Increased dipeptoid diversity resulting from post-condensational manipulation of the Ugi reaction products

Article abstract of DOI:10.1016/j.mencom.2012.01.016

5,6-Dihydropyrazolo[1,5-a]pyrazines prepared via the Ugi reaction involving pyrazole-3-carboxylic convertible tert-butyl isocyanide and subsequent microwave-promoted cyclization, were found to be prone to opening with primary and secondary amines, thereby

Full text of DOI:10.1016/j.mencom.2012.01.016

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 41–42
Increased dipeptoid diversity resulting from post-condensational
manipulation of the Ugi reaction products
Mikhail Krasavin*a,b and Mikhail M. Nikulnikova,b
a Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, 150000 Yaroslavl,
Russian Federation
b Chemical Diversity Research Institute, 141400 Khimki, Moscow Region, Russian Federation.
Fax: +7 495 626 9780; e-mail: mkrasavin@hotmail.com
DOI: 10.1016/j.mencom.2012.01.016
5,6-Dihydropyrazolo[1,5-a]pyrazines prepared via the Ugi reaction involving pyrazole-3-carboxylic convertible tert-butyl isocyanide
and subsequent microwave-promoted cyclization, were found to be prone to opening with primary and secondary amines, thereby
providing a facile, three-step access to a greater diversity of Ugi-type dipeptoids, some of which cannot be accessed via the Ugi
reaction itself.
The Ugi reaction (Scheme 1) has undoubtedly occupied a central
place both in the toolbox of combinatorial chemistry1 and in the
minds of organic chemists as probably the most prominent multi-
component reaction that can offer access (via so-called post-Ugi
modifications) to a wide variety of drug-like heterocycles.2
vertible reagent. We believe the cyclization 1®2 may involve
generation of the primary amide 3 (on tert-butyl elimination)
that is more easily cyclized than its N-alkyl amide counterparts.
This is indirectly confirmed by the presence of the respective
carboxylic acid 4 in the reaction mixtures after microwave irra-
diation (presumably resulting from the hydrolysis of 3 by adven-
titious water) and may explain lower reactivity of primary and
secondary alkyl amides in similar microwave-assisted cyclization.5
While many azole carboxylic acids can be incorporated into
dipeptoids similar to 1 via the Ugi reaction, many of them fail to
participate in microwave-assisted cyclization. Among the azole
residues supplied by the carboxylic acid components shown in
Figure 1, only 5-methoxylindole moiety participated efficiently in
the cyclization onto the terminal tert-butyl amide in the respective
Ugi reaction products 5 (under higher temperature and upon
prolonged exposure to microwave irradiation) to give rise to novel
2,3-dihydropyrazino[1,2-a]indole-1,4-diones 6 (Scheme 3).6 Thus,
the pyrazole moiety appears to be a unique accessory in the intra-
molecular ex-isocyanide residue conversion in 1 providing easy
access to conformationally restricted peptidomimetics 2.
R2
R3
R2 R3
O
O
+
H
MeOH, H+
C
N
R4
N
R1 NH2
R5
N
R4
R1
O
HO
O
R5
Scheme 1
Our group has been actively investigating novel synthetic
approaches to medicinally relevant molecular scaffolds,3 largely
stemming from the Ugi reaction itself as well as other isocyanide-
based chemistries. Recently, we discovered that products of the Ugi
reaction 1 incorporating residues of 1H-pyrazole-3-carboxylic acid
and tert-butylisocyanide can undergo a facile cyclization into the
medicinally important 5,6-dihydropyrazolo[1,5-a]pyrazines 2 when
MeO
heated under microwave irradiation in glacial acetic acid (Scheme 2) 4
.
