Palladium-catalyzed direct Heck arylation of dual π-deficient/π- excessive heteroaromatics. Synthesis of C-5 arylated imidazo[1,5-a]pyrazines

Article abstract of DOI:10.1021/ol800761r

(Chemical Equation Presented) A general and efficient synthesis of 5-aryl imidazo[1,5-a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives with aryl halides is described. The scope of this new reaction for the imidazo[1,5-a]pyrazine ring system was explored using three readily available 8-substituted precursors, X = NH₂, NMe₂, and OMe, as well as 8-aryl derivatives, X = Ar?. On the basis of these results as well as studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation.

Full text of DOI:10.1021/ol800761r

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2923-2926
Palladium-Catalyzed Direct Heck
Arylation of Dual π-Deficient/
π-Excessive Heteroaromatics. Synthesis
of C-5 Arylated Imidazo[1,5-a]pyrazines
Jian-Xin Wang,† J. Adam McCubbin,† Meizhong Jin,‡ Radoslaw S. Laufer,‡
Yunyu Mao,‡ Andrew P. Crew,‡ Mark J. Mulvihill,‡ and Victor Snieckus*,†
Department of Chemistry, Queen’s UniVersity, Kingston, Ontario, Canada K7L 3N6,
and OSI Pharmaceuticals, Inc., 1 Bioscience Park DriVe,
Farmingdale, New York 11735
snieckus@chem.queensu.ca
Received April 3, 2008
ABSTRACT
A general and efficient synthesis of 5-aryl imidazo[1,5-a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives
with aryl halides is described. The scope of this new reaction for the imidazo[1,5-a]pyrazine ring system was explored using three readily
available 8-substituted precursors, X ) NH2, NMe2, and OMe, as well as 8-aryl derivatives, X ) Ar′. On the basis of these results as well as
studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation.
Transition metal catalyzed reactions1 have assumed a
dominant position in CsC as well as CsN and CsO bond-
forming reactions of synthetic value, especially for the
construction of biaryls of medicinal, natural product, and
material science significance.2 In recent years, a new
generation of transition metal catalyzed direct arylation
reactions3 has emerged in which one of the preactivated
species of the standard cross coupling mode (ArX or ArMet)
is a bare aromatic (ArH)3a,4,5 (Figure 1) as a prelude perhaps
to the ultimate regioselective coupling of two unactivated
coupling partners. The Heck reaction, of the same vintage6
as some of the other cross coupling named reactions1 and
(2) (a) Synthesis of Biaryls; Cepanec, I., Ed.; Elsevier: Oxford, U.K.,
2004. (b) Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653,
150. (c) Echavarren, A. M.; Gomez-Lor, B.; Gonzalez, J. J.; de Frutos, O.
Synlett 2003, 585. (d) Hassan, J.; Sevignon, M.; Gozzi, C.; Schultz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359. (e) Bringmann, G.; Tasler, S.;
Pfeifer, R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49. (f)
Stanforth, S. P. Tetrahedron 1998, 54, 263. (g) Bringmann, G. Angew.
Chem., Int. Ed. Engl. 1990, 29, 977. (h) Zapf, A.; Beller, M.; Riermeier,
T. H. In Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 231.
(3) For a rationale for the adoption of this terminology over the currently
widely used C-H activation designation: (a) Campeau, L.-C.; Fagnou, K.
Chem. Commun. 2006, 1253. See also: (b) Sezen, B.; Sames, D. In
Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-VCH: Wein-
heim, 2005; p 3.
† Queen’s University.
‡ OSI Pharmaceuticals, Inc.
