Intramolecular radical additions to pyridines

Article abstract of DOI:10.1039/b309331j

Intramolecular 6-exolendo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the α-, β- P- and γ-carbons of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether, ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation pathways. All attempts to effect 5-exolendo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane, tris(trimethylsilyl)germane and, in part, samarium(II) iodide can each be employed as mediators of the reaction.

Full text of DOI:10.1039/b309331j

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Intramolecular radical additions to pyridines
David C. Harrowven,*a Benjamin J. Suttona and Steven Coultonb
a Department of Chemistry, University of Southampton, Southampton,
UK. E-mail: dch2@soton.ac.uk; Fax: 44 8059 6805; Tel: 44 8059 3302
b GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex,
UK CM19 5AW
Received 5th August 2003, Accepted 17th September 2003
First published as an Advance Article on the web 13th October 2003
Intramolecular 6-exo/endo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the α-, β- and γ-carbons
of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the
pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether,
ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is
employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation
pathways. All attempts to effect 5-exo/endo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane,
tris(trimethylsilyl)germane and, in part, samarium() iodide can each be employed as mediators of the reaction.
gain some insight as to the factors determining whether cyclis-
Introduction
ation proceeded via the 6-exo/endo-trig mode or the alternative
5-exo-trig mode favoured in the majority radical cyclisation
reactions involving alkenes (Scheme 1). If examples of the latter
could be found, it was unclear whether the resulting radical
intermediates would undergo hydrogen atom abstraction from
tributyltin hydride leading to a spirocycle or undergo rearrange-
ment so as to facilitate re-aromatisation.
The first example of a radical addition to a pyridine was
reported in 1893 by Mohlau and Berger. They found that the
thermal decomposition of benzene diazonium chloride in pyrid-
ine resulted in the formation of 2-phenylpyridine and 4-phenyl-
pyridine in low yield.1 Later, Overhoff and Tilman attained a
similar result when heating dibenzoyl peroxide in pyridine. In
this case a 2 : 1 mixture of 2- and 4-phenylpyridine was formed
in 18% yield with respect to dibenzoyl peroxide and 4% yield
with respect to pyridine.2 These findings were reassessed by Hey
and Walker, using UV spectroscopy to analysed the product
mixture.3 From the data attained they concluded that 2-, 3- and
4-phenylpyridine were all produced in the reaction and esti-
mated the yields for each to be 17%, 10% and 4.4% respectively.
The reaction lay dormant for many years, the low yields and
poor selectivity doubtless limiting its appeal to the synthetic
community. Interest was rekindled in the 1960’s through the
seminal work of Dou and Minisci.4,5 These groups showed that
radical additions to pyridines could be effected in good yield
when carried out in an acidic medium. Moreover, reactions
conducted under such conditions displayed greater selectivity
towards addition at C-2, adding further to its synthetic
appeal. More recently intramolecular variants of the Minisci
reaction have come to the fore.6–9 Murphy and Sherburn,
for example, showed that many N-haloalkylpyridinium salts
underwent cyclisation to C-2 of the pyridine ring on treatment
with tributyltin hydride. Notably, a non-reducing pathway
was observed in each of the cases studied – cyclisation being
followed by re-aromatisation of the heterocycle.7
In contemporaneous work Motherwell showed that ipso sub-
stitution could outpace ortho cyclisation when the radical pre-
cursor and pyridine ring were conjoined with an appropriate
tether.8 Latterly, ortho-cyclisation to a pyridine featured as a key
step in a total synthesis of the alkaloid toddaquinoline.9,10 Not-
ably, cyclisation of a 2Ј-bromo-3-azastilbene proceeded in good
yield when mediated by tributyltin hydride but gave rise to
products derived from radical addition to both the C-2 and C-4
centres of the pyridine. By contrast, cyclisation to C-2 was the
only outcome observed when cobalt()salophen was employed
as a mediator.10
Following our completion of the total synthesis of todda-
quinoline, we started to consider further extensions of the
methodology.11–14 In particular, we wondered whether radical
additions to C-3 of a pyridine would be effective when con-
ducted intramolecularly at neutral pH. We were also keen to
Scheme 1
Results and discussion
Radical cyclisations to C-2, C-3 and C-4 of a pyridine
Our first task was to examine cyclisation reactions involving the
addition of aryl radical intermediates to C-3 of a pyridine.15,16
When Z-azastilbene 1 was treated with tributyltin hydride
under standard radical forming conditions the expected benzo-
[f ]quinoline 2 was formed in low yield with recovered starting
material accounting for much of the outstanding mass balance.
Indeed, to achieve complete conversion it was found necessary
to employ 4.4 equivalents of tributyltin hydride and 30 mol%
AIBN. Using these unusual conditions, benzo[f ]quinoline 2 was
given in 47% yield. As with radical additions to C-2 and C-4 of
a pyridine, cyclisation followed the non-reducing pathway lead-
ing to re-aromatisation (Scheme 2).9–14
By way of contrast, the related cyclisation of Z-azastilbene 5
to benzo[h]isoquinoline 7 was extremely facile, proceeding in
98% yield using the standard radical forming conditions of 1.1
equivalents of tributyltin hydride and 10 mol% AIBN. A strik-
ing dichotomy was uncovered when the analogous bromide 6
was exposed to the aforementioned conditions. In this case
alkene isomerisation outpaced C–Br bond homolysis as evi-
denced by the formation of E-azastilbene 8 in 97% yield
(Scheme 3).
For completeness the tin-mediated radical cyclisation of
Z-azastilbene 9 was examined. In this case the product mixture
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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mode over the alternative 5-exo-trig pathway. Our reasoning
was based on the need to contract bond angles in going to a
cyclopentadiene intermediate, a barrier that would be less
severe in the formation of cyclohexadiene intermediates akin to
4. To test this hypothesis, each of the substrates 1, 5, 6 and 9 were
reduced to the corresponding dihydroazastilbenes with diimide.
These materials were then exposed to tributyltin hydride and
the resulting product mixtures analysed.
Three products were evident when iodide 12 was treated
under standard tin-mediated radical forming conditions,
accounting for 95% of the mass balance. The presence of 13,
the product of C–I bond reduction, showed that the 6-exo/
endo-trig cyclisation mode had indeed been slowed by the
inclusion of a more flexible tether. This was further evidenced
by the production of both dihydrobenzo[f ]quinoline 18 and
dihydrobenzo[h]quinoline 19, formed respectively by 6-exo/
endo-trig and 5-exo-trig cyclisation of the aryl radical inter-
mediate 14 (Scheme 5). The formation of 19 can be viewed as a
direct rearrangement of spirocycle 15 to tetracycle 17, or as a
stepwise process involving scission of the indane followed by
6-exo/endo-trig cyclisation of the resultant alkyl radical.17
Scheme 2
Scheme 3
attained comprised of a 5 : 4 mixture of benzo[h]quinoline 10
and benzo[f ]isoquinoline 11 (Scheme 4). As expected, cyclis-
ation to C-2 and C-4 occurred with almost equal propensity
and in excellent yield. Indeed, no products derived from alkene
isomerisation or radical addition to C-3 were observed. Once
again, standard radical forming conditions could be used to
effect the transformation and just 6 mol% AIBN was needed to
achieve complete reaction.
Scheme 5
Irrespective of the nature of that rearrangement, it
appears to be quite general within the pyridine series. Thus,
aryl iodide 20 gave a similar product mixture when treated
with tributyltin hydride, comprising of dihydrostilbene 21, di-
hydrobenzo[h]isoquinoline 22 and dihydrobenzo[f ]isoquinoline
23. These correspond to the products of reduction, ortho-
cyclisation, and ipso-cyclisation and rearrangement, respect-
ively (Scheme 6).
Scheme 4
A new rearrangement
In each of the aforementioned examples we believed that the
use of a cis-alkene to conjoin the radical donor to the pyridine
ring biased reactions in favour of the 6-exo/endo-trig cyclisation
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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Scheme 8
Scheme 9
Scheme 6
For aryl iodide 24 the situation was even more complex. With
two 6-exo/endo-trig cyclisation pathways available and two
courses by which rearrangement could occur, we envisioned a
product mixture comprising at least five components. In the
event, all five of the anticipated products were observed,
though dihydrobenzo[h]quinoline 19 was formed as the major
product (Scheme 7).
Scheme 10
odology. It also seemed apposite to determine the appropriate-
ness of various commonly employed solvents. The systems
chosen for the study were azastilbene 5 and the corresponding
dihydroazastilbene 20.
Use of other radical mediators
Cyclisation of Z-azastilbene 5 to benzo[h]isoquinoline 7 pro-
ceeded equally well with tris(trimethylsilyl)silane and tris(tri-
methylsilyl)germane.18,19 Samarium() iodide was also effective
but gave a poorer conversion.20 No reaction was observed with
the indium() chloride – sodium borohydride reagent.21 Photo-
induced homolysis of the C–I bond was also investigated.22
Though some cyclisation was observed when an acetonitrile
solution of 5 was irradiated with a medium pressure mercury
lamp, the reaction was slow and complicated by photo-isomer-
isation of the alkene. That side reaction was of less significance
when hexabutylditin was included in the reaction mixture,
though yields remained low (Scheme 11).
Scheme 7
Attempted 5-exo/endo-trig cyclisations
Scheme 11
All attempts to effect the corresponding 5-exo/endo-trig cyclis-
ation reaction met with failure.16 In each of the cases studied
carbon to halogen bond reduction outpaced cyclisation,
indicating that such processes are more akin to 5-endo-trig
reactions than 5-exo-trig reactions (Schemes 8 to 10).11–14
Unexpectedly, treatment of aryl pyridyl ketone 32 with tributyl-
tin hydride and AIBN led to reduction of the ketone rather
than carbon to halogen bond homolysis.
Dihydroazastilbene 20 likewise reacted smoothly with both
tris(trimethylsilyl)silane and tris(trimethylsilyl)germane. Not-
ably, tris(trimethylsilyl)germane gave more of the reduction
product 21 while tris(trimethylsilyl)silane gave more of the
cyclisation products 22 and 23. The result was in line with
expectation as it reflects the relative strengths of the Si–H,
Sn–H and Ge–H bonds and hence the relative rate of hydro-
gen atom abstraction from the mediator. These experiments
also revealed an inconsistency in the distribution of cyclis-
ation products 22 and 23. At this time we have no satisfactory
explanation for the phenomenon as that ratio can display
Comparing different methodologies
To conclude our study we decided to explore the use of other
mediators as well as ‘catalytic’ variants of the tributyltin meth-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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considerable variation within parallel experiments on the same
substrate. In most cases the ratio of products 22 and 23 given
falls in the region of 1 : 1 to 2 : 1. Samarium() iodide was also
examined and in this case gave only the product of reduction,
21 (Scheme 12).
