Triflic anhydride mediated synthesis of imidazo[1,5-a]azines

Article abstract of DOI:10.1021/ol400870b

Imidazo[1,5-a]azines are synthesized in moderate to excellent yields using a mild cyclodehydration/aromatization reaction triggered by the use of triflic anhydride (Tf₂O) and 2-methoxypyridine (2-MeOPyr). Various substitution patterns and functional groups were found to be compatible under the optimized conditions. In addition, a 5-bromo-3-aryl derivative was also shown to be active in a Sonogashira cross-coupling and direct arylation reactions. A tertiary amide was compatible as a substrate leading to the synthesis of an imidazo[1,5-a]pyridinium triflate.

Full text of DOI:10.1021/ol400870b

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2290–2293
Triflic Anhydride Mediated Synthesis
of Imidazo[1,5‑a]azines
ꢀ
Guillaume Pelletier and Andre B. Charette*
ꢀ
Centre in Green Chemistry and Catalysis, Department of Chemistry, Universite de
Montreal, P.O. Box 6128, Station Downtown, Montreal, Quebec, Canada, H3C 3J7
ꢀ
ꢀ
ꢀ
andre.charette@umontreal.ca
Received March 29, 2013
ABSTRACT
Imidazo[1,5-a]azines are synthesized in moderate to excellent yields using a mild cyclodehydration/aromatization reaction triggered by the use of
triflic anhydride (Tf2O) and 2-methoxypyridine (2-MeOPyr). Various substitution patterns and functional groups were found to be compatible under
the optimized conditions. In addition, a 5-bromo-3-aryl derivative was also shown to be active in a Sonogashira cross-coupling and direct arylation
reactions. A tertiary amide was compatible as a substrate leading to the synthesis of an imidazo[1,5-a]pyridinium triflate.
The imidazo[1,5-a]pyridine motif is a heterocyclic fused
bicyclic system1 applicable in materials chemistry2 as well
as potent pharmacophores.3 Recently, derivatives of this
heterocyclic system were embedded in the structure of
many biologically active molecules tested for the treatment
of inflammation,3a,b cancer,3a,c cardiovascular diseases,3a
fertility disorders,3d and HIV.3e Moreover, Pettit et al.
reported in 2003 a unique example of a naturally occurring
imidazo[1,5-a]isoquinolinedione in the tricyclic structure
Figure 1. Imidazo[1,5-a]isoquinolinedione highlighted in the
of cribrostatin 6, a highly active antimicrobial and anti-
structure of cribostatin 6.
neoplasic agent (Figure 1).4
Early synthetic methods targeting various imidazo-
(1) For the numbering of these heterocycles, see: Davey, D. D. J. Org.
Chem. 1987, 52, 1863.
(2) For selected recent applications, see: (a) Shibahara, F.; Dohke,
Y.; Murai, T. J. Org. Chem. 2012, 77, 5381. (b) Yamaguchi, E.;
Shibahara, F.; Murai, T. J. Org. Chem. 2011, 76, 6146 and references
cited therein.
[1,5-a]azine derivatives were inspired from variants of
either Wallach’s imidazole synthesis5 or a Vilsmeier-type
cyclization.6 Indeed, various reagents (POCl3,3b,c,4cꢀ7a
(3) For selected recent applications, see: (a) Alcouffe, C.; Kirsch, R.;
Herbert, C.; Lassale, G. 2012004732 A1, 2012. (b) Trotter, B. W..; et al.
Bioorg. Med. Chem. Lett. 2011, 21, 2354. (c) Kamalaaa, A.;
Ramakrishna, G.; Raju, P.; Subba Rhao, A. V.; Viswanath, A.;
Lakshma Nayak, V.; Ramakrishna, S. Eur. J. Med. Chem. 2011, 46,
2427. (d) Loozen, H. J. J.; Timmer, C. M. WO 2010136438, 2010.