(1) For summaries of state of the art for various, including name,
reactions, see: (a) Metal Catalyzed Cross Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. Dedicated
special issue of 30 years of cross-coupling: (b) Tamao, K.; Hiyama, T.;
Negishi, E.-i. J. Organomet. Chem. 2002, 653. For recent updated reviews,
see Stille: Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
4704. Hiyama: (c) Denmark, S. E.; Sweis, T. F. Acc. Chem. Res. 2002, 35,
835. Suzuki-Miyaura: (d) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871.
(4) For other reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. ReV. 2007, 107, 174. (b) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077. (c) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35,
826. (d) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (e)
Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
10.1021/ol800761r CCC: $40.75
Published on Web 06/25/2008
2008 American Chemical Society

ladium-catalyzed regioselective direct C-5 arylation reaction,
1 f 2. Herein, we report the first Heck-like reaction on this
combined π-deficient/π-excessive ring system which has a
broad scope and, in consonance with aims of the evolving
nonactivated coupling methods,3a,4 demonstrates the advan-
tages of minimizing waste and overcomes the requirement
for frequently unstable organometallic coupling partners, a
factor which is of wide-ranging significance in the construc-
tion of heterocyclic systems.10 Electronic substituent variation
on substrates and deuterium isotope studies suggest a Heck-
like mechanism for this reaction.
Figure 1. Direct arylation of aromatic compounds.
receiving similar broad adoption in synthesis in inter- and
intramolecular processes,7 has in fact been recently identified
in the oxidative mode in which both arene and olefinic
partners are unfunctionalized. Such reactions, as yet scattered
in the literature, named either oxidative Heck or Heck-type
processes, appear to be dependent in terms of rate and
regioselectivity on substrate electrophilicity, especially in
π-excessive heteroaromatics, and on coordination factors.8
As part of the continuing exploration of new chemistry
of the imidazo[1,5-a]pyrazine core,9 we discovered a pal-
The initial C-5 arylation reaction was observed when the
model 8-amino-3-methylimidazo[1,5-a]pyrazine 111 was
subject to Pd-catalyzed coupling with 4-bromotoluene under
Cs2CO3/PPh3/DMF/120 °C conditions. The structure of the
11
1
product 2 was established by H NMR. The low yield of
the reaction (Table 1, entry 1) prompted screening studies,
(5) For recent reports categorized by classes of compounds, see, inter
alia: simple aromatics: (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 16496. (b) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 581. (c) Lafrance, M.; Rowley, C. N.; Woo,
T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (d) Huang, Q.; Fazio,
A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2004, 126,
7460. ArBr with aromatics bearing Lewis basic directing groups: (e)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (f)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (g) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 1698. (h) Bedford, R. B.; Coles, S. J.;
Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112.
Pyrroles and indoles: (i) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 4996. (j) Lane, B. S.; Brown, M. A.; Sames, D. J. Am.
Chem. Soc. 2005, 127, 8050. (k) Lane, B. S.; Sames, D. Org. Lett. 2004,
6, 2897. (l) Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2002, 124, 5286. Thiazoles: (m) Mori, A.; Sekiguchi, A.; Masui, K.;
Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am.
Chem. Soc. 2003, 125, 1700. Intramolecular cases: (n) Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (o)
Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc.
2004, 126, 9186. (p) Huang, Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock,
R. C. J. Am. Chem. Soc. 2004, 126, 7460.
Table 1. Optimization of C-5 Arylation Conditions for 1c
entry
[Pd]/liganda
Pd(OAc)2/PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2/P(tBu)3·HBF4
Pd(OAc)2/PCy3·HBF4
Pd(OAc)2/MeP(tBu)2·HBF4 DMF
PdCl2/MeP(tBu)2·HBF4
Pd2dba3/MeP(tBu)2·HBF4
solventb
X
conversion/%
1
2
3
4
5
6
7
8
9
10
DMF
DMF
DMSO Br
DMF
DMF
DMF
Br
Br
25
37
46
30
53
44
69
68
22
34
I
Br
Br
Br
Br
Br
Cl
(6) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(7) For a review, see: (a) Bra¨se, S.; de Meijere, A. In Metal Catalyzed
Cross Coupling Reactions; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 217-317. For insightful mechanistic
discussion, see: (b) Beletskaya, I.; Cheprakov, A. V. Chem. ReV. 2000, 100,
3009.
DMF
DMF
Pd(OAc)2/MeP(tBu)2·HBF4 DMF
a Pd:L ) 1:2 (molar ratio). b Substrate concentration ) 0.2 M.
c Conversion determined by reverse-phase HPLC using 4-methoxy-benzoic
acid as an internal standard.
