Intermolecular 'oxidative' aromatic substitution reactions of the imidazol-5-yl radical mediated by the 'reductant' Bu3SnH

Article abstract of DOI:10.1016/j.tet.2004.06.120

The reactivity of the imidazol-5-yl in comparison to the imidazol-2-yl and phenyl radical under the reductive conditions of Bu₃SnH, in intermolecular substitution reactions onto various aromatic substrates is reported. The directing effect of the hetero atom or methyl substituent in aromatic substrates was found to be more important than the polarity of the attacking σ-radical in determining the major product isomer. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.06.120

Tetrahedron 60 (2004) 8065–8071
Intermolecular ‘oxidative’ aromatic substitution reactions of the
imidazol-5-yl radical mediated by the ‘reductant’ Bu3SnH
*
´
Padraig T. F. McLoughlin, Mairead A. Clyne and Fawaz Aldabbagh
Department of Chemistry, National University of Ireland, Galway, Ireland
Received 26 April 2004; revised 7 June 2004; accepted 24 June 2004
Available online 22 July 2004
Abstract—The reactivity of the imidazol-5-yl in comparison to the imidazol-2-yl and phenyl radical under the reductive conditions of
Bu3SnH, in intermolecular substitution reactions onto various aromatic substrates is reported. The directing effect of the hetero atom or
methyl substituent in aromatic substrates was found to be more important than the polarity of the attacking s-radical in determining the major
product isomer.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The imidazol-5-yl radical 2 was generated from 5-bromo-
1,2-dimethylimidazole 1 using Bu3SnH and azo-initiators
AIBN or 1,10-azobis(cyclohexanecarbonitrile) (ACN). The
rate of addition of s-aryl radicals, such as 2 onto aromatics
should be between 1000 and 2000 times slower than
reduction by Bu3SnH (or at least it is for phenyl radicals15,
16), however we made the addition process favourable by
having the aromatic substrate as the reaction solvent and by
keeping the concentration of Bu3SnH low during the course
of the reaction. In the case of benzene and p-xylene optimal
yields of rearomatised products were obtained, when
Bu3SnH (1.5 equiv.) and AIBN (4.0 equiv.) in benzene or
p-xylene were added over 18 h to the refluxing solution of 1
(1.0 equiv., 0.06 M) and AIBN (1.0 equiv.) in the same
aromatic solvents. The requirement for a large excess of
AIBN is in agreement with literature conjecture3–5,8–12 that
AIBN or an AIBN derived radical is implicated in the
oxidative rearomatisation of the intermediated cyclohexa-
dienyl radicals 3–4 to yield 5-arylimidazoles 5 and 7 in a
non-chain process (Scheme 1). The reaction with benzene
gave rearomatised product 5 in isolated yield of 35% along
with significant amounts of the unexpected conjugated 2,4-
cyclohexadiene 6 in 25% yield. Cyclohexadiene 6 was
isolated as a single isomer, as confirmed by GC analysis and
NMR spectra. The vicinal H-1 and H-6 atoms of 6 showed
Over the past 15 years, there have been many reported
syntheses of heterocyclic compounds using intramolecular
homolytic aromatic substitutions mediated by tributyltin
hydride (Bu3SnH) and azobisisobutyronitrile (AIBN).1–9
Such reactions have become a mechanistic curiosity, since
upon radical addition an intermediate cyclohexadienyl
radical is generated, which loses a hydrogen atom to
regenerate aromaticity, and thus represent a formal
oxidation in the presence of the reductant Bu3SnH.
However, using the reducing radical initiators Bu3SnH
and tris(trimethylsilyl)silane [(CH3)3Si]3SiH, there are
relatively few examples of the intermolecular oxidative
reaction; Minisci and co-workers10 and Togo and co-
workers11 demonstrated the influence of polar effects on the
regioselective substitution of nucleophilic alkyl radicals
onto heteroaromatic bases, and more recently Alvarez-
Builla and co-workers12 reported the synthesis of biaryl
compounds using radical substitution of phenyl and pyridyl
radicals onto arenes. The following paper details our
investigations into the intermolecular substitution of the
s-imidazol-5-yl radical onto aromatic substrates, and
comparisons are made with the reactivity of s-imidazol-2-
yl and phenyl radicals. We are aware of only two reported
reactions of s-imidazole radicals; the imidazol-5-yl radical
has been shown to undergo an efficient intramolecular 5-exo
radical cyclization,13 and a facile photochemical arylation
of the imidazole-2-position has been demonstrated.14
1
no coupling to one another in H NMR spectra indicating
that they are effectively at 908 with each other. Using this
conformation, molecular geometry optimisations were
carried out; however, we were unable to unequivocally
establish whether the cis or trans isomer had been isolated.
Therefore no stereochemistry is shown for 2,4-cyclohexa-
diene 6. Substituting Bu3SnH for the weaker reductant
Keywords: Free radicals; Heterocycles; Imidazoles; Tributyltin hydride.
