Multicomponent Reaction Based Synthesis of 1-Tetrazolylimidazo[1,5- a]pyridines

Article abstract of DOI:10.1021/acs.orglett.8b01452

A series of unprecedented tetrazole-linked imidazo[1,5-a]pyridines are synthesized from simple and readily available building blocks. The reaction sequence involves an azido-Ugi-deprotection reaction followed by an acetic anhydride-mediated N-acylation-cyclization process to afford the target heterocycle. Furthermore, the scope of the methodology was extended to diverse R₃-substitutions by employing commercial anhydrides, acid chlorides, and acids as an acyl component. The scope for the postmodification reactions are explored and the usefulness of the synthesis is exemplified by an improved three-step synthesis of a guanylate cyclase stimulator.

Full text of DOI:10.1021/acs.orglett.8b01452

This is an open access article published under a Creative Commons Non-Commercial No
Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and
redistribution of the article, and creation of adaptations, all for non-commercial purposes.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Multicomponent Reaction Based Synthesis of
1‑Tetrazolylimidazo[1,5‑a]pyridines
Santosh Kurhade,† Elmar Diekstra,† Fandi Sutanto,† Katarzyna Kurpiewska,§
§
,†
́
̈
Justyna Kalinowska-Tłuscik, and Alexander Domling*
†Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
§Jagiellonian University, Faculty of Chemistry, Gronostajowa 2, 30-387 Krakow, Poland
S
* Supporting Information
ABSTRACT: A series of unprecedented tetrazole-linked
imidazo[1,5-a]pyridines are synthesized from simple and
readily available building blocks. The reaction sequence
involves an azido-Ugi-deprotection reaction followed by an
acetic anhydride-mediated N-acylation−cyclization process to
afford the target heterocycle. Furthermore, the scope of the
methodology was extended to diverse R3-substitutions by
employing commercial anhydrides, acid chlorides, and acids as
an acyl component. The scope for the postmodification reactions are explored and the usefulness of the synthesis is exemplified
by an improved three-step synthesis of a guanylate cyclase stimulator.
yield (Scheme 2).8 Therefore, developing more practical and
he design and synthesis of new bis-heterocyclic systems are
efficient synthetic approaches for tetrazole-linked imidazo[1,5-
Thighly appreciated in modern drug discovery to achieve
specific drug−receptor interactions.1 Tetrazole-linked imidazo-
a] pyridines is highly desirable. Our synthetic strategy for such a
bis-heterocyclic system involves the Ugi-azide four component
reaction (azido-Ugi 4CR)-deprotection to obtain the corre-
sponding pyridin-2-yl(1H-tetrazol-5-yl)methanamine inter-
mediate.13 The intermediate amine is then converted to
tetrazolyl-imidazo[1,5-a]pyridine via an N-acylation−cycliza-
tion process (Figure 1).14
Thus, we describe the Ugi-azide four-component reaction
(azido-Ugi 4CR) mediated synthesis of diverse analogues of 1-
tetrazolylimidazo[1,5-a]pyridines.
Example 6a (Table 1, entry 1a) was selected as a model for
screening and optimizing the reaction conditions. Equimolar
amounts of aldehyde (1, R1 = H), tritylamine 2, isocyanide (3,
R2 = benzyl), and azidotrimethylsilane 4 were combined
sequentially in MeOH (0.5 M) at room temperature. The
corresponding azido-Ugi product 5 was isolated in high yield of
85% after 18 h. Trityl group removal under acidic conditions (4
N HCl/dioxane) gave the (1-benzyl-1H-tetrazol-5-yl)(pyridin-
2-yl)methanamine hydrochloride. We then tested the cycliza-
tion reaction under different reaction conditions using Ac2O to
form 6a. We screened several conditions and varyied reaction
parameters such as temperature, base, and Ac2O concentration.
To our surprise, no base was required, only Ac2O (0.5 M) and
warming (75 °C). A reaction time of 1 h was found to be
optimal, with 6a being isolated in quantitative yield. With these
optimized conditions in hand, we decided to switch to a one-pot
protocol to avoid the isolation of the azido-Ugi intermediate.
