tert-Butyl isocyanide as a convertible reagent in Ugi reaction: Microwave-assisted preparation of 5,6-dihydropyrazolo[1,5-a]pyrazine-4,7-diones

Article abstract of DOI:10.1055/s-0028-108766

tert-Butyl amides resulting from Ugi MCR of t-BuNC and 5-substituted- ¹H-pyrazole-3-carboxylic acids with various aldehydes and amines undergo cyclization into 5,6-dihydropyrazolo[ 1,5-a]pyrazine-4,7-diones in glacial acetic acid under microwav

Full text of DOI:10.1055/s-0028-108766

260
LETTER
tert-Butyl Isocyanide as a Convertible Reagent in Ugi Reaction: Microwave-
Assisted Preparation of 5,6-Dihydropyrazolo[1,5-a]pyrazine-4,7-diones
P
reparation of 5,6-Dih
i
k
razolo[1,5-
a
]
h
pyrazine-4,7
a
-
diones il Nikulnikov,a,b Sergey Tsirulnikov,a Volodymyr Kysil,c Alexandre Ivachtchenko,c Mikhail Krasavin*a,b
a
b
c
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Region 114401, Russian Federation
Fax +7(495)6269780; E-mail: myk@chemdiv.com
Department of Organic and Biological Chemistry, L. N. Tolstoy State Pedagogical University, 125 Lenin Avenue, Tula 300026,
Russian Federation
ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA
Received 29 August 2008
recently reported 1-isocyano-2-(2,2-dimethoxyethyl)ben-
zene (termed as ‘indole isonitrile’).5 1,1,3,3-Tetramethyl-
butyl isocyanide (‘Walborsky reagent’6) has been
successfully employed7 in isocyanide-based multicompo-
Abstract: tert-Butyl amides resulting from Ugi MCR of t-BuNC
and 5-substituted-1H-pyrazole-3-carboxylic acids with various al-
dehydes and amines undergo cyclization into 5,6-dihydropyrazo-
lo[1,5-a]pyrazine-4,7-diones in glacial acetic acid under microwave
irradiation. This reaction is a remarkable case of neighboring- nent reactions with subsequent conversion of the isooctyl-
group-assisted cleavage of tert-butyl amides and demonstrates util-
ity of t-BuNC as a new convertible isocyanide.
amino moiety into a primary amino group potentially suit-
able for functionalization.
Key words: Ugi multicomponent reaction, convertible isocya-
In our ongoing research, we aim at developing efficient
nides, microwave-assisted cyclization, post-Ugi MCR cyclization
approaches to combinatorial libraries based on medicinal-
ly relevant scaffolds. Our recent interest was attracted by
5,6-dihydropyrazolo[1,5-a]pyrazine-4,7-diones 2. This
While designing reaction arrays based on the Ugi multi-
drug-like core fragment has a strong potential for identi-
component reaction (Ugi MCR),1 it is often desirable not
fying various biological activities, as witnessed by several
to rely on the isocyanide component as the source of prod-
antibacterial,8 anti-inflammatory,9 antitumor,10 and CNS-
uct diversity and rather take advantage of this efficient
active11 compounds reported in the literature. However,
process to unite the other three reaction components with
rapid approaches to generating vast arrays of such com-
a single convertible isocyanide. The resulting Ugi reaction
pounds with controlled diversity have not been described.
products are then suitable for use as substrates for selec-
This, and also the opportunity to explore a post-MCR con-
tive post-MCR modification of the former isocyanide por-
densation strategy (not dissimilar to that described for
tion. Notably, such modifications can involve an ‘internal
nucleophile’ and result in a cyclization process, as exem-
diketopiperazinones – vide supra) as a novel way to pre-
pare 2 (Scheme 2) constituted the premise for this study.
plified by preparation of diketopiperazine library de-
An important aspect that we considered before prepara-
tion of the Ugi reaction products as precursors to the target
5,6-dihydropyrazolo[1,5-a]pyrazine-4,7-diones 2 was the
choice of an appropriate convertible isocyanide. Although
the Armstrong’s isocyanide was demonstrated to be the
reagent of choice to prepare Ugi-type substrates for post-
MCR cyclizations (and superior to benzyl, n-butyl, cyclo-
hexyl, isopropyl isocyanides, and Walborsky reagent),2 it
has obvious disadvantages.
scribed by Hulme and co-workers2 (Scheme 1).
