1,3-Dipolar cycloaddition of nitrile imines with functionalized acetylenes: Regiocontrolled Sc(OTf)3-catalyzed synthesis of 4- and 5-substituted pyrazoles

Article abstract of DOI:10.1055/s-0029-1217714

1,3-Dipolar cycloaddition of C-aryl-N-aryl- and C-carboxymethyl-N-aryl- nitrile imines with functionalized acetylenes have been studied. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Under scandium triflate catalysis a reversal in the regiochemistry was observed, especially in the case of C-carboxymethyl-N-aryl-nitrile imines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217714

2328
LETTER
1,3-Dipolar Cycloaddition of Nitrile Imines with Functionalized Acetylenes:
Regiocontrolled Sc(OTf)3-Catalyzed Synthesis of 4- and 5-Substituted
Pyrazoles
S
ynthesis of 4- an
i
d
5-Su
a
bstituted Py
n
razole
s
ca Flavia Bonini, Mauro Comes Franchini,* Denis Gentili, Erika Locatelli, Alfredo Ricci
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: mauro.comesfranchini@unibo.it
Received 6 May 2009
5- and 4-phenyl pyrazoles was obtained with C-phenyl N-
Abstract: 1,3-Dipolar cycloaddition of C-aryl-N-aryl- and C-car-
boxymethyl-N-aryl-nitrile imines with functionalized acetylenes
have been studied. Regioisomeric mixtures have been obtained with
the 5-substituted pyrazole as the major cycloadduct. Under scandi-
methyl nitrile imine.7 Moreover, alkynes with electron-
withdrawing substituents have a higher propensity to form
4-substituted pyrazoles, and methyl propiolate adds to
um triflate catalysis a reversal in the regiochemistry was observed, diphenyl nitrile imine to yield mixtures of 5- and 4-substi-
tuted pyrazoles in 78:22 ratio.8 Recent works9 reported
especially in the case of C-carboxymethyl-N-aryl-nitrile imines.
the regioselective synthesis of 5-substituted 3-dimeth-
oxyphosphonopyrazoles9a through the 1,3-DC of C-
dimethoxyphosphono N-aryl nitrile imines with mono-
substituted acetylenes and methyl propiolate with yields
in the range 12–40% and computational study for the cy-
cloaddition of nitrilimines to methyl propiolate.9b
Keywords: dipolar cycloadditions, regiochemistry, nitrile imines,
pyrazoles, scandium triflate
Owing to its high synthetic efficiency and high regio- and
stereoselectivity, the 1,3-dipolar cycloaddition (1,3-DC)
of 1,3-dipoles with p-electronic-deficient systems has
emerged as a popular way for obtaining five-membered
heterocycles.1 The synthetic utility of the 1,3-DC reaction
stems from the wide scope and from the relevance of nu-
merous targets achievable by this chemistry,2 since many
1,3-dipolar species are readily available and react with a
variety of dipolarophiles. In particular, nitrogen-contain-
ing heterocycles have attracted widespread attention in
the field of synthetic organic chemistry as well as in me-
dicinal chemistry.3 Among them, pyrazoles are synthetic
targets of utmost importance in the pharmaceutical indus-
try, since such a five-membered heterocyclic moiety rep-
resents the core structure of numerous drugs.4
With the aim to extend the scope of nitrile imines cycload-
dition and following our interest for the [3+2] cycloaddi-
tion of 1,3-dipoles for the synthesis of heterocycles of
pharmaceutical interest,10 we report herein the 1,3-DC of
C-aryl-N-aryl- and C-carboxymethyl-N-aryl-nitrile im-
ines with functionalized acetylenes such as benzyl propi-
olate and N-phenyl-propiolamide, with a particular focus
addressed toward the regiochemistry of the final pyra-
zoles in both the uncatalyzed and the Sc(OTf)3-catalyzed
reaction. Even though Lewis acids were found to be effec-
tive in controlling the stereoselectivity in 1,3-DC of rela-
tively stable 1,3-dipoles such as nitrones,11 azomethine
ylides,12 and carbonyl ylides,13 cycloadditions of nitrile
imines with alkenes in the presence of Lewis acids have
been scarcely reported.14 Moreover, Lewis acid catalysts,
including rare-earth-metal triflates, have never been used
to control the regioselectivity of 1,3-DC of nitrile imines
and acetylenes.
