Synthesis and Oxidative Cleavage of 1- and 2-Alkyl Derivatives of (exo,exo)-5,6-Dihydroxy-4,5,6,7-tetrahydro-4,7-methanoindazoles

Article abstract of DOI:10.1055/s-2003-41047

Reaction of hydrazine with exo,exo-3-hydroxymethylene-5,6-isopropylidenedioxybicyclo[2.2.1]heptan-2-one led to norbornenepyrazole 7, which was converted to its 1- and 2-alkyl derivatives. Deprotection of the vicinal hydroxyls, oxidative cleavage of the resulting glycol and reduction of the dialdehyde so obtained afforded 1- and 2-alkylcyclopenta[c]pyrazole-4,6-dimethanols, which are of interest as intermediates in the preparation of nucleoside analogues derived from 1H- and 2H-cyclopenta[c]pyrazole.

Full text of DOI:10.1055/s-2003-41047

2138
PAPER
Synthesis and Oxidative Cleavage of 1- and 2-Alkyl Derivatives of (exo,exo)-
5,6-Dihydroxy-4,5,6,7-tetrahydro-4,7-methanoindazoles
Alkyl
Derivatives of
(
e
a
xo
,
exo)-5,6
r
-Dihydr
o
xy-4,5,6,7
o
-tetrahydro-4
s
,7-methanoinda
D
zoles aniel García,a Olga Caamaño,*a Franco Fernández,a María José Figueira,a Generosa Gómezb
a
Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Fax +34(98)1594912; E-mail: qoolga@usc.es
b
Departamento de Química Orgánica, Facultade de Ciencias, Lagoas-Marcosende, Universidade de Vigo, 36200 Vigo, Spain
Received 20 June 2003
We ourselves recently prepared analogous carbocyclic
compounds,7,8 in which a purine or pyrimidine base is
linked to an indan system. Some of these show consider-
able cytostatic activity against human T lymphocytes
Abstract: Reaction of hydrazine with exo,exo-3-hydroxymethyl-
ene-5,6-isopropylidenedioxybicyclo[2.2.1]heptan-2-one led to nor-
bornenepyrazole 7, which was converted to its 1- and 2-alkyl
derivatives. Deprotection of the vicinal hydroxyls, oxidative cleav-
age of the resulting glycol and reduction of the dialdehyde so ob- (Molt4/C8 and CEM/0). We are currently9 interested in
tained afforded 1- and 2-alkylcyclopenta[c]pyrazole-4,6-dimeth-
anols, which are of interest as intermediates in the preparation of nu-
replacing the benzene ring of these compounds with a va-
riety of heterocyclic systems with a view to modifying
cleoside analogues derived from 1H- and 2H-cyclopenta[c]pyra-
both lipophilicity and the polar interactions of the pseu-
zole.
dosugar moiety while retaining structural rigidity.
Key words: indazoles, pyrazoles, heterocycles, alkylations, cleav-
Here we report the synthesis of 1- and 2-alkyl derivatives
of exo,exo-5,6-dihydroxy-4,5,6,7-tetrahydro-4,7-metha-
noindazole (5 and 6, respectively) (Figure 2), and of 1-
and 2-alkylcyclopenta[c]pyrazole-4,6-dimethanols ob-
tained these by oxidative cleavage of the glycol and re-
duction of the resulting dialdehyde. It is envisaged that the
dimethanols will be easily convertible into carbocyclic
analogues of nucleosides by well-known synthetic proce-
dures.10
age, nucleosides
Among the many modifications that have been made to
nucleosides with a view to increasing their therapeutic
power and scope, one of the most successful has been the
introduction of a double bond between positions 2 and 3
of the sugar ring, which gives 2 ,3 -didehydro-2 ,3 -
dideoxyribonucleosides (d4Ns). It has been known since
the original work of Balzarini et al.1 that the d4Ns derived
from cytosine (d4C) 1 and thymidine (d4T) 2 (Figure 1),
both possess anti-HIV activity, and the latter is now mar-
keted for clinical use under the name (Stavudine®).2 It has
been hypothesized that its antiviral activity is in great part
due to the conformational restrictions imposed by the dou-
ble bond in the pseudosugar moiety3 and to its lipophilic-
ity facilitating access to the central nervous system, which
is a major HIV reservoir.4 The carbocyclic nucleoside an-
alogues carbovir (3) and abacavir (4), which have double
bonds in the same position as d4Ns, also possess great
anti-HIV activity.5,6
R
HO
HO
HO
HO
N
N
N
R
N
5a (R = Et)
6a (R = Et)
5b (R = Me)
6b (R = Me)
Figure 2
Compounds 5 and 6 were prepared by constructing the
pyrazole ring on the bicyclic hydroxymethylene ketone
711 (Scheme 1). In a first attempt, compound 7 was treated
for 45 minutes with hydrazine dihydrochloride in reflux-
ing anhydrous ethanol, and after removal of the solvent
the product of this reaction was taken into methanol and
passed through a basic ion exchange resin [Amberlite
IRA-400 (OH)], affording exo,exo-5,6-dihydroxy-
4,5,6,7-tetrahydro-4,7-methano-2H-indazole (8). In order
to prevent deprotection of the hydroxyl groups, the reac-
tion was then carried out using hydrazine hydrate, after
which the solvent was removed and the resulting residue
was refluxed in toluene for 12 hours, giving compound 9.
In both cases the major product was the 2H tautomer (vide
infra), which was attributed, following Elguero et al.12
(who worked with the simpler compound, 1,4,5,6-tetrahy-
drocyclopenta[c]pyrazole), to the strained ring favouring
the Mills–Nixon tautomer (the one with the ring-fusing
X
X
R
N
N
NH
NH2
O
O
N
N
HO
N
HO
3: X = OH
4: X = NH
1: X = NH2, R = H
2: X = OH, R = CH3
Figure 1
Synthesis 2003, No. 14, Print: 02 10 2003. Web: 22 08 2003.
Art Id.1437-210X,E;2003,0,14,2138,2144,ftx,en;P05203SS.pdf.
DOI: 10.1055/s-2003-41047
© Georg Thieme Verlag Stuttgart · New York