In order to qualify as convertible, an isocyanide should be
designed so as to allow selective cleavage of the respec-
tive amide in the Ugi reaction product without affecting
the other amide moiety present in the same product. Con-
vertible isocyanides reported to date include notable ex-
amples of cyclohex-1-enyl isocyanide (1, ‘Armstrong’s
isonitrile’),3 2-isocyano-2-methylpropyl carbonates,4 and
H
N
O
R1 CHO
O
R1
O
H
N
O
OH
R3
HN
R2
R1
H
MeOH, r.t.
72–92%
TFA–DCE (1:9)
O
N
N
O
R3
N
R2
r.t.
14–50%
O
R3
O
R2 NH2
NC
O
internal nucleophile
generated via
Boc-deprotection
1
Scheme 1 Post-MCR cyclization leading to diketopiperazines2
SYNLETT 2009, No. 2, pp 0260–0262
x
x.
x
x.
2
0
0
8
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-108766; Art ID: D30608ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 5,6-Dihydropyrazolo[1,5-a]pyrazine-4,7-diones
261
O
R1
conv-R NC
N
HO
R2
O
O
post-MCR
cyclization
R1
O
convertible
isocyanide
conv-R
HN
NH
N
Ugi-4CR
+
N
N
R3
R3
N
O
O
R2 HN
N
R1
H2N R2
R3
2
H
internal nucleophile?
Scheme 2 5,6-Dihydropyrazolo[1,5-a]pyrazine-4,7-diones 2 via post-MCR cyclization?
O
R1
N
HO
R1
O
NC
R2
O
O
NH
H
N
MeOH
N
AcOH
MW, 20 min, 180 °C
N
+
N
R2
3
NH
R3
R3
N
50 °C to r.t., 24 h
O
H
O
N
R1
H2N R2
R3
2a–k
Scheme 3 Synthesis of quinoxalines 5a–h via intermediate formation of 1,4-dihydroquinoxalines 4a–h
It is commercially unavailable, has limited stability, re-
Table 1 5,6-Dihydropyrazolo[1,5-a]pyrazine-4,7-diones 2
quires freezer storage, and cannot be prepared on a large
scale.12 Herein we report that for preparation of 5,6-di-
hydropyrazolo[1,5-a]pyrazine-4,7-diones 2, the Arm-
strong’s isocyanide can be replaced with readily available
tert-butyl isocyanide and the desired post-MCR cycliza-
tion of 3 is efficiently promoted by microwave irradiation
in glacial acetic acid (Scheme 3).13
Prepared in this Work
R1
R2
O
O
N
N
N
R3
2a–k
The two-step procedure to prepare 2 was designed so as to
allow carrying out both steps in the same reaction vessel
(microwave reactor tube) and thus be amenable for prep-
aration of large arrays of the final compounds in parallel
format. To prepare each of the bisamides 3, equimolar
amounts of an aldehyde and amine were combined in
methanol (0.5 mmol each/1 mL MeOH) and heated at
50 °C for two hours to ensure complete imine formation.
Then a solution of a 1H-pyrazole-3-carboxylic acid (0.5
mmol) in methanol (1 mL) was added followed, after five
minutes of stirring, by a solution of t-BuNC (0.5 mmol) in
methanol (1 mL). Then the mixtures were left under stir-
ring at room temperature for 24 hours. The solvent was re-
moved in vacuo14 and the resulting products were shown
to be at least 85% pure by LC-MS analysis in all cases.15
Without further purification, these were dissolved in gla-
cial AcOH (3 mL each) and the reaction vessels were
capped. After heating the reaction mixtures at 180 °C un-
der microwave irradiation for 20 minutes (using Biotage
InitiatorTM microwave synthesizer operating at 100 W),
these were poured into water (25 mL), and the resulting
thick precipitates were collected by filtration. In all cases,
the resulting products were isolated in at least 90% purity,
and their molecular weight was indicative of a loss of a
tert-butylamino group, as determined by LC-MS
(Scheme 2). Further purification of the products by col-
umn chromatography on silica (gradients of ethyl acetate
in hexanes) afforded analytically pure products in fair to
good yields over two steps (Table 1). The identity of the
Entry
2
R1
R2
R3
Yield
(%)
1
2
3
4
2a 4-EtOC6H4
2b 4-EtOC6H4
2c 4-EtOC6H4
2d 4-EtOC6H4
Ph
2-MeC6H4 61
65
4-MeOC6H4CH2 4-FC6H4
4-MeOC6H4CH2 3-MeC6H4 56
4-MeOC6H4CH2 2-MeC6H4 42
5
6
2e 4-EtOC6H4
2-MeC6H4 43
2f 3-MeOC6H4 4-MeOC6H4CH2 2-MeC6H4 45
7
2g 3-MeOC6H4
4-FC6H4
4-FC6H4
38
8
9
2h
2i
Ph
67
52
4-MeOC6H4CH2 4-FC6H4
S
10
11
2j
Ph
4-FC6H4
4-FC6H4
70
46
S
2k
products was confirmed as 5,6-dihydropyrazolo[1,5-
a]pyrazine-4,7-diones 2 by 1H NMR and 13C NMR spec-
troscopy as well as elemental analyses.16
Synlett 2009, No. 2, 260–262 © Thieme Stuttgart · New York

