Synthesis of 1-hydroxypyrazole glycine derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00021-2

A series of novel α-amino acids containing the 1-hydroxypyrazole ring has been prepared by addition of organomagnesium or organolithium intermediates to diethyl N-Boc-iminomalonate as an electrophilic glycine equivalent. Electrophiles, aryl and heteroaryl

Full text of DOI:10.1016/S0040-4020(02)00021-2

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1595±1605
Synthesis of 1-hydroxypyrazole glycine derivatives
p
Â
Patrizia Calõ and Mikael Begtrup
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
Received 15 October 2001; accepted 3 January 2002
AbstractÐA series of novel a-amino acids containing the 1-hydroxypyrazole ring has been prepared by addition of organomagnesium or
organolithium intermediates to diethyl N-Boc-iminomalonate as an electrophilic glycine equivalent. Electrophiles, aryl and heteroaryl
substituents were introduced in the pyrazole ring. q 2002 Published by Elsevier Science Ltd.
1. Introduction
The synthesis of new and structurally diverse unnatural
amino acids is a continuous challenge for organic
chemists.1,2 Non-proteinogenic amino acids play a key
role in the drug discovery process. Their incorporation in
peptides and proteins often increases metabolic stability and
Scheme 1.
generates unusual secondary structures. Furthermore,
aromatic and heteroaromatic glycine derivatives have
found valuable applications as antagonists of the glutamate
of functionalized arylglycines.13 The reaction with various
arylmagnesium reagents afforded arylaminomalonates in
good yields after mild deprotection of the N-Boc group
(Scheme 2). The corresponding amino acids were
obtained after acidic or basic hydrolysis, followed by
decarboxylation.
receptors in the central nervous system,3 in b-lactam
antibiotics4,5 or in glycopeptide antibiotics such as
vancomycin.6
Herein, we report the synthesis of a novel class of
1-hydroxypyrazole a-amino acids 1. 1-Hydroxypyrazoles
can be regarded as analogues of both weak carboxylic
acids and phenols, due to the presence of the relatively
acidic N-hydroxy functionality (pKa 6.3).7 Our group is
currently investigating this hypothesis. 1-Hydroxypyrazoles
have so far been used to replace the phenol group in
Tamoxiphen analogues,8 or to mimic the action of the distal
carboxylic acid of (S)-Glu.9 Extensive methodology for
Scheme 2.
regioselective metalation and functionalization of the ring,
allowing the introduction of electrophiles, aryl, heteroaryl
2. Results and discussion
and acyl groups have been developed in recent years.10±12
We now wish to report the application of this chemistry to
the preparation of functionalized heteroaromatic amino
2.1. 1-Hydroxypyrazolylglycines 6 and 10
acids. In our strategy the key step for the introduction of
We ®rst investigated the preparation of the amino acid 6,
the glycine functionality is the addition of lithium and
introducing the glycine functionality at C-5 of 3 (Scheme 3).
magnesium 1-benzyloxypyrazole derivatives to diethyl
Lithiation of 1-benzyloxypyrazole 3 with n-BuLi at
N-Boc iminomalonate 2 (Scheme 1).
2788C,11 followed by addition of 1.1 equiv. of imine 2,
afforded the expected intermediate 4 in 92% yield. The
addition of the organolithium compound occurred selec-
tively at the imine carbon and no competing addition at
the ester or the carbamate group was observed. The ®rst
We recently demonstrated the utility of this stable and
reactive electrophilic glycine equivalent for the preparation
attempt to remove all the protecting groups (ethyl, benzyl
and N-Boc) in one step by re¯uxing 4 in conc HCl or HBr,
gave complex, inseparable mixtures. Therefore, the benzyl
Keywords: arylglycine; amino acid; 1-hydroxypyrazole; imino malonate.
Corresponding author. Tel.: 145-35-30-60-00; fax: 145-35-30-60-40;
e-mail: begtrup@dfh.dk
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00021-2

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1596
Scheme 3. Reagents and conditions: (a) n-BuLi, THF, 2788C, 5 min; then 2, 2788C, 1 h; (b) H2 (1 atm), 10% Pd/C, MeOH, 08C, 30 min; (c) LiOH, THF/H2O,
rt, 12 h; (d) 2N HCl, 608C, 30 min.
Scheme 4. Reagents and conditions: (a) i-PrMgCl, THF, 08C, 30 min, then cooling to 2788C, imine 2, 3 h; (b) H2 (1 atm), 10% Pd/C, MeOH, 08C, 30 min;
(c) LiOH, THF, rt, 4 h; (d) 2N HCl, 608C, 30 min.
group was ®rst removed by mild hydrogenolysis (10% Pd/C
at 08C)11 to produce the free N-hydroxy derivative 5 in
quantitative yield. The liberation of the amino acid
functionality was then attempted by standard acidic or
basic hydrolysis of the diethyl malonate followed by
decarboxylation,14 and removal of the N-Boc group.15
Re¯uxing the intermediate 5 in 6N HCl for 12 h gave a
mixture of the expected product 6 and the partially
deprotected diethyl aminomalonate. All attempts to drive
the hydrolysis of the ester to completion by increasing
reaction time and concentration of the acid, only led to
progressive decomposition of the thermally sensitive
®nal product. Instead basic hydrolysis was attempted.
1-Hydroxypyrazole 5 was treated with LiOH in THF±
water to hydrolyze the esters. Subsequent stirring in 2N
HCl at 608C for 30 min gave decarboxylation and deprotec-
tion of the amino functionality. The pure crystalline 6 was
so obtained in 80%.
decarboxylation (2N HCl), gave the pure crystalline 10 in
84% yield by simple evaporation to dryness.
2.2. 5-Substituted 1-hydroxypyrazolylglycines (14)
With these results in hand, we focused on the synthesis of
5-substituted 1-hydroxypyrazole glycine derivatives
(Scheme 5). The strategy involves the preparation of 11 as
the key intermediate, where aryl, heteroaryl and electro-
philes would be introduced at C-5. Halogen±metal
exchange, followed by addition of the imine 2, would afford
the amino acid precursor 12.
Aryl and heteroaryl substituents were introduced at C-5 by
Pd(0) catalyzed Negishi cross-coupling from 1-benzyloxy-
pyrazole 3 and commercially available aryliodides.12
Iodination of the crude products with ICl gave 5-aryl-4-
iodopyrazoles 11a±f in 54±92% overall yields (Table 1,
entries 1±6). Electrophiles were also introduced in the
5-position affording 11g±j (Table 1, entries 7±10). When
7 was treated with the hard base16 LDA at 2788C, selective
deprotonation at C-5 occurred without any competing
halogen±metal exchange at C-4.17 Quenching with electro-
philes gave adducts 11g±i in good yields. When 2 was used
as electrophile, 11j was generated in 54% yield.
A similar strategy was employed for the preparation of
regioisomer 10 introducing the glycine functionality at
C-4 (Scheme 4). Treatment of 1-benzyloxy-4-iodopyrazole
7 with i-PrMgCl at 08C generated a 4-pyrazolylmagnesium
chloride intermediate by halogen±metal exchange.10 Low
temperature addition of 2 gave the expected adduct 8 in
82% yield, as the sole product. The ®nal deprotection of
the debenzylated intermediate 9 was attempted both by
acidic and basic hydrolysis. Even though the target amino
acid 10 could be obtained by acidic treatment (6N HCl for
12 h), cumbersome puri®cation by ion exchange was
required. On the other hand, basic hydrolysis (2N LiOH)
followed by mild acidic N-Boc deprotection and
The glycine functionality was then introduced at C-4.
Halogen±metal exchange was previously performed with
i-PrMgCl from 7, generating the positionally stable
4-magnesium intermediate, since the corresponding
4-lithium intermediate has proved to be very unstable.10
Recently it was observed that this instability is considerably
reduced when substituents are present at C-5, allowing the
successful use of the more reactive organolithium inter-
mediate.18,19 Treatment of 11a with i-PrMgCl at 08C,
followed by addition of imine 2, afforded 12a in 54%
yield. The yield increased to 78% when the halogen±
metal exchange was performed with n-BuLi. Therefore,
the latter protocol was used to prepare compounds 12a±i.
The synthesis of 12f proved to be more troublesome due to
the presence of the sensitive nitro group. The reaction of 11f
Scheme 5. Rˆaryl, heteroaryl, electrophiles.

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1597
Table 1. Synthesis of intermediates 12a±i
Table 2. Synthesis of 1-hydroxypyrazole amino acids 14a±i
Entry
1
R
13
Yield (%)
99
14
Yield (%)
96
Entry
1
R
11
Yield (%)
73
12a
Yield (%)
78
13a
14a
11ab
12a
2
3
13b
13c
100
98
14b
14c
96
86
2
3
11bb
11cb
92
81
12b
12c
75
70
4
13d
99
14d
83
4
11db
75
12d
69
5
6
13e
13f
98
±
14e
89
94
5
6
11eb
11fb
81
54
12e
81
72
14fa
12fc
7
8
9
CH3
SCH3
Cl
13g
13h
13i
97
92
95
14g
14h
14i
81
89
84
7
8
9
CH3
SCH3
Cl
11gd
11hd
11id
94
73
98
12g
12h
12i
84
75
83
a
Product obtained directly from 12f. See Section 4.
10
11jd
54
approaches could be envisaged for the synthesis of this class
of compounds (Scheme 6). The more convergent path A
involves the previously prepared 11j as the key intermediate
(Scheme 6). Therefore, we attempted to introduce aryl
substituents by Pd(0) catalysed Suzuki cross-coupling22,23
between aryl boronic acids and 11j. Unfortunately, the
desired products could be obtained only in very low yields.
Extensive decomposition of the starting material was
observed by increasing temperature and reaction time, indi-
cating the thermal instability of 11j. All attempts to
improve this preliminary result by changing solvent, base
or catalyst were unsuccessful, and the strategy was therefore
abandoned.
a
Reagents and conditions: n-BuLi, 2788C then imine 2.
b
Isolated yields based on the starting material 3. Reagents and conditions:
n-BuLi, 2788C, 10 min; ZnCl2 rt; RI, Pd(P Ph3)4, DMF, 808C, 2 h; ICl,
CH2Cl2, rt.
Reagents and conditions: PhLi, 21058C, then imine 2.
Isolated yields based on the starting material 7. Reagents and conditions:
LDA, 2788C, 5 min, then electrophile.
c
d
with both i-PrMgCl and n-BuLi gave rise to a complex
mixture of products. This problem could be overcome by
the use of PhLi at 21058C, providing the desired product
12f in 72% yield (Table 1, entry 6).20,21
Deprotection of 12a±i was performed in two steps (Table 2).