Only two routes of general importance for the assembly of
4- and 5-substituted pyrazoles have been reported so far.
The first is the ring closure using hydrazines with b-
diketones5a or a derivative of comparable reactivity and
the second is the 1,3-DC of diazoalkanes with unfunction-
alised and carboxyalkyl acetylenes.5b–d
The syntheses of benzylpropiolate15 (1) and of N-
phenylpropiolamide16 (2, Figure 1) have been performed
according to the literature procedure for 1 and with slight
modification in the case of 2 (see Supporting Informa-
tion).
The 1,3-DC of nitrile imines in situ generated from hydra-
zonoyl halides and a base to triple-bond derivatives is a
potentially powerful method for the synthesis of the pyra-
zole ring. However, a deep search in the literature re-
vealed a lack of general investigation about this reaction,
in contrast with the impressive number of papers related
to the use of alkenes as dipolarophiles. Alkynes have a re-
duced dipolarophilic activity and react more slowly than
alkenes by a power of 10.1 Simple alkynes such as phenyl
acetylene react with diphenyl nitrile imine to give in 72%
yield the 1,3,5-triphenyl pyrazole6 but a 90:10 mixture of
O
O
NHPh
OBn
2
1
Figure 1 Functionalized acetylenes: benzyl propiolate (1) and
N-phenylpropiolamide (2)
The C-carboxymethyl-N-aryl hydrazonoyl chlorides 3
have been scarcely reported in the literature in contrast
with C-aryl-N-aryl derivatives. 4-Fluoroaniline dissolved
in MeOH was first converted to its diazonium salt with
SYNLETT 2009, No. 14, pp 2328–2332
Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217714; Art ID: G10909ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

LETTER
Synthesis of 4- and 5-Substituted Pyrazoles
2329
NaNO2/HCl and then by treatment with methyl-2-chloro-
acetoacetate in MeOH gave 3a in 96% yield after crystal-
lization.17 With the same procedure the unknown
hydrazonoyl chloride 3b was obtained starting from me-
thyl-4-aminobenzoate18 while compound 3c19 was ob-
tained from 4-methoxyaniline using as solvent a mixture
1:1 of pyridine and water (Scheme 1).
O
X
X
Cl
X
BnO
O
O
BnO
N
N
N
N
Y
OBn
NH
+
N
Y
1
dioxane
base, 80 °C, 18 h
+
Y
6a–c X = CO2Me
8a–c X = Ph
O
3a–c X = CO2Me
5a–c X = Ph
7a–c X = CO2Me
9a–c X = Ph
Ph
Cl
MeO2C
Cl
Ph
NH
N
N
NH
Scheme 2 1,3-DC of 1 with 3a–c and 5a–c
NH
NH
The C-carboxymethyl-N-aryl-nitrile imines derived from
3a–c in the absence of any Lewis acid gave balanced mix-
tures of the cycloadducts 6b/7b and 6c/7c (entries 2 and
3) with the exception of the two pyrazoles 6a/7a derived
from the 1,3-dipole 3a that were obtained in a 74:26 ratio
in favor of the 5-isomer (entry 1). In the case of the nitrile
imines derived from the C-aryl-N-aryl hydrazonoyl chlo-
rides 5a–c a higher preference for the 5-substituted pyra-
zoles has been observed. In particular 5b gave the two
cycloadducts 8b/9b in 84:16 ratio (entry 5), while ratios of
65:35 and 55:45 were observed for 5a and 5c, respectively
(entries 4 and 6).
