First copper-catalyzed intramolecular amidation in substituted 4-iodopyrazoles leading to the synthesis of pyrazolo [4,3-b] pyridin-5-onesn

Article abstract of DOI:10.1002/adsc.200900438

An unprecedented copper-catalyzed intramolecular amidation of substituted 4-iodopyrazoles generated either via Baylis-Hillman or Horner-Wadsworth-Emmons chemistry for the synthesis of pyrazolo[4,3-b]pyridine-5-ones is described. In addition, the effect of

Full text of DOI:10.1002/adsc.200900438

UPDATES
DOI: 10.1002/adsc.200900438
First Copper-Catalyzed Intramolecular Amidation in Substituted
4-Iodopyrazoles Leading to the Synthesis of Pyrazolo
pyridin-5-ones **
A C H bT]-U N G T R E N
n
Somnath Nag,a Maloy Nayak,a and Sanjay Batraa,*
a
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, PO Box 173, Lucknow 226001, India
Fax : (+91)-522-2623405, 2623938; phone: (+91)-522-2621411-18 extn. 4234, 4368; e-mail: batra_san@yahoo.co.uk or
s_batra@cdri.res.in
**
CDRI communication number 7866.
Received: June 25, 2009; Revised: September 8, 2009; Published online: October 22, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900438.
Abstract: An unprecedented copper-catalyzed in-
tramolecular amidation of substituted 4-iodopyra-
zoles generated either via Baylis–Hillman or
Horner–Wadsworth–Emmons chemistry for the syn-
lated systems via intramolecular cross-coupling reac-
tions. For example, the synthesis of pyrazolo C H T U N G T R
A
b]pyridine-5-one, which is the core unit of a Jun-N
terminal kinase (JNK) inhibitor,[7] could be accom-
plished via a Cu-mediated Goldberg-type amidation
of halides.[8] The retrosynthetic pathway delineated in
Figure 1 outlines the strategy for this work.
thesis of pyrazoloA C H bT]pU yrN idG inT eR-5E-oNneN sU N isG [d4,e3--
scribed. In addition, the effect of the stereochemis-
try of the acrylamide on the cross-coupling reaction
has been investigated and it is demonstrated that
only the Z-isomer is favoured to undergo the intra-
molecular cyclization.
Carbon-heteroatom bond formation by transition
metal-catalyzed cross-coupling reactions is a standard
technique used widely in synthetic organic chemistry.
Although Pd-catalyzed[9] reactions have found broad-
er applicability, Cu catalysts are preferred due to
their low cost and easy handling procedures.[10] In this
regard, work accomplished by several groups has
shown that a combination of appropriate Cu salts,
bases and ligands works efficiently for accomplishing
À
Keywords: amidation; Baylis–Hillman reaction; C
N coupling; copper; Horner–Wadsworth–Emmons
reaction; pyrazoles
À
the vast majority of aryl and heteroaryl C N cross-
coupling reactions.[11] Surprisingly, however, the
recent compilations[1a,2b] covering the literature on
cross-coupling reactions of pyrazoles reflected that
Introduction
The pyrazole ring constitutes the substructural unit of most such endeavours using halopyrazoles were di-
an array of pharmacologically active compounds.[1] rected to generate a C C bond. It is significant to
The syntheses of many of these derivatives are con- note that C N cross-coupling reactions in pyrazoles
À
À
veniently achieved from substituted halopyrazoles via have been exemplified only by arylation of the ring
cross-coupling as well as other halogen-metal ex- nitrogen atom.[12] Literature pertaining to Cu-promot-
change reactions.[2] In particular, substituted 4-iodo- ed amidation reveals that prior to the work by Dai
pyrazoles, which can be easily synthesized,[3] are at- and co-workers on microwave-assisted N-arylation of
tractive substrates for such endeavours. But it is also
known that iodine at the 4-position in pyrazole has a
low order of reactivity.[4] In the context of our pro-
gram aimed at demonstrating the synthetic applica-
tions of Baylis–Hillman derivatives for affording
cyclic frameworks,[5] we have recently reported[6] a rel-
atively fast Baylis–Hillman reaction of substituted 4-
iodopyrazole-3-carbaldehyde. It was envisaged that
adducts of this substrate can be effectively used as
building blocks for the construction of pyrazole-annu- dine-5-ones.