The benzyl group was ®rst removed by hydrogenolysis to
afford 1-hydroxypyrazole derivatives 13a±i in essentially
quantitative yields. These conditions were not applicable
to derivative 12f, since reduction of the nitro group took
place during debenzylation. Basic hydrolysis and
decarboxylation of 1-hydroxypyrazoles 13a±e and 13g±i
were accomplished following the above mentioned method-
ology, to provide the pure ®nal amino acids 14a±e and
14g±i in good yields (Table 2, entries 1±5 and 7±9).
Compound 14f was obtained in 94% yield by re¯uxing
12f in 12N HCl for 12 h. Analytically pure 14f precipitated
upon cooling of the reaction mixture.
An alternative strategy involves the synthesis of 4-aryl-1-
benzyloxypyrazole 15 followed by introduction of the
2.3. 4-Substituted 1-hydroxypyrazolylglycines (18)
Several 4-substituted hydroxypyrazole glycines were
prepared by introducing aryl groups at C-4. Two different
Scheme 6.

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1598
Table 3. Synthesis of 1-hydroxypyrazole glycine 18a±d
Entry
1
Ar
16
Yield (%)
69
17
Yield (%)
99
18
Yield (%)
87
16a
17a
18a
2
3
4
16b
16c
16d
75
69
65
17b
17c
17d
100
99
18b
18c
18d
80
97
74
98
glycine moiety at C-5 (Path B, Scheme 6). Intermediates
15a±d were generated by Negishi cross-coupling from 7
and aryliodides as previously reported.10,19 Deprotonation
at C-5 with n-BuLi followed by addition of the imine 2
gave the desired products 16a±d in 65±75% yields
(Table 3). These intermediates were debenzylated in
quantitative yields prior to the ®nal deprotection. Acidic
treatment of 1-hydroxypyrazole derivative 17a (6N HCl
for 12 h), gave the pure diethyl aminomalonate derivative
as the only product. No traces of the desired amino acid
were detected by NMR even after prolonged re¯uxing in
conc HCl or HBr. However, the target amino acids 18a±d
could be obtained in 74±94% yields by basic hydrolysis±
acidi®cation±decarboxylation.
solvents and reagents were of analytical grade purchased
from Aldrich or Fluka and used without further puri®cation.
N-Boc iminomalonate 2 was prepared as previously
described.13 THF was distilled from Na/benzophenone
Ê
ketyl under N2. DMF was dried and stored over 3 A
molecular sieves. 1 M solutions of ZnCl2 were prepared
by ¯ame drying the zinc salt under vacuum before
dissolving it in dry THF. n-BuLi24 and i-PrMgCl25 solutions
were titrated prior to use. Pd(PPh3)4 was prepared as
previously described.26
4.1.1. Diethyl 2-(1-benzyloxypyrazol-5-yl)-2-tert-butoxy-
carbonylamino-malonate (4). To a stirred solution of 3
(1 mmol) in THF (10 mL) at 2788C, was added dropwise
1.6 M n-BuLi in hexane (0.75 mL, 1.1 mmol) over 2 min.
After 5 min, a solution of imine 2 (300 mg, 1.1 mmol) in
THF (1 mL) was added, and the mixture was stirred for 1 h
at 2788C, before quenching cold with water. The reaction
was allowed to warm to rt, NH4Cl (10 mL) was added and
the mixture was extracted with EtOAc (3£15 mL). The
combined organic layers were dried over Na2SO4, ®ltered
and concentrated to afford the crude product. FC (petroleum
ether/EtOAc 6:1!4:1) gave 4 (412 mg, 92%) as a colorless
oil. Rf 0.2 (petroleum ether/EtOAc 5:1). IR (KBr) 3421,
2981, 1751, 1726, 1482, 1368, 1256, 1203, 1162,
1023 cm2.1 1H NMR (CDCl3) d 7.44±7.34 (m, 5H), 7.26
(d, Jˆ2.4 Hz, 1H), 6.70 (d, Jˆ2.4 Hz, 1H), 6.16 (br s, 1H),
5.24 (s, 2H), 4.29±4.11 (m, 4H), 1.37 (s, 9H), 1.17 (t,
Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 165.3, 153.5, 133.1,
132.1, 130.8, 129.7, 129.2, 128.5, 106.7, 80.7, 79.9, 63.2,
62.8, 27.9, 13.5. HRMS [M1H]1 calcd for C22H30N3O7:
448.2084. Found: 448.2065.
3. Conclusions
In summary, we have presented the synthesis of a new class
of a-heteroaryl glycines based on the addition of lithium
and magnesium 1-benzyloxypyrazole intermediates to an
electrophilic glycine equivalent. This reaction was succes-
fully combined with selective functionalisation of the
1-hydroxypyrazole ring giving access to a broad range of
N-Boc heteroaryl malonic esters. The corresponding substi-
tuted 1-hydroxypyrazole amino acids could be obtained
after deprotection±decarboxylation under mild conditions.
4. Experimental
4.1. General
All reactions involving air-sensitive reagents were
performed under N2 using syringe-septum cap technique.
All glassware was ¯amed-dried prior to use. Flash chroma-
tography (FC) was performed using silica Merck 60
4.1.2. Diethyl 2-tert-butoxycarbonylamino-2-(1-hydroxy-
pyrazol-5-yl)-malonate (5). Compound
4
(447 mg,
1 mmol), 10% Pd/C (65 mg) in MeOH (8 mL), were
vigorously stirred under hydrogen (1 atm) at 08C for
30 min. Filtration through celite, washing with MeOH and
evaporation of the solvent gave the crude product as a pale
yellow oil that crystallized on standing. FC (petroleum
ether/EtOAc 1:1!1:2) gave 5 as colorless crystals
(357 mg, 100%). Mp 97±988C (petroleum ether/Et2O). Rf
1
(230±460 mesh). H (300 MHz) and 13C NMR (75 MHz)
were recorded on a Varian instrument using TMS as internal
standard. Melting points are uncorrected. HRMS was
performed on a Micromass LCT instrument. IR were
performed on a Equinox55 instrument in 0.3% KBr. All

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1599
0.22 (petroleum ether/EtOAc 1:1). IR (KBr) 3419, 2981,
1H), 4.29 (m, 2H), 4.21 (dq, Jˆ10.5, 7.2 Hz, 2H), 1.41 (s,
9H), 1.24 (t, Jˆ7.2 Hz, 6H). 13C NMR (CDCl3) d 166.9,
153.9, 130.5, 122.5, 114.9, 80.7, 63.5, 62.9, 27.9, 13.7.
Anal. calcd for C15H23N3O7: C, 50.42; H, 6.49; N, 11.76.
Found: C, 50.67; H, 6.37; N 11.75.
1
1752, 1718, 1475, 1368, 1256, 1203, 1162, 1024 cm21. H
NMR (CDCl3) d 7.12 (d, Jˆ2.4 Hz, 1H), 6.66 (br d,
Jˆ2.4 Hz, 1H), 6.46 (br s, 1H, NH), 4.38±4.18 (m, 4H),
1.36 (s, 9H), 1.24 (t, Jˆ7.2 Hz, 6H). 13C NMR (CDCl3) d
165.2, 153.9, 131.4, 130.4, 106.1, 80.9, 63.4, 62.9, 27.9,
13.6. Anal. calcd for C15H23N3O7: C, 50.42; H, 6.49; N,
11.76. Found: C, 50.61; H, 6.38; N 11.51.
4.1.6. Hydrochloride salt of amino-(1-hydroxypyrazol-4-
yl)-acetic acid (10). To a solution of 9 (357 mg, 1 mmol) in
THF (4 mL) was added a 2.5 M aqueous solution of LiOH
(3.5 mL, 9 mmol). The mixture was vigorously stirred at rt
for 4 h. The solution was cooled to 08C and 1 M HCl was
added dropwise until pH 2. The mixture was extracted with
EtOAc (3£20 mL), the combined organic layers were
washed with brine (10 mL), ®ltered and evaporated to
dryness. The residue was stirred in 2 M HCl (3 mL) at
608C for 30 min. After evaporation of HCl, 10 (161 mg,
84%) was obtained as a colorless oil that slowly crystallized.
The crystals were triturated with Et2O and dried under
vacuum. Mp.1908C. IR (KBr) 3029, 2935, 2612, 1743,
4.1.3. Hydrochloride salt of amino-(1-hydroxypyrazol-5-
yl)-acetic acid (6). To a solution of 5 (357 mg, 1 mmol) in
THF (4 mL) was added a 2.5 M aqueous solution of LiOH
(3.5 mL, 9 mmol). The mixture was vigorously stirred at rt
for 12 h. The solution was cooled to 08C and 1 M HCl was
added dropwise until pH 2. The mixture was extracted with
EtOAc (3£20 mL), the combined organic layers were
washed with brine (10 mL), ®ltered and evaporated to
dryness. The residue was stirred in 2 M HCl (3 mL) at
608C for 30 min. After evaporation to dryness 6 (155 mg,
80%) was obtained as a pale yellow oil that slowly crystal-
lized under vacuum. The crystals were triturated twice with
Et2O and dried under vacuum. Mp decomposition above
1308C. IR (KBr) 3205, 3164, 2885, 2622, 1729, 1489,
1
1497, 1285, 1219 cm21. H NMR (DMSO-d6) d 8.77 (br
s, 3H), 7.68 (d, Jˆ1.0 Hz, 1H), 7.24 (d, Jˆ1.0 Hz, 1H),
4.96 (br q, Jˆ5.0 Hz, 1H). 13C NMR (DMSO-d6) d 169.8,
131.3, 122.8, 111.2, 48.0. HRMS [M2HCl±H]2 calcd for
C5H6N3O3: 156.0409. Found: 156.0469.
1
1236 cm21. H NMR (DMSO-d6) d 8.91 (br s, 3H), 7.19
(d, Jˆ2.4 Hz, 1H), 6.34 (d, Jˆ2.4 Hz, 1H), 5.21 (br q,
Jˆ5.0 Hz, 1H). 13C NMR (DMSO-d6) d 160.9, 124.7,
120.5, 97.4, 39.7. HRMS [M2HCl±H]2 calcd for
C5H6N3O3: 156.0409. Found: 156.0460.
