Fused bicyclic piperidines and dihydropyridines by dearomatising cyclisation of the enolates of nicotinyl-substituted esters and ketones

Article abstract of DOI:10.3762/bjoc.6.22

The silyl enol ether derivatives of ketones or esters tethered by a hydrocarbon or ether linkage to the 3-position of a pyridine ring undergo dearomatising nucleophilic attack on the ring once it is activated (as an acylpyridinium species) by the addition of methyl chloroformate. The bicyclic dihydropyridine products are in some cases unstable, but may be isolated after hydrogenation as fused bicyclic piperidines.

Full text of DOI:10.3762/bjoc.6.22

Fused bicyclic piperidines and dihydropyridines by
dearomatising cyclisation of the enolates of
nicotinyl-substituted esters and ketones
Heloise Brice, Jonathan Clayden* and Stuart D. Hamilton
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
School of Chemistry, University of Manchester, Oxford Rd.,
Manchester M13 9PL, United Kingdom
doi:10.3762/bjoc.6.22
Received: 05 January 2010
Accepted: 11 February 2010
Published: 02 March 2010
Email:
Jonathan Clayden* - clayden@man.ac.uk
* Corresponding author
Associate Editor: J. Murphy
Keywords:
© 2010 Brice et al; licensee Beilstein-Institut.
License and terms: see end of document.
bicyclic; cyclisation; dearomatisation; enol ether; heterocycle;
pyridine; quinoline
Abstract
The silyl enol ether derivatives of ketones or esters tethered by a hydrocarbon or ether linkage to the 3-position of a pyridine ring
undergo dearomatising nucleophilic attack on the ring once it is activated (as an acylpyridinium species) by the addition of methyl
chloroformate. The bicyclic dihydropyridine products are in some cases unstable, but may be isolated after hydrogenation as fused
bicyclic piperidines.
Introduction
Oxidative [1-3] or reductive (nucleophilic) [4-21] dearomat- extended to much less reactive nucleophiles with a more elec-
ising cyclisation reactions are effective strategies for rapidly tron deficient aromatic acceptor [39-41]. Thus enolates of
building complexity and new reactivity from simple, readily glycine esters 1 carrying isonicotinoyl or nicotinoyl N-substitu-
made starting materials. We have used cyclisations of benz- ents cyclise readily to yield bicyclic amino acid derivatives 2
amide-stabilised carbanions, for example, to give bicyclic func- (Scheme 1a for example) [39]. Even greater reactivity towards
tionalised indolinones as intermediates in the synthesis of the intramolecular nucleophilic attack is exhibited by isonicotinam-
neuroactive amino acids [22-32], while related cyclisations of ides when activated by N-sulfonation [40,41]. For example, the
pyridyl-, nicotinamide- and isonicotinamide-containing carban- N-furylmethyl isonicotinamide 3 cyclises to the doubly dearo-
ions yield related bicyclic dihydropyridines [33,34].
matised bis-spirocycle 4 on treatment with triflic anhydride in
the presence of an alcohol [41] (Scheme 1b).
While reactive carbanions derived from allyl or benzyllithiums
will undergo dearomatising addition even into relatively elec- In this paper we report the results of cyclising the enolates of
tron rich rings [35-38], the scope of the dearomatisation can be ester and ketones tethered to a nicotinyl nucleus via chains
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Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
Scheme 1: Dearomatising cyclisations (a) of enolates; (b) of electron-
Scheme 3: Dearomatising cyclisation to a 5-benzoylhexahy-
rich heteroaromatics.
droisoquinoline.
which do not incorporate an amide linkage. The starting mater- We assume, in line with previous results [39], that cyclisation
ials for these cyclisations do not benefit from the favourable occurs only after the addition of the electrophilic trap (which,
conformational disposition of amides 1 and 3, making the reac- precedent suggests, attacks the pyridine lone pair and activates
tions more challenging. Likewise, the products are evidently the ring as an acylpyridinium species even in the presence of
less stable than those produced by the reactions in Scheme 1a, the lithium enolate). Attempts to use bases with a sodium or
but nonetheless they allow new, partially saturated “drug-like” potassium counter ion led instead to a high yield of the Claisen
heterocyclic systems to be formed.
product 6 (R = Me), presumably because the sodium and
potassium enolates are more reactive than the lithium enolate
and compete too well with N-acylation.