Figure 1. Retrosynthetic pathway for pyrazoloA C H bT]pU yrN i-G T R E N N U
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Somnath Nag et al.
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sterically hindered acyclic secondary amides, such re- fied as 6a and 7a. This exercise further revealed that
actions were restricted to primary amides, anilides the best yield of the desired product 6a was achieved
and lactams.[13] Simultaneously, Hoogenband et al. when the reaction was performed with CuI
also reported a Cu-mediated intramolecular amida- (0.2 equiv.) in the presence of Cs2CO3 (2 equiv.) as
tion for the synthesis of N-substituted oxyindoles.[14] base and ethylenediamine (0.4 equiv.) as ligand in
But, to the best of our knowledge, the amidation of 4- DMF at 1008C (entry 3, Table 1). It was also observed
iodopyrazoles via cross-coupling reaction remains un- that lowering the temperature increased the reaction
reported. In our interest to demonstrate the synthetic time considerably. Beside CuI, we evaluated CuBr2,
applications of the Baylis–Hillman derivatives for het- CuCl and Cu2O under similar conditions to affect the
erocyclic synthesis, we embarked on a study to inves- intended intramolecular cyclization. All these Cu salts
tigate the intramolecular amidation reaction in substi- successfully induced the cyclization reaction but the
tuted 4-iodopyrazoles using Cu catalysts.
best yields of 6a were achieved with CuI. It is signifi-
cant to note that under all conditions formation of
the annulated pyrazole was accompanied by the deio-
dinated product. However, it is worth mentioning that
although the annulated pyrazole starts forming imme-
Results and Discussion
The objective of realizing the synthesis of an amide diately, the presence of the deiodinated product be-
from the Baylis–Hillman adduct of 4-iodopyrazole-3- comes prominent only after 12 h of reaction time. De-
carbaldehyde was achieved following the procedure iodination during the intramolecular amidation was in
outlined in Scheme 1. Initial optimization was carried coherence with the observation of Dai et al.[13] The
out with 1a. The Baylis–Hillman reaction of 1a with isomerization of the double bond to the endocyclic
acrylonitrile yielded 2a which upon acetylation pro- position in 6a was attributed to the presence of
duced the acetate 3a (Scheme 1). The SN2-displace- base.[17] Notably, however, the ligandless reaction was
ment reaction of 3a with NaBH4 in the presence of found to be sluggish and the required product 6a was
DABCO in aqueous medium afforded 4a which was isolated in traces only. Compounds 5b and c prepared
hydrolyzed with TFA/H2SO4 to yield 5a.[15] With the under conditions similar to 5a, undergo the coupling
amide in hand we next investigated Buchwaldꢁs proto- reaction in identical conditions to yield 6b and c,
À
col for the Cu-mediated C N cross-coupling reac- thereby indicating the general applicability of the pro-
tion.[16] With the aim of optimizing the conditions, ini- tocol.