4.2. General procedure for the preparation of 11a±f
To a stirred solution of 3 (174 mg, 1 mmol) in THF (8 mL)
at 2788C, was added dropwise 1.6 M n-BuLi in hexane
(0.68 mL, 1.1 mmol) over 2 min. After 5 min, a 1 M solu-
tion of ZnCl2 in THF (1.5 mL, 1.5 mmol) was added. The
solution was allowed to warm to rt, the aryl halide
(1.5 mmol) and Pd(PPh3)4 (2 mol%) in DMF (4 mL) were
added. The mixture was heated to 808C for 2 h before
quenching with sat. aq. NH4Cl (10 mL). Water (5 mL)
was added and the mixture was extracted with Et2O
(3£15 mL). The combined organic layers were dried over
Na2SO4, ®ltered and concentrated to afford the crude
product, which was iodinated without further puri®cation.
4.1.4. Diethyl 2-(1-benzyloxypyrazol-4-yl)-2-tert-butoxy-
carbonylamino-malonate (8). To a stirred solution of 7
(300 mg, 1 mmol) in THF (10 mL) at 08C, was added drop-
wise 2.0 M i-PrMgCl in THF (0.6 mL, 1.2 mmol). After
stirring at 08C for 30 min, the mixture was cooled to
2788C and a solution of the imine 2 (300 mg, 1.1 mmol)
in THF (1 mL) was added. Stirring was continued at 2788C
for 3 h before quenching cold with water. The reaction
mixture was allowed to warm to rt, NH4Cl (10 mL) was
added and the mixture was extracted with EtOAc
(3£15 mL). The combined organic layers were dried over
Na2SO4, ®ltered and concentrated. FC (petroleum ether/
EtOAc 5:1!3:1) afforded 8 (366 mg, 82%) as a colorless
oil. Rf 0.19 (petroleum ether/EtOAc 4:1). IR (KBr) 3431,
The crude 5-aryl-1-benzyloxypyrazole was dissolved in
CH2Cl2 (10 mL), K2CO3 (357 mg, 2.2 mmol) and ICl
(276 mg, 2 mmol) were added. After stirring at rt for 1 h,
1 M aq. Na2SO3 was added to destroy the excess of ICl. The
mixture was extracted with CH2Cl2 (3£20 mL), dried over
Na2SO4, ®ltered and evaporated to dryness. Puri®cation of
the residue by FC (petroleum ether/EtOAc) gave the title
compound.
2980, 1744, 1719, 1368, 1269, 1165 cm21 1H NMR
.
(CDCl3) d 7.38±7.32 (m, 7H), 6.26 (br s, 1H), 5.26 (s,
2H), 4.30±4.19 (m, 2H), 4.14 (dq, Jˆ10.7, 7.1 Hz, 2H),
1.40 (s, 9H), 1.19 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d
167.0, 153.9, 133.7, 132.1, 129.5, 129.1, 128.6, 123.0,
115.0, 80.6, 80.5, 63.3, 62.7, 27.9, 13.6. HRMS [M1H]1
calcd for C22H30N3O7: 448.2084. Found: 448.2072.
4.2.1. 1-Benzyloxy-4-iodo-5-(4-tolyl)-pyrazole (11a).
From 4-iodotoluene. FC (petroleum ether/EtOAc 6:1).
Yield 73%. Pale yellow oil. Rf 0.26 (petroleum ether/
4.1.5. Diethyl 2-tert-butoxycarbonylamino-2-(1-hydroxy-
7
1
pyrazol-4-yl)-malonate (9). Compound
(447 mg,
EtOAc 5:1). H NMR (CDCl3) d 7.41 (s, 1H), 7.30±7.24
1 mmol), 10% Pd/C (65 mg) in MeOH (8 mL), were
vigorously stirred under hydrogen (1 atm) at 08C for
30 min. Filtration through celite, washing with MeOH and
evaporation of the solvent gave the crude product as a pale
yellow oil that crystallized on standing. FC (petroleum
ether/EtOAc 1:1!1:2) gave 9 as colorless crystals
(349 mg, 98%). Mp 134±1358C (Et2O/petroleum ether). Rf
0.22 (petroleum ether/EtOAc 1:1). IR (KBr) 3250, 2984,
(m, 2H), 7.22±7.16 (m, 5H), 7.04±7.01 (m, 2H), 5.66 (s,
2H), 2.40 (s, 3H). 13C NMR (CDCl3) d 139.2, 138.5, 136.8,
132.9, 129.7, 129.6, 129.2, 129.0, 128.5, 124.1, 80.6, 55.9,
21.4. Anal. calcd for C17H15N2OI: C, 52.33; H, 3.87; N 7.18.
Found: C, 52.07; H, 3.62; N 7.16.
4.2.2. 1-Benzyloxy-4-iodo-5-(4-methoxyphenyl)-pyrazole
(11b). From 4-iodoanisole. FC (petroleum ether/EtOAc
5:1). Yield 92%. Pale yellow oil. Rf 0.48 (petroleum ether/
1
1749, 1676, 1407, 1266, 1211 cm21. H NMR (CDCl3) d
1
7.58 (d, Jˆ0.9 Hz, 1H), 7.24 (d, Jˆ0.9 Hz, 1H), 6.31 (br s,
EtOAc 4:1). H NMR (CDCl3) d 7.40 (s, 1H), 7.32 (br d,

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1600
Jˆ8.9 Hz, 2H), 7.21 (m, 3H), 7.03 (m 2H), 6.92 (br d,
Jˆ8.9 Hz, 2H), 5.06 (s, 2H), 3.85 (s, 3H). 13C NMR
(CDCl3) d 160.0, 138.3, 136.5, 132.8, 131.0, 129.8, 129.1,
128.4, 119.2, 113.6, 80.4, 55.7, 55.1. Anal. calcd for
C17H15N2OI: C, 50.26; H, 3.72; N 6.90. Found: C, 50.47;
H, 3.72; N 6.80.
4.3.1. 1-Benzyloxy-4-iodo-5-methylpyrazole (11g). Using
iodomethane as electrophile. FC (petroleum ether/EtOAc
5:1). Yield 94 %. Colorless crystals. Mp 73±748C
(petroleum ether/EtOAc). Rf 0.42 (petroleum ether/EtOAc
1
5:1). H NMR (CDCl3) d 7.38 (m, 3H), 7.29 (s, 1H), 7.27
(m, 2H), 5.25 (s, 2H), 1.87 (s, 3H). 13C NMR (CDCl3) d
137.4, 134.4, 133.5, 130.1, 129.6, 128.7, 80.2, 55.7, 9.7.
Anal. calcd for C11H11IN2O: C, 42.06; H, 3.53; N 8.92.
Found: C, 42.20; H, 3.27; N 8.79.
4.2.3. 1-Benzyloxy-4-iodo-5-(2-methoxyphenyl)-pyrazole
(11c). From 2-iodoanisole. FC (petroleum ether/EtOAc
5:1). Yield 81%. Pale yellow oil. Rf 0.24 (petroleum ether/
EtOAc 5:1). 1H NMR (CDCl3) d 7.43 (s, 1H), 7.14 (m, 1H),
7.23 (m, 3H), 6.90 (m, 5H), 5.12 (s, 2H), 3.74 (s, 3H). 13C
NMR (CDCl3) d 157.3, 137.9, 134.9, 133.3, 132.1, 131.2,
129.5, 128.9, 128.4, 120.3, 116.2, 110.0, 80.3, 58.1, 55.4.
Anal. calcd for C17H15N2OI: C, 50.26; H, 3.72; N 6.90.
Found: C, 50.14; H, 3.68; N 6.86.
4.3.2. 1-Benzyloxy-4-iodo-5-methylsulfanylpyrazole (11h).
Using dimethyldisul®de as electrophile. FC (petroleum ether/
EtOAc 7:1). Yield 73%. Colorless crystals. Mp 46±488C
(petroleum ether/EtOAc). Rf 0.21 (petroleum ether/EtOAc
1
8:1). H NMR (CDCl3) d 7.40 (m, 5H), 7.39 (s, 1H), 5.31
(s, 2H), 2.23 (s, 3H). 13C NMR (CDCl3) d 138.3, 133.2,
131.7, 130.1, 129.5, 128.7, 81.1, 65.7, 18.1. Anal. calcd for
C11H11IN2OS: C, 38.16; H, 3.20; N 8.09. Found: C, 38.41; H,
2.97; N 8.03.
4.2.4. 1-Benzyloxy-5-(2-¯uorophenyl)-4-iodo-pyrazole
(11d). From 2-iodo¯uorobenzene. FC (petroleum ether/
EtOAc 5:1). Yield 75%. Pale yellow oil. Rf 0.24 (petroleum
ether/EtOAc 5:1). 1H NMR (CDCl3) d 7.47 (s, 1H), 7.41 (m,
1H), 7.28 (m, 1H), 7.20±7.09 (m, 4H), 7.05 (dd, Jˆ7.2,
2.0 Hz, 1H), 6.99 (m, 2H), 5.17 (s, 2H). 13C NMR
(CDCl3) d 159.7 (d, Jˆ250 Hz), 138.5, 132.9, 132.6,
132.3 (d, Jˆ2.3 Hz), 131.5 (d, Jˆ8.3 Hz), 129.7, 129.2,
128.5, 123.9 (d, Jˆ3.7 Hz), 115.9 (d, Jˆ21 Hz), 115.4 (d,
Jˆ15 Hz), 80.5, 57.9. Anal. calcd for C16H12FIN2O: C,
48.75; H, 3.07; N 7.11. Found: C, 48.54; H, 2.93; N 7.17.
4.3.3. 1-Benzyloxy-5-chloro-4-iodopyrazole (11i). Using
hexachloroethane as electrophile. FC (petroleum ether/
EtOAc 7:1). Yield 98%. Colorless crystals. Mp 69±708C.
1
Rf 0.52 (petroleum ether/EtOAc 5:1). H NMR (CDCl3) d
7.39 (m, 5H), 7.37 (s, 1H), 5.27 (s, 2H). 13C NMR (CDCl3) d
138.1, 132.6, 130.1, 129.7, 128.7, 125.4, 81.2, 56.2. Anal.
calcd for C10H8ClIN2O: C, 35.90; H, 2.41; N 8.37. Found: C,
36.17; H, 2.32; N 8.09.
4.2.5. 1-Benzyloxy-4-iodo-5-(thien-2-yl)-pyrazole (11e).
