Tributyltin hydride-mediated radical cyclisation of carbonyls to form functionalised oxygen and nitrogen heterocycles

Article abstract of DOI:10.1039/b202077g

The tributyltin hydride-mediated cyclisation of unsaturated ethers and amines bearing an aldehyde or α,β-unsaturated ketone group is reported. Cyclisation proceeds via reversible addition of the tributyltin radical to the carbonyl double bond to form an intermediate O-stannyl ketyl. This nucleophilic radical can add intramolecularly to electron-rich double bonds to form substituted 5- or 6-membered rings. The efficiency of the cyclisation to form, for example, hydroxytetrahydrofurans, chromanols or quinolones, is shown to depend on the nature of the acceptor double bond and also on the stability of the intermediate O-stannyl ketyl. Thus, resonance-stabilised allylic or benzylic O-stannyl ketyl radicals have been shown, for the first time, to have a particular application in slow radical cyclisations leading to butyrolactones or pyrans.

Full text of DOI:10.1039/b202077g

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Tributyltin hydride-mediated radical cyclisation of carbonyls to
form functionalised oxygen and nitrogen heterocycles
Jon Bentley,a Paul A. Nilssonb and Andrew F. Parsons*b
1
a Vernalis Research Ltd., Oakdene Court, 613 Reading Road, Winnersh, Wokingham,
UK RG41 5UA
b Department of Chemistry, University of York, Heslington, York, UK YO10 5DD.
E-mail: afp2@york.ac.uk; Fax: ϩ44-1904-432516; Tel: ϩ44-1904-432608
Received (in Cambridge, UK) 27th February 2002, Accepted 1st May 2002
First published as an Advance Article on the web 27th May 2002
The tributyltin hydride-mediated cyclisation of unsaturated ethers and amines bearing an aldehyde or
α,β-unsaturated ketone group is reported. Cyclisation proceeds via reversible addition of the tributyltin radical to the
carbonyl double bond to form an intermediate O-stannyl ketyl. This nucleophilic radical can add intramolecularly to
electron-rich double bonds to form substituted 5- or 6-membered rings. The efficiency of the cyclisation to form, for
example, hydroxytetrahydrofurans, chromanols or quinolones, is shown to depend on the nature of the acceptor
double bond and also on the stability of the intermediate O-stannyl ketyl. Thus, resonance-stabilised allylic or
benzylic O-stannyl ketyl radicals have been shown, for the first time, to have a particular application in slow
radical cyclisations leading to butyrolactones or pyrans.
1
Introduction
2
Results and discussion
The cyclisation of unsaturated organohalides, or related com-
pounds, using tributyltin hydride has attracted considerable
synthetic interest in recent years.1 A wide variety of 5- and
6-membered rings in particular, can be prepared under mild,
neutral reaction conditions using this method of cyclisation.
However, one important drawback to these types of radical
reaction is the loss of two functional groups (e.g. C–X and
2.1 O-Stannyl ketyl cyclisations
2.1.1 Tetrahydrofurans and tetrahydropyrans. Initial work
concentrated on the formation and cyclisation of aldehydes
1a,b (Scheme 1). These were prepared by mono-alkylation of
C᎐C) on cyclisation of the halide precursor to form the cyclic
᎐
product. To avoid this, other methods of radical cyclisation
have been developed including atom transfer reactions, which
typically use hexabutylditin2 or alternative transition metal
catalysts3 to tributyltin hydride. In contrast, Enholm and
co-workers have investigated the reaction of tributyltin hydride
with unsaturated aldehydes, rather than halides, to form
cyclopentanes bearing a versatile hydroxy group.4 These
reactions proceed via addition of the tributyltin radical to the
carbonyl double bond to form an intermediate O-stannyl ketyl,
which can undergo cyclisation onto an alkene double bond.
Allylic O-stannyl ketyls were also shown to undergo related
cyclisations leading to cyclopentanes possessing a ketone
group.5 In these reactions an activating or electron-withdrawing
group on the alkene double bond was found to be essential for
cyclisation and related reactions have also been investigated
using oxime acceptors.6 Recently, we have extended this method
of cyclisation of alkenes to the formation of substituted
pyrrolidines and piperidines.7 Both O-stannyl ketyls and allylic
O-stannyl ketyls were shown to undergo cyclisation, onto
electron-rich or -poor alkenes, to produce 5- or 6-membered
nitrogen heterocycles. Having established that these nucleo-
philic radicals can undergo cyclisation on to electron-rich
alkenes, we now describe the use of this method in the synthesis
of hydroxy tetrahydrofurans, chromanols and quinolones.8
Prior to this work, we were only aware of an isolated report
of a related ketyl cyclisation reaction [mediated by tributyl-
tin hydride or samarium() iodide] on to an electron-poor
(unsaturated ester) double bond leading to a substituted tetra-
hydrofuran.9
Scheme 1
ethylene glycol using potassium hydroxide and cinnamyl brom-
ide or prenyl bromide in DMSO,10 followed by Swern oxidation
of the resulting primary alcohols in 46–58% overall yield. The
cyclisation of 1a,b was then investigated by reaction with tri-
butyltin hydride. Slow addition of tributyltin hydride (1.1
equiv.) and AIBN (0.3 equiv.) over 1 h, to a solution of 1a,b
(1 equiv.) in boiling degassed benzene produced the desired
hydroxy tetrahydrofurans 3a,b in 59–64% yield. The cyclic
products were isolated as a 1 : 1 mixture of diastereoisomers (as
indicated by the NMR spectra), which proved to be inseparable
DOI: 10.1039/b202077g
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by column chromatography on silica. These reactions are
expected to proceed via 5-exo-trig cyclisation of the inter-
mediate O-stannyl ketyls 2a,b followed by hydrogen-atom
transfer from tributyltin hydride and hydrolysis of the tributyl-
tin alkoxide on aqueous work-up. Interestingly, no alicyclic
alcohols, derived from reaction of 2a,b with tributyltin hydride,
were isolated from these reactions. This contrasts with the reac-
tion of tin hydride with (Z)-undec-5-enal, which showed a
preference for simple reduction over cyclisation under similar
reaction conditions.4 Presumably, O-stannyl ketyl cyclisation
to form tetrahydrofurans is faster than cyclisation to give
cyclopentanes because of the introduction of an oxygen atom
within the chain, which affects both the length of the chain and
bond angles (i.e. 106.8Њ versus 109Њ for C–O–C and C–C–C,
respectively).11
resulted in the isolation of cinnamyl alcohol 11 (in 40% yield),
which may have been formed via an initial 1,5-hydrogen atom
transfer. The resultant allylic radical 10 could then undergo
fragmentation to form cinnamaldehyde, which may be reduced
with a further equivalent of tributyltin hydride to give 11. As
for the 5-exo cyclisations, no simple reduction of 8 was
observed and this contrasts with the related reaction of citron-
ellal with tributyltin hydride.4 In this case, only trace amounts
of the cyclised product were isolated while the simple reduced
product (citronellol) was formed in 95% yield.
2.1.2 Chromanols. The cyclisation of aromatic aldehydes
was then investigated with a view to making chromanols. This
novel method of cyclisation would complement the variety of
other synthetic approaches, which have been developed to pre-
pare these biologically important compounds.14 Reaction of
the benzaldehyde derivative 12a, prepared by O-alkylation
of 2-hydroxybenzaldehyde,15 with tributyltin hydride (under the
same conditions as for 1a,b) produced chromanol 13a, as a 5.5 :
1 mixture of separable trans–cis isomers, in an excellent 78%
yield (Scheme 4). The assignment of stereochemistry was based
The synthesis of bicyclic compounds is also possible as
illustrated by the cyclisation of the cyclohexenyl aldehyde 4
(Scheme 2). Under the same reaction conditions as employed for
Scheme 2
1a,b, the cyclisation of 4 proceeded smoothly to afford octa-
hydrobenzofuran 5 in an excellent 73% yield after column
chromatography. This compound was isolated as an inseparable
1
1 : 1 mixture of diastereoisomers as indicated by both the H
and 13C NMR spectra. Whereas aldehydes 1a,b and 4 under-
went facile cyclisation, reaction of the related ketone 6 with
tributyltin hydride gave no cyclised product and only unreacted
starting material was recovered. A similar result was observed
on reaction of the unsaturated ester 7 with tributyltin hydride.
None of the desired cyclic product was observed in the crude 1H
NMR spectrum and this may be attributed to the conform-
ational effects of the ester group, which is known to lower the
rate of radical cyclisation (in related systems).12
Scheme 4
on NMR data, which was compared with literature values.16
A
This method of cyclisation could also be applied to the
formation of a tetrahydropyran (Scheme 3). Reaction of
similar diastereoisomer ratio was observed when the tributyltin
hydride was added to 12a over 5 rather than 1 h. This contrasts
with the much lower yield of 44% for tetrahydropyran 9, which
was isolated as an equal mixture of diastereoisomers. The
introduction of a benzene ring, which is expected to lead to
the formation of a more stable O-stannyl ketyl, clearly has a
pronounced effect on both the efficiency and stereoselectivity of
the 6-exo-trig cyclisation. Hence, the formation of a relatively
stable O-stannyl ketyl radical, could lead to a reversible radical
cyclisation,17 which may explain the predominance of the
thermodynamically more stable trans-isomer of 13a.
