5.2, 4.0, SeCHCHHꢀ), 1.98 (1 H
app. dpent, J 11.0, 1.6) and 2.07 (1 H, dd, J 11.0, 1.4, apical-
CH2), 2.22 (1 H, ddd, J 13.2, 8.4, 1.6, CHHꢀCHSePh), 3.42 (1 H,
(0.5 H, app. s) and 3.86 (0.5 H, app. s, CHOH), 5.26–5.29 (1 H,
=
m, CH ), 6.10 (0.5 H, d, J 1.2) and 6.14 (0.5 H, d, J 1.2, CHBr2);
dC (100 MHz, CDCl3) 19.1, 19.6, 23.2, 23.3, 26.7, 26.9, 30.7, 31.6,
34.6, 34.8, 37.6, 37.7, 48.8, 48.9, 82.7, 83.0, 118.2, 119.0, 132.2,
133.2; m/z (CI+) 313 (10%, M(81Br79Br)H+), 215 (13), 213 (12),
153 (32), 151 (59), 135 (58), 134 (19), 133 (31), 109 (100), 108 (46);
Accurate Mass: Found: 310.9642; C10H1779Br2O (MH+) requires:
310.9646.
3-Dibromomethyl-1,4-dimethyl-6-phenylseleno-2-
oxabicyclo[2.2.2]octane (31)
=
d, J 2.4, CHC(OR) ), 3.56 (1 H, ddd, J 8.4, 5.2, 1.6, CHSe),
=
4.72 (1 H, app. s (unresolved m), CHOC ), 7.31–7.35 (3 H, m)
and 7.51–7.57 (2 H, m, Ph); dC (100 MHz, CDCl3) 33.5, 37.0,
40.6, 41.9, 85.6, 92.6, 127.8, 129.4 (two peaks), 133.6, 155.3;
m/z (CI+) 339 (19%, M(37Cl280Se)H+), 337 (62, M(37Cl278Se and
35Cl37Cl80Se)H+), 335 (100, M(35Cl280Se and 35Cl37Cl78Se)H+), 333
(41, M(35Cl278Se)H+), 178 (14), 157 (13); Accurate Mass: Found:
334.9450; C13H1235Cl2O80Se requires: 334.9509.
Following the general procedure for selenocyclisation, halo-
carbinol 30 (1.87 g, 6.0 mmol), gave, after column chromatography
(50 : 1 petrol : ether), selenide 31 (2.49 g, 89%), a ca. 1 : 1 mixture
of diastereomers, as a yellow oil; Rf 0.54 (4 : 1 petrol : ether);
mmax (thin film)/cm−1 2931s, 1578m, 1464s, 1380m, 1350w, 1300w,
1231m, 1145s, 1073s, 1022s; dH (400 MHz, CDCl3) 0.92 (1.5 H,
s) and 0.96 (1.5 H, s, CH3CCH(OR)), 1.29 (3 H, s, CH3C(OR)),
1.35–1.58 (2.5 H, m), 1.65 (0.5 H, dd, J 13.8, 5.7), 1.81–1.89 (1 H,
m), 2.04–2.20 (1 H, m), 2.25 (0.5 H, ddd, J 14.4, 11.0, 3.8) and
2.87 (0.5 H, ddd J 14.8, 10.9, 3.6, 3 × CH2), 3.65 (0.5 H, ddd,
J 10.6, 5.7, 2.6) and 3.81 (0.5 H, ddd, J 10.9, 6.2, 2.8, CHSe),
4.06 (0.5 H, d, J 3.2) and 4.11 (0.5 H, d, J 1.6, CH(OR)), 5.84–
5.85 (1 H, m, CHBr2), 7.26–7.30 (3 H, m) and 7.51–7.61 (2 H, m,
Ph); dC (100 MHz, CDCl3) 22.3, 23.4, 25.7, 25.8, 26.7, 28.4, 29.4,
34.1, 34.7, 36.6, 38.5, 45.1, 45.2, 45.4, 45.9, 47.1, 74.6, 75.0, 85.2,
85.5, 127.3, 127.4, 129.1 (two peaks), 130.1, 130.3, 133.7, 133.8;
m/z (CI+) 467 (8%, M(79Br280Se and 79Br81Br78Se)H+), 224 (14),
207 (10), 131 (27), 70 (100); Accurate Mass: Found: 466.9113;
C16H2179Br2O80Se (MH+) requires: 466.9124.
7,7-Dichlorobicyclo[3.2.0]hept-2-en-6-one (28)22
To a stirred solution of selenide 27 (192 mg, 0.57 mmol) in THF
(3.5 mL) at 0 ◦C was added sequentially pyridine (0.07 mL,
0.86 mmol) and a solution of H2O2 (0.09 mL of a 35% w/v
aq. solution, 0.86 mmol) in THF (0.9 mL). After 10 min, the
cooling bath was removed and stirring continued a further 10 h
whereupon the mixture was poured onto water (15 mL) and
extracted with ether (3 × 15 mL). The combined organic extracts
were washed successively with sat. aq. NaHCO3 (15 mL), 10%
aq. Na2S2O3 (15 mL), water (15 mL) and brine (15 mL) before
drying over MgSO4 and concentration in vacuo. Purification by
column chromatography (20 : 1 petrol : ether) gave the product
(28) (100 mg, 99%) as a colourless oil; Rf 0.59 (2 : 1 petrol : ether);
dH (400 MHz, CDCl3) 2.58 (1 H, app. ddq, J 17.6, 8.8, 2.1, CHHꢀ),
2.83 (1 H, dm, J 17.6, CHHꢀ), 4.06–4.10 (1 H, m, CHCCl2), 4.27
(1 H, dddd, J 8.8, 7.3, 1.2, 0.4, CHCO), 5.79–5.83 (1 H, m) and
3-(Z)-Bromomethylene-1,4-dimethyl-6-phenylseleno-2-
oxabicyclo[2.2.2]octane
To a stirred solution of dibromide 31 (225 mg, 0.48 mmol) in
THF (5 mL) at 0 ◦C was added potassium tert-butoxide (216 mg,
1.93 mmol). After 15 min, the cooling bath was removed and
stirring continued a further 3 h whereupon the mixture was poured
onto water (20 mL) and extracted with ether (3 × 20 mL). The
combined organic extracts were washed with water (20 mL) and
brine (20 mL), dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (15 : 1 petrol : ether)
gave the title compound as a yellow oil (168 mg, 91%); Rf
0.55 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2931s, 1578s,
1465s, 1380s, 1350m, 1300w, 1231m, 1145s, 1073s, 1022s; dH
(400 MHz, C6D6) 0.67 (3 H, s, CH3CC(OR)), 1.26–1.31 (2 H,
m, MeC(OR)CHHꢀCHHꢀ), 1.40 (3 H, s, CH3C(OR)), 1.48–1.60
(2 H, m, MeC(OR)CH2CHHꢀ overlays SeCHCHHꢀ), 1.90 (1 H,
app. tdd, J 12.6, 2.0, 1.0, SeCHCHHꢀ), 2.06–2.13 (1 H, m,
MeC(OR)CHHꢀ), 3.47 (1 H, ddd, J 12.6, 6.0, 2.8, CHSe), 4.87
(1 H, s, CHBr), 7.02–7.09 (3 H, m) and 7.37–7.45 (2 H, m,
Ph); dC (100 MHz, C6D6) 22.2, 25.6, 29.3, 32.3, 36.0, 43.0, 46.7,
73.6, 79.2, 127.8, 129.6, 130.6, 134.1, 161.8; m/z (CI+) 389 (32%,
M(81Br80Se)H+), 387 (41, M(81Br78Se and 79Br80Se)H+), 385 (21,
M(79Br78Se)H+), 307 (11), 231 (15), 153 (53), 151 (100), 148 (60),
122 (31), 109 (43), 107 (40), 93 (31), 78 (57), 70 (42); Accu-
rate Mass: Found: 386.9865; C16H2079BrO80Se (MH+) requires:
386.9863.