From 2-iodothiophene. FC (petroleum ether/EtOAc
8:1!6:1). Yield 81%. Pale yellow oil. Rf 0.52 (petroleum
4.3.4. Diethyl 2-(1-benzyloxy-4-iodopyrazol-5-yl)-2-tert-
butoxycarbonylamino-malonate (11j). Using 2 as electro-
phile. FC (petroleum ether/EtOAc 7:1). Yield 54%. Color-
less crystals. Mp 92±938C. Rf 0.47 (petroleum ether/EtOAc
1
ether/EtOAc 5:1). H NMR (CDCl3) d 7.56 (dd, Jˆ3.7,
1
1.0 Hz, 1H), 7.42 (dd, Jˆ5.1, 1.0 Hz, 1H), 7.40 (s, 1H),
7.26 (m, 5H), 7.08 (dd, Jˆ5.1, 3.7 Hz, 1H), 5.19 (s, 2H).
13C NMR (CDCl3) d 139.0, 132.7, 131.2, 129.9, 129.3,
128.9, 128.5, 127.6, 127.0, 126.9, 80.7, 55.7. Anal. calcd
for C17H15N2OI: C, 43.99; H, 2.90; N 7.33. Found: C, 43.79;
H, 2.76; N 7.19.
5:1). H NMR (CDCl3) d 7.50 (m, 2H), 7.39 (s, 1H), 7.38
(m, 3H), 6.04 (br s, 1H), 5.36 (s, 2H), 4.18 (dq, Jˆ10.7,
7.1 Hz, 2H), 4.04 (m, 2H), 1.44 (s, 9H), 1.16 (t, Jˆ7.1 Hz,
6H).13C NMR (CDCl3) d 165.9, 153.9, 138.8, 133.9, 133.3,
130.5, 130.4, 129.4, 128.6, 80.6, 80.3, 63.5, 63.4, 27.9, 13.3.
Anal. calcd for C22H28IN3O7: C, 46.08; H, 4.92; N 7.33.
Found: C, 46.31; H, 4.73; N 7.36.
4.2.6. 1-Benzyloxy-4-iodo-5-(4-nitrophenyl)-pyrazole (11f).
From 4-iodonitrobenzene. FC (petroleum ether/EtOAc 5:1).
Yield 54%. Yellow crystals. Mp 120±1218C (petroleum ether/
EtOAc). Rf 0.41 (petroleum ether/EtOAc 4:1). 1H NMR
(CDCl3) d 8.16 (m, 2H), 7.49 (s, 1H), 7.41 (m, 2H), 7.25
(m, 1H), 7.11 (m, 2H), 6.87 (m, 2H), 5.14 (s, 2H). 13C
NMR (CDCl3) d 147.4, 139.0, 135.1, 133.2, 132.2, 130.4,
129.9, 129.5, 128.4, 123.1, 80.8, 56.6. Anal. calcd for
C16H12N3O3I: C, 45.63; H, 2.87; N 9.98. Found: C, 45.83;
H, 2.95; N 9.83.
4.4. General method for the synthesis of derivatives
12a±e and 12g±i
To a stirred solution of 11a±e and 11g±i (1 mmol) in THF
(10 mL) at 2788C, was added dropwise 1.6 M n-BuLi in
hexane (0.75 mL, 1.2 mmol) over 2 min. After 10 min, a
solution of imine 2 (300 mg, 1.1 mmol) in THF (1 mL)
was added, and the mixture was stirred for 2788C for 1 h,
before quenching with water. The reaction was allowed to
warm to rt, NH4Cl (10 mL) was added and the mixture was
extracted with EtOAc (3£15 mL). The combined organic
layers were dried over Na2SO4, ®ltered and concentrated
to afford the crude product. Puri®cation of the residue by
FC (petroleum ether/EtOAc) gave the title compound.
4.3. General procedure for the synthesis of 11g±j
To a stirred solution of 7 (300 mg, 1 mmol) in THF (8 mL)
at 2788C, was added dropwise a solution of freshly
prepared LDA (1.3 mmol) in THF. After 5 min, the electro-
phile was added and stirring was continued at 2788C for
1 h. The solution was then allowed to warm to rt, sat. aq.
NH4Cl (10 mL) was added and the mixture was extracted
with CH2Cl2 (3£15 mL). The combined organic layers were
dried over Na2SO4, ®ltered and concentrated in vacuum.
Puri®cation by FC (petroleum ether/EtOAc) afforded the
title compound.
4.4.1. Diethyl 2-[1-benzyloxy-5-(4-tolyl)-pyrazol-4-yl]-2-
tert-butoxycarbonylamino-malonate (12a). From 11a. FC
(petroleum ether/EtOAc 6:1!4:1). Yield 78%. Colorless
crystals. Mp 82±838C. Rf 0.25 (petroleum ether/EtOAc
4:1). IR (KBr) 3287, 2978, 1768, 1749, 1719, 1500, 1262,
1198, 1170 cm21. 1H NMR (CDCl3) d 7.86 (s, 1H), 7.27 (m,
1H), 7.18 (m, 2H), 7.12 (d, Jˆ7.9 Hz, 2H), 6.94 (d,

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1601
Jˆ7.2 Hz, 2H), 5.88 (s, 1H), 5.05 (s, 2H), 4.14 (m, 2H), 3.98
(dq, Jˆ10.7, 7.1 Hz, 2H), 2.39 (s, 3H), 1.30 (s, 9H), 1.16 (t,
Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 167.1, 153.3, 138.7,
134.5, 133.4, 130.4, 129.8, 129.0, 128.5, 128.4, 122.3,
113.0, 80.1 63.7, 62.7, 27.9, 21.3, 13.7, one signal missing.
Anal. calcd for C29H35N3O7: C, 64.79; H, 6.56; N 7.82.
Found: C, 64.84; H, 6.61; N 7.83.
13.7, one signal missing. Anal. calcd for C26H31N3O7S: C,
58.96; H, 5.90; N 7.93. Found: C, 58.67; H, 5.97; N 7.71.
4.4.6. Diethyl 2-(1-benzyloxy-5-methylpyrazol-4-yl)-2-
tert-butoxycarbonylamino-malonate (12g). From 11g.
FC (petroleum ether/EtOAc 4:1). Yield 84%. Colorless
oil. Rf 0.20 (petroleum ether/EtOAc 4:1). 1H NMR
(CDCl3) d 7.53 (s, 1H), 7.35 (m, 3H), 7.28 (m, 2H), 6.18
(br s, 1H), 5.25 (s, 2H), 4.27 (m, 2H), 4.18 (dq, Jˆ10.7,
7.1 Hz, 2H), 1.95 (s, 3H), 1.42 (s, 9H), 1.24 (t, Jˆ7.1 Hz,
6H). 13C NMR (CDCl3) d 167.1, 153.6, 133.7, 132.7, 131.4,
129.9, 129.3, 128.5, 80.4, 79.9, 64.0, 62.6, 28.0, 13.7, 9.3,
one signal missing. Anal. calcd for C23H31N3O7: C, 59.86;
H, 6.77; N 9.10. Found: C, 60.12; H, 6.76; N 9.18.
4.4.2. Diethyl 2-[1-benzyloxy-5-(4-methoxyphenyl)-pyra-
zol-4-yl]-2-tert-butoxycarbonylamino-malonate (12b).
From 11b. FC (petroleum ether/EtOAc 4:1). Yield 75%.
Colorless crystals. Mp 94±968C. Rf 0.13 (petroleum ether/
EtOAc 4:1). 1H NMR (CDCl3) d 7.86 (s, 1H), 7.28 (m, 1H),
7.19 (m, 2H), 6.96 (m, 4H), 6.84 (m, 2H), 5.90 (s, 1H), 5.06
(s, 2H), 4.16 (m, 2H), 4.01 (dq, Jˆ10.7, 7.1 Hz, 2H), 3.85 (s,
3H), 1.32 (s, 9H), 1.18 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3)
d 167.1, 159.9, 153.3, 134.5, 134.4, 133.3, 131.8, 129.8,
128.9, 128.4, 119.7, 113.3, 112.6, 80.1, 80.0, 63.7, 62.6,
55.2, 27.9, 13.62. Anal. calcd for C29H35N3O8: C, 62.92;
H, 6.37; N 7.59. Found: C, 62.68; H, 6.30; N 7.46.
4.4.7. Diethyl 2-(1-benzyloxy-5-methylsulfanylpyrazol-4-
yl)-2-tert-butoxycarbonylamino-malonate (12h). From
11h. FC (petroleum ether/EtOAc 4:1). Yield 75%. Colorless
crystals. Mp 42±438C. Rf 0.24 (petroleum ether/EtOAc 4:1).
1H NMR (CDCl3) d 7.84 (s, 1H), 7.46 (m, 2H), 7.38 (m,
2H), 6.34 (br s, 1H), 5.34 (s, 2H), 4.33 (m, 2H), 4.25 (dq,
Jˆ10.7, 7.1 Hz, 2H), 2.20 (s, 3H), 1.40 (s, 9H), 1.26 (t,
Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 166.7, 153.7, 134.5,
133.5, 129.9, 129.3, 128.6, 126.2, 81.0, 80.9, 63.9, 62.8,
28.1, 18.2, 13.7, one signal missing. Anal. calcd for
C23H31N3O7S: C, 55.97; H, 6.33; N 8.51. Found: C, 56.27;
H, 6.07; N 8.79.
4.4.3. Diethyl 2-[1-benzyloxy-5-(2-methoxyphenyl)-pyra-
zol-4-yl]-2-tert-butoxycarbonylamino-malonate
(12c).
From 11c. FC (petroleum ether/EtOAc 4:1). Yield 70%.
Colorless crystals. Mp 99±1008C. Rf 0.13 (petroleum
1
ether/EtOAc 4:1!3:1). H NMR (CDCl3) d 7.83 (s, 1H),
7.41 (m, 1H), 7.24 (m, 3H), 6.93 (m, 5H), 5.94 (br s, 1H),
5.17 (d, Jˆ10.2 Hz, 1H), 4.99 (d, Jˆ10.2 Hz, 1H), 4.31±
4.00 (m, 3H), 3.88 (m, 1H), 3.70 (s, 3H), 1.31 (s, 9H), 1.24
(t, Jˆ7.1 Hz, 3H), 1.14 (t, Jˆ7.1 Hz, 3H). 13C NMR
(CDCl3) d 166.8, 166.5, 157.15, 153.3, 133.7, 133.3,
132.2, 130.7, 130.3, 129.3, 128.6, 126.1, 119.9, 116.2,
113.2, 110.1, 80.0, 79.4, 63.5, 63.2, 62.0, 54.8, 27.7, 13.4,
13.4. Anal. calcd for C29H35N3O8: C, 62.92; H, 6.37; N 7.59.
Found: C, 62.82; H, 6.27; N 7.56.