* Corresponding author. Tel.: C353-91-524411; fax: C353-91-525700;
e-mail: fawaz.aldabbagh@nuigalway.ie
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.120

8066
P. T. F. McLoughlin et al. / Tetrahedron 60 (2004) 8065–8071
Scheme 1.
[(CH3)3Si]3SiH did not result in any improvement in yields
of 5 and 6, which were both isolated in 21% yield, and using
ACN in place of AIBN resulted in lower yields of 5-phenyl-
1,2-dimethylimidazole 5 (20%), along with an inseparable
mixtures of dienes which were difficult to characterise. The
formation of 6 can be rationalized by the trapping of the
relatively long-lived resonance stabilized p-cyclohexa-
dienyl radical 3 by the AIBN derived 2-cyano-2-propyl
radical. Although, non-conjugated 2,5-cyclohexadienes are
normally the major products of homolytic aromatic
substitution reactions carried out under non-oxidative
conditions,17 only traces of such diene were detected in
the 1H NMR of the crude reaction mixtures and the amounts
were too small for isolation by column chromatography.
However, the efficient rearomatisation of non-conjugated
dienes in the presence of radical initiators is well
documented.18 There are however other accounts of AIBN
derived initiator radicals being incorporated into the pro-
ducts of radical reactions.5,8,9 Motherwell and co-workers5
have isolated products of the trapping of p-cyclohexadienyl
radicals by 2-cyano-2-propyl radicals, when large amounts
of AIBN were added, but these were all aromatised
products. Bennasar and co-workers8 have reported the
trapping of an intramolecular 5-endo cyclization product
radical by the 2-cyano-2-propyl radical to yield an unstable
tetracycle that was partially converted into an oxidized
rearomatised product upon column chromatography. In
contrast, diene 6 is a stable crystalline compound isolated
after an acid–base work up and column chromatography.
We confirmed that diene 6 was not an intermediate in the
formation of 5 by independently refluxing benzene solutions
of 6 for several days, in which negligible decomposition of 6
was observed. However, diene 6 could be converted into
rearomatised product 5 in quantitative yield by refluxing the
former at much higher temperatures of refluxing xylene (bp
140–145 8C) for 48 h. This increased the overall isolated
yields to 60% for 5-phenylimidazole 5. The reaction with
p-xylene (bp 138 8C) gave low yields of rearomatised
product 7 of only 15%, with no dienes observed in the
1H NMR of the crude reaction mixtures. For this
reaction, we can assume that any dienes formed as a
result of the trapping of p-radical 4 by the 2-cyano-2-
propyl radical would be thermally unstable, and rapidly
rearomatise to 7. GC analysis of the crude reaction
mixture indicated that 1,2-dimethylimidazole was the
major product formed via the reduction of s-radical 2
by Bu3SnH. It can therefore be assumed that the
addition of 2 onto p-xylene is slow, and analogous to
the addition of phenyl radicals, which has been
previously described as reversible.19
In these reactions, other possible rearomatisation pathways
for p-radicals 3–4 including their disproportionation or
hydrogen atom transfer from Bu3SnH are considered
unlikely. In view of the fact that the resultant cyclohexa-
dienes should have been stable enough for detection or
isolation prior to oxidation to the 5-arylimidazoles 5 and 7.
Experimental evidence9 has also most recently been
provided to disprove hydrogen atom transfer from
Bu3SnH, oxidation of cyclohexadienyl radicals by Bu3Sn$,
along with an earlier mechanism proposed by Bowman and
co-workers2,6 based on the SRN1 pathway. According to the
latter chain-reaction mechanism Bu3SnH acts as a base, as
well as an initiator to produce hydrogen gas from
cyclohexadienyl radicals 3–4, along with their respective
oxidizable radical-anions. We confirmed the latter mech-
anism was not operational by refluxing bromide 1 in
benzene with catalytic amounts (0.2 equiv.) of Bu3SnH and
AIBN in the presence of the base DABCO (1,4-diazabicy-
clo[2.2.2]octane, 1.5 equiv.). DABCO would thus replace
Bu3SnH as the base, and only catalytic amounts of Bu3SnH
would therefore be required for the initiation of the
proposed chain reaction. This led to the isolation of
products 5 and 6 in poor respective yields of 5 and 2%

P. T. F. McLoughlin et al. / Tetrahedron 60 (2004) 8065–8071
8067
Scheme 2.
Scheme 3.
with 46% of 1 recovered. Furthermore, whenever less than
full equivalents of AIBN were used, a significant amount of
unaltered imidazole 1 was always recovered, indicating that
a greater amount of AIBN was required to support the non-
chain reaction.
