Synthetic applications of aryl radical building blocks for cyclisation onto azoles

Article abstract of DOI:10.1016/j.tet.2005.01.064

2-(2-Bromophenyl)ethyl groups have been used as building blocks in radical cyclisation reactions onto azoles to synthesise tri- and tetra-cyclic heterocycles. 2-(2-Bromophenyl)ethyl methanesulfonate was used to alkylate azoles (imidazoles, pyrroles, indol

Full text of DOI:10.1016/j.tet.2005.01.064

Tetrahedron 61 (2005) 2689–2696
Synthetic applications of aryl radical building blocks for
cyclisation onto azoles
a
a
a
Steven M. Allin,a W. Russell Bowman,a, Mark R. J. Elsegood, Vickie McKee, Rehana Karim
*
and Shahzad S. Rahmanb
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE1 3TU, GB
bGlaxoSmithKline, New Frontier Science Park North, Harlow, Essex CM19 5AW, GB
Received 2 September 2004; revised 21 December 2004; accepted 13 January 2005
Abstract—2-(2-Bromophenyl)ethyl groups have been used as building blocks in radical cyclisation reactions onto azoles to synthesise tri-
and tetra-cyclic heterocycles. 2-(2-Bromophenyl)ethyl methanesulfonate was used to alkylate azoles (imidazoles, pyrroles, indoles and
pyrazoles) for the synthesis of the radical precursors. Cyclisations of the intermediate aryl radicals yield new 6-membered rings attached to
the azoles. The aryl radicals undergo intramolecular homolytic aromatic substitution onto the azole rings. Tributylgermanium hydride
has been used with success to replace the toxic and troublesome tributyltin hydride. Initial studies show that the protocol can be used on
solid phase resins. The molecular and crystal structures of methyl 5,6-dihydroimidazo[5,1-a]iso-quinoline-1-carboxylate and methyl
5,6-dihydroimidazo[2,1-a]isoquinoline-3-carboxylate were determined by X-ray crystallography.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The use of radical cyclisations for the synthesis of
heterocyclic compounds has become commonplace.1 One
of the advances, that has proved most useful, is the
cyclisation of radicals onto heteroarenes to yield bi- and
tri-cyclic heterocycles. In these reactions, which are
mediated by Bu3SnH and related hydrides, the heteroarene
undergoes rearomatisation in the radical cyclisation. With
the use of NH-heteroarenes, N-alkylation provides a facile
route for the addition of ‘radical’ building blocks. These
Scheme 1. Radical building blocks.
units can then be used for cyclisation onto a range of
different NH-heteroarenes and also in other radical
cyclisations.
have been used in the cyclisation onto other heteroarenes
which include indoles4,5,6 pyrroles,4 pyridinium salts,7
1,2,3-triazoles,8 and quinolones.9 More recently, we have
shown that acyl radical building blocks (4) can be used for
cyclisation onto electron deficient pyrroles (pyrroles with
electron withdrawing groups).10
Our earlier studies have reported the application of N-(u-
phenylselanyl)alkyl 3 and N-(u-bromo)alkyl building
blocks for the cyclisation of N-(u-alkyl)-radicals onto
pyrroles,2 imidazoles2 and pyrazoles3 with electron with-
drawing groups or radical stabilising groups such as phenyl.
The protocol is illustrated in Scheme 1; a bicyclic
heterocycle (1) is synthesised via cyclisation of an
intermediate alkyl radical (2). The moiety (3) is added by
N-alkylation. Similar methodologies using alkyl radicals
The analogous use of these protocols to yield intermediate
aryl radicals instead of alkyl radicals can also be envisaged.
In this paper we report our studies of the development of the
use of components derived from 2-(2-bromophenyl)ethyl
groups (Scheme 2, e.g. (8)). The cyclisation of the
intermediate aryl radicals (9) yield new 6-membered rings
attached to the azoles (11). One of the aims of our study was
to develop building blocks to facilitate diversity for use in
Keywords: Aryl radicals; Radical cyclisation; Building blocks; Azoles;
Heterocycles.
* Corresponding author. Tel.: C44 1509 222569; fax: C44 1509 223925;
e-mail: w.r.bowman@lboro.ac.uk
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.064

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2. Discussion
We chose four different representative azole esters for
testing the ‘building block’ protocol. The esters were used in
each case to provide a handle for solid phase studies and to
facilitate lower electron density on the azole rings. Aryl
radicals are nucleophilic and therefore lower electron
density on the azole rings would help with cyclisation.
We have previously shown that electron withdrawing and/or
radical stabilising groups improve cyclisation.2,3
The alkylations were carried out by standard procedures
using sodium hydride (NaH) in DMF to deprotonate the
azoles followed by addition of 2-(2-bromophenyl)ethyl
methane-sulfonate (7) as shown in Scheme 2. In the
alkylation using 1H-imidazole-4-carboxylic acid methyl
ester (12) two products are possible due to the ambident
nature of the anion (Scheme 3). Alkylation with 1-iodo-2-
(iodomethyl)benzene (15) gave only the 4-ester product in
moderate yield. This regioselectivity was as expected from
studies of alkylation of other imidazoles with electron
withdrawing groups (e.g. aldehyde and nitro groups) in the
4/5-position.2 The nitrogen anion furthest from the ester (as
represented by the canonical form (13)) is more nucleophilic
than the nitrogen anion nearest to the ester (as represented
by the canonical form (14)) and normally facilitates
selective alkylation to yield the product with the substituent
in the 4-position (Scheme 3). Steric hindrance may also be a
factor in the regioselectivity. Surprisingly, alkylation with
2-(2-bromo-phenyl)ethyl methane-sulfonate (7) gave both
isomers (17) and (18). In the alkylation of 3-trifluoromethyl-
1H-pyrazole-4-carboxylic acid ethyl ester which could yield
two isomers, only the required isomer was obtained.
Scheme 2. General protocol for use of 2-(2-bromophenyl)ethyl building
blocks for the synthesis of tricyclic heterocycles.
solid phase synthesis and combinatorial chemistry. We also
report our further studies of the use of tributylgermanium
hydride (Bu3GeH) as the radical generating reagent in place
of the toxic and troublesome tributyltin hydride (Bu3SnH).11
Bu3GeH has a number of advantages over Bu3SnH which
include lower toxicity, better shelf life, ease of work-up and
slower rates of H-abstraction by intermediate radicals which
helps to facilitate cyclisation over reduction.