4.4.8. Diethyl 2-(1-benzyloxy-5-chloropyrazol-4-yl)-2-
tert-butoxycarbonylamino-malonate (12i). From 11i. FC
(petroleum ether/EtOAc 4:1). Yield 83%. Colorless oil. Rf
0.26 (petroleum ether/EtOAc 4:1). 1H NMR (CDCl3) d 7.85
(s, 1H), 7.37 (m, 5H), 6.24 (br s, 1H), 5.27 (s, 2H), 4.29 (m,
2H), 4.21 (dq, Jˆ10.7, 7.1 Hz, 2H), 1.40 (s, 9H), 1.25 (t,
Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 166.1, 153.7, 143.5,
132.8, 129.9, 129.4, 128.6, 119.8, 111.2, 80.7, 80.4, 63.2,
62.9, 27.9, 13.6. Anal. calcd for C22H28ClN3O7: C, 54.83; H,
5.86; N 8.72. Found: C, 54.60; H, 5.57; N 8.58.
4.4.4. Diethyl 2-[1-benzyloxy-5-(2-¯uorophenyl)-pyra-
zol-4-yl]-2-tert-butoxycarbonylamino-malonate (12d).
From 11d. FC (petroleum ether/EtOAc 4:1!2:1). Yield
69%. Pale yellow crystals. Mp 140±1428C. Rf 0.13
4.4.9. Diethyl 2-[1-benzyloxy-5-(4-nitrophenyl)-pyrazol-
4-yl]-2-tert-butoxycarbonylamino-malonate (12f). To a
stirred solution of 11f (421 mg, 1 mmol) in THF (10 mL)
at 21058C, was added dropwise 1.6 M PhLi in cyclohexane/
ether 70:30 (0.75 mL, 1.2 mmol), keeping the internal
temperature below 21028C. The dark green solution was
stirred for 30 min at 21058C. A solution of 2 (382 mg,
1.4 mmol) in THF (1 mL) was slowly added. Stirring was
continued for 2 h at 21058C before quenching cold with
NH4Cl (1 mL). The reaction mixture was allowed to warm
to rt, NH4Cl (10 mL) was added and the mixture was
extracted with EtOAc (3£15 mL). The combined organic
layers were dried over Na2SO4, ®ltered and concentrated.
FC (petroleum ether/EtOAc 3:1! 2:1) gave 12f (409 mg,
72%) as pale yellow crystals: mp 112±1138C (petroleum
ether/EtOAc). Rf 0.45 (petroleum ether/EtOAc 2:1). 1H
NMR (CDCl3) d 8.08 (m, 2H), 7.94 (s, 1H), 7.30 (m, 1H),
7.15 (m, 2H), 7.06 (m, 2H), 6.82 (m, 2H), 5.79 (s br, 1H),
5.12 (s, 2H), 4.27±4.17 (m, 2H), 4.09 (dq, Jˆ10.7, 7.1 Hz,
2H), 1.23 (s, 9H), 1.20 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3)
d 166.8, 153.1, 147.5, 134.9, 134.5, 132.9, 132.7, 131.5,
129.9, 129.3, 128.5, 122.4, 113.0, 80.2, 80.0, 63.5, 62.9,
27.8, 13.6. Anal. calcd for C28H32N4O9: C, 59.15; H, 5.67;
N 9.85. Found: C, 59.36; H, 5.45; N 9.81.
1
(petroleum ether/EtOAc 4:1). H NMR (CDCl3) d 7.94 (s,
1H), 7.40 (m, 1H), 7.28 (tt, Jˆ7.3, 1.3 Hz, 1H), 7.19 (m,
2H), 7.08 (m, 2H), 6.96 (m, 3H), 5.93 (br s, 1H), 5.21 (d,
Jˆ9.7 Hz, 1H), 5.04 (d, Jˆ9.7 Hz, 1H), 4.21 (m, 2H), 4.10
(m, 2H), 1.28 (s, 9H), 1.21 (t, Jˆ7.1 Hz, 6H). 13C NMR
(CDCl3) d 166.9, 166.7, 160.1 (d, Jˆ250 Hz), 153.4,
134.7, 133.3, 132.8, 131.2 (d, Jˆ7.0 Hz), 129.7, 129.0,
128.5, 128.0, 123.7 (d, Jˆ3.6 Hz), 116.0 (d, Jˆ13.7 Hz),
115.3 (d, Jˆ21.5 Hz), 113.7, 80.2, 80.0, 63.6, 62.8, 62.6,
27.9, 13.6. Anal. calcd for C28H32FN3O7: C, 62.10; H, 5.96;
N 7.76. Found: C, 62.34; H, 5.97; N 7.55.
4.4.5. Diethyl 2-[1-benzyloxy-5-(thien-2-yl)-pyrazol-4-
yl]-2-tert-butoxycarbonylamino-malonate (12e). From
11e. FC (petroleum ether/EtOAc 4:1). Yield 81%. Colorless
crystals. Mp 104±1068C. Rf 0.20 (petroleum ether/EtOAc
1
4:1). H NMR (CDCl3) d 7.89 (s, 1H), 7.45 (dd, Jˆ5.1,
1.1 Hz, 1H), 7.31±7.21 (m, 3H), 7.05 (m, 2H), 7.02 (dd,
Jˆ5.1, 3.6 Hz, 1H), 6.81 (dd, Jˆ3.6, 1.0 Hz, 1H), 6.01 (br
s, 1H), 5.15 (s, 2H), 4.19 (m, 2H), 4.05 (dq, Jˆ10.7, 7.1 Hz,
2H), 1.36 (s, 9H), 1.19 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3)
d 166.9, 153.5, 134.7, 133.2, 131.0, 129.8, 129.1, 128.5,
127.7, 126.7, 126.4, 114.6, 80.6, 80.1, 63.8, 62.8, 28.1,

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1602
4.5. General method for the synthesis of 16a±e
0.25 (petroleum ether/EtOAc 5:1). 1H NMR (CDCl3) d 7.52
(m, 2H), 7.41 (m, 3H), 7.38 (s, 1H), 7.25 (dd, Jˆ5.1, 1.0 Hz,
1H), 7.16 (br s, 1H), 7.03 (dd, Jˆ5.1, 3.5 Hz, 1H), 6.14 (br s,
1H, NH), 5.37 (s, 2H), 3.99 (dq, Jˆ10.6, 7.1 Hz, 2H), 3.73
(m, 2H), 1.46 (s, 9H), 1.01 (t, Jˆ7.1 Hz, 6H). 13C NMR
(CDCl3) d 165.8, 154.0, 133.6, 133.3, 133.1, 130.1, 129.2,
128.6, 127.5, 127.2, 125.3, 113.7, 80.3, 80.3, 64.1, 63.3,
28.1, 13.4, one signal missing. Anal. calcd for
C26H31N3O7S: C, 58.96; H, 5.90; N 7.93. Found: C, 59.03;
H, 5.98; N 7.88.
To a stirred solution of 15a±d (1 mmol) in THF (10 mL) at
2788C, was added dropwise 1.6 M n-BuLi in hexane
(0.75 mL, 1.2 mmol) over 2 min. After 5 min, a solution
of imine 2 (382 mg, 1.4 mmol) in THF (1 mL) was added,
and the mixture was stirred at 2788C for 3 h, before quench-
ing cold with water. The reaction was allowed to warm to rt,
NH4Cl (10 mL) was added and the mixture was extracted
with EtOAc (3£15 mL). The combined organic layers were
dried over Na2SO4, ®ltered and concentrated to afford the
crude product. Puri®cation of the residue by FC (petroleum
ether/EtOAc) gave the title compound.
4.6. General method for the hydrogenolysis of the benzyl
group. Synthesis of 13a±e, 13g±i and 17a±d
4.5.1. Diethyl 2-[1-benzyloxy-4-(4-tolyl)-pyrazol-5-yl]-2-
tert-butoxycarbonylamino-malonate (16a). From 15a. FC
(petroleum ether/EtOAc 6:1!4:1). Yield 69%. Colorless
crystals. Mp 111±1138C (petroleum ether/EtOAc). Rf 0.25
(petroleum ether/EtOAc 4:1). IR (KBr) 3401, 2971, 1760,
Compounds 12a±e, 12g±i and 16a±d (1 mmol), 10% Pd/C
(65 mg) in MeOH (8 mL), were vigorously stirred under
hydrogen (1 atm) at 08C for 45 min. Filtration through
celite, washing with MeOH and evaporation of the solvent
gave the crude product. The pure products were obtained
after ®ltration by ¯ash chromatography (petroleum ether/
EtOAc).
1733, 1722, 1481, 1301, 1272, 1160 cm21 1H NMR
.
(CDCl3) d 7.52 (m, 2H), 7.41 (m, 3H), 7.32 (d, Jˆ7.8 Hz,
2H), 7.29 (s, 1H), 7.17 (d, Jˆ7.8 Hz, 2H), 6.10 (br s, 1H),
5.38 (s, 2H), 3.91 (dq, Jˆ10.7, 7.1 Hz, 2H), 3.65 (m, 2H),
2.35 (s, 3H), 1.44 (s, 9H), 0.98 (t, Jˆ7.1 Hz, 6H). 13C NMR
(CDCl3) d 165.9, 153.9, 136.7, 133.4, 132.6, 129.9, 129.4,
129.1, 128.8, 128.5, 126.2, 120.6, 80.2, 80.0, 64.3, 63.0,
28.0, 20.9, 13.3, one signal missing. Anal. calcd for
C29H35N3O7: C, 64.79; H, 6.56; N 7.82. Found: C, 65.09;
H, 6.65; N 7.77.
4.6.1. Diethyl 2-tert-butoxycarbonylamino-2-[1-hydroxy-
5-(4-tolyl)-pyrazol-4-yl]-malonate (13a). From 12a. FC
(petroleum ether/EtOAc 3:1!1:1). Yield 99%. Colorless
crystals. Mp decomposition above 1608C. Rf 0.2 (petroleum
ether/EtOAc 2:1). IR (KBr) 3405, 2981, 1763, 1747, 1722,
1474, 1256, 1203, 1165, 1024, 1024 cm21 1H NMR
.
