A concise approach toward tetrazolyl-substituted benzazocines via a novel isocyanide-based multicomponent reaction

Article abstract of DOI:10.1055/s-0033-1340861

The synthesis of pharmacologically relevant isoquinoline-tetrazoles and benzazocine-tetrazoles via sequential azido-Ugi and alkyne-induced ring-expansion reactions starting from cotarnine chloride are reported. A one-pot, multicomponent reaction protocol

Full text of DOI:10.1055/s-0033-1340861

LETTER
▌955
lAetteCr oncise Approach Toward Tetrazolyl-Substituted Benzazocines via a
Novel Isocyanide-Based Multicomponent Reaction
Ugi-Azide Reaction: Synthesis of Benzazocine-tetrazoles
Roman S. Borisov,a Leonid G. Voskressensky,*b Anatoly I. Polyakov,c Tatiana N. Borisova,b Alexey V. Varlamovb
a
A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Science, 29, Leninsky Avenue, Moscow 119991, Russian
Federation
b
Peoples Friendship University of Russia, 6, Miklukho-Maklaia Street, Moscow 117198, Russian Federation
Fax +7(495)9550779; E-mail: lvoskressensky@sci.pfu.edu.ru
c
N. N. Blohin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russian Federation
Received: 20.11.2013; Accepted after revision: 04.02.2014
ing the reactivity of cotarnine chloride (2) in condensation
Abstract: The synthesis of pharmacologically relevant isoquino-
reactions with an isonitrile and sodium azide (the Ugi-
line-tetrazoles and benzazocine-tetrazoles via sequential azido-Ugi
azide reaction), followed by activated alkyne triggered
and alkyne-induced ring-expansion reactions starting from cotar-
isoquinoline ring-expansion leading to the formation of
1,5-disubstituted tetrazoles bearing isoquinoline or azo-
cine substituents. 1,5-Disubstituted tetrazoles are impor-
tant drug-like scaffolds, which are known for their ability
to mimic the cis-amide bond conformation. Replacement
of the amide bonds by surrogates in order to enhance met-
abolic stability and/or probe receptor specificity has be-
come an increasingly important topic of research, as the
central biological role of peptides as chemical effectors
becomes more understood.8 Apparently, the development
of reliable protocols toward novel 1,5-disubstituted tetra-
zole derivatives has the potential to deliver small mole-
cule probes for new or known protein receptors, thereby
enabling studies on protein function.9
nine chloride are reported. A one-pot, multicomponent reaction pro-
tocol toward the ring-expanded product is also described.
Key words: alkaloids, multicomponent reaction, domino reaction,
ring expansion, alkynes
Historically, the majority of new drugs have been created
from natural products (secondary metabolites), or from
compounds derived from natural sources. Natural prod-
ucts, especially alkaloids, continue to attract significant
attention due to their unique ability to serve as starting
points for the development of novel modulators of bio-
molecule function.1 It is thought that the tendency of nat-
ural products, or natural product derived compounds to be
recognized by a therapeutic protein molecule is concerned
with their molecular structure, that is in itself created by a
series of biosynthetic enzymes.2 Natural products have
therefore not only served as precursors for semi-synthetic
derivative libraries,3 but have also inspired significant in-
terest in creating synthetic protocols aimed at complex,
‘natural-like’ novel synthetic compounds.4
Herein, we report a concise route toward pharmacologi-
cally relevant isoquinoline-tetrazoles and previously un-
reported benzazocine-tetrazoles.
Originally reported in 1961, the Ugi-azide reaction in-
volves Schiff base formation from appropriately substitut-
ed aldehydes or ketones and primary amines, followed by
its reaction with an isocyanide. The resulting intermediate
nitrilium ion then reacts with an azide to afford substituted
tetrazoles in good yields.10
The chemistry of cotarnine (1) (Figure 1) and related het-
erocyclic pseudo-bases has attracted considerable atten-
tion due to their diverse chemical reactivity and important
biological and medicinal implications.5
Initial studies concentrated on exploring the suitability of
commercially available cotarnine chloride (2) in reactions
with isonitriles 3 and sodium azide to provide the tetrazo-
lyl-isoquinolines 4a–i (Scheme 1, Table 1).