(8) For original studies, see: (a) Moritani, I.; Fujiwara, Y. Tetrahedron
Lett. 1967, 12, 1119. (b) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.;
Teranish, S. J. Am. Chem. Soc. 1969, 91, 7166. For recent work, see: (c)
Jia, C. G.; Lu, W. J.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097.
(d) Yokta, T.; Tani, S.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003,
125, 1476. (e) Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69,
1221. For current activity, according to compound type, see carbo- and
heterocycles and intramolecular reactions: (f) Garcia-Cuadrado, D.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128,
1066. (g) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa,
M.; Ihara, M. Org. Lett. 2002, 4, 4293. (h) Hennessy, E. J.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 12084. (i) Hughes, C. C.; Trauner, D.
Angew. Chem., Int. Ed. 2002, 41, 1569. Thiophenes, furans: (j) Glover, B.;
Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003,
5, 301. Pyrroles, indoles: (k) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am.
Chem. Soc. 2004, 126, 9552. (l) Zhang, H. M.; Ferreira, E. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2004, 43, 6144. (m) Grimster, N. P.; Gauntlett, C.;
Godfrey, C. D.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (o)
Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc.
2006, 128, 2528. Indolizines: (p) Park, C.-H.; Ryabova, V.; Seregin, I. V.;
Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. Imidazo[1,2-
a]pyrimidines: (q) Li, W. J.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.;
Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835. Anilides: (r)
Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586. (s) Lee, G. T.; Jiang, X.; Prasad, K.; Repic, O.; Blacklock,
T. J. AdV. Synth. Catal. 2005, 347, 1921.
a selection of which is given in Table 1 and deserves brief
comment. Use of preformed Pd(PPh3)4 in DMF or DMSO
in reactions of 1 with 4-bromo- or 4-iodotoluene showed
modest improvement or little change in the efficiency of the
reaction (entries 2-4). Significant improvement resulted
(9) This ring system shows remarkable antitumor, antimicrobial, and
cardiovascular activities. See: (a) Beck, P. A.; Cesario, C.; Cox, M.; Dong,
H.-Q.; Foreman, K.; Mulvihill, M. J.; Nigro, A. I.; Saroglou, L.; Steinig,
A. G.; Sun, Y.; Weng, Q.; Werner, D.; Wilkes, R.; Williams, J. U.S. Patent
0084654, 2006. (b) Mulvihill, M. J.; Ji, Q.-S.; Coate, H. R.; Cooke, A.;
Dong, H.; Feng, L.; Foreman, K.; Rosenfeld-Franklin, M.; Honda, A.; Mak,
G.; Mulvihill, K. M.; Nigro, A. I.; O’Connor, M.; Pirrit, C.; Steinig, A. G.;
Siu, K.; Stolz, K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.; Gibson, N. W.
Bioorg. Med. Chem. 2008, 16, 1359. See also (c) Demrayak, S.; Kayagil,
I. J. Heterocycl. Chem. 2005, 42, 319.
(10) Tyrrell, E.; Brooks, P. Synthesis 2003, 469.
(11) See Supporting Information.
2924
Org. Lett., Vol. 10, No. 14, 2008

when the reactions were carried out using catalytic
Pd(OAc)25b and the stable and easily handled phosphonium-
BF4 salts12 as ligands (entries 5-7) with the MeP(tBu)2·HBF4
(entry 7) showing the best conversion.13 Variation of the Pd
source in the coupling of 1 with 4-bromotoluene resulted in
either no significant change or a decrease in yield of product
(entries 8 and 9). The lower yields in reactions of aryl iodide
compared to aryl bromide (entries 2 and 4) are consistent
with previous observations in similar reactions5b as is the
lower reactivity of aryl chlorides (entry 10).14
Scheme 1
.