=
6.04–6.07 (1 H, m, HC CH); dC (100 MHz, CDCl3) 35.2, 58.6,
59.5, 88.0, 128.4, 136.8, 197.8.
2,2-Dibromo-1-(1,4-dimethylcyclohex-3-enyl)ethanol (30)
To a stirred solution of diisopropylamine (2.33 mL, 16.6 mmol)
in THF (10 mL) at 0 ◦C was added butyllithium (9.4 mL of a
1.6 M solution in hexanes, 15.1 mmol). After 30 min this solution
was added dropwise via cannula to a −78 C stirred solution of
◦
aldehyde 29 (1.39 g, 10.1 mmol) and dibromomethane (2.12 mL,
30.2 mmol) in THF (20 mL) over ca. 30 min. After a further 5 min,
the mixture was poured onto 1 M hydrochloric acid (75 mL) and
extracted with ether (3 × 50 mL). The combined organic extracts
were washed successively with water (50 mL) and brine (50 mL),
dried over MgSO4 and concentrated in vacuo. Purification by
column chromatography (15 : 1 petrol : ether) gave the product (30)
(2.71 g, 86%), a ca. 1 : 1 mixture of diastereomers, as a colourless
oil; Rf 0.43 (4 : 1 petrol : ether); mmax (thin film)/cm−1 3463s, br,
2914s, 1446s, 1379s, 1206m, 1146m, 1082s, 1031m; dH (400 MHz,
CDCl3) 1.03 (3 H, s, CH3CCH(OH)), 1.24–1.32 (0.5 H, m), 1.34–
1.43 (0.5 H, m), 1.48–1.58 (1 H, m), 1.66–1.77 (1 H, m), 1.87–2.02
(2 H, m) and 2.17–2.23 (1 H, m, 3 × CH2) overlays 1.64 (1.5 H,
=
s) and 1.65 (1.5 H, s, CH3C ), 2.54 (1 H, app. br s, OH), 3.81
4314 | Org. Biomol. Chem., 2006, 4, 4307–4318
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3-(Z)-Bromomethylene-1,4-dimethyl-2-oxabicyclo[2.2.2]oct-5-ene
(32)
1.93–2.06 (1 H, m), 2.18–2.27 (0.5 H, m), 2.30–2.40 (1 H, m) and
3.10 (0.5 H, ddd, J 15.2, 10.2, 3.2, 3 × CH2), 3.99 (0.5 H, d, J
4.0) and 4.09 (0.5 H, s, CH(OR)), 4.07–4.15 (0.5 H, m) and 4.29
(0.5 H, ddd, J 10.2, 4.6, 1.8, CHBr), 5.80–5.81 (1 H, CHBr2); dC
(100 MHz, CDCl3) 21.7, 23.7, 24.9, 25.0, 26.0, 26.9, 27.7, 34.2,
35.1, 36.0, 41.4, 44.5, 44.9, 49.2, 51.0, 51.2, 72.1, 73.5, 84.9, 85.5
(two peaks); m/z (CI+) 391 (10%, M(81Br79Br2)H+), 389 (12), 313
(31), 311 (74), 309 (33), 266 (22), 264 (17), 249 (43), 247 (44), 233
(67), 231 (77), 219 (37), 217 (36), 186 (17), 169 (100), 151 (66),
141 (32), 125 (22); Accurate Mass: Found: 387.8619; C10H1579Br3O
(M+) requires: 387.8673.
Method A. To a stirred solution of 3-(Z)-bromomethylene-
1,4-dimethyl-6-phenylseleno-2-oxabicyclo[2.2.2]octane (306 mg,
0.79 mmol) in THF (5 mL) and water (2 mL) at 0 ◦C was
added Na2CO3·1.5H2O2 (248 mg, 1.58 mmol). After 15 min, the
cooling bath was removed and stirring continued 16 h, whereupon
the mixture was poured onto water (20 mL) and extracted with
ether (3 × 20 mL). The combined organic extracts were washed
with water (20 mL) and brine (20 mL), dried over MgSO4 and
concentrated in vacuo. Purification by column chromatography
(50 : 1 petrol : ether) gave the product (32) (164 mg, 91%) as an
oil; Rf 0.55 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2961s, 1641s,
1454m, 1380m, 1367m, 1325m, 1272m, 1245m, 1107s, 1084s, 940s;
dH (400 MHz, C6D6) 0.93–1.06 (1 H, m, MeC(OR)CH2CHHꢀ)
obscured by 1.00 (3 H, s, CH3CC(OR)), 1.15 (1 H, ddd, J 12.6,
12.0, 3.0, MeC(OR)CHHꢀ), 1.31 (1 H, ddd, J 12.0, 9.4, 3.0,
8-Bromo-3,6-dimethylbicyclo[4.2.0]oct-2-en-7-one (33)
To a stirred solution of enol ether 32 (165 mg, 0.72 mmol) in
dichloromethane (2 mL) at 0 ◦C was added dropwise dimethylalu-
minium chloride (0.14 mL of a 1 M solution in dichloromethane,
0.14 mmol). After 10 min the mixture was poured onto sat.
aq. NaHCO3 (10 mL) and extracted with ether (3 × 10 mL).