PAPER
Alkyl Derivatives of (exo,exo)-5,6-Dihydroxy-4,5,6,7-tetrahydro-4,7-methanoindazoles
2139
bond of lesser order). In our case the plausibility of this ar-
gument is increased by the methylene bridge making the
rings of 8 and 9 more strained than in 1,4,5,6-tetrahydro-
cyclopenta[c]pyrazole, as in the camphor derivative 7,8,8-
trimethyl-4,5,6,7-tetrahydro-4,7-methanoindazole.13
However, the predominance of the 2H tautomers is also in
keeping with the well-known fact that for a 3,4-dialkyl-
substituted pyrazole the most abundant tautomer is the
less acidic (Gustafsson’s paradox).14
Treatment of 9 with triethyloxonium tetrafluoroborate af-
1
forded, according to H NMR spectroscopy, an approxi-
Figure 3
mately 9:1 mixture of the 1- and 2-ethyl derivatives 10
and 11, which were converted almost quantitatively into
the desired products 5a and 6a, respectively, by hydroly-
sis of their isopropylidene protecting groups.
of 9 with methyl iodide in the presence of sodium hydride
gave a mixture (1:2, 1H NMR) of 13 and 14 in 90%. This
mixture was cleanly separated in 79% yield by MPLC.
Hydrolysis of 13 and 14 then afforded the desired prod-
ucts 5b and 6b, respectively, in high yield (88–90%).
To obtain the corresponding methyl derivatives 5b and
6b, we first attempted a convergent approach, reacting ke-
tone 7 with N-methylhydrazine; but the only product of
the reaction after 15 minutes in toluene was the alcohol
12, the structure of which was confirmed by X-ray crys-
tallographic analysis of a single crystal (Figure 3),15 while
reaction in ethanol gave only a 24% yield of 5b.
The assignment of the hydrogens of 8 and 9, and of the
alkyls of 6a, 6b, 11 and 14, to position 2, and of the alkyls
of 5a, 5b, 10 and 13 to position 1, was based on the chem-
ical shifts of C3 and C7a (Table 1).13,16 The C3 signals in
the spectra of 8 ( =121.10), 9 ( = 121.71) and 6a, 6b, 11
and 14 ( = 122.17–123.60) were all very close and lay
about 9 ppm upfield from those of 5a, 5b, 10 and 13 ( =
131.00–132.46), while the C-7a signals of 8, 9, 6a, 6b, 11
and 14 lay in the interval = 161.08–162.27, about 10
ppm downfield from those of 5a, 5b, 10 and 13 ( =
150.66–151.90).
We therefore proceeded as for the ethyl derivatives, ob-
taining the intermediates 13 and 14 by methylation of 9.
An attempt at methylation with diazomethane completely
failed; only unreacted 9 could be isolated. Methylation
with trimethyloxonium tetrafluoroborate afforded the 1-
methyl derivative 13 in only 51% yield, whereas reaction
Me
i) N2H4·(HCl)2, EtOH
HO
CH3N2H3
toluene
O
O
O
O
ii) Amberlite IRA-400 (OH-)
N
O
N
NH
OH
N
OH
59%
39%
HO
7
8
12
i) N2H4·H2O, EtOH
ii) toluene, reflux
52%
i) CH3N2H3, EtOH
ii) HCl, 1N
24%
NaH, MeI
THF
O
N
13 + 14
NH
90%
O
9
80%
Et3OBF4, CH2Cl2
Me
N
Et
N
HCl 12N
O
O
O
O
N
N
EtOH
5b
N
Et
N
+
88%
O
O
13
10
11
+
HCl 12N
EtOH
HCl 12N
EtOH
99%
97%
64%
HCl 12N
O
N
EtOH
6b
N
Me
5a
6a
90%
O
i) SiO2, NaIO4, H2O, CH2Cl2
ii) NaBH4, MeOH
70%
14
HO
OH
OH
HO
15
16
N
N
Et
N
N
Et
Scheme 1
Synthesis 2003, No. 14, 2138–2144 © Thieme Stuttgart · New York

