Cycloaddition of nitrile imines to resin-bound enamines: A solid phase synthesis of 1,4-diarylpyrazoles

Article abstract of DOI:10.1039/b102913b

The 1,3-dipolar cycloaddition reaction between nitrile imines and resin-bound enamines gives resin-bound pyrazoline intermediates. The piperazine resin functions as a traceless linker and allows these intermediates to be cleaved directly from the resin un

Full text of DOI:10.1039/b102913b

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Cycloaddition of nitrile imines to resin-bound enamines:
a solid phase synthesis of 1,4-diarylpyrazoles
Andrew C. Donohue, Sue Pallich and Tom D. McCarthy*†
1
Synthetic Chemistry Laboratory, Biomolecular Research Institute, Bag 10, Clayton, Vic 3169,
Victoria, Australia
Received (in Cambridge, UK) 30th March 2001, Accepted 10th September 2001
First published as an Advance Article on the web 11th October 2001
The 1,3-dipolar cycloaddition reaction between nitrile imines and resin-bound enamines gives resin-bound pyrazoline
intermediates. The piperazine resin functions as a traceless linker and allows these intermediates to be cleaved directly
from the resin under mild acid conditions to afford 1,4-diarylpyrazoles. Alternatively they may be chemically modified
on the resin prior to elimination from the polymer. The cycloaddition–elimination sequence is regiospecific for the
3,4-disubstituted pyrazole isomer and the products are obtained in good to high yield and in high purity.
As part of our drug discovery program we needed to synthesise
a range of 1,4-diarylpyrazoles such as pyrazole amide 7
(Scheme 1). A review of the literature indicated that 1,4-diaryl-
give the shelf stable hydrazonyl chloride 1.2 Exposure of the
hydrazonyl chloride 1 to basic conditions generated the nitrile
imine 2 in situ which underwent a 1,3-dipolar cycloaddition
reaction with compound 3, the morpholine enamine of phenyl-
acetaldehyde. Pyrazoline 4 was obtained in 85% yield and acid
catalysed elimination of morpholine from cycloadduct 4 gave
the pyrazole 5a in quantitative yield. Saponification of ester
5a afforded acid 6 which, upon treatment with aniline and
HBTU, gave the desired amide adduct 7 in 56% yield for the
two steps.3
In order to streamline the generation of a library of pyrazole
adducts we sought to transfer the above methodology to the
solid phase (Scheme 2). While the two aromatic rings at the 1
and 4 positions of the pyrazole core offered no obvious point of
attachment to a resin, we were intrigued by the possibility of
using the amino group of the phenylacetaldehyde enamine as a
traceless linker.4 In this way the product would be released from
the resin at the end of the synthesis and would simultaneously
regenerate the amino functionalised resin. Despite the advances
in solid phase organic chemistry, there are few examples of the
formation of resin-bound enamines5 and no examples of nitrile
imine cycloaddition methodology being transferred to the solid
phase.6 This paper describes our results in this area.
Results and discussion
The piperazine resin 8 was chosen as the starting point of
the synthesis. It is easy to prepare from Merrifield’s resin7 and
has recently become commercially available.8 Reaction of resin
8 with phenylacetaldehyde under Dean–Stark conditions gave
product 9 (Y = H). Formation of the desired enamine was
supported by infrared analysis which showed the presence of an
Scheme 1 Reagents and conditions: (i) NEt3, CHCl3, reflux, 3 h to RT
16 h; (ii) 2 M aq. HCl, dioxane, 100 ЊC, 90 min; (iii) NaOH, DMSO,
H2O, 100 ЊC, 4 h; (iv) N(iPr)2Et, HBTU, aniline, DMF, RT, 16 h.
pyrazole-3-carboxylates could be prepared via the cyclo-
addition of an appropriately substituted nitrile imine and
phenylacetaldehyde enamines followed by elimination.1 We
sought to apply this chemistry in order to prepare our target
compounds and, using solution phase chemistry, the reaction
sequence outlined in Scheme 1 proved to be particularly
efficient for this purpose. Thus, commercially available ethyl
2-chloroacetoacetate underwent a Japp–Klingemann reaction
with the diazonium salt derived from 3-methoxyaniline to
enamine C᎐C absorption at 1636 cmϪ1. Treatment of this resin
᎐
with 2 mol equivalents of the in situ generated nitrile imine 2
gave a product that, by infrared analysis, showed a peak at 1726
cmϪ1 and the absence of an absorption maximum at 1636 cmϪ1
.
The structure of this product was presumed to be compound
12a (X = 3-MeO, Y = H, R = OEt). Ultimately, the success of
the enamine formation–cycloaddition sequence was confirmed
by subjecting the crude product to acidic conditions (3% TFA–
DCM) which resulted in elimination of resin 8 as its TFA salt
and formation of the pyrazole 5a. The latter material was
obtained in 95% purity and in 79% yield for the three steps
(Table 1, entry 1).
† Current address: TDM and SP, Starpharma Limited, Synthetic
Chemistry Laboratory, c/o CSIRO Molecular Science, Bag 10, Clayton,
Vic 3169, Australia. E-mail: tom.mccarthy@starpharma.com; Fax:
61 3 9545 2446. ACD, Walter and Eliza Hall Institute of Medical
Research, Royal Parade, Parkville, Vic 3050, Australia.
Having successfully demonstrated the transfer of the
enamine formation–cycloaddition methodology to the solid
DOI: 10.1039/b102913b
J. Chem. Soc., Perkin Trans. 1, 2001, 2817–2822
This journal is © The Royal Society of Chemistry 2001
2817

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Scheme 2 Reagents and conditions: (i) benzene, Dean–Stark, 22 h; (ii) NEt3, 1, 10 or 11, CHCl3, reflux, 16 h; (iii) 3% TFA in DCM, RT, 10–20 min.
