Novel 5-substituted 1-pyrazolol analogues of ibotenic acid: Synthesis and pharmacology at glutamate receptors

Article abstract of DOI:10.1016/j.bmc.2007.02.047

5-Substituted 1-pyrazolol analogues of ibotenic acid have been synthesized and pharmacologically characterized on ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs). The syntheses involved introduction of bromide, alkyls, phenyl and aryla

Full text of DOI:10.1016/j.bmc.2007.02.047

Bioorganic & Medicinal Chemistry 15 (2007) 3524–3538
Novel 5-substituted 1-pyrazolol analogues of ibotenic acid:
Synthesis and pharmacology at glutamate receptors
Charlotte G. Jørgensen,a Hans Bra¨uner-Osborne,a Birgitte Nielsen,a Jan Kehler,b
Rasmus P. Clausen,a Povl Krogsgaard-Larsena and Ulf Madsena,*
aThe Danish University of Pharmaceutical Sciences, Department of Medicinal Chemistry, 2100 Copenhagen, Denmark
bH. Lundbeck A/S, 2500 Valby, Copenhagen, Denmark
Received 3 May 2006; revised 23 November 2006; accepted 26 February 2007
Available online 3 March 2007
Abstract—5-Substituted 1-pyrazolol analogues of ibotenic acid have been synthesized and pharmacologically characterized on ion-
otropic and metabotropic glutamate receptors (iGluRs and mGluRs). The syntheses involved introduction of bromide, alkyls, phe-
nyl and arylalkyls in the 5-position of 1-benzyloxypyrazole leading to 5-substituted (RS)-2-amino-(1-hydroxy-4-pyrazolyl)acetic
acids (5a–l). The pharmacological activities of the synthesized analogues ranged from the 5-cyclopropylmethyl analogue (5f) with
weak but selective affinity for NMDA receptors (IC50 = 35 lM), over the 5-n-propyl analogue (5c), which was a selective mGluR2
agonist (EC50 = 72 lM), to the 5-cyclohexylmethyl analogue (5g), which was a selective mGluR2 antagonist (Ki = 32 lM), and the
5-phenylethyl analogue (5j), which was a weak but apparently selective mGluR1 antagonist (Ki = 230 lM). This series of com-
pounds afforded GluR ligands with a broad spectrum of pharmacological profiles, and showing potential for development of
new compounds with subtype-selective activities at various GluRs.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
mGluR5), Group II (mGluR2 and mGluR3) and Group
III (mGluR4, mGluR6, mGluR7 and mGluR8).4
(S)-Glutamic acid (Glu) is the main excitatory neuro-
transmitter in the central nervous system and is in-
volved in many important physiological and
pathophysiological functions.1–4 The action of Glu is
mediated by activation of two groups of receptors,
the ionotropic and metabotropic Glu receptors (iGluRs
and mGluRs).
Several heterocyclic amino acids, which are mimicking
Glu structurally and pharmacologically, have been iso-
lated from nature or synthesized in the laboratory.
Ibotenic acid ((RS)-2-amino-(3-hydroxy-5-isoxazol-
yl)acetic acid, Ibo) isolated from Amanita muscaria
and the synthetic analogue (S)-AMPA both contain a
3-isoxazolol moiety, which is acidic and mimics the dis-
tal carboxyl group in Glu (Fig. 1).5–8
The iGluR family is divided according to the agonists
that were originally identified to activate the receptors
selectively.2 The compounds are N-methyl-D-aspartic
acid (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-4-
isoxazolyl)propionic acid ((S)-AMPA) and kainic acid
(KA).2
The 1-pyrazolols 1–4 are analogues of Ibo and (S)-
AMPA and have shown interesting pharmacological
activity at both iGluRs and mGluRs (Fig. 1).8,9
Compounds 1 and 3 are equipotent agonists and com-
pound 2 is a partial agonist at mGluR2 receptors,
whereas 1 is a weak agonist and 2 and 3 weak antag-
onists at NMDA receptor subtypes.9 Based on these re-
sults, four groups of derivatives were selected in order
to gain further knowledge of the structure–activity rela-
tionship of the compounds: the bromo analogue (5a),
the alkyl analogues (5b–e), the more bulky alkyl ana-
logues (5f, g) and the phenylalkyl analogues (5h–l)
(Fig. 2).
The eight mGluRs are separated into three groups
according to protein sequence homology and signal
transduction pathways, Group
I
(mGluR1 and
Keywords: Synthesis; Pyrazole; 1-Pyrazolol; Ibotenic acid; Amino
acids; Ionotropic and metabotropic glutamate receptor ligands.
*
Corresponding author. Fax: +45 35306040; e-mail: um@dfuni.dk
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.02.047

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
OH
OBn
3525
OBn
OBn
R
R
a
b
N
N
N
H2N
HO
O
N
N
N
8b-g,i-l
7b-g,i,k,l
6
O
c
b
Glu
O
OH
OBn
I
OBn
HO
Ph
OBn
Bn
OH
OH
OH
d
e
N
N
N
H2N
N
N
H2N
HO
N
N
N
O
O
8h
9
7j
O
Ibo
(S)-AMPA
8b-g,i-l:
b R = CH2CH3
c R = CH2CH2CH3
d R = CH2CH2CH2CH3
e R = CH2CH2CH2CH2CH3
f R = CH2-cyclo-Pr
g R = CH2-cyclo-Hex
i R = CH2Ph
7b-g,i,k,l:
O
b R = CHOHCH3
c R = CHOHCH2CH3
HO
OH
R
d R = CHOHCH2CH2CH3
N
N
H2N
e R = CHOHCH2CH2CH2CH3
f R = CHOH-cyclo-Pr
g R = CHOH-cyclo-Hex
i R = CHOHPh
H2N
HO
N
N
O
j R = CH2CH2Ph
k R = CH2CH2CH2Ph
l R = CHPh2
k R = CHOHCH2CH2Ph
l R = COHPh2
4
1 R = H
2 R = Cl
3 R = CH3
Scheme 1. Reagents: (a) n-BuLi, aldehyde or ketone, THF; (b) Et3SiH,
TFA, CH2Cl2; (c) n-BuLi, I2, THF; (d) PhB(OH)2, PdCl2(PPh3)2,
K2CO3 (aq), DMF; (e) i-PrMgCl, PhCH2CHO, THF (yields in Table 1).
Figure 1. Structures of Glu, Ibo, (S)-AMPA, three 1-pyrazolol
analogues of Ibo (1–3) and the 1-pyrazolol analogue of AMPA (4).
5a R = Br
5b R = CH2CH3
LDA/tetrabromomethane or iodine monochloride,
respectively (Scheme 2 and Table 1).
5c R = CH2CH2CH3
5d R = CH2CH2CH2CH3
5e R = CH2CH2CH2CH2CH3
Derivatization of the 4-position of 1-benzyloxypyrazole
can be achieved using an iodine–magnesium exchange
reaction of 4-iodo compound, 9, followed by addition
of an electrophile (Scheme 3).13,14 Recurrent problems
were encountered concerning storage of the ketimine,
2-(N-tert-butoxycarbonylimino)malonic acid diethyl
ester, used previously for the synthesis of amino acids
1–3,15,16 and the purification of the resulting protected
amino acids. Therefore, the aldimine, (N-tert-butoxycar-
bonylimino)acetic acid ethyl ester (11), was used instead.
The aldimine, 11, was prepared from a-bromoglycine
using a scavenger amine, morpholinomethyl-polysty-
rene.17 The freshly prepared aldimine, 11, was kept in
solution and added to the reactors with the magnesium
halides of compounds 9 and 10a–l. The protected amino
acids, 12 and 13a–l, were achieved in moderate yields
(Scheme 3 and Table 1).
R
OH
N
5f R = CH2-cyclo-Pr
5g R = CH2-cyclo-Hex
H2N
N
HOOC
5h R = Ph
5i R = CH2Ph
5j R = CH2CH2Ph
5k R = CH2CH2CH2Ph
5l R = CHPh2
Figure 2. Structures of new 1-pyrazolol analogues (5a–l).
2. Chemistry
The 5-position of 1-benzyloxypyrazole (6) has been met-
allated with N,N,N0,N0-tetramethylethylenediamine
(TMEDA) and n-BuLi and reacted with a variety of
electrophiles, such as D2O, MeI, DMF, C2Cl6, CBr4,
Br2 and I2.10 We took advantage of this reactivity and
synthesized a variety of alcohols 7b–g, i, k–l using
n-BuLi (Scheme 1). The use of TMEDA resulted in low-
er yields of alcohols. The alcohols were reduced by ionic
hydrogenation11,12 to the alkyls 8b–g, i–l using trifluoro-
acetic acid and triethylsilane. The synthesis of phenyl-
For compounds 12 and 13a–e, g–l, the deprotection was
performed in two steps using basic hydrolysis and acidic
treatment to generate the amino acids 5a–e, g–l and 2.
The amino acids were obtained as zwitterions after
adjustment of pH. In the case of the cyclopropylmethyl
analogue (5f), which was unstable upon hydrogen bro-
mide treatment, a previously described three-step depro-
tection16 was employed starting with 13f (Scheme 3 and
Table 1).
ethylalcohol
(7j)
posed
problems
due
to
polymerization of phenylacetaldehyde. Therefore, the
5-iodo compound (9) was prepared and treated with
i-PrMgCl and phenylacetaldehyde to give alcohol 7j.
The phenyl 8h was obtained in high yields using stan-
dard Suzuki conditions (Scheme 1 and Table 1).
Iodination of the 4-position of compounds 8b–l was
achieved in high yields using iodine monochloride under
neutral conditions (Scheme 2).13 The dihalogenated
compound (10a) was synthesized from 9 or 8a using
3. pKa values
The pKa values of 1-pyrazolol and derivatives 5b, e and
g were determined by potentiometric titration (Table 2).

3526
C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
Table 1. Isolated yields (%) of intermediates and amino acids 2 and 5a–la
Compound.
Substituent in
5-position
Alcohol
Substituent
(halogen, alkyl, aryl)
Iodideb
Protected
amino acid
Deprotected amino
acid 1. LiOHb/2. HBr
2
Hydrogen
Bromine
Ethyl
—
—
90
88
85
80
84
83
—
76
57d
63
77
—
81c
69
29
69
73
65
70
78e
77
71
65
46
—
42
33
64
44
48
46
48
51
74
60
49
43
46
98/35
99/66
5a
5b
5c
5d
5e
5f
5g
5h
5i
21
98
86/58
83/50
Propyl
Butyl
Pentyl
97
100
100
100
100
97
100/36
100/41
69/100/89d
100/15
88/60
Cyclopropylmethyl
Cyclohexylmethyl
Phenyl
Benzyl
97
96
98/54
76/49
5j
Phenylethyl
Phenylpropyl
Benzhydryl
5k
5l
99
97
80/25
74/60
a Reactions described in Schemes 1–3.
b Crude yields.
c From 1-benzyloxypyrazole (6).
d Used other protocol: 1. Pd/C/H2, 69%, 2. LiOH, 100% (crude yield), 3. HCl, 89%.
e From 1-benzyloxy-5-iodo-pyrazole (9).
R
R
Table 2. pKa Values of heterocyclic hydroxy moieties and amino
groups determined by potentiometric titrationa
OBn
OBn
N
N
a
N
N
I
OH
NH2
8a-l
a
10b-l
1-Pyrazolol
6.1 (6.3)b
5.85
5.04
6.0
—
—
3-Isoxazololc
Ibod
5b (Ethyl)
OBn
Br
OBn
8.16
9.6
N
b
N
N
N
I
I
5e (Pentyl)
6.2
6.1
9.5
9.4
9
10a
5g (Cyclohexylmethyl)
4, 1-pyrazolol-AMPAe
AMPAf
5.89
5.12
9.81
10.09
a R = Br
g R = CH2-cyclo-Hex
h R = Ph
i R = CH2Ph
j R = CH2CH2Ph
k R = CH2CH2CH2Ph
l R = CHPh2
a Due to the low pKa values of the carboxyl group, the determinations
b R = CH2CH3
c R = CH2CH2CH3
of these values were not reliable.
d R = CH2CH2CH2CH3
e R = CH2CH2CH2CH2CH3
f R = CH2-cyclo-Pr
b Ref. 20.
c Ref. 18.
d Ref. 19.
e Ref. 8.
Scheme 2. Reagents: (a) I–Cl, K2CO3, CHCl3; (b) LDA, CBr4, THF
(yields in Table 1).
f Ref. 21.
The pKa values of 1-pyrazolol and 3-isoxazolol18 were
found to be of equal magnitude. With the presence of
the amino acid moiety in Ibo,19 the pKa value of 3-iso-
xazolol was lowered by almost one unit, whereas for
the 1-pyrazolol analogues 5b, e and g, the pKa value
was retained. Interestingly, the pKa value of the amino
group was approximately one and a half unit higher in
compounds 5b, e and g as compared to Ibo19. Based
on the determined pKa values of 5b, e and g, all the
1-pyrazolol analogues (5a–l) are expected to be fully
ionized at physiological pH.
OBn
R
a
BocN
N
+
N
MeOOC
11
I
9 R = H
10a-l
OBn
OH
R
R
b,c
N
N
BocHN
H2N
N
N
or d,e,f
MeOOC
HOOC
2 (R = H)
12
13a-l
5a-l
4. Pharmacology
a R = Br
g R = CH2-cyclo-Hex
h R = Ph
b R = CH2CH3
c R = CH2CH2CH3
i R = CH2Ph
All compounds were pharmacologically characterized at
native iGluRs on rat cortical membranes using
[3H]AMPA, [3H]KA and [3H]CGP39653 binding assays
representing AMPA, KA and NMDA receptors, respec-
tively (Table 3). The bromo and ethyl compounds (5a,b)
showed weak affinity for NMDA receptors and were
approximately equipotent with the chloro and methyl
d R = CH2CH2CH2CH3
e R = CH2CH2CH2CH2CH3
f R = CH2-cyclo-Pr
j R = CH2CH2Ph
k R = CH2CH2CH2Ph
l R = CHPh2
Scheme 3. Reagents: (a) i-PrMgCl, THF, then 11, THF; (b) LiOH
(aq), THF; (c) HBr (aq). For 13f–5f; (d) H2, Pd/C, MeOH; (e) LiOH
(aq), THF; (f) HCl (aq) (yields in Table 1).