(e) Anthony, N. J.; Gomez, R.; Jolly, S. M.; Su, D.-S.; Lim, J. WO
2008076225 A2, 2008.
(4) (a) Pettit, G. R.; Collins, J. C.; Knight, J. C.; Herald, D. L.;
Nieman, R. A.; Williams, M. D.; Pettit, R. K. J. Nat. Prod. 2003, 66, 544.
For recent total syntheses of cribrostatin 6, see: (b) Mubina, M.;
Gonc-alves, T. P.; Whitby, R. J.; Sneddon, H. F.; Harrowven, D. C.
Chem.;Eur. J. 2011, 17, 13698. (c) Knueppel, D.; Martin, S. F. Angew.
Chem., Int. Ed. 2009, 48, 2569. (d) Markey, M. D.; Kelly, T. R. J. Org.
Chem. 2008, 73, 7441.
(5) (a) Benincori, T.; Brenna, E.; Sannicolo, F. J. Chem. Soc., Perkin
Trans. 1 1993, 675. (b) Wallach, O. Justus Liebigs Ann. Chem. 1877,
184, 1.
(6) For a seminal report, see: Bower, J. D.; Ramage, C. R. J. Chem.
Soc. 1955, 2834.
(7) For selected examples, see: (a) Satyanarayana, V. A.; Guangwu,
C.; Kosarev, S.; Meifen, E. T.; Deijan, X.; Yet, L. Tetrahedron Lett.
2010, 51, 284. (b) Tachikawa, R.; Tanaka, S.; Terada, A. Heterocycles
1981, 15, 369. (c) Crawforth, J. M.; Paoletti, M. Tetrahedron Lett. 2009,
50, 4916. (d) Wamhoff, H.; Zahran, M. Synthesis 1987, 876. (e) Li, J. J.;
Li, J. J.; Li, J.; Trehan, A. K.; Wong, H. S.; Krishnananthan, S.;
Kennedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.; Balasubramanian, B.;
Chen, B.-C. Org. Lett. 2008, 10, 2897. (f) Kim, D..; et al. Bioorg. Med.
Chem. Lett. 2005, 15, 2129.
r
10.1021/ol400870b
Published on Web 04/24/2013
2013 American Chemical Society

PCl5,7b 1-propanephosphoric anhydride (T3P),7c Ph3PCl2,7d
Burgess’ reagent,7e and polyphosphoric acid (PPA)7f)
were reported to trigger the latter intramolecular cyclo-
dehydration/aromatization sequence from a secondary
N-(2-pyridinylmethyl)amide. The respective secondary
thioamides could also be cyclized by treatment with
an oxidant.8 However, the most commonly disclosed
procedures imply the use of a large excess of activating
reagent, have a narrow scope, and/or are performed at
elevated temperatures. Alternatively, these heterocycles
can be accessed through a Rh-catalyzed transannula-
tion of pyridotriazoles,9 via nucleophilic addition of
2-aminomethylpyridine onto 1,1-gem-dibromoalkenes,10 or
from oxidative cyclization between a 2-pyridocarboxaldehyde
and an amino acid equivalent.11 While these methods are
milder than the previous electrophilic activations, there is
still aneedforgeneralproceduressuitedforthe synthesisof
imidazo[1,5-a]azines at ambient temperatures. To address
thisissue, wedecidedtoelaboratea triflic anhydride (Tf2O)
mediated cyclodehydration/aromatization strategy under
operationally simple and mild conditions applicable to a
wide variety of substitution patterns.
