Diversity-oriented pyrazol-3-one synthesis based on hydrazinodipeptide-like units prepared via the Ugi reaction

Article abstract of DOI:10.1016/j.tetlet.2010.05.133

N-Cyanoacetyl-N′-trifluoroacetyl-N′-alkylhydrazines, prepared via hydrazino-Ugi reaction, provided different pyrazol-3-ones when exposed to mildly acidic and mildly basic conditions at 60 °C. These approaches offer a facile access to two different pyrazol-3-one-containing chemotypes in a diversity-oriented fashion, in only two chemical operations from simple precursors.

Full text of DOI:10.1016/j.tetlet.2010.05.133

Tetrahedron Letters 51 (2010) 4095–4099
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diversity-oriented pyrazol-3-one synthesis based on hydrazinodipeptide-like
units prepared via the Ugi reaction
*
Ekaterina Lakontseva, Mikhail Krasavin
Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, 150000, Russia
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 141400, Russia
a r t i c l e i n f o
a b s t r a c t
N-Cyanoacetyl-N0-trifluoroacetyl-N0-alkylhydrazines, prepared via hydrazino-Ugi reaction, provided dif-
ferent pyrazol-3-ones when exposed to mildly acidic and mildly basic conditions at 60 °C. These
approaches offer a facile access to two different pyrazol-3-one-containing chemotypes in a diversity-ori-
ented fashion, in only two chemical operations from simple precursors.
Article history:
Received 13 April 2010
Revised 13 May 2010
Accepted 28 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reactions
Post-Ugi modifications
Hydrazino-Ugi reaction
Monoalkylated pyrazol-3-ones
Peptidomimetics
Diversity-oriented synthesis
Reaction of hydrazine or a substituted hydrazine with 1,3-dicar-
bonyl compounds or synthetic equivalents thereof (b-oxoesters, b-
oxonitriles, b-dialkylamino- or b-alkoxyvinyl ketones) is a classical
way to pyrazole cores known as the Knorr pyrazole synthesis.1 We
have reported2 on the preparation of hydrazinodipepetide-like
units 1 via Ugi reaction involving trifluoroacetic acid as the acid
component. The hydrazino-Ugi reaction initially yields hydrolyti-
cally prone trifluoroacetamides 2 which can be isolated and also
converted in situ into 1 (Scheme 1). As compounds 1 can contain
labile Nb-acyl groups (such as Ac or Boc), we thought it important
to explore the potential of compounds 1 as synthons in the Knorr
pyrazole synthesis, as such an approach may provide novel pyra-
zoles regiospecifically decorated with substituted acetamide side
chains (to our knowledge, no reliable strategy to this end has been
reported in the literature).
instance, we observed no reaction with bis-electrophiles 6–8 that
we had previously condensed quite efficiently with hydrazine.
The reasons for the inert character of 4 in these condensations
are unclear. It may be rationalized by the steric bulk on one of
the hydrazine nitrogen atoms (this should not preclude the com-
pound from reacting at Nb). It is also possible that the secondary
amide functionality deactivates Nb as well, via intramolecular
hydrogen bonding (Fig. 1).
Prompted by these observations, we designed pyrazole precur-
sors 9 containing both an electrophilic nitrile functionality and a
a
reactive N atom (which we had shown previously to be a suitable
reactive center for reductive amination2 and a second Ugi reac-
tion4). These precursors for intramolecular cyclization5 (presum-
ably, into 1-alkyl-5-amino-1,2-dihydro-3H-pyrazol-3-ones 10)
could be derived from the hydrazino-Ugi reaction products 11 by
facile removal of the trifluoroacetyl group (Fig. 2). Such methodol-
ogy was expected to allow exploration of the potential of post-con-
densation modifications of the hydrazino-Ugi core, an approach
that had yielded numerous novel heterocyclic scaffolds when ap-
plied to classical Ugi products.6
To our surprise, initial attempts to realize this approach were
generally not very successful. First we tried to perform a stepwise
condensation3 of representative compound 1a with cyanoacetone.