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
3527
Table 3. Receptor binding affinities at native iGluRs on rat cortical membranes and pharmacological activities at cloned mGluRs expressed in CHO
cellsa,b
AMPA [3H]AMPA KA [3H]KA
NMDA [3H]CGP-
EC50 (lM) or Ki (lM)
IC50 (lM)
IC50 (lM)
39653 Ki (lM)
mGluR1a
mGluR2
mGluR4a
Glu
Ibo
0.34c
>100f
>100g
47g
>100g
>100
>100
>100
>100
>100
0.38c
22f
0.20d
13e
4.4e
13e
5.3f
43e
110e
>1000e
24g
1 (H)
>100g
>100g
>100g
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
39g,h
85g
230g
51 (67%)g,j
100g
2 (Chloro)
3 (Methyl)
5a (Bromo)
5b (Ethyl)
5c (Propyl)
5d (Butyl)
5e (Pentyl)
64g,i
>1000g
>1000g
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000g
>1000g
56g,i
25 [4.60 0.02]
32 [4.50 0.05]
>100
170 (43%)j [3.82 0.15] >1000
57 [4.25 0.05]
72 [4.17 0.09]
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>100
>100
>1000
>1000
5f (Cyclopropylmethyl) >100
5g (Cyclohexylmethyl) >100
35 [4.47 0.04]
>100
>100
32 [4.50 0.03]
180 [3.75 0.03]
120 [3.93 0.08]
5h (Phenyl)
5i (Benzyl)
>100
>100
>100
>100
>100
67 [4.18 0.03]
>100
54 [4.27 0.02]
5j (Phenylethyl)
5k (Phenylpropyl)
5l (Benzhydryl)
230 [3.71 0.16] >1000
260 [3.59 0.01] 67 [4.19 0.06]
47 [4.33 0.06] >100
>1000
>1000
a iGluRs: data are given as means of at least three to four independent experiments and the numbers in brackets indicate [pIC50 SEM] or
[pKi SEM].
b mGluRs: antagonist activity in bold. Data are given as means of at least three independent experiments and the numbers in brackets indicate
[pEC50 SEM] or [pKi SEM].
c Ref. 22.
d Ref. 9.
e Ref. 23.
f Ref. 24.
g Ref. 9.
h Agonist in functional assay see Ref. 9.
i Antagonist in functional assay see Ref. 9.
j Partial agonist, X% of max. response.
compounds (2,3). The cyclopropylmethyl analogue, 5f,
showed similar affinity, whereas the n-propyl analogue
(5c) showed no affinity. Compounds containing larger
substituents generally resulted in inactive compounds
at NMDA receptors, except for the benzyl (5i) and phe-
nylpropyl compounds (5l), which retained low affinity.
No affinity for AMPA and KA receptors was observed
for any of the compounds except for the diphenylmethyl
compound, 5l, which displayed weak affinity for KA
receptors (Table 3).
mGluR2. The bulky phenylethyl and diphenylmethyl
analogues (5j and l) had no activity at mGluR2, whereas
the phenylpropyl compound (5k) turned out to be an
antagonist almost as potent as compound 5g
(cyclohexylmethyl).
5. Conclusion
New methods were developed for introduction of alkyl
substituents in the 5-position of protected 1-pyrazolols.
Reaction of 5-metallated 1-benzyloxypyrazole with alde-
hydes and ketones gave the corresponding alcohols,
which were reduced to the respective alkanes using tri-
ethylsilane and trifluoroacetic acid. Subsequent iodin-
ation using iodine monochloride to obtain 4-iodinated
pyrazoles followed by metal–halogen exchange and
reaction with aldimine 11 afforded protected amino
acids. Deprotection in two steps gave the desired amino
acids (5a–l) in zwitterionic form.
The compounds (5a–l) were tested functionally at
mGluR1a, mGluR2 and mGluR4a representing Group
I, II and III receptors, respectively. All compounds
were inactive at mGluR1 except for compounds 5j
and 5k, which turned out to be weak antagonists. At
mGluR2, the bromo compound, 5a, was a partial
agonist, which was also observed with the chloro
compound, 2. The ethyl and propyl compounds (5b,c)
were agonists at mGluR2 and with activities compara-
ble to those of the unsubstituted analogue (1) and the
methyl analogue (3).
The pKa determination of three of the pyrazole ana-
logues (5b,e,g) gave pKa values of the 1-pyrazolol moi-
ety ranging from 6.0 to 6.2 as compared to a pKa value
of 5.04 of the 3-isoxazolol moiety in Ibo. This illustrates
the potential of using the 1-pyrazolol moiety for bioisos-
teric replacement of the distal carboxyl group of Glu.
Notably, the pKa values of the ammonium groups of
the 1-pyrazolol amino acids were approximately 1.5 unit
The butyl, pentyl, cyclopropylmethyl substituted com-
pounds (5d–f) were all inactive at mGluR2 both as ago-
nist and antagonists (at 1 mM). The more bulky
cyclohexylmethyl compound, 5g, turned out to be an
antagonist with a Ki value of 32 lM. The phenyl and
benzyl compounds (5h,i) were also antagonists at

3528
C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
higher compared to Ibo. This may be explained by the
stronger inductive effect of the neighbouring oxygen in
the isoxazole ring, compared to the more distant and
less electronegative nitrogen in the pyrazole ring. An
analogous effect can be seen in morpholine (pKa = 8.7)
compared to piperidine (pKa = 11.2).25 However, all of
the compounds are primarily tri-ionized at physiological
pH and the determined pKa values determined for 5b, e
and g show very little variation. Therefore, the observed
differences in pharmacology cannot be explained by dif-
ferences in pKa values.
Current data confirm this hypothesis since the degree
of activation decreases in the substituent series
Me > Cl > Br > Ph.
Clearly, this series of compounds shows potential for
development of ligands with multiple activities at the
various GluR sites, especially the mGluRs, some ana-
logues being selective agonists and some being selective
antagonists.
6. Experimentals
6.1. Chemistry
The pharmacological characterization of the 1-pyrazolol
compounds at iGluRs and mGluRs showed a remark-
able variation of pharmacological profiles. Compounds
containing small substituents, bromide (5a), ethyl (5b)
or cyclopropylmethyl (5f), showed weak affinities for
NMDA receptors, whereas most other analogues were
without affinity for the NMDA site. Compound 5f was
the only analogue with affinity for the NMDA receptor
site showing no activity at any of the mGluRs. Although
weak NMDA receptor affinities were observed for the
benzyl (5i) and phenylpropyl (5k) analogues, the phenyl
(5h) and phenylethyl (5j) analogues were found to be
inactive (IC50 > 100 lM).
All materials were obtained from commercial suppliers
and used without further purification unless otherwise
stated. 1-Benzyloxypyrazole was prepared as previously
described.10 i-PrMgCl and n-BuLi were titrated prior to
use.26,27 THF was distilled from Na/benzophenone un-
der N2. All air-sensitive reactions were carried out under
N2. Melting points were measured in open capillary
tubes by normal oil bath method or an OptiMelt
MPA100 apparatus (SRS) and are all uncorrected.
Compounds were visualized on TLC (silica gel 60
F254 plates) using UV light, FeCl3 or KMnO4. Flash
chromatography (FC) was performed on a glass column
The most intriguing results were related to the activities
observed at mGluRs. In contrast to the unsubstituted
analogue 1, all of the substituted analogues (2, 3 and
5a–l) were inactive at mGluR4. Similarly, most ana-
logues were inactive at mGluR1. However, the phenyl-
ethyl (5j) and the phenylpropyl analogues (5k) were
antagonists at mGluR1. This means that compound 5j
was a weak but selective antagonist at mGluR1. Nota-
bly, the activities at mGluR2 showed remarkable varia-
tions. The ethyl- (5b) and propyl-substituted (5c)
compounds were agonists with EC50 values below
100 lM, and 5c was thus a selective mGluR2 agonist.
The compounds containing extended alkyls, butyl (5d)
and pentyl (5e), and the cyclopropylmethyl (5f) ana-
logue showed no activity at mGluRs, whereas the bulky
and lipophilic cyclohexylmethyl (5g), phenyl (5h), benzyl
(5i) and phenylpropyl (5k) analogues were antagonists
with Ki values in the range of 32–180 lM. The cyclo-
hexylmethyl (5g) and phenylpropyl (5k) analogues
showed the highest potencies. Compound 5g only inhib-
ited mGluR2 and was thus a selective mGluR2 antago-
nist. When comparing mGluR activity with iGluR
activity, it is important to note that mGluR activity gen-
erally is 10- to 50-fold lower than iGluR activity as seen
for Glu itself (Table 3). Thus, the observed mGluR
activities in the range 30–230 lM are indicative of selec-
tivity when comparing with iGluR data.
(silica gel 60, 0.040–0.063 mm), a
FlashMasterTM
Personal one column (FP) (ISOLUTER SPE Columns)
or a FlashMasterTM (F) (ISOLUTER SPE Columns)
apparatus. Preparative HPLC was performed on an
XTerra Prep MS C18 column (10 · 300 mm, 10 lm)
equipped with an XTerra guard column (10 · 10 mm)
connected to a Jasco 880 pump (flow = 10 mL/min), a
Rheodyne 7125 injector, a 5 mL loop, a TSP UV100
spectrophotometer (210 nm) and a Hitachi D-2000
Chromato-Integrator.
1H, 13C and APT NMR spectra were recorded on a 300/
75 MHz Varian (Gemini) instrument or on a 500/
125 MHz Bruker Avance DRX500 instrument. TMS
was used as internal reference for 1H NMR spectra
and CDCl3 was used as internal reference standard for
13C NMR spectra. Elemental analyses were carried out
at the Analytical Research Department, H. Lundbeck
A/S, Denmark.
Accurate mass determination (HRMS) was performed
on a Micromass Q-Tof mass spectrometer (MeOH,
8.74 lL minꢀ1) in electrospray (ES) mode. GCMS anal-
yses were performed using electron ionization. Analyti-
cal LCMS data were obtained on a PE Sciex API
150EX instrument equipped with atmospheric pressure
photo ionization and a Shimadzu LC-10ADvp system.
Column: 30 · 4.6 mm Waters Symmetry C18 column
with 3.5 lm particle size; Solventsystem: A = water/tri-
fluoroacetic acid (100:0.05) and B = water/acetonitrile/
trifluoroacetic acid (5:95:0.035); Method: Linear gradi-
ent elution with 90% A to 100% B in 10 min and with
a flow rate of 2 mL/min. Purity was determined by inte-
gration of the UV (254 nm) and ELSD trace by using a
Shimadzu SPD-10Advp UV detector and a Sedere Sedex
55 ELSD detector. The retention times (TR) are
expressed in minutes.
The results for the mGluR2 agonists indicate limited
space for agonist molecules. We have previously hypoth-
esized that interaction of the substituent of 5-substituted
pyrazol analogues with Gly296 in mGluR2 reduces the
efficacy of the compounds.9 The ligand binding domain
is formed like a venus fly-trap that closes around the
ligand resulting in receptor activation. Reduced domain
closure due to steric clash between the substituent and
Gly296 leads to reduced activation of the receptor.