Scheme 1. Synthesis of Indolizidine and Quinolizidines and Its
Transposition Towards the Synthesis of Imidazo[1,5-a]azines (2)
Table 1. Optimization for the Cyclodehydration/Aromatization
Recently, various electrophilic activations using amides
and Tf2O have found broad application in the synthesis of
various building blocks.12 We reported in 2009 an intra-
molecular activation/dearomatization strategy toward the
synthesis of polysubstituted indolizidine and quinolizidine
alkaloids (Scheme 1).13 In these studies we determined that
the use of 2-chloropyridine (2-ClPyr) as a slightly basic
additive was required to obtain smooth conversion to the
target product. Inspired by these results, we thought to
optimize a generally applicable cyclization/aromatization
route for the synthesis of aromatic imidazo[1,5-a]azines (2)
from N-(2-pyridinylmethyl)benzamide (1) while adding
minimal amounts of Tf2O at ambient temperatures.14,15
We first probed conditions that were operative in second-
ary amide reductions using 2-fluoropyridine (2-FPyr) as a
base additive which gave a reasonable 66% yield (Table 1,
entry 1).12e,16
base
temp
time
(h)
Tf2O
yield 2a
entry
additive
(°C)
(equiv)
(%)a
1
2
3
4
4
5
6
7
8
2-FPyr
ꢀ78 °C to rt
4
1.1
1.1
1.1
1.0
1.2
1.2
1.2
1.2
1.2
66b
69
70
63
75
80
48
89
94
2-FPyr
ꢀ78 °C to rt
4
2-FPyr
rt
4
2-FPyr
rt
4
2-FPyr
rt
4
2-MeOPyr
none
rt
4
rt
4
2-MeOPyr
2-MeOPyr
rt
6
rt to 35 °C
16
a Yields determined on the crude reaction mixture by 1H NMR
analysis using Ph3CH as an internal standard. b Concentration of amide
in DCM of 0.05 M instead of 0.5 M.
(8) (a) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Org.
Lett. 2006, 8, 5621. (b) Moulin, A.; Garcia, S.; Martinez, J.; Fehrentz,
J.-A. Synthesis 2007, 2667. (c) Shibahara, F.; Sugiura, R.; Yamaguchi,
E.; Kitagawa, A.; Murai, T. J. Org. Chem. 2009, 74, 3566 and references
cited therein.
(9) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2007, 46, 4757.
(10) Zhang, A.; Xiaoling, Z.; Junfa, F.; Wang, S. Tetrahedron Lett.
We subsequently determined that the reaction can be
performed in concentrated DCM media (0.5 M, 69%,
entry 2) while adding Tf2O at room temperature (70%,
entry 3). These conditions are in contrast to those obtained
in the indolizidine/quinolizidine synthesis where Tf2O
was added to a diluted DCM solution of 1a (0.05 M)
at ꢀ78 °C.13 A screening of basic additives proved the
importance of having a non-nucleophilic base present, as
a much lower yield was obtained without it (48%, entry 6).
Performing the reaction in the presence of 2-methoxypyr-
idine (2-MeOPyr) for 16 h from 25 to 35 °C gave optimal
conversions and yields for the desired product 2a (94%,
entry 8).17
2010, 51, 828.
(11) Wang, Q.; Shuai, Z.; Fengfeng, G.; Baiqun, Z.; Ping, H.;
Zhiyong, W. J. Org. Chem. 2012, 77, 11161.
(12) For recent examples, see: (a) Valerio, V.; Petkova, D.;
Madelaine, C.; Maulide, N. Chem.;Eur. J. 2013, 19, 2606. (b) Xiao,
K.-J.; Wang, A.-E.; Huang, P.-Q. Angew. Chem., Int. Ed. 2012, 124,
8439. (c) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012,
4, 228. (d) Medley, J. M.; Movassaghi, M. Angew. Chem., Int. Ed. 2012,
51, 4572. (e) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem.
Soc. 2010, 132, 12817.
(13) Barbe, G.; Pelletier, G.; Charette, A. B. Org. Lett. 2009, 11, 3398.
(14) We recently reported the synthesis of pyrazolo[1,5-a]pyridines via a
divergent approach: Mousseau, J. J.; Bull, J. A.; Ladd, C. L.; Fortier, A.;
Sustac Roman, D.; Charette, A. B. J. Org. Chem. 2011, 76, 8243.