Results and Discussion
Formation of a carbocyclic ring by dearomat-
We surmised that effective cyclisation onto the acylpyridinium
species, avoiding the N- vs. C-acylation problem, might be
made possible by decreasing the reactivity of the enolate still
further, transforming it into a silyl enol ether 9. Silyl enol ethers
and ketene acetals are known to add effectively to pyridinium
species in an intermolecular manner [42-46]. Thus 7 was
converted to silyl enol ether 9 in excellent yield under standard
conditions. A single geometrical isomer was obtained, presum-
ably Z as shown. On treatment with methyl chloroformate, enol
ether 9 cyclised to yield 8 again as a single diastereoisomer but
in a greatly improved yield of 93%. The strategy of using a less
nucleophilic specific enolate equivalent is clearly an effective
way of improving selectivity, allowing the chloroformate to
activate the pyridine without competing attack by the enolate.
ising cyclisation
The study was initiated with the synthesis of the δ-nicotinyl
ketone 7 as illustrated in Scheme 2. Ethyl benzoylacetate was
alkylated with 3-(3-iodopropyl)pyridine 5 and the product 6
hydrolysed and decarboxylated to yield the pyridine 7 in
moderate yield.
Next we extended the reaction to the cyclisation of a δ-nicotinyl
butyrate ester 12 encouraged by the observations of Onaka [47],
who demonstrated that silyl ketene acetals can be added (in an
Scheme 2: Synthesis of ketone 7.
On treatment of 7 with LDA in THF at −78 °C, followed by intermolecular fashion) to electron deficient pyridines in the
trapping with methyl chloroformate, a yield of 40% of the presence of trimethylsilyl triflate, tetrabutylammonium fluoride
bicyclic hexahydroisoquinoline 8 was obtained (Scheme 3), or a montmorillonite clay.
which even after extensive experimentation could not be
improved. Lack of crystallinity and overlapping 1H NMR The cyclisation precursor was synthesised by using the
signals prevented us from confirming the relative stereochem- procedure of Hayashi [48] employing a Horner–Wadsworth–
istry, and the assignment shown in Scheme 3 is on the basis that Emmons olefination between nicotinaldehyde and phosphonate
the benzoyl group of 8 is likely to lie on the exo face of the 10. The resulting mixture of dienes 11 gave ester 12 after
azadecalin system.
hydrogenation (Scheme 4).
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Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
ratio of approximately 6:1. A slightly improved yield of 48%
was obtained by the use of an H-cube flow hydrogenation
apparatus at 40 bar and 30 °C.
Unfortunately, again the lack of crystallinity and the large
number of overlapping signals in the 1H NMR spectrum frus-
trated an unequivocal assignment of the stereochemistry.
However, hydrogenation of related fused dihydropyridines has
always led to cis stereochemistry at the ring junction [32,39].
The consequent expected axial–equatorial relationship between
the protons at the ring junction is supported by a coupling
Scheme 4: Synthesis of ester 12.