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
3529
The pKa values were measured potentiometrically using
a Sirius GLpKa Auto-titrator and the data were ana-
lyzed with Sirius pKaLOGP software (version 5.2). Mul-
tiple runs were performed using MeOH/H2O mixtures.
The derived pKa values were extrapolated to zero organ-
ic solvent using Yasuda–Shedlovsky plots.28,29 The sam-
ples were run from low pH to high pH using first HCl
(aq) to obtain a pH of 2 and then titrated with KOH
(aq).
6.1.4.
(RS)-2-Amino-(1-hydroxy-5-propyl-4-pyrazolyl)
acetic acid (5c). The title compound was prepared
according to the procedure described for 2 starting with
13c (258 mg, 0.64 mmol). Treatment with LiOH gave
crude (RS)-2-(1-benzyloxy-5-propyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid (206 mg, 83%)
and further treatment with HBr gave 5c isolated as the
zwitterion (53 mg, 50%). Mp decomp >182 ꢁC. 1H
NMR (DMSO-d6) d 0.91 (t, J = 7 Hz, CH3, 3H), 1.54–
1.58 (m, CH2, 2H), 2.59–2.65 (m, peak partly hidden un-
der DMSO, CH2), 4.04 (s, a-CH, 1H), 7.03 (s, H-3, 1H).
Anal. Calcd for C8H13N3O3Æ1/2H2O: C, 46.15; H, 6.78;
N, 20.18. Found: C, 46.27; H, 6.40; N, 19.94.
6.1.1. (RS)-2-Amino-(1-hydroxy-4-pyrazolyl)acetic acid
(2). Compound 12 (90 mg, 0.25 mmol) was dissolved in
THF (0.4 mL) and 2.5 M LiOH (aq) (0.2 mL, 0.5 mmol)
was added. The reaction mixture was left stirring for 4 h
at rt, then cooled to 0 ꢁC and pH adjusted to ꢁ1 using
1 M HCl (aq). The mixture was extracted using EtOAc
(3·), and the combined organic phases were washed
with brine, dried using MgSO4 and concentrated in va-
cuo yielding crude (RS)-2-(1-benzyloxy-4-pyrazolyl)-2-
(N-tert-butoxycarbonylamino)acetic acid as a foamy
6.1.5. (RS)-2-Amino-(1-benzyloxy-5-butyl-4-pyrazolyl)
acetic acid (5d). The title compound was prepared
according to the procedure described for 2 starting with
13d (462 mg, 1.11 mmol). Treatment with LiOH gave
crude
(RS)-2-(1-benzyloxy-5-butyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid (447 mg, 100%).
Further treatment with HBr gave 5d but instead of iso-
lating the zwitterion using propylene oxide, the pH was
adjusted to 3–4 with 4 M NaOH (aq) followed by HPLC
(15 mM AcOH (aq)) purification and recrystallization
1
oil (85 mg). H NMR (CDCl3) d 1.37 and 1.45 (2· br
s, 9H), 5.06–5.44 (m, a-CH, NH, CH2, 4H), 7.09–7.33
(m, phenyl, H-3, H-5, 7H), 10.23 (br s, COOH, 1H).
48% HBr (aq) (1.1 mL) was added to (RS)-2-(1-benzyl-
oxy-4-pyrazolyl)-2-(N-tert-butoxycarbonyl-amino)acetic
acid (69 mg, 0.2 mmol). The mixture was left stirring
overnight at rt and concentrated in vacuo. The oil was
dissolved in 70% EtOH (aq) (1.5 mL) and treated with
propylene oxide (0.4 mL) to give 2 as the zwitterion
(11 mg, 35%). Mp decomp. >178 ꢁC. 1H NMR
(DMSO-d6) d 4.13 (s, a-CH, 1H), 7.09 (br s, H-3, 1H),
7.41 (br s, H-5, 1H), 7.78 (br s, 1H). Anal. Calcd for
C5H7N3O3Æ1/3H2O: C, 36.81; H, 4.74; N, 25.76. Found:
C, 36.62; H, 4.61; N, 25.45.
1
(H2O) (85 mg, 36%). Mp decomp. >188 ꢁC. H NMR
(DMSO-d6) d 0.89 (t, J = 8 Hz, CH3, 3H), 1.30–1.34
(m, CH2, 2H), 1.49–1.53 (m, CH2, 2H), 2.50–2.55 (m,
peak below DMSO, CH in CH2, 1H), 2.60–2.65 (m,
CH in CH2, 1H), 4.05 (s, a-CH, 1H), 7.02 (s, H-3,
1H). Anal. Calcd for C9H15N3O3Æ1/4H2O: C, 49.65; H,
7.17; N, 19.30. Found: C, 49.59; H, 7.40; N, 19.35.
6.1.6.
(RS)-2-Amino-(1-hydroxy-5-pentyl-4-pyrazolyl)
acetic acid (5e). The title compound was prepared
according to the procedure described for 5d starting
with 13e (545 mg, 1.26 mmol). Treatment with LiOH
gave crude (RS)-2-(1-benzyloxy-5-pentyl-4-pyrazolyl)-
2-(N-tert-butoxycarbonylamino)acetic acid (526 mg,
100%). Further treatment with HBr, pH adjustment
with NaOH (aq), HPLC purification (5% MeOH in
15 mM AcOH (aq)) and recrystallization (H2O) gave
5e (117 mg, 41%). Mp decomp. >183 ꢁC. 1H NMR
(DMSO-d6) d 0.88 (t, J = 8 Hz, CH3, 3H), 1.30–1.31
(m, 2· CH2, 4 H), 1.53–1.55 (m, CH2, 2H), 2.54 (m, be-
low DMSO, CH in CH2aryl, 1H), 2.60–2.65 (m, CH in
CH2aryl, 1H), 4.04 (s, a-CH, 1H), 7.02 (s, H-3, 1H).
Anal. Calcd for C10H17N3O3Æ1/3H2O: C, 51.49; H,
7.63; N, 18.01. Found: C, 51.75; H, 7.66; N, 18.12.
6.1.2.
(RS)-2-Amino-(5-bromo-1-hydroxy-4-pyrazolyl)
acetic acid (5a). The title compound was prepared
according to the procedure described for 2 starting with
13a (81 mg, 0.18 mmol). Treatment with LiOH gave
crude (RS)-2-(1-benzyloxy-5-bromo-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid (77 mg, 99%).
HBr treatment of 69 mg of this intermediate gave 5a
as the zwitterion (25 mg, 66%). Mp decomp. >220 ꢁC.
1H NMR (DMSO-d6) 3.95 (s, a-CH, 1H), 7.22 (s, H-3,
1H), 7.90 (br s, 2H). Anal. Calcd for C5H6BrN3O3Æ2/
3H2O: C, 24.21; H, 2.98; N, 16.94. Found: C, 24.07;
H, 3.01; N, 16.60.
6.1.3. (RS)-2-Amino-(5-ethyl-1-hydroxy-4-pyrazolyl)ace-
tic acid (5b). The title compound was prepared accord-
ing to the procedure described for 2 starting with 13b
(147 mg, 0.38 mmol). Treatment with LiOH gave crude
(RS)-2-(1-benzyloxy-5-ethyl-4-pyrazolyl)-2-(N-tert-but-
oxycarbonylamino)acetic acid (122 mg, 86%). HBr
treatment of 107 mg of this intermediate gave 5b which
was isolated as the zwitterion (31 mg, 58%). Mp de-
comp. >182 ꢁC. 1H NMR (DMSO-d6) d 1.11 (t,
J = 8 Hz, CH3, 3H), peak hidden under DMSO (CH2),
6.1.7. (RS)-2-Amino-(5-cyclopropylmethyl-1-hydroxy-4-
pyrazolyl)acetic acid (5f). Compound 13f (475 mg,
1.1 mmol) was dissolved in MeOH (5 mL). Pd/C
(68 mg) was added and the reaction mixture was hydro-
genated (Schmidlin NM hydrogen generator) at 0 ꢁC for
1 h. The mixture was filtered and concentrated in vacuo
giving 2-(N-tert-butoxycarbonylamino)-2-(5-cyclopro-
pylmethyl-1-hydroxy-4-pyrazolyl)acetic acid methyl es-
1
ter (257 mg, 69%). H NMR (CDCl3) d 0.29–0.31 (m,
1
4.02 (s, a-CH, 1H), 7.00 (s, H-3, 1H). H NMR (D2O)
CH2, 2H), 0.49 (br d, J = 8 Hz, CH2, 2H), 1.02–1.07
(m, CH, 1H), 1.42 (s, t-bu, 9H), 2.67 (br d, J = 7 Hz,
CH2, 2H), 3.73 (s, CH3, 3H), 5.23–5.25 (m, a-CH and
NH, 2H), 7.05 (s, H-3, 1H). 13C NMR (CDCl3) d 4.8
(CH2), 9.9 (CH), 27.5 (CH2), 28.4 (CH3), 49.2 (CH),
d 1.17 (t, J = 8 Hz, CH3, 3H), 2.64–2.73 (m, CH2, 2H),
4.75 (s, a-CH, 1H), 7.20 (s, H-3, 1H). Anal. Calcd for
C7H11N3O3Æ1/6H2O: C, 44.68; H, 6.07; N, 22.33. Found:
C, 44.55; H, 6.35; N, 22.21.

3530
C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
52.8 (CH3), 80.5 (C), 112.4 (C), 129.0 (CH), 134.4 (C),
155.0 (C), 171.7 (C). 2-(N-tert-Butoxycarbonylamino)-
2-(5-cyclopropylmethyl-1-hydroxy-4-pyrazolyl)acetic acid
methyl ester (230 mg, 0.71 mmol) was dissolved in THF
(0.6 mL) and 2.5 M LiOH (aq) (0.57 mL, 1.41 mmol)
was added. The reaction mixture was left stirring for
4 h at rt, then cooled to 0 ꢁC and pH adjusted to ꢁ2
using 1 M HCl (aq). The mixture was extracted using
EtOAc (3·), filtered through Na2SO4 (Isolute SPE col-
umn) and concentrated in vacuo yielding crude 2-(N-
tert-butoxycarbonylamino)-2-(5-cyclopropylmethyl-1-
hydroxy-4-pyrazolyl)acetic acid in quantitative yield.
The compound was finally deprotected using 2 M HCl
(aq) (3.5 mL) under rt overnight. The mixture was con-
centrated in vacuo and titrated several times with dry
Et2O giving 5f as the HCl salt (157 mg, 89%). Mp de-
comp. >176 ꢁC. 1H NMR (D2O) d 0.29 (br d,
J = 4 Hz, CH2, 2H), 0.53 (br d, J = 8 Hz, CH2, 2H),
1.04–1.06 (m, CH, 1H), 2.63–2.77 (m, CH2, 2H) 5.18
(s, a-CH, 1H), 7.37 (s, H-3, 1H). Anal. Calcd for
C9H13N3O3ÆHClÆ1/3H2O: C, 42.61; H, 5.83; N, 16.56.
Found: C, 42.48; H, 6.02; N, 16.49.
CH2, 1H), 4.10 (s, a-CH, 1H), 4.12 (d, JAB = 15 Hz,
CH in CH2, 1H), 7.10 (s, H-3, 1H), 7.17–7.29 (m, 5H),
7.87 (br s, 2H). Anal. Calcd for C12H13N3O3Æ1H2O: C,
54.33; H, 5.70; N, 15.84. Found: C, 54.28; H, 5.79; N,
17.47.
6.1.11. (RS)-2-Amino-(1-hydroxy-5-phenylethyl-4-pyraz-
olyl)acetic acid (5j). The title compound was prepared
according to the procedure described for 2 starting with
13j (150 mg, 0.32 mmol). Treatment with LiOH gave
crude (RS)-2-(1-benzyloxy-5-phenylethyl-4-pyrazolyl)-
2-(N-tert-butoxycarbonylamino)acetic acid (95 mg,
76%) and further treatment with HBr gave 5j isolated
as the zwitterion (27 mg, 49%). Mp decomp. >166 ꢁC.
1H NMR (DMSO-d6) d 2.80–2.91 (m, 2· CH2, 4H),
4.11 (s, a-CH, 1H), 7.05 (s, H-3, 1H), 7.19–7.84 (m,
5H). Anal. Calcd for C13H15N3O3Æ1H2O: C, 55.91; H,
6.13; N, 15.05. Found: C, 56.11; H, 6.42; N, 14.69.
6.1.12. (RS)-2-Amino-[1-hydroxy-5-(3-phenylpropyl)-4-
pyrazolyl]acetic acid (5k). The title compound was pre-
pared according to the procedure described for 2 start-
ing with 13k (219 mg, 0.46 mmol). Treatment with
LiOH gave crude (RS)-2-(1-benzyloxy-5-(3-phenylpro-
pyl)-4-pyrazolyl)-2-(N-tert-butoxycarbonylamino)acetic
acid (171 mg, 80%) and further treatment with HBr gave
5k isolated as the zwitterion (25 mg, 25%). Mp decomp.
6.1.8. (RS)-2-Amino-(5-cyclohexylmethyl-1-hydroxy-4-
pyrazolyl)acetic acid (5g). The title compound was pre-
pared according to the procedure described for 5d start-
ing with 13g (667 mg, 1.46 mmol). Treatment with
LiOH gave crude (RS)-2-(1-benzyloxy-5-cyclohexylmeth-
yl-4-pyrazolyl)-2-(N-tert-butoxycarbonylamino)acetic acid
(646 mg, 100%). Further treatment with HBr, pH
adjustment with NaOH (aq), HPLC (10% MeOH in
15 mM AcOH (aq)) purification and recrystallization
(H2O) gave 5g (58 mg, 15%). Mp decomp. >210 ꢁC.
1H NMR (DMSO-d6) d 0.96 (br s, 2H), 1.12–1.14 (m,
3H), 1.16–1.63 (m, 6H), 2.43 (dd, J = 7, 15 Hz, CH in
CH2, 1H), 2.57 (dd, J = 7, 14 Hz, CH in CH2, 1H),
4.04 (s, a-CH, 1H), 7.03 (s, H-3, 1H). Anal. Calcd for
C12H19N3O3Æ1/3H2O: C, 55.58; H, 7.64; N, 16.20.
Found: C, 55.48; H, 7.56; N, 16.04.
1
>162 ꢁC. H NMR (DMSO-d6) d 1.87–1.90 (m, CH2,
2H), 2.54–2.70 (m, 2· CH2, 4H), 4.03 (s, a-CH, 1H),
7.04 (s, H-3, 1H), 7.17–7.29 (m, 5H). Anal. Calcd for
C14H17N3O3Æ2/3H2O: C, 58.53; H, 6.43; N, 14.63.
Found: C, 58.83; H, 6.39; N, 14.38.
6.1.13. (RS)-2-Amino-(5-benzhydryl-1-hydroxy-4-pyraz-
olyl)acetic acid (5l). The title compound was prepared
according to the procedure described for 2 starting with
13l (246 mg, 0.47 mmol). Treatment with LiOH gave
crude (RS)-2-(1-benzyloxy-5-benzhydryl-4-pyrazolyl)-2-
(N-tert-butoxycarbonylamino)acetic
acid
(178 mg,
74%) and further treatment with HBr gave 5l isolated
as the zwitterion (67 mg, 60%). Mp decomp. >175 ꢁC.
1H NMR (DMSO-d6) d 3.72 (s, a-CH, 1H), 5.95 (s,
CHPh2, 1H), 7.14–7.31 (m, H-3 and 2· Ph, 11H). Anal.
Calcd for C18H17N3O3.1H2O: C, 63.33; H, 5.61; N,
12.31. Found: C, 63.01; H, 5.69; N, 12.10.
6.1.9.
(RS)-2-Amino-(1-hydroxy-5-phenyl-4-pyrazolyl)
acetic acid (5h). The title compound was prepared
according to the procedure described for 2 starting with
13h (106 mg, 0.24 mmol). Treatment with LiOH gave
crude (RS)-2-(1-benzyloxy-5-phenyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid (91 mg, 88%).
HBr treatment of 82 mg of this intermediate gave 5h
as the zwitterion (27 mg, 60%). Mp decomp. >199 ꢁC.
1H NMR (DMSO-d6) d 3.99 (s, a-CH, 1H), 7.29 (s, H-
3, 1H), 7.45 (t, J = 7 Hz, 1H), 7.51 (t, J = 8 Hz, 2H),
7.90 (d and br s, J = 8 Hz, 3H). Anal. Calcd for
C11H11N3O3Æ1/2H2O: C, 54.54; H, 4.99; N, 17.35.
Found: C, 54.83; H, 5.00; N, 17.01.
6.1.14. 1-(1-Benzyloxy-5-pyrazolyl)ethanol (7b). 1-Ben-
zyloxypyrazole (390 mg, 2.2 mmol) in THF (10 mL)
was cooled to ꢀ78 ꢁC and n-BuLi in hexanes (1.68 M,
2 mL, 3.4 mmol) was added over 5 min. The mixture
was left stirring for 5 min at ꢀ78 ꢁC before CH3CHO
(0.2 mL, 158 mg, 3.6 mmol) was added. The mixture
was left stirring at ꢀ78 ꢁC for 1 h and then warmed to
rt over 3 h and left at rt for 1 h. Satd NH4Cl (aq) was
added followed by additional water. The mixture was
extracted using EtOAc (3·). The organic phases were
pooled, washed with brine, dried using MgSO4 and con-
centrated in vacuo. FC (F, petroleum ether/EtOAc) gave
7b (440 mg, 90%) as a clear oil. TLC (petroleum ether/
EtOAc 3:1) Rf 0.14. 1H NMR (CDCl3) d 1.29 (d,
J = 7 Hz, CH3, 3H), 2.55 (br s, OH, 1H), 4.59 (q,
J = 7 Hz, CHOH, 1H), 5.29 (s, CH2, 2H), 6.04 (d,
J = 2 Hz, H-4, 1H), 7.19 (d, J = 2 Hz, H-3, 1H),
6.1.10. (RS)-2-Amino-(5-benzyl-1-hydroxy-4-pyrazolyl)
acetic acid (5i). The title compound was prepared
according to the procedure described for 2 starting with
13i (193 mg, 0.43 mmol). Treatment with LiOH gave
crude (RS)-2-(5-benzyl-1-benzyloxy-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid (184 mg, 98%).
HBr treatment of 159 mg of this intermediate gave 5i
as the zwitterion (49 mg, 54%). Mp decomp. >162 ꢁC.
1H NMR (DMSO-d6) d 3.97 (d, JAB = 15 Hz, CH in