N
O
O
O
Overall, in this two-step sequence (the Ugi reaction + post-
Ugi cyclization), tert-butyl isocyanide may be regarded as a con-
N
N
N
H
H
H
OH
OH
OH
R1
O
R1
O
N
N
H
O
N
O
O
N
N
H2N
But
AcOH
N
R2
N
N
R2
N
NH
N
N
H
NH
MW,
20 min,
180 °C
H
O
H
OH
OH
OH
O
R3
R3
1
Figure 1 Examples of azole carboxylic acids tried in microwave-assisted
3
cyclization of the respective Ugi reaction products.5
H2O
– NH4OAc
– NH4OAc
R1
R1
O
R1
O
R2
R1
O
HO
N
R2
O
N
H
H
N
R2
O
N
N
N
NH
N
N
But
N
R2
O
AcOH
O
N
O
R3
MW
90 min,
180 °C
4
MeO
detected in the reaction mixture,
not stable for isolation
6
5
MeO
R3
2
Scheme 2
Scheme 3
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 41–42
R1
O
R2
R5
N
R1
O
O
N
R1
O
N
N
But
N
C
O
H
HO
H
R4R5NH
N
NH
N
MeOH
AcOH
N
R4
N
But
N
R2
N
R2
+
O
NH
dioxane,
room tem-
perature,
overnight
NH MW, 20 min,
180 °C
50 °C
O
R3
O
H2N R2
room tem-
perature,
24 h
R1
R3
R3
R3
1a–c
2a–c
7a–d, 8a–h
R1
R2
R3
R4
R5
Yield (%)
7a
4-PriC6H4
4-MeOC6H4CH2 4-MeC6H4
4-MeOC6H4CH2 4-MeC6H4
MeO(CH2)2
Bn
H
H
70
65
7b 4-PriC6H4
O
7c
Pri
4-MeOC6H4CH2 Me
4-MeOC6H4CH2 Me
H
H
69
70
7d Pri
Bn
8a
4-PriC6H4
4-MeOC6H4CH2 4-MeC6H4
4-MeOC6H4CH2 4-MeC6H4
4-MeOC6H4CH2 4-MeC6H4
4-MeOC6H4CH2 Me
4-MeOC6H4CH2 Me
4-MeOC6H4CH2 Me
(CH2)2O(CH2)2
(CH2)4
(CH2)2N(CO2Et)(CH2)2
(CH2)2O(CH2)2
67
71
68
71
67
72
68
65
8b 4-PriC6H4
8c
4-PriC6H4
8d Pri
8e
8f
Pri
Pri
Pri
Me
Et
(CH2)2N(c-C5H9)(CH2)9
(CH2)2N(Cy)(CH2)9
(CH2)5
8g
Bn
Bn
Cyclopropyl
Cyclopropyl
8h Pri
Scheme 4
We proceeded to study the chemical behaviour of 5,6-dihydro-
pyrazolo[1,5-a]pyrazines 2 and found them to be prone to alkaline
hydrolysis at elevated temperatures. Indeed, refluxing a solution
of any of 2 in dioxane in the presence of 2 equiv. of aqueous KOH
led to its complete conversion into the corresponding salt of
carboxylic acid 4 (according to LC-MS analysis). However, despite
numerous attempts, we were unable to isolate and purify any of
the acids 4 (presumably, due to facile decarboxylation).
Compounds 2 can be regarded as internal pyrazolides of the
carboxylic acids 4 and therefore it is unsurprising that they are
reactive toward nucleophiles.7 We therefore turned our attention
to the potential of opening 2 with various amines (rather than
hydroxyl anion) that would provide access to a greater variety
of Ugi-type dipeptoids with terminal amide diversity resulting
from generally much more available primary amines (compared
to the variety of isocyanides) (Scheme 4).
to primary and secondary amines at dioxane reflux temperatures.
This seems unsurprising in view of the greater stability (e.g., toward
hydrolysis) of N-acyl indoles compared to N-acyl pyrazoles.8
In summary, we have developed an efficient access to Ugi-type
dipeptoids containing a greater diversity of terminal secondary
amides as well as hitherto undescribed tertiary amide analogs
thereof. This novel protocol stems from our previously disclosed
methodology of microwave- assisted cyclization of pyrazole-
containing Ugi reaction products and significantly expands the
chemical space of dipeptoids rapidly and efficiently accessible
by the multicomponent approach.
This research was supported by the Federal Agency for
Science and Innovation (Russian Federation Government Contract
02.740.11.0092).