Conclusions
We have shown that intramolecular radical additions to the α-,
β- and γ-carbons of a pyridine can be efficient processes, even
at neutral pH. The tether conjoining the radical donor to the
pyridine plays an important role in determining the outcome of
the reaction. When a Z-alkene is employed as a tether a 6-exo/
endo-trig cyclisation to an ortho-carbon follows. A more com-
plex course is followed when a saturated two-carbon tether is
used. In such cases, hydrogen atom abstraction and 5-exo-trig
(ipso-) cyclisation pathways compete with the 6-exo/endo-trig
(ortho-) cyclisation mode. Where cyclisation occurs to the ipso-
carbon, the resulting spirocycle collapses with migration of the
alkyl ‘tether’ leading to a skeletal rearrangement.
Scheme 12
5-exo/endo-trig cyclisations have been attempted but no case
has been found where addition of the aryl radical to the pyrid-
ine occurs. From this we conclude that such 5-exo/endo-trig
cyclisations are more akin to a 5-endo-trig than 5-exo-trig
process.
While the bulk of this work was carried out using stoichio-
metric tributyltin hydride as a mediator, catalytic variants of
the method were also examined. These proved less rewarding as
the requisite change of solvent from toluene to ethanol or THF,
led to the promotion of side reactions. Notably, tris(trimethyl-
silyl)silane, tris(trimethylsilyl)germane and, in part, samariu-
m() iodide were found to be useful substitutes for tributyltin
hydride.
‘Catalytic tin’ methodologies
The use of triorganotin hydrides and halides in conjunc-
tion with a reducing agent has found widespread use as a
means of reducing the quantity of these toxic and relatively
expensive reagents to sub-stoichiometric levels.23 Removal of
tin residues from the product mixture is also eased as the resi-
dual triorganotin hydride can usually be separated from the
product by elution through a silica column. Sodium boro-
hydride and sodium cyanoborohydride are the most commonly
employed reducing agents, limiting the range of solvents that
may be employed.
Cyclisation of azastilbene 5 was attempted in toluene, THF
and ethanol using 0.25 equivalents of tributyltin hydride and
1.5 equivalents of sodium borohydride. Toluene proved to be an
unsatisfactory solvent, with only 9% of the substrate converted
into benzo[h]isoquinoline 7. The low solubility of sodium
borohydride in toluene provides an explanation for the poor
conversion in this case. THF also proved to be a poor solvent
for the reaction, albeit for a quite different reason. In this case
alkene isomerisation outpaced C–I bond homolysis leading to
the production of (E)-azastilbene 8 in 76% yield. Indeed, benz-
o[h]isoquinoline 7 was only observed in significant quantity
(48%) when ethanol was employed. Here too, (E)-8 was
observed as a major by-product accounting for 52% of the mass
balance (Scheme 13).
Experimental
General remarks
Melting points were recorded on a Reichert melting point
apparatus using a Comark digital temperature probe and are
uncorrected. UV spectra were recorded on a Shimadzu UV-
1601 spectrometer. IR spectra were recorded using a Bio-Rad
FTS 135 Fourier transform infrared spectrometer equipped
with a Golden Gate Single Reflection Diamond ATR (n.b. IR
data were attained directly from solid samples). NMR spectra
were recorded on a Bruker AM250 (operating at 250 MHz for
1H and at 62.9 MHz for 13C), or a Bruker AC300 (operating at
300 MHz for 1H and at 75.5 MHz for 13C), or a Bruker AM400
(operating at 400 MHz for 1H and at 100 MHz for 13C). Chemi-
cal shifts (δH) are reported as values in parts per million relative
to tetramethylsilane (δH 0.00, δC 0.00), CDC13 (δC 77.2) or resi-
dual CHCl3 (δH 7.27). Mass spectra were attained using atmos-
pheric pressure chemical ionisation (APCI) or electrospray (ES)
and were recorded on a Micromass Platform quadrupole mass
analyser with an electrospray ion source. The eluent was dis-
tilled acetonitrile and experiments were conducted at a flow rate
of 200 µL minϪ1. Electron impact (EI) mass spectra were
recorded on a VG Analytical 70–250-SE normal geometry
double focusing mass spectrometer using 70 eV ionisation
energy and a 200 ЊC source temperature. High resolution mass
spectra (HRMS) were recorded on the same instrument giving a
resolution of 104.
All reactions were magnetically stirred under an inert atmos-
phere. Reactions were monitored by thin layer chromatography
using Macherey-Nagel Alugram Sil G/UV254 precoated alu-
minium foil plates of layer thickness 0.25 mm. Compounds
were visualised firstly by UV irradiation, then by exposure to
iodine vapour and finally by heating plates exposed to solutions
of phosphomolybdic acid in ethanol or basified aqueous potas-
sium permanganate. Column chromatography was performed
on Sorbsil 60 silica (230–400 mesh), slurry packed and run
under low pressure.
Scheme 13
No satisfactory solvent could be found for the cyclisation
of 20 to 22 and 23 using the ‘catalytic tin’ methodology.
For example, applying the aforementioned conditions using
ethanol resulted in the formation of dihydroazastilbene 21 in
93% yield. The observation suggests that hydrogen atom
abstraction is significantly faster in ethanol than in toluene,
prompting us to examine the influence of the solvent in greater
detail.
Solvent effects
Accordingly, cyclisation of (Z)-azastilbene 5 was carried out in
toluene, THF, ethanol and methanol. With toluene the sole
product of the reaction was benzo[h]isoquinoline 7 (98% yield).
By contrast, alkene isomerisation competed with C–I bond
homolysis when reactions were conducted in ethanol, methanol
and THF. Isomerisation was most pronounced in THF and on
each occasion was accompanied by reduction of the C–I bond
(Scheme 13).
Tetrahydrofuran was dried by distillation over sodium and
benzophenone. Toluene was dried by distillation over sodium.
Dichloromethane was dried by distillation over calcium
hydride. Ether refers to diethyl ether and petrol refers to the
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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fraction of petroleum ether in the boiling point range 40–60 ЊC.
[(6-Iodo-1,3-benzodioxole-5-yl)-methyl]triphenylphosphonium
bromide 37, mp 268–272 ЊC (EtOH) [Lit. 268–272 ЊC
(EtOH)],14 and [(6-bromo-1,3-benzodioxole-5-yl)-methyl]tri-
phenylphosphonium bromide 38, mp 275–279 ЊC (EtOH)
[Lit. 278–280 ЊC (xylene)],10 were prepared by the method of
Harrowven et al.14,10
2 × CH), 149.0 (Ar, C), 148.9 (Ar, C), 144.2 (Ar, C), 136.6 (Ar,
CH), 132.6 (Ar, C), 127.2 (Ar, CH), 120.9 (Ar, 2 × CH), 118.8
(Ar, CH), 106.0 (Ar, CH), 102.0 (OCH2O), 90.1 (Ar, C);
LRMS (APCI) 352 (100%, MHϩ); Anal. Found: C, 47.97; H,
2.82; N, 3.93. C14H10INO2 requires C, 47.89; H, 2.87; N, 3.99%.
(Z )-4-[2-(6-Bromo-1,3-benzodioxol-5-yl)-1-ethenyl]pyridine
(Z )-6 and (E )-4-[2-(6-bromo-1,3-benzodioxol-5-yl)-1-ethenyl]-
pyridine (E )-6. NaH (84 mg, 3.50 mmol, 60% dispersion in oil)
was washed with THF (10 mL) then cooled to 0 ЊC and stirred
in suspension with THF (40 mL) under argon. Phosphonium
salt 38 (1.70 g, 3.06 mmol) was added and the reaction warmed
to RT and stirred for 18 h. The mixture was re-cooled to 0 ЊC
and 4-pyridinecarbaldehyde (0.24 mL, 269 mg, 2.51 mmol)
added. After 2 h the precipitated triphenylphosphine oxide was
removed by filtration and the liquors concentrated in vacuo.
Purification by column chromatography (silica, 2 : 3 – Et2O :
petrol) gave firstly (Z)-6 (471 mg, 1.55 mmol, 51%) as a white
soild; mp 93–94 ЊC (Et2O); IR (solid, cmϪ1) υmax 3111 w, 3036 w,
2911 w, 1629 m, 1544 m, 1491 s, 1470 m, 1385 m, 1318 m, 1276
m, 1155 m, 1106 s, 1030 m; UV (MeOH, nm) λmax (εmax) 297
Preparation of substrates
(Z )-2-[2-(6-Iodo-1,3-benzodioxol-5-yl)-1-ethenyl]pyridine 1.
NaH (400 mg, 10.0 mmol, 60% dispersion in oil) was washed
with THF (10 mL) then cooled to 0 ЊC and stirred in suspension
with THF (40 mL) under argon. Phosphonium salt 37 (5.00 g,
8.29 mmol) was added and the reaction stirred for 30 min
whilst warming to RT. The mixture was re-cooled to 0 ЊC and
2-pyridinecarbaldehyde (0.70 mL, 788 mg, 7.36 mmol) added.
After 2 h the precipitated triphenylphosphine oxide was
removed by filtration and the liquors concentrated in vacuo.
Purification by column chromatography (silica, Et2O) and
recrystallisation (EtOH) gave 1 (2.20 g, 6.27 mmol, 85%) as a
white crystalline solid; mp 108–110 ЊC (EtOH); IR (solid, cmϪ1
)
1
(7560); H NMR (300 MHz, CDCl3) δH 8.44 (2H, d, J 4.4 Hz,
υmax 1582 w, 1500 w, 1474 s, 1433 w, 1411 w, 1231 m, 1035 s; UV
(MeOH, nm) λmax (εmax) 294 (12710); 1H NMR (400 MHz,
CDCl3) δH 8.57 (1H, ddd, J 4.8, 1.6, 0.8 Hz, ArH ), 7.45 (1H,
app. td, J 7.7, 1.8 Hz, ArH ), 7.31 (1H, s, ArH ), 7.07 (1H, ddd,
J 7.5, 4.9, 1.0 Hz, ArH ), 7.01 (1H, d, J 8.0 Hz, ArH ), 6.69 (1H,
ArH ), 7.00 (1H, s, ArH ), 7.00 (2H, d, J 4.4, ArH ), 6.66 (1H, d,
J 12.5 Hz, RCH᎐CHR), 6.54 (1H, s, ArH ), 6.46 (1H, d, J 12.5
᎐
Hz, RCH᎐CHR), 5.93 (2H, s, OCH O); 13C NMR (75.5 MHz,
᎐
2
CDCl3) δC 149.9 (Ar, 2 × CH), 148.3 (Ar, C), 147.2 (Ar, C),
143.9 (Ar, C), 133.3 (CH᎐CH), 129.6 (Ar, C), 128.2 (CH᎐CH),
᎐
᎐
d, J 12.2 Hz, RCH᎐CHR), 6.65 (1H, d, J 12.1 Hz, RCH᎐CHR),
᎐
᎐
123.4 (Ar, 2 × CH), 114.7 (Ar, C), 112.7 (Ar, CH), 109.8 (Ar,
6.64 (1H, s, ArH ), 5.93 (2H, s, OCH2O); 13C NMR (62.9 MHz,
CDCl3) δC 155.5 (Ar, C), 149.6 (Ar, CH), 148.2 (Ar, C), 148.0
C), 101.9 (OCH2O); LRMS (APCI) 347 (12%, [M(81Br) ϩ
MeCN]ϩ), 345 (13%, [M(79Br)
ϩ
MeCN]ϩ), 306 (85%,
M(81Br)Hϩ), 304 (100%, M(79Br)Hϩ); Anal. Found: C, 55.30; H,
3.33; N, 4.60. C14H10BrNO2 requires C, 55.29; H, 3.31; N,
4.61%. Then (E)-6 (310 mg, 1.02 mmol, 33%) as a white solid;
mp 112–113 ЊC (Et2O); IR (solid, cmϪ1) υmax 3066 w, 3011 w,
2976 w, 2631 w, 1629 m, 1591 w, 1548 m, 1501 s, 1476 m, 1315
m, 1275 s, 1252 m, 1198 m, 1160 m, 1118 s; UV (MeOH, nm)
λmax (εmax) 341 (12900), 301 (11700); 1H NMR (300 MHz,
(Ar, C), 136.3 (Ar, CH), 135.7 (CH᎐CH), 134.3 (Ar, C), 131.1
᎐
(CH᎐CH), 123.9 (Ar, CH), 121.8 (Ar, CH), 118.4 (Ar, CH),
᎐
110.0 (Ar, CH), 101.7 (OCH2O), 87.9 (Ar, C); LRMS (APCI)
352 (100%, MHϩ); Anal. Found: C, 47.78; H, 2.74; N, 3.90.