262
M. Nikulnikov et al.
LETTER
(12) Pirrung, M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128,
In conclusion, we developed a streamlined two-step, one-
purification approach to medicinally important 5,6-di-
hydropyrazolo[1,5-a]pyrazine-4,7-diones using an Ugi
4CR–post-MCR cyclization approach. We demonstrated
for the first time that in the microwave-assisted cycliza-
tion process, the readily available tert-butyl isocyanide
can function as convertible isocyanide thus offering a
more convenient and economical alternative to previously
used Armstrong’s isocyanide. We are now investigating if
other isocyanides and azole carboxylic acids can be incor-
porated via Ugi reaction into precursors for post-MCR cy-
clization. The results of these studies will be reported in
due course.
11771.
(13) Other reaction conditions that were screened and proved
inefficient for post-MCR cyclization of 3 included
conventional heating in AcOH, conventional and microwave
heating in TFA, as well as using base promoters (KOt-Bu,
NaH) in various solvents (e.g., THF, DMF, dioxane). tert-
Butyl isonitrile was chosen on the basis of its commercial
availability in large quantities. However, we are also finding
it superior to other isocyanides in the present post-MCR
cyclization. These finding will be disclosed in a separate
communication.
(14) Parallel evaporation of volatiles from the microwave reactor
tube was carried out using GeneVac® equipment.
(15) No further purification and characterization (except LC-MS
analysis) of the crude Ugi reaction products 3 were
performed.
Acknowledgment
(16) Characterization Data for Selected Compounds
Compound 2f: white solid, mp 122–123 °C. 1H NMR (300
MHz, CDCl3): d = 7.58 (s, 1 H), 7.50–7.55 (t, J = 8.1 Hz,
1 H), 7.27–7.31 (m, 2 H), 7.19–7.24 (m, 1 H), 7.08–7.13 (m,
3 H), 7.00 (ddd, J = 8.4, 2.5, 1.0 Hz, 1 H), 6.89 (d, J = 8.4
Hz, 2 H), 5.63 (d, J = 14.5 Hz, 1 H), 5.58 (s, 1 H), 3.87 (s, 3
Dr. Dmitry Dmitriev of CDRI is acknowledged for his help in NMR
spectral analyses.
References and Notes
H), 3.82 (s, 3 H), 3.45 (d, J = 14.5 Hz, 1 H), 2.38 (s, 3 H). 13
C
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138.0, 137.3, 132.1, 131.5, 131.1, 129.8, 129.5, 129.1,
126.6, 126.3, 125.7, 119.1, 116.4, 114.1, 111.1, 110.4, 60.6,
55.0, 54.9, 45.6, 19.2. LC-MS: m/z = 433 [M + H]. Anal.
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72.04; H, 5.43; N, 9.02.
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NMR (300 MHz, CDCl3): d = 7.25 (dd, J = 7.4, 5.3 Hz, 2 H),
7.07–7.12 (m, 4 H), 6.83–6.90 (m, 3 H), 5.57 (d, J = 14.5 Hz,
1 H), 5.17 (s, 1 H), 3.79 (s, 3 H), 3.48 (d, J = 14.5 Hz, 1 H),
2.03–2.12 (m, 1 H), 1.05–1.15 (m, 2 H), 0.90–0.96 (m, 2 H).
13C NMR (75Hz, CDCl3): d = 164.0, 162.9 (d, JC–F = 248.5
Hz), 159.5, 159.3, 153.9, 137.2, 129.7, 129.5 (d, JC–F = 2.9
Hz), 128.7 (d, JC–F = 8.6 Hz), 126.1, 116.3 (d, JC–F = 21.7),
114.1, 110.4, 63.3, 54.4, 45.5, 9.2, 9.1, 8.9. LC-MS: m/z =
406 [M + H]. Anal. Calcd for C23H20FN3O3: C, 68.14; H,
4.97; N, 10.36. Found: C, 68.19; H, 5.03; N, 10.39.
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D. Farmaco 1991, 46, 1337.
Compound 2j: white solid, mp 147–149 °C (decomp.). 1H
NMR (300 MHz, CDCl3): d = 7.61 (d, J = 3.5 Hz, 1 H), 7.48
(s, 1 H), 7.46 (d, J = 5.0 Hz, 1 H), 7.25–7.37 (m, 5 H), 7.12–
(9) Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto, G.
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C
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153.7, 153.4, 138.1, 137.5, 132.4, 130.2 (d, JC–F = 2.8 Hz),
129.1, 128.7 (d, JC–F = 8.6 Hz), 129.3, 128.0, 127.9, 127.6,
126.7, 116.1 (d, JC–F = 22.1), 111.0, 68.7. LC-MS: m/z = 404
[M + H]. Anal. Calcd for C22H14FN3O2S: C, 65.50; H, 3.50;
N, 10.47. Found: C, 65.54; H, 3.60; N, 10.51.
Synlett 2009, No. 2, 260–262 © Thieme Stuttgart · New York

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