It proved challenging to isolate cleanly the silyl ketene acetal constant of 4.2 Hz between these protons in 15 (Figure 1) in the
derived from 12, so instead we decided to form and cyclise the major product diastereoisomer. The corresponding 12.9 Hz
silyl derivative in a single pot. Thus, ester 12 was added to LDA coupling to the proton α to the ester group is consistent with
at −78 °C, and the enolate quenched with trimethylsilyl adoption of an exo–equatorial orientation by this substituent.
chloride. After 15 min methyl chloroformate was added and the
solution warmed to room temperature. Complete consumption
of starting material (by TLC) was accompanied by the appear-
ance of a single less polar spot (Rf 0.77; EtOAc–petroleum ether
1:1). 1H NMR analysis of the crude product after rapid work-up
showed two significant sets of new signals at 6.55–6.80 ppm
(2H) and 4.65–5.10 ppm (1H) consistent with the dihydro-
pyridine protons of the expected dearomatised product 14
(Scheme 5). However, in contrast with the clean spectra and
Figure 1: Coupling constants (Hz) in the major diastereoisomer of 15.
dearomatised product 8 derived from ketone 7, duplication of
many of the signals in the crude 1H NMR spectrum of 14
Formation of a tetrahydrofuran by dearomat-
suggested the existence of either a mixture of diastereoisomers
or rotamers caused by restricted rotation of the carbamate ising cyclisation
group.
Encouraged by the successful formation of carbocyclic rings in
dearomatising cyclisations of nicotinyl ketones and esters, we
moved to extend the reaction to the analogous formation of
tetrahydofuranyl esters by cyclisation of starting materials in-
corporating an enolate nucleophile and a nicotinyl electrophile
tethered through an ether linkage. Alkylation of 3-hydroxy-
methylpyridine by t-butyl bromoacetate 17a or bromopropi-
onate 17b suffered from competing N-alkylation but returned
acceptable yields of the esters 18a and 18b (Scheme 6). As with
13, we anticipated that the silyl ketene acetal derivatives 19
Scheme 5: Dearomatising cyclisation of ester 12.
No dihydropyridine was isolable from this mixture by flash
chromatography, probably due to rapid re-aromatisation.
However, immediate hydrogenation at ambient pressure using
the conditions developed by Arnott for related 3,4-fused
dihydropyridines [39] gave 15 in 45% yield after chromato-
graphy as an inseparable mixture of two diastereoisomers in a
Scheme 6: Synthesis of esters 18.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
would be challenging to isolate, so both starting esters 18a and
18b were treated with LDA and Me3SiCl followed by methyl
chloroformate (Scheme 7). As with 14, re-aromatisation was
fast and the crude products 19 were therefore hydrogenated at
atmospheric pressure to give 20a in up to 32% yield from 18a
and 20b in up to 35% yield from 18b. The instability of the two
non-isolable intermediates meant however that these yields
were not consistently reproducible and yields around 25% were
more commonly observed. However, scrupulous avoidance of
contact with oxygen before the hydrogenation step improved
the yield of 20a to 41%. Attempted cyclisation without forma-
tion of the silyl enol ether (i.e. omitting Me3SiCl) led to a
complex mixture of products.
Figure 2: Determination of the stereochemistry of 20b. Arrows indi-
cate nuclear Overhauser enhancements.
Yields are greatest if the enolate is first stabilised as a silyl enol
ether, presumably because acylation of the pyridine ring to give
the electrophilic acylpyridinium species is cleaner. The bicyclic
dihydropyridine products are unstable towards re-aromatisation,
but can be isolated in moderate to excellent yield if they are
hydrogenated in situ, especially when oxygen is excluded prior
to and during the hydrogenation.