Higher overall isolated yields were obtained for substi-
tutions of s-radical 2 onto pyridine. This clearly indicated
that addition of imidazol-5-yl radical 2 onto certain
heteroaromatic bases competed more effectively with
radical reduction by Bu3SnH, since these reactions also
contained higher concentrations of Bu3SnH. For example,
the reaction with pyridine led to the clean isolation of the
2-substituted pyridine 8 in 45% yield along with an
inseparable 1:1 mixture of 3- and 4-substituted isomers 9
and 10 in 48% yield (Scheme 2). The absence of any dienes
analogous to 6 in the reactions with pyridines may be
explained by the electrophilic nature of the 2-cyano-2-
propyl radical (due to the proximity of the cyano group to its
radical centre), which may have prevented it from reacting
with p-radicals derived from heteroaromatic bases. Another
explanation is the elevated reaction temperatures for
pyridine reactions compared to the benzene reaction
would have led to the thermal rearomatisation of any dienes
analogous to 6.
Scheme 4.
of s-radical 2 is only weak and comparable to that of the
phenyl radical, and demonstrated that inductive stabilization
of the p-single-electron pyridyl intermediate (analogous to
3–4) by the methyl substituents was more important.
The reaction with N-methylpyrrole gave exclusively the
2-substituted isomer 18 in 46% yield (Scheme 5). The
reactions with N-methylpyrrole and pyridine are therefore in
agreement with literature reactions of heterocycles with
phenyl radicals produced under non-reductive conditions,
which have been shown to predominately substitute at
positions adjacent to the heteroatom.20
The isolation of 2-substituted pyridine isomer 8 as the major
product may have inferred that s-radical 2 was nucleophilic
in character, however when 4-picoline was the substrate the
3-substituted isomer 12 was the predominate product
(Scheme 3). An identical substitution pattern was observed
when bromobenzene was used in place of 5-bromoimida-
zole 1 in the reaction with 4-picoline (bp 145 8C) carried out
under identical reaction conditions indicating that the
reactivity of the phenyl and imidazol-5-yl radicals 2 was
equivalent. Furthermore, the reaction of 1 with 2,6-lutidine
(bp 143–145 8C) led to the exclusive isolation of the 3-
substituted isomer 15 in 35% yield (Scheme 4). The reaction
with 3,5-lutidine (bp 169–170 8C) was not regioselective,
and led to the formation of an inseparable 1:1 mixture of the
2- and 4-substituted isomers 16 and 17 in only 10% isolated
yield. The high temperatures used for the lutidine reactions
may have made the initial addition of radical 2 reversible in
analogy with the reaction of 1 with p-xylene. The results
with methyl substituted pyridines inferred that the philicity
Scheme 5.
For comparison purposes, the reactivity of the imidazol-2-yl
radical 19 generated from 2-bromo-N-methylimidazole
was also investigated by reacting it with pyridine and
N-methylpyrrole under reaction conditions identical to those
used for the reaction with 5-bromoimidazole 1. Substitution
at the 2-position of pyridine and N-methylpyrrole was
preferred with compounds 20, and 22 isolated in 18 and

8068
P. T. F. McLoughlin et al. / Tetrahedron 60 (2004) 8065–8071
Scheme 6.
48% yield, respectively (Scheme 6). From the pyridine
reaction, a small amount of the 4-isomer 21 was also
isolated in 4% yield. The smaller yields indicate that the
imidazol-2-yl radical 19 is less reactive towards pyridine
than imidazol-5-yl 2 and phenyl radicals, which may be as a
result of an inductive electron-withdrawing effect on the
radical by the adjacent imidazole nitrogen atoms. However
this increased electrophilic character for the imidazol-2-yl
in comparison to the imidazol-5-yl radical did not give
significantly higher yields of substitution product for
reaction with N-methylpyrrole indicating that the inductive
effect may be small.
give the lowest yield of substitution products at the
highest reaction temperatures. The imidazol-5-yl radical
was more reactive towards pyridine than benzene with
reactivity comparable to that of the phenyl radical. The
imidazol-2-yl radical was less reactive than the
imidazol-5-yl radical towards pyridine, but had a similar
reactivity towards N-methylpyrrole. However in deter-
mining product selectivity the directing effect of the
aromatic substrate methyl-substituents was found to be
more important than the polarity of the attacking radi-
cal. For unsubstituted nitrogen-containing heterocyclic
substrates, substitution at the position adjacent to the
nitrogen atom is preferred.
There are reports of s-heteroaromatic radicals generated
from photolysis and thermolysis reactions being regarded as
electrophilic in character,21–24 however in such cases further
oxidation of these radicals to the respective cations cannot
be ruled out.24 The reactivity of the s-imidazole radical 2
is very similar to that of the phenyl25 radical and other
s-heteroaromatic radicals,12,23,24 which have been shown to
be more reactive towards the ortho and para than the meta
position of substituted benzenes irrespective of the polarity
of the attacking radical. Thus, the difference in polarity of
all these s-aromatic radicals does not appear to be great
enough to influence selectivity. This may be expected since
the unpaired electron occupies an orbital orthogonal to the
p-system.