Here, the generally observed precipitation of trityl Ugi-azides
[1,5-a]pyridine is such an unprecedented class of bis-hetero-
cycles. Individually, the imidazo[1,5-a]pyridine heterocycle is
the core of naturally occurring antimicrobial and antineoplastic
agent cribrostatin 62 as well as many bioactive molecules, for
example 5-hydroxytryptamine4 receptor (5-HT4R) antagonists3
and partial agonists,4 CB2 agonists,5 HIV protease inhibitors,6
thromboxane A2 synthesis inhibitors,7 and guanylate cyclase
stimulators.8 It has also found applications in material
chemistry,9 and 1,5-disubstituted tetrazoles (1,5-DS-T’s) are
bioisosteres of the cis-amide bond of peptides,10 which are
present in various drugs,11 such as cilostazol and the antibiotics
cefonicid and latamoxef.12 However, a combination of the two
well-known imidazo[1,5-a]pyridine and 1,5-DS-T into a bis-
heterocyclic systems has not been explored much in medicinal
chemistry due to limitations in synthetic feasibility (Figure 1).
To the best of our knowledge, only Schirok et al. have reported a
seven-step synthesis of guanylate cyclase stimulator 3-(2-
fluorobenzyl)-1-(1H-tetrazol-5-yl)imidazo[1,5-a]pyridine 9,
starting from ethyl 2-(pyridin-2-yl) acetate with 1.8% overall
Received: May 8, 2018
Figure 1. Conceiving the idea.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01452
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
salt.13 In step 2, intermediate a was N-acylated using 7 as a
commercial anhydride or acid chloride in DCM and NEt3 (2.2
equiv) as a base; in the case of acids, classical peptide coupling
conditions EDC, HOBt, and NEt3 in DCM were used.15 Then
the in situ formed corresponding N-acyl intermediate (without
purification) was subjected to cyclization (1.0 equiv 4 N HCl/
dioxane, Ac2O [0.5 M], 120 °C, 1−2 h) after removal of DCM
(Table 2, entries 2a−q). Anhydrides including cyclic glutaric
Table 1. Substrate Scope of the 1-Tetrazolyl-3-
methylimidazo[1,5-a]pyridine Synthesis
Table 2. R3-Substitutions on Tetrazolylimidazo[1,5-
a]pyridine
a
b
c
Reaction scale 1.0 mmol. Isolated yield. Indole N-acylated product
d
was isolated in 15% yield. Azide−Ugi product (5) was isolated in
62% yield along with tetrazole regioisomeric product 20% yield.
was of great help. The azido-Ugi product 5 was quickly isolated
by filtration to remove the solvent methanol and subjected to
cyclization without any further purification with 4 N HCl/
dioxane (3.0 equiv), Ac2O [0.5 M] at 75 °C for 1 h, affording 6a
in 85% overall yield. The reaction proceeds via in situ trityl
deprotection followed by Ac2O-mediated N-acylation−cycliza-
tion to form 6a. Using the optimized conditions, we next
synthesized a series of novel 1-tetrazolyl-3-methylimidazo[1,5-
a]pyridines 6b−m in a one-pot, two-step manner (Table 1,
entries 1b−m). The scope of the substrate was evaluated using
diverse isocyanides (3) and picolinaldehydes (1). Overall good
to excellent yields were obtained. The highest yield of 90% was
observed for product 6h (Table 1, entry 1b). Additionally, a
lower yield was observed for the product 6g (65%, entry 1g) and
6i (60%, entry 1d).
Encouraged by the initial results, we investigated more diverse
synthesis by changing the R3-substitutions on tetrazolylimidazo-
[1,5-a]pyridine core 8 according to our two-step procedure.