Building blocks which yield intermediate aryl radicals for
cyclisation onto heteroarenes and other functional groups
have been reported. For example, aryl radicals generated
from precursors synthesised from 2-bromobenzoyl chloride
(6) have been used in a number of reactions.12 The most
commonly used aryl radical entity has been pendant
N-(2-bromophenyl)methyl moieties synthesised using
(2-bromo-phenyl)methyl bromide (5), nZ1. Examples of
cyclisation using this unit include cyclisation onto
indoles,13,14 pyrroles,4 pyridones15 and 5-amino- and
5-hydroxyuracils.16
The analogous 2-(2-bromophenyl)ethyl components, which
generate new six-membered rings by cyclisation of aryl
radicals, have been less commonly used. These units have
been attached by N-alkylation with 2-(2-bromophenyl)ethyl
bromide (5), nZ2. Cyclisation onto indoles,13 pyridones15
and 2-quinolones17 has given high yields. In contrast, the
5-membered ring cyclisations of aryl radicals onto azoles
have proven less successful. Cyclisation onto 5-membered
ring azoles is less favoured due to the strain of formation of
products with two 5-membered rings, one of which is a
heteroarene.2 In our studies on the alkyl radical cyclisation
onto imidazoles, 6-membered ring cyclisation gave better
yields than 5-membered ring cyclisation, in which reduced
uncyclised products were also obtained. We showed using
X-ray crystallography that the structure of 6,7-dihydro-5H-
pyrrolo-[1,2-c]imidazole-1-carb-aldehyde is completely
planar indicating considerable strain in the new five-
membered ring.2
Scheme 3. Alkylation of 1H-imidazole-4-carboxylic acid methyl ester (12).
The radical cyclisations using Bu3SnH were carried using
syringe pump addition in order to maximise the chance of
cyclisation. Because of the slower H-abstraction from
Bu3GeH, the reagent was added in one portion at the
beginning of the reaction.11 Initially we compared the
cyclisation via a 5-membered ring versus cyclisation via a
6-membered ring in the imidazole system (Scheme 4). The
radical reaction between methyl 1-[(2-iodophenyl)methyl]-
1H-imidazol-4-carboxylate (16) and Bu3SnH or Bu3GeH
gave only the reduced uncyclised methyl 1-benzyl-1H-
imidazole-4-carboxylate. This is surprising for the Bu3GeH
reaction because the rate of H-abstraction from Bu3GeH is
Cyclisation onto heteroarenes of aryl radicals generated
from pendant 2-(2-bromophenyl)ethyl moieties, attached at
atoms other than the nitrogen, have also been reported.
Good yields have been reported for cyclisations onto
indoles,13 quinolines18 and pyridines19 showing that the
6-membered ring cyclisation is particularly favourable.

S. M. Allin et al. / Tetrahedron 61 (2005) 2689–2696
2691
(4%) and methyl 5,6-dihydro-imidazo[5,1-a]isoquinoline-
1-carboxylate (20) (16%) with no uncyclised reduced
material. These results further illustrate the strain involved
in 5-membered ring cyclisation on 5-membered ring azoles.
The use of Bu3GeH and tris-(trimethylsilyl)silane (TTMSS)
gave improved yields ((19) (19%), (20) (38%)] and [(19)
(30%), (20) (30%)), respectively. The latter results illustrate
the advantage of both Bu3GeH and TTMSS over Bu3SnH in
facilitating easier work-up and higher yields. The use of
Bu3GeH along with phenylthiol in a polarity reversal
catalysis (PRC)20 experiment gave only (20) in 44% yield.
The electrophilic phenylthiyl radical should intercept the
nucleophilic aryl radical intermediate at a faster rate than
the Bu3GeH and this may have a bearing on the selectivity.
The structures of (19) and (20) could not be positively
distinguished by normal analysis so the structure of (20) was
confirmed by X-ray crystallography (Fig. 1).
Cyclisation of methyl 1-[2-(2-bromophenyl)ethyl]-1H-imi-
dazole-5-carboxylate (18) yielded methyl 5,6-dihydroimi-
dazo-[2,1-a]isoquinoline-3-carboxylate (21) [Bu3SnH
(71%) and Bu3GeH (54%)] (Scheme 4). The structure of
(21) was also confirmed using X-ray crystallography (Fig.
2). The cyclisation of the intermediate aryl radicals derived
from (17) at both 2-C and 5-C, and from (18) at 2-C, is in
contrast to the cyclisation of alkyl radicals which only give
cyclisation at 5-C.2 The considerably higher reactivity of
aryl radical as compared to alkyl radicals is likely to be the
dominant factor in the difference.
Scheme 4. Radical cyclisation onto imidazoles.
ca. 20 times slower than for Bu3SnH and therefore should
favour cyclisation over reduction.
In contrast, reaction of 1-[2-(2-bromophenyl)ethyl]-1H-
imidazole-4-carboxylate (17) gave a mixture of methyl
5,6-dihydro-imidazo[2,1-a]isoquinoline-2-carboxylate (19)
In the radical reactions of the other azoles, the indole (22)
and the pyrrole (24) radical precursors were cyclised in
good yields using Bu3GeH to give methyl 5,6-dihydro-
indolo[2,1-a]isoquinoline-12-carboxylate (23) (68%) and
ethyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-carboxylate
(25) (82%), respectively (Scheme 5). The pyrazole
precursor (26a) was also cyclised in good yield using
Bu3GeH to give ethyl 2-(trifluoromethyl)-5,6-dihydro-
pyrazolo-[5,1-a]isoquinoline-1-carboxylate (27a) with no
other products (57%) (Scheme 6).
The overall mechanism of the radical cyclisations is shown
in Scheme 2. Formally the mechanisms of these radical
reactions are intramolecular aromatic homolytic substi-
tutions, i.e. hydrogen (H%) substituted by the cyclising aryl
radicals (9) via intermediate aromatic p-radicals (10).
Related Bu3SnH and AIBN mediated ‘oxidative’ cyclisa-
tions have also been reported for cyclisations onto arenes by
alkyl, vinyl and aryl and heteroaryl radicals. While previous
studies have centred on the use of Bu3SnH as the radical
generating reagent, we suggest that similar mechanisms
apply for the cyclisations using Bu3GeH or TTMSS. The
mechanism has been an area of debate and we refer readers
to our recent publication21 and a recent review22 which have
extensive discussion. Both publications contain full lists of
relevant references.
Figure 1. X-ray structure of methyl 5,6-dihydroimidazo[5,1-a]isoquino-
line-1-carboxylate (20) with atom labelling.
The pyrazole radical precursor (26a) was also used for
initial solid phase studies. The ester (26a) was hydrolysed to
the corresponding carboxylic acid (26b) and attached by
standard procedures to Wang resin. Cyclisation using
standard radical conditions but over a longer time, followed
Figure 2. X-ray structure of methyl 5,6-dihydroimidazo[2,1-a]isoquino-
line-3-carboxylate (21) with atom labelling.