4. Experimental
4.1. General
Melting points were measured on a Stuart Scientific melting
point apparatus SMP3, and are uncorrected. IR spectra
were determined using a Perkin–Elmer Spec 1 with ATR
attached. 1H NMR (400 Hz) and 13C NMR (100 Hz) spectra
were recorded in CDCl3 on a Jeol 400 instrument. Chemical
shifts are given in parts per million (ppm). EI-mass spectra
were obtained on a Micro Mass GCT GC–MS. TLC using
silica gel as absorbent was carried out using aluminium
backed plates coated with silica gel (Merck Kieselgel 60
F254). Column chromatography using alumina was carried
out with Aldrich aluminium oxide, activated, neutral,
Brockmann, STD Grade 3, 150 mesh size.
3. Conclusion
We have reported the first intermolecular oxidative aromatic
substitutions of s-imidazole radicals in the presence of the
reductant Bu3SnH. Such reactions require an excess of azo-
initiator, which has been implicated in the oxidative
rearomatization of the intermediate p-cyclohexadienyl
radical to give aromatized products in modest yields. For
the reaction with benzene, along with the rearomatized
5-phenylimidazole, a significant amount of 2,4-cyclo-
hexadiene was isolated, as a result of the trapping of the
p-cyclohexadienyl radical by an AIBN derived 2-cyano-
2-propyl radical. We have also established previously
unknown reactivity patterns for s-imidazole radicals
towards various aromatics. The reaction was found to
4.2. Materials
All reactions were carried out using dried solvents under an
argon atmosphere, however without rigorous freeze–thaw
solvent deoxygenations. Bu3SnH, AIBN and ACN were
obtained commercially and the azo-initiators were recrys-
tallized from methanol at 0 8C prior to use. 5-Bromo-1,2-
dimethylimidazole 1 was obtained cleanly in 65% yield by
stirring 1,2-dimethylimidazole for 2 h with N-bromosucc-
imide (NBS, 1 equiv.) in CH2Cl2 at 0 8C, and 2-bromo-N-
methylimidazole was obtained according to a literature

P. T. F. McLoughlin et al. / Tetrahedron 60 (2004) 8065–8071
8069
procedure26 in 62% yield from the reaction of cyanogen
bromide with N-methylimidazole.
1 h via a syringe pump to 5-bromo-1,2-dimethyimidazole 1
(1.09 g, 6 mmol) and AIBN (0.98 g, 6 mmol) in pyridine
(90 ml). The reaction was refluxed for a further 1 h, cooled
and evaporated to dryness. The work-up and purification
procedure used for the benzene reaction was repeated. The
first product eluted by column chromatography was 8
(0.47 g, 45%) as a yellow oil. (Found MC, 173.0954,
C10H11N3 requires MC 173.0953), nmax/cmK1 1658, 1589,
1562, 1501, 1437, 1401; dH 2.39 (s, 3H, Im-2-Me), 3.85 (s,
3H, N–Me), 7.08 (m, 1H, py-H-5), 7.24 (s, 1H, Im-4-H),
7.46 (d, JZ7.8 Hz, 1H, py-3-H), 7.62 (m, 1H, py-H-4), 8.53
(d, JZ2.4 Hz, 1H, py-6-H); dC 13.5 (Me), 32.4 (N–Me),
121.0 (py-CH), 121.5 (py-CH), 128.3 (Im-4-CH), 132.0 (C),
136.4 (CH), 147.5 (C), 148.7 (py-6-CH), 150.6 (C); m/z 173
(MC, 100%), 172 (90), 158 (10). The second products
4.3. Intermolecular radical reactions
4.3.1. General procedure for reactions of the imidazol-5-
yl radical 2 with benzene and p-xylene; 5-phenyl-1,2-
dimethylimidazole 5 and 2-[1,6-trans-6-(1,2-dimethyli-
midazol-5-yl)-2,4-cyclohexadien-1-yl]-2-methylpropane-
nitrile 6. Bu3SnH (2.2 ml, 8 mmol) and AIBN (3.51 g,
21.4 mmol) in benzene (50 ml) was added over 18 h via a
syringe pump to 5-bromo-1,2-dimethyimidazole 1 (0.96 g,
5.3 mmol) and AIBN (0.88 g, 5.3 mmol) in benzene
(90 ml). The reaction was refluxed for a further 1 h, cooled
and evaporated to dryness. 2 M HCl (50 ml) added, and tin
residues were eliminated by repeated washing with hexane
(z20!50 ml). The acidic solution was neutralised with
solid Na2CO3 and the pH brought up to 14 by addition of
NaOH pellets. The solution was extracted with CH2Cl2 (2!