Changing the substituents on the alkene acceptor also
influences the 6-exo cyclisation. When the corresponding
O-allyl derivative 12b was treated under the same conditions the
main product was benzyl alcohol 14b, which was derived from
simple reduction. Even when the tributyltin hydride was added
over 5 h (rather than 1 h), benzyl alcohol 14b was formed in
62% yield while chromanol 13b was only isolated in 24% yield.
Chromanol 13b was isolated as an inseparable 5 : 1 mixture of
diastereoisomers, the major isomer of which was tentatively
assigned (from the NMR spectra) as the trans-isomer. Cyclis-
ation of aromatic ketones, as well as aldehydes, is also possible
as illustrated by the reaction of the acetophenone derivative
Scheme 3
aldehyde 8 with tributyltin hydride (added over 1 h) produced
the desired 6-ring product 9 in 44% yield (as a 1 : 1 mixture of
diastereoisomers). The lower yield of 9, compared to tetra-
hydrofuran 3b, is presumably due to the slower rate of 6-exo-
trig radical cyclisation and the possibility of a competing
1,5-hydrogen atom transfer.13 Indeed, the reaction of 8 also
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12c. This underwent cyclisation to afford chromanol 13c, as an
inseparable (4.2 : 1) mixture of diastereoisomers, in an excellent
82% yield. The relative stereochemistry of the major diastereo-
isomer was tentatively assigned as trans-, with respect to the
hydroxy and benzyl groups, on the basis of NOE experiments.
For example, for the major isomer, irradiation of the methyl
group at C-4 resulted in an enhancement of the signals due to
both benzylic hydrogens at C-3. The benzene ring clearly plays
an important role in facilitating the cyclisation of ketone 12c, as
the related aliphatic ketone 6 failed to undergo 5-exo cyclisation
under the same conditions.
The influence of the acceptor double bond was further
examined by the preparation of unsaturated ester 15 (Scheme
5). On being heated with tributyltin hydride, cyclisation of
Scheme 7
form the desired hydroxy-dihydroquinolinones 21a and 21b,
respectively. Whereas cyclisation of 20a produced 21a as a
6.8 : 1 mixture of diastereoisomers in 93% yield, the cyclisation
of 20b was less efficient (73%) and less stereoselective (2 : 1
mixture of diastereoisomers). The stereochemistry of the major
diastereomer of 21b was tentatively assigned as cis on the basis
of NOE experiments (which showed a correlation between the
C-3 and C-4 hydrogens).
Similar results were obtained using the 2-aminoaceto-
phenone derivatives 20c and 20d. In each case, the cyclisation
proceeded smoothly and, after aqueous work-up and purifica-
tion via column chromatography, dihydroquinolinones 21c and
21d were isolated in excellent yield (i.e. 73% and 82%, respect-
ively). Both cyclisations proceeded so as to form a similar ratio
of diastereoisomers (i.e. 1.2 : 1 and 1.6 : 1). It should be noted
that the N-methyl substituent plays an important role in these
cyclisations, as reaction of the related secondary amide 22 with
tributyltin hydride, produced only trace amounts (<3%) of the
desired dihydroquinolinone. This is presumably due to the
methyl group influencing the amide conformer population.19
Having established that unsaturated aryl amides derived from
2-aminoacetophenone undergo 6-exo-trig radical cyclisation,
the synthesis and subsequent radical cyclisation of the unsatur-
ated aryl amine 23 was also investigated (Scheme 8). Alkylation
Scheme 5
15 was observed to give an inseparable mixture of trans-
substituted chromanol 16 and tricyclic lactone 17 (in a 1 : 1.6
ratio) in a combined 84% yield. The tricycle 17 is thought to
arise via a second, non-radical cyclisation, which involves
attack of the intermediate tin alkoxide on to the ester. None of
the bicyclic cis-chromanol was isolated, which indicates that the
lactonisation occurs rapidly under the reaction conditions. The
facile cyclisation of 15, which involves attack of the inter-
mediate O-stannyl ketyl on to an electron-poor (rather than
electron-rich) double bond, is therefore consistent with the
efficient carbocyclisations (of unsaturated esters) reported pre-
viously.4,5 Indeed, cyclisation on to an electron-poor double
bond could also be used to prepare chromanones as illustrated
by the cyclisation of ester 18 to give lactone 19 in 50% yield (as
a 2 : 1 mixture of diastereoisomers) (Scheme 6).
Scheme 8
of N-methyl-2-aminoacetophenone with cinnamyl bromide
proceeded smoothly using potassium carbonate in refluxing
acetone and the desired unsaturated aryl amine 23 was isol-
ated in 64% yield. On heating 23 with tributyltin hydride and
AIBN, it was pleasing to see the formation of the desired
tetrahydroquinoline 24 as a 4.2 : 1 mixture of inseparable dia-
stereoisomers in 69% yield. Cyclisation onto electron-rich, as
well as electron-poor alkenes can therefore be used to prepare
tetrahydroquinoline derivatives.
Scheme 6
2.1.3 Quinolines. Following the successful formation of
a chromanone, our attention turned to the preparation of
quinolines. Quinoline alkaloids are found in the Rutaceae
family of plants and over two hundred examples have been
isolated.18 The synthesis of these compounds is of interest
because of the variety of important biological properties,
including anti-bacterial, anti-fungal and anti-viral activities,
which they exhibit.
Initially, amino-benzaldehydes 20a,b were prepared by reduc-
tion of N-methyl isatoic anhydride followed by N-acylation and
oxidation of the alcohol (Scheme 7). On reaction with tributyl-
tin hydride both 20a and 20b, underwent 6-exo cyclisation to
2.2 Allylic O-stannyl ketyl cyclisations
As the cyclisation of O-stannyl ketyls proved such an effective
route to a variety of 5- and 6-ring heterocycles, our atten-
tion turned to the cyclisation of related allylic O-stannyl ketyls.
This required the formation of precursor α,β-unsaturated
ketones and compounds 25a–d were readily prepared from the
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reaction of unsaturated ketone 28, which produced butyrol-
actone 31 in 56% yield as a 3 : 1 mixture of (inseparable) trans–
cis isomers, respectively. The stereochemistry was assigned on
the basis of the 13C NMR spectrum and confirmed by base-
induced epimerisation using DBU in refluxing toluene, which
produced a 10 : 1 mixture of trans–cis isomers, respectively. This
contrasts with reaction of the related aldehyde 7 (under similar
conditions), which did not lead to any butyrolactone. Cyclis-
ations of similar unsaturated esters are known to be relatively
slow12 and so the intermediacy of a longer-lived allylic
O-stannyl ketyl (compared to the O-stannyl ketyl) appears to
be crucial, presumably because this allows time for the radical
to cyclise onto the unsaturated ester double bond. An allylic
O-stannyl ketyl can also undergo 6-exo-trig cyclisation and
reaction of the unsaturated ketone 29 with tributyltin hydride
afforded tetrahydropyran 32 in 48% yield (as a 2 : 1 mixture of
diastereoisomers). It is of interest to note that no 4-phenyl-
but-3-en-1-ol, derived from a competitive 1,5-hydrogen atom
abstraction mechanism, was isolated in this case. This may be
attributed to the increased stability of the intermediate
allylic ketyl radical compared to the radical derived from the
corresponding aldehyde 8.
Scheme 9
corresponding aldehydes and Ph P᎐CHCOMe (Scheme 9). In
᎐
3
each case, only the E-alkene isomer was formed in the Wittig
reaction, as indicated by the 1H NMR spectra. On reaction with
tributyltin hydride, ketones 25a–d underwent cyclisation to give
the expected disubstituted tetrahydrofurans 26a–d in 50–82%
yield. The trans-diastereomers of 26a–d were the major prod-
ucts isolated from each of these reactions and the stereo-
chemistry was assigned on the basis of γ-gauche effects in the
13C NMR spectra. For example, for 26a, the CH3CH carbon in
the cis-isomer is more shielded (δ 13.4 ppm) than that in the
trans-isomer (δ 16.6 ppm). The predominant formation of the
thermodynamically more stable trans-isomer in each of these
reactions could be explained by reversible radical cyclisation
mechanisms.3,17 Clearly, the substituents on the alkene double
bond are expected to influence the reversibility of these reac-
tions, and the electronic/steric effects of the two methyl groups
could explain the surprisingly high diastereoselectivity observed
for cyclisation of the trisubstituted alkene 26c. In this case,
cyclisation produces a tertiary carbon-centred radical which is
expected to react less rapidly with Bu3SnH than secondary or
particularly, primary carbon-centred radicals formed on cyclis-
ation of 26a,b. The fact that the cyclisation of 26d showed
a much lower preference for the trans-isomer could reflect
the increased stability of the intermediate benzylic radical,
which is expected to lower the rate of fragmentation leading to
ring-opening.
Finally, the use of an allylic O-stannyl ketyl radical cyclis-
ation to prepare a chroman was investigated as shown in
Scheme 11. On being heated with tributyltin hydride, diene 33
underwent 6-exo-trig cyclisation to form chroman 34 in 50%
yield (as a 2.3 : 1 mixture of diastereoisomers).