While the enamine adduct 3 appeared to form (according to TLC
analysis), addition of an equimolar amount of concd HCl led only
to the formation of (DL)-N0-cyclohexyl-N-aminoleucineamide 4.
However, when compounds 11 were prepared (notably, this
further extends the scope of the hydrazino-Ugi reaction) and triflu-
oroacetyl group removal was attempted, the isolated products
were the unexpected (and hitherto not described) 1-alkyl-3-oxo-
5-(trifluoromethyl)-2,3-dihydro-1H-pyrazole-4-carbonitriles 12.
Under the typical conditions we had previously used2 for CF3CO
group removal (10% K2CO3 in aqueous methanol, rt, 3 h) the con-
version was slow (>3 days). Hence, the temperature was raised to
The latter could be condensed directly with aliphatic
a-cyanoke-
tones to give moderate yields of single regioisomers (as confirmed
by HSQC spectra) of pyrazoles 5a,b (Scheme 2). However, the range
of suitable condensation partners for 4 appeared rather limited: for
* Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.133

4096
E. Lakontseva, M. Krasavin / Tetrahedron Letters 51 (2010) 4095–4099
CF3
R2
O
O
R3NC, TFA
O
NH2
R1
N
O
1,4-dioxane
rt, 16 - 20 h
R1
N
H
N
H
R3
O
R2
+
N
H
2
1) R3NC
TFA
1,4-dioxane
rt, 16-20 h
10% aq. K2CO3
rt, 3 h
2)10% aq. K2CO3
rt, 3 h
O
α
H
N
R2
R1
N
H
β
R3
O
N
H
1
Scheme 1. The hydrazino-Ugi reaction and removal of a labile trifluoroacetyl group.2
H
H
N
H
N
O
N
N
CN
O
O
N
HCl
H
N
O
(conc.)
H
N
O
O
N
X
N
H
H2N
EtOH, reflux 4 h
O
O
CN
1a
3
1) HCl in 1,4-dioxane
2) neutralize
H
N
O
N
H
N
R
O
O
CN
N
R
H2N
N
H
EtOH, reflux
18-20 h
NH2
5a, R = t-Bu, 44%
4
5b, R = 1-adamantyl, 52%
Scheme 2. The use of 1a as a synthon in the Knorr pyrazole synthesis.
60 °C to increase the rate of reaction. In contrast, treatment with
0.5 M HCl in aqueous methanol at the same temperature led to
the expected removal of the CF3CO group and the clean formation
of the pyrazol-3-ones 10 (Scheme 3). The isolated yields of both
sets of pyrazol-3-ones 10 and 12 were good to excellent (Table
1). In some cases, products of analytical purity were isolated by
simple filtration, whilst in other cases additional crystallization
or column chromatographic purification was required. The struc-
tures of all the synthesized compounds were supported by 1H
and 13C NMR spectra, LC–MS data, and elemental analyses.7
Mechanistically, theunexpectedformationof 12underbasiccon-
ditions can be rationalized by deprotonation at the activated meth-
ylene group of 11 with subsequent cyclization onto the CF3CO group
CF3
N
N
O
N
O
O
H
6
7
H
H
α
N
CN
N
β
F
H
N
4
8
Figure 1. Suggested intramolecular hydrogen bonding in
unreactive bis-electrophile partners.
4
and examples of
H
H
N
H
N
O
N
N
R2
O
N
O
R2
R2
H
N
H
N
H
N
R1
α
R1
O
N
R1
β
N
N
H
O
O
NH2
O
CF3
10
9
11
Figure 2. Cyanoacetyl hydrazine 9 designed as precursor for pyrazol-3-ones 10.