50 ml), dried (MgSO4) and evaporated to dryness to yield a
yellow residue, which was purified by column chromatog-
raphy on neutral alumina using mixtures of ethyl acetate and
hexane as eluent. The first product eluted was 5 (0.32 g,
35%) as white crystals, mp 71–75 8C (lit.27 74 8C). (Found
1
eluted were an inseparable 1:1 mixture (by H NMR) of 9
and 10 (0.50 g, 48%) as a yellow oil. (Found MC, 173.0952,
C10H11N3 requires MC 173.0953); 9, dH 2.47 (s, 3H, Im-2-
Me), 3.55 (s, 3H, N–Me), 7.02 (s, 1H, Im-4-H), 7.37 (dd, JZ
4.8, 8.2 Hz, 1H, Py-5-H), 7.68 (d, JZ8.2 Hz, 1H, Py-4-H),
8.59 (d, JZ4.8 Hz, 1H, Py-H-6), 8.64 (s, 1H, Py-2-H); 10,
dH 2.36 (s, 3H, Im-2-Me), 3.63 (s, 3H, N–Me), 7.14 (s, 1H,
Im-4-H), 7.29 (d, JZ6.0 Hz, 2H, Py-3,5-H), 8.63 (d, JZ
6.0 Hz, 2H, Py-2,6-H).
MC, 172.1003, C11H12N2 requires MC 172.1000), nmax
/
cmK1 3372, 1604, 1638, 1506, 1145; dH 2.45 (s, 3H, Im-2-
Me), 3.50 (s, 3H, N–Me), 6.95 (s, 1H, Im-4-H), 7.40 (m, 5H,
Ar-H); dC 13.6 (Me), 31.2 (N–Me), 125.8 (Im-4-CH), 127.5,
128.5, 128.6, 130.5, 133.4, 145.9 (Im-2-C); m/z 172 (MC,
100%), 130 (5), 118 (8). The second product eluted was 6
(0.32 g 25%) as white crystals; mp 105–106 8C. (Found:
MC, 241.1579. C15H18N3 requires M, 241.1573); nmax/cmK
1 2233 (CN), 1411, 1182; dH 1.32 (s, 3H, CMeCN), 1.36 (s,
3H, CMeCN), 2.31 (s, 3H, Im-2-Me), 2.49 (d, JZ5.6 Hz,
1H, diene-1-H), 3.53 (s, 3H, N–CH3), 3.69 (d, JZ5.6 Hz,
1H, diene-6-H), 5.47 (dd, JZ5.6, JZ9.6 Hz, 1H, diene-2-
H), 5.71 (dd, JZ5.6, 9.2 Hz, 1H, diene-5-H), 5.97 (dd, JZ
5.2, 9.2 Hz, 1H, diene-4-H), 6.17 (dd, JZ5.2, 9.6 Hz, 1H,
diene-3-H), 6.62 (s, 1H, Im-4-H); dC 13.5 (Im-2-Me), 21.6
(CMeCN), 24.3 (CMeCN), 29.0 (N–Me), 31.9 (CCN), 38.9
(diene-CH), 45.5 (diene-CH), 120.27 (CH), 123.1 (CN),
125.3 (CH), 126.1 (Im-5-C), 126.5 (CH), 127.1 (CH), 128.5
(CH), 145.7 (Im-2-C); m/z 241 (MC, 100%), 226 (39), 173
(87), 147 (39), 132 (32), 117 (29), 91 (10).
The above procedure was repeated with 4-picoline replacing
pyridine. The first product eluted by column chromatog-
raphy was 2-(1,2-dimethylimidazol-5-yl)-4-methylpyridine
11 (0.22 g, 20%) as a yellow oil. (Found MC, 187.1108.
C11H13N3 requires MC 187.1109); nmax/cmK1 1659, 1604,
1507, 1436, 1401; dH 2.36 (s, 3H, Im-2-Me), 2.44 (s, 3H, Py-
Me), 3.88 (s, 3H, N–Me), 6.96 (d, JZ5.2 Hz, 1H, Py-5-H),
7.29 (s, 1H, Im-4-H), 7.34 (s,1H, Py-3-H), 8.44 (d, JZ
5.2 Hz, 1H, Py-6-H); dC 13.5 (Im-2-Me), 20.9 (Py-Me), 32.4
(N–Me), 113.4 (C), 122.2 (CH), 122.4 (CH), 128.0 (CH),
131.6 (C), 147.5 (C), 148.8 (Py-6-CH), 150.6 (C); m/z 187
(MC, 100%). The second product eluted was 3-(1,2-
dimethylimidazol-5-yl)-4-methylpyridine 12 (0.39 g, 36%)
as a yellow oil. (Found MC, 187.1110, C11H13N3 requires
MC 187.1109); nmax/cmK11659, 1604, 1507, 1436, 1401;
dH 2.24 (s, 3H, Im-2-Me), 2.47 (s, 3H, Py-Me), 3.34 (s, 3H,
N–Me), 6.90 (s, 1H, Im-4-H), 7.24 (d, JZ5.7 Hz, 1H, Py-5-
H), 8.41 (s, 1H, Py-2-H), 8.49 (d, JZ5.7 Hz, 1H, Py-6-H);
dC 13.4 (Im-2-Me), 19.3 (Py-Me), 30.5 (N–Me), 124.9 (CH),
126.4 (C), 127.1 (CH), 128.1 (C), 145.9 (C), 1473 (C), 149.4
(CH), 151.0 (CH); m/z 187 (MC, 100%).