Table 1 Yield and purity of 1,4-diarylpyrazoles
phase, we briefly examined if additional points of diversity
(i.e. at positions 1, 3 and/or 4 of the pyrazole ring) could be
incorporated into the synthetic sequence. To this end, we
modified the nitrile imine component to include an iodine
atom (i.e. compounds 10 and 11) thereby allowing access to
palladium catalysed coupling chemistry (Table 1, entries 2–4).
A ketone functionality was also tolerated within the nitrile
imine component (Table 1, entry 4) and offers an additional
point of diversity through either imine formation or reductive
amination protocols. Electron deficient phenylacetaldehydes
also participated readily in the enamine formation–cyclo-
addition chemistry (Table 1, entries 3, 5 and 6).‡ The presence
of a nitro group9 also introduces further potential for chemical
modification via a range of methods (e.g. reduction and
acylation).
In addition to preparing 1,4-diarylpyrazoles, we attempted to
incorporate non-aromatic acetaldehyde derivatives in order to
prepare pyrazoles with an alkyl group in the 4-position. Thus,
the resin-bound enamines of hexanal and (R)-(ϩ)-citronellal
were prepared, reacted with dipole 2 then cleaved with TFA
following the general procedure outlined in Scheme 2. This gave
the 4-alkyl-1-arylpyrazole adducts 13 and 14 in yields of 15–
Entry
Cmpd
Y
X
R
Yielda
Purityb
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
H
H
NO2
H
Br
Cl
3-MeO
4-I
4-I
OEt
OEt
OEt
Me
OEt
OEt
OEt
79
64
55
59
62
61
52
>95%
>95%
>95%
>95%
>90%
>90%
>90%
4-I
3-MeO
3-MeO
3-MeO
5g
Me
a Over the 3 steps from 8. b Determined by 1H and 13C NMR
spectroscopy.
20% and 36% respectively. While the purities of these products
were comparable to that of the 1,4-diarylpyrazoles (>95%), the
yields were significantly lower.§
In all the cases studied, only one of the two possible regio-
isomeric products was detected after analysis by H and 13C
1
NMR spectroscopy. Pyrazole 5a was subjected to a series of 2D
NMR experiments (COSY, HSQC, HMBC, NOE difference)
that strongly suggested that the expected 1,3,4-substituted
pyrazole had been obtained. An authentic sample of the alter-
nate possible regioisomer, the 1,3,5-substituted pyrazole, was
‡ In general, enamine formation was performed in refluxing benzene
with a Dean–Stark apparatus (see the Experimental section). These
conditions, however, were found not to be optimal for the 4-bromo or 4-
chlorophenylacetaldehydes. For these examples better results (higher
yields and greater purities) were obtained when the acetaldehyde
and piperazine resin were stirred gently at room temperature or 40 ЊC
for 24 h. Removal of water by azeotropic distillation or addition of a
dehydrating agent (e.g. sieves or K2CO3) was found to be unnecessary.
§ This result is not entirely unexpected as conjugation of a double bond
leads to a significant increase in dipolarophilic reactivity. The rate
constants for the 1,3-dipolar cycloaddition of some monosubstituted
ethylenes to a number of dipoles, including nitrile imines, have been
measured and shows a rate increase of 1.5 to 20 times when the double
bond is conjugated with an aromatic ring.10,11
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J. Chem. Soc., Perkin Trans. 1, 2001, 2817–2822

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Table 2 Yield and purity of amides 17h–m
prepared¶ and its 1D and 2D NMR spectral data analysed and
then compared with that of pyrazole 5a. This confirmed that
the 1,3,4-substituted pyrazole was the exclusive product of the
cycloaddition. Similar work by Huisgen on the cycloaddition
of β-pyrrolidinostyrenes to nitrile oxides and nitrile imines
shows the same regiospecificity with only the 3,4-disubstituted
isoxazoles or pyrazoles being formed.11,14
With confidence in our ability to form resin-bound pyrazo-
lines, conversion to their corresponding amide derivatives
was investigated next (Scheme 3). Initially we tried to convert
Entry
Cmpd
R
Yielda
Purityb
1
2
3
4
5
6
17h
17i
PhCH2
49
70
80
48
88
18c
>95%
>95%
>95%
>95%
>95%
>95%
4-CF3(C6H4)CH2
4-NO2(C6H4)CH2
CH3OCOCH2
CH2᎐᎐CHCH2
(CH2)7CH3
17j
17k
17l
17m
a Over the 5 steps from 9 (Y = H). b Determined by H and 13C NMR
spectroscopy. c The yield was low due to handling difficulties as the resin
developed a waxy texture after amide bond formation.
1
saponification–amidation process. LiOH mediated hydrolysis
of resin 12a cleanly gave the acid 15, however, when it was
treated with benzylamine in the presence of HBTU, again,
incomplete amide bond formation was observed. Eventually we
applied methods developed by chemists at Glaxo Wellcome15
and treated resin acid 15 with pentafluorophenol and trifluoro-
acetic anhydride to give the pentafluorophenyl active ester
intermediate. Subsequent treatment of this material with a
limited range of primary amines generated compounds of the
general type 16 (Table 2). TFA-mediated cleavage of each of the
resin-bound adducts furnished amides 17 (Table 2) in varying
yields but with a high degree of purity. Future work in this area
will include examining other reactions of resin-bound enamines
(e.g. nitrile oxide cycloadditions).
Experimental
General
Short-path distillations were performed using a Kugelrohr
(bulb-to-bulb) distillation apparatus. IR spectra were recorded
as KBr disks (unless stated otherwise) using either a Perkin-
Elmer 842 spectrometer or a Bio-Rad Excalibur Series
spectrometer. 1H NMR spectra were recorded at 200 MHz
with a Bruker AC-200, 250 MHz with a Bruker ACP-250 or
at 500 MHz with a Bruker DRX-500 spectrometer. Spectra
were acquired in deuteriochloroform solution with residual
chloroform as the internal standard (δH 7.27), unless other-
wise stated. 13C NMR spectra were recorded at either 50 MHz
with a Bruker AC-200 spectrometer or at 63 MHz with a
Bruker DRX-500 spectrometer. Spectra were acquired in
deuterio-chloroform solution with residual chloroform as
the internal standard (δC 77.0). Accurate mass determinations
were recorded on a Finnigan MA95XL mass spectrometer.