2140
M. D. García et al.
PAPER
Table 1 13C NMR Chemical Shift ( ) Data of Bicyclopyrazoles 5, 6, 8–11, 13 and 14.
C7a
C3a
C3
C4,C7
C5,C6
C8
NCH3
37.24
NCH2CH3 NCH2CH3 C(CH3)3
C(CH3)3
5a
5b
150.73
127.32
131.68
45.79,
45.12
72.06,
71.09
46.31,
46.08
46.08,
46.31
16.09
151.50
150.66
151.90
162.15
161.78
161.08
162.27
161.64
161.94
126.85
127.55
127.50
126.71
125.31
124.75
124.62
124.62
125.09
131.00
132.25
132.46
121.10
122.17
123.47
121.71
122.09
123.60
45.09,
44.89
71.44,
69.99
46.09
10
43.15,
42.39
83.54,
81.82
46.81,
46.16
46.16,
46.81
16.01
114.55
114.56
26.42,
24.76
13
8
42.81,
42.75
83.44,
81.69
46.96
37.70
38.38
38.84
26.41,
24.73
45.08,
44.06
72.18,
71.15
45.20
6a
46.22,
44.82
72.93,
71.27
47.00,
45.20
45.20,
47.00
16.17
16.18
6b
9
72.09,
71.08
44.78
45.24,
44.26
42.87,
41.71
83.29,
82.24
45.91
113.63
113.56
113.58
26.31,
24.68
11
43.09,
42.00
83.41,
82.42
47.04,
45.66
45.66,
47.04
26.33,
24.70
14
43.02,
41.96
83.39,
82.40
45.64
26.31,
24.66
Finally, oxidative cleavage of 5a and 6a, followed by re-
duction of the resulting dialdehydes, afforded the
corresponding cyclopenta[c]pyrazole-4,6-dimethanol de-
rivatives 15 and 16 in satisfactory yields (64 and 70%,
respectively). Oxidative cleavage of 5a and 6a was
performed using sodium periodate on silica gel,17 subse-
quently followed by reduction of the the dialdehyde inter-
mediate with NaBH4 in MeOH; no attempt was made at
1
isolation, because in the H NMR spectrum of the crude
oxidation products, the existence of two aldehyde groups
was clearly shown by the presence of two distinct singlets
in the = 9.65–9.70 region. Unequivocal determination of
the structure of 15 by X-ray crystallography (Figure 4)15
corroborated the position of the ethyl group of 5a and
showed that no epimerization had occurred during the tan-
dem oxidation–reduction process (which was presumably
also the case for 16).
All chemicals used were of reagent grade and were obtained from
Aldrich Chemical Co. and used without further purification. Mps
were measured in a Reichert Kofler Thermopan and are uncorrect-
ed. Infrared spectra were recorded on a Perkin–Elmer 1640 FTIR
Figure 4
1
spectrophotometer. H and 13C NMR spectra were recorded in a
Bruker AMX 300 spectrometer at 300 and 75.47 MHz, respectively,
using TMS as internal standard (chemical shifts in values, J in
Hz). Mass spectra were recorded on a Kratos MS-59 spectrometer.
Microanalyses were performed in a Perkin–Elmer 240B Elemental
Analyser at the University of Santiago Microanalysis Service. Anal-
yses indicated by the symbols of elements were within 0.4% of the
theoretical values. Flash chromatography was performed on silica
gel (Merck 60, 230–240 mesh) and analytical TCL on pre-coated
silica gel plates (Merck 60 F254, 0.25 mm). MPLC separations were
carried out using a Biotage Flash 4Di system with a Biotage column
(Si-40B, silica gel). X-ray diffraction data were collected in an En-
raf–Nonius CAD4 automatic diffractometer using the program
CAD4-EXPRESS.
( )-(exo,exo)-5,6-Dihydroxy-4,5,6,7-tetrahydro-4,7-methano-
2H-indazole (8)
Hydrazine dihydrochloride (0.15 g, 1.44 mmol) was added under
argon to a solution of freshly prepared 7 (0.30 g, 1.44 mmol) in an-
Synthesis 2003, No. 14, 2138–2144 © Thieme Stuttgart · New York