The combined organic extracts were washed successively with
1 M hydrochloric acid (10 mL) and brine (10 mL), dried
over MgSO4 and concentrated in vacuo. Purification by column
chromatography (30 : 1 petrol : ether) afforded the product (33),
as an oil and as a 3 : 1 mixture of endo : exo diastereomers
(119 mg, 72%); Rf 0.38 (4 : 1 petrol : ether); mmax (thin film)/cm−1
2927s, 1784s, 1445m, 1379m, 1265m, 1037m, 1003s; Data for
MeC(OR)CH2CHHꢀ), 1.41 (3 H, s, CH3CO), 1.67 (1 H, ddd, J
ꢀ
=
12.6, 9.4, 5.0, MeC(OR)CHH ), 4.88 (1 H, s, CHBr), 5.84 (1 H, d,
=
J 7.9) and 5.93 (1 H, d, J 7.9, HC CH); dC (100 MHz, C6D6) 20.2,
23.2, 31.7, 33.8, 40.6, 72.0, 76.6, 135.5, 137.4, 159.9; m/z (CI+)
248 (22%, M(81Br)NH4 ), 246 (20), 231 (41), 229 (40), 168 (25),
+
108 (100), 93 (22); Accurate Mass: Found: 229.0230; C10H1479BrO
(MH+) requires: 229.0228.
Method B. To
a stirred solution of 3-dibromomethyl-
=
exo-bromide: dH (400 MHz, CDCl3) 1.33 (3 H, s, CH3CC O),
6-bromo-1,4-dimethyl-2-oxabicyclo[2.2.2]octane (prepared from
halocarbinol 30 as detailed below) (163 mg, 0.42 mmol) in THF
(4 mL) at 0 ◦C was added potassium tert-butoxide (374 mg,
3.34 mmol). After 15 min, the cooling bath was removed and
stirring continued for 16 h. The mixture was then poured onto
water (10 mL) and extracted with ether (3 × 10 mL), The
combined organic extracts were washed with water (10 mL) and
brine (10 mL), dried over MgSO4 and concentrated in vacuo.
Purification, as above, gave the product (32) (93 mg, 96%); data as
above.
ꢀ
=
1.56 (1 H, app. dt, J 13.5, 4.9, C(Me)CH2CHH ), 1.71–1.80
ꢀ
=
=
(1 H, m, C(Me)CHH ) overlays 1.77 (3 H, s, CH3C ), 1.84–
2.01 (2 H, m, CHHꢀCHHꢀ), 2.61 (1 H, app. s, CHCHBr), 4.62
=
(1 H, d, J 6.6, CHBr), 5.75–5.80 (1 H, m, CH); dC (100 MHz,
CDCl3) 21.1, 24.0, 25.4, 25.8, 44.3, 53.2, 58.0, 118.9, 137.7,
206.2; Data for endo-bromide: dH (400 MHz, CDCl3) 1.32–1.42
ꢀ
=
=
(1 H, m, C(Me)CH2CHH ) overlays 1.37 (3 H, s, CH3CC O),
ꢀ
=
=
1.74 (3 H, s, CH3C ), 1.81–2.05 (3 H, m, C(Me)CH2CHH ),
2.89 (1 H, app. ddd, J 8.4, 4.5, 1.3, CHCHBr), 5.28 (1 H,
=
d, J 8.4, CHBr), 5.37–5.40 (1 H, m, CH); dC (100 MHz,
CDCl3) 23.2, 24.0, 26.8, 28.7, 37.7, 53.8, 58.9, 119.3, 138.3, 207.3;
Method C (variant of Method B). Following the individually
detailed procedures with no intermediate purification aldehyde 29
(5.35 g, 38.8 mmol) afforded bromoenol ether 32 (5.4 g, 61% over
three steps).
m/z (CI+) 248 (12%, M(81Br)NH4 ), 246 (12, M(79Br)NH4 ),
+
+
151 (37), 121 (21), 108 (100), 93 (20), 91 (16), 69 (35); Accu-
+
rate Mass: Found: 246.0506; C10H1779BrNO (MNH4 ) requires:
246.0494.
3-Dibromomethyl-6-bromo-1,4-dimethyl-2-oxabicyclo[2.2.2]octane
3-(Z)-(p-Methoxyphenyl)methylene-1,4-dimethyl-2-
oxabicyclo[2.2.2]oct-5-ene (36)
To a stirred solution of halocarbinol 30 (402 mg, 1.29 mmol)
in dichloromethane (10 mL) at 0 ◦C was added CSA (30 mg,
0.129 mmol) and NBS (287 mg, 1.61 mmol). After 15 min,
the cooling bath was removed and stirring continued for 4 h,
whereupon the mixture was poured onto water (50 mL) and
extracted with ether (3 × 50 mL). The combined organic extracts
were washed successively with sat. aq. NaHCO3 (50 mL), 10%
aq. Na2S2O3 (50 mL), water (50 mL) and brine (50 mL), dried
over MgSO4 and concentrated in vacuo. Purification by column
chromatography (50 : 1 petrol : ether) afforded the title compound
(459 mg, 91%), a ca. 1 : 1 mixture of, as a colourless oil; Rf 0.60
(4 : 1 petrol : ether); mmax (thin film)/cm−1 2934s, 1465s, 1381s,
1145m, 1074s, 1041s, 877m; dH (400 MHz, CDCl3) 0.92 (1.5 H,
s) and 1.00 (1.5 H, s, CH3CCH(OR)), 1.34 (1.5 H, s) and 1.37
(1.5 H, s, CH3C(OR)), 1.45–1.60 (1 H, m), 1.76–1.92 (2 H, m),
Following the general procedure for cross coupling, bromide 32
(228 mg, 1.0 mmol) gave, after column chromatography (50 :
1 petrol : ether), enol ether 36 as a colourless oil (202 mg,
79%); Rf 0.47 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2933m,
1654s, 1609m, 1509s, 1460m, 1381m, 1349m, 1244s, 1177m,
1106s, 1036m, 950m, 836m; dH (400 MHz, C6D6) 1.22 (1 H,
app. td, J 11.4, 4.7, MeC(OR)CH2CHHꢀ), 1.25–1.32 (1 H, m,
ꢀ
=
MeC(OR)CHH ) overlays 1.29 (3 H, s, CH3CC(OR) ), 1.46–1.45
(1 H, m, MeC(OR)CH2CHHꢀ) overlays 1.50 (3 H, s, CH3CO),
1.80 (1 H, app. ddd, J 12.1, 9.6, 4.7, MeC(OR)CHHꢀ), 3.45 (3 H,
=
=
s, OCH3), 5.36 (1 H, s, ArCH ), 6.03 (2 H, app. s, HC CH), 7.02
(2 H, d, J 9.0) and 7.93 (2 H, d, J 9.0, Ar); dC (100 MHz, C6D6)
21.2, 23.6, 32.3, 34.2, 39.9, 54.9, 75.8, 94.9, 114.1, 129.4, 131.2,
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Org. Biomol. Chem., 2006, 4, 4307–4318 | 4315
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+
134.7, 138.3, 157.1, 157.6; m/z (CI+) 274 (MNH4 , 24%), 257
3-(Z)-(p-Nitrophenyl)methylene-1,4-dimethyl-2-
oxabicyclo[2.2.2]oct-5-ene (40)
(MH+, 62), 224 (31), 131 (100), 94 (24); Accurate Mass: Found:
257.1537; C17H21O2 requires: 257.1542.