Scheme 11
Similar cyclisations can be used to prepare bicyclic, butyrol-
actone and tetrahydropyran ring systems as shown by the
cyclisation of methyl ketones 27–29 (Scheme 10). Reaction of
3
Conclusions
This work has demonstrated that aldehydes and α,β-unsat-
urated ketones can undergo radical cyclisation to form
substituted tetrahydrofurans, tetrahydropyrans, chromanols,
quinolinones and related compounds on reaction with tri-
butyltin hydride. The intermediate O-stannyl ketyls or allylic
O-stannyl ketyls, which are nucleophilic, have been shown to
cyclise onto a variety of electron-rich double bonds to give a
range of 5- and 6-membered heterocycles. In general, the yields
are good, particularly for the 5-exo-trig cyclisation reactions,
and those involving allylic O-stannyl ketyls range from 50 to
85%. Many of these cyclisations are believed to be reversible,
especially those involving allylic or benzylic O-stannyl ketyls.
The importance of using these types of radical in relatively slow
6-exo-trig or unsaturated ester radical cyclisation reactions is
reported for the first time.
4
Experimental
1H and 13C NMR spectra were recorded using a JEOL EX 270
MHz or Bruker DPX 400 MHz spectrometer; the carbon
spectra were recorded at 67.5 MHz and these were assigned
with the aid of DEPT and/or COSY experiments. Coupling
constants (J) were recorded to the nearest 0.5 Hz. IR spectra
were recorded on an ATI Mattson Genesis Series FT IR spectro-
meter or a Perkin–Elmer Paragon 1000 FT IR spectrometer.
Mass spectra were recorded on a Fisons Instruments VG
Analytical Autospec spectrometer system for both low and high
resolution EI and CI spectra. Thin layer chromatography was
performed on Merck 5554 aluminium-backed silica gel plates
Scheme 10
27 with tributyltin hydride afforded the substituted octa-
hydrobenzofuran 30 in 85% yield as a 2.7 : 1.0 mixture of
inseparable diastereoisomers. A similar result was obtained on
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and compounds were visualised by UV light or by staining with
alkaline potassium permanganate solution. Column chrom-
atography was carried out under gravity using silica gel (Fisons
Matrex Silica 60, 70–200 microns or Fluorochem Ltd, Silica gel
60, 35–70 microns) and the specified eluant. Melting points
were recorded on a Gallenkamp melting point apparatus and
are uncorrected. The Chemical Analytical Services Unit at
the University of Newcastle performed the elemental analyses.
Petroleum ether refers to the fraction of boiling range 40–60 ЊC.
Tributyltin hydride was purchased from Lancaster Synthesis
Ltd and distilled before use. Experimental procedures for
the preparation of the following compounds are given in the
supplementary information: (E)-(3-phenylprop-2-enyloxy)-
ethanal 1a; (3-methylbut-2-enyloxy)ethanal 1b; (cyclohex-2-
enyloxy)ethanal 4; (E)-3-phenylprop-2-enyloxypropan-2-one 6;
(E)-3-(3-phenylprop-2-enyloxy)propanal 8; (E)-2-(3-phenyl-
prop-2-enyloxy)benzaldehyde 12a; 2-allyloxybenzaldehyde 12b;
(E)-1-[2-(3-phenylprop-2-enyloxy)phenyl]ethanone 12c; (E)-
methyl 4-(2-formylphenoxy)but-2-enoate 15; (E)-2-formyl-
phenyl 3-phenylprop-2-enoate 18; (E)-N-(2-formylphenyl)-N-
methyl-3-phenylprop-2-enamide 20a; N-(2-formylphenyl)-N,3-
dimethylbut-2-enamide 20b; (E)-N-(2-acetylphenyl)-N-methyl-
3-phenylprop-2-enamide 20c; N-(2-acetylphenyl)-N,3-dimethyl-
but-2-enamide 20d; (E)-1-[2-(N-methyl-3-phenylprop-2-enyl-
amino)phenyl]ethanone 23; (E)-5-(allyloxy)pent-3-en-2-one
25a; (3E)-5-[(E)-but-2-enyloxy]pent-3-ene-2-one 25b; (E)-5-
(3-methylbut-2-enyloxy)pent-3-en-2-one 25c; (3E)-5-[(E)-3-
phenylprop-2-enyloxy]pent-3-en-2-one 25d; (E)-5-cyclohex-
2-enyloxypent-3-en-2-one 27; (E)-4-oxopent-2-enyl (E)-3-phen-
ylprop-2-enoate 28; (3E)-5-[(E)-4-phenylbut-3-enyloxy]pent-3-
en-2-one 29; (3E)-4-{2-[(E)-3-phenylprop-2-enyloxy]phenyl}-
but-3-en-2-one 33.
The presence of a further diastereoisomer was indicated by
13C NMR spectroscopy; δC (67.90 MHz, CDCl3) 140.3 (q, Ar),
128.7 (CH, Ar), 128.5 (CH, Ar), 128.5 (CH, Ar), 126.3 (CH,
Ar) and 126.1 (CH, Ar), 72.4 (CHOH), 71.0 (CH2CHCH2Ph),
67.1 (CH2CHOH), 46.4 (CHCH2Ph), 31.8 (CH2Ph).
(3RS,4RS)-4-Isopropyltetrahydrofuran-3-ol 3b. Oil; 64%
(1.0 : 1.0 mixture of inseparable diastereoisomers); Rf 0.2 (2 : 1,
Et2O–petroleum ether); νmax/cmϪ1 (thin film) 3416 (s, br), 2957
(s), 1469 (s) and 1077 (m); δH (270 MHz, CDCl3) 4.32–3.70 (4H,
m, OCH2 and CCHACHB and HOCH ), 3.68–3.45 (1H, m,
CCHACHB), 2.12–1.48 [3H, m, CHCH(CH3)2 and HOCH],
1.12 (3H, d, J 7.0, CHCH3), 1.00 (3H, d, J 7.0, CHCH3); δC
(67.90 MHz, CDCl3) 77.0 (CHOH), 76.8 and 71.6 (CH2O),
53.1 [CHCH(CH3)2], 30.0 [CH(CH3)2], 21.4 [CH(CH3)2], 21.0
[CH(CH3)2]; m/z (CI, NH3) 148 (M ϩ NH4ϩ, 100%) 113 (27)
and 35 (38); [Found: M ϩ NH4ϩ (CI, NH3) 148.1337. C7H14O2
requires M ϩ NH4ϩ 148.1338].
The presence of a further diastereoisomer was indicated by
13C NMR spectroscopy; δC (67.90 MHz, CDCl3) 72.5 (CHOH),
56.0 [CHCH(CH3)2], 26.1 [CH(CH3)2], 22.2 [CH(CH3)2], 22.0
[CH(CH3)2].
(3RS,3aR*,7aR)-Octahydro-1-benzofuran-3-ol 5.20 Oil; 73%
(1.0 : 1.0 mixture of diastereoisomers); Rf 0.15 (2 : 1, isohexane–
EtOAc); νmax/cmϪ1 (thin film) 3397 (s, br), 2934 (s), 2863 (m),
1448 (w), 1117 (m) and 1022 (m); δH (270 MHz, CDCl3) 4.22
(1H, dd, J 10.0 and 4.5, OCHAHB), 4.15 (1H, appt. q, J 3.5,
OCHCH), 4.12–4.07 (1H, m, CHOH), 3.68–3.60 (1H, m,
OCHAHB), 2.05–1.95 (1H, m, OCHCH ), 1.80–1.08 (8H, m,
CH2CH2CH2CH2); δC (67.90 MHz, CDCl3) 77.8 (HOCH), 75.2
(OCH), 72.2 (OCH2), 46.6 (OCHCH), 27.8 (OCHCH2); m/z
(CI, NH3) 160 (M ϩ NH4ϩ, 75%), 141 (100) and 123 (60);
[Found: M ϩ NH4ϩ (CI, NH3) 160.1333. C6H12O2 requires M ϩ
NH4ϩ 160.1338].
General procedure for tributyltin hydride mediated radical
cyclisation
The presence of a further diastereoisomer was indicated by
1H and 13C NMR spectroscopy; δH (270 MHz, CDCl3) 4.55
(1H, m, CHOH), 4.02 (1H, dd, J 9.0 and 8.0, OCHAHB), 3.93
(1H, appt. q, J 3.5, OCHCH), 3.67–3.61 (2H, m, OCHAHB
and OCHACHB), 1.89–1.81 (1H, m, OCHCH ), 1.40 (8H, m,
CH2CH2CH2CH2); δC (67.90 MHz, CDCl3) 76.7 (HOCH), 74.8
(OCHCH), 74.6 (OCH2), 41.6 (OCHCH), 28.5 (OCHCH2),
23.8 (CH2CH2CH2), 21.0 (CH2CH2CH2), 20.6 (CH2CH2CH2).
To a stirred solution of the aldehyde/methyl ketone (0.025 M,
0.13–0.22 g, 0.76–1.57 mmol, 1.0 equiv.) and degassed benzene
(30–63 cm3) at reflux, under an atmosphere of nitrogen/
argon, was added a solution of tributyltin hydride (0.042 M,
0.24–0.50 g, 0.84–1.73 mmol, 1.1 equiv.), AIBN (0.025–0.038 g,
0.15–0.23 mmol, 0.3 equiv.) and degassed benzene (20–41 cm3)
over 1 h via a syringe pump. The reaction mixture was stirred at
reflux until consumption of starting material was indicated by
TLC analysis (4–24 h) and then cooled to rt. The benzene was
then removed in vacuo and the resultant residue was dissolved
in EtOAc (20–30 cm3) and stirred vigorously (2–4 h) with an
aqueous potassium fluoride solution (10%, 20–30 cm3). The
solution was filtered and the organic layer was separated,
washed with water (2 × 20 cm3) and brine (2 × 20 cm3), dried
over anhydrous MgSO4, filtered and evaporated to dryness
to afford crude product. Purification via column chromato-
graphy (silica) afforded the desired cyclic products (0.03–0.19 g,
24–85%).