tially the reaction of 5a with CuI was screened in the
The successful formation of 6a–c prompted us to in-
presence of several bases such as Cs2CO3, K2CO3, vestigate the scope of this approach by applying it to
K3PO4 and ligands including ethylenediamine, N,N’- a variety of substituted acrylamides which were alter-
dimethylethylenediamine, phenanthroline, l-proline natively prepared from Baylis–Hillman adducts 8a–c
in DMF or dioxane (Table 1). Under all conditions following the protocol displayed in Scheme 2. Acety-
two major spots were observed in the TLC analysis lating 8a–c with acetyl chloride gave 9a–c in 87–91%
but the reaction was much cleaner with Cs2CO3 than yields. Treating 9a–c with NaBH4 in the presence of
with K2CO3 or K3PO4. These two products after isola- DABCO under aqueous conditions smoothly provid-
tion and spectroscopic characterization were identi- ed 10a–c (82–87%). Saponification of 10a–c with
Scheme 1. Reaction conditions: i) Ref.[6] ii) AcCl (1.5 equiv.), pyridine (1.3 equiv.), CH2Cl2, 08C to room temperature, 2 h. iii)
1) DABCO (1 equiv.), THF-H2O (1:1, v/v), room temperature, 15 min; iii) 2) NaBH4 (1 equiv.), room temperature, 30 min.
iv) TFA-H2SO4 (1:1, v/v), room temperature, 4 h. v) CuI (0.2 equiv.), NH2ACHTUNTRGNENG(U CH2)2NH2 (0.4 equiv.), Cs2CO3 (2 equiv.), DMF,
1008C, 24 h.
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First Copper-Catalyzed Intramolecular Amidation in Substituted 4-Iodopyrazoles
UPDATES
Table 1. Optimization of the conditions for the intramolecular amidation with substrate 5a.
Entry
Cu salt
mol%
Base
Ligand
Solvent
Time [h]
Isolated yields [%][a]
6a
7a
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr2
CuCl
Cu2O
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
NH
NH
NH
NH
G
DMF
DMF
DMF
Dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
96
72
24
48
24
36
36
24
36
36
36
48
48
48
48
24
36
24
18
26
45
38
30
25
22
26
24
30
9
22
16
10
6
38
30
19
39
31
21
23
18
29
24
30
18
24
38
23
25
28
26
35
28
31
10
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
MeNH
1,10-phenanthroline
l-proline
NH
MeNHACHTGNUTRENNUNG
1,10-phenanthroline
l-proline
NH
MeNHAHCTNUGTRENNNUG
1,10-phenanthroline
l-proline
NH
NH
NH
9
10
11
12
13
14
15
16
17
18
[a]
Reactions under several conditions showed multiple spots on TLC analysis.
Scheme 2. Reactions conditions: i) AcCl (1.5 equiv.), pyridine (1.3 equiv.), CH2Cl2, 08C to room temperature, 2 h. ii) 1)
DABCO (1 equiv.), THF-H2O (1:1, v/v), room temperature, 15 min; 2) NaBH4 (1 equiv.), room temperature, 30 min. iii)
Aqueous LiOH (5 equiv.), THF-MeOH, (5:1, v/v), room temperature, 5 h. iv) 1) DCC (1 equiv.), HOBt (1 equiv.), DMF,
room temperature, 30 min; 2) RNH2 (1.1 equiv.), 2 h. v) CuI (0.2 equiv.), NH2ACTHUNGTRENGN(U CH2)2NH2 (0.4 equiv.), Cs2CO3 (2 equiv.),
DMF, 1008C, 24 h.
LiOH yielded the corresponding acid 11a–c in 93– mented that the sterically hindered acyclic secondary
96% as solids. The coupling reaction of 11a with dif- amides furnish the cross-coupled product in low
ferent aliphatic primary amines produced the re- yields.[12,13] In order to settle the issue of the stereo-
quired amides 12aA–G. Fortunately, all acrylamides chemistry across the double bond in the deiodinated
À
under optimized conditions for the intramolecular C
analogues, NOE experiments with a representative
N coupling reaction resulted in a mixture of annulat- compound 14aE were conducted. The results of this
ed derivative 13aA–G and deiodinated product study showed the relative stereochemistry of the com-
14aA–G (Table 2). Except for substrates 14aC, 14aD pound to be E. More amides 12aH–L were prepared
and 14aG generated from sec-butylamine, cyclohexyl- via coupling of acid 11a with substituted anilines. Sub-
amine and isopropylamine (entries 3,
4 and 7, jecting these amides (12aH–L) to CuI-promoted in-
Table 2), all compounds produced annulated pyra- tramolecular coupling resulted in the formation of
zoles in moderate yields. It has been already docu- compounds 13aH–L and the deiodinated products
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Somnath Nag et al.