Accordingly, step 1 involved the trityl deprotection of the azido-
Ugi 4CR product 5 under acidic conditions (4 N HCl/dioxane,
10 min) to give the corresponding intermediate pyridin-2-
yl(1H-tetrazol-5-yl)methanamine (intermediate a) as a HCl
a
b
c
Reaction scale 1.0 mmol. Isolated yield. The reaction scale was 5.0
mmol; reaction mixture was heated at 75 °C for 8 h.
anhydride (entries 2a−c) worked well under the optimized
conditions and produced 8a−c in 70−85% overall yield. A
diverse set of acid chlorides (entries 2d−i) as the acyl
component worked well, and the corresponding products were
formed in generally very good yield. We observed a drop in
overall yields in the case of acids (40−79%, entries 2k−o)
compared to anhydrides and acid chlorides, which may reflect
worse coupling yields. In the case of N-Boc-protected amino
B
DOI: 10.1021/acs.orglett.8b01452
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acids, the corresponding N-acyl products 8m−o (entries 2m−p)
were isolated in 40−60% yields. Deborylation was observed in
the case of the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)benzoic acid, and 8b was isolated with 70% yield. Thus,
Boc and pinacol−borane groups were found to be labile under
the optimized condition. In case of cyanoacetic acid, a trace
amount of product 8q was formed (Table 2, entry 2q).
Scheme 2. Improved Route to the Guanylate Cyclase
Stimulator (9)
Several structures have been confirmed by X-ray single-crystal
analyses (Figure 2 and Supporting Information). The following
onstrate the scope of the method by synthesizing unsubstituted
(R3 = H) examples and explore their postmodification.
Examples 8r and 8s were prepared from intermediates 6r and
6s in 74% and 78% yields, respectively, via one pot N-
formylation followed by POCl3-mediated dehydration−cycliza-
tion process (Scheme 3).16 While attempting the debenzylation
Figure 2. X-ray structures of selected products.
interesting motifs could be observed in the solid state: the
scaffold in general is flat, and therefore, stocking interactions
with neighboring molecules are always observed. In 6b the
tetrazole and in 6l the imidazopyridine moieties stack
antiparallel. In 6m, a halogen bond with 3.1 Å between the p-
Br and N3 of an adjacent tetrazole can be found.
Scheme 3. Postmodification Scope
A mechanism is proposed in Scheme 1. The Azido-Ugi
reaction mechanism has been documented.13
Scheme 1. Proposed Mechanism
of 8r under hydrogenation condition, we observed the selective
pyridyl ring saturation product, and 10 was isolated in 98% yield.
The interesting low molecular weight free tetrazole 11 building
block was obtained in 88% yield by deprotection of the tert-butyl
group of 8s under acidic conditions (Scheme 3).17
In continuation of exploring the post modification scope, the
phthalimide group in 8i was deprotected to form the free amine
12 (90% yield), which was subjected to three different types of
reactions: (i) sulfonamide, (ii) urea, and (iii) thiourea
formation.18 All three types of reactions worked well and
furnished the desired products 13a−c in very good yields of 75−
85% (Scheme 3).
Then the azido-Ugi product 5 undergoes N-acylation and
forms intermediate 5-I via acid-mediated trityl group depro-
tection. Further, 5-I undergoes an O-acylation−elimination
process and provides nitrilium intermediate 5-II. Attacking the
ring nitrogen lone pair of electrons from 5-II leads to the cyclic
intermediate 5-III, which upon aromatization leads to the
formation of the target product 6 (Scheme 1).
As an application of the methodology, we could improve upon
the synthetic route of the guanylate cyclase stimulator 9 in three
simple steps with 76% overall yield, via acid mediated tert-octyl
group deprotection13 of 8j in the final step (Scheme 2). After
demonstrating the successful synthesis of diverse substituted
tetrazolylimidazo[1,5-a]pyridines, we wanted to further dem-
Taken together, we have developed a novel, simple, and
efficient two-step method for the synthesis of tetrazolylimidazo-
C
DOI: 10.1021/acs.orglett.8b01452
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Martin, S. F. Angew. Chem., Int. Ed. 2009, 48, 2569. (e) Markey, M. D.;
Kelly, T. R. J. Org. Chem. 2008, 73, 7441.