General Synthesis of 8-Aryl-3-Substituted
Imidazo[1,5-a]pyrazines
With optimized conditions in hand, the scope of the C-5
arylation reaction was investigated (Table 2). First, the
2). Using the same conditions, product 4 was obtained in
significantly improved yields (entry 2). Extension to two
other aryl bromides gave products 4b and 4c (entries 3 and
4) in good yields. Generalization was then extensively carried
out on the 8-methoxy derivative 5.11 As gleaned from Table
2, synthetically useful yields of products were observed for
coupling reactions of a variety of aryl bromides. As was the
case for 3, the 8-methoxy system 5 underwent smooth
coupling at accelerated rates compared to the corresponding
8-amino imidazopyrazine 1 (entries 2 and 5 vs entry 1).
Using EWG (entries 6-10) and EDG (entries 11-15)
bearing aryl bromide coupling partners gave products in very
good to excellent yields. However, while strong EDG 3- and
4-OMe substitution (entries 17 and 18) was well tolerated,
the corresponding 2-OMe and 2,4-diOMe derivatives (entries
16 and 19) provided product with decreased efficacy. Ester
and amide EWG substituted coupling partners gave moderate
yields of products (entries 21-24), while cyano and nitro
substituted aryl bromides were found to be unstable to the
reaction conditions and resulted in decomposition. The
sterically hindered mesityl bromide16 failed to react under
the specified conditions (120 °C, 36 h). Unequivocal
confirmation of the structure of a representative C-5 arylated
product was obtained in the form of the X-ray structure of
compound 6a and 6n.
Table 2. Scope of Coupling of 8-Substituted Imidazopyrazines
entry
R′
Ar-X
time/h product (% yield)
(61)
1
NH2
4-Me-C6H4Br
36
12
24
36
12
12
12
12
12
12
24
12
36
12
12
24
12
12
24
12
12
12
36
36
2
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
NMe2 4-Me-C6H4Br
NMe2 4-F-C6H4-Br
NMe2 4-MeO-C6H-Br
4a (85)
4b (88)
4c (74)
6a (85)
6b (95)
6c (87)
6d (80)
6e (87)
6f (85)
6g (81)
6h (92)
6i (84)
6i (73)
6j (84)
6k (45)
6l (80)
6m(89)
6n (65)
6o (51)
6p (70)
6q (66)
6r (47)
6s (55)
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
PhBr
4-F-C6H4Br
2-F-C6H4Br
4-CF3-C6H4Br
3-CF3-C6H4Br
4-Cl-C6H4Br
4-Me-C6H4Br
3-Me-C6H4Br
2-Me-C6H4Br
2-Me -C6H4I
4-Ph-C6H4Br
To understand the mechanism of the direct arylation
reaction, the 8-arylimidazopyrazines 8a-d, positing EDGs
2-MeO-C6H4Br
3-MeO-C6H4Br
4-MeO-C6H4Br
2,4-diMeO-C6H3Br
4-Me2N-C6H4Br
4-MeO2C-C6H4Br
3-MeO2C-C6H4Br
2-MeO2C-C6H4Br
3-Me2NOC-C6H4Br
Table 3. EWG and EDG Substituent Effects on Coupling of 8
hypothesis that the 8-amino primary amine functionality may
compromise yields15 was tested by changing the substrate
to the corresponding 8-dimethylamino derivative 311 (Table
(12) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(13) Increasing the ligand to catalyst ratio to 4:1 had no significant effect,
whereas decreasing it to 1:1 resulted in a ca. 30% decrease in conversion.
Changing the concentration of the reaction to 0.4 M and to 0.8 M resulted
in a moderate but steady decrease in conversion.
(14) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(15) For a proposal in the reaction of aminopyrimidine, see: Itoh, T.;
Mase, T Tetrahedron Lett. 2005, 46, 3573.
entry substrate
R′′
time/h product (yield/%)
1
2
3
4
8a
8b
8c
8d
4-MeO-C6H4
4-F-C6H4
3-NO2-C6H4
4-NO2-C6H4
11
10
8
9a(99)
9b(99)
9c(98)
9d(97)
4
Org. Lett., Vol. 10, No. 14, 2008
2925

abstraction,5a,c,8f and σ-bond metathesis.8h,21 In addition, an
electrophilic substitution5j,8i,j,p,q mechanism, which would be
expected to give an inverse secondary KIE, is ruled out on
the basis of the results in Table 3.22 For the imidazopyrazine
core bearing EDGs, the controlling features may be associ-
ated with facile carbopalladation reactivity which is due to
a balance of electronic (combined π-deficient/π-excessive)
and N-coordination features.
