Pyridine radicals in synthesis. Part 3: Cyclopentannulation of pyridine via the 3-pyridyl radical and a formal synthesis of (±)-oxerine

Article abstract of DOI:10.1016/S0040-4020(99)00999-0

The allylation and propargylation of 3-bromo-4-formylpyridine under zinc-mediated Barbier conditions is described. The homoallylic alcohols produced are cyclised via the derived 3-pyridyl radical to give cyclopentannulated pyridines. One of these bicyclic compounds is converted into an advanced intermediate in a previous synthesis of the monoterpene alkaloid (±)-oxerine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)00999-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 397–406
Pyridine Radicals in Synthesis. Part 3: Cyclopentannulation of
Pyridine via the 3-Pyridyl Radical and a Formal Synthesis
of (^)-Oxerine
a,b
a
Keith Jones,a,b, Andrea Fiumana and Maria L. Escudero-Hernandez
*
aDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
bSchool of Applied Chemistry, Kingston University, Penrhyn Road, Kingston-upon-Thames, Surrey KT1 2EE, UK
Received 26 August 1999; revised 18 October 1999; accepted 4 November 1999
Abstract—The allylation and propargylation of 3-bromo-4-formylpyridine under zinc-mediated Barbier conditions is described. The
homoallylic alcohols produced are cyclised via the derived 3-pyridyl radical to give cyclopentannulated pyridines. One of these bicyclic
compounds is converted into an advanced intermediate in a previous synthesis of the monoterpene alkaloid (^)-oxerine. ᭧ 2000 Elsevier
Science Ltd. All rights reserved.
As part of a programme of research designed to extend the
use of aryl radicals in synthesis to the development and use
of heteroaryl radicals, we have previously reported on the
formation and cyclisation of radicals derived from 3-bromo-
pyridines,1 2-bromopyridinium salts2 and 2-bromoindoles.3
In this paper we wish to describe in full our early work on
the cyclisation of 3-pyridyl radicals which led to a formal
synthesis of the alkaloid (^)-oxerine.4 Prior to our work in
this area, Snieckus and co-workers5 reported the first cycli-
sation reaction involving 4-pyridyl radicals and Harrowven6
reported on the cyclisation of the 2-pyridyl radical to
ketenedithioacetals as a route to condensed thiophenes.
Subsequent to our work, a recent report7 describes the
synthesis of tricyclic pyridones as GABAA receptor agonists
via 3- and 4-pyridyl radical cyclisations. Our attention was
attracted by the monoterpene alkaloids (Ϫ)-actinidine 18
and (Ϫ)-oxerine 29 which possess the cyclopentano[c]-
pyridine ring system. Our retrosynthetic analysis of this
bicyclic system is shown in Scheme 1. The key steps
involve formation of the cyclopentane ring by a reductive
5-exo radical cyclisation leading to a methyl group in the
correct position for both natural products, and allylation of
Scheme 1.
Keywords: pyridine radicals; cyclopentannulation; (^)-oxerine.
* Corresponding author. School of Applied Chemistry, Kingston University, Kingston-upon-Thames, Surrey, UK; e-mail: keith.jones@kingston.ac.uk
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00999-0

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K. Jones et al. / Tetrahedron 56 (2000) 397–406
the known 3-bromo-4-formylpyridine 3. In the case of acti-
nidine 1 an extra methyl group is needed on the pyridine
5-position and reductive removal of the alcohol is required.
Oxerine 2 requires a homopropargylic alcohol derived from
propargylation of 3 in order to allow for the formation of the
tertiary alcohol. We reported the synthesis of (^)-actini-
dine1 recently and we would now like to report in detail
on the allylation/propargylation reaction and its limitations,
the radical cyclisation to create the cyclopentano[c]pyridine
and the formal synthesis of (^)-oxerine.
poor yield (entry 2) and although allyltributylstannane/
boron trifluoride13 gave a good yield (entry 3), the problems
involved in separating the product 6 from the tin residues
made this reaction practically difficult. The most successful
and practically convenient method proved to involve
Barbier-type reaction with an allyl zinc species.14 Reaction
of zinc and allyl bromide in THF followed by addition of 5
gave alcohol 6 in 73% yield.
The zinc Barbier procedure was applied to the allylation of
3-bromo-4-formylpyridine 3 and gave the homoallylic alco-
hol 7 in 87% yield (Scheme 4). Pyridine 7 was also obtained
in 13% yield by ortholithiation of alcohol 6 with 2 molar
equivalents of t-BuLi followed by bromination with
1,2-dibromotetrafluoroethane. The use of s-BuLi in this
The key starting material for all the work described in this
paper is 3-bromo-4-formylpyridine 3, the synthesis of which
was described by Corey et al.10 and involves ortholithiation
and formylation of 3-bromopyridine 4 (Scheme 2). This
Scheme 2.
reaction proved to be very sensitive to reaction conditions
(especially temperature and the purity of the DMF used) and
in our hands a yield of 60% was obtained rather than the
73% reported.10 During the course of work on this reaction,
an alternative was explored using the addition of lithium
trimethylethylene diamine (LTMEDA) to 4-formylpyridine
5 followed by in situ ortholithiation and bromination.11 This
gave 3 in only 15% yield.
reaction led to addition of the organolithium to the
2-position of the pyridine. Reaction with other allylic
bromides under similar conditions also gave satisfactory
yields of homoallylic alcohols. Thus reaction of 3 with
prenyl bromide gave the dimethyl-substituted homoallylic
alcohol 8 in 66% yield via an allylic rearrangement.15
Reaction with the symmetrical allyl bromide, 3-bromocy-
clohexene, gave rise to the expected product 9 as a mixture
of diastereoisomers in a 2:1 ratio. Similarly, reaction with
crotyl bromide gave 10 as a 7:6 mixture of diastereoisomers
in 53% yield and reaction with cinnamyl bromide gave 11 in
60% yield as a 5:1 mixture of diastereoisomers. Although
we did not assign the stereochemistry to the diastereo-
isomers of 9, 10 and 11, the fact that allylic rearrangement
had occurred would suggest the reaction proceeds via a
cyclic transition state. Assuming that the pyridine and the
substituent on the allylic double bond are pseudo-equatorial
in such a transition state would allow a tenuous assignment
of stereochemistry. However, the only evidence for assign-
ment of stereochemistry, the vicinal coupling constant of the
In order to explore the allylation, commercially available
4-formylpyridine 5 was used to test a variety of allylation
reagents and conditions (Scheme 3, Table 1). The reaction
of 5 with allylmagnesium bromide (entry 1) led to a low
yield and some pyridine-4-methanol was also obtained.
Allyltrimethylsilane and titanium (IV) chloride12 gave a
1
benzylic proton, was either not discernible in the H NMR
(compound 10), had the same value for both diastereo-
isomers (compound 9, Jˆ4 Hz) or differed by a small
amount (compound 11, Jˆ6 Hz for major isomer and
Jˆ4 Hz for minor isomer). Finally, the reaction of 3 with
propargyl bromide was carried out in the same way leading
to the homopropargyl alcohol 12 in 84% yield.
Scheme 3.