(3) King, F. D.; Gaster, L. M.; Joiner, G. F. Imidazopyridines and
indolizines as 5-HT4 antagonists. PCT Pat. Appl. WO 1993/
008187A1, 29 Apr 1993.
(4) Nirogi, R.; Mohammed, A. R.; Shinde, A. K.; Bogaraju, N.;
Gagginapalli, S. R.; Ravella, S. R.; Kota, L.; Bhyrapuneni, G.; Muddana,
N. R.; Benade, V.; Palacharla, R. C.; Jayarajan, P.; Subramanian, R.;
Goyal, V. K. Eur. J. Med. Chem. 2015, 103, 289−301.
(5) Trotter, B. W.; Nanda, K. K.; Burgey, C. S.; Potteiger, C. M.; Deng,
J. Z.; Green, A. I.; Hartnett, J. C.; Kett, N. R.; Wu, Z.; Henze, D. A.;
Penna, K. D.; Desai, R.; Leitl, M. D.; Lemaire, W.; White, R. B.; Yeh, S.;
Urban, M. O.; Kane, S. A.; Hartman, G. D.; Bilodeau, M. T. Bioorg. Med.
Chem. Lett. 2011, 21, 2354−2358.
(6) Kim, D.; Wang, L.; Hale, J. J.; Lynch, C. L.; Budhu, R. J.; MacCoss,
M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino, J. A.; Springer,
M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.; Carver, G.;
Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A.; Emini, E. A. Bioorg.
Med. Chem. Lett. 2005, 15, 2129.
(7) Ford, F. F.; Browne, L. J.; Campbell, T.; Gemenden, C.; Goldstein,
R.; Gude, C.; Wasley, J. W. F. J. Med. Chem. 1985, 28, 164.
(8) Schirok, H.; Mittendorf, J.; Stasch, J.-P.; Wunder, F.; Stoll, F.;
Schlemmer, K.-H. Pyrazolopyridine, Indazole, Imidazopyridine,
Imidazopyrimidine, Pyrazolopyrazine and Pyrazolopyridine derivatives
as stimulator of guanylate cyclase for cardiovascular disorders. PCT Pat.
Appl. WO 2008/031513 A1, 20 Mar 2008.
[1,5-a]pyridines, a bis-heterocyclic system via the well-known
azido-Ugi 4CR reaction, and an unprecedented acetic anhydride
mediated post cyclization reaction. Work is ongoing to
investigate the further synthetic applications and biological
properties of the new compound class.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01452.
General procedures, characterization data, spectra
(1H,13C NMR, HRMS), single crystal X-ray details
(PDF)
Accession Codes
CCDC 1828260−1828262 and 1839326−1839329 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
(9) (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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: a.s.s.domling@rug.nl.
ORCID
(10) (a) Zabrocki, J.; Smith, G. D.; Dunbar, J. B., Jr.; Iijima, H.;
Marshall, G. R. J. Am. Chem. Soc. 1988, 110, 5875−5880. (b) Rentería-
́
Gomez, A.; Islas-Jacome, A.; Díaz-Cervantes, E.; Villasen
̃
or-Granados,
T.; Robles, J.; Gamez-Montan
2333−2338.
̃
o, R. Bioorg. Med. Chem. Lett. 2016, 26,
́
Justyna Kalinowska-Tłuscik: 0000-0001-7714-1651
̈
Alexander Domling: 0000-0002-9923-8873
(11) Drugs containing tetrazole moiety (review): Myznikov, L. V.;
Hrabalek, A.; Koldobskii, G. I. Chem. Heterocycl. Compd. 2007, 43, 1−9.
(12) Ostrovskii, V. A.; Trifonov, R. E.; Popova, E. A. Russ. Chem. Bull.
2012, 61, 768−780.
Notes
The authors declare no competing financial interest.