Following the general procedure for cross coupling, bromide 32
(228 mg, 1.0 mmol) gave, after column chromatography (30 : 1
petrol : ether), enol ether 40 as a yellow oil (149 mg, 55%); Rf
0.47 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2934w, 1636m,
1585m, 1506s, 1335s, 1245w, 1183w, 1109m, 1081s, 1057m, 949m,
858m; dH (400 MHz, C6D6) 1.11–1.18 (1 H, m) and 1.19–1.25 (1 H,
3-(Z)-(p-Methylphenyl)methylene-1,4-dimethyl-2-
oxabicyclo[2.2.2]oct-5-ene (37)
Following the general procedure for cross coupling, bromide
32 (228 mg, 1.0 mmol) gave, after column chromatography
(50 : 1 petrol : ether), enol ether 37 as an oil (185 mg, 77%);
Rf 0.63 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2932s,
1652s, 1512m, 1455m, 1076m, 948m; dH (400 MHz, C6D6) 1.17–
1.31 (2 H, m, MeC(OR)CHHꢀCHHꢀ) overlays 1.26 (3 H, s,
CH3CO), 1.42–1.55 (1 H, m, MeC(OR)CH2CHHꢀ) overlays 1.50
ꢀ
ꢀ
=
m, MeC(OR)CHH CHH ) overlays 1.20 (3 H, s, CH3CC(OR) ),
1.30–1.38 (1 H, m, MeC(OR)CH2CHHꢀ), 1.44 (3 H, s, CH3CO),
ꢀ
=
1.59–1.66 (1 H, m, MeC(OR)CHH ), 5.17 (1 H, s, ArCH ), 5.91
=
(1 H, d, J 7.9) and 5.95 (1 H, d, J 7.9, CH CH), 7.59 (2 H, d, J
7.2) and 8.13 (2 H, d, J 7.2, Ar); dC (100 MHz, C6D6) 20.7, 22.7,
31.7, 33.7, 40.6, 77.5, 94.2, 123.9, 127.8, 134.9, 137.5, 144.8, 145.0,
163.7; m/z (CI+) 272 (5%, MH+), 225 (12), 224 (48), 149 (100), 132
(15), 131 (62), 87 (21), 70 (23); Accurate Mass: Found: 272.1287;
C16H18NO3 (MH+) requires: 272.1287.
=
(3 H, s, CH3CC(OR) ), 1.79 (1 H, app. ddd, J 12.1, 9.6, 4.7,
MeC(OR)CHH ), 2.28 (3 H, s, Ar-CH3), 5.38 (1 H, s, ArCH ),
ꢀ
=
=
6.01 (2 H, app. s, HC CH), 7.23 (2 H, d, J 7.9) and 7.90 (2 H,
d, J 7.9, Ar); dC (100 MHz, C6D6) 21.2, 21.4, 23.6, 32.3, 34.1,
40.0, 76.0, 95.4, 128.6, 129.8, 134.0, 134.7, 135.6, 138.2, 158.1;
m/z (CI+) 242 (25%), 241 (100, MH+), 131 (56); Accurate Mass:
Found: 241.1592; C17H21O (MH+) requires: 241.1592.
3-(Z)-(2-Furyl)methylene-1,4-dimethyl-2-oxabicyclo[2.2.2]oct-5-
ene (41)
Following the general procedure for cross coupling, bromide 32
(228 mg, 1.0 mmol) gave, after column chromatography (50 : 1
petrol : ether), enol ether 41 as a colourless oil (112 mg, 52%); Rf
0.63 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2934s, 1658s, 1615s,
1495m, 1458m, 1381s, 1337s, 1220m, 1085s, 1058m, 955s, 936s;
dH (400 MHz, C6D6) 1.09–1.13 (1 H, m, MeC(OR)CH2CHHꢀ)
3-(Z)-Benzylidene-1,4-dimethyl-2-oxabicyclo[2.2.2]oct-5-ene (38)
Following the general procedure for cross coupling, bromide 32
(230 mg, 1.0 mmol) gave, after chromatography (50 : 1 petrol :
ether), enol ether 38 (150 mg, 66%) as a colourless oil; Rf 0.57 (4 :
1 petrol : ether); mmax (thin film)/cm−1 2933s, 1651s, 1600w, 1448m,
1381m, 1245w, 1079s, 949s; dH (400 MHz, C6D6) 1.16–1.33 (2 H,
=
overlays 1.13 (3 H, s, CH3CC(OR) ), 1.23 (1 H, ddd, J 12.6,
ꢀ
ꢀ
=
m, MeC(OR)CHH CHH ) overlays 1.27 (3 H, s, CH3CC(OR) ),
1.47–1.54 (1 H, m, MeC(OR)CH2CHHꢀ) overlays 1.48 (3 H,
s, CH3CO), 1.74–1.80 (1 H, m, MeC(OR)CHHꢀ), 5.39 (1 H,
11.0, 2.8, MeC(OR)CHHꢀ), 1.39 (1 H, ddd, J 11.4, 9.5, 2.8,
MeC(OR)CH2CHHꢀ), 1.46 (3 H, s, CH3C(OR), 1.71 (1 H, ddd, J
ꢀ
=
12.6, 9.5, 4.6, MeC(OR)CHH ), 5.57 (1 H, s, furan-CH ), 5.88–
=
=
s, PhCH ), 6.01 (2 H, app. s, HC CH), 7.16 (1 H, app. td,
J 7.3, 1.1), 7.47 (2 H, app. t, J 7.3) and 7.98 (2 H, app. dd,
J 7.3, 1.1, Ph); dC (100 MHz, C6D6) 21.1, 23.5, 32.2, 34.1,
40.0, 76.1, 95.5, 125.0, 128.7, 128.9, 134.8, 138.1, 138.4, 159.0;
m/z (CI+) 227 (10%, MH+), 131 (15), 87 (22), 70 (100), 55
(22); Accurate Mass: Found: 227.1443; C16H19O (MH+) requires:
227.1436.