Experimental
5-Benzoyl-5,6,7,8-tetrahydro-4aH-isoquino-
line-2-carboxylic acid methyl ester (8)
Methyl chloroformate (0.056 ml, 0.722 mmol) was added to a
solution of 9 (45 mg, 0.144 mmol) and triethylamine (0.02 ml,
0.144 mmol) in dichloromethane (5 ml) at −78 °C. After
warming to room temperature, dichloromethane was added (30
ml), and the solution washed with water (3 × 10 ml) and brine
(10 ml). The combined aqueous layers were extracted with
dichloromethane (10 ml) and the combined organic layers dried
(Na2SO4), filtered and concentrated under reduced pressure to
furnish a light yellow oil. The oil was purified by flash column
chromatography (SiO2; petroleum ether–EtOAc 9:1) to yield
the title compound as a colourless oil (40 mg, 0.135 mmol,
93%); silica gel TLC Rf 0.38 (petroleum ether–EtOAc 4:1); IR
(thin film) νmax (cm−1): 1721 (carbamate C=O), 1677 (ketone
C=O); 1H NMR (500 MHz, CDCl3, δH): 7.80 (2H, d, J = 7.5
Hz, Ph-H), 7.41 (1H, t, J = 8.0 Hz, Ph-H), 7.32 (2H, t, J = 8.0
Hz, Ph-H), 6.67 (1H, br, py-H2), 6.54 (1H, br, py-H6), 4.60
(2H, br, py-H5) 3.64 (3H, br, OCH3), 3.33 (2H, m, py-H4 and
CH), 2.1–1.3 (6H, br-m, CH2); 13C NMR (125 MHz, CDCl3,
δC): 202.9 (ketone C=O), 152.2 (carbamate C=O), 137.3, 133.6,
129.1 and 128.8 (aromatic), 123.4 and 123.0 (py-C6), 120.9 and
119.9 (py-C3), 117.1 and 116.8 (py-C2), 108.1 and 107.7 (py-
C5), 60.8 (py-C4), 53.8 and 53.7 (OCH3), 38.0 and 37.8 (CH),
32.5 and 32.4 (CH2), 31.7 and 31.6 (CH2), 27.5 (CH2); CIMS
m/z (relative intensity): 298 (100%, M+H+), 238 (40%,
M-CO2Me); EIMS m/z (relative intensity): 297 (10%, M+).
[Found: M+H+, 298.1436. C18H20NO3 requires 298.1438].
Scheme 7: Dearomatising cyclisation to form tetrahydrofurans.
In both cases the cyclic products were obtained as single dia-
stereoisomers, indicating a diastereoselective cyclisation and a
face-selective hydrogenation. An nOe experiment on cyclic
ether 20b, irradiating the 7a ring junction proton, showed nOe
enhancements of protons 3a, 6 (1H) and 7 (1H) (Figure 2). This
result is consistent with a cis-fused ring junction. A lack of
conclusive nOes prevented determination of the stereochem-
istry at the ester-bearing centres of 20a or 20b. However, a
similar cyclisation with an amide tether [39] had resulted in an
endo-orientated ester substituent, and the stereochemistries of
20 are accordingly shown with the ester orientated endo.
Conclusion
Tethered ketone or ester enolate nucleophiles undergo dearo-
matising attack on a pyridine ring to yield bicyclic products.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
5-Ethyl 2-methyl octahydroisoquinoline-2,5-
(1H) dicarboxylate (15)
charcoal (0.053 g, 0.05 mmol) was added and the suspension
immediately placed under a hydrogen atmosphere. The suspen-
n-Butyllithium (0.36 mL of a 1.8 M solution in hexane) was sion was warmed to 45 °C for 18 h, filtered through Celite and
added to a solution of diisopropylamine (0.11 mL, 0.75 mmol) evaporated under reduced pressure. The residue was purified by
in THF (15 mL) at 0 °C and the mixture stirred for 15 min flash chromatography (SiO2; EtOAc–petroleum ether 1:4 to
before cooling to −78 °C. A solution of ester 12 (0.104 g, 0.5 1:1) to yield the title compound (0.058 g, 41%) as white prisms;
mmol) in THF (5 mL) and then trimethylsilyl chloride (0.10 m.p. 49–51 °C (from Et2O); Rf (EtOAc–petroleum ether 1:1)