Y
X
X
5a X = F
5b X = CO2Me
5c X = OMe
4a X = F
4b X = CO2Me
4c X = OMe
3a X = F
3b X = CO2Me
3c X = OMe
Scheme 1 C-Carboxymethyl-N-aryl hydrazonoyl chlorides 3a–c
and C-aryl-N-aryl hydrazonoyl chlorides 5a–c
The C-aryl-N-aryl hydrazonoyl chlorides were obtained
starting from the corresponding 4-substituted hydrazines.
The reaction with benzoyl chloride in THF in the presence
of Et3N gave the benzoylhydrazines 4a–c. The subsequent
reaction of 4a–c with triphenylphosphine–CCl4 in
MeCN20 gave the hydrazonoyl chlorides 5a–c. (see Sup-
porting Information). Only product 5c, prepared by reac-
tion of PCl5 with 4c, was reported in the literature.21
Upon addition of a catalytic amounts of Sc(OTf)3, a gen-
erally good improvement in term of efficiency of these
reactions was observed leading to better yields in the case
of cycloadducts 6a/7a, 6b/7b, and 6c/7c (entries 1–3), but
the most interesting effect was the reversal in the regio-
chemistry in favor of the 4-substituted pyrazoles. Cy-
cloadducts 6a/7a were obtained in 21:79 ratio, 6b/7b in
18:82 ratio while 6c/7c gave the highest value for the 4-
isomer with a 9:91 ratio (entries 1–3). Interestingly, the
reaction using 5a–c did not work with Ag2CO3 under
scandium catalysis leading to unidentified byproducts,
whereas satisfactory yields were obtained by using Et3N.
On the other hand the reversal of regioselectivity was low-
er starting from 5a–c under Sc(OTf)3 catalysis (entries 4
and 5), the 4-isomer increased slightly starting from 5a
and 5b, giving a 54:46 and a 60:40 ratio for 8a/9a and 8b/
9b, in contrast 5c gave 8c/9c in 75:25 ratio thus maintain-
ing the 5-pyrazole as major regioisomer.
We next examined the conditions required for the cy-
cloaddition of 1 with 3a–c and 5a–c. The cycloadditions
were carried out in dry dioxane at 80 °C for 18 hours using
2.5 equivalents of Ag2CO3 until complete conversion of 1,
which was always used in stoichiometric amount with re-
spect to the dipoles (Scheme 2). The regioisomeric ratio
1
was always calculated by H NMR analysis of the crude
mixtures using diagnostic signals. The good yields rang-
ing from 58–84% were always referred to the sum of the
two isolated regioisomers after column chromatography.
The identification of the 5-pyrazoles and the 4-pyrazoles
was based on the 1H NMR signals taking advantage from
the CH signal on the C5 for the 4-substituted pyrazole
which resonates at about d = 8.0 ppm.
Table 1 1,3-DC of 1 with 1,3-Dipoles Derived from 3a–c and 5a–c
Entry
1,3-Dipole
Base
Cycloadducts
6a/7a
Yield (%)a
Ratioa
74:26
52:48
53:47
65:35
84:16
55:45
Yield (%)b
Ratiob
21:79
18:82
9:91
1
2
3
4
5
6
3a
3b
3c
5a
5b
5c
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
61
58
84
76
63
65
90
88
92
70
65
61
6b/7b
6c/7c
8a/9a
54:46
60:40
75:25
Et3N
8b/9b
Et3N
8c/9c
a Without Sc(OTf)3.
b With 10 mol% Sc(OTf)3.
Synlett 2009, No. 14, 2328–2332 © Thieme Stuttgart · New York

2330
B. F. Bonini et al.
LETTER
Under the same reaction conditions, also in the case of the tion of several unidentified byproducts arising from the
1,3-DC of 2, satisfactory yields in the range of 56–90% fragmentation of the molecular skeleton. With hydra-
were achieved (Scheme 3). The ratios 5-pyrazole/4-pyra- zonoyl chlorides 3a–c, the high affinity of scandium tri-
zole were higher with respect to the reaction with 1 for flate for the oxygen of the carbomethoxy group seems to
both the C-carboxymethyl-N-aryl- and C-aryl-N-aryl- allow the 1,3-DC improving the yield as well, probably
nitrile-imines in the absence of Lewis acid (entries 1–6, due to the enhanced electrophilicity of the carbon
Table 2). Under Sc(OTf)3 catalysis, also in this case a sub- (Figure 2).