Table 1. Allylation of 4-formylpyridine 5
Entry
Metal
Solvent
T (ЊC)
Yield of 6 (%)
Radical cyclisation of this range of unsaturated bromo-
pyridine alcohols was now investigated using the standard
conditions of tributyltin hydride (TBTH) in refluxing
toluene at low concentration with azobisisobutyronitrile
(AIBN) as the initiator.16 Reaction of 7 under these
conditions gave rise to cyclopentannulated pyridines 13a
and 13b in a combined yield of 86% (Scheme 5). The
1
2
3
4
MgBr
Ether
25
25
Ϫ78
25
35
19
60
73
Me3Sia
n-Bu3Snb
ZnBrc
Dichloromethane
Dichloromethane
Tetrahydrofuran
a 1 molar equivalent of freshly distilled TiCl4 was used as Lewis acid
catalyst.12
1
b 1 molar equivalent of BF3 etherate was used as catalyst.13
c Barbier procedure was used (see Experimental).14
assignment of the structure was clear from H NMR as the
olefinic protons were lost and replaced by a doublet for the

K. Jones et al. / Tetrahedron 56 (2000) 397–406
399
Scheme 4.
methyl group. No trace of reduced product (i.e. debromi-
nated 7) was detected, indicating an efficient cyclisation
reaction, and there was also no sign of the product arising
from 6-endo cyclisation. The ratio of diastereoisomers 13a
and 13b was found to be 7:3 and they proved to be insepar-
able by flash chromatography. The assignment of the trans-
stereochemistry to the minor isomer 13b was based on an
nOe between the proton adjacent to the alcohol and the
methyl group in the nOesy spectrum of the mixture. That
the major isomer 13a has the cis-arrangement of alcohol and
methyl group is in accord with the Beckwith model for
radical cyclisations.17 Reaction of pyridine 8 under the
same conditions led to an inseparable mixture of three
compounds derived via radical cyclisation in overall 63%
yield and in a ratio of 8:5:3. The major compound proved to
be the cyclopentannulated pyridine 14a with cis-stereo-
chemistry. The trans-isomer 14b was the intermediate
compound and the minor compound was assigned the tetra-
hydroisoquinoline structure 15 owing to the presence of two
CH2 peaks in the 13C NMR. Compound 15 clearly arises
from a 6-endo cyclisation of the pyridine radical and is in
marked contrast to the result obtained for cyclisation of
pyridine 7. Presumably, the presence of the gem-dimethyl
group both creates some hindrance to 5-exo cyclisation and
enhances 6-endo cyclisation via a Thorpe–Ingold effect.18
Cyclisation of cyclohexenylpyridine 9 gave two products in
42% yield as an inseparable mixture of diastereoisomers.
Although this cyclisation substrate is already a mixture of
diastereoisomers and another stereogenic centre is gener-
ated in the cyclisation, only two diastereoisomeric products
were obtained. We believe that this is because in both
products, the cyclohexane unit is cis-fused to the newly
created cyclopentane. Inspection of molecular models and
literature precedent19 indicates the more favourable nature
of cis-ring fusion in this case. Further, the major product 16a
showed a vicinal coupling constant of 8 Hz for the proton
adjacent to the alcohol which fits well for the all cis-struc-
ture based upon a dihedral angle of 0–10Њ between the
coupled protons. The minor product 16b was assigned the
stereostructure shown on the basis of a 6 Hz vicinal
coupling constant for the same hydrogen. Models indicate
a dihedral angle of about 130Њ in this isomer which is
reasonably consistent with a coupling constant of this
value. However, these assignments must be treated as tenta-
tive and owing to the fact that an inseparable mixture was
obtained, further information could not be gleaned from
spectroscopic experiments. The assignment of 16a as the
structure of the major product might cast light on the stereo-
chemical nature of the starting material 9 but such infer-
ences must be treated with caution.
Cyclisation of pyridines 10 and 11 followed by chroma-
tography led to material assigned the cyclopentanopyridine
skeleton in 68 and 70% yield, respectively. However in both
cases a large number of diastereoisomers was obtained and
structure assignment by spectroscopic techniques was not

400
K. Jones et al. / Tetrahedron 56 (2000) 397–406
Scheme 5.
possible. With a synthesis of oxerine 2 in mind, the cycli-
sation of the propargyl alcohol 12 was studied. It is known
that alkynes are not as good radical acceptors as alkenes20
and that addition of TBTH across the unprotected triple
bond can occur.21 We were delighted to find that reaction
under the usual conditions gave a 10:1 mixture of cyclised
material 17 and reduced product 18 in a combined yield of
84%. Although not separable by chromatography, 17 could
be obtained pure by recrystallisation in 57% yield from 12
(Scheme 5).
Two more radical reactions were carried out to further
explore the properties of the pyridyl radical. The first
involved introducing a bulky silyl-group onto the alcohol
function of 7. The radical reactions do not need OH-protec-
tion but we wanted to explore the change in ratio of the
diastereoisomers produced in the cyclisation reaction with
a bulky group at this position. Silylation of 7 under the
usual conditions with tert-butyldimethylsilyl chloride
(TBDMSCl) proceeded to give silyl ether 19 in 83% yield
(Scheme 6). Cyclisation of 19 under the same conditions as
Scheme 6.

K. Jones et al. / Tetrahedron 56 (2000) 397–406
401
Scheme 7.
Scheme 8.
used for the other cyclisation reactions gave 20 as a 3:1
mixture of diastereoisomers in quantitative yield. The
assignment of stereochemistry was carried out by
deprotecting 20 in 88% yield to give 13a and 13b as
a 3:1 mixture. Thus, a bulky group produces a slightly
enhanced ratio of cis:trans isomers as predicted by the
Beckwith model.
resistant to reaction. This could be caused by the electron-
withdrawing pyridine reducing the usual reactivity of the
double bond. Ozonolysis of the double bond proceeded
smoothly to give ketone 23 in 69% yield (Scheme 8).
However, reaction with MeMgBr23 in an attempt to create
the desired tertiary alcohol resulted only in starting material
being recovered. Finally, we abandoned the plan of directly
producing oxerine from 17 and instead benzylated the alco-
hol to give ether 24 which had been used in the previous
synthesis of (^)-oxerine 2.24 The spectral data of 24 were in
agreement with that reported apart from a typographical
error in the previous report.25
The final radical reaction involved exploring the ability of
the 3-pyridyl radical to carry out [1,5]-hydrogen atom
abstraction on a saturated side-chain at C-4 with a view to
investigating whether the alkyl radical so generated would
add to the pyridine based on the chemistry published by
Storey and Beckwith.22 Reaction of 3-bromopyridine 4
with LDA at low temperature followed by quenching with
butanal gave the saturated alcohol 21 in 87% yield (Scheme
7). Reaction of 21 under the conditions of Storey and
Beckwith using tributyltin deuteride delivered by syringe
pump over 10 h in tert-butylbenzene at 160ЊC gave in
32% combined yield 22a and 22b in a ratio of 3:1 favouring
the product in which the initial 3-pyridyl radical has
abstracted a hydrogen atom from the side-chain prior to
reduction. Although the yield is low, this demonstrates
the feasibility of [1,5]-hydrogen atom abstraction using
pyridyl radicals. However, there was no sign of addition
of this side-chain radical to the pyridine and presumably
stabilising groups would be required to achieve this
process.