mL, 0.75 mmol) were added using a cannula. The solution was 0.23; IR (film) νmax (cm−1): 1745 (C=O ester), 1705 (C=O
stirred at −78 °C for 15 min, methyl chloroformate (0.19 mL, carbamate; 1H NMR (300 MHz, CDCl3, δH): 4.37 (1H, d, J =
2.5 mmol) was added and the solution warmed to room tem- 5.0 Hz, 1-H), 3.95–4.10 (2H, m, 4-H (1H) and 6-H (1H)), 3.98
perature. The solution was rapidly added to a saturated sodium (1H, t, J = 8.5 Hz, OCHaHb), 3.79 (1H, t, J = 8.5 Hz, OCHaHb),
hydrogen carbonate solution (30 mL), extracted with EtOAc (2 3.67 (3H, s, OMe), 3.14–3.28 (1H, m, 4-H), 2.71–2.87 (1H, m,
× 30 mL), dried (MgSO4), and concentrated to yield an oil. The 6-H), 2.44–2.57 (2H, m, 3a-H and 7a-H), 1.50–1.58 (2H, m,
crude oil was dissolved in isopropanol (6 mL), and 10% palla- 7-H), 1.47 (9H, s, (CH3)3); 13C NMR (CDCl3, δC): 169.9
dium/carbon (0.053 g, 0.05 mmol) was added and the suspen- (C=O), 156.2 (C=O), 82.1(C(CH3)3), 81.3 (1-C), 69.2 (3-C),
sion immediately placed under a hydrogen atmosphere. The 52.9 (OMe), 42.6 (6-C), 41.7 (4-C), 39.6 (7a-C), 38.3 (3a-C),
suspension was warmed to 60 °C for 50 h, filtered through 28.4 ((CH3)3), 22.2 (7-C); MS m/z (relative intensity): 286
celite and evaporated under reduced pressure. The residue was (15%, MH+), 230 (100%, MH+−C(CH3)3); (Found: MH+,
purified by flash chromatography (SiO2; EtOAc–petroleum 286.1646. C14H23NO5 requires MH+, 286.1649).
ether 1:19 to 1:1) to yield the title compound (0.061 g, 45%) as
Dimethyl 1-methylhexahydrofuro[3,4-
a yellow oil which was approximately a 6:1 mixture of dia-
stereoisomers; Rf (EtOAc–petroleum ether 1:1) 0.45; IR (film) c]pyridine-1,5(3H)-dicarboxylate (20b)
νmax (cm−1): 1730 (C=O ester), 1702 (C=O carbamate); 1H n-Butyllithium (0.34 mL of a 1.9 M solution in hexane) was
NMR (300 MHz, CDCl3, δH): 3.95–4.25 (2H, m, 1-H and/or added to a solution of diisopropylamine (0.11 mL, 0.75 mmol)
3-H), 4.13 (2H, q, J = 7.5 Hz, CH2CH3), 3.68 (3H, s, OMemaj), in THF (15 mL) at 0 °C and stirred for 20 min before cooling to
3.65 (OMemin), 2.85–3.00 (1H, br m, 1-H or 3-H), 2.63–2.76 −78 °C. A solution of the ester 18b (0.098 g, 0.5 mmol) in THF
(1H, br, m, 1-H or 3-H), 2.49 (1H, dt, J = 13.0 Hz, 4.0, 5-H), (5 mL) was added using a cannula followed by trimethylsilyl
2.24 (1H, ap dq, J = 13.0 Hz, 4.0, CH), 1.83 (1H, dt, J = 12.5 chloride (0.10 mL, 0.75 mmol). The solution was then stirred at
Hz, 3.0, CH), 1.65–1.74 (3H, m, CH2), 1.57 (1H, dd, J = 13.0 −78 °C for 15 min and methyl chloroformate (0.19 mL, 2.5
Hz, 3.5, CH2), 1.37–1.51 (2H, m, CH2), 1.17–1.35 (3H, m, mmol) was added and the solution warmed to room tempera-
CH2), 1.25 (3H, t, J = 7.5 Hz, CH2CH3); 13C NMR (CDCl3, ture. The solution was rapidly worked-up by addition of satur-
δC):174.6 (C=O), 156.7 (C=O), 60.5 (OCH2), 52.8 (OMe), 49.9 ated sodium hydrogen carbonate solution (30 mL), extracted
(CH2), 47.0 (COCH), 44.4 (NCH2), 40.8 (CH), 37.1 (CH), 37.1 with EtOAc (2 × 30 mL), dried (MgSO4) and evaporated under
(CHmin), 30.0 (CH2), 25.2 (CH2), 24.5 (CH2min), 24.0 (CH2), reduced pressure. The residue was dissolved in propan-2-ol (7
22.1 (CH2), 21.5 (CH2min), 14.6 (CH2CH3); MS m/z (relative mL), 10% palladium on charcoal (0.053 g, 0.05 mmol) was
intensity): 270 (100%, MH+); (Found: MH+, 270.1699. added and the suspension was immediately placed under a
C14H24NO4 requires MH+, 270.1700).
