Synthesis of substituted imidazo[1,5-a]pyrazines via Mono-, Di-, and directed remote metalation strategies

Article abstract of DOI:10.1021/ol901889e

Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a-2g (Table 1), and 4a-4d (Table 2). Under similar conditions, the C3-methyl derivatives 2a and 5 undergo surprising reg

Full text of DOI:10.1021/ol901889e

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5118-5121
Synthesis of Substituted
Imidazo[1,5-a]pyrazines via Mono-, Di-,
and Directed Remote Metalation
Strategies
Johnathan Board,† Jian-Xin Wang,† Andrew P. Crew,*,‡ Meizhong Jin,‡
Kenneth Foreman,‡ 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; acrew@osip.com
Received August 13, 2009
ABSTRACT
Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a-2g
(Table 1), and 4a-4d (Table 2). Under similar conditions, the C3-methyl derivatives 2a and 5 undergo surprising regioselective C5-deprotonation
to afford, after electrophile quench, products 4b and 6a-6p (Table 3), results that are rationalized by quantum mechanical calculations.
Benzamide 7b, obtained from such metalation chemistry followed by Suzuki cross coupling, undergoes directed remote metalation-cyclization
to afford 8, representing the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one tricyclic ring system.
We have recently reported1 the first palladium catalyzed
Heck-type direct substitution reaction on the π-deficient
pyrazine ring of the imidazo[1,5-a]pyrazine framework
(Figure 1A). The dearth of knowledge concerning metalation
reactivity of this and related ring systems stimulated our
interest to undertake a systematic study to contribute to the
signficant area of carbanionic heteroaromatic chemistry.2
Herein we report results which demonstrate (a) regioselective
mono- as well as dimetalation of derivative 1 (Figure 1C)
and (b) C5 metalation of the C3-methyl derivative (Figure
1B), both leading to new imidazo[1,5-a]pyrazine derivatives
† Queen’s University.
‡ OSI Pharmaceuticals, Inc.
(2) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV. Hetero-
cycl. Chem. 1991, 52, 187. Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G.
Tetrahedron 2001, 57, 4489.
(1) Wang, J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew,
A. P.; Mulvihill, M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923.
10.1021/ol901889e CCC: $40.75
Published on Web 10/20/2009
 2009 American Chemical Society