In conclusion, we have shown that pyridine radicals can be
generated, and react in the same manner as radicals derived
from halobenzenes. This methodology provides a valuable
method for the intramolecular creation of carbon/carbon
bonds to pyridine and in particular the formation of
the cyclopentanopyridine skeleton. To exemplify this
chemistry, we have achieved a formal synthesis of the
alkaloid (^)-oxerine.
Experimental
General details
All reactions were carried out under argon and solutions
dried with magnesium sulphate. Diethyl ether, tetrahydro-
furan (THF) and toluene were distilled from sodium benzo-
phenone ketyl immediately before use. Zinc was activated
by washing with 10% hydrochloric acid. Sodium and
potassium hydride were washed with petrol or hexane
(which was discarded) at least three times before use.
Column chromatography was performed with silica gel
With unsaturated alcohol 17 in hand, we believed that
addition of water to the exo-methylene group would lead
to a short synthesis of (^)-oxerine 2. However, under a wide
variety of conditions (mercuric acetate, sodium boro-
hydride; mercuric trifluoroacetate, sodium borohydride;
epoxidation with peracids) the double bond proved to be

402
K. Jones et al. / Tetrahedron 56 (2000) 397–406
(Merck 7734) using the flash chromatography technique.
Thin layer chromatographic analysis was performed using
plastic-backed silica plates (Merck 5735). Components
were visualised by either UV or phosphomolybdic acid
dip. All melting points were determined on a Gallenkamp
melting point apparatus and are uncorrected. Infrared spec-
tra were recorded on a Perkin Elmer 1605 FT-IR
7.53 (1H, d, Jˆ5 Hz, C(5)H), 8.49 (1H, d, Jˆ5 Hz, C(6)H),
8.6 (1H, s, C(2)H); dC(CDCl3) 41.3 (C(20)H), 70.8 (C(10)H),
119.5 (C(40)H), 119.9 (C(3)Br), 122.2 (C(5)H), 133.3
(C(30)H, 148.5 (C(6)H), 151.6 (C(2)H), 151.8 (C(4)); m/z
229/227 (73%, Mϩ), 188/186 (100%, MϩϪCH2CHyCH2),
148 (55%, MϩϪBr); Found: Mϩ, 228.9927. C9H1081BrON
requires Mϩ, 228.9927.
1
spectrophotometer. H NMR and 13C NMR spectra were
recorded on a Bruker AM360 spectrometer operating at
3-Bromo-4-(2,2-dimethyl-but-3-en-1-ol)pyridine (8). 3-
Bromo-pyridine-4-carbaldehyde 3 (0.2 g, 1.07 mmol) was
added to a stirred mixture of prenyl bromide (0.25 ml,
2.15 mmol) and activated zinc powder (0.4 g, 6.15 mmol)
in THF (10 ml) following the same procedure for 7. The
residue was purified by flash chromatography (ethyl acetate:
hexane 2:1) to give the title compound 8 (0.180 g, 66%) as
an oil. Rf 0.55 (ethyl acetate:hexane 2:1); nmax/cmϪ1 3300
(OH), 1637 (CyC), 1580 (pyr-CyC); dH(CDCl3) 0.93 (3H,
s, C(20)CH3), 1.03 (3H, s, C(20)CH3), 4.83 (1H, s, C(10)H),
4.86 (1H, dd, Jˆ17.5 and 1.1 Hz, C(40)H), 5.00 (1H, dd,
Jˆ10.7 and 1.1 Hz, C(40)H), 5.88 (1H, dd, Jˆ10.7 and
1.1 Hz, C(30)H), 7.32 (1H, dd, Jˆ5 Hz, C(5)H), 8.20
(1H, d, Jˆ5 Hz, C(6)H), 8.37 (1H, s, C(2)H); dC(CDCl3)
21.9 (C(20)CH3), 24.2 (C(20)CH3), 43.1 (C(20)), 76.8
(C(10)H), 114.0 (C(40)H), 122.4 (C(3)Br), 124.8 (C(5)H),
143.5 (C(30)H), 147.0 (C(6)H), 150.7 (C(2)H), 151.1
(C(4)); m/z 257/255 (35%, Mϩ), 188/186 (100%, MϩϪ
CMe2CHyCH2); Found: Mϩ, 255.0261. C11H1479BrON
requires Mϩ, 255.0259.
360 MHz for proton and 90 MHz for carbon. Tetramethyl-
1
silane (TMS) was adopted as the internal standard for H
NMR spectra and the solvent peaks for 13C NMR spectra.
Chemical shifts (dH and dC) values are reported as parts per
1
million (ppm). The multiplicity of a H NMR signal is
designated by one of the following abbreviations: sˆsinglet,
dˆdoublet, tˆtriplet, qˆquartet, brˆbroad and mˆmulti-
plet. High resolution mass spectra were performed at the
Chemistry Department, King’s College London. Elemental
analysis of compounds was carried out at the Chemistry
Department, University College London.
3-Bromopyridine-4-carbaldehyde (3). To a THF solution
(50 ml) of LDA, prepared from diisopropylamine (1.57 ml,
12 mmol) and n-BuLi (4 ml of 2.5 M solution in hexane,
10 mmol), 3-bromopyridine (0.96 ml, 10 mmol) in THF
solution (5 ml) was added dropwise at Ϫ78ЊC under
argon. The resulting solution was stirred for 10 min at this
temperature. A THF solution (10 ml) of DMF (2.32 ml,
30 mmol) was then added. The mixture was stirred for 1 h
at Ϫ78ЊC, warming to room temperature over 1 h. The reac-
tion was poured into cold stirred 5% NaHCO3 (50 ml),
diluted with diethyl ether (100 ml) and the organic layer
was separated. The aqueous layer was extracted with diethyl
ether (3×50 ml). The combined organic solution was
washed with brine (2×100 ml), dried over MgSO4 and
evaporated under reduced pressure. The residue was
chromatographed (ethyl acetate:hexane 3:2) to give the
aldehyde 1 (1.12 g, 60%) as a solid, which was recrys-
tallised from hexane to give white needles, mp 80–82ЊC
3-Bromo-4-(cyclohex-2-enyl-methanol)pyridine (9). 3-
Bromo-pyridine-4-carbaldehyde 3 (0.15 g, 0.8 mmol) was
added to
a stirred mixture of 3-bromocyclohexene
(0.184 g, 1.6 mmol) and activated zinc powder (0.3 g,
4.28 mmol) in THF (10 ml) following the same procedure
for as 7. The residue was purified by flash chromatography
(ethyl acetate:hexane 2:1) to give the title compound 9
(0.132 g, 60%) as a 2:1 mixture of diastereoisomers. Rf
0.55 (ethyl acetate:hexane 2:1); nmax/cmϪ1 3280 (OH),
1645 (CyC), 1588 (pyr-H); m/z 269/267 (28%, Mϩ), 188/
186 (100%, MϩϪC6H9); Found: Mϩ, 267.0250.