=
6.02 (2 H, m, CH CH), 6.46 (1 H, app. s), 6.89 (1 H, app. s) and
7.29 (1 H, app. s, Fu); dC (100 MHz, C6D6) 20.4, 23.3, 32.0, 34.0,
39.6, 76.4, 86.6, 106.1, 111.8, 134.9, 137.8, 139.1, 153.7, 158.2;
m/z (CI+) 217 (21%, MH+), 70 (100); Accurate Mass: Found:
217.1228; C14H17O2 (MH+) requires: 217.1229.
endo-8-p-Methoxyphenyl-3,6-dimethylbicyclo[4.2.0]oct-2-en-
3-(Z)-(p-Trifluoromethylphenyl)methylene-1,4-dimethyl-2-
7-one (42)
oxabicyclo[2.2.2]oct-5-ene (39)
An NMR tube charged with a solution of enol ether 36 (116 mg,
0.45 mmol) in C6D6 (0.5 mL) was heated to 100 ◦C for 10 h.
The mixture was concentrated in vacuo and purified by column
chromatography (50 : 1 petrol : ether) to afford the product (42)
(90 mg, 78%) as a colourless oil (dr = 8 : 1); Rf 0.53 (4 : 1 petrol :
ether); mmax (thin film)/cm−1 2973s, 1765s, 1601s, 1513s, 1458s,
Following the general procedure for cross coupling, bromide 32
(228 mg, 1.0 mmol) gave, after column chromatography (50 :
1 petrol : ether), enol ether 39 as a colourless oil (179 mg,
61%); Rf 0.62 (4 : 1 petrol : ether); mmax (thin film)/cm−1 2937s,
1648s, 1611s, 1459m, 1415m, 1324s, 1245m, 1211s, 1163s, 1113s,
1069s, 1017s, 951s, 849s; dH (400 MHz, C6D6) 1.15 (1 H, ddd,
1421m, 1381m, 1255s, 1173s, 1113s, 1030s, 835s; dH (400 MHz,
J 11.5, 11.4, 4.7, MeC(OR)CH2CHHꢀ), 1.22–1.28 (1 H, m,
CDCl3) 1.39–1.47 (1 H, m, C(Me)CH2CHH ) overlays 1.45
ꢀ
=
ꢀ
=
=
MeC(OR)CHH ) overlays 1.24 (3 H, s, CH3CC(OR) ), 1.43–1.48
(3 H, s, CH3CCO), 1.63 (3 H, s, CH3C ), 1.85–1.91 (1 H,
m, C(Me)CHH ), 2.04–2.09 (2 H, m, C(Me)CHH CHH ),
2.90–2.95 (1 H, m, CHCH ), 3.78 (3 H, s, OCH3), 4.80 (1 H,
d, J 10.0, CHCO), 5.07–5.08 (1 H, m, CH ), 6.81 (2 H, d, J
8.8) and 6.98 (2 H, d, J 8.8, Ar); dC (100 MHz, CDCl3) 24.0,
24.2, 27.4, 27.9, 38.7, 55.2, 58.6, 63.3, 113.5, 120.7, 126.8, 130.0,
137.0, 158.5, 214.9; m/z (CI+) 257 (11%, MH+), 71 (41), 70
(100); Accurate Mass: Found: 257.1543; C17H21O2 (MH+) requires:
257.1542.
(1 H, m, MeC(OR)CCH2CHHꢀ) overlays 1.45 (3 H, s, CH3CO),
1.69 (1 H, app. ddd, J 12.2, 9.6, 4.7, MeC(OR)CHHꢀ), 5.23 (1 H,
ꢀ
ꢀ
ꢀ
=
=
=
=
=
=
s, ArCH ), 5.90–6.00 (2 H, m, HC CH), 7.56 (2 H, d, J 8.1)
and 7.76 (2 H, d, J 8.1, Ar); dC (100 MHz, C6D6) 21.3, 23.2, 32.6,
33.9, 40.2, 76.8, 94.2, 125.4 (q, J 4.0), 125.8 (q, J 269.0), 126.0 (q,
J 32.0), 126.8, 134.8, 137.8, 142.0, 161.6; dF (376.5 MHz, C6D6)
−61.41; m/z (CI+) 296 (22%), 295 (100, MH+); Accurate Mass:
Found: 295.1296; C17H18F3O (MH+) requires: 295.1310.
4316 | Org. Biomol. Chem., 2006, 4, 4307–4318
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=
endo-8-p-Methylphenyl-3,6-dimethylbicyclo[4.2.0]oct-2-en-
7-one (43)
1.61* (3 H, s) and 1.80 (3 H, s, CH3C ), 1.69 (1 H, app. dt, J 13.2,
ꢀ
ꢀ
=
=
4.2, C(Me)CH2CHH ), 1.84–2.10 (3 H, m, C(Me)CH2CHH ),
2.55–2.58 (1 H, m) and 2.98–3.04* (1 H, m, CHCHAr), 4.30
(1 H, d, J 8.0) and 4.89* (1 H, d, J 10.0, CHAr), 5.05–5.06*
An NMR tube charged with a solution of enol ether 37 (114 mg,
0.48 mmol) in C6D6 (0.5 mL) was heated to 100 ◦C for 16 h.