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
3531
7.27–7.37 (m, phenyl, 5H). 13C NMR (CDCl3) d 21.8
(CH3), 60.4 (CH), 80.1 (CH2), 100.5 (CH), 128.8 (CH),
129.5 (CH), 130.1 (CH), 132.6 (C), 133.6 (C), 139.9
(C). LCMS m/z 219 (M+H+); TR = 1.98; purity (UV,
ELSD): 87%, 98%. The reaction was also tried using
TMEDA (1.1 equiv), n-BuLi (1.1 equiv) and CH3CHO
(5 equiv) and the conditions described in the literature
but the reaction resulted in lower yields.10
OH, 1H), 3.71 (d, J = 8 Hz, CHOH, 1H), 5.35 (s, CH2,
2H), 6.14 (d, J = 2 Hz, H-4, 1H), 7.26–7.39 (m, phenyl,
H-3, 6H). 13C NMR (CDCl3) d 2.4 (CH2), 3.65 (CH2),
16.1 (CH), 68.8 (CH), 80.3 (CH2), 101.4 (CH), 128.9
(CH), 129.6 (CH), 130.2 (CH), 132.8 (CH), 133.9 (C),
138.3 (C).
6.1.19. (1-Benzyloxy-5-pyrazolyl)cyclohexylmethanol (7g).
The title compound was prepared according to the pro-
cedure described for 7b starting with 1-benzyloxypyraz-
ole (1.00 g, 5.7 mmol). FC (F, petroleum ether/EtOAc)
gave 7g as a clear oil (1.36 g, 83%). TLC (petroleum
6.1.15. 1-(1-Benzyloxy-5-pyrazolyl)propan-1-ol (7c). The
title compound was prepared according to the procedure
described for 7b starting with 1-benzyloxypyrazole
(1.00 g, 5.7 mmol). FC (F, petroleum ether/EtOAc) gave
7c as a clear oil (1.18 g, 88%). TLC (petroleum ether/
EtOAc 3:1) Rf 0.19. 1H NMR (CDCl3) d 0.79
(t, J = 8 Hz, CH3, 3H), 1.55 (m, CH, 1H), 1.68 (m,
CH, 1H), 3.27 (br s, OH, 1H), 4.37 (t, J = 7 Hz, CHOH,
1H), 5.24 (d, JAB=10 Hz, CH in CH2, 1H), 5.25 (d,
JAB = 10 Hz, CH in CH2, 1H), 6.02 (d, J = 2 Hz, H-4,
1H), 7.16 (d, J = 2 Hz, H-3, 1H), 7.27–7.32 (m, phenyl,
5H). 13C NMR (CDCl3) d 9.8 (CH3), 28.9 (CH2), 65.5
(CH), 80.0 (CH2), 100.8 (CH), 128.5 (CH), 129.2
(CH), 129.8 (CH), 132.4 (CH), 133.5 (C), 139.0 (C).
1
ether/EtOAc 2:1) Rf 0.32. H NMR (CDCl3) d 0.78–
0.84 (m, 1H), 0.89–0.97 (m, 1H), 1.03–1.19 (m, 3H),
1.31 (d, J = 13 Hz, 1H), 1.51–1.61 (m, 3H), 1.70
(d, J = 13 Hz, 1H), 1.93 (d, J = 13 Hz, 1H), 2.29 (d,
J = 5 Hz, 1H), 4.21 (dd, J = 5, 8 Hz, CHOH), 5.25
(d, JAB = 11 Hz, CH in CH2, 1H), 5.29 (d, JAB = 11 Hz,
CH in CH2, 1H), 6.02 (d, J = 2 Hz, H-4, 1H), 7.20
(d, J = 2 Hz, H-3, 1H), 7.28–7.37 (m, phenyl, 5H). 13C
NMR (CDCl3) d 25.7 (CH2), 25.8 (CH2), 26.3 (CH2),
28.7 (CH2), 28.9 (CH2), 43.1 (CH), 69.3 (CH), 80.0
(CH2), 101.3 (CH), 128.7 (CH), 129.3 (CH), 130.0
(CH), 132.7 (CH), 133.7 (C), 138.4 (C).
6.1.16. 1-(1-Benzyloxy-5-pyrazolyl)butan-1-ol (7d). The
title compound was prepared according to the procedure
described for 7b starting with 1-benzyloxypyrazole
(1.00 g, 5.7 mmol). FC (F, petroleum ether/EtOAc) gave
7d as a clear oil (1.19 g, 85%). TLC (petroleum ether/
EtOAc 2:1) Rf 0.29. 1H NMR (CDCl3) d 0.86 (t,
J = 7 Hz, CH3, 3H), 1.20 (m, CH, 1H), 1.33 (m, CH,
1H), 1.49 (m, CH, 1H), 1.56 (br s, 1H, OH), 1.68 (m,
CH, 1H), 4.38 (dd, J = 6, 8 Hz, CHOH, 1H), 5.33 (d,
JAB = 11 Hz, CH in CH2, 1H), 5.37 (d, JAB = 11 Hz,
CH in CH2, 1H), 6.03 (d, J = 2 Hz, H-4, 1H),
7.25–7.40 (m, phenyl, H-3, 6H). 13C NMR (CDCl3) d
13.8 (CH3), 18.9 (CH2), 38.0 (CH2), 64.4 (CH), 80.1
(CH2), 100.8 (CH), 129.0 (CH), 129.7 (CH), 130.3
(CH), 133.0 (CH), 133.9 (C), 139.3 (C).
6.1.20. (1-Benzyloxy-5-pyrazolyl)phenylmethanol (7i).
The title compound was prepared according to the pro-
cedure described for 7b starting with 1-benzyloxypyraz-
ole (1.00 g, 5.7 mmol). FC (F, petroleum ether/EtOAc)
gave 7i as a clear oil (1.21 g, 76%). TLC (petroleum
1
ether/EtOAc 2:1) Rf 0.29. H NMR (CDCl3) d 2.41 (br
s, OH, 1H), 5.19 (d, JAB = 10 Hz, CH in CH2, 1H),
5.26 (d, JAB = 10 Hz, CH in CH2, 1H), 5.53 (s, CHOH,
1H), 5.85 (d, J = 2 Hz, H-4, 1H), 7.20 (d, J = 2 Hz, H-3,
1H), 7.21-7.40 (m, 2· Ph, 10H). 13C NMR (CDCl3) d
67.1 (CH), 80.2 (CH2), 102.6 (CH), 126.4 (CH), 128.2
(CH), 128.6 (CH), 128.9 (CH), 129.6 (CH), 130.2
(CH), 132.8 (CH), 133.7 (C), 138.7 (C), 140.7 (C).
LCMS m/z 281 (M+H+); TR = 2.77; purity (UV,
ELSD): 85%, 98%.
6.1.17. 1-(1-Benzyloxy-5-pyrazolyl)pentan-1-ol (7e). The
title compound was prepared according to the procedure
described for 7b starting with 1-benzyloxypyrazole
(1.00 g, 5.7 mmol). FC (F, petroleum ether/EtOAc) gave
7e as a clear oil (1.19 g, 80%). TLC (petroleum ether/
EtOAc 2:1) Rf 0.29. 1H NMR (CDCl3) d 0.85
(t, J = 7 Hz, CH3, 3H), 1.10–1.35 (m, 2· CH2, OH, 5H),
1.50–1.70 (2· m, CH2, 2H), 4.36 (br t, J = 8 Hz, CHOH,
1H), 5.32 (d, JAB = 11 Hz, CH in CH2, 1H), 5.37
(d, JAB = 11 Hz, CH in CH2, 1H), 6.03 (d, J = 2 Hz, H-
4, 1H), 7.25–7.40 (m, H-3, phenyl, 6H). 13C NMR
(CDCl3) d 14.1 (CH3), 22.5 (CH2), 27.8 (CH2), 35.7
(CH2), 64.7 (CH), 80.1 (CH2), 100.8 (CH), 129.0 (CH),
129.7 (CH), 130.3 (CH), 132.9 (CH), 133.9 (C), 139.3 (C).
6.1.21. 1-(1-Benzyloxy-5-pyrazolyl)-2-phenylethanol (7j).
1-Benzyloxy-5-iodopyrazole (9) (743 mg, 2.5 mmol) in
THF (10 mL) was cooled to 0 ꢁC. i-PrMgCl (2.1 M,
1.4 mL, 3.0 mmol) was added to the solution dropwise.
The mixture was warmed to rt and left stirring for 1 h.
The mixture was cooled to 0 ꢁC and freshly prepared
phenylacetaldehyde30 in THF (2 mL) was added where-
upon the mixture turned from turbid to clear. The mix-
ture was left for 1 h at rt, whereupon satd NH4Cl (aq)
was added followed by extraction using EtOAc (3·).
The pooled organic phases were washed with brine
and dried using MgSO4. FC (FP, petroleum ether/
EtOAc 2:1) gave 7j as a clear oil (304 mg, 57%). TLC
(petroleum ether/EtOAc 2:1) Rf 0.20. 1H NMR (CDCl3)
d 2.34 (s, OH, 1H), 2.80–2.95 (m, CH2, 2H), 4.66
(t, J = 6 Hz, CHOH, 1H), 5.07 (d, JAB = 11 Hz, CH in
CH2, 1H), 5.20 (d, JAB = 11 Hz, CH in CH2, 1H), 6.05
(d, J = 2 Hz, H-4, 1H), 7.05–7.07 (m, 2H), 7.17–7.36
(m, 9H). 13C NMR (CDCl3) d 42.5 (CH2), 65.6 (CH),
80.2 (CH2), 101.3 (CH), 126.7 (CH), 128.4 (CH), 128.8
(CH), 129.5 (CH), 130.0 (CH), 132.7 (CH), 133.7 (C),
137.2 (C), 138.3 (C). The compound could also be
6.1.18.
(1-Benzyloxy-5-pyrazolyl)cyclopropylmethanol
(7f). The title compound was prepared according to
the procedure described for 7b starting with 1-ben-
zyloxypyrazole (1.00 g, 5.7 mmol). FC (F, petroleum
ether/EtOAc) gave 7f as a clear oil (1.18 g, 84%). TLC
(petroleum ether/EtOAc 2:1) Rf 0.22. 1H NMR (CDCl3)
d 0.09 (m, CH, 1H), 0.33 (m, CH, 1H), 0.46 (m, CH,
1H), 0.59 (m, CH, 1H), 1.18 (m, CH, 1H), 1.95 (br s,