C12H1479BrON requires Mϩ, 267.0259. Major isomer:
dH(CDCl3) 1.52–1.75 (4H, m, C(60)H and C(70)H), 1.96
(2H, m, C(50)H), 2.66 (1H, m, C(20)H), 4.95 (1H, d
Jˆ4 Hz, C(10)H), 5.48 (1H, m, C(40)H), 5.93 (1H, m,
C(30)H), 7.44 (1H, d, Jˆ5 Hz, C(5)H), 8.43 (1H, d,
Jˆ5 Hz, C(6)H), 8.57 (1H, s, C(2)H); dC(CDCl3) 21.3,
22.1 and 25.1 (cyclohexene), 40.0 (C(20)H), 74.4
(C(10)H), 120.4 (C(3)Br), 123.4 (C(5)H), 127.5 and
132.5 (C(40)H and C(30)H), 148.2 (C(6)H), 150.4
(C(4)), 151.8 (C(2)H). Minor isomer: dH(CDCl3)
1.52–1.75 (4H, m, C(60)H and C(70)H), 1.96 (2H, m,
C(50)H), 2.56 (1H, m, C(20)H), 4.81 (1H, d Jˆ4 Hz,
C(10)H), 5.42 (1H, m, C(30)H), 5.93 (1H, m, C(30)H),
7.38 (1H, d, Jˆ5 Hz, C(5)H), 8.44 (1H, d, Jˆ5 Hz,
C(6)H), 8.58 (1H, s, C(2)H); dC(CDCl3) 21.7, 25.1
and 26.7 (cyclohexene), 40.6 (C(20)H), 74.9 (C(10)H),
122.9 (C(3)Br), 124.1 (C(5)H), 127.5 (C(40)H), 132.5
(C(30)H, 148.4 (C(6)H), 150.0 (C(4)), 151.9 (C(2)H).
(lit.,10 82ЊC). Rf 0.7 (ethyl acetate:hexane 3:2); nmax
/
cmϪ1 1693 (CO); dH(CDCl3) 7.36 (1H, d, Jˆ5 Hz,
C(5)H), 8.7 (1H, d, Jˆ5 Hz, C(6)H), 8.92 (1H, s,
C(2)H), 10.37 (1H, s, CHO); dC(CDCl3) 122.1
(C(5)H), 122.8 (C(3)Br), 138.7 (C(4)), 149.4 (C(6)H),
154.0 (C(2)H), 190.7 (CO); m/z 187/185 (60%, Mϩ),
106 (100%, MϩϪBr).
3-Bromo-4-(but-3-en-1-ol)pyridine (7) (general procedure).
3-Bromo-pyridine-4-carbaldehyde 3 (0.372 g, 2 mmol) was
added to a stirred mixture of allylbromide (0.43 ml, 5 mmol)
and activated zinc powder (0.523 g, 8 mmol) in THF
(10 ml). The reaction was stirred for 3 h at room tempera-
ture, quenched with saturated NaHCO3 and filtered through
a celite plug which was washed with diethyl ether. The
aqueous layer was extracted with diethyl ether (3×50 ml)
and the combined organic extracts were washed with brine
(2×50 ml), dried over MgSO4 and evaporated under reduced
pressure. The residue was chromatographed (ethyl acetate:-
hexane 2:1) to give the alcohol 7 (0.397 g, 87%) as a brown-
red oil. Rf 0.52 (ethyl acetate:hexane 2:1); nmax/cmϪ1 3290
(OH), 1641 (CyC), 1587 (pyr-CyC); dH(CDCl3) 2.31 (1H,
m, C(20)H), 2.66 (1H, m, C(20)H, 5.04 (1H, dd, Jˆ8 and
3 Hz, C(10)H), 5.20 (2H, m, C(40)H), 5.86 (1H, m, C(30)H),
3-Bromo-4-(2-methyl-but-3-en-1-ol)pyridine (10). 3-Bromo-
pyridine-4-carbaldehyde 3 (0.1 g, 0.53 mmol) was added to
a stirred mixture of 1-bromo-2-butene (0.15 ml, 1.34 mmol)
and activated zinc powder (0.4 g, 6.15 mmol) in THF (5 ml)

K. Jones et al. / Tetrahedron 56 (2000) 397–406
403
following the same procedure as for 7. The residue was
purified by flash chromatography (ethyl acetate:hexane 2:1)
to give the title compound 10 (0.100 g, 53%) as a 7:6
mixture of diastereoisomers. Rf 0.47 (ethyl acetate:hexane
2:1); nmax/cmϪ1 3250 (OH), 1632 (CyC), 1591 (pyr-CyC);
m/z 243/241 (45%, Mϩ), 188/186 (100%, MϩϪC4H7);
Found: Mϩ, 241.0103. C10H1279BrNO requires Mϩ,
241.0102. Major isomer: dH(CDCl3) 0.94 (3H, d Jˆ7 Hz,
C(20)CH3), 2.72 (1H, m, C(20)H), 4.87–5.15 (3H, m, C(10)H
and C(40)H), 5.95 (1H, m, C(30)H), 7.49 (1H, d, Jˆ5 Hz,
C(5)H), 8.44 (1H, d Jˆ5 Hz, C(6)H), 8.59 (1H, s, C(2)H);
dC(CDCl3) 12.1 (C(20)CH3), 41.8 (C(20)H), 74.2 (C(10)H),
117.6 (C(40)H), 120.9 (C(3)Br), 123.3 (C(5)H), 137.9
(C(30)H), 147.9 (C(6)H), 151.2 (C(4)), 151.5 (C(2)H).
Minor isomer: dH(CDCl3) 1.12 (3H, d, Jˆ7 Hz,
C(20)CH3), 2.70 (1H, m, C(20)H), 4.87–5.15 (3H, m,
C(10)H and C(40)H), 5.73 (1H, m, C(30)H), 7.40 (1H, d,
Jˆ5 Hz, C(5)H), 8.44 (1H, d, Jˆ5 Hz, C(6)H), 8.58 (1H,
s, C(2)H); dC(CDCl3) 16.8 (C(20)CH3), 43.9 (C(20)H),
74.8 (C(10)H), 116.1 (C(40)H), 120.6 (C(3)Br), 123.5
(C(5)H), 140.1 (C(30)H), 148.0 (C(6)H), 151.2 (C(4)),
151.4 (C(2)H).
C(2)H); dC(CDCl3) 27.1 (C(20)H), 69.8 (C(40)H), 71.8
(C(10)H), 79.2 (C(30)), 119.8 (C(3)Br), 122.4 (C(5)H),
148.4 (C(6)H), 150.4 (C(4)H), 151.5 (C(2)H); m/z 225
(42%, Mϩ) 186 (100%, MϩϪCH2CCH); Found: Mϩ,
226.9769. C9H881BrNO requires Mϩ, 226.9770. Found:
C, 47.51; H, 3.86; N, 6.02. C9H8BrNO requires C,
47.82; H, 3.57; N, 6.20.
