Convenient method for the 3-functionalization of isoindazoles

Article abstract of DOI:10.1080/00397910500376570

The C-3 position of isoindazoles is readily functionalized by metalation with lithium diisopropylamide followed by reaction with a variety of electrophiles. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500376570

Synthetic Communicationsw, 36: 285–293, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500376570
Convenient Method for the
3-Functionalization of Isoindazoles
Aaron Bunnell, Counde O’Yang, Andra Petrica, and
Michael J. Soth
Department of Medicinal Chemistry, Roche Palo Alto LLC,
Palo Alto, California, USA
Abstract: The C-3 position of isoindazoles is readily functionalized by metalation with
lithium diisopropylamide followed by reaction with a variety of electrophiles.
Keywords: Deprotonation, functionalization, 2H-indazoles, isoindazoles
We recently needed a general method for functionalization of the C-3 position
of isoindazoles (also called 2H-indazoles). A perusal of the literature revealed
that this position can be metalated with alkyllithium reagents, and the resulting
organolithium species then reacted with electrophiles.[1] This method
appeared to us to be the most suitable of the limited number of examples
that we found (For a review on the chemistry of indazoles and isoindazoles,
see).[2] However, the use of alkyllithium reagents was incompatibile with
some of our requisite substrates. We wondered if the same transformation
could be effected with other bases and found that lithium diisopropylamide
is an effective base for this purpose.
Addition of 2-methylisoindazole 1 to a solution of freshly prepared
lithium diisopropylamide, followed by stirring at 0–58C for 15 min, resulted
in a clean generation of presumed 3-lithio-2-methylisoindazole, which was
quenched by methyl iodide at 2788C to afford 2,3-dimethylisoindazole 1a
Received in the USA July 28, 2005
Address correspondence to Michael J. Soth, Department of Medicinal Chemistry,
Roche Palo Alto LLC, 3431 Hillview Avenue, R6-201, Palo Alto, CA 94304, USA.
E-mail: michael.soth@roche.com
285

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A. Bunnell et al.
in 82% yield. The same reaction could be performed using commercially
available lithium diisopropylamide solution (2.0 M in heptane/tetrahydro-
furan/ethylbenzene, Aldrich), but the yields were slightly lower (73%). The
same generated anion could be quenched with a variety of electrophiles, in
good to excellent yields (Table 1).
When benzaldehyde was used as the electrophile (to generate alcohol 1f),
a significant side product was also isolated, ketone 1g. This ketone was
presumably generated by Oppenauer oxidation of the expected intermediate
Table 1. Preparation of 3-substituted isoindazoles
Substrate
Electrophile R0X
Product (yield, %)
1
1
1
1
1
1
MeI
I2
1a, R0 ¼ Me (82)
1b, R0 ¼ I (80)
TMSCl
ClCO2Me
PhSSPh
PhCHO
1c, R0 ¼ TMS (65)
1d, R0 ¼ CO2Me (86)
1e, R0 ¼ SPh (79)
1f,R0 ¼ CHOHPh (59)
1g, R0 ¼ COPh (24)
MeI
MeI
MeI
—
2
3
4
3a (65)
—
MeI
5
5a (85)

3-Functionalization of Isoindazoles
287
Scheme 1.
lithium alkoxide, with concomitant reduction of benzaldehyde to benzyl
alcohol (Scheme 1). Although this type of reaction is generally associated
with aluminum alkoxides, examples are known for other metal alkoxides,
including those of lithium.[3]
We further investigated the scope of this 3-functionalization with the
attempted methylations of the additional substrates shown in Table 1. We
obtained a good yield for the methylation of 2-methyl-5-bromoisoindazole
3. This result is particularly noteworthy because it demonstrates the compat-
ibility of our method with halide substituents. The method was, however,
unsatisfactory for 2-benzylisoindazole 2 and for 2-methyl-5-nitroisoindazole
4. In both cases, multiple products were evident by TLC analysis, and the
reactions were not investigated further.
We also attempted to methylate 1-methylindazole 5 using the same con-
ditions used to methylate 2-methylisoindazole 1, and we observed a clean
reaction, but it did not give the desired 1,3-dimethylindazole product.
Instead, we isolated 2-dimethylaminobenzonitrile 5a in 85% yield. A
probable mechanism for this transformation is shown in Scheme 2. Initial
formation of the expected 3-lithioindazole could be followed by a Kemp-
type elimination reaction,[4] with concomitant N-N bond cleavage, to form
an intermediate 2-lithioamidobenzonitrile. This species would be the one
quenched by methyl iodide to form the observed product. A closely related
reaction has been reported in which 1-substituted indazoles yield
Scheme 2.