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S. M. Allin et al. / Tetrahedron 61 (2005) 2689–2696
1
plates. H (250 MHz) and 13C (62.5 MHz) NMR spectra
were recorded on a Bruker AC-250 spectrometer as
solutions in CDCl3 with tetramethylsilane (TMS) as the
1
internal standard for H NMR spectra and deuteriochloro-
form the standard for 13C NMR spectra unless otherwise
specified. Chemical shifts are given in parts per million
(ppm) and J values in Hertz (Hz). Mass spectra were
recorded on a JEOL SX102 mass spectrometer or carried out
by the EPSRC Mass Spectrometry Service at University of
Wales, Swansea. All mass spectra are electron impact
spectra (EI) unless otherwise stated. TLC using silica gel as
absorbent was carried out with aluminium backed plates
coated with silica gel (Merck Kieselgel 60 F254). Column
chromatography was carried out using neutral alumina
unless otherwise specified.
Scheme 5.
Tributylgermanium hydride was prepared using literature
procedures.11,24
3.1.1. 2-(2-Bromophenyl)ethyl methanesulfonate (7).
Methanesulfonyl chloride (0.43 mL, 5.6 mmol) was added
to a solution of 2-(bromophenyl)ethyl alcohol (0.5 mL,
3.7 mmol) and triethylamine (1.54 mL, 11.1 mmol) in
toluene (30 mL) which was cooled to 0 8C. The reaction
mixture was stirred at room temperature for 18 h and then
extracted into water and DCM. The DCM layers were
combined and dried and evaporated under reduced pressure
to afford (7) as a pale yellow oil (1.0 g, 3.7 mmol, 99%);
nmax(neat) 3057, 3024, 2939, 1594, 1568, 1473, 1442, 1353,
1173, 1038, 1022, 958, 905, 858, 805, 755, 657 cmK1; dH
2.88 (3H, s, CH3), 3.21 (2H, t, JZ6.8 Hz, CH2), 4.45 (2H, t,
JZ6.8 Hz, OCH2), 7.11–7.15 (1H, m, ArH), 7.28–7.29
(2H, m, ArH), 7.55 (1H, d, JZ8.1 Hz, Ar-3-H); dC 35.86
(2-CH2), 37.2 (CH3), 68.5 (OCH2), 124.4 (Ar-2-C), 127.7,
128.9, 131.5 and 132.9 (Ar-3,4,5,6-C), 135.6 (Ar-1-C); m/z
278 (MC, 3), 220 (26), 182 (68), 169 (100), 103 (38), 90
(40), 77 (34%); HRMS: MC, found: MC, 277.9611.
C9H11BrO3S requires 277.9612.
Scheme 6. (i) NaOH, EtOH, reflux, 8 h, 97% (26b); (ii) Wang resin
(swollen in DCM), DMF, DMAP. DIC, 48 h; (iii) Bu3GeH or TTMSS,
AIBN, toluene, reflux, 30 h; (iv) TFA, DCM (9:1).
by cleavage from the resin with TFA, yielded a mixture of
products. The use of Bu3GeH gave (27b) (20%) and
unreacted starting acid (26b) (70%).
The use of TTMSS gave a better yield of cyclised pyrazole
(27b) (53%) but also yielded reduced uncyclised (26c)
(27%). Although the results were disappointing as com-
pared to the solution phase reaction, the results do give
further indication that radical chemistry can be used for
solid phase synthesis.23
3.1.2. 1-Iodo-2-(iodomethyl)benzene (15). A solution of
1-iodo-2-(chloromethyl)benzene (10.0 g, 39.6 mmol) and
sodium iodide (30.0 g, 0.20 mol) in dry acetonitrile
(250 mL) was heated under reflux for 18 h. The precipitated
sodium chloride was removed by filtration on a Celitew bed
and the solution was evaporated under reduced pressure.
The residue was triturated with diethyl ether and the
solution filtered a second time. The ether solution was
evaporated under reduced pressure to afford (15) as a dark
brown oil (13.48 g, 39.2 mmol, 99%). Found: MC,
343.8552. C7H6I2 requires 343.8559); nmax(neat) 2360,
2342, 1580, 1560, 1464, 1433, 1424, 1273, 1212, 1152,
1012, 827, 757, 644 cmK1; dH 4.54 (2H, s, CH2), 6.92 (1H,
dd, JZ7.6, 7.6 Hz, 5-H), 7.28 (1H, dd, JZ7.6, 7.6 Hz, 4-H),
7.47 (1H, d, JZ7.6 Hz, 3-H), 7.80 (1H, d, JZ7.6 Hz, 6-H);
dC 12.2 (CH2), 99.7 (1-C), 129.3, 129.6 and 129.8 (3,4,5-C),
140.23 (6-C), 141.4 (2-C); m/z 344 (MHC, 5), 254 (12), 217
(100), 90 (47%).
3. Experimental
3.1. General
Commercial dry solvents were used in all reactions except
for light petroleum and ethyl acetate which were distilled
from CaCl2 and dichloromethane (DCM) was distilled over
phosphorus pentoxide. Light petroleum refers to the bp
40–60 8C fraction. Sodium hydride was obtained as 60%
dispersion in oil and was washed with light petroleum.
Melting points were determined on an Electrothermal 9100
melting point apparatus and are uncorrected. Elemental
analyses were determined on a Perkin Elmer 2400 CHN
Elemental Analyser in conjunction with a Perkin Elmer
AD-4 Autobalance. IR spectra were recorded on a Perkin-
Elmer Paragon 1000 FT-IR spectrophotometer on NaCl
3.2. General procedure for alkylation
The azole was added slowly to a suspension of NaH
(1.5 equiv) in dry DMF (40 mL). The mixture was stirred
and heated at 80 8C for 1 h. A solution of the alkylating

S. M. Allin et al. / Tetrahedron 61 (2005) 2689–2696
2693
agent (1.5 equiv) in DMF (10 mL) was added drop wise to
the reaction mixture which was heated at 80 8C for a further
12 h. The salts were removed by filtration on a Celitew bed
and the solution evaporated under reduced pressure to yield
the crude product. The crude product was purified by
column chromatography using light petroleum/ethyl acetate
(1:4) as the eluent.
7.42 (1H, m), 7.57 (1H, dd, JZ7.2, 2.0 Hz, Ar-3-H), 7.70
(1H, s, 2-H), 8.15–8.19 (1H, m, indole 4-H); dC 37.1 (CH2),
46.6 (NCH2), 51.0 (OCH3), 107.2 (3-C), 109.9 (7-C), 121.8,
121.9 and 122.8 (4,5,6-C), 124.2 (Ar-2-C), 126.6 (3a-C),
127.8, 128.9, 131.1, 133.1 and 134.2 (2-C and Ar-3,4,5,6-
C), 136.4 and 136.8 (7a-C and Ar 1-C), 165.5 (C]O); m/z
357 (MC, 14), 278 (8), 138 (100), 129 (10), 77 (8%); HRMS:
found: MC, 357.0371. C18H16BrNO2 requires 357.0364.