6,7-Dihydro-7-methyl-5H-[2]pyrindin-5-ol (13) (general
procedure). Tributyltin hydride (0.14 ml, 0.53 mmol) was
added to a solution of 7 (100 mg, 0.44 mmol) in toluene
(20 ml) and heated to 110ЊC under argon. AIBN (10% in
mole) was added and the mixture heated under reflux under
argon for 3 h. After cooling, the toluene was removed under
reduced pressure. The crude product was purified by flash
chromatography (hexane followed by hexane:ethyl acetate
1:2) to give the cyclised product 13 (56 mg, 86%) as a 3:1
mixture of diastereoisomers. Rf 0.26 (ethyl acetate); nmax
/
cmϪ1 3149 (OH), 1605 (pyr-CyC); m/z 149 (79%, Mϩ), 148
(67%, MϩϪH), 132 (77%, MϩϪOH), 116 (100%); Found:
Mϩ, 149.0839. C9H11NO requires Mϩ, 149.0841. 13a:
dH(CDCl3) 1.36 (3H, d, Jˆ7 Hz, C(7)CH3), 1.54 (1H, m,
C(6)H), 2.75 (1H, m, C(6)H), 3.11 (1H, dd, Jˆ16 and 7 Hz,
C(7)H), 5.18 (1H, t, Jˆ8 Hz, C(5)H), 7.35 (1H, d, Jˆ5 Hz,
C(3)H), 8.41 (2H, br, C(2)H and C(4)H); dC(CDCl3) 19.5
(C(7)CH3), 34.8 (C(7)H), 45.5 (C(6)H), 74.0 (C(5)H), 119.0
(C(3)H), 142.6 (C(7a)), 144.7 (C(4)H), 147.3 (C(2)H),
155.0 (C(5a)). 13b: dH(CDCl3) 1.28 (3H, d, Jˆ7 Hz,
C(7)CH3), 2.02 (1H, m, C(6)H), 2.26 (1H, m, C(6)H),
3.46 (1H, q, Jˆ7 Hz, C(7)H), 5.29 (1H, dd, Jˆ7 and
4 Hz, C(5)H), 7.35 (1H, d, Jˆ5 Hz, C(3)H), 8.41 (2H, br,
C(2)H and C(4)H); dC(CDCl3) 20.5 (C(7)CH3), 35.4
(C(7)H), 44.2 (C(6)H), 74.0 (C(5)H), 119.7 (C(3)H),
144.0 (C(7a)), 145.5 (C(6)H), 147.4 (C(2)H), 153.8 (C(5a)).
3-Bromo-4-(2-phenyl-but-3-en-1-ol)pyridine (11). 3-Bromo-
pyridine-4-carbaldehyde 3 (0.1 g, 0.53 mmol) was added to a
stirred mixture of 1-bromo-3-phenyl-2-propene (0.234 g,
1.34 mmol) and activated zinc powder (0.4 g, 6.15 mmol) in
THF (5 ml) following the same procedure as for 7. The residue
was purified by flash chromatography (ethyl acetate:hexane
2:1) to give the title compound 11 (0.097 g, 60%) as a 5:1
mixture of diastereoisomers. Rf 0.41 (ethyl acetate:hexane
2:1); m/z 305/303 (22%, Mϩ), 188/186 (30%, MϩϪC9H9),
117 (100%); Found: Mϩ, 303.0234. C15H1479BrNO requires
Mϩ, 303.0259. Major isomer: dH(CDCl3) 3.76 (1H, m,
C(20)H), 4.87–5.11 (2H, m, C(40)H), 5.24 (1H, d, Jˆ4 Hz,
C(10)H), 6.25 (1H, m, C(30)H), 7.22–7.32 (5H, m, C(Ar)H),
7.47 (1H, d, Jˆ5 Hz, C(5)H), 8.43 (1H, d, Jˆ5 Hz, C(6)H),
8.55 (1H, s, C(2)H); dC(CDCl3) 54.6 (C(20)), 75.2 (C(10)H),
119.4 (C(40)H), 120.8 (C(3)Br), 123.7 (C(5)H), 127.2–129.1
(5×C(Ar)H), 134.3 (C(30)H), 140.9 (C(Ar)), 147.8 (C(6)H),
150.6 (C(4)), 151.3 (C(2)H). Minor isomer: dH(CDCl3) 3.77
(1H, m, C(20)H), 4.87–5.11 (2H, m, C(40)H), 5.37 (1H, d,
Jˆ6 Hz, C(10)H), 6.20 (1H, m, C(30)H), 7.11–7.16 (5H, m,
C(Ar)H), 7.38 (1H, d, Jˆ6 Hz, C(5)H), 8.30 (1H, d, Jˆ6 Hz,
C(6)H), 8.59 (1H, s, C(2)H); dC(CDCl3) 54.5 (C(20)), 75.3
(C(10)H), 119.5 (C(40)H), 120.6 (C(3)Br), 123.3 (C(5)H),
127.2–129.1 (5×C(Ar)H), 133.8 (C(30)H), 140.7 (C(Ar)),
147.6 (C(6)H), 150.7 (C(4)), 151.2 (C(2)H).
6,7-Dihydro-6,6,7-trimethyl-5H-[2]pyrindin-5-ol (14) and
6,6-dimethyl-5-hydroxy-5,6,7,8-tetrahydroisoquinoline
(15). Tributyltin hydride (0.10 ml, 0.40 mmol) and AIBN
(10% in mole) was added to a solution of 8 (84 mg,
0.33 mmol) in refluxing toluene (15 ml) for 3 h following
the same procedure as for 13. The crude product was
purified by flash chromatography (hexane followed by hex-
ane:ethyl acetate 1:2) to give the cyclised products 14 and
15 (oil, 37 mg, 63%) as a mixture of diastereoisomers and
regioisomers in a ratio 8:5:3. Rf 0.18 (ethyl acetate:hexane
2:1); nmax/cmϪ1 3290 (OH), 1582 (pyr-CyC); m/z 177
(88%, Mϩ), 144 (100%, MϩϪ(H2OϩCH3)), 134 (89%,
MϩϪC3H7); Found: Mϩ, 177.1153. C11H15NO requires
Mϩ, 177.1153. 14a: dH(CDCl3) 0.94 (3H, s, C(6)CH3),
1.07 (3H, s, C(6)CH3), 1.17 (3H, d, Jˆ7.2 Hz, C(7)CH3),
3.03 (1H, q, Jˆ7.2 Hz, C(7)H), 4.68 (1H, s, C(5)H), 7.30
(1H, d, Jˆ4.5 Hz, C(3)H), 8.34 (1H, s, C(2)H), 8.38 (1H, d,
Jˆ4.5 Hz, C(4)H); dC(CDCl3) 14.1 (C(7)CH3), 21.3
(C(6)CH3), 21.4 (C(6)CH3), 44.9 (C(7)H), 50.9 (C(6)),
81.7 (C(5)H), 119.9 (C(3)), 143.0 (C(7a)), 145.6 (C(4)H),
147.8 (C(2)H), 152.9 (C(5a)). 14b: dH(CDCl3) 0.65 (3H, s,
C(6)CH3), 1.24 (3H, s, C(6)CH3), 1.24 (3H, d, Jˆ7.2 Hz,