C14H10INO2 requires C, 47.89; H, 2.87; N, 3.99%.
(Z )-4-[2-(6-Iodo-1,3-benzodioxol-5-yl)-1-ethenyl]pyridine
(Z )-5 and (E )-4-[2-(6-iodo-1,3-benzodioxol-5-yl)-1-ethenyl]-
pyridine (E )-5. NaH (400 mg, 10.0 mmol, 60% dispersion in oil)
was washed with THF (10 mL) then cooled to 0 ЊC and stirred
in suspension with THF (40 mL) under argon. Phosphonium
salt 37 (5.00 g, 8.29 mmol) was added and the reaction stirred
for 30 min whilst warming to RT. The mixture was re-cooled to
0 ЊC and 4-pyridinecarbaldehyde (0.70 mL, 785 mg, 7.33 mmol)
added. After 2 h the precipitated triphenylphosphine oxide was
removed by filtration and the liquors concentrated in vacuo.
Purification by column chromatography (silica, Et2O) gave
firstly (Z)-5 (1.63 g, 4.65 mmol, 63%) as a pale yellow crystal-
line solid after recrystallisation from EtOH; mp 100–102 ЊC
(EtOH); IR (solid, cmϪ1) υmax 1741 m, 1593 m, 1489 m, 1473 m,
1429 m, 1365 m, 1235 s, 1032 s; UV (MeOH, nm) λmax (εmax) 298
(13340), 245 (27010); 1H NMR (250 MHz, CDCl3) δH 8.44 (2H,
dd, J 4.6, 1.6 Hz, ArH ), 7.30 (1H, s, ArH ), 7.00 (2H, dd, J 4.6,
CDCl3) δH 8.58 (2H, br s, ArH ), 7.58 (1H, d, J 16.2 Hz, RCH᎐
᎐
CHR), 7.35 (2H, d, J 4.4, ArH ), 7.12 (1H, s, ArH ), 7.04 (1H, s,
ArH ), 6.77 (1H, d, J 16.2 Hz, RCH᎐CHR), 6.00 (2H, s,
᎐
OCH2O); 13C NMR (75.5 MHz, CDCl3) δC 150.2 (Ar, 2 × CH),
149.0 (Ar, C), 148.1 (Ar, C), 144.8 (Ar, C), 132.0 (CH᎐CH),
᎐
129.4 (Ar, C), 127.0 (CH᎐CH), 121.1 (Ar, 2 × CH), 116.4
᎐
(Ar, C), 113.1 (Ar, CH), 106.1 (Ar, C), 102.2 (OCH2O);
LRMS (APCI) 347 (15%, [M(81Br) ϩ MeCN]ϩ), 345 (15%,
[M(79Br) ϩ MeCN]ϩ), 306 (95%, M(81Br)Hϩ), 304 (100%,
M(79Br)Hϩ), 251 (22%), 165 (18%), 163 (9%); Anal. Found: C,
55.14; H, 3.29; N, 4.59. C14H10BrNO2 requires C, 55.29; H, 3.31;
N, 4.61%.
(Z )-3-[2-(6-Iodo-1,3-benzodioxol-5-yl)-1-ethenyl]pyridine
(Z )-9 and (E )-3-[2-(6-iodo-1,3-benzodioxol-5-yl)-1-ethenyl]-
pyridine (E )-9. NaH (400 mg, 10.0 mmol, 60% dispersion in oil)
was washed with THF (10 mL) then cooled to 0 ЊC and stirred
in suspension with THF (40 mL) under argon. Phosphonium
salt 37 (5.00 g, 8.29 mmol) was added and the reaction stirred
for 1 h whilst warming to RT. The mixture was re-cooled to 0 ЊC
and 3-pyridinecarbaldehyde (0.70 mL, 795 mg, 7.42 mmol)
added. After 2 h the precipitated triphenylphosphine oxide was
removed by filtration and the liquors concentrated in vacuo.
Purification by column chromatography (silica, Et2O) gave
firstly (Z)-9 (1.50 g, 4.27 mmol, 58%) as a pale yellow crystal-
line solid after recrystallisation from EtOH; mp 102–103 ЊC
(EtOH); IR (solid, cmϪ1) υmax 1496 m, 1473 s, 1432 m, 1244 m,
1229 m, 1105 w, 1037 s; UV (MeOH, nm) λmax (εmax) 290
1.5 Hz, ArH ), 6.62 (1H, d, J 11.9 Hz, RCH᎐CHR), 6.54 (1H, s,
᎐
ArH ), 6.46 (1H, d, J 11.9 Hz, RCH᎐CHR), 5.93 (2H, s,
᎐
OCH2O); 13C NMR (62.9 MHz, CDCl3) δC 149.9 (Ar, 2 × CH),
148.3 (Ar, C), 148.2 (Ar, C), 143.7 (Ar, C), 137.4 (CH᎐CH),
᎐
133.7 (Ar, C), 128.0 (CH᎐CH), 123.4 (Ar, 2 × CH), 118.4 (Ar,
᎐
CH), 109.7 (Ar, CH), 101.7 (OCH2O), 87.7 (Ar, C); LRMS
(APCI) 352 (100%, MHϩ); Anal. Found: C, 47.84; H, 2.85; N,
3.92. C14H10INO2 requires C, 47.89; H, 2.87; N, 3.99. Then (E)-
5 (796 mg, 2.27 mmol, 31%) as a pale yellow crystalline solid
after recrystallisation from EtOH; mp 115–117 ЊC; (EtOH); IR
(solid, cmϪ1) υmax 1742 w br., 1591 w, 1498 m, 1469 s, 1407 w,
1232 s, 1111 w, 1032 s; UV (MeOH, nm) λmax (εmax) 346 (18560),
303 (17810), 258 (18540); 1H NMR (250 MHz, CDCl3) δH 8.58
1
(11180); H NMR (250 MHz, CDCl3) δH 8.40 (2H, app. dd,
(2H, dd, J 4.6, 1.6 Hz, ArH ), 7.45 (1H, d, J 16.0 Hz, RCH᎐
CHR), 7.35 (2H, dd, J 4.6, 1.6 Hz, ArH ), 7.30 (1H, s, ArH ),
J 4.8, 1.8 Hz, ArH ), 7.40 (1H, dt, J 8.0, 1.9 Hz ArH ), 7.30 (1H,
s, ArH ), 7.12 (1H, ddd, J 7.9, 4.8, 0.8 Hz, ArH ), 6.57 (1H, d,
᎐
7.12 (1H, s, ArH ), 6.72 (1H, d, J 16.0 Hz, RCH᎐CHR), 6.00
J 11.8 Hz, RCH᎐CHR), 6.56 (1H, s, ArH ), 6.51 (1H, d, J 12.0
᎐
᎐
(2H, s, OCH2O); 13C NMR (62.9 MHz, CDCl3) 150.3 (Ar,
Hz, RCH᎐CHR), 5.92 (2H, s, OCH O); 13C NMR (62.9 MHz,
᎐
2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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CDCl3) δC 150.2 (Ar, CH), 148.4 (Ar, C), 148.2 (Ar, C), 148.1
(Ar, CH), 135.8 (Ar, CH), 135.8 (CH᎐CH), 134.1 (Ar, C),
3-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]pyridine 24. A mix-
ture of the azastilbenes (Z)-9 and (E)-9 (1.05 g, 2.99 mmol),
tosyl hydrazine (2.90 g, 15.6 mmol) and sodium acetate (1.28 g,
15.6 mmol) in THF (15 mL) and water (15 mL) were heated at
reflux for 72 h. After cooling to RT, potassium carbonate solu-
tion (2M, 100 mL) was added. The reaction mixture was
extracted with Et2O (4 × 50 mL) and the combined organic
phases were dried (MgSO4), concentrated in vacuo and purified
by column chromatography (silica, Et2O) to give 24 (1.00 g, 2.83
mmol, 95%) as a white crystalline solid; mp 86–87 ЊC (Et2O); IR
(solid, cmϪ1) υmax 1501 m, 1478 s, 1226 s, 1135 m, 1044 s, 1028
m; UV (MeOH, nm) λmax (εmax) 295 (2550), 269 (2030), 263
᎐
132.0 (Ar, C), 127.0 (CH᎐CH), 123.1 (Ar, CH), 118.5 (Ar,
᎐
CH), 109.6 (Ar, CH), 101.7 (OCH2O), 87.9 (Ar, C); LRMS
(APCI) 352 (100%, MHϩ), 225 (62%), 224 (88%); Anal. Found:
C, 47.87; H, 2.87; N, 3.95. C14H10INO2 requires C, 47.89; H,
2.87; N, 3.99%. Then (E)-9 (1.05 g, 2.98 mmol, 40%) as a
pale yellow crystalline solid after recrystallisation from EtOH;
mp 132–133 ЊC (EtOH); IR (solid, cmϪ1) υmax 1500 m, 1475 s,
1407 w, 1285 w, 1248 m br., 1187 m, 1113 m, 1040 m; UV
(MeOH, nm) λmax (εmax) 338 (13410), 297 (14720), 250 (15070);
1H NMR (250 MHz, CDCl3) δH 8.71 (1H, d, J 4.6, 2.2 Hz,
ArH ), 8.50 (1H, dd, J 4.8, 1.6 Hz, ArH ), 7.84 (1H, dt, J 8.0, 1.8
1
(2490), 244 (4770); H NMR (400 MHz, CDCl3) δH 8.47 (2H,
Hz, ArH ), 7.31 (1H, d, J 16.0 Hz, RCH᎐CHR), 7.31 (1H, d,
d, J 2.8 Hz, ArH ), 7.52 (1H, app. dt, J 7.8, 1.8 Hz, ArH ), 7.24
(1H, s, ArH ), 7.22 (1H, dd, J 7.7, 4.8 Hz, ArH ), 6.65 (1H, s,
ArH ), 5.93 (2H, s, OCH2O), 2.95–2.90 (2H, m, RCH2CH2R),
2.87–2.82 (2H, m, RCH2CH2R); 13C NMR (62.9 MHz, CDCl3)
δC 150.1 (Ar, CH), 148.5 (Ar, C), 147.7 (Ar, CH), 147.0 (Ar, C),
136.6 (Ar, C), 136.3 (Ar, C), 136.0 (Ar, CH), 123.3 (Ar, CH),
118.7 (Ar, CH), 109.4 (Ar, CH), 101.6 (OCH2O), 87.7 (Ar, C),
42.4 (ArCH2), 33.8 (ArCH2); LRMS (APCI) 354 (100%,
MHϩ), 228 (35%), 226 (50%); Anal. Found: C, 47.80; H, 3.43;
N, 3.96. C14H12INO2 requires C, 47.61; H, 3.42; N, 3.97%.