(15) For application in the synthesis of the kedarcidin chromophore,
see: Yoshimura, F.; Lear, M. J.; Ohashi, I.; Koyama, Y.; Hirama, M.
Chem. Commun. 2007, 3057.
(17) We think that 2-methoxypyridine provides an ideal basicity and
nucleophilicity needed for this transformation versus other pyridine
derivatives. For a discussion on the basicity of 2-MeOPyr and deriva-
tives, see: Murphy, R. A.; Sarpong, R. Org. Lett. 2012, 14, 632–635 and
references cited therein.
(16) See Supporting Information for more details.
Org. Lett., Vol. 15, No. 9, 2013
2291

Scheme 2. Synthesis of Imidazo[1,5-a]azines Using Optimized Cyclodehydration/Aromatization Conditionsa
a Reaction performed on 1.0 mmol scale. Isolated yield. b Reaction was performed at 50 °C instead of 35 °C. c Reaction was performed in presence of
2.4 equiv of Tf2O and 2.2 equiv of 2-MeOPyr instead of 1.2 equiv and 1.1 equiv. d Reaction was performed in DCE [0.5 M] at 65 °C for 16 h instead of
DCM [0.5 M] at 35 °C for 16 h.
Under these optimized conditions, we tested variously
substituted secondary amides toward their cyclization to
the corresponding bicyclic heterocycles (Scheme 2). We
rapidly identified that electron-rich benzamides underwent
clean and high-yielding conversions while electron-poor
substrates furnished moderate yields and conversions to the
desired imidazo[1,5-a]pyridines (compare 2aꢀ2c and 2d).
With the latter 2,4,6-trifluorophenyl substrate 2d, the reac-
tion was found to be more productive when heated to 50°C.
With alkyl substituted substrates, the cyclodehydration/
aromatization sequence gave very high yields and complete
conversions at 35 °C (>92%; see 2hꢀ2k). The reaction is
sluggish only with a very bulky N-(1-adamantyl) amide
substituent (70%, 2l). Moreover, a sharp contrast in re-
activity was observed where a N0,N0-dialkyl urea 1m could
be readily activated by Tf2O while the electron-poor ethyl
oxalate derivative 1n was heated to 65 °C to achieve a
reasonable conversion. Variation of the substituents on the
pyridine moiety was well tolerated (2oꢀ2r), and imidazo-
[1,5-a]pyrazine could also be synthesized without seeing
overtriflation on the pyrazine moiety (2s). A N,N0-bis(2-
pyridinylmethyl)benzamide (1t) was also found to be effi-
ciently doubly activated/cyclized using 2.4 equiv of Tf2O.
To further explore the applicability of the developed
method, we envisioned that the synthesis of 5-bromo-3-
aryl imidazo[1,5-a]pyridine derivative 2u could be possible
(Scheme 3). Recently, some 5-substituted imidazo[1,5-
a]pyridines (pyridinium) have found interesting applica-
tions in the treatment of cancer,18a,b as CCR1 receptor
antagonists,18c and as efficient N-heterocyclic carbene
precursors.18d
First, benzamide 1u underwent clean conversion to the
corresponding heterocycle 2u under the optimized condi-
tions at 50 °C (92%; see Scheme 2). The product was then
treated under unoptimized Sonogashira cross-coupling
conditions, and the 5-alkynyl derivative 2v was isolated
in high yield (90%).19 However, when 2u underwent
SuzukiꢀMiyaura cross-coupling with 4-methoxyphenyl-
boronic acid,20 an inseparable mixture of the desired
(18) (a) Adams, N. D.; Aquino, C. J.; Chaudhari, A. M.; Ghergurovitch,
J. M.; Kiesow, T. J.; Parrish, C. A.; Reif, A. J.; Wiggall, K. WO
2011103546 A1, 2011. (b) Price, S.; Heald, R.; Lee, W.; Zak, M. E.; Hewitt,
J. F. M. WO 2009085983 A1, 2009. (c) Cook, B. N.; Kuzmich, D. WO
2011056440 A1, 2011. (d) Burstein, C.; Lehmann, C. W.; Glorius, F.
Tetrahedron 2005, 26, 6207.