288
A. Bunnell et al.
2-aminobenzophenones upon treatment with organolithiums[5a] (for a related
reaction involving pyrazolo[4,3-d]pyrimidines, see Ref.[5b]).
Our original literature search for methods of functionalizing the 3-position
of isoindazoles yielded only a few additional hits.[2] Uff and coworkers have
reported a multistep methylation sequence, and Boucher and coworkers
have reported an amination reaction applicable to nitroindazoles. There are
also reports of electrophilic brominations. With the exception of some
brominations, the reactions tend to be low yielding, and all are of limited
scope. The simple metalation–electrophilic quench sequence described here
is therefore a particularly attractive route to this class of compound.
EXPERIMENTAL
General
All reactions were run under nitrogen in oven-dried glassware. Preparations
of 2-methylindazole 1,[1d,6] 2-benzylisoindazole 2,[7] 2-methyl-5-bromo-
isoindazole 3,[8] and 1-methylindazole 5[1d] are known in the literature. All
other reagents were commercially available and were used as received.
Anhydrous tetrahydrofuran was purchased from Aldrich Chemical
1
Company and used as received. Melting points recorded are uncorrected. H
NMR and 13C NMR spectra were recorded at 300 MHz and 75.40 MHz
respectively using a Bruker AMX300 instrument using CDCl3 or DMSO-d6
as solvent, with tetramethylsilane as the internal standard. Some of the
products have been previously prepared by alternative methods (2,3-dimethy-
lisoindazole 1a,[2b] 3-iodo-2-methylisoindazole 1b,[1c] 3-methoxycarbonyl-2-
methylisoindazole 1d,[9] 3-(1-hydroxybenzyl)-2-methylisoindazole 1f,[1b] and
2-dimethylaminobenzonitrile 5a[10]).
General Procedure for the Preparation of Isoindazoles 1(a–g)
A 1.6 M solution of n-butyl lithium hexanes (0.59 mL, 0.94 mmol) was added
to a solution of diisopropylethylamine (0.13 mL, 0.93 mmol) in 3 mL of tetra-
hydrofuran at 2 788C. The solution was stirred at 0–5 8C for 10 min and then
rechilled to 2788C. Isoindazole 1 (0.761 mmol) was added, and the resulting
solution was stirred at 0–58C for 10–15 min and then rechilled to 2788C. The
appropriate electrophile was then added all at once. Further details for each
compound are described next.
2,3-Dimethylisoindazole (1a)
After addition of iodomethane (0.060 mL, 0.96 mmol), the solution was stirred
at 2788C for 2 h. A saturated aqueous NH4Cl solution (5 mL) was added, and