᎐
J 5.1 Hz, ArH ), 7.30 (1H, s, ArH ), 7.14 (1H, s, ArH ), 6.79 (1H,
d, J 16.1 Hz, RCH᎐CHR), 6.00 (2H, s, OCH O); 13C NMR
᎐
2
(62.9 MHz, CDCl3) δC 149.0 (Ar, CH), 148.8 (Ar, CH), 148.7
(Ar, C), 148.5 (Ar, C), 134.3 (CH᎐CH), 133.2 (Ar, C), 132.7
᎐
(Ar, CH), 132.7 (Ar, C), 126.2 (CH᎐CH), 123.6 (Ar, CH),
᎐
118.8 (Ar, CH), 105.8 (Ar, CH), 101.9 (OCH2O), 89.5 (Ar, C);
LRMS (APCI) 352 (100%, MHϩ), 226 (41%); Anal. Found: C,
47.82; H, 2.83; N, 3.92. C14H10INO2 requires C, 47.89; H, 2.87;
N, 3.99.
2-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]pyridine 12. Aza-
stilbene 1 (300 mg, 0.854 mmol), tosyl hydrazine (2.90 g, 15.6
mmol) and sodium acetate (1.28 g, 15.6 mmol) in THF (15 mL)
and water (15 mL) were heated at reflux for 72 h. After cooling
to RT, potassium carbonate solution (2M, 100 mL) was added.
The reaction mixture was extracted with Et2O (4 × 50 mL) and
the combined organic phases were dried (MgSO4), concentrated
in vacuo, then purified by column chromatography (silica, Et2O)
to give 10 (278 mg, 0.787 mmol, 92%) as a white crystalline
solid; mp 69–70 ЊC (EtOH); IR (solid, cmϪ1) υmax 1589 w, 1498
m, 1473 s, 1432 w, 1224 s, 1112 w, 1032 s; UV (MeOH, nm) λmax
(εmax) 295 (4650), 269 (4620), 262 (5760), 224 (8860); 1H NMR
(400 MHz, CDCl3) δH 8.57 (1H, d, J 4.6 Hz, ArH ), 7.59 (1H,
app. td, J 7.7, 1.8 Hz, ArH ), 7.24 (1H, s, ArH ), 7.14 (1H, d,
J 7.7 Hz, ArH ), 7.13 (1H, app. t, J 5.2 Hz, ArH ), 6.70 (1H, s,
ArH ), 5.93 (2H, s, OCH2O), 3.09–2.99 (4H, m, RCH2CH2R);
13C NMR (62.9 MHz, CDCl3) δC 160.7 (Ar, C), 149.4 (Ar, CH),
148.4 (Ar, C), 146.8 (Ar, C), 137.3 (Ar, C), 136.4 (Ar, CH),
123.1 (Ar, CH), 121.3 (Ar, CH), 118.6 (Ar, CH), 109.5 (Ar,
CH), 101.5 (OCH2O), 87.7 (Ar, C), 40.9 (ArCH2), 38.9
(ArCH2); LRMS (APCI) 354 (96%, MHϩ), 227 (100%); Anal.
Found: C, 47.64; H, 3.41; N, 3.79. C14H12INO2 requires C,
47.61; H, 3.42; N, 3.97%.
(2-Bromophenyl)(3-pyridyl)methanol 29. tert-Butyllithium
(1.25 M in hexane, 8.30 mL, 10.38 mmol) was added dropwise
over 10 min to a cooled (Ϫ100 ЊC) solution of 3-bromopyridine
(1.0 mL, 1.64 g, 10.38 mmol) in Et2O (20 mL). After 1 h,
2-bromobenzaldehyde (1.25 mL, 1.98 g, 10.71 mmol) in Et2O
(20 mL) was added, dropwise over 5 min. The solution was
warmed to Ϫ60 ЊC over a period of 2 h and saturated sodium
chloride solution (90 mL) added along with THF (50 mL). The
organic phase was separated, dried (MgSO4), concentrated in
vacuo and purified by column chromatography (silica, 50 : 50,
Et2O : petrol) to give 29 (2.27 g, 8.59 mmol, 83%) as a white
solid; mp 125–126 ЊC (CHCl3) [Lit. 125–126 ЊC (ethyl acet-
ate)];24 IR (solid, cmϪ1) υmax 3091 br. m, 2826 w, 1589 w, 1564 w,
1434 m, 1315 w, 1178 w, 1108 w, 1055 m, 1018 w; UV (MeOH,
nm) λmax (εmax) 262 (1930); 1H NMR (400 MHz, CDCl3) δH 8.48
(1H, d, J 2.1 Hz, ArH ), 8.30 (1H, dd, J 4.4, 1.4 Hz, ArH ), 7.69
(1H, dt, J 7.4, 1.5 Hz, ArH ), 7.64 (1H, dd, J 8.1, 2.2 Hz, ArH ),
7.51 (1H, dd, J 8.1, 1.5 Hz, ArH ), 7.35 (1H, td, J 7.4, 1.5 Hz,
ArH ), 7.23–7.12 (2H, m, 2 × ArH ), 6.17 (1H, s, CHOH), 4.99
(1H, s, CHOH ); 13C NMR (75.5 MHz, CDCl3) δC 148.6 (Ar,
CH), 148.2 (Ar, CH), 142.3 (Ar, C), 138.7 (Ar, C), 135.3 (Ar,
CH), 133.0 (Ar, CH), 129.5 (Ar, CH), 128.5 (Ar, CH), 128.1
(Ar, CH), 123.7 (Ar, CH), 122.6 (Ar, C), 72.4 (Ar2CHOH);
LRMS (CI) 266 (4%, M(81Br)Hϩ), 264 (4%, M(79Br)Hϩ), 184
(10%, [M Ϫ Br]ϩ), 170 (100%), 169 (98%), 168 (82%), 167
(36%); Anal. Found: C, 54.53; H, 3.75; N, 5.14. C12H10BrNO
requires C, 54.57; H, 3.82; N, 5.30%.
4-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]pyridine 20. A mix-
ture of azastilbenes (Z)-5 and (E)-5 (500 mg, 1.42 mmol), tosyl
hydrazine (2.90 g, 15.6 mmol) and sodium acetate (1.28 g, 15.6
mmol) in THF (15 mL) and water (15 mL) were heated at reflux
for 72 h. After cooling to RT, potassium carbonate solution
(2M, 100 mL) was added. The reaction mixture was extracted
with Et2O (4 × 50 mL) and the combined organic phases were
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) to give 20 (460 mg, 1.30 mmol,
91%) as a white crystalline solid; mp 49–51 ЊC (Et2O); IR (solid,
cmϪ1) υmax 1601 m, 1501 m, 1475 s, 1228 s, 1039 s; UV (MeOH,
(2-Bromophenyl)(3-pyridyl)methanone 28. To a suspension of
MnO2 (4.00 g, 46 mmol, activated by azeotropic distillation
of toluene (15 mL)) in DCM (50 mL) was added alcohol 29
(500 mg, 1.89 mmol). After 18 h the residual solid was removed
by filtration through celite. Concentration in vacuo and purifi-
cation by column chromatography (silica, chloroform) gave
28 (485 mg, 1.85 mmol, 98%) as a colourless oil; IR (oil,
cmϪ1) υmax 3051 m, 2851 w, 1671 s, 1583 s, 1466 m, 1430 w, 1417
s, 1289 s, 1253 m, 1024 m; UV (MeOH, nm) λmax (εmax) 267
(5100), 235 (10100); 1H NMR (300 MHz, CDCl3) δH 8.89 (1H,
s, ArH ), 8.75 (1H, d, J 3.7 Hz, ArH ), 8.08 (1H, d, J 8.1 Hz,
ArH ), 7.61 (1H, d, J 7.4 Hz, ArH ), 7.43–7.27 (4H, m, 4 ×
ArH ); 13C NMR (75.5 MHz, CDCl3) δC 194.7 (Ar2CO),
154.0 (Ar, CH), 151.7 (Ar, CH), 139.6 (Ar, C), 137.1 (Ar, CH),
133.6 (Ar, CH), 132.0 (Ar, CH), 131.7 (Ar, C), 129.4 (Ar, CH),
127.7 (Ar, CH), 123.8 (Ar, CH), 119.6 (Ar, C); LRMS
(APCI) 305 (65%, [M(81Br) ϩ MeCN]ϩ), 303 (60%, [M(79Br) ϩ
MeCN]ϩ), 264 (100%, M(81Br)Hϩ), 262 (79%, M(79Br)Hϩ), 209
1
nm) λmax (εmax) 295 (4190), 244 (8170); H NMR (300 MHz,
CDCl3) δH 8.52 (2H, d, J 5.2 Hz, ArH ), 7.26 (1H, s, ArH ), 7.16
(2H, d, J 5.9 Hz, ArH ), 6.66 (1H, s, ArH ), 5.96 (2H, s,
OCH2O), 2.97–2.91 (2H, m, RCH2CH2R), 2.87–2.81 (2H, m,
RCH2CH2R); 13C NMR (75.5 MHz, CDCl3) δC 150.0 (Ar, C),
149.7 (Ar, 2 × CH), 148.5 (Ar, C), 147.0 (Ar, C), 136.4 (Ar, C),
124.0 (Ar, 2 × CH), 118.7 (Ar, CH), 109.3 (Ar, CH), 101.6
(OCH2O), 87.7 (Ar, C), 41.6 (ArCH2), 35.9 (ArCH2); LRMS
(ES) 395 (28%, [MH ϩ MeCN]ϩ), 354 (100%, MHϩ); Anal.