Atmospheric pressure chemical ionisation (APCI) MS were
recorded on a FISONS Instrument VG Platform quadrupole
mass spectrometer. Elemental analyses were performed by the
Campbell Microanalytical Laboratory, University of Otago,
Dunedin, New Zealand. Unless otherwise stated, all reagents
were purchased from Aldrich Chemical Company, Inc. and
used without further purification.
Scheme 3 Reagents and conditions: (i) 1 M LiOH, THF, reflux, 18 h;
(ii) pentafluorophenol, pyridine, TFAA, 4 h, RT; (iii) NH2R (see Table
2), DMF, RT, 18 h; (iv) 3% TFA in DCM, RT, 10–20 min.
ester 12a (Y = H, X = 3-MeO, R = OEt) to carboxamide deriv-
ative 16h (R = CH2Ph) by a direct amidation protocol. This
involved heating the resin ester 12a in the presence of excess
benzylamine under a variety of conditions and it invariably led
to partial amide formation.|| We then investigated a two-step
¶ The 1,3,5-substituted pyrazole was prepared using standard literature
procedures for the synthesis of pyrazoles. Thus, ethyl 4-phenyl-2,4-
dioxobutanoate i (CAS 6296-54-4) was prepared as its enol tautomer,
from acetophenone and diethyl oxalate following the procedure
outlined by Brecker et al.12 This material was then reacted with
3-methoxyphenylhydrazine hydrochloride (Lancaster Cat. No. 8091)
following a method similar to that described by Zhang et al.13 to give
the 1-(3-methoxyphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid ethyl
ester ii (see Experimental for details).
Substituted phenylacetaldehydes were prepared according
to the known literature procedure,9 and were purified by dis-
tillation and characterised by 1H NMR, 13C NMR and MS. The
yields of cleaved products were calculated based upon the
commercial resin loading specification for the piperazinomethyl
polystyrene 8 (Novabiochem catalogue number 01–64–0310)
of 0.69 mmol gϪ1
.
Solution phase chemistry
1-(3-Methoxyphenyl)-5-morpholin-4-yl-4-phenyl-4,5-dihydro-
1H-pyrazole-3-carboxylic acid ethyl ester (4). A solution of the
hydrazonyl chloride 12a (2.47 g, 9.64 mmol) in CHCl3 (20 ml)
was added to a stirred solution of morpholine enamine 3 (2.0 g,
10.6 mmol) and triethylamine (1.47 ml, 10.6 mmol) in CHCl3
(30 ml) under an atmosphere of nitrogen. The reaction mixture
|| Conditions included heating of the resin at temperatures of 60, 80
and 120 ЊC for times ranging from 2–36 h in either neat benzylamine or
in the presence of a co-solvent (chloroform or dioxane).
J. Chem. Soc., Perkin Trans. 1, 2001, 2817–2822
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was heated at reflux for 3 h and then stirred at room
temperature overnight. The reaction mixture was washed with
water (150 ml) and the organic phase separated and dried
(MgSO4). Removal of the solvent gave an orange oil which was
triturated with ether–petroleum ether to give the title com-
pound 4 (3.45 g, 85%) as an orange solid, mp 126–127 ЊC
(Found: C, 67.5; H, 6.5; N, 10.3. C23H27N3O4 requires C, 67.5;
H, 6.65; N, 10.3%). νmax(KBr)/cmϪ1 1691, 1597, 1541, 1429,
Solid phase chemistry
The following methods were used to prepare compounds 9,
12a–g and 5a–g.
Preparation of resin bound enamines: representative procedure.
Phenylacetaldehyde (2.0 ml, 17.25 mmol) was added to a gently
stirred suspension of piperazinomethyl polystyrene (Nova-
biochem catalogue no. 01–64–0310) (5.0 g, 0.69 mmol gϪ1
,
1
1282, 1145, 1097. H NMR (200 MHz, CDCl3) δ 1.22 (t, J 7.1
3.45 mmol) in dry benzene (50.0 ml). The reaction flask was
fitted with a Dean–Stark apparatus and heated at reflux for 22 h
under a nitrogen atmosphere. The reaction was cooled to room
temperature and filtered (sinter funnel). The resin was washed
successively with 150 ml portions of benzene, DCM, MeOH,
DCM, acetone and ether before being dried overnight in a
vacuum oven (60 ЊC, 20 mmHg) to give a straw coloured resin 9
(Y = H) (5.37 g).
Hz, 3H), 2.43–2.65 (m, 4H), 3.65 (br s, 4H), 3.81 (s, 3H), 4.19
(q, J 7.1 Hz, 2H), 4.46 (d, J 3.2 Hz, 1H), 4.98 (d, J 3.2 Hz, 1H),
6.55 (dd, J 2.1 and 7.9 Hz, 1H), 7.02–7.32 (m, 8H). 13C NMR
(50 MHz, CDCl3) δ 14.1, 45.7, 48.5, 55.3, 61.1, 66.6, 89.9, 101.5,
107.5, 108.1, 127.0, 127.4, 129.2, 129.7, 139.8, 141.3, 143.4,
160.3, 161.9. m/z (APCI) 410 (MHϩ, 10%), 323 (100). HRMS
calcd for C23H27N3O4 409.2001, found 409.1999.
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic acid
ethyl ester (5a). A solution of dihydropyrazole 4 (3.0 g, 7.3
mmol) and 2 M HCl (11.0 ml, 22.0 mmol) in 1,4-dioxane
(40 ml) was heated at 100 ЊC for 90 min. The solvent was
removed and the residue taken up in EtOAc (100 ml) and
washed with saturated NaHCO3 solution (200 ml) and water
(200 ml). The organic layer was dried (MgSO4), filtered and
concentrated to give the desired product 5a (2.35 g, 100%) as a
yellow solid, mp 121.5–122.5 ЊC (Found: C, 70.7; H, 5.8; N, 8.7.