3-Functionalization of Isoindazoles
289
the mixture was extracted with three 5 mL portions of ethyl acetate. The
combined organic layers were dried over MgSO4, filtered, and concentrated
to an orange oil, which was further purified by silica-gel chromatography
(0 ! 50% EtOAc/hexanes) to afford 0.092 g (82%) of 2,3-dimethylisoinda-
zole as a white solid: mp 76–788C; IR (KBr) 3046, 2921, 1629, 1502, 1437,
1367, 1286 cm21; 1H NMR (CDCl3) d 7.60–7.64 (m, 1 H), 7.53–7.56 (m, 1
H), 7.23–7.28 (m, 2 H), 4.10 (s, 3 H), 2.61 (s, 3 H); 13C NMR (CDCl3) d
148.1, 131.6, 126.4, 121.5, 120.8, 119.9, 117.2, 37.7, 10.3; ESI-MS m/z
147 (M þ 1) 100%. Anal. calc. for C9H10N2: C, 73.94; H, 6.90; N, 19.17.
Found: C, 73.98; H, 6.86; N, 19.16.
3-Iodo-2-methylisoindazole (1b)
After addition of iodine (0.230 g, 0.906 mmol), the solution was stirred at
2788C for 2 h. A 10% aqueous sodium thiosulfate solution (5 mL) was
added, and the mixture was extracted with three 5 mL portions of ethyl
acetate. The combined organic layers were dried over MgSO4, filtered, and
concentrated to an orange solid, which was further purified by silica-gel
chromatography (0 ! 50% EtOAc/hexanes) to afford 0.197 g (80%) of
3-iodo-2-methylisoindazole as a white solid: mp 151–1528C; IR (KBr)
1
3056, 3025, 2935, 1620, 1545, 1497, 1397, 1278, 1232 cm21; H NMR
(CDCl3) d 7.64–7.67 (m, 1 H), 7.37–7.41 (m, 1 H), 7.29–7.34 (m, 1 H),
7.10–7.15 (m, 1 H), 4.26 (s, 3 H); 13C NMR (CDCl3) d 150.2, 128.3, 127.7,
123.3, 121.2, 118.6, 76.6, 41.8; ESI-MS m/z 259 (M þ 1) 100%. Anal. calc.
for C8H17IN2: C, 37.23; H, 2.73; N, 10.86. Found: C, 37.63; H, 2.72; N, 10.66.
2-Methyl-3-trimethylsilylisoindazole (1c)
After addition of chlorotrimethylsilane (0.115 mL, 0.909 mmol), the solution
was stirred at 2788C for 2 h. A saturated aqueous NH4Cl solution (5 mL)
was added, and the mixture was extracted with three 5-mL portions of ethyl
acetate. The combined organic layers were dried over MgSO4, filtered, and
concentrated to a yellow oil, which was further purified by silica-gel chrom-
atography (0 ! 50% EtOAc/hexanes) to afford 0.101 g (65%) of 2-methyl-
3-trimethylsilylisoindazole as a white solid: mp 50–518C; IR (KBr) 3046,
1
2956, 1543, 1457, 1421, 1367, 1339, 1280, 1249 cm21; H NMR (CDCl3) d
7.72–7.78 (m, 2 H), 7.25–7.30 (m, 1 H), 7.04–7.09 (m, 1 H), 4.29 (s, 3 H),
0.53 (s, 9 H); 13C NMR (CDCl3) d 148.2, 135.2, 129.7, 125.4, 121.4, 121.2,
117.1, 41.3, 0.0; ESI-MS m/z 205 (M þ 1) 100%. Anal. calc. for
C11H16N2Si: C, 64.66; H, 7.89; N, 13.71. Found: C, 64.56; H, 7.83; N, 13.54.
3-Methoxycarbonyl-2-methylisoindazole (1d)
After addition of methyl chloroformate (0.07 mL, 0.91 mmol), the solution
was stirred overnight and allowed to slowly warm to room temperature.