C(7)CH3), 2.73–3.81 (1H, m, C(7)H), 4.74 (1H, s, C(5)H),
7.28 (1H, d, Jˆ4.5 Hz, C(3)H), 8.29 (1H, s, C(2)H), 8.39
(1H, d, Jˆ4.5 Hz, C(4)H); dC(CDCl3) 11.7 (C(7)CH3), 14.4
(C(6)CH3), 24.1 (C(6)CH), 44.4 (C(7)H), 50.9 (C(6)),
82.3 (C(5)H), 118.5 (C(3)H), 140.4 (C(7a)), 144.1
(C(4)H), 147.7 (C(2)H), 153.7 (C(5a)). 15: dH(CDCl3)
3-Bromo-4-(but-3-yn-1-ol)pyridine (12). 3-Bromo-4-formyl-
pyridine (3, 0.93 g, 5 mmol) was added to a stirred mixture
of propargyl bromide (1.39 ml, 12.5 mmol) and activated
zinc powder (1.3 g, 20 mmol) in THF (25 ml) following
the same procedure as for 7. The residue was purified by
flash chromatography (ethyl acetate:hexane 2:1) to give the
alcohol 12 (0.928 g, 82%) as a solid, which was recrystal-
lised from hexane–ethyl acetate to give colourless cubes,
mp 91–92ЊC. Rf 0.39 (ethyl acetate:hexane 2:1); nmax/cmϪ1
3238 (CCH), 3140 (OH), 1587 (pyr-CyC); dH(CDCl3) 2.11
(1H, t, Jˆ2 Hz, C(40)H), 2.55 (1H, ddd, Jˆ17, 7 and 2 Hz,
C(20)H), 2.84 (1H, ddd, Jˆ17, 4 and 2 Hz, C(20)H), 5.16
(1H, dd, Jˆ7 and 4 Hz, C(10)H), 7.60 (1H, d, Jˆ5 Hz,
C(5)H), 8.50 (1H, d, Jˆ5 Hz, C(6)H), 8.60 (1H, s,

404
K. Jones et al. / Tetrahedron 56 (2000) 397–406
0.92 (3H, s, C(6)CH3), 1.05 (3H, s, C(6)CH3), 1.57–1.65
(2H, m, C(7)H), 1.75–1.82 (1H, m, C(8)H), 2.73–2.81 (1H,
m, C(8)H), 4.68 (1H, s, C(5)H), 7.42 (1H, d, Jˆ5 Hz,
C(3)H), 8.31 (1H, s, C(2)H), 8.38 (1H, d, Jˆ5 Hz,
C(4)H); dC(CDCl3) 20.3 (C(6)CH3), 22.9 (C(7)H), 26.7
(C(6)CH3), 32.9 C(8)H), 33.9 (C(6)), 75.4 (C(5)H),
122.6 (C(3)H), 131.6 (C(8a)), 146.8 (C(4)H), 146.9
(C(2)H), 149.6 (C(5a)).
(0.17 g, 2.5 mmol) in DMF (5 ml) was stirred at room
temperature for 4 days. The reaction mixture was poured
into water and extracted with diethyl ether (3×50 ml). The
organic layer was washed with brine (2×50 ml), dried over
MgSO4 and evaporated under reduced pressure. The residue
was chromatographed (hexane:ethyl acetate 2:1) to give the
protected alcohol 19 (0.285 g, 83%) as a yellow oil. Rf 0.58
(hexane:ethyl acetate 2:1); nmax/cmϪ1 1640 (CyC), 1577
(pyr-CyC); dH(CDCl3) Ϫ0.98 (3H, s, (CH3)2Si), 0.07 (3H,
s, (CH3)2Si), 0.89 (9H, s, (CH3)3C), 2.28–2.37 (1H, m,
C(20)H), 2.45 (1H, m, C(20)H), 4.99–5.01 (3H, m,
C(40)H) and C(10)H), 5.82 (1H, m, C(30)H), 7.47 (1H, d,
Jˆ5 Hz, C(5)H), 8.49 (1H, d, Jˆ5 Hz, C(6)H), 8.63 (1H, s,
C(2)H); dC (CDCl3) Ϫ4.9 ((CH3)2Si), 18.1 ((CH3)3C–Si),
25.7 ((CH3)3C–Si), 42.4 (C(20)H), 72.5 (C(10)H), 118.1
(C(40)H), 119.2 (C(3)Br), 122.9 (C(5)H), 133.7 (C(30)H),
148.2 (C(6)H), 151.5 (C(2)H), 152.7 (C(4)); m/z 343/341
(13%, Mϩ), 302/300 (85%, MϩϪCH2CHyCH2), 286/284
5a,6,7,8,9,9a-Hexahydro-5H-ideno[2]-pyrindin-5-ol (16).
Tributyltin hydride (0.11 ml, 0.44 mmol) and AIBN (10%
in mole) was added to a solution of 9 (100 mg, 0.37 mmol)
in refluxing toluene (10 ml) for 3 h following the same
procedure as for 13. The crude product was purified by
flash chromatography (hexane followed by hexane:ethyl
acetate 1:2) to give the cyclised product 16 (oil, 30 mg,
42%) as a 3:1 mixture of diastereoisomers. Rf 0.14 (ethyl
acetate:hexane 2:1); nmax/cmϪ1 3300 (OH), 1580 (pyr-
CyC); m/z 189 (15%, Mϩ), 171 (20%), 143 (42%), 113
(40%), 100 (100%); Found: Mϩ, 189.1155. C12H15NO
requires Mϩ, 189.1153. 16a: dH(CDCl3) 1.18–1.67 (8H,
m, cyclohexane), 2.27 (1H, m, C(9a)H), 3.17–3.23 (1H,
m, C(5a)H), 5.00 (1H, d, Jˆ7.8 Hz, C(5)H), 7.36 (1H, d,
Jˆ5 Hz, C(3)H), 8.44 (1H, s, C(2)H), 8.46 (1H, d Jˆ5 Hz,
C(4)H); dC(CDCl3) 21.1, 22.9, 23.4 and 29.1 (C(cyclohex-
ane)), 38.9 (C9(a)), 48.2 (C(5a)), 75.5 (C(5)H), 118.7
(C(3)H), 143.0 (C(2a)), 144.1 (C(4)H), 147.0 (C(2)H),
152.3 (C(3a)). 16b: dH(CDCl3) 1.18–1.67 (8H, m, cyclo-
hexane), 2.27 (1H, m, C(9a)H), 3.17–3.23 (1H, m, C(5a)H),
5.15 (1H, d, Jˆ6 Hz, C(5)H), 7.35 (1H, d, Jˆ4 Hz, C(3)H),
8.41 (1H, s, C(2)H), 8.49 (1H, d, Jˆ4 Hz, C(4)H);
dC(CDCl3) 20.6, 23.0, 24.1 and 25.8 (C(cyclohexane)),
38.1 (C(9a)), 45.6 (C(5a)), 76.3 (C(5)H), 118.0 (C(3)H),
143.4 (C(2a)), 144.5 (C(4)H), 146.9 (C(2)H), 152.3 (C(3a)).
(100%,
MϩϪC(CH3)3);
Found:
Mϩ,
341.0799.
C15H2479BrNOSi requires Mϩ, 341.0811.