C19H18N2O3 requires C, 70.8; H, 5.6; N, 8.7%). νmax(film)/cmϪ1
Cycloadditions: representative procedure.
A solution of
hydrazonyl chloride 2 (354 mg, 1.38 mmol) in dry CHCl3 (3.0
ml) was added to a mixture of enamine resin 9 (Y = H) (1.1 g,
approx. 0.69 mmol) and triethylamine (192 µl, 1.38 mmol) in
dry CHCl3 (12.0 ml). The mixture was heated at reflux under a
nitrogen atmosphere for 16 h. The reaction mixture was cooled
to room temperature, filtered and the resin was washed succes-
sively with 25 ml portions of CHCl3, DCM, MeOH, 1 : 1
MeOH–H2O, DCM, acetone and ether before being dried
overnight in a vacuum oven (60 ЊC, 20 mmHg) (1.24 g).
1
1723, 1608, 1487, 1280, 1170, 1134, 1038, 761. H NMR (200
MHz, CDCl3) δ 1.20 (t, J 7.1 Hz, 3H), 3.76 (s, 3H), 4.25 (q, J 7.1
Hz, 2H), 6.78 (ddd, J 1.5, 2.6 and 7.6 Hz, 1H), 7.14–7.43
(m, 8H), 7.84 (s, 1H). 13C NMR (50 MHz, CDCl3) δ 14.1, 55.5,
61.0, 105.8, 111.8, 113.5, 127.3, 127.5, 127.7, 127.9, 129.3,
130.2, 131.3, 140.4, 141.2, 160.4, 162.4. m/z (APCI) 323 (MHϩ,
52%), 309 (100). HRMS calcd for C19H18N2O3 322.1317, found
322.1315.
Cleavage of resin bound pyrazoline adducts: representative
procedure. A solution of 3% TFA in DCM (2.0 ml) was added
rapidly to resin-bound cycloadduct 12a (R = OEt, X = 3-MeO,
Y = H) (0.62 g, approx. 0.345 mmol) in dry DCM (10.0 ml).
The red solution was stirred at room temperature for 10 min
before being filtered. The resin was washed well with DCM (5 ×
20 ml) and the filtrate concentrated to give the pyrazole 5a
1
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic acid
(6). The ester 5a (174 mg, 0.54 mmol) in DMSO (5.0 ml) was
treated with NaOH (240 mg, 60.0 mmol) in water (3.0 ml)
following the procedure of Biere et al.16 to give the acid 6
(136 mg, 85%). 1H NMR (200 MHz, CDCl3) δ 3.86 (s, 3H), 6.90
(br d, J 7.5 Hz, 1H), 7.20–7.47 (m, 6H), 7.47–7.62 (m, 2H), 7.95
(s, 1H), 11.01 (br s, 1H). 13C NMR (50 MHz, CDCl3) δ 55.7,
105.8, 111.9, 113.9, 127.9, 128.16, 128.20, 128.3, 129.4, 130.4,
130.9, 140.1, 140.3, 160.6, 166.5. m/z (APCI) 295 (MHϩ, 41%),
277 (31). HRMS calcd for C19H18N2O3 294.1004, found
294.1011.
(88 mg, 79%) as a yellow solid. Analysis by H and 13C NMR
spectroscopy showed the product to be of >95% purity and was
identical in all respects to the sample prepared via solution
phase chemistry.
1-(4-Iodophenyl)-4-phenyl-1H-pyrazole-3-carboxylic
acid
ethyl ester (5b). νmax(film)/cmϪ1 1721, 1498, 1485, 1390, 1283,
1
1226, 1137, 960, 825, 761, 698. H NMR (200 MHz, CDCl3)
δ 1.31 (t, J 7.1 Hz, 3H), 4.37 (q, J 7.1 Hz, 2H), 7.55 (d, J 8.9 Hz,
2H), 7.29–7.51 (m, 5H), 7.81 (d, J 8.9 Hz, 2H), 7.94 (s,
1H).13C NMR (50 MHz, CDCl3) δ 14.1, 61.2, 92.2, 121.4,
127.3, 127.7, 127.8, 128.0, 129.3, 131.1, 138.5, 139.0, 141.7,
162.3. m/z (APCI) 419 (MHϩ, 52%), 405 (100), 373 (100).
HRMS calcd for C18H15IN2O2 418.0178, found 418.0177.
1-(4-Iodophenyl)-4-(4-nitrophenyl)-1H-pyrazole-3-carboxylic
acid ethyl ester (5c). νmax(film)/cmϪ1 1714, 1604, 1496, 1339,
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic acid
phenylamide (7). Diisopropylethylamine (1.4 ml, 8.2 mmol) was
added dropwise to a solution of the acid 6 (1.0 g, 3.4 mmol),
HBTU (1.53 g, 4.1 mmol) and aniline (381 mg, 4.1 mmol) in dry
DMF (20 ml) and stirred at room temperature for 16 h. The
reaction mixture was diluted with ethyl acetate (100 ml) and
water (150 ml) and the phases separated. The organic layer was
washed sequentially with 10% aqueous citric acid (100 ml),
saturated NaHCO3 solution (100 ml) and brine (100 ml). The
organic fraction was dried (MgSO4), filtered and concentrated
to give the crude product, which was triturated (diethyl ether)
to give the product 7 (826 mg, 66%) as a yellow solid, mp 141–
142.5 ЊC (from diethyl ether–hexane) (Found: C, 74.6; H, 5.5;
N, 11.25. C23H19N3O2 requires C, 74.8; H, 5.2; N, 11.4%).