290
A. Bunnell et al.
A saturated aqueous NH4Cl solution (5 mL) was added, and the mixture was
extracted with three 5-mL portions of ethyl acetate. The combined organic
layers were dried over MgSO4, filtered, and concentrated to an orange
liquid, which was further purified by silica-gel chromatography (0 ! 50%
EtOAc/hexanes) to afford 0.123 g (86%) of 3-methoxycarbonyl-2-methyli-
soindazole as a pale yellow solid: mp 61–628C; IR (KBr) 2956, 1712, 1508,
1477, 1454, 1438, 1402, 1369, 1285, 1211 cm21; 1H NMR (CDCl3) d 8.00–
8.03 (m, 1 H), 7.76–7.79 (m, 1 H), 7.28–7.38 (m, 2 H), 4.53 (m, 3 H), 4.04
(m, 3 H); 13C NMR (CDCl3) d 160.9, 147.3, 126.3, 125.0, 124.1, 123.5,
121.2, 118.1, 52.0, 41.4; ESI-MS m/z 191 (M þ 1) 100%. Anal. calc. for
C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.31; H, 5.28; N, 14.63.
2-Methyl-3-thiophenylisoindazole (1e)
After addition of diphenyl disulfide (0.198 g, 0.907 mmol), the solution was
stirred at 2788C for 3 h. A 10% aqueous NaOH solution (5 mL) was added,
and the mixture was extracted with three 5-mL portions of ethyl acetate.
The combined organic layers were dried over MgSO4, filtered, and
concentrated to a yellow-orange liquid, which was further purified by silic-
gel chromatography (0 ! 50% EtOAc/hexanes) to afford 0.143 g (79%) of
2-methyl-3-thiophenylisoindazole as a yellow liquid: IR (KBr) 3057, 2943,
1
1626, 1582, 1502, 1478, 1286, 1241 cm21; H NMR (CDCl3) d 7.74–7.78
(m, 1 H), 7.65–7.69 (m, 1 H), 7.32–7.38 (m, 1 H), 7.12–7.25 (m, 4 H),
6.98–7.06 (m, 2 H), 4.21 (s, 3 H); 13C NMR (CDCl3) d 148.5, 135.7,
129.8, 127.4, 127.0, 126.9, 126.7, 123.6, 123.5, 120.2, 118.3, 38.5; ESI-MS
m/z 241 (M þ 1) 100%. Anal. calc. for C14H12N2S: C, 69.97; H, 5.03; N,
11.66. Found: C, 70.11; H, 4.99; N, 11.55.
3-(1-Hydroxybenzyl)-2-methylisoindazole (1f) and 2-Methyl-
3-phenylcarbonylisoindazole (1g)
After addition of benzaldehyde (0.09 mL, 0.88 mmol), the solution was stirred
overnight and allowed to slowly warm to room temperature. A saturated
aqueous NH4Cl solution (5 mL) was added, and the mixture was extracted
with three 5-mL portions of ethyl acetate. The combined organic layers
were dried over MgSO4, filtered, and concentrated to a yellow oil, which
was further purified by silica-gel chromatography (0 ! 50% EtOAc/
hexanes) to afford two products: 2-Methyl-3-phenylcarbonylisoindazole
(1g) eluted first (0.043 g, 24%) as a yellow oil: IR (KBr) 3056, 2952, 1639,
1597, 1578, 1453, 1405, 1361, 1279, 1226 cm21; 1H NMR (CDCl3) d 7.79–
7.88 (m, 3 H), 7.65–7.70 (m, 1 H), 7.51–7.56 (m, 2 H), 7.29–7.34 (m, 1
H), 7.04–7.13 (m, 2 H), 4.52 (s, 3 H); 13C NMR (CDCl3) d 186.6, 147.8,
139.1, 133.6, 131.9, 130.1, 129.0, 126.5, 125.0, 123.9, 120.9, 118.6, 41.8;
ESI-MS m/z 237 (M þ l), 100%. Anal. calc. for C15H12N2O: C, 76.25;