(CDCl3) d 7.72 (s, 1H), 7.26 (s, 4H), 5.98 (s, 1H), 4.16
(m, 2H), 3.98 (dq, Jˆ10.7, 7.1 Hz, 2H), 2.42 (s, 3H), 1.31
(s, 9H), 1.17 (t, Jˆ1.2 Hz, 6H). 13C NMR (CDCl3) d 167.0,
153.4, 139.1, 133.3, 132.7, 130.5, 128.8, 124.5, 112.5, 80.0,
63.6, 62.7, 27.9, 21.3, 13.6. Anal. calcd for C22H29N3O7:
C, 59.05; H, 6.53; N, 9.39. Found: C, 58.76; H, 6.36;
N 9.43.
4.5.2. Diethyl 2-[1-benzyloxy-4-(4-methoxyphenyl)-pyra-
zol-5-yl]-2-tert-butoxycarbonylamino-malonate (16b).
From 15b. FC (petroleum ether/EtOAc 6:1!4:1). Yield
75%. Pale yellow oil. Rf 0.17 (petroleum ether/EtOAc
1
5:1). H NMR (CDCl3) d 7.53 (m, 2H), 7.40 (m, 5H),
7.27 (s, 1H), 6.90 (m, 2H), 6.12 (s, 1H), 5.37 (s, 2H), 3.92
(dq, Jˆ10.7, 7.1 Hz, 2H), 3.82 (s, 3H), 3.68 (m, 2H), 1.45 (s,
9H), 1.00 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 165.9,
158.9, 153.9, 133.4, 132.7, 130.7, 129.9, 129.2, 128.6,
126.2, 125.3, 120.4, 113.6, 80.3, 80.1, 63.4, 63.1, 55.2,
28.1, 13.4. HRMS [M1H]1 calcd for C29H36N3O8:
554.2502. Found: 554.2491.
4.6.2. Diethyl 2-tert-butoxycarbonylamino-2-[1-hydroxy-
5-(4-methoxyphenyl)-pyrazol-4-yl]-malonate (13b). From
12b. FC (petroleum ether/EtOAc 2:1!1:2). Yield 100%.
Colorless crystals. Mp 148±1498C. Rf 0.30 (petroleum
1
ether/EtOAc 1:1) H NMR (CDCl3) d 7.70 (s, 1H), 7.29
(d, Jˆ8.8 Hz, 2H), 6.97 (d, Jˆ8.8 Hz, 2H), 6.02 (s, 1H),
4.18 (br dq, Jˆ10.7, 7.1 Hz, 2H), 4.00 (dq, Jˆ10.7,
7.1 Hz, 2H), 3.86 (s, 3H), 1.31 (s, 9H), 1.17 (t, Jˆ7.1 Hz,
6H). 13C NMR (CDCl3) d 167.0, 160.2, 153.5, 133.3, 132.7,
131.9, 119.5, 113.5, 112.5, 80.1, 63.6, 62.7, 55.2, 28.0, 13.6.
Anal. calcd for C22H29N3O8: C, 57.01; H, 6.31; N 9.07.
Found: C, 57.10; H, 6.13; N 9.01.
4.5.3. Diethyl 2-[1-benzyloxy-4-(2-¯uorophenyl)-pyra-
zol-5-yl]-2-tert-butoxycarbonylamino-malonate
(16c).
From 15c. FC (petroleum ether/EtOAc 5:1!2:1). Yield
69%. Colorless crystals. Mp 115±1168C (petroleum ether/
EtOAc). Rf 0.21 (petroleum ether/EtOAc 5:1). H NMR
1
(CDCl3) d 7.52 (m, 3H), 7.41 (m, 3H), 7.35 (d, Jˆ1.3 Hz,
1H), 7.29 (m, 1H), 7.12 (m, 2H), 6.05 (br s, 1H), 5.41 (s,
2H), 3.95 (dq, Jˆ10.7, 7.1 Hz, 2H), 3.73 (m, 2H), 1.40 (s,
9H), 1.05 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 165.8,
160.2 (d, Jˆ247 Hz), 153.7, 133.5, 133.4, 132.8 (d,
Jˆ65.9 Hz), 129.8, 129.1, 128.9 (d, Jˆ7.6 Hz), 128.6,
127.0, 123.5 (d, Jˆ3.7 Hz), 120.1 (d, Jˆ14.4 Hz), 115.3
(d, Jˆ22.0 Hz), 113.3, 80.3, 79.9, 64.3, 63.1, 28.0, 13.3.
Anal. calcd for C28H32FN3O7: C, 62.10; H, 5.96; N 7.76.
Found: C, 62.17; H, 5.96; N 7.59.
4.6.3. Diethyl 2-tert-butoxycarbonylamino-2-[1-hydroxy-
5-(2-methoxyphenyl)-pyrazol-4-yl]-malonate (13c). From
12c. FC (petroleum ether/EtOAc 2:1!2:1). Yield 98%.
Colorless crystals. Mp 147±1488C. Rf 0.32 (petroleum
1
ether/EtOAc 1:1). H NMR (CDCl3) d 7.65 (s, 1H), 7.43
(dd, Jˆ7.5, 1.7 Hz, 1H), 7.24 (d, Jˆ7.3 Hz, 1H), 7.03 (dt,
Jˆ7.5, 0.7 Hz, 1H), 6.96 (d, Jˆ8.3 Hz, 1H), 6.02 (s, 1H),
4.10 (m, 3H), 3.88 (m, 1H), 3.78 (s, 3H), 1.31 (s, 9H), 1.17
(t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 166.7, 166.4, 157.3,
153.4, 132.2, 132.1, 130.9, 129.9, 120.1, 116.1, 113.0,
110.5, 80.0, 63.6, 62.4, 62.2, 55.1, 27.9, 13.6. Anal. calcd
for C22H29N3O8: C, 57.01; H, 6.31; N 9.07. Found: C, 56.84;
H, 6.16; N 8.85.
4.5.4. Diethyl 2-[1-benzyloxy-4-(thien-2-yl)-pyrazol-5-
yl]-2-tert-butoxycarbonylamino-malonate (16d). From
15d. FC (petroleum ether/EtOAc 5:1!4:1). Yield 65%.
Colorless crystals. Mp 1408C (petroleum ether/EtOAc). Rf

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1603
4.6.4. Diethyl 2-tert-butoxycarbonylamino-2-[5-(2-¯uoro-
phenyl)-1-hydroxy-pyrazol-4-yl]-malonate (13d). From
12d. FC (petroleum ether/EtOAc 2:1!1:1). Yield 100%.
Colorless crystals. Mp 154±1558C. Rf 0.46 (petroleum
Jˆ10.7, 7.1 Hz, 2H), 2.35 (s, 3H), 1.50 (s, 9H), 1.07 (t,
Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 164.9, 156.8, 136.7,
130.7, 129.9, 128.9, 128.4, 126.2, 120.4, 82.5, 63.8, 63.5,
27.9, 20.9, 13.2. Anal. calcd for C22H29N3O7: C, 59.05; H,
6.53; N, 9.39. Found: C, 58.81; H, 6.37; N 9.25.
1
ether/EtOAc 1:1). H NMR (CDCl3) d 7.79 (s, 1H), 7.46
(m, 1H), 7.34 (br dt, Jˆ7.5, 1.5 Hz, 1H), 7.23 (dt, Jˆ7.5,
1.0 Hz, 1H), 7.16 (t, 1H), 5.99 (s, 1H), 4.20 (m, 2H), 4.05
(m, 1H), 1.27 (s, 9H), 1.19 (t, Jˆ7.1 Hz, 6H). 13C NMR
(CDCl3) d 166.6, 160.3 (d, Jˆ250 Hz), 153.4, 132.9,
132.8 (d, Jˆ1.9 Hz), 131.4, 127.6, 123.8 (d, Jˆ3.6 Hz),
115.9, 115.4 (d, Jˆ21 Hz), 113.5, 80.0, 63.6, 62.7, 27.9,
13.6. Anal. calcd for C21H26FN3O7: C, 55.87; H, 5.81; N
9.31. Found: C, 56.14; H, 5.84; N 9.31.
4.6.10. Diethyl 2-tert-butoxycarbonylamino-2-[1-hydroxy-
4-(4-methoxyphenyl)-pyrazol-5-yl]-malonate (17b). From
16b. FC (petroleum ether/EtOAc 2:1!1:2). Yield 96 %.
Off-white crystals (petroleum ether/EtOAc). Mp 149±
1508C. Rf 0.27 (petroleum ether/EtOAc 2:1). 1H NMR
(CDCl3) d 11.53 (br s, 1H), 7.27 (s, 1H), 7.18 (d,
Jˆ8.7 Hz, 2H), 6.90 (d, Jˆ8.7 Hz, 2H), 6.74 (s, 1H), 4.10
(dq, Jˆ10.7, 7.1 Hz, 2H), 3.81 (s, 3H), 3.71 (dq, Jˆ10.7,
7.1 Hz, 2H), 1.49 (s, 9H), 1.09 (t, Jˆ7.1 Hz, 6H). 13C NMR
(CDCl3) d 165.0, 158.8, 156.9, 130.8, 129.8, 126.2, 125.4,
120.1, 113.8, 82.6, 64.0, 63.6, 55.2, 28.0, 13.4. Anal. calcd
for C22H29N3O8: C, 57.01; H, 6.31; N 9.07. Found: C, 56.93;
H, 6.12; N 9.26.
4.6.5. Diethyl 2-tert-butoxycarbonylamino-2-[1-hydroxy-
5-(thien-2-yl)-pyrazol-4-yl]-malonate (13e). From 12e.
FC (petroleum ether/EtOAc 2:1!1:1). Yield 98%. Color-
less crystals. Mp decomposition abobe 698C. Rf 0.55
1
(petroleum ether/EtOAc 1:1). H NMR (CDCl3) d 7.79 (s,
1H), 7.52 (dd, Jˆ5.1, 1.2 Hz, 1H), 7.18 (dd, Jˆ3.6, 1.2 Hz,
1H), 7.12 (dd, Jˆ5.1, 3.6 Hz, 1H), 6.1 (s, 1H), 4.20 (dq,
Jˆ10.7, 7.1 Hz, 2H), 4.05 (dq, Jˆ10.7, 7.1 Hz, 2H), 1.59
(s, 9H), 1.20 (t, Jˆ1.2 Hz, 6H). 13C NMR (CDCl3) d 166.7,
153.6, 132.8, 131.1, 128.6, 127.2, 126.7, 126.2, 114.2, 80.0,
63.6, 62.8, 27.9, 13.6, one signal missing. Anal. calcd for
C19H25N3O7S: C, 51.93; H, 5.73; N, 9.56. Found: C, 52.18;
H, 5.73; N 9.28.