which provide considerable potential for further manipulation
of this heterocyclic ring system. In addition, we establish a
new illustration of the directed remote metalation (DreM)
concept3 on the Suzuki-derived heterobiaryl 7 leading to the
new heterocyclic 2,5,11c-triazadibenzo[cd,f]azulen-7(6H)-
one framework 8. These results constitute the first investiga-
tion of carbanionic chemistry on the imidazo[1,5-a]pyrazine
ring system which is of current interest in the development
of new antimicrobial, cardiovascular, and antitumor drugs4
and which also portends broader significance for synthetic
studies for this and related heterocyclic systems.
Table 1. Synthesis of 3-Substituted
8-Chloroimidazo[1,5-a]pyrazines 2a-2g
EX
R1
product (%)a
1
2
3
4
5
6
7
8
MeI
DMF
Me
CHO
4-MeOC6H4CHOH
MesCHOH
CO2Me
Et2NCO
H
I
2a (70)b
2b (72)
2c (74)
2d (83)
2e (86)c
2f (65)
n.r.d
4-MeOC6H4C(O)H
Mesitaldehyde
CO2
ClCONEt2
ClSiMe3
I2
2g (78%)
a Yield of isolated material. b Purified by supercritical fluid chroma-
tography to remove bis-Me byproduct. c Isolated as the methyl ester due to
purification difficulties. d No reaction as confirmed by 1H NMR of the
recovered material.
Figure 1. The direct Heck and Suzuki-Miyaura reaction sites (A)
and observed metalation sites (B, C) for imidazo[1,5-a]pyrazines.
introduction of various electrophiles. Compound 1 was
treated with 2.3 equiv of nBuLi (optimal conditions)
followed by quench with 2.5 equiv of several electrophiles
to give C3/C5-disubstituted imidazopyrazines 4a-4d in
moderate to excellent yields (Table 2). The formation of
product with high deuterium incorporation (entry 1)
constitutes evidence for the intermediacy of the dilithiated
species 3.7 Consistent with the observation of Table 1,
entry 7, quench with 2.5 equiv of TMSCl gave only the
C5-silylated product 4d in moderate yield, presumably
owing to the derived C3-TMS derivative instability.
Nevertheless, this result remains of value since it poten-
tially offers access to other C5 analogues, either directly
through ipso-desilylation8 or through Hiyama type cross-
coupling chemistries via C5 siloxanes or fluorosilanes.9
To initiate this study, the readily accessible5 8-chloroimi-
dazo[1,5-a]pyrazine 1 was subjected to reaction with nBuLi
(1 equiv) and quenched with various electrophiles to afford
exclusively C3-substitution products 2a-2g (Table 1). Reac-
tions with carbon electrophiles at three oxidation states
(entries 1-6) and iodine (entry 8) proceeded uneventfully
whereas that with TMSCl failed, an observation which may
be due to product instability, related to the known lability
of the imidazole C2-Si bond.6
Efforts then turned to investigating the potential for
dimetalation of this heterocyclic core and for the sequential
(3) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206.
(4) Examples of such biological applications are: IGF-IR inhibitors, for
example: (a) 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. c-SRC inhibition and treatment of acute
ischemic stroke: (b) Mukaiyama, H.; Nishimura, T.; Kobayashi, S.; Ozawa,
T.; Kamada, N.; Komatsu, Y.; Kikuchi, S.; Oonota, H.; Kusama, H. Bioorg.
Med. Chem. 2007, 15, 868. Corticotropin releasing hormone receptor
ligands: (c) Hartz, R. A.; Gilligan, P. J.; Nanda, K. K.; Tebben, A. J.;
Fitzgerald, L. W.; Miller, K. Bioorg. Med. Chem. Lett. 2002, 12, 291.
(5) Initial syntheses of imidazo[1,5-a]pyrazines: (a) Abushanab, E.;
Bindra, A. P.; Goodman, L.; Peterson, H., Jr. J. Org. Chem. 1973, 38, 2049.
(b) Abushanab, E.; Bindra, A. P.; Lee, D. Y.; Goodman, L. J. Heterocycl.
Chem. 1975, 12, 211. (c) Abushanab, E.; Bindra, A. P.; Goodman, L.
J. Heterocycl. Chem. 1975, 12, 207. (d) Abushanab, E.; Bindra, A. P.; Lee,
D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 3373. (e) Abushanab, E.;
Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 3376. (f) Abushanab,
E.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 33792. Syntheses of
more highly substituted imidazo[1,5-a]pyrazines: (g) Albert, A.; Ohta, K.
J. Chem. Soc. (C) 1970, 11, 1540. (h) Davey, D. D. J. Org. Chem. 1987,
52, 4379. (I) Chattopadhyay, G.; Ray, S. J. Chem. Res. Synop. 1992, 5,
170. (j) Marchand, E.; Morel, G. Tetrahedron Lett. 1993, 34, 2319. (k)
Trcˇek, T.; Meden, A.; Vercˇek, B. Synlett 2000, 10, 1458. (l) Eltsov, O. S.;
Mokrushin, V. S.; Tkachev, A. V. Russ. Chem. Bull., Int. Ed. 2004, 53,
2293. (m) Trcˇek, T.; Vercˇek, B. Synthesis 2006, 20, 3437. (n) Mulvihill,
K. M.; Castelhano, A. L. US Patent 2007/0129547 A1.
In view of the selective C3 over C5 kinetic anion
reactivity established by the results of Table 1, we tested
the thereby expected greater nucleophilic reactivity at the
C5 site of the dianion 3.10 Thus, treatment of 1 with 2
equiv of nBuLi11 followed by 1 equiv of iodine or CD3OD
initially provided evidence of selectivity; however, sub-
sequent results were inexplicably inconsistent giving ratios
between 4:1 and 1:8 of C5:C3 products within the same
batch of reactions, and despite close control of the various
reaction variables.12
With the results of studies on compound 1 in hand, we
turned our attention to the metalation of the equally
accessible5 8-chloro-3-methylimidazo[1,5-a]pyrazine 2a.
In contrast to expectation,13 treatment of 2a with 1.1 equiv
(6) The N-protected imidazole C2-TMS system is moderately unstable
towards nucleophilic attack at silicon even when generated in situ, and its
isolation can be highly problematic due to hydrolysis: Carpenter, A. J.;
Chadwick, D. J. Tetrahedron 1986, 42, 2351.
Org. Lett., Vol. 11, No. 22, 2009
5119