stantial reversal of regioselectivity was observed for the
cycloadducts 10a/11a, 10b/11b, and 10c/11c derived
from 3a–c (entries 1–3), with the obtainment of a very
Sc(OTf)3
O
Y
NH
N C
good value of 8:92 for cycloadducts 10a/11a. Starting
from dipoles 5a,b, the amount of 4-pyrazoles slightly in-
creased as shown by the variation of the ratios between
cycloadducts 12a/13a and 12b/13b, from 73:27 to 63:37
and from 68:32 to 51:49, respectively (entries 4 and 5).
Also in this case we observed, for the 4-MeO-substituted
1,3-dipole derived from 5c, the cycloadducts 12c/13c in
77:23 ratio, very similar to the 75:25 obtained without
Sc(OTf)3 catalysis (entry 6).
OMe
3a–c
Figure 2 Intermediate nitrilium-like carbocation derived from 3a–c
As it can be observed from Tables 1 and 2, the regiochem-
istry of this 1,3-DC shows interesting features and de-
serves some comments. Domingo24 recently reported the
use of the global electrophilicity index w proposed by
Parr25 and introduced a unique absolute hierarchy of elec-
trophilicity that is expected to predict the reactivity of a
set of dipoles/dipolarophiles for Diels–Alder and for 1,3-
DC. In the global electrophilicity scale for common di-
poles, the nitrile imines are classified as marginal electro-
philes (w = 0.28), which means that they could act as
nucleophiles with strong electrophiles as the dipolaro-
phile 1 (w = 1.52); therefore they should react with nitrile
imines in a normal electron-demand (NED) fashion con-
sistent with a polar mechanism due to the high Dw, lead-
ing to 5-substituted cycloadduct mainly. No data are
available for 2, but it is likely that the value of w would be
similar (or higher) to 1.
Chemistry for entries 4–6, under scandium catalysis,
worked again only in the presence of Et3N as base. To ten-
tatively explain the failure in the reaction of 5a–c with
both dipolarophiles 1 and 2 under scandium catalysis we
could invoke the different mechanism of generation of ni-
trile imines from hydrazonoyl chlorides in the presence of
Et3N or Ag2CO3. In the former case the deprotonation oc-
curs first, quickly followed by the loss of halide ion,22
leading for both 3a–c and 5a–c to the formation of the di-
pole. With Ag2CO3 the first step is a silver ion promoted
dehalogenation to give an intermediate nitrilium-like car-
bocation,2,23 which, in the case of 5a–c, led to the forma-
O
X
O
X
X
Cl
Ph
PhHN
PhHN
N
N
N
+
N
H
2
NH
N
N
O
dioxane
+
base, 80 °C, 18 h
Y
Y
Y
3a–c X = CO2Me
5a–c X = Ph
10a–c X = CO2Me
12a–c X = Ph
11a–c X = CO2Me
13a–c X = Ph
Scheme 3 1,3-DC of 2 with 3a–c and 5a–c
Table 2 1,3-DC of 2 with 1,3-Dipoles Derived from 3a–c and 5a–c
Entry
1,3-Dipole
Base
Cycloadducts
10a/11a
10b/11b
10c/11c
Yield (%)a
Ratioa
83:17
Yield (%)b
Ratiob
8:92
1
2
3
4
5
6
3a
3b
3c
5a
5b
5c
Ag2CO3
Ag2CO3
Ag2CO3
Et3N
66
63
90
56
71
60
94
89
95
60
68
58
72:28
88:12
73:27
68:32
75:25
39:61
32:68
63:37
51:49
77:23
12a/13a
12b/13b
12c/13c
Et3N
Et3N
a Without Sc(OTf)3.