3.2.1. Methyl 1[(2-iodophenyl)methyl]-1H-imidazole-4-
carboxylate (16). Colourless oil (43%); nmax(neat)/cmK1
2947, 1718, 1545, 1437, 1380, 1224, 1204, 1119, 1014, 765,
742, 660; dH 3.88 (3H, s, CH3), 5.20 (2H, s, CH2), 7.02 (1H,
dd, JZ7.6, 1.2 Hz, Ar-6-H), 7.07 (1H, ddd, JZ7.6, 7.6,
1.2 Hz, Ar-4-H), 7.36 (1H, ddd, JZ7.6, 7.6, 1.2 Hz, Ar-5-
H), 7.59 (1H, s, 2- or 5-H), 7.60 (1H, s, 2- or 5-H), 7.89 (1H,
dd, JZ7.6, 1.2 Hz, Ar-3-H); dC 51.7 (CH3), 55.86 (CH2),
98.6 (Ar-2-C), 125.4, 129.1, 129.2 and 130.5 (5-C and Ar-
4,5,6-C), 134.1 (4-C), 137.4 (Ar-1-C), 138.4 and 140.2 (2-C
and Ar-3-C), 163.2 (C]O); m/z 342 (MC, 27), 311 (12),
284 (13), 217 (100), 183 (46), 121 (15), 90 (43%); HRMS:
found: MC, 341.9860. C12H11IN2O2 requires 341.9865).
3.2.4. Ethyl 1-[2-(2-bromophenyl)ethyl]-1H-pyrrole-2-
carboxylate (24). Pale yellow oil (97%); nmax(neat) 3109,
3056, 2979, 2869, 1694, 1567, 1531, 1470, 1415, 1325,
1241, 1171, 1101, 1077, 1027, 917, 738, 657 cmK1; dH 1.36
(3H, t, JZ7.2 Hz, CH3), 3.20 (2H, t, JZ7.2 Hz, CH2), 4.30
(2H, q, JZ7.2 Hz, OCH2), 4.52 (2H, t, JZ7.2 Hz, NCH2),
6.02 (1H, dd, JZ3.9, 2.5 Hz, 4-H), 6.59 (1H, dd, JZ2.5,
1.9 Hz, 3- or 5-H), 6.95 (1H, dd, JZ3.9, 1.9 Hz, 3- or 5-H),
7.02–7.16 (3H, m, Ar-4, 5,6-H), 7.53 (1H, dd, JZ7.9,
1.2 Hz, Ar-3-H); dC 14.5 (CH3), 37.2 (CH2), 48.7 (NCH2),
59.8 (OCH2), 107.8 (3-C), 118.2 (4-C) 124.4 (Ar-2-C),
128.3 (pyrrole 5-C), 121.6, 126.7, 127.5, 131.3 and 132.7
(2-C, Ar-3,4,5,6-C), 137.7 (Ar-1-C), 161.1 (C]O); m/z 321
(MC, 2), 276 (11), 242 (100), 169 (98), 152 (22), 124 (100),
103 (24), 94 (46), 77 (25%); HRMS: found: MC, 321.0367.
C15H16BrNO2 requires 321.0364.
3.2.2. Methyl 1-[2-(2-bromophenyl)ethyl]-1H-imidazole-
4-carboxylate (17) and methyl 1-[2-(2-bromophenyl)-
ethyl]-1H-imidazole-5 carboxylate (18). (17), pale yellow
oil (50%), nmax(neat) 2948, 1724, 1547, 1472, 1439, 1382,
1225, 1197, 1120, 1029, 997, 757, 660 cmK1; dH 3.10 (2H,
t, JZ7.2 Hz, CH2), 3.79 (3H, s, OCH3), 4.16 (2H, t, JZ
7.2 Hz, NCH2), 6.88 (1H, dd, JZ7.2, 1.6 Hz, Ar-6-H), 7.04
(1H, ddd, JZ7.6, 7.6, 1.6 Hz, Ar-4- or 5-H), 7.11 (1H, ddd,
JZ7.6, 7.6, 1.6 Hz, Ar-4- or 5-H), 7.24 (1H, s, 5-H), 7.47–
7.50 (2H, m, imidazole 2-H and Ar-3-H); dC 37.04 (CH2),
45.95 (NCH2), 50.61 (OCH3), 123.16 (Ar-2-C), 124.11,
126.98, 128.14, 129.97 and 132.18 (5-C and Ar-3,4,5,6-C),
132.84 and 134.93 (4-C and Ar-1-C), 136.89 (imidazole
2-C), 162.19 (C]O); m/z 309 (MHC, 1), 229 (34), 197 (95),
169 (52), 115 (53), 108 (100), 89 (68), 77 (69), 53 (77%).
HRMS: found: MC, 308.0157. C13H13BrN2O2 requires
308.0160. Further elution yielded the other regioisomer (18)
as a colourless crystalline powder (48%), mp 92.0–95.9 8C.
(Found: C, 50.29; H, 4.05; N, 9.25. C13H13BrN2O2 requires
C, 50.50; H, 4.24; N, 9.06%); nmax(KBr) 3079, 1715, 1539,
1475, 1437, 1362, 1236, 1162, 1108, 1025, 947, 867, 761,
660 cmK1; dH 3.22 (2H, t, JZ7.0 Hz, CH2), 3.89 (3H, s,
OCH3), 4.55 (2H, t, JZ7.0 Hz, NCH2), 6.98 (1H, d, JZ
7.4 Hz, Ar 6-H), 7.10 (1H, ddd, JZ7.4, 7.4, 1.9 Hz, Ar-4- or
5-H), 7.17 (1H, ddd, JZ7.4, 7.4, 1.9 Hz, Ar-4- or 5-H), 7.28
(1H, s, 4-H), 7.56 (1H, d, JZ7.4 Hz, Ar-3-H), 7.73 (1H, s,
2-H); dC 37.7 (CH2), 46.4 (NCH2), 51.5 (OCH3), 122.1
(5-C), 124.4 (Ar-2-C), 127.8, 128.7, 131.1 and 133.0
(Ar-3,4,5,6-C), 136.8 (Ar-1-C), 138.0 (4-C), 142.1 (2-C),
160.7 (C]O); m/z 309 (MHC, 1), 277 (2), 229 (100), 197
(15), 182 (8), 169 (25), 103 (18), 89 (13), 77 (29%); HRMS:
found: MHC, 309.0239. C13H13BrN2O2 requires 309.0238).