4.6.11. Diethyl 2-tert-butoxycarbonylamino-2-[4-(2-
¯uorophenyl)-1-hydroxypyrazol-5-yl]-malonate (17c).
From 16c. FC (petroleum ether/EtOAc 2:1 (1:1). Yield
99%. Colorless crystals. Mp decomposition above 1808C.
1
Rf 0.40 (petroleum ether/EtOAc 1:1). H NMR (CDCl3) d
7.34 (d, Jˆ1.4 Hz, 1H), 7.32±7.08 (m, 4H), 6.71 (s, 1H),
4.10 (dq, Jˆ10.7, 7.1 Hz, 2H), 3.69 (dq, Jˆ10.7, 7.1 Hz,
2H), 1.49 (s, 9H), 1.11 (t, Jˆ7.1 Hz, 6H). 13C NMR
(CDCl3) d 164.7, 159.7 (d, Jˆ248 Hz), 156.9, 132.0 (d,
Jˆ2.5 Hz), 131.6 (d, Jˆ2.8 Hz), 129.3 (d, Jˆ7.9 Hz),
127.1, 123.9 (d, Jˆ3.7 Hz), 120.5 (d, Jˆ16 Hz), 115.6 (d,
Jˆ22 Hz), 113.3, 82.7, 64.04, 63.5, 28.1, 13.3. Anal. calcd
for C21H26FN3O7: C, 55.87; H, 5.81; N 9.31. Found: C,
55.91; H, 5.74; N 9.21.
4.6.6. Diethyl 2-tert-butoxycarbonylamino-2-(1-hydroxy-
5-methylpyrazol-4-yl)-malonate (13g). From 12g. Yield
97%. Colorless crystals. Mp 108±1108C. 1H NMR
(CDCl3) d 7.42 (s, 1H), 6.27 (s, 1H), 4.31 (br dq, Jˆ10.7,
7.1 Hz, 2H), 4.22 (dq, Jˆ10.7, 7.1 Hz, 2H), 2.31 (s, 3H),
1.41 (s, 9H), 1.26 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d
167.0, 153.8, 130.5, 130.4, 112.1, 80.6, 64.1, 62.7, 28.0,
13.8, 9.6. Anal. calcd for C16H25N3O7: C, 51.74; H, 6.78;
N 11.31. Found: C, 52.03; H, 6.84; N 11.24.
4.6.12. Diethyl 2-tert-butoxycarbonylamino-2-[1-hy-
droxy-4-(thien-2-yl)-pyrazol-5-yl]-malonate (17d). From
16d. FC (petroleum ether/EtOAc 2:1!1:1). Yield 98 %.
Pale yellow crystals. Mp 1508C. Rf 0.31 (petroleum ether/
4.6.7. Diethyl 2-tert-butoxycarbonylamino-2-(1-hydroxy-
5-methylsulfanylpyrazol-4-yl)-malonate (13h). From
12h. Yield 92%. Colorless oil. H NMR (CDCl3) d 7.76
1
EtOAc 2:1). H NMR (CDCl3) d 7.33 (s, 1H), 7.24 (dd,
1
Jˆ5.2, 1.1 Hz, 1H), 7.00 (dd, Jˆ5.2, 3.5 Hz, 1H), 6.80
(dd, Jˆ3.5, 1.1 Hz, 1H), 6.70 (s, 1H), 4.17 (dq, Jˆ10.7,
7.1 Hz, 2H), 3.83 (dq, Jˆ10.7, 7.1 Hz, 2H), 1.48 (s, 9H),
1.13 (t, Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 164.7, 156.9,
133.6, 131.7, 127.4, 127.1, 126.4, 125.3, 113.1, 82.7, 64.1,
63.5, 28.0, 13.4. Anal. calcd for C19H25N3O7S: C, 51.93; H,
5.73; N, 9.56. Found: C, 51.82; H, 5.64; N 9.51.
(s, 1H), 6.43 (s, 1H), 4.34 (dq, Jˆ10.7, 7.1 Hz, 2H), 4.22
(dq, Jˆ10.7, 7.1 Hz, 2H), 2.35 (s, 3H), 1.38 (s, 9H), 1.26 (t,
Jˆ7.1 Hz, 6H). 13C NMR (CDCl3) d 166.6, 153.7, 132.4,
126.3, 118.0, 80.4, 63.8, 62.8, 28.0, 17.5, 13.6. HRMS
[M1H]1 calcd for C16H26N3O7S: 404.1491. Found:
404.1503.
4.6.8. Diethyl 2-tert-butoxycarbonylamino-2-(5-chloro-1-
hydroxypyrazol-4-yl)-malonate (13i). From 12i. Yield
95%. Colorless oil. H NMR (CDCl3) d 7.74 (s, 1H), 6.37
4.7. General method for the deprotection of the amino
acid functionality. Synthesis of 14a±e, 14g±i and 18a±d
1
(s, 1H), 4.28 (m, 4H), 1.40 (s, 9H), 1.26 (t, Jˆ7.1 Hz, 6H).
13C NMR (CDCl3) d 166.0, 153.6, 132.9, 120.6, 111.2, 80.5,
62.9, 60.3, 27.8, 13.5. HRMS [M1H]1 calcd for
C15H23ClN3O7: 392.1224. Found: 392.1246.
To a solution of 13a±e, 13g±i, 17a±d (0.5 mmol) in THF
(4 mL) was added a 2.5 M aq. LiOH (3.5 mL, 9 mmol). The
mixture was vigorously stirred at rt for 4 h in case of
compounds 13a±e and 13g±i, and at 508C for 12 h in case
of compounds 17a±d. The solution was cooled to 08C and
1 M HCl was added dropwise until pH 2. The mixture was
extracted with EtOAc (3£20 mL), the combined organic
layers were washed with brine (10 mL), dried over
Na2SO4, ®ltered and evaporated to dryness. Decarboxyl-
ation and N-Boc deprotection were accomplished by stirring
the residue in 2 M HCl at 608C for 30 min. The hydro-
chloride salts were obtained after removal of the HCl
4.6.9. Diethyl 2-tert-butoxycarbonylamino-2-[1-hydroxy-
4-(4-tolyl)-pyrazol-5-yl]-malonate (17a). From 16a. FC
(petroleum ether/EtOAc 3:1!1:1). Yield 99%. Colorless
crystals. Mp 1508C. Rf 0.37 (petroleum ether/EtOAc 1:1).
IR (KBr) 3364, 2983, 1758, 1725, 1675, 1498, 1290, 1202,
1160 cm21. 1H NMR (CDCl3) d 7.29 (s, 1H), 7.15 (m, 4H),
6.74 (br s, 1H), 4.10 (dq, Jˆ10.7, 7.1 Hz, 2H), 3.66 (br dq,

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P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1604
under reduced pressure (unless otherwise stated). Where
possible, the crystals were triturated with Et2O.
formed was ®ltered washing with ice cold water. Pale green
crystals (147 mg, 94%). Recrystallization (MeOH/EtOAc)
gave colorless crystals. Mp.1908C. 1H NMR (DMSO-d6) d
8.76 (br s, 3H), 8.41 (d, Jˆ8.8 Hz, 2H), 7.94 (d, Jˆ8.8 Hz,
2H), 7.54 (s, 1H), 4.78 (s, 1H). 13C NMR (CD3OD) d 170.5,
149.9, 134.7, 134.4, 132.3, 131.7, 125.1, 111.7, 54.8. HRMS
[M2HCl±H]2 calcd for C11H9N4O5: 227.0573. Found:
227.0598.
4.7.1. Hydrochloride salt of amino-[1-hydroxy-5-(4-
tolyl)-pyrazol-4-yl]-acetic acid (14a). From 13a. Precipita-
tion of the product occurred by cooling the solution to rt.
The precipitate was ®ltered and washed with cold water.
Yield 96%. Colorless crystals. Mp decomposition above
1
1808C. H NMR (DMSO-d6) d 8.84 (br s, 3H), 7.56 (d,
Jˆ8.0 Hz, 2H), 7.46 (s, 1H), 7.36 (d, Jˆ8.0 Hz, 2H), 4.62
(br s, 1H), 2.38 (s, 3H). 13C NMR (DMSO-d6) d 170.8,
139.8, 135.5, 131.1, 130.7, 130.4, 125.0, 110.4, 48.4, 21.9.
HRMS [M2HCl±H]2 calcd for C12H12N3O3: 246.0879.
Found: 246.0915.
4.7.7. Hydrochloride salt of amino-(1-hydroxy-5-methyl-
pyrazol-4-yl)-acetic acid (14g). From 13g. The crude
product was triturated twice with Et2O, to afford pale yellow
sticky crystals. The product was very hygroscopic and
turned quickly into a wax in contact with air. Yield 81%.
1H NMR (DMSO-d6) d 8.76 (br s, 3H), 7.17 (s, 1H), 4.89 (br
s, 1H), 2.20 (s, 3H). 13C NMR (DMSO-d6) d 169.9, 131.2,
130.1, 108.4, 47.5, 8.3. HRMS [M2HCl±H]2 calcd for
C6H8N3O3: 170.0566: Found: 170.0637.
4.7.2. Hydrochloride salt of amino-[1-hydroxy-5-(4-
methoxyphenyl)-pyrazol-4-yl]-acetic acid (14b). From
13b. Yield 96%. Colorless crystals (MeOH/EtOAc). Mp
1
decomposition above 1758C. H NMR (DMSO-d6) d 8.71
(br s, 3H), 7.58 (d, Jˆ8.8 Hz, 2H), 7.43 (s, 1H), 7.12 (d,
Jˆ8.8 Hz, 2H), 4.54 (br s, 1H), 3.83 (s, 3H). 13C NMR
(DMSO-d6) d 170.8, 160.9, 135.3, 132.1, 131.0, 119.9,
115.3, 110.1, 56.3, 48.5. HRMS [M2HCl±H]2 calcd for
C12H12N3O4: 262.0828. Found: 262.0856.
4.7.8. Hydrochloride salt of amino-(1-hydroxy-5-methyl-
sulfanylpyrazol-4-yl)-acetic acid (14h). From 13h. The
crude product was triturated twice with Et2O, to afford
off-white crystals. Yield 89%. Mp decomposition above
1
1708C. H NMR (DMSO-d6) d 8.74 (br s, 3H), 7.39 (s,
1H), 4.89 (s, 1H), 2.36 (s, 3H). 13C NMR (DMSO-d6) d
169.5, 130.4, 127.6, 115.2, 47.8, 18.0. HRMS [M2HCl±
H]2 calcd for C6H8N3O3S: 202.0286. Found: 202.0318.