hydrogen atmosphere. The suspension was warmed to 50 °C for
24 h, filtered through celite, washed with EtOAc (5 × 10 mL)
and evaporated under reduced pressure. The residue was puri-
fied by flash chromatography (SiO2; EtOAc–petroleum ether
1-tert-Butyl 5-methyl hexahydrofuro[3,4-
c]pyridine-1,5(3H)-dicarboxylate (20a)
n-Butyllithium (0.34 mL of a 1.9 M solution in hexane) was 3:17 to 1:1) to yield the title compound (0.033 g, 35%) as a
added to a solution of diisopropylamine (0.11 mL, 0.75 mmol) colourless oil; Rf (EtOAc–petroleum ether 1:1) 0.25; IR (film)
in THF (10 mL) at 0 °C and stirred for 15 min before cooling to νmax (cm−1): 1752 (C=O ester), 1702 (C=O carbamate); 1H
−78 °C. A solution of the ester 18a (0.112 g, 0.5 mmol) in THF NMR (300 MHz, CDCl3, δH): 4.07 (1H, t, J = 8.5 Hz,
(5 mL) was added using a cannula followed by trimethylsilyl OCHaHb), 3.81 (1H, t, J = 9.0 Hz, OCHaHb), 3.75–4.02 (2H, m,
chloride (0.10 mL, 0.75 mmol). The solution was then stirred at 4-H and 6-H), 3.75 (3H, s, OMe), 3.24 (1H, br d, J = 12.5 Hz,
−78 °C for 45 min, methyl chloroformate (0.19 mL, 2.5 mmol) 4-H or 6-H), 2.79 (1H, t, J = 12.0 Hz, 4-H or 6-H), 2.66 (1H, br
was added and the solution warmed to room temperature. The s, 3a-H), 2.17–2.27 (1H, m, 7a-H), 1.49–1.64 (2H, m, 7-H),
solution was rapidly worked-up under a nitrogen atmosphere by 1.46 (3H, s, (CH3); 13C NMR (CDCl3, δC): 174.0 (C=O ester),
addition to saturated sodium hydrogen carbonate solution (30 156.4 (C=O carbamate), 87.5 (1-C), 69.1 (3-C), 53.0 (OMe),
mL) and extraction with EtOAc (15 mL). 10% Palladium on 52.4 (OMe), 45.1 (7a-C), 42.6 (6-C), 41.8 (4-C), 36.9 (3a-C),
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Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
17.Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun. 1999, 231.
doi:10.1039/a808218i
25.1 (CCH3), 23.6 (7-C); MS m/z (relative intensity): 258
(100%, MH+), 275 (55%, MNH4+); (Found: MH+, 258.1340.
C12H19NO5 requires MH+, 258.1336).