3.2.5. Ethyl 1-[2-(2-bromophenyl)ethyl]-3-(trifluoro-
methyl)-1H-pyrazole-4-carboxylate (26a). Pale yellow
oil (85%); nmax(neat) 3135, 3070, 2984, 1732, 1543, 1474,
1443, 1368, 1303, 1223, 1143, 1054, 847, 776, 752 cmK1
;
dH 1.33 (3H, t, JZ7.2 Hz, CH3), 3.32 (2H, t, JZ7.2 Hz,
CH2), 4.30 (2H, q, JZ7.2 Hz, OCH2), 4.42 (2H, t, JZ
7.2 Hz, NCH2), 6.99 (1H, dd, JZ7.4, 1.8 Hz, Ar-6-H), 7.12
(1H, ddd, JZ7.5, 7.5, 1.2 Hz, Ar-4- or 5-H), 7.20 (1H, ddd,
JZ7.5, 7.5, 1.6 Hz, Ar-4- or 5-H), 7.58 (1H, dd, JZ7.5,
1.2 Hz, Ar-3-H), 7.74 (1H, s, pyrazole 5-H); dC 14.1 (CH3),
36.8 (CH2), 52.4 (NCH2), 60.9 (OCH2), 113.0 (CF3), 119.1,
121.7 and 124.3 (3-C, 4-C, Ar-2-C), 127.9, 129.1, 131.1,
133.2 and 135.8 (5-C, Ar-3.4.5.6-C), 136.1 (Ar-1-C), 160.8
(C]O); m/z 391 (MC, 1), 345 (10), 311 (100), 283 (29), 265
(18), 182(100), 169 (48), 103 (78), 77 (51%); HRMS: found:
MHC, 391.0269. C15H14BrF3N2O2 requires 391.0269.
3.3. General procedure for radical reactions
Bu3SnH. A deoxygenated solution of Bu3SnH (2.2 equiv) in
toluene was added drop wise using a syringe pump to a
solution of the radical precursor (0.25–1.0 mmol) in
anhydrous toluene under reflux under an atmosphere of
nitrogen. The radical initiator (AIBN) was added, followed
by heating under reflux for the time indicated for each
reaction. AIBN (1.2 equiv) was added portion-wise every
45 min. The solution was refluxed for a further set time. The
basic products were extracted from the cooled reaction
mixture with dilute hydrochloric acid and the acidic extracts
washed with light petroleum to remove Bu3Sn-residues. The
acidic aqueous layer was basified with sodium carbonate
and aqueous sodium hydroxide (few drops) to pH 14 and
extracted with DCM. The organic extracts were dried and
evaporated under reduced pressure. The residues were
3.2.3. Methyl 1-[2-(2-bromophenyl)ethyl]-1H-indole-3-
carboxylate (22). Colourless crystals (40%), mp 111.7–
112.8 8C. (Found: C, 60.84; H, 4.27; N, 3.80. requires C,
60.35; H, 4.50; N, 3.91%); nmax(KBr) 2946, 1696, 1534,
1470, 1442, 1267, 1224, 1162, 1116, 1093, 1026, 747 cmK1
;
dH 3.27 (2H, t, JZ7.6 Hz, CH2), 3.90 (3H, s, OCH3), 4.40
(2H, t, JZ7.6 Hz, NCH2), 6.93 (1H, dd, JZ7.2, 2.0 Hz, 7-H
or Ar-6-H), 7.08–7.16 (1H, m), 7.25–7.30 (1H, m), 7.40–
1
analysed by H NMR spectroscopy and TLC. The crude
residues were purified by column chromatography.

2694
S. M. Allin et al. / Tetrahedron 61 (2005) 2689–2696
Bu3GeH. The procedure was the same as the procedure for
Bu3SnH radical reactions except that the Bu3GeH
(1.5 equiv) was added in one portion at the beginning of
the reaction instead of addition using a syringe pump.
of other unidentifiable materials. The yield of unaltered
starting material was not recorded.
Tris(trimethylsilyl)silane (TTMSS). The general procedure
for Bu3SnH reactions was used except that TTMSS was
used in place of Bu3SnH. Reflux (5 h addition, 5 h further
reflux), (20) (30%), (19) (30%).
3.3.1. Methyl 1-benzyl-1H-imidazole-4-carboxylate
(16a). Bu3SnH. Reflux 7 h, methyl 1-benzyl-1H-imida-
zole-4-carboxylate as a colourless oil (16a) (33%);
nmax(neat) 2363, 1720, 1545, 1440, 1380, 1224, 1119,
997, 713 cmK1; dH 3.88 (3H, s, OCH3), 5.14 (2H, s, CH2),
7.17–7.20 (2H, m, Ar-H), 7.25–7.26 (1H, m, Ar-H), 7.37–
7.41 (2H, m, Ar-H), 7.56 (1H, s, 2- or 5-H), 7.60 (1H, m, 2-
or 5-H); dC 51.4 (CH2), 51.73 (OCH3), 118.6 (4-C), 125.4,
127.6, 128.8 and 129.2 (5-C and Ph-2,3,4-C), 138.1 (2-C),
142.9 (Ph-1-C), 163.2 (C]O); m/z 216 (MC, 10), 185 (5),
158 (8), 128 (4), 91 (100), 77 (8), 65 (18%); HRMS: found:
MHC, 217.0976. C12H12N2O2 requires 217.0977.
3.3.3. Methyl 5,6-dihydroimidazo[2,1-a]isoquinoline-3-
carboxylate (21). Bu3SnH. Reflux (5 h addition, 7 h further
reflux), colourless crystals (71%), mp 122.0–124.9 8C;
nmax(KBr) 2372, 1710, 1509, 1441, 1387, 1337, 1252,
1184, 1108, 1072, 980 cmK1; dH 3.17 (2H, t, JZ7.2 Hz,
6-CH2), 3.88 (3H, s, OCH3), 4.62 (2H, t, JZ7.2 Hz, NCH2),
7.26–7.28 (1H, m), 7.33–7.39 (2H, m), 7.83 (1H, s, 2-H),
8.07 (1H, m, 10-H); dC 28.1 (6-C), 42.2 (5-C), 51.5 (OCH3),
122.1 (3-C), 126.2 (10a-C), 124.7, 127.6, 127.7 and 129.8
(7,8,9,10-C), 133.2 (6a-C), 137.9 (imidazole 2-C), 148.3
(10b-C), 161.0 (C]O); m/z 228 (MC, 100), 213 (8), 197
(42), 183 (7), 169 (17), 140 (13), 128 (17), 115 (35), 84
(29%); HRMS: found: MHC, 229.0981. (C13H12N2O2CH)
requires 229.0977. The structure was confirmed using X-ray
crystallography.
Bu3GeH. 10 h reflux, methyl 1-benzyl-1H-imidazole-4-
carboxylate (56%). The TLC and H NMR and IR spectra
were identical to an authentic sample.