UPDATES
Table 2. Yields[a] of compounds 12–14 afforded in Scheme 2.
Entry Compd no Ar
R
12 13 14
1
2
3
4
5
6
7
8
aA
aB
aC
aD
aE
aF
aG
aH
aI
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
84 47 22
78 57 21
76 10 47
88 14 49
91 38 31
75 54 14
83 21 43
83 39 27
79 62 22
cyclopropyl
sec-butyl
cyclohexyl
ACHTUGNRTNE(NUNG CH2)2Ph
n-propyl
isopropyl
Ph
4-Me-C6H4
4-OMe-C6H4 70 58 18
9
10
11
12
13
14
15
16
17
18
aJ
aK
aL
bA
bB
bH
cA
cB
cH
3-Cl-C6H4
4-Cl-C6H4
72 28 20
76 13 22
81 57 24
82 54 21
78 33 23
85 46 33
73 50 28
72 37 19
4-Me-C6H4 Bn
4-Me-C6H4 cyclopropyl
4-Me-C6H4 Ph
4-Cl-C6H4 Bn
4-Cl-C6H4 cyclopropyl
4-Cl-C6H4 Ph
[a]
Isolated yields after column chromatography.
14aH–L. As can been seen from the entries in the
Table 2, the nature of the substitution on the phenyl
ring of the anilide influenced the formation of the cy-
clized product. The presence of electron-donating
groups such as methoxy or methyl produced the annu-
lated pyrazoles (13aI–J) in relatively better yields. In
contrast, placing a mild electron-withdrawing group
represented by chloro had a deleterious effect on the
Scheme 3. Reaction conditions: i) AcCl (1.5 equiv.), pyridine
(1.3 equiv.), CH2Cl2, 08C to room temperature, 2 h. ii) 1)
DABCO (1 equiv.), THF-H2OACTHNUTRGNE(UNG 1:1, v/v), room temperature,
15 min; 2) NaBH4 (1 equiv.), room temperature, 30 min. iii)
TFA-H2SO4 (1:1, v/v), room temperature, 4 h. iv) CuI
yield of the corresponding annulated products ACTHNUGTRNEUNG(13aK–
L).
Next we prepared other amides (12bA, B, H, 12cA,
B, H) from acids 11b and c to investigate whether
substitution on the phenyl ring present at the 5-posi-
tion of the pyrazole influences the outcome of the for-
mation of product. Subjecting these amides to the Cu-
mediated coupling reactions gave the required prod-
ucts 13bA, B, H and 13cA, B, H along with the deio-
dinated analogues 14bA, B, H and 14cA, B, H.
(0.2 equiv.), NH2ACHTNUTRGNEUNG(CH2)2NH2 (0.4 equiv.), Cs2CO3 (2 equiv.),
DMF, 1008C, 30 h. v) Aqueous LiOH (5 equiv.), THF-
MeOH (5:1, v/v), room temperature, 5 h. vi) 1) DCC
(1 equiv.), HOBt (1 equiv.), DMF, room temperature,
24 min; 2) RNH2 (1.1 equiv.), 2 h.