Found: C, 47.79; H, 3.43; N, 3.96. C14H12INO2 requires C,
47.61; H, 3.42; N, 3.97.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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(22%); HRMS (ES) Found: MNaϩ, 283.9680. C12H879BrNNaO
requires 283.9681.24,25
MHz, CDCl3) δC 159.7 (Ar, C), 148.6 (Ar, C), 147.6 (Ar, CH),
142.6 (Ar, C) 132.9 (Ar, CH), 129.3 (Ar, CH), 129.3 (Ar, CH),
128.0 (Ar, CH), 124.0 (Ar, CH), 123.3 (Ar, C), 122.2 (Ar, CH),
73.0 (Ar2CHOH), 21.3 (ArCH3); LRMS (CI) 280 (22%,
M(81Br)Hϩ), 278 (24%, M(79Br)Hϩ), 184 (59%), 119 (24%), 109
(55%), 94 (100%); Anal. Found: C, 56.03; H, 4.31; N, 4.93.
C13H12BrNO requires C, 56.14; H, 4.35; N, 5.04%.
(2-Bromophenyl)(2-pyridyl)methanol 33. n-Butyllithium (1.44
M in hexane, 2.19 mL, 3.15 mmol) was added dropwise over
2 min to a cooled (Ϫ90 ЊC) solution of 2-bromopyridine
(0.3 mL, 497 mg, 3.15 mmol) in THF (20 mL). The solution
turned dark brown immediately. 2-Bromobenzaldehyde (0.37
mL, 586 mg, 3.17 mmol) was then added dropwise over 1 min
causing the solution to turn light yellow. After 5 min saturated
ammonium chloride (50 mL) was added and the solution was
allowed to warm to RT over 30 min. The organic phase was
separated, washed with water (30 mL), dried (MgSO4), concen-
trated in vacuo and purified by column chromatography (silica,
1 : 4 – Et2O : petrol) and recrystallisation from petrol to give
33 (626 mg, 2.37 mmol, 75%) as a white solid; mp 77–79 ЊC
(petrol); IR (solid, cmϪ1) υmax 3371 br. m, 3070 w, 3018 w, 2927
w, 1594 s, 1571 m, 1472 s, 1438 s, 1402 s, 1191 m, 1062 m, 1022 s;
Radical reactions mediated by Bu3SnH
[1,3]Dioxolo[4Ј5Ј:4,5]benzo[f]quinoline 2.
A solution of
azastilbene 1 (600 mg, 1.71 mmol), Bu3SnH (0.6 mL, 649 mg,
2.23 mmol) and AIBN (20 mg, 0.122 mmol) in toluene
(140 mL) was heated at 80 ЊC under argon for 18 h. Further
portions of Bu3SnH (1.4 mL, 1.51 g, 5.20 mmol) and AIBN
(60 mg, 0.365 mmol) were then added and heating was con-
tinued for 24 h. After cooling to RT, a 2M KF solution (200
mL) was added and the biphasic mixture was stirred vigorously
for 24 h. The organic phase was separated, dried (MgSO4),
concentrated in vacuo and purified by column chromatography
(silica, Et2O) to yield 2 (180 mg, 0.81 mmol, 47%) as a pale
yellow crystalline solid; mp 200–201 ЊC (EtOH); IR (solid,
cmϪ1) υmax 1497 m, 1478 s, 1374 w, 1257 s, 1195 s, 1084 w, 1030 s;
UV (MeOH, nm) λmax (εmax) 286 (19400), 256 (12870), 237
(22130); 1H NMR (400 MHz, CDCl3) δH 8.91 (1H, dd, J 4.3, 1.5
Hz, ArH ), 8.75 (1H, d, J 8.4 Hz, ArH ), 7.95 (1H, s, ArH ), 7.90
(1H, d, J 9.1 Hz, ArH ), 7.86 (1H, d, J 9.1 Hz, ArH ), 7.51 (1H,
dd, J 8.4, 4.3 Hz, ArH ), 7.26 (1H, s, ArH ), 6.14 (2H, s,
OCH2O); 13C NMR (62.9 MHz, CDCl3) δC 149.1 (Ar, CH),
148.7 (Ar, C), 148.2 (Ar, C), 147.3 (Ar, C), 130.5 (Ar, CH),
130.2 (Ar, CH), 128.3 (Ar, C), 126.5 (Ar, CH), 125.9 (Ar, C),
125.2 (Ar, C), 121.0 (Ar, CH), 105.9 (Ar, CH), 101.6 (OCH2O),
100.7 (Ar, CH); LRMS (APCI) 224 (100%, MHϩ); Anal.
Found: C, 75.07; H, 4.06; N, 6.25. C14H9NO2 requires C, 75.33;
H, 4.06; N, 6.27%.
1
UV (MeOH, nm) λmax (εmax) 260 (4800); H NMR (300 MHz,
CDCl3) δH 8.58 (1H, d, J 5.2 Hz, ArH ), 7.66–7.57 (2H, m, 2 ×
ArH ), 7.40–7.12 (5H, m, 5 × ArH ), 6.27 (1H, s, Ar2CHOH),
5.64 (1H, s, Ar2CHOH ); 13C NMR (75.5 MHz, CDCl3)
δC 159.9 (Ar, C), 148.0 (Ar, CH), 142.4 (Ar, C), 137.2 (Ar, CH),
133.0 (Ar, CH), 129.4 (Ar, CH), 129.3 (Ar, CH), 128.1 (Ar,
CH), 123.3 (Ar, C), 122.9 (Ar, CH), 121.6 (Ar, CH), 73.2
(Ar2CHOH); LRMS (CI) 266 (9%, M(81Br)Hϩ), 264 (11%,
M(79Br)Hϩ), 170 (100%), 168 (38%), 94 (23%), 80 (21%);
HRMS (ES) Found: MHϩ, 264.0023. C12H11NO79Br requires
264.0024; Anal. Found: C, 54.47; H, 3.82; N, 5.23. C12H10BrNO
requires C, 54.57; H, 3.82; N, 5.30%.
(2-Bromophenyl)(2-pyridyl)methanone 32. To a suspension of
MnO2 (2.00 g, 23.0 mmol, activated by azeotropic distillation
of toluene (15 mL)) in DCM (50 mL) was added alcohol 33
(200 mg, 0.76 mmol). After 24 h the residual solid was removed
by filtration through celite. Concentration in vacuo and re-
crystallisation from ethanol yielded 32 (167 mg, 0.673 mmol,
84%) as a colourless solid; mp 72–73 ЊC (EtOH/petrol) [Lit. 63–
63.5];26 IR (solid, cmϪ1) υmax 3056 w, 2925 w, 2853 w, 1682 s,
1583 m, 1467 w, 1434 m, 1310 s, 1243 m, 1043 m, 1026 m; UV
[1,3]Dioxolo[4Ј5Ј:4,5]benzo[h]isoquinoline 7. A solution of
azastilbene 5 (450 mg, 1.28 mmol), Bu3SnH (0.45 mL, 487 mg,
1.67 mmol) and AIBN (20 mg, 0.122 mmol) in toluene
(110 mL) was heated at 80 ЊC under argon for 72 h. After co-
oling to RT, a 2M KF solution (100 mL) was added and the
biphasic mixture was stirred vigorously for 18 h. The organic
phase was separated, dried (MgSO4), concentrated in vacuo and
purified by column chromatography (silica, Et2O) and recrystal-
lisation from ethanol to yield 7 (280 mg, 1.25 mmol, 98%) as a
yellow solid; mp 182–183 ЊC (EtOH); IR (solid, cmϪ1) υmax 1739
m br., 1501 m, 1468 s, 1431 m, 1375 m, 1241 m, 1226 s, 1038 s;
UV (MeOH, nm) λmax (εmax) 354 (7090), 338 (5670), 322 (3670),
1
(MeOH, nm) λmax (εmax) 269 (5400), 235 (7300); H NMR (300
MHz, CDCl3) δH 8.69 (1H, d, J 4.4 Hz, ArH ), 8.17 (1H, d, J 8.1
Hz, ArH ), 7.92 (1H, td, J 8.1, 1.5 Hz, ArH ), 7.64 (1H, d, J 7.4
Hz, ArH ), 7.51–7.34 (4H, m, 4 × ArH ); 13C NMR (75.5 MHz,
CDCl3) δC 196.0 (Ar2CO), 153.6 (Ar, C), 149.5 (Ar, CH), 140.4
(Ar, C), 137.2 (Ar, CH), 133.2 (Ar, CH), 131.7 (Ar, CH), 130.0
(Ar, CH), 127.3 (Ar, CH), 127.2 (Ar, CH), 124.1 (Ar, CH),
120.2 (Ar, C); LRMS (CI) 264 (27%, M(81Br)Hϩ), 262 (26%,
M(79Br)Hϩ), 170 (100%), 168 (37%), 94 (19%), 80 (19%); Anal.
Found: C, 54.90; H, 3.02; N, 5.23. C12H8BrNO requires C,
54.99; H, 3.08; N, 5.34%.
1
280 (17590), 259 (32690), 237 (34190); H NMR (400 MHz,
CDCl3) δH 9.84 (1H, s, ArH ), 8.62 (1H, d, J 5.5 Hz, ArH ), 8.11
(1H, s, ArH ), 7.80 (1H, d, J 8.8 Hz, ArH ), 7.66 (1H, d, J 5.4
Hz, ArH ), 7.58 (1H, d, J 8.8 Hz, ArH ), 7.25 (1H, s, ArH ), 6.14
(2H, s, OCH2O); 13C NMR (62.9 MHz, CDCl3) δC 149.1 (Ar,
C), 148.2 (Ar, C), 146.7 (Ar, CH), 144.0 (Ar, CH), 135.0 (Ar,
C), 131.0 (Ar, CH), 128.9 (Ar, C), 125.8 (Ar, C), 125.0 (Ar, C),
123.2 (Ar, CH), 121.1 (Ar, CH), 106.1 (Ar, CH), 101.7
(OCH2O), 100.1 (Ar, CH); LRMS (APCI) 224 (100%, MHϩ);
Anal. Found: C, 75.14; H, 4.06; N, 6.25. C14H9NO2 requires C,
75.33; H, 4.06; N, 6.27%.