(3RS,4RS)-3-Benzyltetrahydropyran-4-ol 9.21 Oil; 44%
(1.0 : 1.0 mixture of inseparable diastereoisomers); Rf 0.25
(2 : 1, isohexane–EtOAc); νmax/cmϪ1 (thin film) 3520 (s), 2956
(m), 1455 (m), 1052 (m), 923 (m) and 724 (w); δH (270 MHz,
CDCl3) 7.42–7.10 (5H, m, CH, Ar), 3.70–3.58 (2H, m, OCH2),
3.40 (1H, dt, J 11.5 and 2.5, OCHAHBCH2), 3.10–3.00 (1H,
m, OCHAHBCH2), 2.66 (1H, dd, J 13.5 and 7.5, CHAHBPh),
2.55 (1H, dd, J 13.5 and 8.5, CHAHBPh), 2.15–1.70 (3H, m,
OCH2CH2CHOH and CHCH2Ph); δC (67.90 MHz, CDCl3)
139.8 (q, Ar), 128.8, 128.7, 127.9 and 126.0 (CH, Ar), 71.8
(HOCH), 70.4 (CH2O), 66.8 (CH2O), 46.3 (PhCH2CH), 35.5
(PhCH2CH), 33.7 (OCH2CH2); m/z (CI, NH3) 194 (M ϩ Hϩ,
100%).
The presence of a further diastereoisomer was indicated by
1H and 13C spectroscopy; δH (270 MHz, CDCl3) 3.10–3.00 (1H,
m, CHAHBPh), 2.35 (1H, dd J 14.0 and 9.5, CHAHBPh); δC
(67.90 MHz, CDCl3) 139.5 (q, Ar), 128.8, 128.7, 127.9 and
126.0 (CH, Ar), 67.6 (CH2O), 63.6 (CH2O), 66.3 (HOCH),
43.2 (PhCH2CH), 35.4 (PhCH2CH), 33.6 (OCH2CH2).
(3RS,4RS)-4-Benzyltetrahydrofuran-3-ol 3a. Oil; 59%
(1.0 : 1.0 mixture of inseparable diastereoisomers); Rf 0.25
(1 : 1, petroleum ether–EtOAc); νmax/cmϪ1 (thin film) 3609 (m),
3490 (m), 2942 (m), 2867 (m), 1495 (w), 1454 (w), 1073 (m) and
1052 (m); δH (270 MHz, CDCl3) 7.50–7.10 (5H, m, CH, Ar),
4.30–4.10 (1H, m, CHOH), 4.06–3.45 (4H, m, CH2OCH2),
2.95 (1H, dd, J 13.5 and 8.0, CHAHBPh), 2.80–2.50 (1H, m,
CHAHBPh), 2.45–2.37 (1H, m, PhCH2CH ), 2.00–1.88 (1H, m,
CHOH ); δC (67.90 MHz, CDCl3) 139.6 (q, Ar), 128.7 (CH,
Ar), 128.5 (CH, Ar), 128.5 (CH, Ar), 126.3 (CH, Ar) and 126.1
(3R*,4RS)-3-Benzylchroman-4-ol 13a.16 White solid; 78%
(5.5 : 1.0 mixture of diastereoisomers). Major diastereoisomer:
Rf 0.25 (2 : 1, Et2O–petroleum ether); m.p 137–138 ЊC (lit.,16
138–139 ЊC); νmax/cmϪ1 (CHCl3) 3603 (s), 2923 (s), 1488 (s),
1454 (s), 797 (s), 490 (s) and 683 (s); δH (270 MHz, CDCl3) 7.34–
7.13 (7H, m, CH, Ar), 6.90–6.85 (2H, m, CH, Ar), 4.52–4.48
(CH, Ar), 76.3 (CHOH), 74.4 and 71.7 (CH2O), 49.7
ϩ
(CHCH2Ph), 37.4 (CH2Ph); m/z (CI, NH3) 196 (M ϩ NH4
,
100%), 161 (7), 143 (6), 117 (11), 105 (9), 91 (13) and 35 (23);
ϩ
[Found: M ϩ NH4 (CI, NH3) 196.1335. C11H14O2 requires
M ϩ NH4ϩ 196.1338].
J. Chem. Soc., Perkin Trans. 1, 2002, 1461–1469
1465

View Article Online
(1H, m, CHOH), 4.22 (1H, dd, J 11.0 and 2.5, OCHAHB), 3.97
(1H, dd, J 11.0 and 4.5, OCHAHB), 2.72 (1H, dd, J 13.5 and 6.5,
CHAHBPh), 2.54 (1H, dd, J 13.5 and 9.5, CHAHBPh), 2.30–2.17
(1H, m, CHCH2Ph), 1.90 (1H, s, br, OH ); δC (67.90 MHz,
CDCl3) 154.2 (q, Ar), 139.2 (q, Ar), 130.1, 129.8, 129.1, 128.5,
126.3, 123.2, 120.9 and 116.9 (CH, Ar), 67.6 (CHOH), 64.6
(CH2O), 41.5 (CHCH2Ph), 34.6 (CH2Ph); m/z (EI) 240 (Mϩ,
55%), 148 (100), 131 (40), 121 (55) and 91 (70); [Found: Mϩ (EI)
240.1153. C16H16O2 requires M ϩ Hϩ 240.1150].
Minor diastereoisomer: Rf 0.32 (2 : 1, Et2O–petroleum ether);
δH (270 MHz, CDCl3) 7.42–715 (7H, m, CH, Ar), 7.00–6.83
(2H, m, CH, Ar), 4.54–4.49 (1H, m, HOCH ), 4.18–4.07 (2H,
m, OCH2), 2.90 (1H, dd, J 14.0 and 8.5, OCHAHB), 2.70 (1H,
dd, J 13.5 and 7.0, OCHAHB), 2.40–2.22 (1H, m, CHCH2Ph),
1.73 (1H, s, CHOH ); δC (67.90 MHz, CDCl3) 155.1 (q, Ar),
140.2 (q, Ar), 123.0 (q, Ar), 129.6, 129.4, 128.6, 128.1, 125.8,
120.0 and 116.4 (CH, Ar), 64.5 (CH2O and CHOH), 39.5
(CHCH2Ph), 32.4 (CH2Ph).
1585 (m), 1489 (m), 1269 (m), 1227 (s), 1165 (s), 760 (s) and
735 (s).
Chromanol 16: δH (270 MHz, CDCl3) 7.47–6.72 (4H, m, Ar),
4.43 (1H, d, J 4.5, CHOH), 4.30 (1H, dd, J 11.5 and 2.5,
OCHAHB), 4.02 (1H, dd, J 11.0 and 5.0, OCHAHB), 3.66 (3H, s,
CO2CH3), 3.04 (1H, s, br, CHOH ), 3.00–2.90 (1H, m,
OCH2CH ), 2.48–2.28 (2H, m, CHCHAHBCOCH3); δC (67.90
MHz, CDCl3) 172.5 (CO2CH3), 153.8 (q, Ar), 129.8 (CH, Ar),
129.4 (CH, Ar), 118.3 (CH, Ar), 67.3 (CHOH), 65.2 (OCH2),
51.6 (CO2CH3), 36.4 (CHCH2CO2CH3), 32.8 (CH2CO2CH3),
30.9 (CH2CO2CH3); m/z (EI) 222 (Mϩ, 20%), 190 (80), 148 (98),
131 (100), 121 (56), 39 (38) and 32 (40); [Found: Mϩ (EI),
222.0895. C12H14O4 requires Mϩ 222.0892].
The presence of 17 was indicated by 1H and 13C NMR
spectroscopy; δH (270 MHz, CDCl3) 7.47–6.72 (4H, m, CH,
Ar), 5.42 (1H, d, J 6.0, CHOCO), 4.16 (1H, dd, J 11.5 and 4.0,
OCHAHB), 3.76 (1H, dd, J 11.5 and 9.5, OCHAHB), 3.00–2.90
(1H, m, OCH2CH ), 2.80 (1H, dd, J 17.5 and 8.5, CHAHBCO),
2.28–2.22 (1H, m, CHAHBCO); δC (67.90 MHz, CDCl3) 175.4
(3RS,4RS)-3-Methylchroman-4-ol 13b.22 Oil; 24% (1.0 : 1.3
mixture of inseparable diastereoisomers); Rf 0.4 (1 : 1,
isohexane–Et2O); νmax/cmϪ1 (thin film) 3398 (s, br), 2958 (m),
2926 (s), 1603 (m), 1489 (s), 1226 (s), 1047 (m) and 754 (s); δH
(270 MHz, CDCl3) 7.08–6.78 (4H, m, CH, Ar), 4.35 (1H, d,
J 5.5, CHOH), 4.20 (1H, dd, J 3.0 and 11.0, OCHAHB), 3.90
(1H, dd, J 11.0 and 6.0, OCHAHB), 1.00 (3H, d, J 7.5, CHCH3);
m/z (EI) 164 (Mϩ, 70%), 122 (100), 106 (46), 78 (44), 41 (57);
[Found: Mϩ (EI) 164.0838. C10H12O2 requires Mϩ 164.0832].