18.Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun. 1998, 297.
doi:10.1039/a707683e
19.Ahmed, A.; Clayden, J.; Rowley, M. Synlett 1999, 1954.
doi:10.1055/s-1999-2977
Supporting Information
20.Bragg, R. A.; Clayden, J. Tetrahedron Lett. 1999, 40, 8323.
doi:10.1016/S0040-4039(99)01765-7
Supporting Information File 1
21.Clayden, J.; Purewal, S.; Helliwell, M.; Mantell, S. J.
Angew. Chem., Int. Ed. 2002, 41, 1049.
Synthesis and characterisation data of starting materials
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-22-S1.pdf]
doi:10.1002/1521-3773(20020315)41:6<1049::AID-ANIE1049>3.0.CO;
2-7
22.Clayden, J. Total synthesis of kainoids by dearomatizing anionic
cyclisation. In Strategies and Tactics in Organic Synthesis;
Harmata, M., Ed.; Academic Press, 2004; Vol. 4, pp 72–96.
doi:10.1016/S1874-6004(04)80008-X
Acknowledgements
We are grateful to the EPSRC, GlaxoSmithKline (HB) and
AstraZeneca (SH) for studentships, and to Drs Emma Blaney
and Rukhsana Mohammed for valuable discussions.
23.Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005,
127, 2412. doi:10.1021/ja042415g
24.Clayden, J.; Knowles, F. E.; Menet, C. J. Tetrahedron Lett. 2003, 44,
3397. doi:10.1016/S0040-4039(03)00570-7
25.Clayden, J.; Knowles, F. E.; Menet, C. J. Synlett 2003, 1701.
doi:10.1055/s-2003-40993
References
1. Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
26.Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58,
4727. doi:10.1016/S0040-4020(02)00379-4
doi:10.1021/cr800332c
2. Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 404. doi:10.1021/ja077457u
27.Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 317.
doi:10.1039/a909325g
And references therein.
28.Ahmed, A.; Bragg, R. A.; Clayden, J.; Tchabanenko, K.
Tetrahedron Lett. 2001, 42, 3407. doi:10.1016/S0040-4039(01)00501-9
29.Bragg, R. A.; Clayden, J.; Bladon, M.; Ichihara, O. Tetrahedron Lett.
2001, 42, 3411. doi:10.1016/S0040-4039(01)00502-0
30.Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem. Commun. 2002, 38.
doi:10.1039/b109188c
3. Hamamoto, H.; Anilkumar, G.; Hirofumi, T.; Kita, Y. Chem.–Eur. J.
2002, 8, 5377.
doi:10.1002/1521-3765(20021202)8:23<5377::AID-CHEM5377>3.0.C
O;2-H
4. Dai, M.; Danishefsky, S. J. Heterocycles 2009, 77, 157.
doi:10.3987/COM-08-S(F)6
31.Clayden, J.; Kenworthy, M. N. Synthesis 2004, 1721.
doi:10.1055/s-2004-829138
5. López-Ortiz, F.; Iglesias, M. J.; Fernández, I.; Andujar Sanchez, C. M.;
Ruiz-Gómez, G. Chem. Rev. 2007, 107, 1580. doi:10.1021/cr030207l
(see for review).
32.Clayden, J.; Read, B.; Hebditch, K. R. Tetrahedron 2005, 61, 5713.
doi:10.1016/j.tet.2005.04.003
6. Wang, Z.; Xi, Z. Synlett 2006, 1275. doi:10.1055/s-2006-939083
7. Nevárez, Z.; Woerpel, K. A. J. Org. Chem. 2008, 73, 8113.
doi:10.1021/jo801502x
33.Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005, 7,
3673. doi:10.1021/ol051214u
34.Clayden, J.; Hennecke, U. Org. Lett. 2008, 10, 3567.
doi:10.1021/ol801332n
8. Liu, L.; Wang, Z.; Zhao, F.; Xi, Z. J. Org. Chem. 2007, 72, 3484.
doi:10.1021/jo070160u
35.Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett. 2004, 6, 609.