1
3.3.2. Methyl 5,6-dihydroimidazo[5,1-a]isoquinoline-1-
carboxylate (20) and methyl 5,6-dihydroimidazo[2,1-a]-
isoquinoline-2-carboxylate (19). Bu3SnH. Reflux (5 h
addition, 5 h further reflux), (20) as crystalline colourless
needles (16%), mp 179.0–182.9 8C; nmax(KBr) 3118, 2951,
2368, 1689, 1546, 1469, 1432, 1347, 1217, 1182, 1164,
1107, 939, 769, 655 cmK1; dH 3.10 (2H, t, JZ6.5 Hz,
6-CH2), 3.96 (3H, s, OCH3), 4.17 (2H, t, JZ6.5 Hz, NCH2),
7.27 (1H, dd, JZ8.0, 1.0 Hz, 7-H), 7.32 (1H, ddd, JZ8.0,
8.0, 1.0 Hz, 8- or 9-H), 7.38 (1H, ddd, JZ8.0, 8.0, 1.0 Hz, 8-
or 9-H), 7.54 (1H, s, 3-H), 8.74 (1H, dd, JZ8.0, 1.0 Hz,
10-H); dC 29.6 (5-C), 42.5 (6-C), 51.9 (OCH3), 125.9 (1-C),
127.6, 127.8, 128.4 and 129.1 (7,8,9,10-C), 128.2, 133.0 and
133.8 (6a,10a,10b-C), 135.5 (3-C), 164.2 (C]O); m/z 228
(MC, 74), 197 (100), 170 (54), 140 (13), 115 (25%); HRMS:
found: MC, 228.0900. C13H12N2O2 requires 228.0900. The
structure was confirmed by X-ray crystallography.
Bu3GeH. Reflux (10 h), (54%) starting material (18) (20%).
3.3.4. Methyl 5,6-dihydroindolo[2,1-a]isoquinoline-12-
carboxylate (23). Bu3GeH. Clear oil (68%); nmax(neat)
2947, 1698, 1530, 1468, 1455, 1404, 1282, 1224, 1188,
1154, 1110, 1022, 768, 747 cmK1; dH 3.15 (2H, t, JZ
6.5 Hz, 5-CH2), 3.99 (3H, s, OCH3), 4.24 (2H, t, JZ6.5 Hz,
NCH2), 7.25–7.40 (6H, m), 8.19 (1H, m, 11-H) and 8.53
(1H, dd, JZ7.2, 1.8 Hz, 1-H); dC 29.7 (5-C), 40.4 (6-C),
51.1 (OCH3), 103.0 (12-C), 109.1 (8-C), 122.0, 122.4,
122.9, 126.7, 127.7, 129.3 and 129.7 (1, 2, 3, 4, 9, 10, 11-C),
133.2, 134.8, 135.3, 138.0 and 134.0 (4a, 7a, 11a, 12a, 12b-
C), 166.4 (C]O); m/z 277 (MC, 100), 246 (92), 217 (38),
188 (30), 108 (14), 77 (9%); HRMS: found: MC, 277.1104.
C18H15NO2 requires 277.1103.
3.3.5. Ethyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-3-
carboxylate (25). Bu3GeH. Clear oil (82%); nmax(neat)
2928, 1694, 1489, 1446, 1260, 1224, 1150, 1105, 1068,
749 cmK1; dH 1.37 (3H, t, JZ7.1 Hz, CH3), 3.08 (2H, t, JZ
6.8 Hz, CH2), 4.31 (2H, q, JZ7.1 Hz, OCH2), 4.64 (2H, t,
JZ6.8 Hz, NCH2), 6.52 (1H, d, JZ4.0 Hz, 1-H), 7.02 (1H,
d, JZ4.0 Hz, 2-H), 7.20–7.28 (3H, m, 7,8,9-H), 7.56 (1H, d,
JZ7.6 Hz, Ar 10-H); dC 14.5 (CH3), 28.9 (6-CH2), 42.2
(NCH2), 59.8 (OCH2), 104.4 (1-C), 118.2 (2-C), 113.7 and
122.1 (3,10b-C), 123.6, 127.1, 127.4 and 128.4 (7,8,9,10-C),
131.7 (10a-C), 136.0 (6a-C), 161.4 (C]O); m/z 241 (MC,
100), 213 (39), 196 (28), 168 (32), 139 (11), 115 (11), 77
(3%); HRMS: found: MC, 241.1103. C15H15NO2 requires
241.1103.
Further elution yielded (19) as a pale yellow oil (4%);
nmax(neat) 3134, 2953, 2925, 2359, 1723, 1542, 1461, 1437,
1349, 1326, 1258, 1225, 1199, 1181, 1124, 1103, 1006, 808,
777, 737, 718 cmK1; dH 3.11 (2H, t, JZ7.2 Hz, 6-CH2),
3.84 (3H, s, OCH3), 4.15 (2H, t, JZ7.2 Hz, NCH2), 7.17
(1H, dd, JZ6.8, 2.0 Hz, 7-H), 7.23–7.30 (2H, m, 8,9-H),
7.58 (1H, s, 3-H), 8.10 (1H, dd, JZ7.6, 2.0 Hz, 10-H); dC
27.2 (6-C), 42.7 (5-C), 50.8 (OCH3), 123.5, 124.4, 126.7,
126.8 and 128.3 (3.7,8,9,10-C), (C), 125.1 (2-C), 127.3 and
131.7 (6a,10a-C), 144.0 (10b-C), 162.5 (C]O); m/z 228
(MC, 100), 197 (92), 170 (75), 140 (12), 115 (28), 77 (10%);
HRMS: found: MC, 228.0900. C13H12N2O2 requires
228.0900. A considerable amount of the two products was
also obtained as a mixture after chromatography and was
not further separated.
3.3.6. Ethyl 2-(trifluoromethyl)-5,6-dihydropyra-
zolo[5,1-a]isoquinoline-1-carboxylate (27a). Bu3GeH.
Colourless oil (57%); nmax(neat) 2928, 2369, 1717, 1473,
1199, 1142, 1042 cmK1; dH 1.39 (3H, t, JZ7.2 Hz, CH3),
3.19 (2H, t, JZ6.8 Hz, 6-CH2), 4.36–4.42 (4H, m, 5-CH2
and OCH2), 7.30–7.40 (3H, m, ArH), 8.30–8.32 (1H, m,
10-H); dC 13.8 (CH3), 29.3 (6-CH2), 47.1 (5-CH2), 61.4
(OCH2), 109.0 (1-C), 119.5 (CF3), 122.1 (2-C), 125.0 and
Bu3GeH. Reflux (10 h), (20) (38%), (19) (19%).