E. Lakontseva, M. Krasavin / Tetrahedron Letters 51 (2010) 4095–4099
4097
R1
H
N
H
O
N
O
N
N
R2
R2
R2NC, TFA
H
N
H
N
H
N
O
K2CO3
R1
R1
O
NH2
N
N
aq. MeOH
60 ºС, 18 h
1,4-dioxane, rt, 18-24 h
O
O
O
CF3
CF3
NC
11a-h
12a-h
52 - 88%
0.5 M HCl / МеОН
º
60 С, 18 h
H
O
N
N
R2
H
N
R1
O
NH2
10a-h
61 - 92%
Scheme 3. Hydrazino-Ugi reaction of cyanoacetyl hydrazine and further transformations of the products 11.
Table 1
Compounds 10–12 prepared in this work
Entry
Product
R1
R2
Yield of 11 (%)
Yield of 10 (%)
Yield of 12 (%)
1
2
3
4
5
6
7
8
10a, 12a
10b, 12b
10c, 12c
10d, 12d
10e, 12e
10f, 12f
10g, 12g
10h, 12h
i-Bu
n-Pr
Et
t-Bu
c-Hex
Me
t-Bu
c-Hex
c-Hept
i-PrO(CH2)3
4-MeC6H4CH2
EtO(CH2)3
4-FC6H4CH2
t-Bu
76a
82a
64a
58b
78a
68a
47b
83a
52a
69a
56a
88a
59b
65b
52b
86a
66a
74b
77b
61b
89b
74b
69b
92a
i-Pr
c-Hex
a
Yield of the analytically pure product isolated by filtration or by trituration with Et2O.
Yield after chromatography.
b
to give, after dehydration, the observed pyrazol-3-one 12. Given the
labile character of the trifluoroacetamide, the cyclization may be
preceded by N?C migration of the CF3CO group (Scheme 4).
The ability of 11 (or 9) to undergo cyclization into the pyrazol-
3-one should depend on the steric bulk, both at the activated
H
N
O
N
O
NH
H
H
N
N
N
a
N
N
methyl group of the cyanoacetyl side chain and at N . We discov-
O
O
O
ered that the products 13a,b (Fig. 3) synthesized via hydrazino-Ugi
reaction from acetone and cyclohexanone as the carbonyl compo-
nents, respectively, were completely inert toward such cyclization
under acidic or basic treatment and only provided the respective
de-trifluoroacetylated products. Moreover, we found that even a
O
CF3
CF3
13a
13b
Figure 3. Bulky hydrazine derivatives that are inert toward cyclization into a
pyrazol-3-one.
H
B:
H
O
N
N
R2
O
N
N
H
R2
H
N
H
N
R1
(a)
R1
O
- H2O
N
O
O
CF3
CF3
NC
11
H+
12
H+
H
N
R1
- H2O
B:
N
O
N
H
R2
H
N
CF3
O
H
N
HN
NH
R2
R1
H+
(b)
O
O
N
O
CF3
O
11
Scheme 4. Mechanistic rationale for the formation of the pyrazol-3-ones 12.

4098
E. Lakontseva, M. Krasavin / Tetrahedron Letters 51 (2010) 4095–4099
O
NH
O
N
NH
H
N
H
N
0.5 M HCl / МеОН
O
N
N
60 ºС, 18 h
84%
O
NH2
15
O
CF3
14
K2CO3
aq. MeOH
60 оС, 18 h
<40%
Scheme 5. Cyclization of
a-methyl derivative 14.
O
N
NH
O
N
NH
H
N
O
NH
H
N
O
H
O
K2CO3
0.5 M HCl / МеОН
N
N
N
O
O
aq. MeOH
º
NH2
18, 48%
60 С, 18 h
NH
17, 70%
º
60 С, 18 h
CF3
Cl
16
Scheme 6. Cyclization of the cyclopropane derivative 16.
small substituent such as a methyl group, when located at the
methylene group of 10 (presumably, involved in cyclization lead-
ing to 12), can affect the outcome of further cyclizations. Com-
pound 14 (also prepared via hydrazino-Ugi reaction) provided an
excellent yield of pyrazol-3-one 15 when treated with dilute acid
(Scheme 5) and under basic conditions, the same compound
yielded a complex mixture of products (including 15), none of
which contained a trifluoromethyl group.