6,7-Dihydro-7-methyl-5-tert-butyldimethylsilyloxy-5H-
[2]pyrindine (20). Tributyltin hydride (0.14 ml,
0.55 mmol) was added to a solution of 19 (156 mg,
0.46 mmol) in toluene (20 ml) and after being heated to
110ЊC under argon, AIBN (10% in mole) was added and
the mixture continued to be refluxed under argon for 3 h,
following the same procedure as for 13. The crude product
was purified by flash chromatography (hexane followed by
hexane:ethyl acetate 2:1) to give the cyclised product 20
(120 mg, 0.46 mmol, quantitative yield) as an inseparable
mixture. Rf 0.37 (hexane:ethyl acetate 2:1); nmax/cmϪ1 1600
(pyr-CyC); m/z 206 (94%, MϩϪ(CH3)3C), 132 (100%,
MϩϪTBDMSO). cis-20: dH(CDCl3) 0.16 (6H, s,
Si(CH3)2), 0.97 (9H, s, (CH3)3C), 1.39 (3H, d, Jˆ7 Hz,
C(7)CH3), 1.60 (1H, m, C(6)H), 2.65 (1H, m, C(6)H),
3.10 (1H, m, C(7)H), 5.14 (1H, t, Jˆ8 Hz, C(5)H), 7.22
(1H, d, Jˆ5 Hz, C(3)H), 8.48 (2H, br, C(2)H and C(4)H);
dC(CDCl3) 13.6 (Si(CH3)2), 18.2 (SiC(CH3)3), 19.3
(C(7)CH3), 25.8 ((CH3)3C), 34.7 (C(7)H), 46.0 (C(6)H),
74.7 (C(5)H), 118.6 (C(3)H), 142.7 (C(7a)), 145.1
(C(4)H), 147.8 (C(2)H), 154.6 (C(5a)). trans-20: dH(CDCl3)
0.19 (6H, s, Si(CH3)2), 0.93 (9H, s, (CH3)3C), 1.27 (3H, d,
Jˆ7 Hz, C(7)CH3), 2.03 (1H, m, C(6)H), 2.18 (1H, m,
C(6)H), 3.46 (1H, m, C(7)H), 5.30 (1H, t, Jˆ8 Hz,
C(5)H), 7.22 (1H, d, Jˆ5 Hz, C(3)H), 8.48 (2H, br, C(2)H
and C(4)H); dC(CDCl3) 13.6 (Si(CH3)2), 18.2 (SiC(CH3)3),
21.0 (C(7)CH3), 25.9 ((CH3)3C), 35.4 (C(7)H), 44.6
(C(6)H), 74.8 (C(5)H), 118.8 (C(3)H), 142.6 (C(7a)),
145.9 (C(4)H), 147.9 (C(2)H), 154.8 (C(5a)).
6,7-Dihydro-7-methylene-5H-[2]pyrindin-5-ol (17). Tributyl-
tin hydride (0.52 ml, 1.87 mmol) was added to a solution of
12 (0.352 g, 1.55 mmol) in toluene (70 ml) and after being
heated to 110ЊC under argon, AIBN (10% in mole) was
added and the mixture continued to be refluxed under
argon for 2 h, following the same procedure as for 13.
Purification by flash chromatography (hexane followed by
hexane:ethyl acetate 1:3) give the cyclised product and
reduced starting material 18 (0.192 g, 84%, 10:1 mixture).
Recrystallisation from hexane–ethyl acetate give pure 17
(0.131 g, 57%) as colourless needles, mp 99–100ЊC. Rf
0.2 (ethyl acetate:hexane 3:1); nmax/cmϪ1 3152 (OH),
1645 (CyC), 1602 (pyr-CyC); dH(CDCl3) 2.68 (1H, ddt,
Jˆ17, 5 and 2 Hz, C(6)H), 3.19 (1H, ddt, Jˆ17, 7 and
2 Hz, C(6)H), 5.19 (1H, t, Jˆ2 Hz, C(7)CH2), 5.28 (1H,
dd, Jˆ7 and 5 Hz, C(5)H), 5.60 (1H, t, Jˆ2 Hz,
C(7)CH2), 7.39 (1H, d, Jˆ5 Hz, C(3)H), 8.38 (1H, d,
Jˆ5 Hz, C(4)H), 8.66 (1H, s, C(2)H); dC(CDCl3) 42.3
(C(6)H), 72.7 (C(5)H), 106.5 (C(7)CH2), 120.0 (C(3)H),
135.9 (C(7)), 143.1 (C(4)H), 143.8 (C(7a)), 148.7
(C(2)H), 155.2 (C(3a)); m/z 147 (100%, Mϩ), 130 (14%,
MϩϪOH); Found: Mϩ, 147.0697. C9H9NO requires Mϩ,
147.0684; Found: C, 73.33; 6.10; N, 9.33. C9H9NO requires
C, 73.45; H, 6.16; N, 9.52.
6,7-Dihydro-7-methyl-5H-[2]pyrindin-5-ol (13) from 20.
Tetra-n-butylammonium fluoride (0.46 ml of a 1 M solution
in THF, 0.45 mmol) was added to a solution of 20 (60 mg,
0.23 mmol) in THF (5 ml) at 0ЊC under argon. The mixture
was stirred for 15 min at that temperature and at 25ЊC
overnight. The reaction was quenched with water (5 ml),
extracted with diethyl ether (3×10 ml), dried over MgSO4
and concentrated under reduced pressure. The residue was
purified by flash chromatography (2:1 ethyl acetate:hexane)
to give the deprotected alcohol 13 (30 mg, 88%) as a
3:1 mixture of diastereoisomers (see above for spectral
data).
3-Bromo-4-(1-tert-butyldimethylsilyloxy-but-3-enyl)-
pyridine (19). A mixture of 7 (0.228 g, 1 mmol), tert-butyl-
dimethylsilyl chloride (0.19 g, 1.2 mmol) and imidazole

K. Jones et al. / Tetrahedron 56 (2000) 397–406
405
3-Bromo-4-(butan-1-ol)pyridine (21). To a THF solution
(50 ml) of LDA, prepared from diisopropylamine (1.57 ml,
12 mmol) and n-BuLi (4 ml of 2.5 M solution in hexane,
10 mmol), 3-bromopyridine 4 (0.96 ml, 10 mmol) in THF
solution (5 ml) was added dropwise at Ϫ78ЊC under argon.