Bu3GeH and phenylthiol. Benzenethiol (10 mol%) was
added at the beginning of the reaction. Reflux (10 h), (20)
(44%). 1H NMR spectroscopic analysis of the crude reaction
product showed the presence of starting material and traces

S. M. Allin et al. / Tetrahedron 61 (2005) 2689–2696
2695
133.3 (2,6a,10a-C), 127.6, 127.8, 128.1 and 130.2 (7,8,9,10-
C), 141.5 (10b-C), 162.6 (C]O); m/z 310 (MC, 43), 282
(10), 265 (100), 238 (14), 140 (5), 104(38), 91 (10), 77
(6%); HRMS: found: MC, 310.0926. C15H13F3N2O2
requires 310.0929.
cyclised adduct 2-(trifluoromethyl)-5,6-dihydropyra-
zolo[5,1-a]isoquinoline-1-carboxylic acid (27b) and the
starting material (26b). The 1H NMR spectrum of the
cleaved sample showed a mixture the cyclised product (27b)
(20%) and the unreacted starting material (26b) (70%). The
separation of these products by column chromatography
was unsuccessful due to co-elution and therefore products
were not fully characterised.
3.4. Solid phase studies
3.4.1. 1-[2-(2-bromophenyl)ethyl]-3-(trifluoromethyl)-
1H-pyrazole-4-carboxylic acid (26b). Ethyl 1-[2-(2-bro-
mophenyl)ethyl]-3-(trifluoromethyl)-1H-pyrazole-4-car-
boxylate (26a) (1.20 g, 3.1 mmol) was dissolved in ethanol
(10 mL) followed by addition of aqueous sodium hydroxide
(2 M, 15 mL). The reaction mixture was heated under reflux
for 8 h and the progress monitored by TLC. The reaction
mixture was cooled and washed with ethyl acetate. The
aqueous layer was acidified to pH 3 with hydrochloric acid
and extracted with DCM. The organic layers were washed
with water, dried and evaporated under reduced pressure to
afford (26b) as light yellow crystals (1.10 g, 3.0 mmol,
97%); nmax(KBr) 3300, 2953, 2683, 2600, 1697, 1547, 1499,
1438, 1309, 1236, 1191, 1145, 1048, 945, 754 cmK1; dH
3.34 (2H, t, JZ7.2 Hz, 6-CH2), 4.45 (2H, t, JZ7.2 Hz,
NCH2), 6.97 (1H, dd, JZ7.6, 1.6 Hz, Ar 6-H), 7.15 (1H,
ddd, JZ7.6, 7.6, 1.6 Hz, Ar 4- or 5-H), 7.20 (1H, ddd, JZ
7.6, 7.6, 1.6 Hz, Ar 4- or 5-H), 7.58 (1H, dd, JZ7.6, 1.6 Hz,
Ar 3-H), 7.75 (1H, s, pyrazole 5-H); dC 36.7 (CH2), 52.7
(NCH2), 111.6 (CF3), 118.8 (pyrazole 4-C), 121.5 (pyrazole
3-C), 124.2 (Ar-2-C), 127.9, 129.2, 131.1, 133.2 and 136.8
(5-C, Ar-3,4,5,6-C), 135.9 (Ar 1-C),165.6 (C]O); m/z 283
(95), 182 (100), 169 (60), 103 (62), 90 (52), 77 (45), 69
(32%); HRMS: found: MHC, 362.9956. C13H10BrF3N2O2
requires 362.9961.
Use of TTMSS. The above procedure was used with TTMSS
(1.3 mL, 4.2 mmol), AIBN (0.20 g, 1.2 mmol) and resin-
bound pyrazole moiety (27b) (111 mg, 0.09 mmol).
Cleavage from the resin yielded a brown oil (30 mg)
which LC-MS analysis confirmed a mixture of the cyclised
adduct (27b) and the reduced product (26c). 1H NMR
spectral analysis showed a mixture of (27b) (53%) and the
reduced product (26c) (27%) with no other products.
(27b): dH 3.20 (2H, t, JZ6.8 Hz, 6-CH2), 4.40 (2H, t, JZ
6.8 Hz, 5-CH2), 7.16–7.34 (3H, m, ArH), 8.33–8.35 (1H, m,
10-H); dC 29.35 (6-CH2), 47.25 (5-CH2), 108.0 (1-C), 119.2
(CF3), 121.9, 124.7 and 133.7 (2,6a,10a-C), 127.7, 128.1,
128.4 and 130.5 (7,8,9,10-C), 142.7 (pyrazole 10b-C), 166.9
(C]O).
(26c): dH 3.20 (2H, t, JZ6.8 Hz, CH2), 4.40 (2H, m, NCH2),
7.08 (1H, d, JZ7.6 Hz, ArH), 7.16–7.34 (1H, m, ArH),
7.39–7.42 (3H, m, ArH), 7.75 (1H, s, 5-H); dC 36.2 (CH2),
54.8 (NCH2), 111.7 (CF3), 118.9 (4-C), 121.6 (3-C), 127.3
(PhCH), 128.6 (PhCH), 128.9 (PhCH), 133.6 (Ph-1-C),
136.7 (5-C), 165.4 (C]O).
3.5. X-ray crystallography
3.4.2. Synthesis of solid-supported 1-[2-(2-bromophenyl)-
ethyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate
(28). DCM (8.0 mL) was added to a portion of Wang resin
(0.40 g, 0.7 mmol). The resin was allowed to swell for
30 min under an atmosphere of nitrogen. (26b) (0.62 g,
1.7 mmol) in DMF (8.0 mL), DMAP (0.25 g, 2.1 mmol) and
diisopropylcarbodiimide (DIC) (0.64 mL, 4.1 mmol) were
added sequentially. The suspension was shaken for 48 h at
room temperature. The reaction mixture was filtered and
washed with DCM, MeOH, DMF, MeOH and DCM (20 mL
each). The resin was dried at 40 8C under vacuum for 24 h.
The coupling reaction was repeated with equimolar
reagents. nmax(KBr) 3458, 3026, 2922, 2370, 1723, 1602,
Both sets of data for methyl 5,6-dihydroimidazo[5,1-a]-
isoquinoline-1-carboxylate (20) and methyl 5,6-dihydro-
imidazo[2,1-a]isoquinoline-3-carboxylate (21) were col-
lected on a Bruker SMART 1000 diffractometer at
150(2) K using Mo Ka radiation. The structures were
solved by direct methods and refined by full-matrix least-
squares on F2 using all the data. All non-hydrogen atoms
were refined with anisotropic atomic displacement para-
meters and hydrogen atoms were included at calculated
positions using a riding model. Data collection and
Table 1. Crystal data for heterocycles 20 and 21
1508, 1370, 1290, 1211, 1138, 1037, 815, 747, 693 cmK1
.