Table 2. Synthesis of C3/C5 Disubstituted
8-Chloroimidazo[1,5-a]pyrazines 4a-4d
Table 3. Synthesis of 5-Substituted
8-Chloro-3-methylimidazo[1,5-a]pyrazines 4b and 6a-6p
EX
R1
R2
product (%)a
EX
X
R1
product (%)a
1
2
3
CD3OD
MeI
Cl2
D
D
Me
Cl
4a (94)b
4b (82)
4c (62)
4d (48)c
1
2
3
4
5
6
7
8
9
MeIb
DMF
Cl
Cl
CH3
4b (91)
6a (79)c
6b (83)
6c (84)d
6d (87)
6e (quan)
n.r.e
6f (81)
6g (98)
6h (59)
6h (74)
6i (quan)
6j (65)
Me
Cl
CHO; ClfNMe2
4-O2NOC6H4CHOH
4-MeOC6H4CHOH
MesCHOH
4-O2NC6H4CHO Cl
4-MeOC6H4CHO Cl
Mesitaldehyde
CO2
ClCONEt2
ClSiMe3
Cl3CCCl3
4
ClSiMe3
SiMe3
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
a Yield of isolated material. b 86% deuterium incorporation as determined
by integration of the appropriate signals in the 1H NMR spectrum. c Average
of two independent reactions.
CO2H
Et2NCO
SiMe3
Cl
Br
Br
10 CBr4
11 Br2
12 I2
13 MeI
14 DMF
of nBuLi and subsequent reaction with methyl iodide
afforded the C5-methylated product 4b in excellent yield
(entry 1, Table 3). Similarly, and usually with greater
efficacy than the reactions of compound 1 (Table 1),
compound 2a underwent reaction with other carbon
(entries 2-7), silicon (entry 8), and halogen (entries 9-12)
electrophiles to afford C5-substituted products 6a-6i in
good to excellent yields. To extend the scope of the
reaction, the C8-methoxy derivative 5 was subjected to
the same metalation/quenching conditions to provide
similarly synthetically useful yields of products 6j-6p
(entries 13-20).
Quantum calculations on compound 2a suggest that the
approximate difference in pKa values are in accord with
the observation of C5 over C3-methyl deprotonation.
Figure 2a shows the calculated partial charges on the
carbons bound to the most acidic protons, with more
electron richness on the carbons correlating with a lower
absolute calculated pKa. Use of perturbative methods has
previously successfully predicted unexpected lithiation
sites14 and its application here confirms the predictions
from the more approximate pKa calculation. Figure 2b
shows the calculated Fukui indices, with values closer to
1 indicating, in this case, a greater proclivity to undergo
I
OMe Me
OMe CHO
6k (77)
6l (76)d
6m (62)
6n (64)f
n.r.e
15 4-MeOC6H4CHO OMe 4-MeOC6H4CHOH
16 Mesitaldehyde
17 CO2
18 ClCONEt2
19 ClSiMe3
20 I2
a Yield of isolated material. b Sequential addition of 2 portions of 1.2
equiv of MeI. c Isolated as the C-8 dimethylamino analogue due to
unavoidable nucleophilic displacement of Cl by NMe2. d Average of two
independent reactions. e No reaction as confirmed by 1H NMR of the
recovered starting material. f Isolated as the methyl ester due to purification
difficulties.
OMe MesCHOH
OMe CO2Mef
OMe Et2NCO
OMe SiMe3
6o (70)d
6p (79)
OMe
I
lithiation. Both calculations are in accord with the
experimentally observed C5 lithiation of 2a.15
(7) For previous work on benzamide dianions, see: Mills, R. J.; Horvath,
R. F.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett. 1985, 26, 1145.
(8) Zhao, Z.; Jaworski, A.; Piel, I.; Snieckus, V. Org. Lett. 2008, 10,
2617.
(9) Denmark, S. E.; Sweis, R. F. Metal-Catalysed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 1, Chapter 4, p 163.
Figure 2. Key calculated properties for 8-chloro-3-methylimi-
dazo[1,5-a]pyrazine 2a at potential reactive sites. (a) Partial charges
(10) For successful results of such an expectation in furan and thiophene
amide directed ortho metalation derived dianions, see: Doadt, E. G.;
Snieckus, V. Tetrahedron Lett. 1985, 26, 1149.
on the molecule. (b) Fukui indices for the LUMO of the molecule.
n
(11) An investigation of bases, BuLi, KOtBu, MeMgBr, EtMgBr, and
n
iPrMgBr:LiCl, showed that only the use of BuLi led to the formation of
the dianion. Interestingly, although normal Grignard reagents were insuf-
ficiently basic to form the dianion, application of iPrMgBr:LiCl led
exclusively to the formation of the C3 monoanion, as established by I2
quench experiment, even when excess base was used.
The knowledge that remote lateral metalation of vinylo-
gously acidic 2′-methylbiaryl-2-amides to give phenanthrols
may be achieved3,16 suggested that compound 7 (Scheme
5120
Org. Lett., Vol. 11, No. 22, 2009