3532
C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
synthesized from 1-benzyloxypyrazole-5-carbaldehyde10
(200 mg, 1 mmol) in THF followed by the addition of
benzyl magnesium chloride in THF (2 M, 0.6 ml,
1.2 mmol) at 0 ꢁC and left stirring for 150 min at rt.
The reaction was worked-up according to the above-
mentioned synthesis. FC (F, petroleum ether/EtOAc)
gave 7j as a clear oil (57 mg, 20%).
J = 2 Hz, H-4, 1H), 7.22 (d, J = 2 Hz, H-3, 1H), 7.29–
7.37 (m, phenyl, 5H). 13C NMR (CDCl3) d 12.5
(CH3), 17.5 (CH2), 79.9 (CH2), 101.0 (CH), 128.7
(CH), 129.4 (CH), 130.1 (CH), 132.7 (CH), 134.1 (C),
138.4 (C). m/z (EI) 202 (7%), 185, 105, 91 (100%).
HRMS m/z found: 225.1006 [M+Na+]. Calcd for
C12H14N2ONa: 225.1004 [M+Na+].
6.1.22. 1-(1-Benzyloxy-5-pyrazolyl)-3-phenylpropan-1-ol
(7k). The title compound was prepared according to
the procedure described for 7b starting with 1-ben-
zyloxypyrazole (1.00 g, 5.7 mmol). FC (F, petroleum
ether/EtOAc) gave 7k as a clear oil (1.12 g, 63%). TLC
(petroleum ether/EtOAc 2:1) Rf 0.19. 1H NMR (CDCl3)
d 1.36 (d, J = 4 Hz, OH, 1H), 1.82–2.03 (2· m, CH2,
2H), 2.50–2.68 (2· m, CH2, 2H), 4.36 (m, CHOH,
1H), 5.26 (d, JAB = 11 Hz, CH in CH2, 1H), 5.35 (d,
JAB = 11 Hz, CH in CH2, 1H), 6.04 (d, J = 2 Hz, H-4,
1H), 7.13–7.38 (m, 2· phenyl and H-3, 11H). 13C
NMR (CDCl3) d 31.8 (CH2), 37.4 (CH2), 63.9 (CH),
80.1 (CH2), 100.9 (CH), 126.1, 128.6, 128.6, 129.0,
129.6, 130.3, 133.0, 133.8, 139.0, 141.3.
6.1.26. 1-Benzyloxy-5-propylpyrazole (8c). The title
compound was prepared according to the procedure
described for 8b starting with 7c (1.18 g, 5.1 mmol),
but with modifications. After work up and chromatog-
raphy (FC (F, petroleum ether/EtOAc)), NMR showed
a 1:1 mixture of R–O–COCF3 and product. The mixture
was heated at 60 ꢁC with MeOH overnight and concen-
trated in vacuo. FC (F, petroleum ether/EtOAc) gave 8c
as a clear oil (322 mg, 29%). TLC (petroleum ether/
EtOAc 9:1) Rf 0.44. 1H NMR (CDCl3) d 0.84 (t,
J = 8 Hz, CH3, 3H), 1.39–1.46 (m, CH2, 2H), 2.22 (t,
J = 8 Hz, CH2Ar, 2H), 5.24 (s, CH2, 2H), 5.83 (d,
J = 2 Hz, H-4, 1H), 7.19 (d, J = 2 Hz, H-3, 1H), 7.26–
7.30 (m, phenyl, 5H). 13C NMR (CDCl3) d 13.6
(CH3), 21.3 (CH2), 29.6 (CH2), 79.6 (CH2), 101.4
(CH), 128.5 (CH), 129.1 (CH), 129.8 (CH), 132.4
(CH), 133.9 (C), 136.5 (C). m/z (EI) 216 (7%), 199,
105, 91 (100%). HRMS m/z found: 239.1166 [M+Na+].
Calcd for C13H16N2ONa: 239.1160 [M+Na+].
6.1.23. (1-Benzyloxy-5-pyrazolyl)diphenylmethanol (7l).
The title compound was prepared according to the pro-
cedure described for 7b starting with 1-benzyloxypyraz-
ole (1.00 g, 5.7 mmol). FC (F, petroleum ether/EtOAc)
gave 7l as a white solid (1.56 g, 77%). TLC (petroleum
1
ether/EtOAc 2:1) Rf 0.5. H NMR (CDCl3) d 3.96 (s,
6.1.27. 1-Benzyloxy-5-butylpyrazole (8d). The title com-
pound was prepared according to the procedure de-
scribed for 8b starting with 7d (877 mg, 3.6 mmol). FC
(petroleum ether/EtOAc 1:0–2:1) gave 8d as a clear oil
(569 mg, 69%). TLC (petroleum ether/EtOAc 2:1) Rf
OH, 1H), 4.91 (s, CH2, 2H), 5.57 (d, J = 2 Hz, H-4,
1H), 6.93 (br d, J = 7 Hz, 2H), 7.19 (d, J = 2 Hz, H-3,
1H), 7.26–7.38 (m, 13H).
6.1.24. 1-Benzyloxy-5-bromopyrazole (8a). 1-Ben-
zyloxypyrazole (1.05 g, 6.0 mmol) in THF (35 ml) was
cooled to ꢀ78 ꢁC. n-BuLi in hexanes (2 M, 3.2 mL,
6.4 mmol) was added to the solution. The mixture was
left stirring at ꢀ78 ꢁC for 15 min followed by the addi-
tion of solid CBr4 (3.8 g, 11.5 mmol) in THF (7 ml).
The mixture was left stirring at ꢀ78 ꢁC for 1 h, where-
upon satd NH4Cl (aq) was added. The mixture was ex-
tracted using EtOAc (3·). The organic phases were
pooled, washed with brine, dried using MgSO4 and con-
centrated in vacuo. FC (FP, toluene/petroleum ether
0:1–1:1) gave 8a as an oil (1.24 g, 81%). TLC (toluene/
petroleum ether/EtOAc 4:4:1) Rf 0.5. The NMR data
were consistent with the literature data.10
1
0.6. H NMR (CDCl3) d 0.83 (t, J = 7 Hz, CH3, 3H),
1.23 (m, CH2, 2H), 1.37 (m, CH2, 2H), 2.23 (t,
J = 8 Hz, CH2Ar, 2H), 5.25 (m, CH2, 2H), 5.83 (d,
J = 2 Hz, H-4, 1H), 7.20 (d, J = 2 Hz, H-3, 1H), 7.27–
7.33 (m, phenyl, 5H). 13C NMR (CDCl3) d 13.6
(CH3), 22.2 (CH2), 23.5 (Ar–CH2), 30.1 (CH2), 79.6
(CH2), 101.4 (CH), 128.5 (CH), 129.1 (CH), 129.9
(CH), 132.5 (CH), 133.9 (C), 136.8 (C). m/z (EI) 230
(3%), 213, 171, 91 (100%). HRMS m/z found: 253.1325
[M+Na+]. Calcd for C14H18N2ONa: 253.1317 [M+Na+].
6.1.28. 1-Benzyloxy-5-pentylpyrazole (8e). The title com-
pound was prepared according to the procedure de-
scribed for 8b starting with 7e (1.13 g, 4.3 mmol), but
instead of using satd NaHCO3 (aq), a 1:1 solution of
concentrated NH4OH and H2O was used to adjust the
pH to ꢁ7. FC (petroleum ether/EtOAc 1:0–2:1) gave
8e as a clear oil (775 mg, 73%). TLC (petroleum ether/
EtOAc 2:1) Rf 0.6. 1H NMR (CDCl3) d 0.84 (t,
J = 7 Hz, CH3, 3H), 1.16–1.26 (m, 2· CH2, 4H), 1.36–
1.42 (m, CH2, 2H), 2.22 (t, J = 8 Hz, CH2Ar, 2H),
5.25 (s, CH2, 2H), 5.83 (d, J = 2 Hz, H-4, 1H), 7.19 (d,
J = 2 Hz, H-3, 1H), 7.26–7.32 (m, phenyl, 5H). 13C
NMR (CDCl3) d 13.9 (CH3), 22.2 (CH2), 23.7 (CH2),
27.6 (CH2), 31.2 (CH2), 79.6 (CH2), 101.3 (CH), 128.5
(CH), 129.1 (CH), 129.8 (CH), 132.4 (CH), 133.9 (C),
136.8 (C). m/z (EI) 244 (1%), 171, 105, 91 (100%).
HRMS m/z found: 267.1465 [M+Na+]. Calcd for
C15H20N2ONa: 267.1473 [M+Na+].
6.1.25. 1-Benzyloxy-5-ethylpyrazole (8b). Compound 7b
(1.16 g, 5.3 mmol) was dissolved in dry CH2Cl2
(15 mL). The mixture was put under N2 and cooled to
0 ꢁC. Triethylsilane (4.2 mL, 26.4 mmol) was added fol-
lowed by the addition of trifluoroacetic acid (12 mL).
The mixture was left refluxing at 50 ꢁC overnight. The
mixture was cooled to 0 ꢁC and H2O was added to the
reaction mixture followed by extraction with Et2O
(3·). The pooled organic phases were washed with satd
NaHCO3 (aq) until a pH of ꢁ7 was obtained. The or-
ganic phase was washed with brine, dried with MgSO4
and concentrated in vacuo. FC (4:4:1 toluene/petroleum
ether/EtOAc) afforded 8b as a yellow oil (745 mg, 69%).
1H NMR (CDCl3) d 1.04 (t, J = 8 Hz, CH3, 3H,), 2.28
(q, J = 8 Hz, CH2, 2H), 5.27 (s, CH2, 2 H), 5.86 (d,