(13) (a) Ugi, I.; Steinbruckner, C. Angew. Chem. 1960, 72 (7−8),
ACKNOWLEDGMENTS
■
̈
267−268. (b) Zhao, T.; Boltjes, A.; Herdtweck, E.; Domling, A. Org.
This research has been supported to (A.D.) by the National
Institute of Health (NIH) (2R01GM097082-05), the European
Lead Factory (IMI) under Grant Agreement No. 115489, and
the Qatar National Research Foundation (NPRP6-065-3-012).
Moreover, funding was received through ITN “Accelerated
Early stage drug discovery” (AEGIS, Grant Agreement No.
675555), COFUND ALERT (Grant Agreement No. 665250),
and KWF Kankerbestrijding grant (Grant Agreement No.
10504). The research was carried out with equipment purchased
thanks to the financial support of the European Regional
Development Fund in the framework of the Polish Innovation
Economy Operational Program (Contract No. POIG.02.01.00-
12-023/08).
Lett. 2013, 15, 639−641. (c) Zhao, T.; Kurpiewska, K.; Kalinowska-
́
̈
Tłuscik, J.; Herdtweck, E.; Domling, A. Chem. - Eur. J. 2016, 22, 3009.
(d) Cioc, R. C.; Schuckman, P.; Preschel, H. D.; Vlaar, T.; Ruijter, E.;
Orru, R. V. A. Org. Lett. 2016, 18, 3562−3565.
(14) (a) Pelletier, G.; Charette, A. Org. Lett. 2013, 15, 2290.
(b) Crawforth, J.; Paoletti, M. Tetrahedron Lett. 2009, 50, 4916.
(c) Arvapalli, V.; Chen, G.; Kosarev, S.; Tan, M.; Xie, D.; Yet, L.
Tetrahedron Lett. 2010, 51, 284.
(15) Peptide coupling conditions: El-Faham, A.; Albericio, F. Chem.
Rev. 2011, 111, 6557−6602.
(16) (a) Gerack, C. J.; McElwee-White, L. Molecules 2014, 19, 7689−
7713. (b) Ford, N. F.; Browne, L. J.; Campbell, T.; Gemenden, C.;
Goldstein, R.; Gude, C.; Wasley, J. W. F. J. Med. Chem. 1985, 28, 164.
(17) Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Sandulenko, Y.;
Bukhryakov, K. Tetrahedron Lett. 2008, 49, 7318.
(18) (a) For sulfonamide formation, see: Bahrami, K.; Khodaei, M.
M.; Soheilizad, M. J. Org. Chem. 2009, 74, 9287−9291. (b) For urea
and thiourea formation, see: Chayah, M.; Camacho, M. E.; Carrion, M.
D.; Gallo, M. A.; Romero, M.; Duarte. MedChemComm 2016, 7, 667−
678.
REFERENCES
■
(1) Bis- heterocyclic system and its applications: (a) Unnamatla, M. V.
̃
́
́
́
B.; Islas-Jacome, A.; Quezada-Soto, A.; Ramarez-Lopez, S. C.; Flores-A
́
lamo, M.; Gamez-Montano, R. J. Org. Chem. 2016, 81, 10576−10583.
̃
(b) Murru, S.; Nefzi, A. ACS Comb. Sci. 2014, 16, 39−45. (c) Soural,
̌
M.; Bouillon, I.; Krchnak, V. J. Comb. Chem. 2008, 10, 923. (d) Kurhade,
S.; Ramaiah, P. A.; Prathipati, P.; Bhuniya, D. Tetrahedron 2013, 69,
1354−1362. (e) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39,
2887−2893.
(2) (a) Pelletier, G.; Charette, A. B. Org. Lett. 2013, 15, 2290−2293.
(b) 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.
(c) Mohamed, M.; Goncalves, T. P.; Whitby, R. J.; Sneddon, H. F.;
Harrowven, D. C. Chem. - Eur. J. 2011, 17, 13698. (d) Knueppel, D.;
D
DOI: 10.1021/acs.orglett.8b01452
Org. Lett. XXXX, XXX, XXX−XXX