4.7.3. Hydrochloride salt of amino-[1-hydroxy-5-(2-
methoxyphenyl)-pyrazol-4-yl]-acetic acid (14c). From
13c. Yield 86%. Colorless crystals (MeOH/EtOAc).
Mp.2008C. 1H NMR (DMSO-d6) d 8.70 (br s, 3H),
7.50±7.40 (m, 2H), 7.40 (s, 1H), 7.15 (d, Jˆ8.8 Hz, 1H),
7.06 (dt, Jˆ7.4, 0.8 Hz, 1H), 4.50 (q, Jˆ5.1 Hz, 1H), 3.75
(s, 3H). 13C NMR (CD3OD) d 170.8, 158.9, 134.2, 133.4,
132.9, 131.3, 121.9, 116.5, 112.8, 111.6, 56.2, 49.5. HRMS
[M2HCl±H]2 calcd for C12H12N3O4: 262.0828. Found:
262.0859.
4.7.9. Hydrochloride salt of amino-(5-chloro-1-hydroxy-
pyrazol-4-yl)-acetic acid (14i). From 13i. The crude
product was triturated twice with Et2O, to afford colorless
crystals. Yield 84%. The product was very hygroscopic and
1
turned quickly into a wax in contact with air. H NMR
(DMSO-d6) d 8.83 (br s, 3H), 7.46 (s, 1H), 4.89 (br q,
Jˆ5.1 Hz, 1H). 13C NMR (DMSO-d6) d 168.8, 131.2,
120.2, 108.4, 46.9. HRMS [M2HCl±H]2 calcd for
C5H5ClN3O3: 190.0020. Found: 190.0075.
4.7.4. Hydrochloride salt of amino-[5-(2-¯uorophenyl)-1-
hydroxypyrazol-4-yl]-acetic acid (14d). From 13d. Yield
83%. Pale green crystals. Mp decomposition above 1778C.
1H NMR (DMSO-d6) d 8.86 (br d, Jˆ4.7 Hz, 3H), 7.69±
7.55 (m, 2H), 7.50 (s, 1H), 7.43±7.35 (m, 2H), 4.54 (br q,
Jˆ5.1 Hz, 1H). 13C NMR (DMSO-d6) d 170.5, 160.7 (d,
Jˆ250 Hz), 133.3, 133.1 (d, Jˆ8.0 Hz), 131.4, 130.0,
125.7 (d, Jˆ3.5 Hz), 117.1 (d, Jˆ21 Hz), 115.8 (d,
Jˆ15 Hz), 111.5, 47.5. HRMS [M2HCl±H]2 calcd for
C11H9FN3O3: 250.0628. Found: 250.0658.
4.7.10. Hydrochloride salt of amino-[1-hydroxy-4-(4-
tolyl)-pyrazol-5-yl]-acetic acid (18a). From 17a. Yield
87%. Pale yellow crystals were obtained after removal of
HCl and trituration with Et2O. Mp decomposition above
1
1608C. H NMR (DMSO-d6) d 8.99 (br s, 3H), 7.41 (s,
1H), 7.37 (d, Jˆ8.1 Hz, 2H), 7.25 (d, Jˆ8.1 Hz, 2H), 5.21
(s, 1H), 2.33 (s, 3H). 13C NMR (DMSO-d6) d 167.3, 136.6,
130.3, 129.6, 128.9, 128.0, 124.1, 121.0, 45.8, 20.7. HRMS
[M2HCl±H]2 calcd for C12H12N3O3: 246.0879. Found:
246.0911.
4.7.5. Hydrochloride salt of amino-[1-hydroxy-5-(thien-
2-yl)-pyrazol-4-yl]-acetic acid (14e). From 13e. Yield
89%. Thick oil that slowly crystallized on standing. Color-
less crystals (MeOH/EtOAc). Mp decomposition above
4.7.11. Hydrochloride salt of amino-[1-hydroxy-4-(4-
methoxyphenyl)-pyrazol-5-yl]-acetic acid (18b). From
17b. Yield 80%. Pale yellow crystals were obtained after
evaporation of HCl and trituration with Et2O. Mp decom-
position above 1588C. 1H NMR (CD3OD) d 7.39 (d,
Jˆ8.5 Hz, 2H), 7.35 (s, 1H), 7.01 (d, Jˆ8.5 Hz, 2H), 5.34
(s, 1H), 3.81 (s, 3H). 13C NMR (CD3OD) d 166.9, 159.6,
130.5, 129.3, 123.6, 123.1, 121.8, 114.2, 54.4, 46.1. HRMS
[M2HCl±H]2 calcd for C12H12N3O4: 262.0828. Found:
262.0860.
1
1858C. H NMR (DMSO-d6) d 8.92 (br s, 3H), 7.87 (dd,
Jˆ5.1, 1.1 Hz, 1H), 7.63 (dd, Jˆ3.7, 1.1 Hz, 1H), 7.53 (s,
1H), 7.29 (dd, Jˆ5.1, 3.7 Hz, 1H), 4.91 (br q, Jˆ4.8 Hz,
1H). 13C NMR (DMSO-d6) d 169.7, 154.4, 130.4, 129.3,
128.7, 127.7, 126.8, 109.7, 47.6. Anal. calcd for
C9H9N3O3S. HCl: C, 39.21; H, 3.66; N, 15.24. Found: C,
39.97; H, 3.97; N 14.41.
4.7.6. Hydrochloride salt of amino-[1-hydroxy-5-(4-
nitrophenyl)-pyrazol-4-yl]-acetic
(284 mg, 0.5 mmol) was re¯uxed in 6N HCl (4 mL) for
12 h. The solution was cooled to rt, and the precipitate so
acid
(14f).
12f
4.7.12. Hydrochloride salt of amino-[4-(2-¯uorophenyl)-
1-hydroxypyrazol-5-yl]-acetic acid (18c). From 17c. Yield
97%. Pale yellow crystals were obtained after evaporation

Â
P. Calõ, M. Begtrup / Tetrahedron 58 (2002) 1595±1605
1605
6. Williams, D. H.; Waltho, J. P. Biochem. Pharmacol. 1988, 37,
133±141.
of HCl and trituration with Et2O. Mp decomposition above
1558C. H NMR (DMSO-d6) d 8.95 (br s, 3H), 7.53 (dt,
1
7. Reuther, W.; Baus, U. Liebigs Ann. Chem. 1995, 1563±1566.
8. Wenckens, M.; Begtrup. M. Unpublished results.
9. Stenbùl, T. B.; Ullmann, P.; Morel, S.; Eriksen, B. L.; Felding,
J.; Kromann, H.; Hermit, M. B.; Greenwood, J. R.; BrauÈner-
Osborne, H.; Madsen, U.; Krogsgaard-Larsen, P.; Begtrup,
M.; Vedsù, P. J. Med. Chem. 2002, 45, 19±31.
Jˆ7.7, 1.7 Hz, 1H), 7.41 (m, 2H), 7.29 (m, 2H), 5.15 (s,
1H). 13C NMR (DMSO-d6) d 167.2, 159.4 (d, Jˆ245 Hz),
131.9 (d, Jˆ3.5 Hz), 131.3 (d, Jˆ2.8 Hz), 129.7 (d, Jˆ
8.0 Hz), 125.6, 125.0 (d, Jˆ3.4 Hz), 119.3 (d, Jˆ
14.8 Hz), 116.1 (d, Jˆ22 Hz), 114.2, 46.1. HRMS
[M2HCl±H]2 calcd for C11H9FN3O3: 250.0628. Found:
250.0658.
10. Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.; Vedsù,
P.; Begtrup, M. J. Org. Chem. 1999, 64, 4196±4198.
11. Vedsù, P.; Begtrup, M. J. Org. Chem. 1995, 60, 4995±4998.
12. Kristensen, J.; Begtrup, M.; Vedsù, P. Synthesis 1998, 1604±
1608.
4.7.13. Hydrochloride salt of amino-[1-hydroxy-4-(thien-
2-yl)-pyrazol-5-yl]-acetic acid (18d). From 17d. Yield
74%. The product was obtained after removal of the HCl
1
Â
13. Calõ, P.; Begtrup, M. Synthesis 2002, 1, 63±66.
as a pale yelllow thick oil. H NMR (CD3OD) d 7.44 (d,
14. For recent examples of malonates hydrolysis-decarboxylation,
see: (a) Falch, E.; Brehm, L.; Mikkelsen, I.; Johansen, T. N.;
Skjñrbñk, N.; Nielsen, B.; Stensbùl, T. B.; Ebert, B.;
Krogsgaard-Larsen, P. J. Med. Chem. 1998, 41, 2513±2523.
(b) Madsen, U.; Bang-Andersen, B.; Brehm, L.; Christensen,
I. T.; Ebert, B.; Kristoffersen, I. T. S.; Lang, Y.; Krogsgaard-
Larsen, P. J. Med. Chem. 1996, 39, 1682±1691. (c) Skjñrbñk,
N.; Brehm, L.; Johansen, T. N.; Hansen, L. M.; Nielsen, B.;
Ebert, B.; Sùby, K. K.; Stensbùl, T. B.; Falch, E.; Krogsgaard-
Larsen, P. Bioorg. Med. Chem. 1998, 6, 119±131.
15. Kocienski, P. J. Protecting Groups; Georg Thieme Verlag:
Stuttgart, 1994.
Jˆ4.9 Hz, 1H), 7.41 (s, 1H), 7.19 (d, Jˆ3.3 Hz, 1H), 7.12
(dd, Jˆ4.9, 3.3 Hz, 1H), 5.44 (s, 1H). 13C NMR (DMSO-d6)
d 168.0, 133.5, 132.3, 129.2, 127.2, 126.9, 124.8, 116.5,
47.5. The product was only 95% pure according to NMR.
Acknowledgements
This work was supported by Leo Pharmaceuticals,
Copenhagen, Denmark and the Danish Natural Science
Research Council. We also thanks Dr N. Rastrup-Andersen
and Mr J. Henriksen of the Analytical Department of Leo
Pharmaceuticals for performing HRMS and IR analysis.
16. Ho, T. L. Tetrahedron 1985, 41, 1±86.
17. Balle, T.; Vedsù, P.; Begtrup, M. J. Org. Chem. 1999, 64,
5366±5370.
18. Pawlas, J.; Vedsù, P.; Jacobsen, P.; Huusfeldt, P. O.; Begtrup,
M. J. Org. Chem. 2000, 65, 9001±9006.
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