νmax(KBr)/cmϪ1 3313, 1666, 1597, 1530, 1500, 1424, 1211, 1046,
976, 837, 754, 692. 1H NMR (200 MHz, CDCl3) δ 3.92 (s, 3H),
6.94 (ddd, J 1.2, 2.4 and 8.0 Hz, 1H), 7.05–7.19 (m, 1H), 7.28–
7.54 (m, 8H), 7.61–7.77 (m, 4H), 8.00 (s, 1H), 8.90 (br s, 1H).
13C NMR (50 MHz, CDCl3) δ 55.5, 104.4, 110.7, 112.4, 118.5,
119.7, 123.3, 123.9, 126.7, 127.7, 127.9, 128.2, 130.1, 130.8,
138.3, 139.7, 143.9, 159.7, 160.6. m/z (APCI) 370 (MHϩ, 100%).
HRMS calcd for C23H19N3O2 369.1477, found 369.1480.
1
1309, 1299, 1230, 1149, 858, 816, 698. H NMR (200 MHz,
CDCl3) δ 1.33 (t, J 7.1 Hz, 3H), 4.37 (q, J 7.1 Hz, 2H), 7.54
(d, J 8.9 Hz, 2H), 7.68 (d, J 8.9 Hz, 2H), 7.82 (d, J 8.9 Hz, 2H),
8.05 (s, 1H), 8.24 (d, J 8.9 Hz, 2H). 13C NMR (50 MHz, CDCl3)
δ 14.2, 61.6, 92.8, 121.5, 123.3, 125.6, 127.9, 130.1, 138.1, 138.7,
141.5, 147.1, 161.9. m/z (APCI) 464 (MHϩ, 75%), 450 (100).
HRMS calcd for C18H14IN3O4 463.0029, found 463.0037.
1-[1-(4-Iodophenyl)-4-phenyl-1H-pyrazol-3-yl]ethanone
(5d). νmax(film)/ cmϪ1 1677, 1496, 1484, 1220, 825, 766, 698. 1H
NMR (200 MHz, CDCl3) δ 2.69 (s, 3H), 7.34–7.50 (m, 3H),
7.49–7.60 (m, 2H), 7.55 (d, J 8.7 Hz, 2H), 7.82 (d, J 8.7 Hz,
2H), 7.94 (s, 1H). 13C NMR (50 MHz, CDCl3) δ 28.0, 92.0,
121.0, 126.7, 127.5, 127.7, 128.1, 129.2, 131.1, 138.6, 139.1,
147.5, 194.5. m/z (APCI) 389 (MHϩ, 100%). HRMS calcd for
C17H13IN2O 388.0073, found 388.0069.
4-(4-Bromophenyl)-1-(3-methoxyphenyl)-1H-pyrazole-3-
carboxylic acid ethyl ester (5e). νmax(KBr)/cmϪ1 1721, 1609,
1
1595, 1485, 1277, 1205, 1174, 1136, 1072, 684. H NMR (200
MHz, CDCl3) δ 1.32 (t, J 7.1 Hz, 3H), 3.88 (s, 3H), 4.36 (q, J 7.1
2820
J. Chem. Soc., Perkin Trans. 1, 2001, 2817–2822

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Hz, 2H), 6.91 (ddd, J 1.0, 2.3 and 7.9 Hz, 1H), 7.16–7.67
(m, 7H), 7.92 (s, 1H). 13C NMR (63 MHz, CDCl3) δ 14.2, 55.6,
61.3, 106.0, 112.1, 113.6, 121.7, 126.3, 127.9, 130.4, 131.0,
131.2, 140.4, 141.1, 160.6, 162.3. m/z (APCI) 403, 401 (MHϩ,
27, 28%), 389, 387 (53, 53), 357, 355 (92, 100). HRMS calcd for
C19H1779BrN2O3 400.0422, found 400.0421.
resin was treated with 3% TFA in DCM as described above
to give the carboxamide 17i (R = 4-CF3(C6H5)CH2) (19 mg,
70%).
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic
acid benzylamide (17h). νmax(KBr)/cmϪ1 3410 br w, 3330 br w,
1669, 1608, 1528, 1500, 1209, 1172, 762, 699. 1H NMR
(200 MHz, CDCl3) δ 3.88 (s, 3H), 4.64 (d, J 5.9 Hz, 1H),
6.90 (m, 1H), 7.21–7.53 (m, 12H), 7.57–7.68 (m, 2H), 7.97
(s, 1H). 13C NMR (50 MHz, CDCl3) δ 43.4, 55.6, 105.7, 111.6,
113.1, 126.3, 127.6, 127.7, 127.9, 128.2, 128.7, 129.3, 130.4,
131.0, 137.8, 140.3, 142.7, 160.5, 162.4. m/z (APCI) 384
(MHϩ, 100%) HRMS calcd for C24H21N3O2 383.1633, found
383.1637.
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic
acid 4-trifluoromethylbenzylamide (17i). νmax(KBr)/cmϪ1 3414
br w, 3333 br w, 1668, 1608, 1529, 1501, 1326, 1163, 1120, 1067,
850, 761, 696. 1H NMR (500 MHz, CDCl3) δ 3.88 (s, 3H), 4.69
(d, J 6.2 Hz, 2H), 6.90 (ddd, J 0.7, 2.4 and 8.3 Hz, 1H), 7.24–
7.43 (m, 6H), 7.45 (br m, 1H, NH), 7.48 (d, J 8.1 Hz, 2H), 7.59
(d, J 8.1 Hz, 2H), 7.63–7.68 (m, 2H), 7.98 (s, 1H). 13C NMR
(125 MHz, CDCl3) δ 42.7, 55.7, 106.0, 111.7, 113.0, 124.2 (q,
J 272 Hz), 125.7 (q, J 4 Hz), 126.5, 127.7, 128.0, 128.1, 128.2,
129.4, 129.7 (q, J 32 Hz), 130.5, 131.2, 140.5, 142.6, 143.0,
160.7, 162.1. m/z (APCI) 452 (MHϩ, 100%). HRMS calcd for
C25H20N3O2F3 451.1507, found 451.1498.