O
N
O
Me
O
OMe OH
O
MeOH–H2O
N+
1
O
Me
N
N
– NaCl
O
Cl–
R
Me
R
51–69%
C–
OMe
Na
Figure 1 The structure of cotarnine (1)
2
N+
OMe
N
4a–i
3a–i
N
N
As part of our research program on isocyanide
multicomponent6 and alkyne-induced N-heterocyclic
ring-expansion reactions,7 we became interested in study-
N
N+
N–
Scheme 1 Ugi-azide reaction using cotarnine chloride (2)
SYNLETT 2014, 25, 0955–0958
Advanced online publication: 11.03.2014
DOI: 10.1055/s-0033-1340861; Art ID: ST-2013-B1071-L
© Georg Thieme Verlag Stuttgart · New York
In a typical experiment, cotarnine chloride (2) (1 mmol),
isonitrile 3 (1.2 mmol) and sodium azide (1.2 mmol) were
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

956
R. S. Borisov et al.
LETTER
dissolved in a mixture of water–methanol (1:5, 5 mL), and
the resulting solution stirred at room temperature for 18–
24 hours (TLC monitoring). In most cases, the target tet-
razolyl-isoquinolines 4 precipitated from the reaction
mixtures (see the Supporting Information for details). Af-
ter completion of the reaction (monitored by the disap-
pearance of the isocyanide spot according to TLC), LC–
MS analysis showed the presence of a multicomponent
mixture containing compounds 4 as the major products
(65–81% according to LC–MS), along with several by-
products, which we were unable to isolate or identify.
Table 1 Formation of Compounds 4a–i and 5a–d
Product R
R1
R2
Yield
(%)
4a
4b
4c
4d
cyclohexyl
–
–
–
–
–
–
–
–
51
53
63
57
cyclopentyl
Bn
2-ethyl-6-methylphenyl
Next, the post-Ugi ring-expansion reaction was studied
using isoquinolines 4c,d and methyl propiolate, dimethyl-
acetylene dicarboxylate (DMAD) or acetyl acetylene
(Scheme 2).
4e
–
–
69
N
O
H
R2
4f
–
–
–
–
58
63
Me
R2
O
O
O
O
N
R3
OEt
O
N
N
CF3CH2OH, 35 °C
64–94%
Me
R1
OMe
N
R3
R1
OMe
N
N
N
N
N
4g
N
4c,d
5a–d
NHNH2
O
Scheme 2 Post-Ugi ring-expansion reaction
O
The experimental protocol employed was analogous to
that previously reported11 for 1-arylisoquinolines. Thus,
DMAD, methyl propiolate or acetyl acetylene (1.2 mmol)
was added to a solution of the derivative 4c,d (1 mmol) in
2,2,2-trifluoroethanol (TFE) (10 mL). The reaction mix-
ture was stirred for four to eight hours at 35 °C (TLC mon-
itoring). Following completion, the solvent was
evaporated under reduced pressure and the residue was
crystallized to give the corresponding benzazocine-tetra-
zoles 5a–d (Scheme 2, Table 1). Being distinct from pre-
viously reported data,11 the use of 2,2,2-trifluoroethanol
instead of acetonitrile was mandatory for the efficient ring
expansion in this case. We presume that the reason for this
is the presence of a highly potent electron-withdrawing
tetrazolyl substituent at the C1 position of the isoquinoline
core, which favors the C1–N bond cleavage (SN1-like pro-
cess) after attack of the activated alkyne.
NHNH2
4h
4i
–
–
–
–
55
62
N
O
H
MeO2C
5a
5b
5c
5d
Bn
Bn
Bn
H
H
CO2Me
CO2Me
75
64
94
73
COOMe CO2Me
CO2Me
2-ethyl-6-methylphenyl
H
el four (pseudo-five) component condensation of cotar-
nine chloride (2), sodium azide, isocyanide 3d and methyl
propiolate in methanol (Scheme 3).
In an attempt to combine these two transformations into a
single multicomponent reaction (MCR), we studied a nov-
After stirring for 24 hours at room temperature, the sol-
vent was evaporated and the residue was purified by flash
chromatography to yield the azocine 5d in 35% yield. A
plausible mechanistic rationale for this MCR is depicted
in Scheme 4. The reaction begins with the attack of the
isocyanide 3d on the C1 atom of cotarnine chloride (2) to
yield the immonium cation A, which subsequently reacts
with the azide anion and methyl propiolate (MP) to pro-
duce the zwitterionic intermediate B. Finally, intramolec-
ular nucleophilic attack of the anion of B results in ring
expansion to give product 5d.
Me
O
O
O
O
N
CO2Me
N+
Me
+
Cl–
OMe
N
MeOH–H2O
35%
CO2Me
OMe
2
N
R
N
N
R = 2-ethyl-6-methylphenyl
N
Na
N+
N+
5d
N–
C–
3d
Scheme 3 MCR route towards benzazocine-tetrazoles
Synlett 2014, 25, 955–958
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ugi-Azide Reaction: Synthesis of Benzazocine-tetrazoles
(3) (a) Shevyakov, S. V.; Davydova, O. I.; Kiselyov, A. S.;
957
Me
O
O
N
O
O
Kravchenko, D. V.; Ivachtchenko, A. V.; Krasavin, M. Nat.