The resulting solution was stirred for 10 min at this tempera-
ture. A THF solution (10 ml) of butyraldehyde (2.7 ml,
30 mmol) was then added. The mixture was stirred for 1 h
at Ϫ78ЊC, warming to room temperature over 1 h. The reac-
tion was poured into cold stirred 5% NaHCO3 (50 ml),
diluted with diethyl ether (100 ml) and the organic layer
was separated. The aqueous layer was extracted with ethyl
acetate (3×50 ml). The combined organic solution was
washed with brine (2×100 ml), dried over MgSO4 and
evaporated under reduced pressure. The residue was chro-
matographed (ethyl acetate:hexane 2:1) to give the alcohol
21 (2.00 g, 87%) as a brown/red oil. Rf 0.53 (ethyl acetate:-
hexane 2:1); nmax/cmϪ1 3333 (OH), 1583 (pyr-CyC);
dH(CDCl3) 0.97 (3H, t, Jˆ7 Hz, C(40)H), 1.49–1.66 (2H,
m, C(30)H), 1.69–1.75 (2H, m, C(20)H), 5.00 (1H, dd, Jˆ5
and 4 Hz, C(10)H), 7.52 (1H, d, Jˆ5 Hz, C(5)H), 8.45 (1H,
d, Jˆ5 Hz, C(6)H), 8.58 (1H, s, C(2)H); dC(CDCl3) 13.8
(C(40)H), 18.8 (C(30)H), 39.2 (C(20)H), 71.6 (C(10)H), 120.0
(C(3)Br), 122.2 (C(5)H), 148.4 (C(6)H), 151.5 (C(2)H),
153.2 (C(4)); m/z 232 (15%, Mϩϩ1), 186 (13%,
MϩϪCH2CH2CH3); Found: Mϩ, 231.0101. C9H1281BrON
requires Mϩ, 231.0082.
residue was chromatographed (ethyl acetate:hexane 4:3) to
give the protected alcohol 2424 (129 mg, 80%) as an oil. Rf
0.59 (ethyl acetate:hexane 4:3); nmax/cmϪ1 1647 (CyC),
1597 (pyr-CyC); dH(CDCl3) 2.82 (1H, ddt, Jˆ16,4 and
2 Hz, C(6)H), 3.10 (1H, ddt, Jˆ16, 7 and 2 Hz, C(6)H),
4.62 (1H, ABq, Jˆ12 Hz, PhCH2), 4.68 (1H, ABq,
Jˆ12 Hz, PhCH2), 5.07 (1H, dd, Jˆ7 and 4 Hz, C(5)H),
5.20 (1H, t, Jˆ2 Hz, C(7)CH2), 5.64 (1H, t, Jˆ2 Hz,
C(7)CH2), 7.28–7.39 (6H, m, C(3)H and C(Ar)H), 8.50
(1H, d, Jˆ5 Hz, C(4)H), 8.83 (1H, s, C(2)H); dC(CDCl3)
39.0 (C(6)H), 71.3 (CH2O), 78.9 (C(5)H), 106.3 (C(7)CH2),
120.4 (C(3)H), 127.8 (2×C(Ar)H), 127.9 (C(Ar)H), 128.5
(2×C(Ar)H), 136.2 (C(7)), 137.8 (C(Ar)), 144.0 (C(7a)),
148.9(C(2)H), 152.9 (C(5a)).
Acknowledgements
We should like to thank the EU for funding through the
Erasmus scheme (A.F. and M.L.E.-H.) and Kingston
University for a studentship (A.F.).
References
1. Jones, K.; Escudero-Hernandez, M. L. Tetrahedron 1998, 54,
2275–2280.
2. Dobbs, A. P.; Jones, K.; Veal, K. Tetrahedron Lett. 1997, 38,
5383–5386.
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5,6-Dihydro-7-hydroxy-5H-[2]pyrindin-7-one (23). 7-Methyl-
ene-6,7-dihydro-5H-[2]pyrindin-5-ol 17 (221 mg, 1.5 mmol) in
5:1 dichloromethane:methanol (90 ml) was ozonised at
Ϫ78ЊC. The reaction was monitored by TLC and judged
complete after 4 h at Ϫ78ЊC. Dimethyl sulfide (8 ml) was
added to the reaction mixture, which was slowly warmed to
room temperature overnight. The solvent was then removed
under reduced pressure to give a residue, which was
dissolved in acetone (2×50 ml). The acetone solution was
filtered and evaporated in vacuo. The residue was chroma-
tographed (chloroform:methanol 9:1) to give the ketone 23
(154 mg, 69%) as a solid, mp 105–106ЊC (decomp). Rf 0.31
(chloroform:methanol 9:1); nmax/cmϪ1 3318 (OH), 1723
(CO), 1602 (pyr-CyC); dH(acetone-d6) 2.54 (1H, dd,
Jˆ19 and 3 Hz, C(6)H), 3.10 (1H, dd, Jˆ19 and 7 Hz,
C(6)H), 5.47 (1H, dd, Jˆ7 and 3 Hz, C(5)H), 7.78 (1H, d,
Jˆ5 Hz, C(3)H), 8.82 (1H, d, Jˆ5 Hz, C(4)H), 8.87 (1H, s,
C(2)H); dC(acetone-d6) 47.4 (C(6)H), 68.3 (C(5)H), 122.1
(C(3)H), 132.6 (C(7a)), 145.8 (C(4)H), 155.1 (C(2)H),
164.7 (C(5a)), 202.7 (C(7)); m/z 149 (100%, Mϩ), 132
(21%, MϩϪOH); Found: Mϩ, 149.0472. C8H7NO2 requires
Mϩ 149.0477.
13. Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25,
265–268.
´
14. (a) Mauze, B.; Miginiac, L. Bull. Soc. Chim. Fr. 1973, 1832–
1840. (b) Ranu, B. C.; Majee, A.; Das, A. S. Tetrahedron Lett.
1995, 36, 4885–4888. These authors report the use of unactivated
zinc dust in the zinc-Barbier reaction.
5-Benzyloxy-6,7-dihydro-7-methylene-5H-[2]pyrindine
(24). 7-Methylene-6,7-dihydro-5H-[2]pyrindin-5-ol 17 (100 mg,
0.68 mmol) in THF (2 ml) was added at 0ЊC to a THF (3 ml)
suspension of 35% KH (93 mg, 0.81 mmol) under argon.
After the mixture was stirred for 1 h, benzyl bromide
(0.12 ml, 1 mmol) was added dropwise. The resulting
mixture was stirred at 0ЊC for 2 h. The mixture was
quenched with saturated NH4Cl (5 ml) and diluted with
diethyl ether (5 ml). The organic layer was separated, and
the aqueous layer was extracted with diethyl ether
(2×10 ml). The combined organic layer was washed with
brine, dried over MgSO4 and concentrated in vacuo. The
´
15. Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910–912.
16. Motherwell, W. B.; Crich, D. Free Radical Reactions in
Organic Synthesis; Academic Press: London, 1992.
17. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,
3925–3941.
18. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994; p 682.
19. Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994; p 773ff.
20. Motherwell, W. B.; Crich, D. Free Radical Reactions in
Organic Synthesis; Academic Press: London, 1992; p 224.

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K. Jones et al. / Tetrahedron 56 (2000) 397–406
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2829–2831.
22. Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc., Chem.
Commun. 1995, 977–978.
23. A similar reaction of an aldol with methylmagnesium bromide
to give the tertiary alcohol has been reported by Yarnold, C. J.
Ph.D. Thesis, London University, 1992.
24. Aoyagi, Y.; Inariyama, T.; Arai, Y.; Tschuida, S.; Matuda, Y.;
Kobayashi, H.; Ohta, A.; Kurihara, T.; Fujihira, S. Tetrahedron
1994, 50, 13575–13582.
25. In Ref. 24 there is a typographical error in the 1H NMR
spectrum reported for compound 24. The resonance at d 2.82
is a ddt with Jˆ16, 4, 2 Hz and not a ddt with Jˆ16, 4,
7 Hz.