The presence of a minor diastereoisomer was indicated by 1H
NMR spectroscopy; δH (270 MHz, CDCl3) 1.10 (3H, d, J 7.5,
CHCH3).
(C᎐O), 154.9 (q, Ar), 131.2 (CH, Ar), 130.5 (CH, Ar), 123.0
᎐
(q, Ar), 121.7 (CH, Ar), 117.2 (CH, Ar), 74.1 (CHOCO), 64.6
(OCH2), 36.4 (CHCH2CO2CH), 30.9 (CHCH2CO); m/z (EI)
190 (Mϩ).
(3RS,4RS)-3-Benzyl-4-hydroxy-3,4-dihydrochromen-2-one
19. Oil; 50% (2.0 : 1.0 mixture of inseparable diastereoisomers);
Rf 0.2 (2 : 1, isohexane–Et2O); νmax/cmϪ1 3320 (s, br), 2958 (s),
1714 (s), 1610 (s), 1493 (s), 1492 (m), 1389 (m) and 1246 (m);
δH (270 MHz, CDCl3) 7.45–7.09 (9H, m, CH, Ar), 4.68 (1H, t,
J 4.0, CHOH), 3.32–3.24 (1H, m, CHCH2Ph), 3.05 (1H, dd,
J 13.5 and 5.5, CHAHBPh), 2.75 (1H, dd, J 14.0 and 9.0,
CHAHBPh), 1.90 (1H, s, br, CHOH ); δC (67.90 MHz, CDCl3)
165.2 (C᎐O), 156.0 (q, Ar), 139.6 (q, Ar), 129.0 (CH, Ar), 128.8
᎐
[2-(Allyloxy)phenyl]methanol 14b. Oil; 62%. The presence of
this compound was indicated by 1H NMR spectroscopy;
δH (270 MHz, CDCl3) 7.08–6.78 (4H, m, CH, Ar), 6.15–5.98
(CH, Ar), 128.7 (CH, Ar), 128.1 (CH, Ar), 127.3 (CH, Ar),
124.4 (q, Ar), 126.1 (CH, Ar), 119.9 (CH, Ar), 117.3 (CH, Ar),
75.8 (CHOH), 56.6 (CHCH2Ph), 34.4 (CHCH2Ph); m/z (CI,
NH3) 272 (M ϩ NH4ϩ, 15%), 254 (40), 237 (100), 210 (20),
163 (15), 155 (24), 131 (15), 102 (18), 91 (14); [Found: M ϩ
(1H, m, CH᎐CH ), 5.41 (1H, dd, J 16.0 and 0.3, CH᎐CH ), 5.35
᎐
᎐
2
2
(1H, dd, J 10.0 and 0.3, CH᎐CH ), 4.70 (2H, s, CH OH),
᎐
2
2
4.61–4.52 (2H, m, OCH2).
ϩ
ϩ
NH4 (CI, NH3) 272.1287. C16H14O3 requires M ϩ NH4
272.1287].
(3RS,4RS)-3-Benzyl-4-methylchroman-4-ol 13c. Oil; 82%
(4.0 : 1.0 mixture of inseparable diastereoisomers); Rf 0.3 (2 : 1,
isohexane–EtOAc); νmax/cmϪ1 (Nujol) 3407 (s), 1608 (m), 1582
(m), 1488 (s), 1453 (s), 1225 (s), 2980 (m), 2933 (m), 1043 (m),
756 (s) and 705 (m); δH (270 MHz, CDCl3) 7.48–7.44 (1H, m,
CH, Ar), 7.27–7.05 (6H, m, CH, Ar), 6.89–6.85 (1H, m, CH,
Ar), 6.77–6.71 (1H, m, CH, Ar), 4.10 (1H, dd, J 11.5 and 3.0
OCHAHB), 3.82 (1H, dd, J 11.5 and 8.0, OCHAHB), 3.06 (1H,
m, PhCHAHB), 2.33–2.18 (2H, m, PhCHAHB and CHCH2Ph),
1.82 (1H, s, br, CHOH ), 1.52 (3H, s, CH3); δC (67.90 MHz,
CDCl3) 153.0 (q, Ar), 139.8 (q, Ar), 128.9, 128.6, 128.4, 126.4,
121.0 and 117.0 (CH, Ar), 70.0 [C(CH3)OH], 65.7 (OCH2),
45.7 (CH2Ph), 32.1 (CHCH2Ph), 25.7 (CH3); m/z (CI, NH3)
254 [M(–H2O) ϩ Hϩ, 25%], 237 (100), 136 (16), 121 (16), 91
(17); [Found: M(–H2O) ϩ Hϩ, (CI, NH3) 254.1314. C17H18O2
requires: M(–H2O) ϩ Hϩ, 254.1307].
The presence of a minor diastereoisomer was indicated by
13C NMR spectroscopy; δ (67.90 MHz, CDCl ) 163.8 (C᎐O),
᎐
C
3
150.8 (q, Ar), 137.3 (q, Ar), 124.4 (q, Ar), 68.2 (CHOH), 49.6
(CHCH2Ph), 33.6 (CHCH2Ph).
(3R*,4R)- and (3R*,4S)-3-Benzyl-4-hydroxy-1-methyl-3,4-
dihydroquinolin-2(1H)-one 21a. Major diastereoisomer: oil;
81%; Rf 0.4 (7 : 3, EtOAc–petroleum ether); νmax/cmϪ1 (thin
film) 2933 (s), 2864 (s), 1689 (s), 1598 (s), 1456 (s), 1383 (m),
1286 (m), 991 (m) and 602 (m); δH (270 MHz, CDCl3) 7.45–6.95
(9H, m, CH, Ar), 4.40 (1H, d, J 2.5, CHOH), 3.40 (3H, s,
NCH3), 3.20–3.12 (1H, m, CHCH2Ph), 2.97 (1H, dd, J 15.0 and
6.0, PhCHAHB), 2.60 (1H, s, br, OH ), 2.45 (1H, dd, J 15.0 and
9.0, PhCH H ); δ (67.90 MHz, CDCl ) 170.8 (C᎐O), 139.1 (q,
᎐
A
B
C
3
Ar), 138.0 (q, Ar), 129.7 (CH, Ar), 129.0 (CH, Ar), 128.9 (CH,
Ar), 128.5 (CH, Ar), 126.6 (CH, Ar), 125.4 (q, Ar), 123.3 (CH,
Ar), 114.9 (CH, Ar), 68.8 (CHOH), 51.0 (PhCH2CH), 34.5
(PhCH2), 29.6 (NCH3); m/z (CI, NH3) 285 (M ϩ NH4ϩ, 35%),
268 (M ϩ Hϩ, 75), 250 (100), 176 (12) and 160 (45); [Found:
M ϩ Hϩ (CI, NH3) 268.1335. C17H17NO2 requires M ϩ Hϩ
268.1338].
Minor diastereoisomer: oil; 12%; Rf 0.5 (7 : 3, EtOAc–
petroleum ether); δH (270 MHz, CDCl3) 7.45–6.90 (9H, m, CH,
Ar), 4.44 (1H, d, J 3.0, CHOH), 3.55 (1H, dd, J 13.5 and 4.5,
PhCHAHB), 3.40 (3H, s, NCH3), 3.00 (1H, dd, J 13.5 and 10.0,
PhCHAHB), 2.86–2.80 (1H, m, CHCH2Ph); δC (67.90 MHz,
The presence of a minor diastereoisomer was indicated by 1H
and 13C NMR spectroscopy: δH (270 MHz, CDCl3) 3.97 (1H,
dd, J 7.5 and 2.5, OCHAHB), 3.84 (1H, dd, J 8.0 and 5.0,
OCHAHB), 2.44 (1H, dd, J 9.0 and 8.0, PhCHAHB), 2.16–2.08
(1H, m, CHCH2Ph), 1.63 (3H, s, CH3); δC (67.90 MHz, CDCl3)
153.6 (q, Ar), 140.1 (q, Ar), 128.9, 128.6, 128.4, 126.4, 121.0
and 117.0 (CH, Ar), 69.1 [C(CH3)OH], 65.4 (OCH2), 44.3
(CH2Ph), 31.6 (CHCH2Ph), 22.9 (CH3).
(3R*,4S)-Methyl 4-hydroxy-3,4-dihydro-2H-chromen-3-yl-
acetate 16 and (3R*,4R)-3a,9b-dihydro-4H-furo[3,2-c]chromen-
2(3H)-one 17. Oil; 84%, 1.0 : 1.6 inseparable mixture of 16 : 17,
respectively; Rf 0.25 (1 : 1, EtOAc–petroleum ether); νmax/cmϪ1
(thin film) 3483 (s, br), 2953 (m), 1772 (s), 1734 (s), 1612 (m),
CDCl ) 170.0 (C᎐O), 139.8 (q, Ar), 139.6 (CH, Ar), 129.8 (CH,
᎐
3
Ar), 129.3 (CH, Ar), 128.6 (CH, Ar), 128.1 (CH, Ar), 127.0 (q,
Ar), 126.3 (CH, Ar), 122.9 (CH, Ar), 115.0 (CH, Ar), 66.8
(CHOH), 48.4 (PhCH2CH), 31.4 (PhCH2), 29.8 (NCH3).