Prod. Res. 2006, 20, 871. (b) Floss, H. G. J. Biotechnol.
2006, 124, 242.
CO2Me
N+
Me
OMe
N
Cl–
MeOH–H2O
35%
CO2Me
OMe
(4) (a) Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 9, 281.
(b) Sandulenko, Y.; Krasavin, M. Chem. Heterocycl.
Compd. 2012, 48, 606.
(5) (a) Beke, D. Adv. Heterocycl. Chem. 1963, 1, 167.
(b) Krasnov, K. A.; Kartsev, V. G.; Khrustalev, V. N.
Heterocycles 2007, 71, 13. (c) Ukhin, L. Yu.; Suponitskii, K.
Yu.; Kartsev, V. G. Chem. Nat. Compd. 2003, 39, 482.
(d) Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
Org. Biomol. Chem. 2007, 5, 1466.
2
N
R
+
N
N
5d
N
Na
N+
N+
N–
C–
3d
CO2Me
MP =
R = 2-ethyl-6-methylphenyl
(6) (a) Voskressensky, L. G.; Borisov, R. S.; Kulikova, L. N.;
Kleimenov, A. V.; Borisova, T. N.; Varlamov, A. V. Chem.
Heterocycl. Compd. 2012, 48, 680. (b) Borisov, R. S.;
Polyakov, A. I.; Medvedeva, L. A.; Khrustalev, V. N.;
Guranova, N. I.; Voskressensky, L. G. Org. Lett. 2010, 12,
3894.
(7) (a) Voskressensky, L. G.; Borisova, T. N.; Soklakova, T. A.;
Kulikova, L. N.; Borisov, R. S.; Varlamov, A. V. Lett. Org.
Chem. 2005, 2, 18. (b) Voskressensky, L. G.; Borisova, T.
N.; Kostenev, I. S.; Vorobiev, I. V.; Varlamov, A. V.
Tetrahedron Lett. 2005, 46, 1975.
(8) Zabrocki, J.; Smith, G. D.; Dunbar, J. B. Jr.; Iijima, H.;
Marshall, G. R. J. Am. Chem. Soc. 1988, 110, 5875.
(9) Gunawan, S.; Hulme, C. Org. Biomol. Chem. 2013, 11,
6036.
(10) For examples of Ugi-azide reactions, see: (a) Ugi, I.;
Steinbruckner, C. Chem. Ber. 1961, 94, 734. (b) Ugi, I.
Angew. Chem., Int. Ed. Engl. 1962, 1, 8. (c) Yue, T.; Wang,
M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem. Int. Ed. 2008,
47, 9454. (d) Mayer, J.; Umkehrer, M.; Kalinski, C.; Ross,
G.; Kolb, J.; Burdack, C.; Hiller, W. Tetrahedron Lett. 2005,
46, 7393. (e) Soeta, T.; Tamura, K.; Fujinami, S.; Ukaji, Y.
Org. Biomol. Chem. 2013, 11, 2168.
O
Cl–
O
O
Me
1) NaN3
2) MP
N
O
+
N
MeO
Me
+
– NaCl
OMe
–
CO2Me
N
N
N
R
N
N
A
B
Scheme 4 A plausible mechanism for the MCR
Our attempts to examine a one-pot, stepwise reaction by
first combining cotarnine, the isocyanide and sodium
azide, and then adding the alkyne also resulted in the for-
mation of a multicomponent mixture, which after purifi-
cation by column chromatography provided the target
azocine 5d in 38% yield.
To date, we have been unable to isolate any other low mo-
lecular weight by-products from this MCR procedure.
(11) Voskressensky, L. G.; Borisova, T. N.; Listratova, A. V.;
Kulikova, L. N.; Titov, A. A.; Varlamov, A. V. Tetrahedron
Lett. 2006, 47, 4585.
In conclusion, we have described the synthesis of isoquin-
oline-tetrazoles and benzazocine-tetrazoles via sequential
azido-Ugi and alkyne-induced ring-expansion reactions.12
A one-pot, multicomponent reaction protocol toward the
ring-expanded product is also reported. Further work
aimed toward optimization of the reaction conditions and
a study of the scope and limitations of this procedure is
underway, and the results will be reported in due course.
(12) Isoquinoline-Tetrazoles 4a–i; General Procedure
Cotarnine chloride (2) (1 mmol), isonitrile 3 (1.2 mmol) and
NaN3 (1.2 mmol) were dissolved in H2O–MeOH (1:5, 5
mL), and the mixture was stirred at r.t. for 18–24 h (TLC
monitoring). Products 4a,b were isolated using flash
chromatography (EtOAc–hexanes, from 1:50 to 1:10).