The above procedure was repeated with p-xylene replacing
benzene. 5-(2,5-Dimethylphenyl)-1,2-dimethylimidazole 7
(0.16 g, 15%) was isolated as a yellow oil. (Found MC,
200.1311, C13H16N2 requires MC 200.1313), nmax/cmK1
2920, 1613, 1559, 1505, 1435, 1403; dH 2.13 (s, 3H, Me),
2.33 (s, 3H, Me), 2.43 (s, 3H, Me), 3.29 (s, 3H, N–Me), 6.81
(s, 1H, Im-4-H), 7.00 (s, 1H, Ar-H), 7.11 (d, JZ7.8 Hz, 1H,
Ar-H), 7.17 (d, JZ7.8 Hz, 1H, Ar-H); dC 13.3 (Im-Me),
19.3 (Me), 20.6 (Me), 30.6 (N–Me), 125.3, 127.5, 128.5,
128.6, 130.5 133.4, 145.9 (Im-2-C); m/z 200 (MC, 100%),
158 (33).
The above procedure was repeated with bromobenzene
replacing 1. The first product eluted by column chromatog-
raphy was 4-methyl-2-phenylpyridine 1328 (0.21 g, 20%) as
a yellow oil. (Found MC 169.0895, C12H11N requires
169.0891), nmax/cmK1 3026, 1590, 1556, 1478, 1444, 1401;
dH 2.38 (s, 3H, Me), 7.03, (d, JZ4.8 Hz, 1H, Py-5-H), 7.43
(m, 3H, Ph-H), 7.53, (s, 1H, Py-3-H), 7.96 (m, 2H, Ph-H),
8.53 (d, JZ4.8 Hz, 1H, Py-6-H); dC 21.1 (Me), 121.4 (CH),
123.0 (CH), 126.9 (CH), 128.7 (CH), 139.5 (C), 147.6 (C),
149.3 (Py-6-CH), 157.3 (Py-2-C); m/z 170 (MHC, 2%), 169
(81), 168 (100), 167 (19), 154 (3). The second product
eluted was 4-methyl-3-phenylpyridine 14 (0.35 g, 36%) as a
yellow oil. (Found MC 169.0889, C12H11N requires
169.0891), nmax/cmK1 3026, 1590, 1556, 1478, 1444,
1401; dH 2.28 (s, 3H, Me), 7.18 (d, JZ4.9 Hz, 1H, Py-5-
H), 7.31–7.46 (m, 5H, Ph-H), 8.44 (bs, 2H, Py-2 and 6-H);
4.3.2. General procedure for reactions of the imidazol-5-
yl 2, imidazol-2-yl 19 and phenyl radicals with pyridines;
2-(1,2-dimethylimidazol-5-yl)-pyridine 8, 3-(1,2-
dimethylimidazol-5-yl)pyridine 9 and 4-(1,2-dimethyli-
midazol-5-yl)pyridine 10. Bu3SnH (2.5 ml, 9 mmol) and
AIBN (2.46 g, 15 mmol) in pyridine (50 ml) was added over

8070
P. T. F. McLoughlin et al. / Tetrahedron 60 (2004) 8065–8071
dC 19.8 (Me), 124.7 (CH), 127.6 (CH), 128.4 (CH), 129.2
(CH), 137.8 (C), 144.5 (C), 148.2 (Py-CH), 149.9 (Py-CH);
m/z 170 (2%), 169 (MC, 81), 168 (100), 154 (3).
procedure used for the benzene reaction was repeated.
Purification by column chromatography led to the isolation
of 18 (0.24 g, 46%) as a brown oil. (Found MC 175.1108,
C10H13N3 requires 175.1109); nmax/cmK1 2940, 1700, 1666,
1520, 1401, 1301; dH 2.42 (s, 3H, Im-2-Me), 3.49 (s, 3H, N–
Me), 3.51 (s, 3H, N–Me), 6.17 (m, 1H, Pyl-3-H), 6.20 (m,
1H, Pyl-4-H), 6.76, (s, 1H, Pyl-5-H), 6.92 (s, 1H, Im-4-H);
dC 13.6 (Im-2-Me), 30.7 (N–Me), 34.3 (N–Me), 107.7 (Pyl-
3-CH), 111.1 (Pyl-4-CH) 122.0 (C) 123.4 (CH) 127.9 (CH)
132.5 (C) and 145.4 (Im-2-C); m/z 176 (5%), 175 (MC,
100), 174 (5), 119 (5).
The above procedure was repeated with 2-bromo-N-
methylimidazole and pyridine. The first product eluted by
column chromatography was 2-(1-methylimidazol-2-
yl)pyridine 2023 (0.17 g, 18%) as a yellow oil. (Found
MC 159.0797, C9H9N3 requires 159.0796); nmax/cmK1
1588, 1491, 1464, 1278, 1034; dH 4.11 (s, 3H, Me), 6.96 (s,
1H, Im-5-H), 7.11 (s, 1H, Im-4-H), 7.21 (dd, JZ0.8, 4.8 Hz,
1H, Py-5-H), 7.73 (m, 1H, Py-4-H), 8.16 (d, JZ8.0 Hz, 1H,
Py-3-H), 8.57 (d, JZ4.8 Hz, 1H, Py-6-H); dC 36.1 (Me),
122.2 (CH), 122.5 (CH), 124.3 (CH), 128.0 (CH), 136.4
(CH), 148.1 (Py-6-CH), 150.62 (C); m/z 159 (MC, 100%).