The mixture was concentrated in vacuo and purified by column
chromatography (50 : 1 petrol : ether) to afford the product (43)
(102 mg, 89%) as a colourless oil (dr = 28 : 1); Rf 0.53 (4 : 1 petrol :
ether); mmax (thin film)/cm−1 2922s, 1771s, 1516m, 1450m, 1378w,
=
(1 H, m) and 5.79–5.80 (1 H, m, CH ), 7.21* (2 H, app. d, J
8.4), 7.34 (2 H, app. d, J 8.0), 7.53* (2 H, app. d, J 8.4) and
7.60 (2 H, app. d, J 8.0, Ar); dC (100 MHz, CDCl3, unable to
resolve 13C–19F coupling in this spectrum) 18.9, 23.9, 24.0 (two
peaks), 25.2, 27.3, 27.8, 28.0, 38.5, 40.4, 57.2, 59.2, 63.1, 67.5,
119.9, 120.8, 122.8, 122.9, 124.9, 125.0, 125.3, 125.5, 127.4, 129.0,
136.8, 137.8, 138.7, 140.6, 211.2, 213.2; dF (376.5 MHz, CDCl3)
−62.49; m/z (CI+) 296 (14%, MH+), 295 (100), 131 (63), 87 (28);
Accurate Mass: Found: 295.1313; C17H18F3O (MH+) requires:
295.1310.
1291w, 1123w, 1014m; dH (400 MHz, CDCl3) 1.40–1.48 (1 H, m,
ꢀ
=
C(Me)CH2CHH ) overlays 1.47 (3 H, s, CH3CCO), 1.64 (3 H, s,
ꢀ
=
=
CH3C ), 1.87–1.93 (1 H, m, C(Me)CHH ), 2.05–2.11 (2 H, m,
C(Me)CHH CHH ), 2.33 (3 H, s, CH3Ar), 2.93–2.98 (1 H, m,
ꢀ
ꢀ
=
=
=
CHCH ), 4.83 (1 H, d, J 10.1, CHCO), 5.10–5.11 (1 H, m, CH ),
6.97 (2 H, d, J 7.8) and 7.09 (2 H, d, J 7.8, Ar); dC (100 MHz,
CDCl3) 21.2, 24.0, 24.2, 27.9, 28.2, 38.6, 58.7, 63.6, 120.5, 128.8,
128.9, 136.1, 136.5, 137.0, 214.8; m/z (CI+) 241 (15%, MH+), 132
(12), 131 (21), 87 (19), 71 (24), 70 (100), 55 (23); Accurate Mass:
Found: 241.1596; C17H21O (MH+) requires: 241.1592.
8-p-Nitrophenyl-3,6-dimethylbicyclo[4.2.0]oct-2-en-7-one (46)
An NMR tube charged with a solution of enol ether 40 (108 mg,
0.40 mmol) in C6D6 (0.5 mL) was heated to 100 ◦C for 100 h. The
mixture was then concentrated in vacuo and purified by column
chromatography (50 : 1 petrol : ether) to afford the product (46)
(39 mg, 36%), a 3.3 : 1 exo : endo mixture of diastereomers, as a
colourless oil; Rf 0.31 (4 : 1 petrol : ether); mmax (thin film)/cm−1
2925m, 1771s, 1599m, 1519s, 1448w, 1346s, 1109w, 1018w; dH
(400 MHz, CDCl3; resonances attributable solely to the minor
isomer are marked with an asterisk) 1.22 (3 H, s) and 1.49*
(3 H, s, CH3CCO), 1.40–1.48* (1 H, m, C(Me)CH2CHH ), 1.60*
(3 H, s) and 1.81 (3 H, s, CH3C ), 1.70 (1 H, app. dt, J 13.6,
4.4, C(Me)CH2CHH ), 1.85–2.10 (3 H, m, C(Me)CH2CHH ),
2.57–2.60 (1 H, m) and 3.02–3.08* (1 H, m, CHCHAr), 4.34 (1 H,
d, J 8.3) and 4.94* (1 H, d, J 10.0, CHAr), 4.95–5.04* (1 H, m)
endo-8-Phenyl-3,6-dimethylbicyclo[4.2.0]oct-2-en-7-one (44)
An NMR tube charged with a solution of enol ether 38 (93 mg,
0.41 mmol) in C6D6 (0.5 mL) was heated to 100 ◦C for 30 h
whereupon analysis by 1H NMR spectroscopy indicated complete
consumption of the starting material. The mixture was concen-
trated in vacuo and purified by column chromatography (50 : 1
petrol : ether) to afford the product (44) (68 mg, 73%), a 10.5 :
1 mixture of endo : exo isomers, as a colourless oil; Rf 0.52
(4 : 1 petrol : ether); mmax (thin film)/cm−1 2929s, 1770s, 1597m,
1497s, 1449m, 1219m, 1016m; dH (400 MHz, CDCl3) Data for
endo isomer: 1.40–1.48 (1 H, m), 1.48 (3 H, s, CH3CCO), 1.63
ꢀ
=
=
ꢀ
ꢀ
=
=
=
and 5.80–5.81 (1 H, m, CH ), 7.27* (2 H, app. d, J 9.2), 7.43
=
(3 H, s, CH3C ), 1.85–1.92 (1 H, m), 2.06–2.17 (2 H, m), 2.98
(2 H, app. d, J 8.8), 8.14* (2 H, app. d, J 9.2) and 8.20 (2 H, app.
d, J 8.8, Ar); dC (100 MHz, CDCl3) 18.9, 24.0 (two peaks), 25.2,
27.3, 27.8, 28.0, 38.6, 40.3, 57.5, 59.4, 65.8, 67.4, 119.6, 120.4,
123.3, 123.6, 123.9, 127.8, 128.7, 129.5, 137.2, 138.3, 142.4, 143.9,
210.2, 212.3; m/z (CI+) 272 (6%, MH+), 218 (100), 201 (12), 131
(82), 70 (30); Accurate Mass: Found: 272.1287; C16H18NO3 (MH+)
requires: 272.1287.
=
(1 H, dddt, J 10.0, 5.6, 2.8, 1.4, CHCH ), 4.87 (1 H, d, J 10.0,
=
CHPh), 5.06–5.10 (1 H, m, CH ), 7.06–7.09 (2 H, m) and 7.20–
7.37 (3 H, m, Ph); Data for exo isomer: 1.21 (3 H, s, CH3CCO),
=
1.40–1.48 (1 H, m), 1.62–1.70 (1 H, m), 1.79 (3 H, s, CH3C ),
=
2.06–2.17 (2 H, m), 2.55–2.59 (1 H, m, CHCH ), 4.26 (1 H, d, J
=
8.1, CHPh), 5.82 (1 H, app. s, CH ), 7.06–7.09 (2 H, m) and 7.20–
7.37 (3 H, m, Ph); dC (100 MHz, CDCl3) Data for endo isomer:
24.0, 24.2, 27.3, 27.9, 38.6, 58.8, 63.8, 120.5, 126.9, 128.0, 128.9,
134.7, 137.1, 214.6; Data for exo isomer: 18.9, 24.0, 25.3, 28.2,
40.7, 56.9, 68.1, 121.3, 127.1, 128.1, 128.7, 134.7, 136.2, 212.6;
m/z (CI+) 227 (12%, MH+), 131 (25), 87 (26), 71 (53), 70 (100), 58
(13); Accurate Mass: Found: 227.1447; C16H19O (MH+) requires:
227.1436.