4-(4-Chlorophenyl)-1-(3-methoxyphenyl)-1H-pyrazole-3-
carboxylic acid ethyl ester (5f). νmax(KBr)/cmϪ1 1721, 1606,
1
1595, 1487, 1277, 1207, 1174, 1136, 1092, 850, 835, 685. H
NMR (200 MHz, CDCl3) δ 1.32 (t, J 7.1 Hz, 3H), 3.88 (s, 3H),
4.36 (q, J 7.1 Hz, 2H), 6.93 (ddd, J1.0, 2.3 and 7.9 Hz, 1H),
7.20–7.51 (m, 7H), 7.93 (s, 1H). 13C NMR (50 MHz, CDCl3)
δ 14.1, 55.6, 61.4, 106.1, 112.2, 114.0, 126.3, 128.3, 129.7, 130.4,
130.7, 133.7, 140.2, 141.0, 160.6, 162.3. m/z (APCI) 359, 357
(MHϩ, 5, 15%), 345, 343 (20, 60), 313, 311 (30, 100). HRMS
calcd for C19H1735ClN2O3 356.0927, found 356.0928.
1-(3-Methoxyphenyl)-4-(4-tolyl)-1H-pyrazole-3-carboxylic
acid ethyl ester (5g). νmax(KBr)/cmϪ1 1723, 1609, 1493, 1279,
1205, 1175, 1133, 1031, 807, 685. 1H NMR (200 MHz, CDCl3) δ
1.34 (t, J 7.1 Hz, 3H), 2.39 (s, 3H), 3.88 (s, 3H), 4.38 (q, J 7.1
Hz, 2H), 6.86–6.98 (m, 1H), 7.00–7.70 (m, 7H), 7.93 (s, 1H). 13
C
NMR (50 MHz, CDCl3) δ 14.2, 21.2, 55.6, 61.1, 105.9, 112.0,
113.6, 127.4, 127.7, 128.4, 128.7, 129.2, 130.2, 137.4, 140.6,
160.5, 162.5. HRMS calcd for C20H20N2O3 336.1473, found
336.1470.
4-(Butyl)-1-(3-methoxyphenyl)-1H-pyrazole-3-carboxylic
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic
acid 4-nitrobenzylamide (17j). νmax(KBr)/cmϪ1 3402 br w, 3321
br w, 1669, 1607, 1519, 1344, 1212, 979, 762, 697. 1H NMR (250
MHz, CDCl3) δ 3.89 (s, 3H), 4.73 (d, J 6.3 Hz, 2H), 6.91 (m,
1H), 7.28–7.60 (m, 6H), 7.53 (d, J 8.6 Hz, 2H), 7.64 (dd, J 1.4
and 8.0 Hz, 2H), 8.00 (s, 1H), 8.19 (d, J 8.6 Hz, 2H). 13C NMR
(63 MHz, CDCl3) δ 42.4, 55.6, 105.9, 111.6, 112.9, 123.8, 126.6,
127.7, 128.15, 128.17, 128.24, 129.4, 130.5, 131.0, 140.3, 142.6,
146.1, 147.2, 160.6, 162.2. m/z (APCI) 429 (MHϩ, 95%). HRMS
calcd for C24H20N4O4 428.1484, found 428.1485.
acid ethyl ester (13). νmax(KBr)/cmϪ1 2957, 2929, 1723, 1606,
1
1497, 1225, 1171, 1106. H NMR (500 MHz, CDCl3) δ 0.95
(t, J 7.2 Hz, 3H), 1.21–1.35 (m, 2H), 1.42 (t, J 7.1 Hz, 3H),
1.57–1.67 (m, 2H), 2.80 (t, J 7.5 Hz, 2H), 3.86 (s, 3H), 4.43 (q,
J 7.1 Hz, 2H), 6.88 (dd, J 1.8 and 8.1 Hz, 1H), 7.20–7.38 (m,
3H), 7.71 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 13.9, 14.4,
22.5, 24.2, 32.4, 55.6, 60.8, 105.9, 112.0, 113.4, 127.2, 127.6,
130.2, 140.9, 142.2, 160.6, 162.9.m/z (APCI) 303 (MHϩ, 48%),
289 (100), 257 (90). HRMS calcd for C17H22N2O3 302.1630,
found 302.1637.
4-[(1R)-1,5-Dimethylhex-4-enyl]-1-(3-methoxyphenyl)-1H-
pyrazole-3-carboxylic acid ethyl ester (14). νmax(KBr)/cmϪ1
1719, 1609, 1497, 1478, 1370, 1223, 1174, 1088, 978, 686.
1H NMR (200 MHz, CDCl3) δ 1.18 (d, J 6.9 Hz, 3H), 1.35 (t,
J 7.1 Hz, 3H), 1.48 (s, 3H), 1.60 (s, 3H), 1.60–1.78 (m, 2H),
1.88–2.00 (m, 2H), 3.30 (m, 1H), 3.79 (s, 3H), 4.35 (q, J 7.1 Hz,
2H), 5.04 (m, 1H), 6.77 (m, 1H), 7.15–7.30 (m, 3H), 7.65
(s, 1H). 13C NMR (50 MHz, CDCl3) δ 14.3, 17.6, 21.6, 25.7,
26.0, 29.0, 37.9, 55.6, 60.8, 105.7, 111.9, 113.2, 124.3, 125.7,
130.1, 131.5, 133.4, 140.8, 141.8, 160.4, 162.8. m/z (APCI) 357
(MHϩ, 100%), 311 (57). HRMS calcd for C21H28N2O3 356.2099,
found 356.2089.