Identification code
20
21
Empirical formula
Formula weight
Crystal system
C13H12N2O2
228.25
C13H12N2O2
228.25
3.4.3. Radical cyclisations of solid-supported 1-[2-(2-
bromo-phenyl)ethyl]-3-(trifluoromethyl)-1H-pyrazole-
4-carboxylate (28). Use of Bu3GeH. Bu3GeH (0.55 mL,
2.1 mmol) was added to the solid supported pyrazole (28)
(140 mg, 0.11 mmol) in toluene (10 mL) under reflux.
AIBN (0.25 g, 1.5 mmol) was added to the refluxing
reaction mixture at equal intervals of 1 h. The reaction
mixture was heated under reflux for 30 h. The reaction
mixture was cooled to room temperature, filtered and
washed with toluene, DCM and MeOH. The resin was dried
at 40 8C under vacuum for 24 h. The products were cleaved
from the resin using TFA/DCM (9:1) and a crystalline
material was recovered (44 mg). LC-MS analysis of the
cleaved sample from the resin showed a mixture of the
Triclinic
7.077(3)
7.830(3)
9.856(4)
100.317(6)
92.468(6)
93.062(6)
535.7(3)
2
ꢀ
P1
0.098
4162
2332 (0.0314)
0.0701, 0.2164
0.0829, 0.2253
Monoclinic
11.9248(13)
11.9615(13)
7.6375(8)
90
98.895(2)
90
1076.3(2)
4
P21/c
˚
a (A)
˚
b (A)
˚
c (A)
a (8)
b (8)
g (8)
3
˚
U (A )
Z
Space group
m (mmK1
Refl. collected
Unique refl. (Rint
)
0.097
5967
1861 (0.0292)
0.0363, 0.0924
0.0475, 0.0985
)
R1, wR2 [IO2s(I)]
R1, wR2 (all data)

2696
S. M. Allin et al. / Tetrahedron 61 (2005) 2689–2696
Tetrahedron Lett. 2000, 41, 381–384. (b) Marco-Contelles,
refinement parameters are summarized in Table 1. All
programs used in structure solution and refinement are
included in the SHELXTL package.25 Crystallographic data
(excluding structure factors) for the structures in this paper
have been deposited at the Cambridge Crystallographic
Data Centre supplementary publication numbers, (20)
(CCDC 244723) and (21) (CCDC 244724).
´
J.; Rodrıquez-Fernandez, M. J. Org. Chem. 2001, 66,
´
3717–3725.
9. Osornio, Y. Z.; Miranda, L. D.; Cruz-Almaza, R.; Muchowski,
J. D. Tetrahedron Lett. 2004, 45, 2855–2858.
10. Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; McInally, T.
Tetrahedron Lett. 2001, 42, 7887–7890.
11. Bowman, W. R.; Krintel, S. L.; Schilling, M. B. Org. Biomol.
Chem. 2004, 585–592.
12. (a) Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 3009–3018 and
4237–4247 and references therein. (b) Tsuge, O.; Hatta, T.;
Tsuchiyama, H. Chem. Lett. 2003, 1998, 155–156.
13. Flannagan, S. R.; Harrowven, D. C.; Bradley, M. Tetrahedron
Lett. 2003, 44, 1795–1798.
Acknowledgements
We thank GlaxoSmithKline and Loughborough University
for a Postgraduate Studentship (R.K.), GlaxoSmithKline for
generous financial support and the EPSRC Mass Spectro-
metry Unit, Swansea University, Wales for mass spectra.
14. Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294.
15. Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40,
4073–4076.
16. (a) Mujumbar, K. C.; Mukhopadhyay, P. P. Synthesis 2003,
920–924. (b) Mujumbar, K. C.; Basu, P. K.; Mukhopadhyay,
P. P.; Sarkar, S.; Ghosh, S. K.; Biswas, P. Tetrahedron 2003,
59, 2151–2157.
References and notes
1. (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc.,
Perkin Trans. 1 2000, 1–14. (b) Bowman, W. R.; Cloonan;,
M. O.; Krintel, S. L. J. Chem. Soc., Perkin Trans. 1 2001,
2885–2991. (c) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S.
J. Chem. Soc., Perkin Trans. 1 2002, 2747–2762.
2. (a) Aldabbagh, F.; Bowman, W. R.; Mann, E. Tetrahedron
Lett. 1997, 38, 7937–7940. (b) Aldabbagh, F.; Bowman,
W. R.; Mann, E.; Slawin, A. M. Z. Tetrahedron 1999, 55,
8111–8128.
17. Orito, K.; Satoh, Y.; Nishizawa, H.; Harada, R.; Tokuda, M.
Org. Lett. 2000, 2, 2535–2537.
18. (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron
2002, 58, 3387–3400. (b) Harrowven, D. C.; Sutton, B. J.;
Coulton, S. Tetrahedron Lett. 2001, 42, 2907–2910.
19. (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetrahedron
Lett. 2001, 42, 9061–9064. (b) Harrowven, D. C.; Sutton, B. J.;
Coulton, S. Org. Biomol. Chem. 2003, 4047–4057.
20. Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25–35.
21. Beckwith, A. L. J.; Bowman, W. R.; Bowry, V. W.; Mann, E.;
Parr, J.; Storey, J. M. D. Angew. Chem., Int. Ed. Engl. 2004,
43, 95–98.
3. Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; McInally, T.
Tetrahedron Lett. 2002, 43, 4191–4193.
4. (a) Antonio, Y.; De La Cruz, E.; Galeazzi, E.; Guzman, A.;
Bray, B. L.; Greenhouse, R.; Kurz, L. J.; Lustig, D. A.;
Maddox, M. L.; Muchowski, J. M. Can. J. Chem. 1994, 72,
15–22.
22. Review: Studer, A.; Bossart, M. In Renaud, P., Sibi, M. P.,
Eds.; Radicals in Organic Synthesis; Wiley-VCH: Weinheim,
2001; Vol. 2, pp 62–80.
5. Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62, 1083–7967.
6. Moody, C. J.; Norton, C. L. J. Chem. Soc., Perkin Trans. 1
1997, 2639–2643.
23. Review: Ganesan, A. In Renaud, P., Sibi, M. P., Eds.; Radicals
in Organic Synthesis; Wiley-VCH: Weinheim, 2001; Vol. 2,
pp 81–91.
7. Murphy, J. A.; Sherburn, M. S. Tetrahedron 1991, 47,
4077–4088.
´ ´
8. (a) Marco-Contelles, J.; Rodrıquez-Fernandez, M.
24. Colacot, T. J. J. Organomet. Chem. 1999, 378–381.
25. Sheldrick, G.M., SHELXTL version 5.1, Bruker-AXS,
Madison WI, 1998.