doi:10.1021/ol0364071
9. Ruiz-Gómez, G.; Iglesias, M. J.; Serrano-Ruiz, M.; García-Granda, S.;
Francesch, A.; López-Ortiz, F.; Cuevas, C. J. Org. Chem. 2007, 72,
3790. doi:10.1021/jo070276q
36.Clayden, J.; Turnbull, R.; Helliwell, M.; Pinto, I. Chem. Commun. 2004,
2430. doi:10.1039/b409150g
10.Ruiz-Gómez, G.; Francesch, A.; Iglesias, M. J.; López-Ortiz, F.;
Cuevas, C.; Serrano-Ruiz, M. Org. Lett. 2008, 10, 3981.
doi:10.1021/ol801463g
37.Clayden, J.; Farnaby, W.; Grainger, D. M.; Hennecke, U.;
Mancinelli, M.; Tetlow, D. J.; Hillier, I. H.; Vincent, M. A.
J. Am. Chem. Soc. 2009, 131, 3410. doi:10.1021/ja808959e
38.Clayden, J.; Dufour, J.; Grainger, D.; Helliwell, M. J. Am. Chem. Soc.
2007, 129, 7488. doi:10.1021/ja071523a
11.Kumaran, R. S.; Brüdgam, I.; Reissig, H.-U. Synlett 2008, 991.
doi:10.1055/s-2008-1072512
12.Ovens, C.; Martin, N. G.; Procter, D. J. Org. Lett. 2008, 10, 1441.
doi:10.1021/ol8002095
39.Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325.
doi:10.1021/ol062126s
13.Clayden, J.; Kenworthy, M. N.; Helliwell, M. Org. Lett. 2003, 5, 831.
doi:10.1021/ol0340585
40.Arnott, G.; Brice, H.; Clayden, J.; Blaney, E. Org. Lett. 2008, 10, 3089.
doi:10.1021/ol801092s
14.Clayden, J.; Kenworthy, M. N. Org. Lett. 2002, 4, 787.
doi:10.1021/ol0172626
41.Brice, H.; Clayden, J. Chem. Commun. 2009, 1964.
doi:10.1039/b901558b
15.Clayden, J.; Menet, C. J.; Mansfield, D. J. Org. Lett. 2000, 2, 4229.
doi:10.1021/ol006786n
42.Raussou, S.; Gosmini, R.; Mangeney, P.; Alexakis, A.; Commerçon, M.
Tetrahedron Lett. 1994, 35, 5433. doi:10.1016/S0040-4039(00)73518-0
43.Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184.
doi:10.1021/ja0203317
16.Clayden, J.; Tchabanenko, K.; Yasin, S. A.; Turnbull, M. D. Synlett
2001, 302. doi:10.1055/s-2001-10772
Page 6 of 7
(page number not for citation purposes)

Beilstein Journal of Organic Chemistry 2010, 6, No. 22.
44.Rudler, H.; Denise, B.; Xu, Y.; Parlier, A.; Vaissermann, J.
Eur. J. Org. Chem. 2005, 3724. doi:10.1002/ejoc.200500162
45.Bosch, J.; Bennasar, M.-L. Synlett 1995, 587. doi:10.1055/s-1995-5007
46.Rudler, H.; Parlier, A.; Sandoval-Chavez, C.; Herson, P.; Daran, J.-C.
Angew. Chem., Int. Ed. 2008, 47, 6843. doi:10.1002/anie.200801879
47.Onaka, M.; Ohno, R.; Izumi, Y. Tetrahedron Lett. 1989, 30, 747.
doi:10.1016/S0040-4039(01)80299-9
48.Tanouchi, T.; Kawamura, M.; Ohyama, I.; Kajiwara, I.; Iguchi, Y.;
Okada, T.; Miyamoto, T.; Taniguchi, K.; Hayashi, M. J. Med. Chem.
1981, 24, 1149. doi:10.1021/jm00142a006
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