(2-Bromophenyl)(4-methyl-2-pyridyl)methanol 35. n-Butyl-
lithium (1.6 M in hexane; 3.7 mL, 5.92 mmol) was added
dropwise over 3 min to a cooled (Ϫ90 ЊC) solution of 2-bromo-
4-methylpyridine (1.00 g, 5.81 mmol) in THF (20 mL). After
30 min, a solution of 2-bromobenzaldehyde (1.08 g, 5.84 mmol)
in THF (5 mL) was added, dropwise over 3 min. After 2 h the
cooling bath was removed and the reaction was allowed to
warm to RT. After 2 h, saturated ammonium chloride (50 mL)
was added and the organic phase was separated, washed with
water (50 mL), dried (MgSO4), concentrated in vacuo and puri-
fied by column chromatography (silica, 2 : 3 – Et2O : petrol) to
give 35 (1.34 g, 4.83 mmol, 83%) as a beige solid; mp 78–80 ЊC
(ethanol/petrol); IR (solid, cmϪ1) υmax 3588 w, 3358 br. m, 3060
w, 2925 w, 1608 s, 1564 m, 1470 m, 1438 m, 1389 m, 1024 m; UV
(MeOH, nm) λmax (εmax) 257 (830); 1H NMR (300 MHz, CDCl3)
δH 8.44 (1H, d, J 4.4 Hz, ArH ), 7.59 (1H, dd, J 8.1, 1.5 Hz,
ArH ), 7.38–7.04 (5H, m, 5 × ArH ), 6.21 (1H, s, Ar2CHOH),
5.62 (1H, s, Ar2CHOH ), 2.31 (3H, s, ArCH3); 13C NMR (75.5
(E )-4-[2-(1,3-Benzodioxol-5-yl)-1-ethenyl]pyridine 8. A solu-
tion of azastilbene 6 (347 mg, 1.14 mmol), Bu3SnH (0.38 mL,
411 mg, 1.41 mmol) and AIBN (20 mg, 0.122 mmol) in toluene
(80 mL) was heated at 80 ЊC under argon for 24 h. After cooling
to RT, a 2M KF solution (40 mL) was added and the biphasic
mixture was stirred vigorously for 24 h. The organic phase was
separated, dried (MgSO4), concentrated in vacuo and purified
by column chromatography (silica, 3 : 7 – Et2O : petrol) to give 8
(250 mg, 1.11 mmol, 97%) as a white solid; mp 102–103 ЊC
(Et2O/petrol) [Lit. 98 ЊC (EtOH/water)];27 IR (solid, cmϪ1) υmax
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
4053

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3072 w, 3031 w, 2892 w, 1635 w, 1594 s, 1549 w, 1504 s, 1488 m,
1441 m, 1416 w, 1361 w, 1245 s, 1096 w, 1036 s; UV (MeOH,
nm) λmax (εmax) 336 (12700), 306 (8280), 239 (9500); H NMR
(4H, m, RCH2CH2R); NOE (400 MHz, CDCl3) Irradiation at
δH 7.80 led to no discernable enhancement; irradiation at δH
7.41 led to enhancement at δH 7.03 and δH 2.92–2.77; irradiation
at δH 6.66 led to enhancement at δH 2.92–2.77; 13C NMR (62.9
MHz, CDCl3) δC 152.9 (Ar, C), 148.7 (Ar, C), 148.0 (Ar, CH),
147.5 (Ar, C), 135.6 (Ar, CH), 133.2 (Ar, C), 131.3 (Ar, C),
129.2 (Ar, C), 121.9 (Ar, CH), 108.4 (Ar, CH), 105.8 (Ar, CH),
101.4 (OCH2O), 28.7 (ArCH2), 28.6 (ArCH2); LRMS (APCI)
226 (100%, MHϩ); Anal. Found: C, 74.53; H, 4.87; N, 6.21.
C14H11NO2 requires C, 74.65; H, 4.92; N, 6.22%. Then 13 (200
mg, 0.88 mmol, 35%) as a white solid; mp 26–27 ЊC (Et2O); IR
(solid, cmϪ1) υmax 1592 w, 1502 m, 1488 s, 1441 m, 1245 s, 1039 s;
UV (MeOH, nm) λmax (εmax) 287 (3670), 269 (3730), 263 (4140),
1
(300 MHz, CDCl3) δH 8.56 (2H, s, ArH ), 7.32 (2H, d, J 4.4 Hz,
ArH ), 7.21 (1H, d, J 15.4 Hz, RCH᎐CHAr), 7.08 (1H, s, ArH ),
᎐
6.98 (1H, d, J 7.0 Hz, ArH ), 6.84 (1H, d, J 7.0 Hz, ArH ), 6.83
(1H, d, J 15.4 Hz, RCH᎐CHR), 6.00 (2H, s, OCH O); 13C
᎐
2
NMR (75.5 MHz, CDCl3) δC 150.1 (Ar, 2 × CH), 148.3 (Ar, C),
148.3 (Ar, C), 144.8 (Ar, C), 132.8 (᎐CH), 130.6 (Ar, C), 124.1
᎐
(᎐CH), 122.6 (Ar, 2 × CH), 120.7 (Ar, CH), 108.5 (Ar, CH),
᎐
105.8 (Ar, CH), 101.4 (OCH2O); LRMS (APCI) 226 (100%,
MHϩ); Anal. Found: C, 74.62; H, 4.92; N, 6.16. C14H11NO2
requires C, 74.65; H, 4.92; N, 6.22%.
1
236 (4270); H NMR (400 MHz, CDCl3) δH 8.54 (1H, d, J 5.1
[1,3]Dioxolo[4Ј5Ј:4,5]benzo[h]quinoline 10 and [1,3]dioxolo-
[4Ј5Ј:4,5]benzo[f]isoquinoline 11. A solution of azastilbene 9
(735 mg, 2.09 mmol), Bu3SnH (0.70 mL, 757 mg, 2.60 mmol)
and AIBN (20 mg, 0.122 mmol) in toluene (150 mL) was heated
at 80 ЊC under argon for 90 h. After cooling to RT, a 2M KF
solution (100 mL) was added and the biphasic mixture was
stirred vigorously for 18 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) and recrystallisation from
ethanol to yield 10 (250 mg, 1.12 mmol, 54%) as a yellow solid;
mp 121–122 ЊC (EtOH); IR (solid, cmϪ1) υmax 1497 m, 1462 s,
1401 w, 1249 s, 1235 w, 1215 w, 1035 s; UV (MeOH, nm) λmax
Hz, ArH ), 7.56 (1H, td, J 7.6, 1.8 Hz, ArH ), 7.11 (1H, dd,
J 7.2, 4.9 Hz, ArH ), 7.07 (1H, d, J 7.7 Hz, ArH ), 6.70 (1H, d,
J 8.0 Hz, ArH ), 6.69 (1H, s, ArH ), 6.63 (1H, dd, J 7.8, 1.7 Hz,
ArH ), 5.91 (2H, s, OCH2O), 3.09–3.02 (2H, m, RCH2CH2R),
3.00–2.93 (2H, m, RCH2CH2R); 13C NMR (62.9 MHz, CDCl3)
δC 161.1 (Ar, C), 149.4 (Ar, CH), 147.5 (Ar, C), 145.7 (Ar, C),
136.3 (Ar, CH), 135.4 (Ar, C), 123.0 (Ar, CH), 121.2 (Ar, CH),
121.2 (Ar, CH), 109.0 (Ar, CH), 108.1 (Ar, CH), 100.8
(OCH2O), 40.5 (ArCH2), 35.7 (ArCH2); LRMS (APCI)
228 (100%, MHϩ); HRMS (ES) Found: MHϩ, 228.1028.
C14H14NO2 requires 228.1024. And finally 18 (187 mg, 0.83
mmol, 33%) as a white solid; mp 143–145 ЊC (EtOH); IR (solid,
cmϪ1) υmax 1744 m, 1712 m, 1502 s, 1457 m, 1365 m, 1237 s, 1114
m, 1030 s; UV (MeOH, nm) λmax (εmax) 326 (18220), 285
(13810); 1H NMR (400 MHz, CDCl3) δH 8.37 (1H, dd, J 5.1, 1.8
Hz, ArH ), 7.82 (1H, dd, J 7.8, 1.5 Hz, ArH ), 7.20 (1H, dd,
J 7.8, 4.8 Hz, ArH ), 7.17 (1H, s, ArH ), 6.75 (1H, s, ArH ), 5.98
(2H, s, OCH2O), 3.09–3.02 (2H, m, RCH2CH2R), 2.94–2.87
(2H, m, RCH2CH2R); NOE (400 MHz, CDCl3) Irradiation at
δH 7.82 led to enhancement at δH 7.20 and δH 7.17; irradiation
at δH 6.75 led to enhancement at δH 2.94–2.87; irradiation at
δH 3.09–3.02 led to no discernable enhancement; irradiation at
δH 2.94–2.87 led to enhancement at δH 6.75 and δH 3.09–3.02;
13C NMR (62.9 MHz, CDCl3) δC 157.1 (Ar, C), 147.6 (Ar, C),
147.2 (Ar, CH), 147.1 (Ar, C), 131.3 (Ar, C), 129.9 (Ar, CH),
129.8 (Ar, C), 126.6 (Ar, C), 122.2 (Ar, CH), 108.7 (Ar, CH),
104.2 (Ar, CH), 101.2 (OCH2O), 31.8 (ArCH2), 28.7 (ArCH2);
LRMS (APCI) 226 (100%, MHϩ); Anal. Found: C, 74.48; H,
4.85; N, 6.17. C14H11NO2 requires C, 74.65; H, 4.92; N, 6.22%.
1
(εmax) 334 (2590), 283 (36440), 254 (25800), 235 (44870); H
NMR (400 MHz, CDCl3) δH 8.93 (1H, dd, J 4.3, 1.7 Hz, ArH ),
8.64 (1H, s, ArH ), 8.12 (1H, dd, J 8.0, 1.7 Hz, ArH ), 7.67 (1H,
d, J 8.8 Hz, ArH ), 7.56 (1H, d, J 8.8 Hz, ArH ), 7.44 (1H, dd,
J 8.0, 4.3 Hz, ArH ), 7.22 (1H, s, ArH ), 6.12 (2H, s, OCH2O);
13C NMR (62.9 MHz, CDCl3) δC 148.9 (Ar, C), 148.6 (Ar, CH),
148.3 (Ar, C), 146.1 (Ar, C), 135.8 (Ar, CH), 130.3 (Ar, C),
128.2 (Ar, C), 127.1 (Ar, CH), 125.7 (Ar, C), 123.7 (Ar, CH),
121.0 (Ar, CH), 105.0 (Ar, CH), 102.4 (Ar, CH), 101.4
(OCH2O); LRMS (APCI) 224 (100%, MHϩ); Anal. Found: C,
75.03; H, 4.06; N, 6.18. C14H9NO2 requires C, 75.33; H, 4.06; N,
6.27%. A second fraction 11 (200 mg, 0.90 mmol, 43%) was also
recrystallised from EtOH, as a yellow solid; mp 182–183 ЊC
(EtOH); IR (solid, cmϪ1) υmax 1740 br. w, 1602 w, 1482 s, 1271 w,
1240 m, 1196 m, 1032 s; UV (MeOH, nm) λmax (εmax) 356 (4210),
339 (4450), 324 (3470), 277 (35870), 256 (39540); 1H NMR (400
MHz, CDCl3) δH 9.20 (1H, s, ArH ), 8.67 (1H, d, J 5.8 Hz,
ArH ), 8.19 (1H, d, J 5.8 Hz, ArH ), 7.98 (1H, s, ArH ), 7.73
(2H, s, ArH ), 7.26 (1H, s, ArH ), 6.15 (2H, s, OCH2O); 13C
NMR (62.9 MHz, CDCl3) δC 152.0 (Ar, CH), 149.3 (Ar, C),
148.6 (Ar, C), 144.5 (Ar, CH), 134.2 (Ar, C), 130.6 (Ar, C),
127.8 (Ar, CH), 126.5 (Ar, C), 124.7 (Ar, C), 123.3 (Ar, CH),
115.8 (Ar, CH), 106.0 (Ar, CH), 101.8 (OCH2O), 101.2 (Ar,
CH); LRMS (APCI) 224 (100%, MHϩ); Anal. Found: C, 75.06;
H, 4.06; N, 6.21. C14H9NO2 requires C, 75.33; H, 4.06; N,
6.27%.