{[1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazol-3-yl-3-carbonyl]-
amino}acetic acid methyl ester (17k). νmax(KBr)/cmϪ1 3403 br
w, 1748, 1672, 1606, 1529, 1501, 1206, 1170, 982, 852, 762,
1
697. H NMR (500 MHz, CDCl3) δ 3.79 (s, 3H), 3.90 (s, 3H),
4.21–4.26 (m, 2H), 6.91 (ddd, J 0.7, 2.3 and 8.3 Hz, 1H), 7.28–
7.46 (m, 6H), 7.51 (t, J 5.5 Hz, 1H), 7.61–7.65 (m, 2H), 7.97
(s, 1H). 13C NMR (125 MHz, CDCl3) δ 41.0, 52.4, 55.7, 105.8,
111.6, 113.2, 126.5, 127.6, 127.9, 128.1, 129.4, 130.4, 131.2,
140.5, 142.7, 160.7, 162.2, 170.4. m/z (APCI) 366 (MHϩ, 95%).
HRMS calcd for C20H19N3O4 365.1375, found 365.1382.
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic
acid allylamide (17l). νmax(KBr)/cmϪ1 3412 w, 3335 br w, 1669,
1608, 1595, 1528, 1501, 1208, 1166, 761, 696. 1H NMR
(500 MHz, CDCl3) δ 3.90 (s, 3H), 4.07 (dddd, J 1.5, 1.5, 5.8,
5.8 Hz, 2H), 5.17 (dddd, J 1.5, 1.5, 1.5 and 10.2 Hz, 1H), 5.28
(dddd, J 1.4, 1.6, 1.7 and 17.1 Hz, 1H), 5.94 (dddd, J 5.5, 5.7,
10.3 and 17.2 Hz, 1H), 6.91 (ddd, J 0.9, 2.5 and 8.3 Hz, 1H),
7.12 (br s, 1H), 7.27–7.35 (m, 3H), 7.36–7.45 (m, 3H), 7.63–7.68
(m, 2H), 7.97 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 41.6, 55.7,
105.8, 111.6, 113.0, 116.5, 126.3, 127.6, 127.9, 128.1, 129.4,
130.5, 131.3, 134.3, 140.6, 143.4, 160.7, 162.0. m/z (APCI) 334
(MHϩ, 100%). HRMS calcd for C20H19N3O2 333.1477, found
333.1482.
Preparation of amides: representative procedure. A suspension
of the resin bound cycloadduct 12a (R = OEt, X = 3-MeO,
Y = H) (665 mg), 1 M aq. LiOH (5.0 ml) in THF (5.0 ml)
was heated at reflux for 18 h. The mixture was filtered and the
resin washed successively with 25 ml portions of water,
THF, 1 : 1 THF–10% aq. citric acid solution, 10% aq. citric
acid and acetone. The resin 15 was dried overnight in a vacuum
oven (60 ЊC, 20 mmHg).
The resin-bound acid 15 (105 mg, approx. 0.06 mmol)
was added to a solution of pentafluorophenol (135.4 mg,
0.74 mmol) and pyridine (100 µl, 1.24 mmol) in dry DMF
(1.0 ml). Trifluoroacetic anhydride (85 µl, 0.60 mmol) was
added and the mixture was stirred for 4 h at room temperature.
The reaction mixture was filtered and washed successively
with 20 ml portions of DMF, THF and DCM. After suction
drying for 30 min the resin was re-suspended in DMF (1.0 ml)
and treated with 4-(trifluoromethyl)benzylamine (86 µl, 0.60
mmol). Stirring was continued at room temperature for 18 h
after which time the resin was filtered and washed successively
with 20 ml portions of DMF, MeOH, 1 : 1 MeOH–10% aq.
citric acid solution, MeOH, acetone, DCM and ether. The
1-(3-Methoxyphenyl)-4-phenyl-1H-pyrazole-3-carboxylic
acid octylamide (17m). νmax(KBr)/cmϪ1 3417 w, 3333 br w, 2927,
1
1666, 1607, 1595, 1531, 1501, 1209, 1165, 852, 760, 696. H
NMR (500 MHz, CDCl3) δ 0.88 (t, J 7.0 Hz, 3H), 1.21–1.45 (m,
10H), 1.56–1.66 (m, 2H), 3.42 (app dd, J 7.2, 13.3 Hz, 2H), 3.90
(s, 3H), 6.91 (ddd, J 0.5, 2.3 and 8.3 Hz, 1H), 7.01 (br t, J ∼5 Hz,
1H, NH), 7.27–7.43 (m, 6H), 7.61–7.67 (m, 2H), 7.96 (s, 1H).
13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 27.1, 29.2, 29.3, 29.7,
31.8, 39.4, 55.7, 105.9, 111.7, 113.0, 126.2, 127.6, 127.9, 128.2,
129.4, 130.4, 131.4, 140.6, 143.7, 160.7, 162.1. m/z (APCI) 406
(MHϩ, 100%). HRMS calcd for C25H31N3O2 405.2416, found
405.2421.
J. Chem. Soc., Perkin Trans. 1, 2001, 2817–2822
2821

View Article Online
could be used without further purification. See M. M. El-Abadelah,
Ethyl 4-phenyl-2,4-dioxobutanoate (i)
A. Q. Hussein and B. A. Thaher, Heterocycles, 1991, 32, 1879.
3 Incorporating the amide functionality within the starting hydra-
zonyl chloride is a less convergent strategy and, in addition, α-
chloro-β-ketoamides have been reported to be unstable and the
precursor β-ketoamide has to be prepared. e.g. L. Garanti, A. Sala
and G. Zecchi, Synth. Commun., 1976, 6, 269.
Ethyl 4-phenyl-2,4-dioxobutanoate i was prepared in 59%
yield following the procedure of Brecker et al.12 Spectral data
acquired on this compound (1H NMR, 13C NMR and MS)
were identical to that reported in the literature.
4 For a lead paper into the area of traceless linkers see F. Zaragoza,
Angew. Chem., Int. Ed., 2000, 39, 2077 and references cited
therein.