27H and deiodinated analogues 28B and 28H were
In order to enhance the diversity of annulated pyra- easily separated.
zoles which could be accessed using the developed
From results of the study at this stage it was appar-
protocol, we next investigated couplings with the ent that the annulated pyrazoles were formed in mod-
amides afforded from the Baylis–Hillman adducts (16 erate yields only and isomerization of the double
and 17) of 3-phenyl-4-iodo-5-pyrazole-carbaldehyde bond accompanied by formation of deiodinated prod-
(15). In the first stage the primary amide 22 was syn- uct bearing E-sterochemistry was common to all reac-
thesized from 16 via 18 and 20 as shown in Scheme 3. tions. Mechanistic considerations generated interest in
À
Treating it with CuI under the optimized condition re- studying the fate of the C N coupling in acrylamides
sulted in a mixture from which 44% of annulated pyr- with defined stereochemistry across the double bond.
azole 23 and 21% of deiodinated pyrazole 24 were These amides were easily obtained from 3 as outlined
isolated. Subsequently 26B and 26H were prepared in Scheme 4. Initially the reaction of 3a with NaBH4
from the Baylis–Hillman adduct 17 using the standard in methanol afforded the alkene 29a as a mixture of
À
methodology. The CuI-mediated intramolecular C N E- and Z-isomers which were readily separated via
cross-coupling reaction in 26B and 26H resulted in a column chromatography. Acid hydrolysis in either iso-
mixture from which the required products 27B and mers of 29a produced the amide 30a with retention of
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First Copper-Catalyzed Intramolecular Amidation in Substituted 4-Iodopyrazoles
UPDATES
Scheme 4. Reaction conditions: i) NaBH4 (1.2 equiv.), MeOH, 08C, 20 min. ii) TFA-H2SO4 (1:1, v/v), room temperature, 6–
8 h. iii) CuI (0.2 equiv.), NH2ACHTUNGTRNEN(UG CH2)2NH2 (0.4 equiv.), Cs2CO3 (2 equiv.), DMF, 1008C, 18 h [for 30 (Z-isomer)] and 24 h [for
30 (E-isomer)].
stereochemistry. It was pleasing to note that the cou-
It is documented that SN2’-displacement reaction of
pling reaction of the Z-isomer of 30a was relatively the Baylis–Hillman acetate of acrylonitrile with an
fast to furnish annulated pyrazole 6a in 86% yield amine is diastereoselective in favour of the Z-
along with a minor amount of the Z-isomer of 7a isomer.[18] It was envisaged that such an allylamine
(8%). In contrast a similar reaction with the E-isomer would allow facile access to an amide with Z-stereo-
of 30a yielded the E-isomer of deiodinated pyrazole chemistry and further enhance the scope of our strat-
7a as the sole product. To further substantiate this egy for obtaining annulated pyrazoles. Thus, in a rep-
outcome, either isomers of 30b and c were prepared resentative study, treating 3a with piperidine in meth-
À
from 3b and c. Gratifyingly, the C N coupling with anol afforded 31 (Scheme 5). Unexpectedly 31 was
the Z-isomer of 30b and c furnished 6b and c in excel- formed as a mixture of Z- and E-isomers (57:43)
lent yields. Small amounts of the Z-isomer of 7b and which were separated. More importantly, however,
c were also isolated.
hydrolysis followed by coupling reaction of the Z-
isomer of 31 yielded the annulated derivative 33 in
Scheme 5. Reaction conditions: i) Piperidine (1 equiv.), MeOH, room temperature, 1 h. ii) TFA-H2SO4 (1:1, v/v), room tem-
perature, 8 h. iii) CuI (0.2 equiv.), NH2ACHTUNRGTNEG(UN CH2)2NH2 (0.4 equiv.), Cs2CO3 (2 equiv.), DMF, 1008C, 18 h [for 32 (Z-isomer)] and
24 h [for 32 (E-isomer)].
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Somnath Nag et al.
UPDATES
88% yield. On the other hand, the E-isomer of 32 re- sulted in the formation of deiodinated product 38 ex-
acted with CuI leading to 34 in 73% yield. clusively. However in the presence of Raney-Ni the
Having established the protocol with the Baylis– deiodination of the pyrazole was accompanied by the
Hillman derivatives, we turned our attention to the reduction of the double bond to yield 39 in 75%
acrylamide produced from the Wittig or Horner– yield.