In conclusion, we have demonstrated useful and conve-
nient metalation routes for the synthesis of C3- and C3/C5-
derived 8-substituted imidazo[1,5-a]pyrazines 2a-2g,
4a-4d, and 6a-6p. Such substitutions serve as functional
handles for further derivatization of this privileged and
biologically significant heterocyclic scaffold. Furthermore,
adaption of the directed remote metalation (DreM) concept,
as yet sparsely investigated within heterocyclic frameworks,3
on the imidazo[1,5-a]pyrazine 7 has afforded the hitherto
unknown triazadibenzo[cd,f]azulen-7(6H)-one 8. The con-
siderably extended scope of this imidazo[1,5-a]pyrazine
metalation chemistry over that of the imidazo[1,2-a]pyrazine
system,20 together with the DFT calculations, provides new
insight into the carbanionic reactivity of this less common
heterocycle and may be of value for synthesizing hetero-
cycles of greater complexity. Further investigations on the
DreM chemistry leading to the new heterocyclic scaffold 8
are in progress.
Scheme 1. Directed Remote Metalation-Cyclization Route to the
Triazadibenzo[cd,f]azulen-7(6H)-one 8
Acknowledgment. We gratefully acknowledge OSI Phar-
maceuticals, Inc. for a grant to V.S. in support of this work.
Dr. Ruiyao Wang of Queen’s University is warmly thanked
for prompt solution of the X-ray crystal structure of
compound 8 and for his enthusiastic interest.
1) may provide similar reactivity at the enhanced acidic C3-
methyl site to afford cyclized products. To this end,
compound 7b, readily prepared from compound 6p via a
Suzuki coupling with 2-(diethylcarbamoyl)phenylboronic
acid,17 was treated at -78 °C with preformed LiTMP (3
equiv) and was observed to undergo cyclization to give the
triazadibenzo[cd,f]azulen-7(6H)-one 8 in modest yield.18,19
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
The methylene H NMR signal at δ ) 4.48 ppm for
compound 8 is clear evidence for the ketonic structure
shown.
OL901889E
(16) Fu, J.-M.; Snieckus, V. Can. J. Chem. 2000, 78, 905.
(17) Zhao, Z.; Snieckus, V. Org. Lett. 2005, 7, 2523.
(12) See Supporting Information.
(13) Strong base deprotonation of N-protected-2-methylimidazole (Iddon,
B.; Ngochindo, R. I. Heterocycles 1994, 11, 2487.) most 2-methyl-
heteroaromatics, (e.g. 2-picoline with NaNH2, see Kantlehner, W.; Kapas-
sakalidis, J. J. Synthesis 1981, 6, 480. with LDA, see Bhasin, K. K.; Singh,
J.; Singh, K. N. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 597.
(18) The structure was confirmed by single crystal X-ray analysis, see
Supporting Information.
(19) Under the same reaction conditions, the C8-Cl analogue 7a gave
only a chromatographically inseparable mixture (silica gel flash chroma-
tography) of at least three compounds, presumably due to complications,
in part, resulting from the greater reactivity of the C8-Cl over C8-OMe
group.
(20) Generation of an imidazo[1,2-a]pyrazine dilithiated species, as
evidenced by the formation of dideuterated product upon DCl quench, has
been previously reported, see: Vitse, O.; Bompart, J.; Subra, G.; Viols, H.;
Escale, R.; Chapat, J. P.; Bonnet, P. A. Tetrahedron 1998, 54, 6485.
n
with BuLi, see Andrews, I. P; Lewis, N. J.; McKillop, A.; Wells, A. S.
Heterocycles 1996, 43, 1151.) usually occurs at the alkyl group.
(14) Ayers, P. W.; Anderson, J. S. M.; Bartolotti, L. J. Int. J. Quantum
Chem. 2004, 101, 520.
(15) The general applicability of this approach to predict metalation sites
is being actively explored.
Org. Lett., Vol. 11, No. 22, 2009
5121