The second product eluted was 4-(1-methylimidazol-2-
yl)pyridine 2129 (30 mg, 4%), which contained inseparable
traces of N-methylimidazole; dH 3.81 (s, 3H, Me), 7.02 (s,
1H, Im-5-H), 7.13 (s, 1H, Im-4-H), 7.34 (d, JZ5.8 Hz, 2H,
Py-3,5-H), 8.57 (d, 1H, JZ5.8 Hz, 2H, Py-2,6-H); dC 36.7
(Me), 120.6 (Im-5-CH), 124.3 (Im-4-CH), 131.8 (Py-3,5-
CH), 150.5 (Py-2,6-CH).
The above procedure was repeated with 2-bromo-N-
methylimidazole replacing 1. Purification by column
chromatography led to the isolation of 1-methyl-2-(1-
methylpyrrol-2-yl)-imidazole 22 (0.24 g, 48%), as a brown
oil. (Found MC 161.0953, C9H11N3 requires 161.0953);
nmax/cmK1 3104, 2930, 1579, 1443, 1407, 1281, 1137; dH
3.71 (s, 3H, N–Me), 3.81 (s, 3H, N–Me), 6.20 (m, 1H, Pyl-3-
H), 6.31 (m, 1H, Pyl-4-H), 6.74, (m, 1H, Pyl-5-H), 6.94 (s,
1H, Im-5-H), 7.12 (s, 1H, Im-4-H); dC 34.2 (Me), 35.5 (Me),
107.4 (Pyl-3-CH) 111.8 (Pyl-4-CH) 121.1 (Im-5-CH) 122.6
(C) 124.4 (Py-5-CH), 128.8 (Im-4-CH), 141.4 (C). m/z 161
(MC, 100%).
The above procedure was repeated using 1, 2,6-lutidine and
ACN in place of AIBN. Purification by column chroma-
tography led to the isolation of 2,6-dimethyl-3-(1,2-
dimethylimidazol-5-yl)pyridine 15 (0.42 g, 35%) as a
yellow oil. (Found MC, 201.1268, C12H15N3 requires MC
201.1266); nmax/cmK1 1659, 1604, 1507, 1436,1401; dH
2.31 (s, 3H, Me), 2.36 (s, 3H, Me), 2.50 (s, 3H, Me), 3.22 (s,
3H, N–Me), 6.88 (s, 1H, Im-4-H), 6.98 (d, JZ7.8 Hz, Py-4
or 5-H), 7.30 (1H, d, JZ7.8 Hz, Py-4 or 5-H); dC 13.6 (Im-
2-Me), 22.9 (Py-Me), 24.5 (Py-Me), 30.6 (N–Me), 118.6
(C), 120.3 (Py-CH),122.3 (C), 126.5 (Im-4-CH) 139.1 (Py-
CH), 145.5 (Im-2-C), 157.5 (Py-C), 158.2 (Py-C); m/z 201
(MC, 100%), 159 (79).
4.4. Molecular geometry optimizations
Molecular geometry optimizations and molecular mech-
anics calculations were performed with Hyperchem 5.1 with
Polak–Ribiere as the minimization algorithm under root-
˚
mean-square gradient conditions of 0.1 kcal/(A) or 420
calculation cycles.
Acknowledgements
The above procedure was repeated using 1, 3,5-lutidine and
ACN in place of AIBN. Purification by column chroma-
tography led to the isolation of an inseparable 1:1 mixture
(by GC and 1H NMR) of 2-(1,2-dimethylimidazol-5-yl)-3,5-
dimethylpyridine 16 and 4-(1,2-dimethylimidazol-5-yl)-
3,5-dimethylpyridine 17 (0.12 g, 10%) as a yellow oil.
(Found MC, 201.1265, C12H15N3 requires MC 201.1266);
16 and 17, dH 2.08 (s, 6H, Me), 2.34 (s, 3H, Me), 2.37 (s, 3H,
Me), 2.45 (s, 3H, Me), 2.46 (s, 3H, Me), 3.22 (s, 3H, N–Me),
3.59 (s, 3H, N–Me), 6.81 (s, 1H, Im-4-H), 7.06 (s, 1H, Im-4-
H), 7.42 (s, 1H, Py-4-H, 16), 8.34 (s, 1H, Py-6-H, 16), 8.40
(s, 2H, Py-2,6-H, 17); dC 13.5 (Im-2-Me), 17.0, 17.9, 19.8,
30.2 (N–Me), 31.6 (N–Me), 125.6 (Im-4-CH), 128.2 (Im-4-
CH), 131.4 (C), 132.4 (C), 139.1 (Py-4-CH, 16), 147.1 (Py-
CH), 148.5 (Py-CH); m/z 201 (MC, 100%), 159 (20), 145
(2).