b With 10 mol% Sc(OTf)3
Synlett 2009, No. 14, 2328–2332 © Thieme Stuttgart · New York

LETTER
Synthesis of 4- and 5-Substituted Pyrazoles
2331
CO2Me
p-Tol
CO2Me
N
N
p-Tol
N
N
dioxane, Ag2CO3
80 °C, 18 h
3a
+
with 10 mol% Sc(OTf)3: 14a/15a = 96:4
without Sc(OTf)3: only 14a
F
F
14a
15a
Scheme 4 1,3-DC of 3a with p-tolylacetylene
The observation for the regioselectivity in favor of 4-sub- ment of the 5-pyrazoles. The 4-substituted regioisomers
stituted pyrazoles with nitrile imines derived from 3a–c can be obtained with the use of Sc(OTf)3 as a catalyst us-
with respect of nitrile imines from 5a–c might be repre- ing C-carboxymethyl-N-aryl nitrile imines both with 1
sented as in Figure 3, in which the presence of the CO2Me and 2. The methodology appears to be suitable for the
group can form a chelate transition state B, where the car- control of the regiochemistry of this 1,3-DC and could be
boxymethyl and the carbonyl groups of the dipolarophiles potentially useful for applications in medicinal chemistry.
coordinate in a bidentate fashion the Sc(OTf)3.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
OMe
O
N
Y
N
N
Y
N
O
MeO
Acknowledgment
Sc(OTf)3
O
A
O
B
We acknowledge financial support from ‘Stereoselezione in Sintesi
Organica Metodologie e Applicazioni’ 2007.
R
R
References and Notes
5-substituted pyrazole
4-substituted pyrazole
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Figure 3 Proposed transition state between generic dipolarophiles
and nitrile imines derived from C-carboxymethyl-N-aryl hydrazonoyl
chlorides.
Moreover, when a dipolarophile is activated by coordina-
tion to a Lewis acid catalyst a reversal in the regioselec-
tivity can occur which has been already observed for 1,3-
DC of nitrones with a,b-unsaturated compounds.26
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The results obtained from 5c (entries 6 in Table 1 and
Table 2) have to be compared with those derived from
5a,b: according to Domingo, the strongly electron-donat-
ing 4-MeO group of 5c must decrease the value of w thus
rendering the Dw with 1 (or 2) higher, and this might be
the explanation for the persistency of 5-pyrazole as the
major regioisomer with or without scandium catalysis.
These hypotheses seem to be strengthened through ob-
serving the results of the reaction of 3a with p-tolylacety-
lene, in which the possibility of a bidentate chelation with
the catalyst is unlikely (Scheme 4). We carried out this re-
action without catalytic Sc(OTf)3 and have found only the
5-pyrazole 14a in 30% yield, while the same reaction run
with 10 mol% of the Sc(OTf)3 gave in 69% yield a 96:4
ratio of 5-pyrazole/4-pyrazole (14a/15a).
In conclusion, we have developed a method for the regio-
controlled synthesis of pyrazoles based on the 1,3-DC of
nitrile imines with functionalized acetylenes.27 Our inves-
tigations revealed that the N-phenylpropiolamide 2 are
better substrates than benzyl propiolate 1 for the obtain-
Synlett 2009, No. 14, 2328–2332 © Thieme Stuttgart · New York

2332
B. F. Bonini et al.
LETTER
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(27) General Procedure for the 1,3-DC of 1 and 2 with with
3a–c and 5a–c
To a solution of 1 or 2 (1 mmol) and the precursor of the 1,3-
dipoles (1 mmol) in 1,4-dioxane (4.4 mL) was added
Ag2CO3 (0.69 g, 2.5 mmol) and catalytic Sc(OTf)3 (0.1
mmol) as specified in Tables 1 and 2. The reaction mixture
was stirred at 80 °C for 18 h. The reaction was then filtered
on Celite and the solvent was removed under vacuum.
Purification was carried out as reported in the Supporting
Information. Characterization for all the compounds is
available as Supporting Information.
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Synlett 2009, No. 14, 2328–2332 © Thieme Stuttgart · New York