Scheme 2
In summary, an efficient, regioselective, and direct C-5
arylation of imidazo[1,5-a]pyrazines 1, 3, and 5 has been
developed. A general methodology has been developed
allowing the synthesis of diverse substituted derivatives
(Table 2) in good to excellent yields. In contrast to direct
arylation of the imidazo[1,2-a]pyrimidines,8q arylation occurs
in the electron-deficient albeit EDG-containing ring. A Heck-
like mechanism, rather than alternative currently proposed
mechanisms for similar reactions, is consistent with reactivity
and KIE studies. This work, together with other contributions
in this area,5a,d,f,i,n,8j,p allows anticipation that transition metal
catalyzed coupling reactions in which one or both partners
are unactivated, thereby eliminating wasted steps and stability
issues, will increasingly appear in the tool box of the
synthetic chemist.
and EWGs, were prepared by treatment of 8-chloro derivative
717 with the corresponding aryl boronic acids by the
venerable Suzuki-Miyaura cross coupling protocol (Scheme
1) and evaluated. As recognized from examination of Table
3, 8a-d underwent rapid arylation under the standard
conditions to afford products 9a-d in quantitative yields.
The lack of an electronic effect (entry 1 vs entry 4) on the
reactivity suggests that an electrophilic palladation mecha-
nism, which is frequently suggested to rationalize arylation
of this type,5l,8j,k,q is not operating in the present case.
To further probe the mechanism of C-5 arylation, the
5-deutero analogue D-5 was prepared18 and subjected to the
optimum conditions using a 1:1 mixture of 5 and D-5
(Scheme 2). This experiment revealed no isotope effect (kH/D
∼ 1),19 a result consistent with a Heck-type mechanism8g
consisting of rate-determining carbopalladation (Scheme 3,
Acknowledgment. We gratefully acknowledge Dr. Joseph
Rechka and Dr. Arlindo L. Castelhano, OSI Pharmaceuticals,
Inc., for their valuable input, Dr. Johnathan Board, Queen’s
University, for assisting with the compilation of supplemen-
tary materials, and OSI Pharmaceuticals, Inc. for a grant to
V.S. in support of this work.
Scheme 3
Supporting Information Available: Preparation of start-
ing materials, experimental procedures, and full spectroscopic
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL800761R
10) followed by formation of an unprecedented π-azaallyl
intermediate 1120 and rapid reductive elimination to product
6. To the contrary, the observation of such a lack of a primary
KIE is inconsistent with C-H oxidative addition,21 proton
(19) The ratio of 5:D-5 in recovered starting material was determined
1
by peak integration in the H NMR spectrum.11
(20) This intermediate is analogous to those proposed for similar systems.
See for example, refs 8j and 4a. Acyclic 2-aza-π-allyl palladium intermedi-
ates have been proposed previously. See, for example: O’Donnell, M. J.;
Chen, N.; Zhou, C.; Murray, A. J. Org. Chem. 1997, 62, 3962.
(21) For computational studies, see: (a) Mota, A. J.; Dedieu, A.; Bour,
C.; Suffert, J. J. Am. Chem. Soc. 2005, 127, 7171. (b) Davies, D. L.; Donald,
S. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754.
(22) Furthermore, electrophilic bromination of such derivatives affords
the C1 bromination product only, which indicates that the imidazole ring
has the highest HOMO population: Abushanab, E.; Bindra, A. P.; Lee, D.-
Y. J. Org. Chem. 1975, 40, 3373.
(16) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 1162.
(17) Attempts to prepare the strongly electron-withdrawing 8-NO2 and
8-CN variants of 1 were unsuccessful.
(18) Treatment of 5 with n-BuLi followed by quench with MeOD
afforded D-5,11 a suprising result in view of the expected acidity of the
C-2 methyl hydrogens which is being experimentally pursued.
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Org. Lett., Vol. 10, No. 14, 2008