1-(3-Methoxyphenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid
ethyl ester (ii)
5 (a) F. Aznar, C. Valdés and M.-P. Cabal, Tetrahedron Lett., 2000, 41,
5683; (b) N. W. Hird, K. Irie and K. Nagai, Tetrahedron Lett., 1997,
38, 7111.
6 Other 1,3-dipolar cycloaddition reactions have been applied to solid
phase organic chemistry K.-I. Washizuka, K. Nagai, S. Minakata,
I. Ryu and M. Komatsu, Tetrahedron Lett., 2000, 41, 691 and
references cited therein.
7 (a) L. A. Carpino, E. M. E. Mansour, C. H. Cheng, J. R. Williams,
R. MacDonald, J. Knapczyk, M. Carman and A. Lopusiñski,
J. Org. Chem., 1983, 48, 661; (b) J. Simpson, D. L. Rathbone and
D. C. Billington, Tetrahedron Lett., 1999, 40, 7031 and corrigendum
J. Simpson, D. L. Rathbone and D. C. Billington, Tetrahedron
Lett., 2000, 41, 283; (c) S. Bräse, D. Enders, J. Köbberling and
F. Avemaria, Angew. Chem., Int. Ed., 1998, 37, 3413.
8 Piperazinomethyl polystyrene; Novabiochem catalogue number
01-64-0310. Novabiochem also sell a piperidine-4-carboxylic acid
polyamine resin, catalogue number 01-64-0256. Piperazine bound to
a Wang resin via a carbamate has also been described F. Zaragoza
and S. V. Petersen, Tetrahedron, 1996, 52, 10823.
9 We found the most convenient preparation of 4-nitrophenyl-
acetaldehyde to be the Pb(OAc)4 oxidation of 4-nitrostyrene A.
Lethbridge, R. O. C. Norman and C. B. Thomas, J. Chem. Soc.,
Perkin Trans. 1, 1973, 35 As a range of substituted styrenes
are commercially available, this process represents a convenient
route to a diverse range of phenylacetaldehydes and we have used
this method to prepare 4-methyl-, 4-chloro- and 4-bromophenyl-
acetaldehyde.
10 R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 633.
11 P. Caramella, and P. Grünanger, in 1,3-Dipolar Cycloaddition
Chemistry, ed. by A. Padwa, Wiley, New York, 1984, vo1. 1,
pp. 291–387.
Triethylamine (60 µl, 46 mg, 0.45 mmol) was added dropwise
to a solution of ethyl 4-phenyl-2,4-dioxobutanoate (100 mg,
0.45 mmol) and 3-methoxyphenyl hydrazine hydrochloride
(79 mg, 0.45 mmol) in dry ethanol (5.0 ml) under a nitrogen
atmosphere. The mixture was heated at reflux for 14 h, cooled
to ambient temperature and then the solvent removed in vacuo.
The residue was subjected to flash chromatography (silica, 40%
ethyl acetate–hexane elution, Rf = 0.32) to give the title com-
pound as a brown oil (52 mg, 36%). νmax (KBr)/cmϪ1 1732, 1720,
1607, 1593, 1489, 1468, 1437, 1243, 1217, 1027, 763. 1H NMR
(500 MHz, CDCl3) δ 1.42 (t, J 7.1 Hz, 3H), 3.70 (s, 3H), 4.45
(q, J 7.1 Hz, 2H), 6.84 (dd, J 0.9 and 7.9 Hz, 1H), 6.88 (dd, J 1.9
and 8.3 Hz, 1H), 6.91 (app t, J 2.0 Hz), 7.03 (s, 1H), 7.19 (t,
J 8.1 Hz, 1H), 7.21–7.25 (m, 2H), 7.28–7.34 (m, 3H). 13C NMR
(125 MHz, CDCl3) δ 14.5, 55.5, 61.2, 110.0, 111.1, 114.8, 118.1,
128.6, 128.8, 129.6, 129.7, 140.5, 144.3, 144.7, 160.0, 162.5.
m/z (APCI) 323 (MHϩ, 100%). HRMS calcd for C19H18N2O3
322.317, found 322.1315.
Acknowledgements
We thank Dr Roger Mulder from CSIRO Molecular Science
for performing high field 2D NMR experiments and Dr Carl
Braybrook from CSIRO Molecular Science for performing
accurate mass determinations.
12 L. Brecker, M. Pogorevc, H. Griengl, W. Steiner, T. Kappe and
D. W. Ribbons, New J. Chem., 1999, 23, 437.
13 J. Zhang, S. Didierlaurent, M. Fortin, D. Lefrançois, E. Uridat and
J. P. Vevert, Bioorg. Med. Chem. Lett., 2000, 10, 2575.
14 (a) K. Bast, M. Christl, R. Huisgen, W. Mack and R. Sustmann,
Chem. Ber., 1973, 106, 3258; (b) R. Huisgen, R. Sustmann and
G. Wallbillich, Chem. Ber., 1967, 100, 1786.
15 J. A. Linn, S. W. Gerritz, A. L. Handlon, C. E. Hyman and D. Heyer,
Tetrahedron Lett., 1999, 40, 2227 and references cited therein.
16 H. Biere, J.-F. Kapp and I. Böttcher, Arch. Pharm. (Weinheim, Ger.),
1983, 316, 588.
References
1 H. Biere, E. Schröder, H. Ahrens, J.-F. Kapp and I. Böttcher, Eur. J.
Med. Chem., 1982, 17, 27.
2 (a) G. Broggini and G. Molteni, J. Chem. Soc., Perkin Trans. 1, 2000,
1685; (b) there is a range of conditions (solvent, base, temperature)
described in the literature for this type of Japp–Klingemann
reaction. We found the most convenient method (aqueous pyridine,
0 ЊC) to be that described by El-Abadelah et al. as the hydrazonyl
chloride precipitated from the reaction mixture and after filtration
2822
J. Chem. Soc., Perkin Trans. 1, 2001, 2817–2822