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
3533
6.1.29. 1-Benzyloxy-5-cyclopropylmethylpyrazole (8f).
The title compound was prepared according to the pro-
cedure described for 8e starting with 7f (620 mg,
2.5 mmol). FC (petroleum ether/EtOAc 1:0–2:1) gave
8f as a clear oil (377 mg, 66%). TLC (petroleum ether/
EtOAc 2:1) Rf 0.6. 1H NMR (CDCl3) d 0.11 (q,
J = 5 Hz, CH2, 2H), 0.53 (q, J = 5 Hz, CH2, 2H),
0.84–0.91 (m, CH, 1H), 2.22 (d, J = 7 Hz, CH2, 2H),
5.35 (s, CH2, 2H), 6.07 (d, J = 1 Hz, H-4, 1H), 7.31 (d,
H-3, J = 2 Hz, 1H), 7.35–7.44 (m, phenyl, 5H). TMS is
hidden in spectra so used CH2 in OBn as internal refer-
ence (5.35 in 8e). 13C NMR (CDCl3) d 4.6 (CH2), 9.2
(CH), 28.8 (CH2), 79.8 (CH2), 101.7 (CH), 128.6 (CH),
129.2 (CH), 130.0 (CH), 132.6 (CH), 134.0 (C), 136.5
(C). m/z (EI) 228 (2%), 211, 171, 91 (100%). HRMS
m/z found: 229.1347 [M+H+]. Calcd for C14H17N2O:
229.1341 [M+H+].
J = 2 Hz, H-4, 1H), 7.00 (d, J = 7 Hz, phenyl, 2H),
7.15–7.35 (m, 9H). 13C NMR (CDCl3) d 30.3 (CH2),
79.7 (CH2), 102.8 (CH), 126.6 (CH), 128.5 (CH), 128.6
(CH), 128.6 (CH), 129.2 (CH), 130.0 (CH), 132.6
(CH), 133.8 (C), 135.4 (C), 137.5 (C).
6.1.33. 1-Benzyloxy-5-phenylethylpyrazole (8j). The title
compound was prepared according to the procedure de-
scribed for 8b starting with 7j (304 mg, 1.0 mmol). FC
(petroleum ether/EtOAc 1:0–2:1) gave 8j as a clear oil
(204 mg, 71%). TLC (petroleum ether/EtOAc 2:1) Rf
1
0.28. H NMR (CDCl3) d 2.54 (t, J = 8 Hz, CH2, 2H),
2.66 (t, J = 8 Hz, CH2, 2H), 5.18 (s, CH2, 2H), 5.81 (s,
H-4, 1H), 7.03–7.04 (m, 2H), 7.16–7.33 (m, 9H). 13C
NMR (CDCl3) d 25.8 (CH2), 34.3 (CH2), 79.7 (CH2),
101.8 (CH), 126.2 (CH), 128.3 (CH), 128.4 (CH), 128.7
(CH), 129.3 (CH), 130.0 (CH), 132.6 (CH), 134.0 (C),
135.9 (C), 140.7 (C). m/z (EI) 278 (6%), 261, 105, 91
(100%). HRMS m/z found: 301.1328 [M+Na+]. Calcd
for C18H18N2ONa: 301.1317 [M+Na+].
6.1.30. 1-Benzyloxy-5-cyclohexylmethylpyrazole (8g).
The title compound was prepared according to the pro-
cedure described for 8e starting with 7g (1.36 g,
4.76 mmol). FC (petroleum ether/EtOAc 1:0–2:1) gave
8g as a clear oil (902 mg, 70%). TLC (petroleum ether/
6.1.34. 1-Benzyloxy-5-(3-phenylpropyl)pyrazole (8k). The
title compound was prepared according to the procedure
described for 8b starting with 7k (1.12 g, 3.6 mmol). FC
(F, petroleum ether/EtOAc) gave 8k as a clear oil
(682 mg, 65%). TLC (petroleum ether/EtOAc 9:1) Rf
0.19. 1H NMR (CDCl3) d 1.73 (quintet, J = 8 Hz,
CH2CH2CH2, 2H), 2.25 (t, J = 8 Hz, CH2, 2H), 2.51 (t,
J = 8 Hz, CH2, 2H), 5.22 (s, CH2, 2H), 5.85 (br s, H-4,
1H), 7.10 (d, J = 8 Hz, 2H), 7.16–7.24 (m, 9H). 13C
NMR (CDCl3) d 23.5 (CH2), 29.6 (CH2), 35.3 (CH2),
79.8 (CH2), 101.6 (CH), 126.0 (CH), 128.4 (CH), 128.5
(CH), 128.6 (CH), 129.3 (CH), 130.0 (CH), 132.7 (CH),
133.9 (C), 136.5 (C), 141.6 (C). m/z (EI) 292 (1%), 188,
171, 91 (100%). HRMS m/z found: 315.1486 [M+Na+].
Calcd for C19H20N2ONa: 315.1473 [M+Na+].
1
EtOAc 2:1) Rf 0.6. H NMR (CDCl3) d 0.78–0.85 (m,
2H), 1.04–1.18 (m, 3H), 1.33 (m, 1H, CH), 1.58–1.65
(m, phenyl, 5H), 2.17 (d, J = 7 Hz, 2H), 5.26 (s, CH2,
2H), 5.83 (d, J = 2 Hz, H-4), 7.20 (d, J = 2 Hz, H-3),
7.29–7.37 (m, phenyl, 5H). 13C NMR (CDCl3) d 26.1
(CH2), 26.3 (CH2), 31.6 (CH2), 33.0 (CH2), 37.2 (CH),
79.7 (CH2), 102.4 (CH), 128.6 (CH), 129.2 (CH), 129.9
(CH), 132.5 (CH), 134.1 (C), 135.4 (C). m/z (EI) 270
(2%), 253, 171, 91 (100%). HRMS m/z found: 271.1801
[M+H+]. Calcd for C17H23N2O: 271.1810 [M+H+].
6.1.31. 1-Benzyloxy-5-phenylpyrazole (8h). 1-Benzyloxy-
5-iodopyrazole (9) (305 mg, 1 mmol) was dissolved in
DMF (2 mL) and purged with N2 for 10 min. PhB(OH)2
(244 mg, 2 mmol) and PdCl2(PPh3)2 (35 mg, 0.05 mmol)
were added. The reaction mixture was purged with
N2ÆK2CO3 (aq) (3 M, 0.67 mL, 2 mmol) was added
and the mixture was left refluxing at 80 ꢁC overnight un-
der N2. The reaction mixture was cooled to rt and H2O
(20 mL) was added. The reaction mixture was extracted
with Et2O (3·) and the organic phases pooled and
washed with 20 mL of 2 M NaOH (2·). The organic
phase was further washed with H2O, brine, dried using
MgSO4 and concentrated in vacuo. FC (petroleum
ether/toluene 1:0–1:1) gave 8h as a clear oil (196 mg,
78%). TLC (petroleum ether/toluene/EtOAc 4:4:1) Rf
6.1.35. 5-Benzhydryl-1-benzyloxypyrazole (8l). The title
compound was prepared according to the procedure de-
scribed for 8b starting with 7l (1.56 g, 4.4 mmol). FC (F,
petroleum ether/EtOAc) gave 8l as a clear oil (680 mg,
46%). TLC (petroleum ether/EtOAc 4:1) Rf 0.44. 1H
NMR (CDCl3) d 5.00 (s, CH2, 2H), 5.20 (s, CH, 1H),
5.66 (d, J = 2 Hz, H-4, 1H), 6.98–7.00 (m, 4H), 7.13–
7.14 (m, 2H), 7.20–7.28 (m, 7H), 7.31–7.39 (m, 3H).
13C NMR (CDCl3) d 47.1 (CH), 79.7 (CH2), 104.3
(CH), 127.0 (CH), 128.6 (CH), 128.8 (CH), 129.4 (CH),
130.2 (CH), 132.5 (CH), 133.8 (C), 138.6 (C), 141.4 (C).
1
0.31. H NMR (CDCl3) d 5.15 (s, CH2, 2H), 6.26 (d,
6.1.36. 1-Benzyloxy-5-iodopyrazole (9). 1-Benzyloxypy-
razole (1.16 g, 6.7 mmol) in THF (35 ml) was cooled
to ꢀ78 ꢁC. n-BuLi in hexanes (2 M, 4.3 mL, 8.6 mmol)
was added to the solution. The mixture was left stirring
at ꢀ78 ꢁC for 10 min followed by the addition of solid I2
under positive flow of N2. The mixture was left stirring
at ꢀ78 ꢁC for 45 min, whereupon 5% Na2S2O3 (aq)
(25 mL) was added. The mixture was extracted using
EtOAc (3·). The organic phases were pooled, washed
with brine, dried using MgSO4 and concentrated in va-
cuo. FC (FP, toluene/petroleum ether 1:1) yielded the
compound as a clear oil (1.77 g, 89%). TLC (toluene/
petroleum ether 1:1) Rf 0.4. The NMR data were consis-
tent with the literature data.10
J = 2 Hz, H-4, 1H), 7.13–7.36 (m, 9H), 7.51–7.53 (m,
2H). 13C NMR (CDCl3) d 80.5 (CH2), 102.8 (CH),
127.7, 128.3, 128.4, 128.5, 129.1, 129.9, 133.0 (CH),
133.2 (C), 136.1 (C). LCMS m/z 251 (M+H+);
TR = 3.39; purity (UV, ELSD): 97%, 99%.
6.1.32. 5-Benzyl-1-benzyloxypyrazole (8i). The title com-
pound was prepared according to the procedure de-
scribed for 8b starting with 7i (400 mg, 1.43 mmol).
FC (FP, petroleum ether/toluene/EtOAc 1:1:0–4:4:1)
gave 8i as a clear oil (290 mg, 77%). TLC (petroleum
1
ether/toluene/EtOAc 4:4:1) Rf 0.17. H NMR (CDCl3)
d 3.55 (s, CH2, 2H), 5.15 (s, CH2, 2H), 5.74 (d,

3534
C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
6.1.37. 1-Benzyloxy-5-bromo-4-iodopyrazole (10a). Com-
pound 8a (500 mg, 2 mmol) was dissolved in CHCl3
(6 mL) and K2CO3 (312 mg, 2.2 mmol) was added fol-
lowed by the addition of ICl (385 mg, 2.4 mmol) in
CHCl3 (2 mL). The reaction mixture was left stirring
overnight at rt. The reaction mixture was quenched
with 1 M Na2SO3 (aq) followed by extraction with
CH2Cl2 (3·). The organic phases were combined,
washed with brine, dried with MgSO4 and concen-
trated in vacuo. FC (toluene/petroleum ether 1:1)
yielded 10a (156 mg, 21%). TLC (toluene/petroleum
6.1.40. 1-Benzyloxy-5-butyl-4-iodopyrazole (10d). The
title compound was prepared according to the procedure
described for 10b starting with 8d (541 mg, 2.4 mmol)
and gave crude 10d (835 mg). TLC (toluene/petroleum
ether/EtOAc 4:4:1) Rf 0.47. 1H NMR (CDCl3) d 0.85 (t,
J = 8 Hz, CH3, 3H), 1.24 (sextet, J = 7 Hz, CH2CH2CH3,
2H), 1.35 (quintet, J = 8 Hz, CH2CH2CH2, 2H), 2.33 (t,
J = 8 Hz, ArCH2, 2H), 5.25 (s, CH2, 2H), 7.27–7.37 (m,
5H). 13C NMR (CDCl3) d 13.7 (CH3), 22.3 (CH2), 24.0
(CH2), 30.0 (CH2), 55.5 (C), 80.0 (CH2), 128.7 (CH),
129.4 (CH), 129.9 (CH), 133.6 (C), 137.5 (CH), 137.7
(C). m/z (EI) 356 (3%), 339, 297, 212, 91 (100%). HRMS
m/z found: 379.0305 [M+Na+]. Calcd for C14H17IN2O-
Na: 379.0283 [M+Na+].
1
ether 1:1) Rf 0.33. H NMR (CDCl3) d 5.27 (s, CH2,
2H), 7.35–7.40 (m, phenyl, H-3, 6H). 13C NMR
(CDCl3) d 60.9 (C), 81.4 (CH2), 113.3 (C), 128.8
(CH), 129.7 (CH), 130.1 (CH), 132.7 (C), 139.1 (CH).
Other method: LDA (1.3 mmol) in THF (5 mL) was
freshly prepared from n-BuLi (2 M, 2.65 mL,
1.3 mmol) and i-Pr2NH (127 mg, 1.3 mmol) in THF
(5 mL) at ꢀ78 ꢁC under N2 and left stirring at rt for
30 min. LDA (1.3 mmol) in THF (5 mL) was added
to 1-benzyloxy-4-iodopyrazole13 (300 mg, 1 mmol) in
THF (5 mL) over 1 min at ꢀ78 ꢁC. The mixture was
left stirring at ꢀ78 ꢁC for 5 min. CBr4 (408 mg,
1.2 mmol) in THF (1 mL) was added over 1 min and
the mixture was left at ꢀ78 ꢁC for 1 h. The reaction
mixture was quenched with satd NH4Cl (aq) at
ꢀ78 ꢁC, warmed to rt and worked-up according to
the procedure described for 7b, although with Et2O
as organic solvent. FC (FP, cyclohexane/toluene 1:0–
18:1) yielded 10a (107 mg, 28%). TLC (cyclohexane/tol-
uene 1:1) Rf 0.30. The NMR data were consistent with
the above-mentioned data.
6.1.41. 1-Benzyloxy-4-iodo-5-pentylpyrazole (10e). The
title compound was prepared according to the procedure
described for 10b starting with 8e (642 mg, 2.6 mmol)
and gave crude 10e (977 mg). TLC (toluene/petroleum
1
ether/EtOAc 4:4:1) Rf 0.5. H NMR (CDCl3) d 0.85 (t,
J = 7 Hz, CH3, 3H), 1.20–1.28 (m, 2· CH2, 4H), 1.38
(quintet, J = 8 Hz, ArCH2CH2CH2, 2H), 2.32 (t,
J = 8 Hz, ArCH2, 2H), 5.25 (s, CH2, 2H), 7.24–7.35
(m, phenyl, H-3, 6H). 13C NMR (CDCl3) d 14.0 (CH3),
22.2 (CH2), 24.1 (CH2), 27.5 (CH2), 31.2 (CH2), 55.4
(C), 80.0 (CH2), 128.7 (CH), 129.4 (CH), 129.8 (CH),
133.5 (C), 137.4 (CH), 137.7 (C). m/z (EI) 370 (1%),
353, 297, 226, 91 (100%). HRMS m/z found: 371.0609
[M+H+]. Calcd for C15H20IN2O: 371.0620 [M+H+].
6.1.42. 1-Benzyloxy-5-cyclopropylmethyl-4-iodopyrazole
(10f). The title compound was prepared according to
the procedure described for 10b starting with 8f
(338 mg, 1.5 mmol) and gave crude 10f (532 mg). TLC
(toluene/petroleum ether/EtOAc 4:4:1) Rf 0.4. 1H
NMR (CDCl3) d 0.19 (q, J = 5 Hz, CH2, 2H) 0.39–
0.42 (m, CH2, 2H), 0.97–0.93 (m, CH, 1H), 2.28 (d,
J = 7 Hz, CH2CH, 2H), 5.28 (s, CH2, 2H), 7.25–7.34
(m, phenyl, H-3, 6H). 13C NMR (CDCl3) d 4.8 (CH2),
9.8 (CH), 28.7 (CH2), 55.6 (C), 80.2 (CH2), 128.8
(CH), 129.4 (CH), 129.8 (CH), 133.5 (C), 137.5 (C),
137.6 (CH).
6.1.38. 1-Benzyloxy-5-ethyl-4-iodopyrazole (10b). Com-
pound 8b (400 mg, 2 mmol) was dissolved in CHCl3
(6 mL). Addition of K2CO3 (400 mg, 2.8 mmol) was fol-
lowed by the addition of ICl (480 mg, 3 mmol) in CHCl3
(2 mL). The reaction mixture was left stirring overnight
at rt. The reaction mixture was quenched with 1 M
Na2SO3 (aq) followed by extraction with CH2Cl2 (3·).
The organic phases were combined, washed with brine,
dried with MgSO4 and concentrated in vacuo yielding
crude 10b as a clear oil (634 mg). TLC (petroleum
6.1.43. 1-Benzyloxy-5-cyclohexylmethyl-4-iodopyrazole
(10g). The title compound was prepared according to
the procedure described for 10b starting with 8g
(374 mg, 1.4 mmol) and gave crude 10g (555 mg). TLC
(toluene/petroleum ether/EtOAc 4:4:1) Rf 0.5. 1H
NMR (CDCl3) d 0.89–0.96 (m, 2H), 1.09–1.18 (m,
3H), 1.54–1.66 (m, 6H), 2.21 (d, J = 7 Hz, ArCH2,
2H), 5.26 (s, CH2, 2H), 7.25–7.39 (m, phenyl, H-3,
6H). 13C NMR (CDCl3) d 26.1 (CH2), 26.3 (CH2),
31.7 (CH2), 33.1 (CH2), 37.4 (CH), 56.6 (C), 80.1
(CH2), 128.8 (CH), 129.5 (CH), 129.9 (CH), 133.7 (C),
136.8 (C), 137.6 (CH).
1
ether/EtOAc 9:1) Rf 0.38. H NMR (CDCl3) d 0.96 (t,
J = 8 Hz, CH3, 3H), 2.36 (q, J = 8 Hz, CH2, 2H), 5.26
(s, CH2, 2H), 7.28–7.36 (m, phenyl, 5H). 13C NMR
(CDCl3) d 12.5 (CH3), 17.8 (CH2), 54.8 (C), 80.1
(CH2), 128.7 (CH), 129.4 (CH), 129.9 (CH), 133.4 (C),
137.4 (CH), 138.6 (C).
6.1.39. 1-Benzyloxy-4-iodo-5-propylpyrazole (10c). The
title compound was prepared according to the procedure
described for 10b starting with 8c (322 mg, 1.5 mmol)
and gave crude 10c (493 mg). TLC (toluene/petroleum
1
ether/EtOAc 4:4:1) Rf 0.45. H NMR (CDCl3) d 0.84
(t, J = 7 Hz, CH3, 3H), 1.40–1.47 (m, CH2, 2H), 2.32
(t, J = 8 Hz, CH2Ar, 2H), 5.25 (s, CH2, 2H), 7.28–7.36
(m, phenyl, H-3, 6H). 13C NMR (CDCl3) d 13.7
(CH3), 21.4 (CH2), 26.1 (CH2), 55.6 (C), 79.6 (CH2),
128.7 (CH), 129.4 (CH), 129.8 (CH), 133.6 (C), 137.5
(CH). C-5 is missing, but must be covered under the sig-
nal of 137.5.
6.1.44. 1-Benzyloxy-4-iodo-5-phenylpyrazole (10h). The
title compound was prepared according to the procedure
described for 10b starting with 8h (373 mg, 1.5 mmol)
and gave crude 10h (543 mg). TLC (toluene/petroleum
1
ether/EtOAc 4:4:1) Rf 0.5. H NMR (CDCl3) d 5.07 (s,
CH2, 2H), 6.97–6.98 (m, 2H), 7.16–7.19 (m, 2H), 7.25–
7.28 (m, 1H), 7.35–7.38 (m, 5H), 7.42 (s, H-3, 1H). 13C