1466
J. Chem. Soc., Perkin Trans. 1, 2002, 1461–1469

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(3R*,4R)- and (3R*,4S)-4-Hydroxy-3-isopropyl-1-methyl-3,4-
dihydroquinolin-2(1H)-one 21b. Major diastereoisomer: white
Minor diastereoisomer: white solid; 31%; Rf 0.4 (1 : 1,
petroleum ether–EtOAc); δH (270 MHz, CDCl3) 7.60–7.20 (2H,
m, CH, Ar), 7.17–6.92 (2H, m, CH, Ar), 3.40 (3H, s, NCH3),
3.00 [1H, s, br, C(OH )CH3], 2.63 [1H, d, J 4.5, CHCH(CH3)2],
1.88–1.60 [4H, m, C(OH)CH3 and CH(CH3)2], 1.08 [3H, d,
J 7.0, CH(CH3)2], 0.50 [3H, d, J 7.0, CH(CH3)2]; δC (67.90
semi-solid; 48%; Rf 0.2 (1 : 1, EtOAc–petroleum ether); νmax
/
cmϪ1 (thin film) 3402 (m, br), 3000 (s), 2404 (m), 1695 (s), 1598
(m), 1508 (m), 1405 (m), 1210 (s) and 900 (m); δH (270 MHz,
CDCl3) 7.42–7.22 (2H, m, CH, Ar), 7.13–6.93 (2H, m, CH, Ar),
4.70 (1H, d, J 3.0, CHOH), 3.34 (3H, s, NCH3), 2.55 [1H, dd, J
9.5 and 3.0, CHCH(CH3)2], 1.59–1.32 [1H, m, CH(CH3)2],
1.00–0.80 [6H, m, CH(CH3)2]; δC (67.90 MHz, CDCl3) 171.6
MHz, CDCl ) 171.0 (C᎐O), 137.9 (q, Ar), 133.0 (q, Ar),
᎐
3
126.3, 123.8, 123.6, 114.3 (4 × CH, Ar), 72.2 [C(OH)CH3],
60.3 [CHCH(CH3)2], 30.9 (NCH3), 29.1 [C(OH)CH3], 26.3
[CH(CH3)2], 24.4 and 19.3 [CH(CH3)2].
(C᎐O), 139.7 (q, Ar), 129.7 (CH, Ar), 129.3 (CH, Ar), 126.0 (q,
᎐
Ar), 123.3 (CH, Ar), 115.0 (CH, Ar), 69.4 (CHOH), 56.8
[CHCH(CH3)2], 29.6 (NCH3), 27.5 [CH(CH3)2], 21.2 (2 ×
CH3); m/z (CI, NH3) 220 (M ϩ Hϩ, 100%), 202 (25) and 160
(15); [Found: M ϩ Hϩ (CI, NH3) 220.1340. C13H17NO2 requires
M ϩ Hϩ 220.1338].
Minor diastereoisomer: white semi-solid; 25%; Rf 0.5 (1 : 1,
EtOAc–petroleum ether); δH (270 MHz, CDCl3) 7.42–7.27 (2H,
m, CH, Ar), 7.12–6.90 (2H, m, CH, Ar), 4.92–4.89 (1H, m,
CHOH), 3.38 (3H, s, NCH3), 2.43–2.10 [2H, m, CHCH(CH3)2],
1.20–1.00 [6H, m, CH(CH3)2]; δC (67.90 MHz, CDCl3) 170.3
(3RS,4RS)-3-Benzyl-1,4-dimethyl-1,2,3,4-tetrahydroquinolin-
4-ol 24. Oil; 69% (4.2 : 1.0 mixture of inseparable diastereo-
isomers); Rf 0.2 (1 : 1, petroleum ether–EtOAc); νmax/cmϪ1
(CHCl3) 3402 (s, br), 2929 (s), 2245 (w), 1604 (s), 1504 (s), 1344
(m), 1213 (m), 1113 (m), 910 (s) and 733 (s); δH (270 MHz,
CDCl3) 7.51–7.41 (1H, m, CH, Ar), 7.36–7.08 (6H, m, CH, Ar),
6.73–6.49 (2H, m, CH, Ar), 3.10–2.96 (1H, m, NCHAHB),
2.88–2.74 (1H, m, NCHAHB), 2.69 (3H, s, NCH3), 2.22–2.00
(3H, m, CH2Ph and CHCH2Ph), 1.90 (1H, s, br, OH ), 1.50 [3H,
s, C(OH)CH3]; δC (67.90 MHz, CDCl3) 145.1 (q, Ar), 140.9 (q,
Ar), 129.7 (q, Ar), 129.4 (CH, Ar) 129.3 (CH, Ar), 128.8 (CH,
Ar), 128.5 (2 × CH, Ar), 126.2, 125.8 and 116.4 (3 × CH, Ar),
111.0 (CH, Ar), 71.7 [C(OH)CH3], 51.4 (NCH2CH), 46.7
(CHCH2Ph), 39.0 (NCH3), 33.9 (CH2Ph), 25.8 [C(OH)CH3];
m/z (CI, NH3) 268 (M ϩ Hϩ, 5%), 250 (100), 35 (12); [Found:
M ϩ Hϩ (CI, NH3) 268.1705. C18H21NO requires 268.1701].
The presence of a minor diastereoisomer was indicated by
13C NMR spectroscopy: δC (67.90 MHz, CDCl3) 145.4 (q, Ar),
141.1 (q, Ar), 129.0 (q, Ar), 128.9 (2 × CH, Ar), 128.1 (2 × CH,
Ar), 126.6 (CH, Ar), 126.4 (CH, Ar), 126.2 (CH, Ar), 116.6
(CH, Ar), 111.1 (CH, Ar), 71.3 [C(OH)CH3], 50.9 (NCH2CH),
45.8 (CHCH2Ph), 39.1 (NCH3), 33.3 (CH2Ph), 30.4 (COCH3).
(C᎐O), 139.7 (q, Ar), 129.3 (CH, Ar), 128.0 (q, Ar), 127.1 (CH,
᎐
Ar), 122.8 (CH, Ar), 114.9 (CH, Ar), 68.0 (CHOH), 52.9
[CHCH(CH3)2], 29.6 (NCH3), 25.4 [CH(CH3)2], 22.8 and 20.8
(2 × CH3).
(3R*,4S)- and (3R*,4R)-3-Benzyl-4-hydroxy-1,4-dimethyl-
3,4-dihydroquinolin-2(1H)-one 21c. Major diastereoisomer:
white semi-solid; 40%; Rf 0.3 (1 : 1, petroleum ether–EtOAc);
νmax/cmϪ1 (CHCl3) 3580 (s, br), 3010 (m), 1674 (s), 1603 (s), 1472
(m), 1374 (m), 1229 (w) and 702 (w); δH (270 MHz, CDCl3)
7.62–7.51 (1H, CH, Ar), 7.37–6.91 (8H, m, CH, Ar), 3.32 (3H,
s, NCH3), 3.08–2.90 (2H, m, CH2Ph), 2.71–2.43 [2H, m,
CHCH2Ph and C(OH )CH3], 1.45 [3H, s, C(OH)CH3]; δC (67.90
MHz, CDCl ) 171.1 (C᎐O), 138.8 (q, Ar), 137.4 (q, Ar), 132.1
᎐
3
(q, Ar), 129.0, 128.9, 128.5, 128.3, 128.2, 126.3, 124.3, 123.6
and 114.4 (9 × CH, Ar), 72.1 [C(OH)CH3], 56.1 (CHCH2Ph),
32.9 (CHCH2Ph), 29.4 and 29.2 [NCH3 and C(OH)CH3]; m/z
(CI, NH3) 282 (M ϩ Hϩ, 100%), 264 (58), 174 (20); [Found: M
ϩ Hϩ (CI, NH3) 282.1491. C18H19NO2 requires M ϩ Hϩ
282.1494].
Minor diastereoisomer: white semi-solid; 33%; Rf 0.4 (1 : 1,
petroleum ether–EtOAc); δH (270 MHz, CDCl3) 7.59–7.50 (1H,
m, CH, Ar), 7.45–6.90 (8H, m, CH, Ar), 3.35 (3H, s, NCH3),
3.23–3.10 (1H, m, CHAHBPh), 3.08–2.88 (2H, m, CHAHBPh
and CHCH2Ph), 2.30 [1H, s, br, C(OH )CH3], 1.40 [3H, s,
1-[(3RS,4RS)-4-Methyltetrahydrofuran-3-yl]propan-2-one
26a. Oil; 50% (1.0 : 3.1 mixture of inseparable diastereo-
isomers); Rf 0.2 (1 : 1, petroleum ether–Et2O); νmax/cmϪ1 (thin
film) 2959 (s), 2929 (s), 2872 (s), 2855 (s), 1713 (s), 1363 (m),
1168 (m), 1038 (m) and 923 (m); δH (270 MHz, CDCl3) 4.01–
3.89 (2H, m, OCH2), 3.44–3.27 (2H, m, OCH2), 2.70 (1H, dd,
J 17.5 and 5.0, CHAHBCOCH3), 2.42 (1H, dd, J 17.5 and 9.0,
CHAHBCOCH3), 2.15 (3H, s, COCH3), 2.19–2.10 (1H, m,
CHCH2COCH3), 1.85 (1H, septet, J 7.0, CH3CH ), 1.03 (3H, d,
J 7.0, CH3CH); δC (67.90 MHz, CDCl3) 208.0 (COCH3), 73.7
and 74.8 (2 × CH2O), 47.0 (CH2COCH3), 42.3 (CHCH2-
COCH3), 39.9 (CHCH3), 30.3 (CH3CO), 16.6 (CH3CH); m/z
(CI, NH3), 143 (M ϩ Hϩ, 100%); [Found: M ϩ Hϩ (CI, NH3)
143.1070. C8H14O2 requires for M ϩ Hϩ 143.1072].
C(OH)CH3]; δC (67.90 MHz, CDCl ) 170.8 (C᎐O), 141.3 (q,
᎐
3
Ar), 138.1 (q, Ar), 134.2 (q, Ar), 129.4, 129.2, 128.9, 128.5,
126.2, 124.0, 123.6, 115.1 (9 × CH, Ar), 72.5 [C(OH)CH3], 60.6
(CHCH2Ph), 55.5 (CHCH2Ph), 30.9 (CHCH2Ph), 30.1
(NCH3), 23.5 [C(OH)CH3].