An interesting result was obtained with the cyclopropane deriv-
ative 16. Under basic conditions, it cyclized to give a good yield of
6-alkyl-7-imino-5,6-diazaspiro[2.4]heptan-4-one 17 (despite the
even greater steric bulk at the nitrile function). Acidic treatment
of 16 resulted in cycloprapane ring opening and isolation of 2-chlo-
roethyl derivative 18 in fair yield (Scheme 6).
In summary, we have reported on a remarkable case of a switch
in reactivity observed for the hydrazino-Ugi reaction products 11
under basic versus acidic conditions. This resulted in diversity-ori-
ented access to two vastly different pyrazol-3-one-based chemo-
types, one of which, 12, has not been described in the literature.
The absence, in these protocols, of regiochemical ambiguity with
regard to alkylation of the pyrazol-3-one nucleus and the technical
simplicity of its construction in two steps from available diverse
reagents should make the described approach a useful method to
prepare these novel peptidomimetic pyrazol-3-ones.
Synthesis of 10; typical procedure: Compound 11 (0.5 mmol) was
dissolved in MeOH (10 mL), treated with 0.5 M HCl (1 mL), and the
resulting solution was stirred at 60 °C overnight. Upon cooling to
rt, the MeOH was evaporated and the residue diluted with H2O
(20 mL), neutralized with solid Na2CO3, and the resulting precipi-
tate was filtered and air-dried. Alternatively, the aqueous mixture
was extracted with CH2Cl2 (3 ꢀ 10 mL) and the combined organic
extract dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by column chromatogra-
phy (SiO2) using an appropriate gradient of MeOH in CH2Cl2 as
eluent.
Synthesis of 12; typical procedure: Compound 11 (0.5 mmol) was
dissolved in MeOH (10 mL), treated 10% aq K2CO3 (5 mL), and the
resulting solution was stirred at 60 °C overnight. Upon cooling to
rt, the MeOH was evaporated and the residue diluted with H2O
(20 mL), neutralized with HCl, and the resulting precipitate was fil-
tered and air-dried. Alternatively, the aqueous mixture was ex-
tracted with CH2Cl2 (3 ꢀ 10 mL) and the combined organic
extract was dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The crude product was purified by column chro-
matography (SiO2) using an appropriate gradient of MeOH in
CH2Cl2 as eluent.
Acknowledgments
Synthesis of 11; typical procedure: Cyanoacetylhydrazine
(10 mmol) was dissolved in anhydrous MeOH (50 mL) and an alde-
hyde (11 mmol) was added. The mixture was stirred at rt for 3 h
and the solvent was evaporated. The solid residue was triturated
with Et2O, filtered, and dissolved in dry 1,4-dioxane (20 mL). Isocy-
anide (12 mmol) and TFA (11 mmol) were added and the resulting
mixture was stirred at rt overnight. It was then diluted with H2O
(100 mL) and extracted with CH2Cl2 (3 ꢀ 50 mL). The combined or-
ganic extract was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The crude product was triturated with Et2O,
filtered, and air-dried to provide analytically pure 11, or further
purified by column chromatography (SiO2) using an appropriate
gradient of MeOH in CH2Cl2 as eluent.
This research was supported by the Federal Agency for Science
and Innovation (Russian Federation Government Contract
02.740.11.0092). Dr. Alexei Shumsky of Chemical Diversity Re-
search Institute is thanked for his help in structure elucidation
by NMR.
References and notes
1. (a) Sakuya, S. M. In Name Reactions in Heterocyclic Chemistry; Li, J.-J., Corey, E. J.,
Eds.; J. Wiley & Sons: Hoboken, 2005; pp 292–300; (b) Yet, L. Prog. Heterocycl.
Chem. 2009, 21, 224–260. and references cited therein.