Wardsworth–Emmons reaction of the 1,5-diphenyl-4-
This failure prompted us to explore an alternative
iodo-3-pyrazolecarbaldehyde. Treating 1a with triethyl route for obtaining the required starting material. In
phosphonoacetate in the presence of NaH gave 35 this strategy it was decided to subject 1,5-diphenyl-3-
that upon hydrolysis with LiOH yielded the acid 36 pyrazolecarbaldehyde (40) to the Horner–Wads-
(Scheme 6). The stereochemistry was assigned as worth–Emmon reaction initially, followed by reduc-
trans on the basis of coupling constants for the signal tion of the alkene and then perform the iodination re-
of protons across the double bond.[19] The coupling re- action. Consequently, in a model study the aldehyde
action of 36 with cyclopropylamine in the presence of 40 was treated with triethyl phosphonoacetate to
DCC yielded the amide 37 in 83% yield. Expectedly, afford 41 which was subjected to hydrogenation in the
the attempted intramolecular cross-coupling reaction presence of Raney-Ni in ethanol to yield 42
in this substrate produced the deiodinated product 38 (Scheme 7). Iodinating 42 with ICl gave the iodinated
in 68% yield exclusively.
pyrazole 43 in 96% yield, which was saponified in the
This further substantiated the previous findings that presence of LiOH to furnish the acid 44 (97%). The
the E-stereochemistry of the alkene is a limiting coupling reaction of 44 either with cyclopropylamine
factor for the intramolecular cyclization. Nonetheless or isopropylamine in the presence of isobutyl chloro-
to establish the utility of our protocol for the develop- formate and N-methylmorpholine (NMM) resulted in
ment of annulated pyrazoles from this chemistry, we the formation of amide 45B or 45G. The CuI-mediat-
decided to reduce the double bond in the amide and ed intramolecular amidation of these substrates were
then investigate the coupling reaction. In a represen- incomplete even after 48 h. Nevertheless, besides re-
tative study the reduction of the double bond in 37 covery of the starting material, we could successfully
was attempted under several conditions. The catalytic isolate the respective annulated pyrazoles 46B and G
[20]
reduction with Pd on carbon or Et3SiH-PdCl2
re- and the deiodinated pyrazoles 39B and G (39B is the
same as 39).
Scheme 7. Reaction conditions: i) (EtO)2P(O)CH=CO2Et
Scheme 6. Reaction conditions: i) (EtO)2POCH2CO2Et
(1.5 equiv.), NaH (3 equiv.), THF, 08C to room temperature,
4 h. ii) Aqueous LiOH (5 equiv.), THF-MeOH (5:1, v/v),
room temperature, 5 h. iii) 1) DCC (1 equiv.), HOBt
(1 equiv.), DMF, room temperature, 30 min; 2) cyclopropyl-
(1.5 equiv.), NaH (3 equiv.), THF, 08C to room temperature,
4 h. ii) Raney-Ni, H2, EtOH, 40 psi, room temperature, 3 h.
iii) ICl (3 equiv.), K2CO3 (3 equiv.), CHCl3, room tempera-
ture, 10 h. iv) Aqueous LiOH (5 equiv.), THF-MeOH (5:1,
v/v), room temperature, 5 h. v) 1) Isobutyl chloroformate
(1.5 equiv.), NMM (1.5 equiv.), THF, À108C, 20 min; 2)
RNH2 (1.2 equiv.), À108C, 30 min. vi) CuI (0.2 equiv.), NH2
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
DMF, 1008C, 24 h. v) Et3SiH, PdCl2, EtOH, room tempera-
ture, 24 h or Pd-C, H2, 40 psi, 3 h. vi) Raney-Ni, H2, MeOH,
40 psi, 3 h.
ACTHGNUTERN(NUNG CH2)2NH2 (0.4 equiv.), Cs2CO3 (2 equiv.), DMF, 1008C,
48 h (yields of 46 and 39 are based on the consumed starting
material).