4-[2-(1,3-Benzodioxol-5-yl)ethyl]pyridine 21, 5,6-dihydro-
[1,3]dioxolo[4Ј5Ј:4,5]benzo[h]isoquinoline 22 and 5,6-dihydro-
[1,3]dioxolo[4Ј5Ј:4,5]benzo[f]isoquinoline 23. A solution of
iodide 20 (500 mg, 1.42 mmol), Bu3SnH (0.48 mL, 519 mg, 1.78
mmol) and AIBN (20 mg, 0.122 mmol) in toluene (200 mL) was
heated at 80 ЊC under argon for 40 h. After cooling to RT, a 2M
KF solution (100 mL) was added and the biphasic mixture was
stirred vigorously for 18 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) to yield firstly a mixture of 21
and 22. Fractional crystallisation of that mixture from EtOH
gave firstly 22 (100 mg, 0.44 mmol, 31%) as a white crystalline
solid; mp 208–210 ЊC (EtOH); IR (solid, cmϪ1) υmax 1640 m br.,
1483 s, 1415 m, 1393 w, 1226 s, 1193 m, 1161 s, 1134 m, 1031 s;
UV (MeOH, nm) λmax (εmax) 322 (17320), 276 (12710), 238
2-[2-(1,3-Benzodioxol-5-yl)ethyl]pyridine 13, 5,6-dihydro-
[1,3]dioxolo[4Ј5Ј:4,5]benzo[f]quinoline 18 and 5,6-dihydro-
[1,3]dioxolo[4Ј5Ј:4,5]benzo[h]quinoline 19. A solution of iodide
12 (900 mg, 2.55 mmol), Bu3SnH (0.82 mL, 887 mg, 3.05 mmol)
and AIBN (20 mg, 0.122 mmol) in toluene (200 mL) was heated
at 80 ЊC under argon for 40 h. After cooling to RT, a 2M KF
solution (100 mL) was added and the biphasic mixture was
stirred vigorously for 18 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) to yield firstly 19 (156 mg, 0.69
mmol, 27%) as a pale yellow solid; mp 73–75 ЊC (EtOH/petrol);
IR (solid, cmϪ1) υmax 1568 w, 1495 m, 1483 m, 1450 s, 1416 w,
1374 w, 1326 w, 1288 w, 1234 s, 1037 s; UV (MeOH, nm) λmax
(εmax) 329 (10840), 290 (5070), 280 (4700); 1H NMR (400 MHz,
CDCl3) δH 8.45 (1H, dd, J 4.8, 1.8 Hz, ArH ), 7.80 (1H, s, ArH ),
7.41 (1H, ddt, J 7.6, 1.8, 0.8 Hz, ArH ), 7.03 (1H, dd, J 7.6, 4.8
Hz, ArH ), 6.66 (1H, s, ArH ), 5.93 (2H, s, OCH2O), 2.92–2.77
1
(24460); H NMR (400 MHz, MeOH) δH 8.89 (1H, s, ArH ),
8.46 (1H, d, J 5.3 Hz, ArH ), 7.60 (1H, d, J 5.3 Hz, ArH ), 7.22
(1H, s, ArH ), 6.68 (1H, s, ArH ), 6.05 (2H, s, OCH2O), 3.13–
3.07 (2H, m, RCH2CH2R), 2.93–2.87 (2H, m, RCH2CH2R);
NOE (400 MHz, MeOH) Irradiation at δH 8.89 led to
enhancement at δH 7.22; irradiation at δH 7.60 led to enhance-
ment at δH 8.46 and δH 3.13–3.07; irradiation at δH 3.13–3.07 led
to enhancement at δH 7.60 and δH 2.93–2.87; 13C NMR (62.9
MHz, MeOH) δC 163.7 (Ar, C), 157.4 (Ar, C), 151.5 (Ar, C),
140.9 (Ar, CH), 137.9 (Ar, CH), 136.3 (Ar, C), 134.4 (Ar, C),
127.4 (Ar, CH), 123.6 (Ar, C), 110.3 (Ar, CH), 105.8 (Ar, CH),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
4054

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103.6 (OCH2O), 30.4 (ArCH2), 28.2 (ArCH2); LRMS (APCI)
226 (100%, MHϩ), 186 (22%); Anal. Found: C, 74.50; H, 4.89;
N, 6.41. C14H11NO2 requires C, 74.65; H, 4.92; N, 6.22. Then 21
(100 mg, 0.44 mmol, 31%) as a white crystalline solid; mp 56–58
ЊC (pentane); IR (solid, cmϪ1) υmax 1600 m, 1489 s, 1443 m, 1416
m, 1243 s, 1191 m, 1037 s; UV (MeOH, nm) λmax (εmax) 287
at 100 ЊC under nitrogen for 30 h. After cooling to RT, a 2M KF
solution (50 mL) was added and the biphasic mixture was
stirred vigorously for 24 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, 4 : 1 – Et2O : petrol) to give 30 (120 mg,
0.655 mmol, 86%) as a white solid; mp 40–41 ЊC (petrol) [Lit.
32–34 ЊC];28 Anal. Found: C, 78.56; H, 4.98; N, 7.60. C12H9NO
requires C, 78.67; H, 4.95; N, 7.65%; other spectral and physical
data were in accord with the literature values.28
1
(4640), 263 (2700), 237 (6150); H NMR (250 MHz, CDCl3)
δH 8.48 (2H, dd, J 4.5, 1.6 Hz, ArH ), 7.06 (2H, dd, J 4.5, 1.6 Hz,
ArH ), 6.71 (1H, d, J 7.9 Hz, ArH ), 6.64 (1H, d, J 1.7 Hz,
ArH ), 6.57 (1H, dd, J 7.9, 1.6 Hz, ArH ), 5.92 (2H, s, OCH2O),
2.86 (4H, s, RCH2CH2R); 13C NMR (62.9 MHz, CDCl3)
δC 150.3 (Ar, C), 149.7 (Ar, 2 × CH), 147.7 (Ar, C), 145.9 (Ar,
C), 134.5 (Ar, C), 123.9 (Ar, 2 × CH), 121.2 (Ar, CH), 108.8
(Ar, CH), 108.2 (Ar, CH), 100.9 (OCH2O), 37.3 (ArCH2), 36.3
(ArCH2); LRMS (APCI) 228 (100%, MHϩ); Anal. Found: C,
74.02; H, 5.79; N, 6.11. C14H13NO2 requires C, 73.99; H, 5.77;
N, 6.16%. Further elution of the column led to 23 (58 mg, 0.26
mmol, 18%) as a pale yellow solid; mp 144–148 ЊC (Et2O); IR
(solid, cmϪ1) υmax 2909 s, 1593 m, 1552 w, 1504 m, 1481 s, 1415
(Phenyl)(3-pyridyl)methanol 31. A solution of bromide 29
(200 mg, 0.757 mmol), Bu3SnH (0.4 mL, 433 mg, 1.484 mmol)
and AIBN (12 mg, 0.073 mmol) in toluene (50 mL) was heated
at 100 ЊC under nitrogen for 30 h. After cooling to RT, a 2M KF
solution (50 mL) was added and the biphasic mixture was
stirred vigorously for 24 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) to give 31 (124 mg, 0.669 mmol,
88%) as a white solid; mp 65–66 ЊC (Et2O) [Lit. 67.5–69 ЊC];28
Anal. Found: C, 77.65; H, 5.99; N, 7.51. C12H11NO requires C,
77.81; H, 5.99; N, 7.56; other spectral and physical data were in
accord with the literature values.28
m, 1369 w, 1282 w, 1235 s, 1036 s; UV (MeOH, nm) λmax (εmax
)
326 (33500), 287 (17800); 1H NMR (400 MHz, CDCl3) δH 8.39
(1H, d, J 5.0 Hz, ArH ), 8.37 (1H, s, ArH ), 7.36 (1H, d, J 5.0
Hz, ArH ), 7.19 (1H, s, ArH ), 6.68 (1H, s, ArH ), 5.93 (2H, s,
OCH2O), 2.76 (4H, s, RCH2CH2R); NOE (400 MHz, CDCl3)
Irradiation at δH 8.39 led to enhancement at δH 7.36; irradiation
at δH 8.37 led to enhancement at δH 2.76; irradiation at δH 7.36
led to enhancement at δH 8.39 and δH 7.19; irradiation at δH 2.76
led to enhancement at δH 8.37 and δH 6.68; 13C NMR (100
MHz, CDCl3) δC 149.0 (Ar, C), 148.7 (Ar, CH), 148.6 (Ar,
CH), 147.5 (Ar, C), 142.4 (Ar, C), 133.4 (Ar, C), 131.4 (Ar, C),
125.8 (Ar, C), 117.4 (Ar, CH), 109.2 (Ar, CH), 104.9 (Ar, CH),
101.6 (OCH2O), 28.9 (ArCH2), 25.8 (ArCH2); LRMS (ES) 267
(13%, [MH ϩ MeCN]ϩ), 226 (16%, MHϩ); Anal. Found: C,
74.50; H, 4.92; N, 6.19. C14H11NO2 requires C, 74.65; H, 4.92;
N, 6.22%.
(2-Bromophenyl)(2-pyridyl)methanol 33. A solution of brom-
ide 32 (434 mg, 1.66 mmol), Bu3SnH (0.67 mL, 725 mg, 2.49
mmol) and AIBN (20 mg, 0.122 mmol) in toluene (150 mL) was
heated at 80 ЊC under argon for 24 h. After cooling to RT, a 2M
KF solution (100 mL) was added and the biphasic mixture was
stirred vigorously for 8 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, 1 : 4 – Et2O : petrol) to give firstly
recovered starting material 32 (223 mg, 0.851 mmol, 51%), then
alcohol 33 (210 mg, 0.795 mmol, 48%) as a white crystalline
solid. Data as described previously.
(Phenyl)(2-pyridyl)methanol 34. A solution of bromide 33
(300 mg, 1.14 mmol), Bu3SnH (0.37 mL, 400 mg, 1.37 mmol)
and AIBN (20 mg, 0.122 mmol) in toluene (80 mL) was heated
at reflux under argon for 100 h. After cooling to RT, a 2M KF
solution (100 mL) was added and the biphasic mixture was
stirred vigorously for 24 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, 2 : 3 – Et2O : petrol) to give 34 (200 mg,
1.08 mmol, 95%) as a white solid; mp 73–74 ЊC (Et2O) [Lit.