8-(2-Furyl)-3,6-dimethylbicyclo[4.2.0]oct-2-en-7-one (47)
An NMR tube charged with a solution of enol ether 41 (87 mg,
0.40 mmol) in C6D6 (0.5 mL) was heated to 100 ◦C for 22 h
whereupon analysis by 1H NMR spectroscopy indicated complete
consumption of the starting material. The mixture was concen-
trated in vacuo and purified by column chromatography (50 : 1
petrol : ether) to afford the product (47) (58 mg, 67%), a 2.9 : 1
mixture of endo : exo diastereomers, as a colourless oil; Rf 0.48 (4 :
1 petrol : ether); mmax (thin film)/cm−1 2925m, 1777s, 1446m, 1009s;
dH (400 MHz, CDCl3; resonances attributable solely to the minor
isomer are marked with an asterisk) 1.27* (3 H, s, CH3CCO), 1.37–
1.46 (1 H, m) overlays 1.42 (3 H, CH3CCO), 1.56–1.65* (1 H, m),
1.66 (3 H, s) and 1.78* (3 H, s, CH3C ), 1.80–2.10 (3 H, m),
2.63–2.68* (1 H, m) and 2.92–2.98 (1 H, m, CH ), 4.21* (1 H,
d, J 7.6) and 4.87 (1 H, d, J 9.6, CHFu), 5.22–5.23 (1 H, m) and
5.74–5.76* (1 H, m, CH ), 6.07–6.08 (1 H, m) and 6.15–6.16*
(1 H, m, 3-Fu), 6.28–6.29 (1 H, m) and 6.33* (1 H, app. td, J 2.2,
0.8, 4-Fu), 7.31 (1 H, dd, J 1.8, 0.6) and 7.36* (1 H, dd, J 2.2,
8-p-Trifluoromethylphenyl-3,6-dimethylbicyclo[4.2.0]oct-2-en-7-
one (45)
An NMR tube charged with a solution of enol ether 39 (106 mg,
0.36 mmol) in C6D6 (0.5 mL) was heated to 100 ◦C for 100 h. The
mixture was then concentrated in vacuo and purified by column
chromatography (50 : 1 petrol : ether) to afford the product (45)
(54 mg, 51%), a 1.4 : 1 mixture of exo : endo diastereomers, as a
colourless oil; Rf 0.43 (4 : 1 petrol : ether); mmax (thin film)/cm−1
2926m, 1774s, 1619m, 1448w, 1415w, 1378w, 1327s, 1165s, 1124s,
1069s, 1019m; dH (400 MHz, CDCl3; resonances attributable solely
=
=
=
to the minor isomer are marked with an asterisk) 1.22 (3 H, s) and
ꢀ
=
1.48* (3 H, s, CH3CCO), 1.43–1.45* (1 H, m, C(Me)CH2CHH ),
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1.0, 5-Fu); dC (100 MHz, CDCl3) 19.2, 23.4, 24.0, 25.4, 25.6, 27.0,
27.8, 27.9, 38.0, 39.4, 57.8 (two peaks), 59.5, 62.0, 106.7, 108.1,
110.2, 110.3, 119.6, 120.9, 136.4, 137.5, 141.5, 142.1, 148.5, 149.9,
210.1, 211.4; m/z (CI+) 217 (15%, MH+), 131 (22), 108 (27), 87
(23), 71 (52), 70 (100), 55 (32); Accurate Mass: Found: 217.1237;
C14H17O2 (MH+) requires: 217.1229.
19 W. T. Brady, J. Ko and S. J. Norton, J. Agric. Food Chem., 1985, 33,
1026.
20 (a) R. M. Coates, B. D. Rogers, S. J. Hobbs, D. R. Peck and D. P.
Curran, J. Am. Chem. Soc., 1987, 109, 1160; (b) J. J. Gajewski, J. Jurayj,
D. R. Kimbrough, M. E. Gande, B. Ganem and B. K. Carpenter,
J. Am. Chem. Soc., 1987, 109, 1170; (c) D. L. Severance and W. L.
Jorgensen, J. Am. Chem. Soc., 1992, 114, 10966; (d) For a recent
synthetic application of this effect see K. C. Nicolaou, H. Xu and
M. Wartmann, Angew. Chem., Int. Ed., 2005, 44, 756.
21 Cycloreversion of the adduct of diethyl ketomalonate and cyclopen-
tadiene is complete at temperatures above ca. −30 ◦C: S. Yao, M.
Roberson, F. Reichel, R. G. Hazell and K. A. Jørgensen, J. Org. Chem.,
1999, 64, 6677.
22 (a) H. C. Stevens, D. A. Reich, D. R. Brandt, K. R. Fountain and
E. J. Gaughan, J. Am. Chem. Soc., 1965, 87, 5257; (b) L. Ghosez,
R. Montaigne and P. Mollet, Tetrahedron Lett., 1966, 135; see also
reference 13.
Acknowledgements
We thank the EPSRC for a studentship and Dr S. J. Bell for
obtaining the X-ray structure in Fig. 2.
References
23 For details of the preparation of bicycles 9–13 see T. G. Fowler, DPhil
Thesis, Oxford, 2005.
1 S. Yamabe, T. Dai, T. Minato, T. Machiguchi and T. Hasegawa, J. Am.
Chem. Soc., 1996, 118, 6518.
2 As presented in current textbooks; e.g. J. Clayden, N. Greeves, S. Warren
and P. Wothers, Organic Chemistry, Oxford University Press, Oxford,
2001, p. 930.
3 H. Staudinger, Justus Liebigs Ann. Chem., 1907, 356, 51.
4 First report (acyclic diene): (a) J. C. Martin, P. G. Gott, V. W. Goodlett
and R. H. Hasek, J. Org. Chem., 1965, 30, 4175; (b) first report (cyclic
diene): D. C. England and C. G. Krespan, J. Org. Chem., 1970, 35,
3300; see also reference 26.