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First Copper-Catalyzed Intramolecular Amidation in Substituted 4-Iodopyrazoles
UPDATES
Scheme 8. Reaction conditions: i) Ref.[6] ii) AcCl (1.5 equiv.), pyridine (1.3 equiv.), CH2Cl2, 08C to room temperature, 2 h. iii)
1) DABCO (1 equiv.), THF-H2O (1:1, v/v), room temperature, 15 min; 2) NaBH4 (1 equiv.), room temperature, 30 min. iv)
Raney-Ni, H2, MeOH, 40 psi, room temperature, 3 h. v) ICl (3 equiv.), K2CO3 (3 equiv.), CHCl3, room temperature, 12 h. vi)
Aqueous LiOH (5 equiv.), THF-MeOH (5:1, v/v), room temperature, 5 h. vii) 1) Isobutyl chloroformate (1.5 equiv.), NMM
(1.5 equiv.), THF, À108C, 15 min; 2) RNH2 (1.2 equiv.), THF, À108C, 30 min. viii) CuI (0.2 equiv.), NH
2ACHTUGNTERN(NUNG CH2)2NH2
(0.4 equiv.), Cs2CO3 (2 equiv.), DMF, 1008C, 48 h (yields of 54 and 55 are based on the consumed starting material).
Inspired by the outcome, we were prompted to either from the Baylis–Hillman or the Horner–Wads-
apply this approach to similar substrates from the worth–Horner chemistry. It has also been demonstrat-
Baylis–Hillman chemistry. Hence, the Baylis–Hillman ed that when an amide function is present across the
acetate 48 was synthetically manipulated to produce double bond, only the Z-isomer has the capability to
À
52 as depicted in Scheme 8. Reaction of 52 with cyclo- undergo intramolecular C N coupling reactions. In
propylamine or isopropylamine in the standard condi- contrast, the E-isomer of acrylamides afforded deiodi-
tions afforded the corresponding amides 53B or 53G. nated pyrazoles as the sole products. Furthermore in
Similar to earlier observations with 45, the coupling the case of saturated amides the coupling reaction
reactions of 53B or 53G were incomplete even after was found to be sluggish and is accompanied by deio-
48 h of reaction time. Importantly however, work-up
and purification of the reaction mixture furnished the
annulated pyrazoles 54B and 54G and deiodinated
products 55B and 55G beside the starting material.
Finally, to investigate the necessity of the 5-aryl
substituent, if any, for this chemistry we were prompt-
ed to examine the protocol with a pyrazole derivative
wherein the 5-position remained unsubstituted. Ac-
cordingly, pyrazolecarbaldehyde 56 was generated
starting from ethyl pyruvate.[21] Iodination of 56 fol-
lowed by the Baylis–Hillman reaction with acryloni-
trile afforded 58 in 95% yields (Scheme 9). Acetyla-
tion of 58 furnished the acetate 59 that reacted with
NaBH4 in methanol to afford acrylamide 60 as a mix-
ture of E- and Z-isomers, in a 1:3 ratio. Separation of
the isomers followed by sequential acid hydrolysis of
the Z-isomer and Cu-mediated coupling reaction
yielded the desired pyrazole 62 in 70% yield.
Conclusions
Scheme 9. Reaction conditions: i) ICl (3 equiv.), K2CO3
(3 equiv.), CHCl3, room temperature, 10 h. ii) CH2=CHCN,
(1.1 equiv.), DABCO (1 equiv.), room temperature, 4 h. iii)
AcCl (1.5 equiv.), pyridine (1.3 equiv.), CH2Cl2, 08C to room
temperature, 2 h. iv) NaBH4 (1.2 equiv.), MeOH, room tem-
In conclusion, a Cu-mediated intramolecular amida-
tion via C N cross-coupling of the amide with the
iodo group present at the 4-position in substituted
pyrazoles to afford the annulated pyrazoles has been
demonstrated for the first time. We have shown that
À
perature, 20 min. v) TFA-H2SO4 (1:1, v/v), room tempera-
ture, 10 h. vi) CuI (0.2 equiv.), NH2A(CH2)2NH2 (0.4 equiv.),
CTHUNGTRENNUNG
this strategy successfully works for substrates derived Cs2CO3 (2 equiv.), DMF, 1008C, 18 h.