76–78 ЊC (distilled)];29 Anal. Found: C, 77.64; H, 6.05; N, 7.59.
C12H11NO requires C, 77.81; H, 5.99; N, 7.56%. Other spectral
data were in accord with the literature values.29
5,6-Dihydro[1,3]dioxolo[4Ј5Ј:4,5]benzo[f]quinoline 18, 5,6-
dihydro[1,3]dioxolo[4Ј5Ј:4,5]benzo[h]quinoline 19, 5,6-dihydro-
[1,3]dioxolo[4Ј5Ј:4,5]benzo[f]isoquinoline 22, 5,6-dihydro[1,3]-
dioxolo[4Ј5Ј:4,5]benzo[h]isoquinoline 22 and 3-[2-(1,3-benzo-
dioxol-5-yl)ethyl]pyridine 25. A solution of iodide 24 (200 mg,
0.566 mmol), Bu3SnH (0.20 mL, 216 mg, 0.744 mmol) and
AIBN (20 mg, 0.122 mmol) in toluene (150 mL) was heated
at 80 ЊC under argon for 48 h. After cooling to RT, a 2M KF
solution (100 mL) was added and the biphasic mixture was
stirred vigorously for 48 h. The organic phase was separated,
dried (MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) to yield firstly 19 (70 mg, 0.31
mmol, 42%); then 25 (58 mg, 0.26 mmol, 35%); mp 37–39 ЊC
(Et2O); IR (solid, cmϪ1) υmax 1503 m, 1490 s, 1443 m, 1246
s, 1191 m, 1039 s; UV (MeOH, nm) λmax (εmax) 287 (4420),
270 (4010), 263 (4280), 235 (5780); 1H NMR (250 MHz,
CDCl3) δH 8.44 (1H, dd, J 4.8, 1.6 Hz, ArH ), 8.40 (1H, d,
J 2.0 Hz, ArH ), 7.42 (1H, dt, J 7.8, 2.0 Hz, ArH ), 7.18 (1H,
ddd, J 7.8, 4.8, 0.8 Hz, ArH ), 6.70 (1H, d, J 7.9 Hz, ArH ),
6.64 (1H, d, J 1.6 Hz, ArH ), 6.56 (1H, dd, J 7.9, 1.7 Hz,
ArH ), 5.92 (2H, s, OCH2O), 2.92–2.79 (4H, m, RCH2CH2R);
13C NMR (62.9 MHz, CDCl3) δC 150.0 (Ar, CH), 147.6 (Ar,
CH), 147.5 (Ar, C), 145.9 (Ar, C), 136.7 (Ar, C), 135.9 (Ar,
CH), 134.6 (Ar, C), 123.2 (Ar, CH), 121.3 (Ar, CH), 108.9
(Ar, CH), 108.2 (Ar, CH), 100.8 (OCH2O), 37.2 (ArCH2),
35.2 (ArCH2); LRMS (APCI) 228 (100%, MHϩ); Anal.
Found: C, 73.94; H, 5.79; N, 6.20. C14H13NO2 requires C,
73.99; H, 5.77; N, 6.16%; then 18 (9.5 mg, 0.042 mmol, 6%);
and finally a 10 : 1 mixture of 23 and 22 (28 mg, 0.13 mmol,
17%).
(4-Methyl-2-pyridyl)(phenyl)methanol 36.
A solution of
bromide 35 (100 mg, 0.360 mmol), Bu3SnH (0.19 mL, 206 mg,
0.706 mmol) and AIBN (20 mg, 0.122 mmol) in toluene
(25 mL) was heated at reflux under argon for 5 h. After cooling
to RT, a 2M KF solution (100 mL) was added and the biphasic
mixture was stirred vigorously for 65 h. The aqueous phase was
extracted with ether (2 × 50 mL) and the combined organic
phases were washed with water (2 × 50 mL), dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography
(silica, 1 : 1 – Et2O : petrol) gave 36 (62 mg, 0.311 mmol, 87%) as
a beige solid; mp 84–86 ЊC (petrol) [Lit. 89–90 ЊC (distilled)];30
IR (solid, cmϪ1) υmax 3595 w, 3373 br. m, 3063 w, 3030 w, 2959 w,
2926 m, 2855 w, 1721 m, 1609 s, 1562 m, 1389 m, 1295 m, 1055
m; UV (MeOH, nm) λmax (εmax) 257 (4000); 1H NMR (300
MHz, CDCl3) δH 8.43 (1H, d, J 5.2 Hz, ArH ), 7.42–7.27 (5H,
m, 5 × ArH ), 7.03 (1H, d, J 4.4 Hz, ArH ), 6.97 (1H, s, ArH ),
5.72 (1H, s, Ar2CHOH), 5.32 (1H, s, Ar2CHOH ), 2.30 (3H, s,
ArCH3); 13C NMR (75.5 MHz, CDCl3) δC 160.8 (Ar, C), 148.3
(Ar, C), 147.6 (Ar, CH), 143.6 (Ar, C), 128.7 (Ar, 2 × CH),
127.9 (Ar, CH), 127.2 (Ar, 2 × CH), 123.8 (Ar, CH), 122.2 (Ar,
CH), 75.0 (Ar2CHOH), 21.3 (ArCH3); LRMS (CI) 200 (58%,
MHϩ), 199 (30%, Mϩ), 184 (100%, [M Ϫ CH3]ϩ), 94 (38%);
(Phenyl)(3-pyridyl)methanone 30. A solution of bromide 28
(200 mg, 0.763 mmol), Bu3SnH (0.40 mL, 433 mg, 1.484 mmol)
and AIBN (12 mg, 0.073 mmol) in toluene (50 mL) was heated
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 0 4 7 – 4 0 5 7
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Anal. Found: C, 78.47; H, 6.64; N, 7.04. C13H13NO requires C,
78.36; H, 6.58; N, 7.03%.
The aforementioned procedure was conducted using ethanol
(30 mL) as solvent and gave 7 (30 mg, 0.136 mmol, 48%) and 8
(33 mg, 0.147 mmol, 52%).
Radical cyclisation reactions of 5 and 20 using other
methodologies
Acknowledgements
(Me3Si)3SiH. A solution of iodide 5 (100 mg, 0.28 mmol),
(Me3Si)3SiH (0.132 mL, 106 mg, 0.428 mmol) and AIBN
(10 mg, 0.061 mmol) in toluene (30 mL) was heated at 80 ЊC
under nitrogen for 12 h. After cooling to RT, 2M NaOH (50
mL) was added. The aqueous phase was extracted with ether
(2 × 50 mL) and the combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by column
chromatography (silica, Et2O) gave 7 (63 mg, 0.28 mmol, 99%).
The aforementioned procedure was also applied to iodide 20
(100 mg, 0.28 mmol) giving 22 (25 mg, 0.11 mmol, 39%), 21
(10 mg, 0.045 mmol, 16%) and 23 (26 mg, 0.12 mmol, 41%).
The authors thank GlaxoSmithKline and the EPSRC for a
CASE award (to B. J. S.) and Joan Street and Neil Wells for
some invaluable NOE studies.
References and notes
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(Me3Si)3GeH. A solution of iodide 5 (100 mg, 0.28 mmol),
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under nitrogen for 12 h. After cooling to RT, 2M NaOH (30
mL) was added. The aqueous phase was extracted with ether
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97%).
The aforementioned procedure was also applied to iodide 20
(100 mg, 0.285 mmol) giving 22 (22 mg, 0.096 mmol, 34%), 21
(28 mg, 0.12 mmol, 16%) and 23 (12 mg, 0.053 mmol, 43%).
SmI2. To a cooled (0 ЊC) solution of iodide 5 (100 mg, 0.285
mmol) and HMPA (1 mL, 1.03 g, 5.75 mmol) in degassed THF
(20 mL) and under argon was added SmI2 in THF (0.1M,
10 mL, 1.00 mmol) dropwise over 5 min. The intense blue col-
our of the SmI2 turned deep purple. The cooling bath was
removed and after 18 h at RT, 2M K2CO3 (30 mL) was
added. The aqueous phase was extracted with diethyl ether (2 ×
30 mL) and the combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was then diluted
with chloroform (30 mL), washed with water (5 × 30 mL),
dried (MgSO4) and concentrated in vacuo. Purification by col-
umn chromatography (silica, Et2O) gave 7 (48 mg, 0.22 mmol,
75%).
10 D. C. Harrowven, M. I. T. Nunn, N. J. Blumire and D. R. Fenwick,
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14 The precise mechanism through which a hydrogen atom is lost from
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15 A 5-iodo-1,3-benzodioxole was chosen as the aryl radical precursor
in our survey of ortho- and ipso-cyclisation reactions to simplify the
task of product characterisation. The simplification of the aromatic
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of products with due rigour through NOE and related 2D NMR
techniques. In contemporaneous studies we have found that oxygen
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abstraction from tributyltin hydride.
16 Two practical considerations led us to employ aryl iodides rather
than aryl bromides in the ortho- and ipso-cyclisation reactions
described herein. Firstly, the dichotomy outlined in Scheme 3
showed that side reactions were more significant when aryl bromides
were employed. Secondly, with aryl bromides it was often necessary
to add substantial quantities of the initiator AIBN in order to bring
about complete conversion (on occasions, greater than a full
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bring about complete conversion using 5–20 mol% AIBN. The
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The aforementioned procedure was also applied to iodide 20
(100 mg, 0.28 mmol) giving 21 (52 mg, 0.23 mmol, 81%) as the
only isolated product.
(Bu3Sn)2, UV light and a triplet sensitiser. A solution of iod-
ide 5 (100 mg, 0.285 mmol), (Bu3Sn)2 (0.15 mL, 172 mg, 0.296
mmol) and 4-methoxyacetophenone (80 mg, 0.533 mmol) in
acetonitrile (100 mL), under nitrogen in a water cooled Quartz
photocell, was irradiated for 24 h using a sodium vapour lamp.
The reaction mixture was concentrated in vacuo and partitioned
between 2M NaOH (100 mL) and DCM (100 mL). The organic
phase was separated, dried (MgSO4), concentrated in vacuo
and purified by column chromatography (silica, Et2O) to give 7
(15 mg, 0.068 mmol, 24%) and recovered starting material 5
(64 mg, 64%).
‘Catalytic’ Bu3SnH. A THF (30 mL) solution of iodide 5 (100
mg, 0.285 mmol), Bu3SnH (0.02 mL, 21.6 mg, 0.074 mmol),
sodium borohydride (15 mg, 0.397 mmol) and AIBN (10 mg,
0.061 mmol) was heated at reflux under nitrogen for 12 h then
cooled to RT. 2M NaOH (30 mL) was added and after 10 min
the aqueous phase was separated and extracted with DCM
(2 × 30 mL). The combined organic phases were then dried
(MgSO4), concentrated in vacuo and purified by column
chromatography (silica, Et2O) to give 8 (46 mg, 0.204 mmol,
72%) as a pale yellow solid.
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