2. Krasavin, M.; Bushkova, E.; Parchinsky, V.; Shumsky, A. Synthesis 2010, 933–942.
3. Krasavin, M.; Konstantinov, I. O. Lett. Org. Chem. 2008, 5, 594–598.

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4. Bushkova, E.; Parchinsky, V.; Krasavin, M. Mol. Divers., in press, doi:10.1007/
s11030-009-9200-6.
5. El-Hawash, S. A. M.; El-Mellah, A. I. Pharmazie 1998, 53, 368–373.
6. Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125–147. and
references cited therein.
36.6, 65.1, 67.0, 69.9, 71.1, 152.5, 165.3, 168.5. LC–MS (M+H+) m/z = 313. Anal.
Calcd for C15H28N4O3: C, 57.67; H, 9.03; N, 17.93. Found: C, 57.60; H, 8.93; N,
17.88. Compound 12a, white solid, mp = 143 °C (dec). 1H NMR (400 MHz,
DMSO-d6) d 0.85 (d, J = 6.6 Hz, 6H), 1.25 (s, 9H), 1.36 (m, 1H), 1.66 (m, 1H), 2.28
(m, 1H), 4.92 (m, 1H), 7.86 (br s, 1H), 12.34 (br s, 1H). 13C NMR (100 MHz,
7. Characterization data for selected compounds: Compound 10a, white solid,
mp = 128–130 °C. 1H NMR (400 MHz, DMSO-d6) d 0.82 (d, J = 6.6 Hz, 3H), 0.86
(d, J = 6.6 Hz, 3H), 1.22 (s, 9H), 1.30 (m, 1H), 1.56 (m, 1H), 1.91 (m, 1H), 4.42 (m,
1H), 4.56 (s, 1H), 5.47 (br s, 2H), 7.14 (br s, 1H), 9.35 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6) d 21.4, 22.9, 24.3, 28.3, 49.9, 58.4, 74.3, 150.2, 161.8, 170.3.
LC–MS (M+H+) m/z = 269. Anal. Calcd for C13H24N4O2: C, 58.18; H, 9.01; N, 20.88.
Found: C, 58.26; H, 8.92; N, 20.81. Compound 10d, white solid, mp = 117–
119 °C. 1H NMR (400 MHz, CDCl3) d 1.05 (s, 9H), 1.12 (d, J = 5.8 Hz, 6H), 1.62 (m,
2H), 3.32 (m, 2H), 3.44 (t, J = 6.6 Hz, 2H), 3.53 (m, 1H), 4.51 (s, 1H), 4.65 (s, 1H),
5.17 (br s, 2H), 8.11 (br s, 1H). 13C NMR (100 MHz, CDCl3) d 21.6, 27.2, 29.2, 36.5,
DMSO-d6) d 20.4, 23.0, 24.4, 28.1, 50.5, 62.3, 79.6, 110.7, 118.0 (q, JC–
F = 256.5 Hz), 133.3 (q, JC–F = 38.2 Hz), 161.6, 167.0. LC–MS (M+H+) m/z = 347.
Anal. Calcd for C15H21F3N4O2: C, 52.02; H, 6.11; N, 16.18. Found: C, 51.96; H,
6.04; N, 16.25. Compound 12d, white solid, mp = 152–154 °C. 1H NMR
(400 MHz, DMSO-d6) d 1.03 (d, J = 5.9 Hz, 6H), 1.06 (s, 9H), 1.58 (m, 2H), 3.11
(m, 2H), 3.31 (t, J = 6.5 Hz, 2H), 3.46 (m, 1H), 4.43 (s, 1H), 7.85 (t, J = 5.4 Hz, 1H),
12.39 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) d 21.9, 27.3, 29.4, 35.7, 36.2, 64.7,
70.5, 70.7, 79.7, 110.6, 117.8 (q, JC–F = 271.3 Hz), 134.3 (q, JC–F = 38.2 Hz), 161.9,
164.7. LC–MS (M+H+) m/z = 391. Anal. Calcd for C17H25F3N4O3: C, 52.30; H, 6.45;
N, 14.35. Found: C, 52.38; H, 6.46; N, 14.41.