Adv. Synth. Catal. 2009, 351, 2715 – 2723
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2721

Somnath Nag et al.
UPDATES
the comments and suggestions by anonymous referees which
led to a significant improvement in the contents of this manu-
script.
dination of pyrazole. This simple and straightforward
synthetic achievement updates the literature for C N
cross-coupling in 4-iodopyrazoles.
À
Experimental Section
References
General Procedure as Exemplified for the Synthesis
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To a solution of amide 5a (0.80 g, 1.86 mmol) in DMF
(10 mL), Cs2CO3 (1.21 g, 3.73 mmol), CuI (0.071 g,
0.37 mmol) and ethylenediamine (50 mL, 0.74 mmol) were
added and the reaction mixture was heated at 1008C for
24 h under a nitrogen atmosphere. Thereafter, the solvent
was removed under reduced pressure and the residue was
taken up in ethyl acetate (40 mL) and washed with water
(50 mL). The aqueous layer was further extracted with ethyl
acetate (2ꢂ25 mL) and the collected organic layer was
washed with brine, dried over anhydrous Na2SO4 and con-
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crude product over silica gel furnished the pure annulated
pyrazole 6a as a white solid (ethyl acetate/hexanes, 3:10;
yield: 0.25 g, 45%) and the deiodinated pyrazole 7a also as a
white solid (ethyl acetate/hexanes, 3:7; yield: 0.12 g, 21%).
6-Methyl-2,3-diphenyl-2,4-dihydro-5H-pyrazoloACTHNUTRGENUG[N 4,3-b]pyr-
idin-5-one (6a): mp 240–2428C; Rf =0.31 (ethyl acetate/hex-
anes, 2:3); IR (KBr): nmax =1611 (C=N), 1654 (CONH),
1
3454 (NH) cmÀ1; H NMR (CDCl3, 300 MHz): d=2.27 (d,
3H, J=1.2 Hz), 7.25–7.28 (m, 3H), 7.34–7.45 (m, 7H), 7.73
(d, 1H, J=1.2 Hz), 9.31 (brs, 1H); 13C NMR (CDCl3,
75 MHz): d=17.9, 123.6, 125.1, 125.6, 127.9, 128.8, 129.1,
129.2, 129.3, 132.3, 137.7, 139.8, 164.0; MS (ES+): m/z=
302.3 (M+ +1); anal. calcd. for C19H15N3O (exact mass:
301.1215): C 75.73, H 5.02, N 13.94; found: C 75.98, H 5.0,
N 13.89.
(E)-3-(1,5-Diphenyl-1H-pyrazol-3-yl)-2-methylprop-2-en-
amide (7a): mp 123–1248C; Rf =0.13 (ethyl acetate/hexanes,
2:3); IR (KBr): nmax =1616 (C=N), 1668 (CONH2), 3417
1
(NH2) cmÀ1; H NMR (CDCl3, 200 MHz): d=2.35 (d, 3H,
J=1.1 Hz), 5.94 (brs, 2H), 6.69 (s, 1H), 7.21–7.36 (m, 11H);
13C NMR (CDCl3, 50 MHz): d=14.8, 109.5, 125.2, 126.1,
127.8, 128.6, 128.8, 129.0, 130.2, 131.9, 139.9, 144.0, 148.8,
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anal. calcd. for C19H17N3O (exact mass: 303.1372): C 75.23,
H 5.65, N 13.85; found: C 75.28, H 5.41, N 13.96.
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2723