3-Functionalization of Isoindazoles
291
H, 5.12; N, 11.86. Found: C, 76.18; H, 5.02; N, 11.65. 3-(1-Hydroxybenzyl)-
2-methylisoindazole (1f) eluted second (0.195 g, 59%) as a pale yellow solid:
mp 1158C; IR (KBr) 3386, 3059, 2923, 2852, 2645, 1623, 1496, 1451, 1432,
1403, 1384, 1288 cm21; 1H NMR (CDC13) d 7.51–7.54 (m, 1 H), 7.22–7.30
(m, 6 H), 7.16–7.21 (m, 1 H), 6.89–6.95 (m, 1 H), 6.29 (s, 1 H), 3.87 (s, 3 H),
3.42–3.64 (br s, 1 H); 13C NMR (CDCl3) d 147.5, 140.5, 136.5, 129.1, 128.5,
126.8, 126.6, 122.2, 121.1, 120.4, 117.1, 68.2, 39.0; ESI-MS m/z 239 (M þ 1)
100%. Anal. calc. for C15H14N2O: C, 75.60; H, 5.92; N, 11.76. Found: C,
75.28; H, 5.88; N, 11.61.
5-Bromo-2,3-dimethylisoindazole (3a)
A 1.6 M solution of n-butyl lithium in hexanes (0.37 mL, 0.60 mmol) was
added to a solution of diisopropylethylamine (0.080 mL, 0.57 mmol) in
3 mL of tetrahydrofuran at 2788C. The solution was stirred at 0–58C for
10 min and then rechilled to 2788C. 5-Bromo-2-methylisoindazole 3
(0.100 g, 0.476 mmol) was added; the solution was stirred at 0–58C for
15 min and then rechilled to 2788C. Iodomethane (0.035 mL, 0.57 mmol)
was added, and the solution was stirred overnight, allowing it to slowly
warm to room temperature. A saturated aqueous NH4Cl solution (5 mL) was
added, and the mixture was extracted with three 5-mL portions of ethyl
acetate. The combined organic layers were dried over MgSO4, filtered, and
concentrated to an orange solid, which was further purified by silica-gel
chromatography (0 ! 50% EtOAc/hexanes) to afford 0.069 g (65%) of
5-bromo-2,3-dimethylisoindazole as a white solid: mp 110–1138C; IR
1
(KBr) 2919, 2852, 1624, 1495, 1443, 1328, 1261 cm21; H NMR (DMSO-
d6) d 7.94 (d, J ¼ 1.9 Hz, 1 H), 7.47 (d, J ¼ 9.1 Hz, 1 H), 7.26 (dd, J ¼ 9.1
Hz, 1.9 Hz, 1H), 4.04 (s, 3 H), 2.58 (s, 3 H); 13C NMR (DMSO-d6) d
145.5, 132.2, 128.8, 122.8, 122.4, 119.1, 112.4, 37.8, 9.7; ESI-MS m/z 225
(M þ 1) 100%, 145 (M-Br) 25%. Anal. calc. for C9H9BrN2: C, 48.03; H,
4.03; N, 12.45. Found: C, 48.07; H, 3.91; N, 12.35.
2-Dimethylaminobenzonitrile (5a)
A 1.6 M solution of n-butyl lithium in hexanes (0.59 mL, 0.94 mmol) was
added to a solution of diisopropylamine (0.13 mL, 0.93 mmol) in 3 mL of
tetrahydrofuran at 2788C. The solution was stirred at 0–58C for 10 min
and then rechilled to 2788C. 1-Methyl indazole 5 (0.101 g; 0.764 mmol)
was added; the solution was stirred at 0–58C for 15 min and then rechilled
to 2788C. Iodomethane (0.060 mL, 0.96 mmol) was added, and the solution
was stirred overnight, allowing it to slowly warm to room temperature. A
saturated aqueous NH4Cl solution (5 mL) was added, and the mixture was
extracted with three 5-mL portions of ethyl acetate. The combined organic
layers were dried over MgSO4, filtered, and concentrated to an oily, orange
solid, which was further purified by silica-gel chromatography (0 ! 50%