The representative 5,6-dihydropyrazolo[1,5-a]pyrazines 2a–c
were prepared in good isolated yields via the microwave-assisted
cyclization of the Ugi adducts 1a–c (without isolation of the
latter), as described previously.4 Subsequent overnight treatment
of 2a–c with 2 equiv. of a primary or a secondary amine in dioxane
at room temperature gave cleanly the expected secondary (7a–d)
or tertiary (8a–h) amides in uniformly good yields (Scheme 4).†
Notably, no similar ring opening was observed for the 2,3-dihydro-
pyrazino[1,2-a]indole-1,4-diones 6, even on prolonged exposure
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2012.01.016.
References
1 (a) I. Ugi, B. Werner and A. Dömling, Molecules, 2003, 8, 53; (b) A. Dömling
Chem. Rev., 2006, 106, 17; (c) L. El Kaim and L. Grimaud, Tetrahedron,
2009, 65, 2153.
,
2 (a) I. Akritopoulou-Zanze and S. W. Djuric, Heterocycles, 2007, 73, 125
and references cited therein; (b) A. V. Ivachtchenko, Ya. A. Ivanenkov,
V. M. Kysil, M. Yu. Krasavin and A. P. Ilyin, Usp. Khim., 2010, 79, 861
(Russ. Chem. Rev., 2010, 79, 787); (c) S. Sadjadi and M. M. Heravi,
Tetrahedron, 2011, 67, 2707.
3 (a) M. Krasavin, S. Shkavrov, V. Parchinsky and K. Bukhryakov, J. Org.
Chem., 2009, 74, 2627; (b) M. Krasavin, V. Parchinsky, A. Shumsky,
I. Konstantinov and A. Vantskul, Tetrahedron Lett., 2010, 51, 1367;
(c) E. Lakontseva and M. Krasavin, Tetrahedron Lett., 2010, 51, 4095;
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4 M. Krasavin, M. Nikulnikov, S. Tsirulnikov, V. Kysil and A. Ivachtchenko,
Synlett, 2009, 260.
†
General procedure for the preparation of compounds 7 and 8. Com-
pound 2 (0.5 mmol) synthesized as described previously,4 was dissolved
in dioxane (2 ml) and treated with an amine (0.6 mmol). The reaction
mixture was stirred at ambient temperature overnight. The solvent was
removed under reduced pressure and the target amide 7 (8) was isolated
by column chromatography on silica gel using an appropriate gradient of
methanol in dichloromethane as eluent.
For 8a: 1H NMR (DMSO-d6, 300 MHz) d: 13.37 (s, 1H), 7.65 (d, 2H,
J 7.7 Hz), 7.27 (d, 2H, J 7.7 Hz), 7.04–7.19 (m, 4H), 6.93 (m, 1H), 6.76
and 6.58 (AB qd, 4H, J 8.3 Hz), 5.09 (s, 1H), 4.42 (s, 1H), 3.65 (s, 3H),
3.09–3.57 (m, 8H), 2.84 (m, 1H), 2.35 (s, 3H), 1.17 (d, 6H, J 6.9 Hz),
1.07 (m, 1H). 13C NMR (DMSO-d6, 75 Hz) d: 167.2, 167.0, 163.9, 157.4,
154.5, 151.6, 148.3, 139.2, 137.1, 131.3, 130.9, 130.2, 129.6, 129.4, 128.7,
127.8, 126.5, 126.0, 125.4, 125.2, 112.8, 66.1, 65.5, 54.9, 33.2, 23.9, 23.7,
20.9. Found (%): C, 72.24; H, 6.83; N, 9.92. Calc. for C34H38N4O4 (%): C,
72.06; H, 6.76; N, 9.89.
5 M. Nikulnikov, Ph.D. Thesis, A. N. Kosygin Moscow State Textile
University, Moscow, 2010.
6 M. M. Nikulnikov and M. Yu. Krasavin, Izv. Vys. Uchebn. Zaved., Khim.
Khim. Tekhnol., 2010, 53 (4), 51 (in Russian).
7 K. Itoh and S. Kanemasa, J. Am. Chem. Soc., 2002, 124, 13394.
8 B. S. Jursic and Z. Zdravkovski, J. Mol. Struct. THEOCHEM, 1994, 303,
177.
For characteristics of compounds 7a–d and 8b–h, see Online Supple-
mentary Materials.
Received: 4th July 2011; Com. 11/3755
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