24 Review: (a) J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508;
(b) Coupling of (Z)-1-ethoxy-2-tributylstannylethene: T. Sakamoto, Y.
Kondo, A. Yasuhara and H. Yamanaka, Tetrahedron, 1991, 47, 1877.
25 The role of anionic ligands in the Stille reaction is summarised in a
recent review: (a) P. Espinet and A. M. Echavarren, Angew. Chem., Int.
Ed., 2004, 43, 4704; (b) The use of added LiCl to promote the cross-
coupling of vinyl triflates with organostannanes was first reported in:
W. J. Scott, G. T. Crisp and J. K. Stille, J. Am. Chem. Soc., 1984, 106,
4630.
26 In these cases a small quantity of starting enol ether was present at
the end of the specified time, the reactions being stopped in order to
maximise the yield of cyclobutanone products. Free cyclohexadiene,
arising from cycloreversion, was observed in the NMR spectra in
increasing quantities as the reaction time was extended; this was
the major contributor to the lowered yields, particularly in table
entries 4 and 5. There was no clear evidence in these spectra of the
presumably co-formed arylketenes; these are expected to oligomerise
under the reaction conditions [(a) H. Staudinger, Ber. Dtsch. Chem.
Ges., 1911, 44, 533; (b) D. A. Efremov, P. M. Zavlin, N. S. Essentseva
and J. C. Tebby, J. Chem. Soc., Perkin Trans. 1, 1994, 3163]. The
reversibility of the interconversion (between the enol ethers and the
cyclobutanones), either directly or via a cycloreversion–cycloaddition
process, is influenced by a combination of substituent differences and
reaction temperature; compare the results in reference 6 and in; (c) C. A.
Pittol, S. M. Roberts, P. W. Sutton and J. O. Williams, J. Chem. Soc.,
Chem. Commun., 1994, 803; (d) S. M. Roberts and P. W. Sutton, J. Chem.
Soc., Perkin Trans. 1, 1995, 1499; (e) S. M. Roberts, P. W. Sutton and
L. Wright, J. Chem. Soc., Perkin Trans. 1, 1996, 1157.
5 T. Machiguchi, T. Hasegawa, A. Ishiwata, S. Terashima, S. Yamabe
and T. Minato, J. Am. Chem. Soc., 1999, 121, 4771.
6 J. Marchand-Brynaert and L. Ghosez, Tetrahedron Lett., 1974, 377.
7 For a recent detailed investigation of the ketene–cyclopentadiene
system which requires a re-casting of the results reported in references
1 and 5 see: B. R. Ussing, C. Hang and D. A. Singleton, J. Am. Chem.
Soc., 2006, 128, 7594.
8 There seems to be little or no precedent for the 2-oxabicyclo[2.2.1]hep-
5-en-3-one system except for an unusual simple bicyclic enol: J. M.
Landesberg, J. Org. Chem., 1975, 40, 2688.
9 J. R. Malpass and N. J. Tweddle, J. Chem. Soc., Perkin Trans. 1, 1977,
874.
10 N. A. Khanjin, J. P. Snyder and F. M. Menger, J. Am. Chem. Soc., 1999,
121, 11831.
11 M. Lakhrissi and Y. Chapleur, Synlett, 1991, 583.
12 D. Seyferth and R. S. Marmor, J. Organomet. Chem., 1973, 59, 237.
13 (a) L. Ghosez, R. Montaigne, A. Roussel, H. Vanlierde and P. Mollet,
Tetrahedron, 1971, 27, 615; (b) D. J. Kertesz and A. F. Kluge, J. Org.
Chem., 1988, 53, 4962.
14 K. Takai, M. Tezuka, Y. Kataoka and K. Utimoto, Synlett, 1989, 27.
15 K. C. Nicolaou, N. A. Petasis and D. A. Claremon, Tetrahedron, 1985,
41, 4835.
16 In a similar reaction, a bicyclic trichloromethyl hemiacetal has been
subjected to halocyclisation: R. F. Bargiband and A. Winston, Tetra-
hedron, 1972, 28, 1427.
27 (a) W. N. White, D. Gwynn, R. Schlitt, C. Girard and W. Fife, J. Am.
Chem. Soc., 1958, 80, 3271; (b) H. L. Goering and R. R. Jacobson,
J. Am. Chem. Soc., 1958, 80, 3277; (c) For a summary of substituent
effects on the rate of Claisen rearrangements and a discussion of
mechanistic interpretations arising from these data see: A. M. Mart´ın
Castro, Chem. Rev., 2004, 104, 2939.
28 C. S. Carman and G. F. Koser, J. Org. Chem., 1983, 48, 2534.
29 The trans-isomer is known: T. Sato, Y. Gotoh, M. Watanabe and T.
Fujisawa, Chem. Lett., 1983, 1533.
17 DBU–CHCl3: (a) V. K. Aggarwal and A. Mereu, J. Org. Chem., 2000,
65, 7211; (b) The slow addition of LDA to a cold (−78 ◦C) THF solution
of chloroform and the requisite aldehyde (Schemes 5 & 6) is based on
H. Taguchi, H. Yamamoto and H. Nozaki, J. Am. Chem. Soc., 1974,
96, 3010.
30 G. M. Kosolapoff, J. Am. Chem. Soc., 1947, 69, 1002.
31 P. G. Williard and S. E. de Laszlo, J. Org. Chem., 1985, 50, 3738.
32 Prepared by Swern oxidation of 3-cyclopentene-1-methanol, itself
prepared by LiAlH4 reduction of 3-cyclopentene-1-carboxylic acid
(J.-P. Depre´s and A. E. Greene, Org. Synth., 2004, Coll. Vol. X, 228);
cf.; K. Griesbaum, W. Volpp, R. Greinert, H.-J. Greunig, J. Schmid and
H. Henke, J. Org. Chem., 1989, 54, 383.
18 Crystal data for 21: C14H15Cl3OSe, M = 384.59, colourless plate,
˚
monoclinic, a = 11.9843(2), b = 5.7355(1), c = 22.2927(4) A, b =
3
˚
104.5181(6), V = 1483.38(4) A , T = 150 K, space group P21/c, Z = 4,
l(Mo-Ka) = 3.060 mm−1, 7682 reflections measured, 3616 used (Rint
0.03), final wR = 0.0277.
=
4318 | Org. Biomol. Chem., 2006, 4, 4307–4318
This journal is
The Royal Society of Chemistry 2006
©