292
A. Bunnell et al.
EtOAc/hexanes) to afford 0.095 g (85%) of 2-dimethylaminobenzonitrile as a
colorless liquid: IR (KBr) 3018, 2917, 2216, 1599, 1502, 1433, 1342, 1216
1
cm21; H NMR (CDCl3) d 7.49–7.52 (m, 1 H), 7.38–7.44 (m, 1 H), 6.88–
6.90 (m, 1 H), 6.81–6.86 (m, 1 H), 3.05 (appar s, 6 H) [lit. (CDCl3, 60
MHz) d 7.20–7.56 (m, 2 H), 6.68–6.93 (m, 2 H), 2.90 (s, 6 H)[10b] 13C
;
NMR (CDCl3) d 155.7, 135.4, 133.8, 120.1, 119.5, 117.1, 101.7, 43.4 [lit.
(CDCl3, 400 MHz) d 155.7, 135.4, 133.9, 120.1, 119.6, 117.2, 101.7,
43.5[10c]; ESI-MS m/z 147 (M þ 1), 100%.
REFERENCES
1. (a) Tertov, B. A.; Onishchenko, P. P. Organolithium compounds of 1-methyl- and
2-methylindazole. Khim. Geterotsiklicheskikh Soedin. 1970, 10, 1435;
(b) Tertov, B. A.; Onishchenko, P. P. Organolithium and -magnesium
compounds of N-substituted indazole. Zh. Obshch. Khim. 1971, 41 (7),
1594–1599; (c) Tertov, B. A.; Onishchenko, P. P.; Morkovnik, A. S.;
Bessonov, V. V. Synthesis of haloazoles. Khim. Geterotsiklicheskikh Soedin.
1973, 8, 1109–1111; (d) da Costa, M. R. G.; Curto, M. J. M.; Davies, S. G.;
Duarte, M. T.; Resende, C.; Teixeira, F. C. Novel synthesis of indazoles from
(n6-arene)tricarbonylchromium complexes. J. Organomet. Chem. 2000, 604 (2),
157–169.
2. (a) Stadlbauer, W. Product class 2: 1H- and 2H-indazoles. Sci. Synth. 2002, 12,
227–325; (b) Uff, B. C.; Ho, Y.-P.; Popp, F. D. Benzologous Reissert
compound formation from 2-methylindazole. Synth. Commun. 1989, 19 (7–8),
1239–1245; (c) Bouchet, P.; Lazaro, R.; Benchidmi, M.; Elguero, J. Photochimie
d’heterocycles azotes-VI: Synthese par voie photochimique d’amino et d’alkoxy
indazoles. Tetrahedron 1980, 36 (24), 3523–3533.
3. Warnhoff, E. W.; Reynolds-Warnhoff, P.; Wong, Y. H. Cation-medium control of
hydride transfer between carbonyl Groups. J. Am. Chem. Soc. 1980, 102 (18),
5956–5957.
4. Casey, M. L.; Kemp, D. S.; Paul, K. G.; Cox, D. D. The physical organic chemistry
of benzisoxazoles. I. The mechanism of the base-catalyzed decomposition of
benzisoxazoles. J. Org. Chem. 1973, 38 (13), 2294–2301.
5. (a) Tertov, B. A.; Onishchenko, P. P.; Koshchienko, Y. V.; Suvorova, G. M.;
Malysheva, Y. N. Splitting of the nitrogen–nitrogen bond in 1-substituted
indazoles in the presence of lithium aryls. Khim. Geterotsiklicheskikh Soedin.
1982, 8, 1078–1081; (b) Stone, T. E.; Eustace, E. J.; Pickering, M. V.;
Daves, G. D., Jr. Pyrazolo [4,3-d]pyrimidines. Regioselectivity of N-alkylation.
Formation, rearrangement, and aldehyde coupling reactions of 3-lithio derivatives.
J. Org. Chem. 1979, 44 (4), 505–509.
6. Cheung, M.; Boloor, A.; Stafford, J. Efficient and regioselective synthesis of
2-alkyl-2H-indazoles. J. Org. Chem. 2003, 68 (10), 4093–4095.
7. Claramunt, R. M.; Elguero, J.; Garceran, R. Synthesis by phase transfer catalysis of
N-benzyl, N-diphenylmethyl and N-triphenylmethyl azoles and benzazoles: Proton
NMR and chromatographic data as a tool for identification. Heterocycles 1985,
23 (11), 2895–2906.
8. Challenger, S.; Cook, A. S.; Gillmore, A. T.; Middleton, D. S.; Pryde, D. C.;
Cameron, D.; Stobie, A. Preparation of cyclopentyl-substituted glutaric acid

3-Functionalization of Isoindazoles
293
monoamides as neutral endopeptidase inhibitors for treating female sexual arousal
disorder arid related conditions. WO, 2002079143, 2002.
9. Fludzinski, P.; Evrard, D. A.; Bloomquist, W. E.; Lacefield, W. B.; Pfeifer, W.;
Jones, N. D.; Deeter, J. B.; Cohen, M. L. Indazoles as indole bioisosteres:
Synthesis and evaluation of the tropanyl ester and amide of indazole-3-carboxylate
as antagonists at the serotonin 5HT3 receptor. J. Med. Chem. 1987, 30 (9),
1535–1537.
10. (a) Idoux, J. P.; Gupton, J. T.; Colon, C. Aromatic nucleophilic substitution II. The
reaction of chlorobenzonitriles and Chloronitrobenzenes with HMPA. Synth.
Commun. 1982, 12 (12), 907–914; (b) Gupton, J. T.; Idoux, J. P.; Baker, G.;
Colon, C.; Crews, A. D.; Jurss, C. D.; Rampi, R. C. Reaction of activated aryl
and heteroaryl halides with hexamethylphosphoramide. J. Org. Chem. 1983,
48 (17), 2933–2936; (c) Zanon, J.; Klapars, A.; Buchwald, S. L. Copper-
catalyzed domino halide exchange-cyanation of aryl bromides. J. Am. Chem.
Soc. 2003, 125 (10), 2890–2891.