We thank Enterprise Ireland for a Basic Research Grant and
a Postgraduate Research Fellowship for Padraig
McLoughlin.
References and notes
1. For recent reviews see: (a) Studer, A.; Bossart, M.; Renaud, P.;
Sibi, M. P., Eds.; Homolytic Aromatic Substitutions Radicals
in Organic Synthesis; Vol. 2; Wiley-VCH: Weinheim; 2001;
pp. 62–80. (b) Bowman, W. R.; Fletcher, A.J.; Potts, G. B. S. J.
Chem. Soc., Perkin Trans. 1; 2002, 2747–2762.
2. Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991,
47, 10119–10128.
3. Murphy, J. A.; Sherburn, M. S. Tetrahedron 1991, 47,
4077–4088.
4.3.3. General procedure for reactions of the imidazol-5-
yl 2 and imidazol-2-yl 19 radicals with N-methylpyrrole;
4. Curran, D. P.; Yu, H.; Liu, H. Tetrahedron 1994, 50,
7343–7366.
1,2-dimethyl-5-(1-methylpyrrol-2-yl)imidazole
18.
Bu3SnH (1.1 ml, 4 mmol) and ACN (1.51 g, 6 mmol) in
N-methylpyrrole (40 ml) was added over 18 h via a syringe
pump to 5-bromo-1,2-dimethyimidazole 1 (0.54 g, 3 mmol)
and ACN (2.27 g, 9 mmol) in N-methylpyrrole (70 ml). The
reaction was refluxed for a further 1 h, cooled and
evaporated to dryness. The work-up and purification
5. da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 137–140.
6. Aldabbagh, F.; Bowman, W. R.; Mann, E.; Slawin, M. Z.
Tetrahedron 1999, 55, 8111–8128.
7. Fiumana, A.; Jones, K. Tetrahedron Lett. 2000, 41,
4209–4211.

P. T. F. McLoughlin et al. / Tetrahedron 60 (2004) 8065–8071
8071
8. Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. J. Org. Chem.
2001, 66, 7547–7551.
19. Henriquez, R.; Mogan, A. R.; Mulholland, P.; Nonhebel,
D. C.; Smith, G. C. J. Chem. Soc., Chem. Commun. 1974,
987–988.
9. Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.;
Parr, J.; Storey, J. M. D. Angew. Chem., Int. Ed. 2004, 43,
95–98.
20. Lynch, B.M.; Chang, H.S. Tetrahedron Lett. 1964, 5 617–620,
and references therein.
10. Minisci, F.; Fontana, F.; Pianese, G.; Yan, Y. M. J. Org. Chem.
1993, 58, 4207–4211.
21. Martelli, P.; Spagnolo, P.; Tiecco, M. J. Chem. Soc., (B) 1968,
901–905.
11. Togo, H.; Hayashi, K.; Yokoyama, M. Chem. Lett. 1993,
641–644.
22. Vernin, G.; Jauffred, R.; Ricard, C.; Dou, H. M. J.; Metzger, J.
J. Chem. Soc., Perkin Trans. 2 1972, 1145–1150.
23. Seki, K.-i; Ohkura, K.; Terashima, M. Heterocycles 1984, 22,
2347–2350.
´
´
12. Martınez-Barrasa, V.; Garcıa de Viedma, A.; Burgos, C.;
Alvarez-Builla, J. Org. Lett. 2000, 2, 3933–3935.
13. Bowman, W. R.; Taylor, P. F. J. Chem. Soc., Perkin Trans. 1
1990, 919–924.
24. Ohkura, K.; Seki, K.; Terashima, M.; Kanaoka, Y.
Tetrahedron Lett. 1989, 30, 3433–3436.
ˆ
25. Ito, R.; Migita, T.; Morikawa, N.; Simamura, O. Tetrahedron
1965, 21, 955–961.
14. D’Auria, M.; De Luca, E.; Mauriello, G.; Racioppi, R.
J. Chem. Soc., Perkin Trans. 1 1998, 271–273.
15. Scaiano, J. C.; Stewart, L. C. J. Am. Chem. Soc. 1983, 105,
3609–3614.
26. McCallum, P. B. W.; Weavers, R. T.; Grimmett, M. R.;
Blackman, A. G. Aust. J. Chem. 1999, 52, 159–165.
27. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn 1998, 71, 467–473.
16. Garden, S. J.; Avila, D.; Beckwith, A. L. J.; Bowry, V. W.;
Ingold, K. U.; Lusztyk, J. J. Org. Chem. 1996, 61, 805–809.
17. Crich, D.; Sochanchingwung, R. Tetrahedron 2004, 60,
1513–1516, and references therein.
28. Comins, D. L.; Killpack, M. O. Heterocycles 1990, 31,
2025–2028.
18. Bella, A.F.; Jackson, L.V.; Walton, J.C. Org. Biomol. Chem.
2004, 421–428, and references therein.
29. Stoyanov, V. M.; El’chaninov, M. M.; Pozharskii, A. F. Chem
Heterocycl. Compd. (Engl. Trans.) 1991, 27, 1140–1144.