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
3535
NMR (CDCl3) d 56.2 (C), 80.8 (CH2), 127.1 (C), 128.3
(CH), 128.5 (CH), 129.1 (CH), 129.3 (CH), 129.8
(CH), 129.9 (CH), 132.9 (C), 136.9 (C), 138.6 (CH).
LCMS m/z 377 (M+H+); TR = 3.66; purity (UV,
ELSD): 90%, 99%.
CH2Cl2 (2·) and THF (2·). The resin was dried under
vacuum at rt. A freshly prepared solution of 2-bromo-
2-(N-tert-butoxycarbonylamino)acetic acid methyl es-
ter31 (800 mg, 3.0 mmol) in THF (10 mL) under argon
was sucked into the syringe containing M-PS. The slurry
was shaken for 30 min at rt. The solution was pressed
out in a dry flask flushed with argon. The syringe was
washed with dry THF (2 mL) leading to a total volume
of 12.5 mL.
6.1.45. 5-Benzyl-1-benzyloxy-4-iodopyrazole (10i). The
title compound was prepared according to the procedure
described for 10b starting with 8i (265 mg, 1 mmol) and
gave crude 10i (379 mg). TLC (toluene/petroleum ether/
1
EtOAc 4:4:1) Rf 0.5. H NMR (CDCl3) d 3.74 (s, CH2,
The concentration of the solution was determined by
taking out 1 mL of the solution and adding this to a
dry flask containing MeOH (1 mL). Concentration of
the mixture gave the a-methoxy compound, 2-(N-tert-
butoxycarbonylamino)-2-methoxyacetic acid methyl es-
ter (37 mg), leading to a calculated concentration of
the solution (0.17 M, overall yield 71%). The yields of
subsequent reactions were in the range of 69–79%.
2H), 5.02 (s, CH2, 2H), 7.10–7.34 (m, 11H). 13C NMR
(CDCl3) d 30.1 (CH2), 56.9 (C), 80.2 (CH2), 126.8
(CH), 128.4 (CH), 128.7 (CH), 128.7 (CH), 129.4
(CH), 129.8 (CH), 133.3 (C), 136.2 (C), 136.8 (C),
137.6 (CH). m/z (EI) 390 (11%), 373, 91 (100%). HRMS
m/z found: 391.0298 [M+H+]. Calcd for C17H16IN2O:
391.0307 [M+H+].
6.1.46. 1-Benzyloxy-4-iodo-5-phenylethylpyrazole (10j).
The title compound was prepared according to the pro-
cedure described for 10b starting with 8j (209 mg,
0.75 mmol) and gave crude 10j (293 mg). TLC (tolu-
ene/petroleum ether/EtOAc 4:4:1) Rf 0.4. 1H NMR
(CDCl3) d 2.62–2.69 (m, 2· CH2, 4H), 5.10 (s, CH2,
2H), 7.07–7.08 (m, 2H), 7.16–7.36 (m, 9H). 13C NMR
(CDCl3) d 26.5 (CH2), 33.9 (CH2), 55.8 (C), 80.1
(CH2), 126.4 (CH), 128.5 (CH), 128.6 (CH), 128.8
(CH), 129.5 (CH), 129.9 (CH), 133.6 (C), 136.5 (C),
137.6 (CH), 140.5 (C).
6.1.50. (RS)-2-(1-Benzyloxy-4-pyrazolyl)-2-(N-tert-but-
oxycarbonylamino)acetic acid methyl ester (12). 1-Ben-
zyloxy-4-iodo-pyrazole (9) (582 mg, 1.94 mmol) was
dissolved in THF and cooled to 0 ꢁC. i-PrMgCl
(1.2 mL, 2.4 mmol, 1.24, 2 M) was added over 1 min.
The mixture was left stirring for 30 min at 0 ꢁC and then
cooled to ꢀ78 ꢁC. The imine 11 (11.5 mL, 0.17 M,
1.96 mmol) in THF was added slowly. The mixture
turned from turbid to clear yellow. The mixture was
slowly warmed from ꢀ78 ꢁC to rt over several hours.
Satd NH4Cl (aq) was added followed by extraction
using EtOAc (3·). The pooled organic phases were
washed with brine and dried using MgSO4. FC (F,
petroleum ether/EtOAc) gave 12 (291 mg, 42%). TLC
(petroleum ether/EtOAc 3:1) Rf 0.25. 1H NMR (CDCl3)
d 1.43 (s, t-bu, 9H), 3.69 (s, CH3, 3H), 5.22–5.24 (m,
CH2, a-CH, 3H), 5.45 (br d, J = 8 Hz, NH, 1H), 7.03
(s, H-5 or H-3, 1H), 7.26–7.36 (m, H-3 or H-5, phenyl,
6H). 13C NMR (CDCl3) d 25.4 (CH3), 49.6 (CH), 52.8
(CH3), 80.4 (C), 80.8 (CH2), 115.1 (C), 121.7 (CH),
128.8 (CH), 129.4 (CH), 129.8 (CH), 131.8 (CH), 133.6
(C), 155.0 (C), 171.3 (C).
6.1.47. 1-Benzyloxy-4-iodo-5-(3-phenyl-propyl)pyrazole
(10k). The title compound was prepared according to
the procedure described for 10b starting with 8k
(663 mg, 2.3 mmol) and gave crude 10e (939 mg). TLC
(toluene/petroleum ether/EtOAc 4:4:1) Rf 0.4. 1H
NMR (CDCl3) d 1.63 (quintet, J = 8 Hz, CH2CH2CH2,
2H), 2.25 (t, J = 8 Hz, CH2, 2H), 2.44 (t, J = 8 Hz, CH2,
2H), 5.10 (s, CH2, 2H), 7.05 (d, J = 7 Hz, 2H), 7.08–7.09
(m, 3H), 7.14–7.22 (m, 6H). 13C NMR (CDCl3) d 23.8
(CH2), 29.2 (CH2), 35.3 (CH2), 55.5 (C), 80.1 (CH2),
126.0 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH), 129.4
(CH), 129.9 (CH), 133.4 (C), 137.3 (C), 137.5 (CH),
141.3 (C). m/z (EI) 418 (2%), 314, 297, 105, 91 (100%).
HRMS m/z found: 441.0450 [M+Na+]. Calcd for
C19H19IN2ONa: 441.0440 [M+Na+].
6.1.51. (RS)-2-(1-Benzyloxy-5-bromo-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13a).
The title compound was prepared according to the pro-
cedure described for 12 starting with 10a (242 mg,
0.64 mmol). FC (F, petroleum ether/EtOAc) and recrys-
tallization (petroleum ether/EtOAc) gave white crystal-
line 13a (92 mg, 33%, recovered 42 mg of a mixture of
8a and 10a). Mp 137.5–137.5 ꢁC. TLC (petroleum
6.1.48. 5-Benzhydryl-1-benzyloxy-4-iodopyrazole (10l).
The title compound was prepared according to the pro-
cedure described for 10b starting with 8l (628 mg,
1.8 mmol) and gave crude 10l (832 mg). TLC (toluene/
petroleum ether/EtOAc 4:4:1) Rf 0.47. 1H NMR
(CDCl3) d 4.80 (s, CH2, 2H), 5.73 (CH), 7.06–7.34 (m,
16H). 13C NMR (CDCl3) d 47.1 (CH), 56.9 (C), 79.6
(CH2), 127.1 (CH), 128.6 (CH), 128.7 (CH), 129.2
(CH), 129.4 (CH), 129.7 (CH), 133.3 (C), 137.1 (C),
138.6 (CH), 139.3 (C).
1
ether/EtOAc 2:1) Rf 0.4. H NMR (CDCl3) d 1.44 (s,
t-bu, 9H), 3.73 (s, CH3, 3H), 5.22–5.39 (m, a-CH,
CH2, NH, 4H), 7.34 (s, H-3, 1H), 7.37–7.40 (m, phenyl,
5H). 13C NMR (CDCl3) d 28.4 (C), 49.5 (CH), 52.9
(CH3), 80.5 (C), 81.3 (CH2), 107.2 (C), 115.5 (C),
128.7 (CH), 129.7 (CH), 130.1 (CH), 132.8 (C.), 132.9
(CH), 154.8 (C), 170.6 (C).
6.1.49. 2-(N-tert-Butoxycarbonylimino)acetic acid methyl
ester (11). The title compound was prepared according
to Nakamura et al.17 with modifications. Morpholinom-
ethyl-polystyrene (1.25 g, 3.6 mmol/g, 4.5 mmol) was
placed in a 20 mL syringe with filter and washed with
6.1.52. (RS)-2-(1-Benzyloxy-5-ethyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13b).
The title compound was prepared according to the proce-
dure described for 12 starting with 10b (194 mg,
0.59 mmol). FC (F, petroleum ether/EtOAc) gave 13b