The presence of a minor diastereoisomer was indicated by 1H
and 13C NMR spectroscopy: δH (270 MHz, CDCl3) 2.60 (1H,
dd, J 16.5 and 3.5, CHAHBCOCH3), 0.91 (3H, d, J 7.0,
CHCH3); δC (67.90 MHz, CDCl3) 208.0 (COCH3), 73.7 and
72.5 (2 × CH2O), 42.1 (CH2COCH3), 37.5 (CHCH2COCH3),
35.5 (CHCH3), 30.5 (CH3CO), 13.4 (CH3CH).
(3R*,4S)- and (3R*,4R)-4-Hydroxy-3-isopropyl-1,4-dimethyl-
3,4-dihydroquinolin-2(1H)-one 21d. Major diastereoisomer:
white solid; 51%; Rf 0.25 (1 : 1, petroleum ether–EtOAc);
(Found: C, 71.80; H, 8.54; N, 6.02. C14H19NO2 requires
C, 72.00; H, 8.20; N 6.00%); νmax/cmϪ1 (CHCl3) 3021 (s,
br), 2399 (s), 1662 (s), 1602 (m), 1519 (m), 1473 (m), 1421
(m), 1369 (m), 1217 (s) and 927 (m); δH (270 MHz,
CDCl3) 7.51–7.61 (1H, m, CH, Ar), 7.36–7.21 (1H, m,
CH, Ar), 7.18–7.08 (1H, m, CH, Ar), 7.00–6.90 (1H, m, CH,
Ar), 3.40 (3H, s, NCH3), 2.58 [1H, d, J 4.5, CHCH(CH3)2],
2.30–2.00 [1H, br s, C(OH )CH3], 1.50 [3H, s, C(OH)CH3],
1.47–1.20 [1H, m, CH(CH3)2], 1.10 [3H, d, J 7.0, CH(CH3)2],
0.56 [3H, d, J 7.0, CH(CH3)2]; δC (67.90 MHz, CDCl3) 170.9
1-[(3RS,4RS)-4-Ethyltetrahydrofuran-3-yl]propan-2-one 26b.
Oil; 80% (3.7 : 1.0 mixture of inseparable diastereoisomers);
Rf 0.25 (1 : 1, petroleum ether–Et2O); νmax/cmϪ1 (thin film) 2960
(s), 2928 (s), 1713 (s), 1361 (m), 1166 (m) and 1044 (m);
δH (270 MHz, CDCl3) 4.07–3.89 (2H, m, OCHAHB), 3.49–3.32
(2H, m, OCHAHB), 2.71 (1H, dd, J 17.5 and 5.0, CHAHB-
COCH3), 2.50 (1H, dd, J 17.5 and 9.5, CHAHBCOCH3), 2.28–
2.20 (1H, m, CHCH2COCH3), 2.15 (3H, s, COCH3), 1.80–1.15
(3H, m, CHCH2CH3 and CHCH2CH3), 0.90 (3H, t, J 7.5,
CH2CH3); δC (67.90 MHz, CDCl3) 207.7 (COCH3), 73.4 and
72.9 (2 × CH2O), 47.5 (CH2COCH3), 46.8 (CHCH2COCH3),
40.2 (CHCH2CH3), 30.1 (COCH3), 25.6 (CH3CH2), 12.6
(CH3CH2); m/z (CI, NH3) 157 (M ϩ Hϩ, 100%); [Found: M ϩ
Hϩ (CI, NH3) 157.1232. C9H16O2 requires for M ϩ Hϩ
157.1232].
(C᎐O), 139.9 (q, Ar), 129.9 (q, Ar), 129.2, 124.5, 123.0, 114.9 (4
᎐
× CH, Ar), 71.3 [C(OH)CH3], 60.2 [CHCH(CH3)2], 29.1
(NCH3), 27.3 [CH(CH3)2], 24.1 [C(OH)CH3], 24.1 and 18.5
[CH(CH3)2]; m/z (CI, NH3) 234 (M ϩ Hϩ, 100%) and 176 (20);
[Found: M ϩ Hϩ (CI, NH3) 234.1497. C14H19NO2 requires
234.1494].
J. Chem. Soc., Perkin Trans. 1, 2002, 1461–1469
1467

View Article Online
The presence of a minor diastereoisomer was indicated
by 13C NMR spectroscopy: δC (67.90 MHz, CDCl3) 207.7
(COCH3), 73.0 and 71.8 (2 × CH2O), 43.2 (CHCH2COCH3),
41.5 (CH2COCH3), 36.7 (CHCH2CH3), 30.3 (COCH3), 20.6
(CH3CH2), 12.8 (CH3CH2).
(3RS,4RS)-3-Benzyl-4-(2-oxopropyl)-4,5-dihydro-2(3H)-
furanone 31. Oil; 56% (3.0 : 1.0 mixture of diastereoisomers);
Rf 0.35 (1 : 1, EtOAc–petroleum ether); νmax/cmϪ1 (thin film)
2918 (w), 1769 (s), 1714 (s), 1364 (m), 1188 (m), 1165 (m) and
1017 (m); δH (270 MHz, CDCl3) 7.45–7.18 (5H, m, CH, Ar),
4.40 (1H, dd, J 9.0 and 7.5, OCHAHB), 3.73 (1H, dd, J 9.0 and
8.0, OCHAHB), 3.25 (1H, dd, J 14.0 and 4.5, PhCHAHB), 2.80
(1H, dd, J 14.0 and 8.5, PhCHAHB), 2.74–2.62 (1H, m,
PhCH2CH ), 2.58–2.50 (1H, m, CH3COCH2CH ), 2.35–2.26
(2H, m, CH3COCH2), 1.98 (3H, s, COCH3); δC (67.50 MHz,
1-[(3RS,4RS)-4-Isopropyltetrahydrofuran-3-yl]propan-2-one
26c. Oil; 63% (9.5 : 1.0 mixture of inseparable diastereoisomers;
Rf 0.3 (1 : 1, Et2O–petroleum ether); νmax/cmϪ1 (thin film)
2959 (s), 2931 (s), 2872 (s), 1715 (s), 1365 (m) and 938 (w);
δH (270 MHz, CDCl3) 3.95–3.90 (2H, m, OCH2), 3.46 (1H, dd,
J 9.0 and 7.0, OCHAHB), 3.36 (1H, dd, J 9.0 and 5.0,
OCHAHB), 2.65 (1H, dd, J 17.5 and 4.5, CHAHBCOCH3), 2.53
(1H, dd, J 17.5 and 10.0, CHAHBCOCH3), 2.38 (1H, m,
CHCH2COCH3), 2.16 (3H, s, COCH3), 1.60 [1H, m,
CHCH(CH3)2], 1.30 [1H, m, CHCH(CH3)2], 0.94 [3H, d, J 6.5,
CH(CH3)2], 0.87 [3H, d, J 6.5, CH(CH3)2]; δC (67.90 MHz,
CDCl3) 207.8 (COCH3), 73.9 (CH2O), 71.1 (CH2O), 51.8
(CHCH2COCH3), 48.9 (CH2COCH3), 37.9 [CHCH(CH3)2],
30.6 [CH(CH3)2], 30.0 (CH2COCH3), 21.3 [CH(CH3)2, 20.0
(CH(CH3)2]; m/z (CI, NH3) 171 (M ϩ Hϩ, 100%); [Found:
M ϩ Hϩ (CI, NH3) 171.1379. C10H18O2 requires for M ϩ Hϩ
171.1385].
CDCl ) 206.1 (COCH ), 177.7 (C᎐O), 138.1 (q, Ar), 129.3 (2 ×
᎐
3
3
CH, Ar), 129.1 (2 × CH, Ar), 127.3 (CH, Ar), 71.8 (CH2OCO),
46.3 (CH2Ph), 46.2 (PhCH2CH), 36.2 (CHCH2COCH3), 35.9
ϩ
,
(CH2COCH3), 30.1 (COCH3); m/z (CI, NH3), 250 (M ϩ NH4
45%), 233 (M ϩ Hϩ, 100), 129 (10), 91 (22), 83 (60) and 43 (10);
[Found: M ϩ Hϩ (CI, NH3) 233.1174. C14H17O3 requires
M ϩ Hϩ 233.1178].