Products 4c–i precipitated from the reaction mixtures and
were removed by filtration, washed with cold MeOH (15
mL) and dried in air.
Acknowledgment
5-(1-Cyclohexyl-1H-tetrazol-5-yl)-4-methoxy-6-methyl-
5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (4а)
Yield: 189 mg (51%); colorless powder; mp 147–149 °C
(EtOAc–hexanes); reaction time = 19 h.1H NMR (600 MHz,
DMSO-d6): δ = 1.18–1.33 (m, 2 H), 1.37–1.47 (m, 1 H),
1.60–1.71 (m, 2 H), 1.72–1.79 (m, 2 H), 1.79–1.87 (m, 2 H),
1.91–1.97 (m, 1 H), 2.21 (s, 3 H), 2.56 (dt, J = 4.8, 11.7 Hz,
1 H), 2.64 (dt, J = 4.8, 16.5 Hz, 1 H), 2.79–2.86 (m, 1 H),
2.90–2.96 (m, 1 H), 3.50 (s, 3 H), 4.51–4.59 (m, 1 H), 5.18
(s, 1 H), 5.90 (d, J = 9.6 Hz, 2 H), 6.50 (s, 1 H). 13C NMR
(150 MHz, DMSO-d6): δ = 25.1, 25.2, 25.3, 26.8, 33.1, 33.2,
42.2, 46.8, 52.7, 57.1, 59.3, 101.4, 103.3, 118.2, 129.5,
134.5, 139.9, 148.8, 154.6. HRMS (MALDI): m/z [M + Na]+
calcd for C19H25N5O3Na: 394.1849; found: 394.1861.
Azocines 5; General Procedure
This work was supported by the Russian Foundation for Basic Re-
search (grant # 13-03-00021а and grant # 14-03-93001 Viet-a).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(1) (a) Li, J. W.-H.; Vederas, J. C. Science 2009, 325, 161.
(b) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461.
(c) Ganesan, A. Curr. Opin. Chem. Biol. 2008, 12, 306.
(d) McChesney, J. D. Phytochemistry 2007, 68, 2015.
(e) Shelar, D. B.; Shirote, P. J. Biomed. Pharm. J. 2011, 4,
141. (f) Mishra, B. B.; Tiwari, V. K. Eur. J. Med. Chem.
2011, 46, 4769.
DMAD, methyl propiolate or acetyl acetylene (1.2 mmol)
was added to a solution of derivative 4a,c (1 mmol) in TFE
(10 mL). The mixture was stirred for 4–8 hours at 35 °C
(TLC monitoring). The solvent was evaporated under
(2) McArdle, B. M.; Quinn, R. J. ChemBioChem 2007, 8, 788.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 955–958

958
R. S. Borisov et al.
LETTER
reduced pressure and the residue was crystallized from
EtOAc–hexane to give the corresponding benzazocine-
tetrazole 5a–d.
Methyl 10-(1-Benzyl-1H-tetrazol-5-yl)-11-methoxy-7-
methyl-5,6,7,10-tetrahydro[1,3]dioxolo[4′,5′:4,5]benzo-
[1,2-d]azocine-9-carboxylate (5a)
Yield: 350 mg (75%), pale brown solid; mp 116–118 °С;
reaction time = 8 h. 1H NMR (400 MHz, CDCl3): δ = 2.74
(dt, J = 5.5, 16.5 Hz, 1 H), 2.80 (s, 3 H), 2.80–2.88 (m, 1 H),
2.49 (dt, J = 5.5, 15.1 Hz, 1 H), 3.68 (s, 3 H), 3.78 (s, 3 H),
3.96–4.08 (m, 1 H), 5.42 (AB, J = 15.6 Hz, 2 H), 5.90 (s, 2
H), 6.25 (s, 1 H), 6.86 (s, 1 H), 7.00–7.44 (m, 2 H), 7.21–7.29
(m, 3 H), 7.33 (s, 1 H). 13C NMR (100 MHz, DMSO-d6):
δ = 29.9, 35.2, 45.3, 50.6, 51.6, 52.4, 60.2, 92.9, 101.3,
105.8, 121.8, 127.2 (2 С), 128.1, 128.6 (2 С), 132.9, 134.3,
136.2, 141.3, 148.1, 154.2, 159.3, 169.7. HRMS (MALDI):
m/z [M + Na]+ calcd for C24H25N5O5Na: 486.1747; found:
486.1758.
Synlett 2014, 25, 955–958
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.