(19) Severin, R.; Reimer, J.; Doye, S. J. Org. Chem. 2010, 75, 3518.
(20) Shibahara, F.; Yamaguchi, E.; Kitagawa, A.; Imai, A.; Murai,
T. Tetrahedron 2009, 65, 5062.
2292
Org. Lett., Vol. 15, No. 9, 2013

Scheme 3. Synthesis of 5-Bromo-3-phenylimidazo[1,5-a]-
pyridine (2u) and Subsequent Catalytic Functionalizationa
Scheme 4. Synthesis of Imidazo[1,5-a]pyridinium Triflate 5ka
a Reaction performed on a 1.0 mmol scale. Isolated yields.
relatively low temperatures while using minimal amounts
ofanactivating reagent. These conditionswere applied toa
largepanel of secondary N-(2-pyridinylmethyl)amides with
various substitution patterns. A 5-bromo-3-aryl imidazo-
[1,5-a]pyridine was shown to be reactive in a Sonogashira
reaction and was used as a handle toward the synthesis
of more complex benzo[a]imidazo[2,1,5-c,d]indolizines.
Tertiary amides are also suitable partners in such reac-
tions as illustrated by an example of an NHC precursor
that was synthesized using the optimized Tf2O activation
conditions.
a Reaction performed on a 0.5 mmol scale. Isolated yields.
5-(4-methoxy)phenyl heterocycle along with benzo[a]-
imidazo[2,1,5-c,d]indolizine 3 was observed. When the
boronic acid was omitted in the reaction conditions, only
3 was isolated in high yield (80%). Interestingly, this
represents an unprecedented example of this type of hetero-
cycle synthesized via an intramolecular direct arylation.21
We decided to explore furthermore the electrophilic
activations of tertiary amides toward the formation
of imidazo[1,5-a]pyridinium salts (Scheme 4). In 2005,
Glorius18d and Lassaletta22 reported the use of such salts
as C,N-substituted NHC and their further uses as ligands
for Pd, Ag, Rh, Ir, and Se catalysts. As shown in Scheme 4,
treatment of 4k under the optimized conditions lead to the
corresponding imidazo[1,5-a]pyridinium triflate 5k in high
yield (89%). Since a tertiary amide was used, the synthesis
of 5k could also be effective without the inclusion of
2-MeOPyr as a basic additive (70%).
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), the Canada Research Chair Program,
the FRQNT Centre in Green Chemistry and Catalysis and
ꢀ
Universite de Montreal. G.P. is grateful to NSERC,
FRQNT and Universite de Montreal for postgraduate
ꢀ
ꢀ
ꢀ
scholarships. The authors would like to thank Serge
ꢀ
Plamondon (IRIC), Dr. Pierre Lavallee (UdeM), and
Prof. Stephen Hanessian (UdeM) for supplying chemi-
cal samples used in the synthesis of some starting
materials.
In conclusion, we successfully developed a mild cyclo-
dehydration/aromatization process that is effective at
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and compound characterization
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Recently, benzo[a]imidazo[5,1,2-c,d]indolizines which are iso-
mers to 3 were synthesized via a tandem [8 þ 2] cycloaddition/[2 þ 6 þ 2]
dehydrogenative sequence: Aginagalde, M.; Vara, Y.; Arrieta, A.;
ꢀ
´
Zanagi, R.; Cebolla, V. L.; Delgado-Camon, A.; Cossıo, F. P. J. Org.
Chem. 2010, 75, 2776.
(22) Alcarazo, M.; Roseblade, S. J.; Cowley, A. R.; Fernandez, R.;
Brown, J. M.; Lassaletta, J. M. J. Am. Chem. Soc. 2005, 127, 3290.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
2293