3536
C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
(147 mg, 64%, recovered 24 mg of 8b). TLC (petroleum
ether/EtOAc 2:1) Rf 0.19. H NMR (CDCl3) d 1.04 (t,
to the procedure described for 12 starting with 10f
(508 mg, 1.43 mmol). FC (F, petroleum ether/EtOAc)
gave 13f (289 mg, 48%, recovered 151 mg of 8f). TLC
(petroleum ether/EtOAc 2:1) Rf 0.37. 1H NMR (CDCl3)
d 0.17 (br t, J = 6 Hz, CH2, 2H), 0.43 (br d, J = 9 Hz,
CH2, 2H), 0.87–0.89 (m, CH, 1H), 1.43 (s, t-bu, 9H),
2.31 (br d, J = 8 Hz, CH2, 2H), 3.71 (s, CH3, 3H),
5.18–5.42 (m, CH2, a-CH and NH, 4H), 7.21 (s, H-3,
1H), 7.27–7.32 (m, phenyl, 5H). 13C NMR (CDCl3) d
4.8 (CH2), 9.7 (CH), 27.3 (CH2), 28.2 (CH3), 49.1
(CH), 52.4 (CH3), 79.9 (CH2 and C), 111.9 (C), 128.5
(CH), 129.2 (CH), 129.6 (CH), 130.8 (CH), 133.5 (C),
134.7 (C), 154.8 (C), 171.5 (C).
1
J = 8 Hz, CH3, 3H), 1.44 (s, t-bu, 9H), 2.42 (q,
J = 7 Hz, CH2, 2H), 3.72 (s, CH3, 3H), 5.15–5.30 (m, a-
CH, NH, CH2, 4H), 7.18 (br s, H-3), 7.28–7.38 (m, phe-
nyl, 5H). 13C NMR (CDCl3) d 13.2 (CH3), 16.4 (CH2),
28.4 (CH3), 49.2 (CH), 52.7 (CH3), 80.1 (CH2), 80.3
(C), 111.7 (C), 128.7 (CH), 129.4 (CH), 129.9 (CH),
130.8 (CH), 133.7 (C), 136.6 (C), 154.9 (C), 171.6 (C).
6.1.53. (RS)-2-(1-Benzyloxy-5-propyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13c).
The title compound was prepared according to the pro-
cedure described for 12 starting with 10c (493 mg,
1.44 mmol). FC (F, petroleum ether/EtOAc) gave 13c
(258 mg, 44%, recovered 153 mg of 8c). TLC (petroleum
6.1.57. (RS)-2-(1-Benzyloxy-5-cyclohexylmethyl-4-pyraz-
olyl)-2-(N-tert-butoxycarbonylamino)acetic acid methyl
ester (13g). The title compound was prepared according
to the procedure described for 12 starting with 10g
(562 mg, 1.42 mmol). FC (F, petroleum ether/EtOAc)
gave 13g (333 mg, 51%, recovered 173 mg of 8g). TLC
(petroleum ether/EtOAc 2:1) Rf 0.39. 1H NMR (CDCl3)
d 0.83–0.91 (m, 2H), 1.09–1.15 (m, 3H), 1.43 (s, t-bu,
9H), 1.50–1.63 (m, 6H), 2.24 (d, J = 7 Hz, CH2, 2H),
3.70 (s, CH3, 3H), 5.13–5.39 (m, a-CH, NH, CH2,
4H), 7.20 (s, H-3, 1H), 7.27–7.35 (m, 5H). 13C NMR
(CDCl3) d 26.0 (CH2), 26.1 (CH2), 28.2 (CH3), 30.1
(CH2), 32.7 (CH2), 32.9 (CH2), 37.2 (CH), 49.0 (CH),
52.3 (CH3), 79.7 (CH2), 79.8 (C), 112.3 (C), 128.5
(CH), 129.2 (CH), 129.6 (CH), 130.6 (CH), 133.6 (C),
134.1 (C), 154.7 (C), 171.5 (C).
1
ether/EtOAc 2:1) Rf 0.4. H NMR (CDCl3) d 0.87 (t,
J = 8 Hz, CH3, 3H), 1.43–1.47 (m and br s, t-bu and
CH2, 11H), 2.36 (t, J = 7 Hz, CH2, 2H), 3.71 (s, CH3,
3H), 5.14–5.32 (m, a-CH, NH, CH2, 4H), 7.19 (br s,
H-3, 1H), 7.28–7.37 (m, phenyl, 5H). 13C NMR (CDCl3)
d 13.8 (CH3), 21.9 (CH2), 24.7 (CH2), 28.3 (CH3), 49.2
(CH), 52.5 (CH3), 79.9 (CH2), 80.1 (C), 112.0 (C),
128.7 (CH), 129.3 (CH), 129.8 (CH), 130.8 (CH), 133.7
(C), 135.2 (C), 154.9 (C), 171.6 (C).
6.1.54. (RS)-2-(1-Benzyloxy-5-butyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13d).
The title compound was prepared according to the pro-
cedure described for 12 starting with 10d (358 mg,
1.01 mmol). FC (F, petroleum ether/EtOAc) gave 13c
(201 mg, 48%, recovered 114 mg of 8d). TLC (petroleum
6.1.58. (RS)-2-(1-Benzyloxy-5-phenyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13h).
The title compound was prepared according to the pro-
cedure described for 12 starting with 10h (266 mg,
0.71 mmol). FC (F, petroleum ether/EtOAc) gave 13h
(229 mg, 74%, recovered 45 mg of 8h). TLC (petroleum
ether/EtOAc 2:1) Rf 0.22. 1H NMR (CDCl3) d 1.42 (s, t-
bu, 9H), 3.66 (s, CH3, 3H), 5.07–5.27 (m, a-CH, NH,
CH2, 4H), 6.97 (d, J = 7 Hz, 2H), 7.17 (t, J = 8Hz,
2H), 7.25–7.40 (m, 7H). 13C NMR (CDCl3) d 28.3
(CH3), 49.3 (CH), 52.6 (CH3), 80.2 (C), 80.6 (CH2),
112.9 (C), 126.7, 128.4, 128.5, 129.0, 129.2, 129.7,
129.9, 131.4 (CH), 133.0, 135.2, 154.8 (C), 171.6 (C).
1
ether/EtOAc 2:1) Rf 0.4. H NMR (CDCl3) d 0.86 (t,
J = 9 Hz, CH3, 3H), 1.25–1.29 (m, CH2, 2H), 1.38–1.43
(m, CH2, 2H), 1.43 (s, t-bu, 9H), 2.34–3.38 (m, CH2,
2H), 3.71 (s, CH3, 3H), 5.14–5.32 (m, a-CH, NH, CH2,
4H), 7.19 (br s, H-3, 1H), 7.28–7.37 (m, phenyl, 5H).
13C NMR (CDCl3) d 13.7 (CH3), 22.4 (CH2), 28.3,
28.3, 30.6, 49.2 (CH), 52.5 (CH3), 79.9 (CH2), 79.9 (C),
111.8 (C), 128.6 (CH), 129.3 (CH), 129.8 (CH), 130.8
(CH), 133.7 (C), 135.4 (C), 154.8 (C), 171.6 (C).
6.1.55. (RS)-2-(1-Benzyloxy-5-pentyl-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13e).
The title compound was prepared according to the pro-
cedure described for 12 starting with 10e (301 mg,
0.81 mmol). FC (F, petroleum ether/EtOAc) gave 13c
(163 mg, 46%, recovered 106 mg of 8e). TLC (petroleum
6.1.59. (RS)-2-(5-Benzyl-1-benzyloxy-4-pyrazolyl)-2-(N-
tert-butoxycarbonylamino)acetic acid methyl ester (13i).
The title compound was prepared according to the pro-
cedure described for 12 starting with 10i (379 mg,
0.97 mmol). FC (F, petroleum ether/EtOAc) gave 13i
(264 mg, 60%, recovered 64 mg of 8i). TLC (petroleum
1
ether/EtOAc 2:1) Rf 0.27. H NMR (CDCl3) d 0.85 (t,
J = 7 Hz, CH3, 3H), 1.21–1.28 (m, 2· CH2, 4H), 1.43
(br s, t-bu and CH2, 11H), 2.36 (t, J = 8 Hz, ArCH2,
2H), 3.69 (s, CH3, 3H), 5.16 (br d, J = 7 Hz, NH or a-
CH), 5.25 (s, CH2, 2H), 5.48 (br d, J = 7 Hz, NH or
a-CH), 7.19–7.35 (m, phenyl and H-3, 6H). 13C NMR
(CDCl3) d 13.7 (CH3), 22.1 (CH2), 22.6 (CH2), 28.0
(CH2 or CH3), 28.1 (CH2 or CH3), 31.3 (CH2), 49.0
(CH), 52.3 (CH3), 79.7 (CH2), 79.7 (C), 111.7 (C),
128.5 (CH), 129.1 (CH), 129.6 (CH), 130.7 (C), 133.5
(CH), 135.2 (C), 154.7 (C), 171.4 (C).
1
ether/EtOAc 2:1) Rf 0.21. H NMR (CDCl3) d 1.41 (s,
t-bu, 9H), 3.63 (s, CH3, 3H), 3.80 (s, CH2, 2H), 5.02-
5.22 (m, a-CH, NH, CH2, 4H), 7.07–7.36 (m, 11H).
13C NMR (CDCl3) d 28.3 (CH3), 28.7 (CH2), 49.3
(CH), 52.6 (CH3), 80.1 (CH2), 80.2 (C), 112.8 (C),
126.8 (CH), 128.4 (CH), 128.7 (CH), 129.4 (CH), 129.9
(CH), 131.3 (CH), 133.4 (C), 133.5 (C), 137.3 (C),
154.8 (C), 171.4 (C).
6.1.56. (RS)-2-(1-Benzyloxy-5-cyclopropylmethyl-4-pyraz-
olyl)-2-(N-tert-butoxycarbonylamino)acetic acid methyl
ester (13f). The title compound was prepared according
6.1.60. (RS)-2-(1-Benzyloxy-5-phenylethyl-4-pyrazolyl)-
2-(N-tert-butoxycarbonylamino)acetic acid methyl ester
(13j). The title compound was prepared according to the

C. G. Jørgensen et al. / Bioorg. Med. Chem. 15 (2007) 3524–3538
3537
procedure described for 12 starting with 10j (274 mg,
0.68 mmol). FC (F, petroleum ether/EtOAc) gave 13j
(155 mg, 49%, recovered 89 mg of 8j). TLC (petroleum
mGluR2 and mGluR4a was assessed by measuring
intracellular cAMP levels as previously described.9,40
1
ether/EtOAc 2:1) Rf 0.3. H NMR (CDCl3) d 1.43 (s,
t-bu, 9H), 2.67–2.73 (m, 2· CH2, 4H), 3.71 (s, CH3,
3H), 5.09–5.18 (m, a-CH, NH, CH2, 4H), 7.07–7.36
(m, 11H). 13C NMR (CDCl3) d 25.2 (CH2), 28.4
(CH3), 34.5 (CH2), 49.3 (CH), 52.6 (CH3), 80.0 (CH2),
80.2 (C), 112.2 (C), 126.4 (CH), 128.5 (CH), 128.6
(CH), 128.8 (CH), 129.4 (CH), 129.8 (CH), 131.1
(CH), 133.7 (C), 134.4 (C), 140.6 (C), 154.9 (C),
171.5 (C).
Acknowledgments
The authors wish to acknowledge Erling B. Jørgensen,
H. Lundbeck A/S, for determining the pKa values. This
work was supported by the Danish Medical Research
Council and the Novo Nordisk Foundation.
References and notes
6.1.61. (RS)-[1-Benzyloxy-5-(3-phenylpropyl)-4-pyrazol-
yl]-tert-butoxycarbonylamino)acetic acid methyl ester
(13k). The title compound was prepared according to
the procedure described for 12 starting with 10k
(447 mg, 1.07 mmol). FC (F, petroleum ether/EtOAc)
gave 13k (219 mg, 43%, recovered 150 mg of 8k). TLC
(petroleum ether/EtOAc 2:1) Rf 0.34. 1H NMR (CDCl3)
d 1.43 (s, t-bu, 9H), 1.77 (br quintet, J = 8 Hz,
CH2CH2CH2, 2H), 2.38 (br t, J = 7 Hz, CH2, 2H),
2.44 (t, J = 8 Hz, CH2, 2H), 3.69 (s, CH3, 3H), 5.13–
5.29 (m, a-CH, NH and CH2, 4H), 7.12–7.26 (m,
11H). 13C NMR (CDCl3) d 22.4 (CH2), 28.3 (CH3),
29.9 (CH2), 35.5 (CH2), 49.2 (CH), 52.6 (CH3), 80.0
(CH2), 80.2 (C), 112.1 (C), 126.0 (CH), 128.4 (CH,
128.3989), 128.4 (CH, 128.4496), 128.7 (CH), 129.3
(CH), 129.8 (CH), 130.9 (CH), 133.5 (C), 135.0 (C),
141.4 (C), 154.9 (C), 171.5 (C).
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´
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