The presence of a minor diastereoisomer was indicated
by 13C NMR spectroscopy; δC (67.90 MHz, CDCl3) 206.1
(COCH ), 177.7 (C᎐O), 137.8 (q, Ar), 128.8 (2 × CH, Ar),
᎐
3
128.1 (2 × CH, Ar), 126.8 (CH, Ar), 71.2 (CH2O), 43.3
(PhCH2CH), 40.6 (CH2Ph), 33.7 (CHCH2COCH3), 31.3
(CH2COCH3), 29.8 (COCH3).
The presence of a minor diastereoisomer was indicated by
1H NMR spectroscopy: δH (270 MHz, CDCl3) 3.62 (1H, dd,
J 13.0 and 9.0, OCHAHB).
1-[(3RS,4RS)-3-Benzyl-3,4,5,6-tetrahydro-2H-pyran-4-yl]-
propan-2-one 32. Oil; 48% (2.0 : 1.0 mixture of inseparable
diastereoisomers; Rf 0.25 (1 : 1, Et2O–petroleum ether); νmax
/
cmϪ1 (thin film) 2945 (s), 2349 (s), 1709 (s), 1400 (s), 1126 (s)
and 901 (m); δH (270 MHz, CDCl3) 7.40–7.05 (5H, m, Ar),
4.00–3.80 (1H, m, OCHAHB), 3.75–3.30 (3H, m, OCHAHB and
OCH2), 2.86–2.15 (8H, m, PhCH2CH, CH2COCH3, CHCH2-
COCH3 and OCH2CH2), 2.12 (3H, s, COCH3); δC (67.90 MHz,
CDCl ) 207.7 (C᎐O), 139.2 (q, Ar), 128.9, 128.4, 128.0, 125.8
1-[(3RS,4RS)-4-Benzyltetrahydrofuran-3-yl)propan-2-one
26d. Oil; 82% (1.8 : 1.0 mixture of inseparable diastereo-
isomers); Rf 0.4 (1 : 1, EtOAc–petroleum ether); νmax/cmϪ1 (thin
film) 2956 (s), 2924 (s), 2855 (m), 1717 (w), 1463 (m), 1377 (w),
1264 (w) and 1075 (w); δH (270 MHz, CDCl3) 7.30–7.14 (5H, m,
CH, Ar), 4.12 (1H, dd, J 9.0 and 7.0, OCH ), 3.82 (1H, dd, J 9.0
and 7.0, OCH ), 3.48 (1H, dd, J 9.0 and 7.0, OCH ), 3.35 (1H,
dd, J 9.0 and 7.0, OCH ), 2.82–2.26 (6H, m, CHCH2COCH3
and CHCH2Ph), 2.04 (3H, s, COCH3); δC (67.90 MHz, CDCl3)
207.5 (COCH3), 140.1 (q, Ar), 128.6, 128.4, 128.4 and 126.1
(CH, Ar), 73.4 and 72.6 (2 × OCH2), 47.3 (CH2COCH3), 46.5
(CHCH2Ph), 40.0 (CHCH2COCH3), 38.9 (PhCH2), 29.8
(COCH3); m/z (CI, NH3) 219 (M ϩ Hϩ, 100%) and 91 (7);
[Found: M ϩ Hϩ (CI, NH3) 219.1381. C14H19O2 requires for
M ϩ Hϩ 219.1385].
The presence of a minor diastereoisomer was indicated by
1H and 13C NMR spectroscopy: δH (270 MHz, CDCl3) 3.98
(1H, dd, J 9.0 and 7.0, OCHAHB), 3.73 (1H, dd, J 9.0 and 7.0,
OCHAHB), 3.56–3.50 (2H, m, 2 × OCHAHB) 2.14 (3H, s,
COCH3); δC (67.90 MHz, CDCl3) 207.3 (COCH3), 140.1 (q,
Ph), 128.6, 128.4, 128.4, 126.1 (4 × CH, Ar), 72.6 and 71.8
(2 × OCH2), 42.4 (CHCH2Ph), 37.0 (CHCH2COCH3), 41.7
(CH2COCH3), 33.8 (CH2Ph), 30.1 (COCH3).
᎐
3
and 125.6 (5 × CH, Ar), 71.2 and 67.3 (2 × CH2O), 47.4
(CH2COCH3), 41.7 (CHCH2Ph), 36.1 (PhCH2CH), 31.8
(CH2CHCH2COCH3), 30.3 (COCH3); m/z (CI, NH3), 250 (M
ϩ NH4ϩ, 25%), 233 (M ϩ Hϩ, 100) and 174 (20); [Found: M ϩ
Hϩ (CI, NH3) 233.1539. C15H20O2 requires for M ϩ Hϩ
233.1542].
The presence of a minor diastereoisomer was indicated by
13C NMR spectroscopy: δ (67.90 MHz, CDCl ) 207.4 (C᎐O),
᎐
C
3
140.3 (q, Ar), 128.8, 128.4, 128.0, 125.8 and 125.6 (CH, Ar),
69.1 and 67.2 (CH2O), 46.2 (CH2COCH3), 39.6 (CHCH2Ph),
33.1 (CHCH2COCH3), 31.2 (CHCH2Ph), 30.1 (COCH3), 28.0
(CH2CHCH2COCH3).
1-[(3RS,4RS)-3-Benzyl-3,4-dihydro-2H-chromen-4-yl]-
propan-2-one 34. Semi-solid; 50% (2.3 : 1.0 mixture of
inseparable diastereoisomers); Rf 0.2 (1 : 1, Et2O–petroleum
ether); νmax/cmϪ1 (CHCl3) 2930 (s), 2860 (s), 1709 (s), 1500 (m),
1450 (s), 1100 (m), 780 (s) and 660 (s); δH (270 MHz, CDCl3)
7.47–6.73 (9H, m, CH, Ar), 4.12–3.83 (2H, m, OCH2), 2.92–
2.52 (4H, m, CH2Ph and CH2COCH3), 2.50–2.32 (1H,
CHCH2COCH3), 2.07 (3H, s, COCH3), 1.98–1.83 (1H, m,
CHCH2Ph); δC (67.90 MHz, CDCl3) 206.8 (COCH3), 153.9 (q,
Ar), 139.7 (q, Ar), 130.1, 129.6, 128.5, 128.4, 127.7, 126.2 (CH,
Ar), 123.7 (q, Ar), 120.8, 116.8 (CH, Ar), 63.7 (OCH2), 52.5
(3RS,3aR*,7aR)-Octahydro-1-benzofuran-3-yl]propan-2-one
30. Oil; 85% (1.0 : 2.7 mixture of inseparable diastereoisomers);
Rf 0.3 (2 : 1, isohexane–EtOAc); νmax/cmϪ1 (thin film) 2955 (s),
2930 (s), 2875 (s), 2865 (s), 1711 (s), 1359 (s), 1112 (s), 1050 (s),
950 (m) and 739 (m); δH (270 MHz, CDCl3) 4.23 (1H, dd, J 9.0
and 7.0, OCHACHB), 3.86 (1H, appt. q, J 4.5, OCHCH), 3.32
(1H, dd, J 9.0 and 7.0, OCHAHB), 2.60 (1H, dd, J 16.5 and
5.5 CHAHBCOCH3), 2.47 (1H, dd, J 16.5 and 8.5, CHAHB-
COCH3), 2.52–2.36 (1H, m, OCH2CH ), 1.84–1.72 (1H, m,
OCHCH ), 1.70–1.00 (8H, m, CH2CH2CH2CH2); δC (67.90
(CH2COCH3), 37.2 (CH2Ph), 38.3 (CHCH2COCH3), 34.2
ϩ
(CHCH2Ph), 30.2 (COCH3); m/z (CI, NH3) 298 (M ϩ NH4
,
100%), 281 (M ϩ Hϩ, 28), 223 (25), 131 (10), 91 (11); [Found:
ϩ
M ϩ NH4ϩ (CI, NH3), 298.1803. C19H24O2 requires M ϩ NH4
298.1807].
MHz, CDCl ) 208.5 (C᎐O), 75.9 (OCH), 71.9 (OCH ), 47.8
᎐
3
2
The presence of a minor diastereoisomer was indicated by
13C NMR spectroscopy: δC (67.90 MHz, CDCl3) 207.1
(COCH3), 67.0 (OCH2), 45.2 (CH2COCH3), 36.9 (CH2Ph),
33.5 (CHCH2COCH3), 30.8 (COCH3).
(CH2COCH3), 43.1 (OCHCH), 38.8 (CHCH2COCH3), 29.8
(COCH3).
The presence of a minor diastereoisomer was indicated by
1H NMR spectroscopy: δH (270 MHz, CDCl3) 4.02 (1H, appt. t,
J 8.5, OCHAHB), 3.98–3.82 (1H, m, OCH ), 3.45 (1H, dd, J 10.0
and 8.5, OCHAHB), 2.80–2.70 (1H, m, CHCH2COCH3),
2.66–2.56 (1H, m, CHAHBCOCH3), 2.52–2.36 (1H, m, CHA-
HBCOCH3), 2.00–1.91 (1H, m, OCHCH ).
Acknowledgements
We thank Vernalis Research Ltd. and the EPSRC for funding.
1468
J. Chem. Soc., Perkin Trans. 1, 2002, 1461–1469

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Chem. Commun., 1986, 85; (c) D. P. Curran and J. Tamine, J. Org.
Chem., 1991, 56, 2746.
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J. Chem. Soc., Perkin Trans. 1, 2002, 1461–1469
1469