PAPER
Alkyl Derivatives of (exo,exo)-5,6-Dihydroxy-4,5,6,7-tetrahydro-4,7-methanoindazoles
2141
hyd EtOH (10 mL) at 5–10 ºC, and the mixture was refluxed for 45
min and then concentrated to dryness. The residue was taken into
MeOH (5 mL) and loaded on a column packed with Amberlite IRA-
400 (OH–) (14 mL), which was then eluted with MeOH (100 mL).
The alkaline eluate was concentrated to dryness and the resulting
solid residue (0.30 g) was washed with cold EtOH (15 mL) leaving
8.
Compound 10
Mp 64–65 ºC.
IR (KBr): 2984, 1534, 1436, 1387, 1369, 1261, 1205, 1167, 1058,
1024, 1012, 986, 964, 907, 870, 787 cm–1.
1H NMR (CDCl3): = 1.31 (s, 3 H, CH3), 1.45 (t, 3 H, J = 7.34 Hz,
CH2CH3), 1.51 (s, 3 H, CH3), 2.22 (dd, 1 H, J = 9.34, 1.43 Hz, HH-
8), 2.49 (dd, 1 H, J = 9.33, 1.51 Hz, HH-8), 3.20 (virtual s, 1 H, H-
7 or H-4), 3.29 (virtual s, 1 H, H-4 or H-7), 4.10 (q, 2 H, J = 7.33
Hz, CH3CH2), 4.16 (d, H, J = 5.24 Hz, H-6 or H-5), 4.22 (d, 1 H,
J = 5.24 Hz, H-5 or H-6), 7.14 (s, 1 H, H-3).
Yield: 0.14 g (59%); white solid (that was recrystallized from
EtOH); mp 246–250 ºC.
IR (KBr): 3493, 3250, 2990, 2933, 2859, 2717, 1150, 1071, 1048,
962 cm–1.
EIMS: m/z (%) = 234 (M, 1), 147 (5), 134 (2), 119 (2), 92 (1), 58
(100).
1H NMR (DMSO-d6): = 1.81 (d, 1 H, J = 8.99 Hz, HH-8), 2.23 (d,
1 H, J = 8.99 Hz, HH-8), 2.95 (d, 2 H, J = 4.08 Hz, H-7, H-4), 3.46
(virtual s, 2 H, H-5, H-6), 4.94 (d, 1 H, D2O exch., J = 4.30 Hz, OH),
4.99 (d, 1 H, D2O exch., J = 4.30 Hz, OH), 7.24 (s, 1 H, H-3), 11.94
(br s, 1 H, D2O exch., NH).
Anal. Calcd for C13H18N2O2 (234.29): C, 66.64; H, 7.74; N, 11.96.
Found: C, 66.86; H, 7.85; N, 12.07.
Compound 11
EIMS: m/z (%) = 166 (M, 6), 137 (21), 121 (14), 119 (15), 109 (11),
107 (22), 106 (100), 105 (35), 92 (12), 80 (17), 79 (30), 65 (12), 54
(12), 53 (12), 52 (26), 51 (13).
Mp 75–76 ºC.
IR (KBr): 2988, 2939, 1570, 1457, 1380, 1332, 1262, 1207, 1177,
1666, 1056, 1026, 981, 961, 867, 796, 775 cm–1.
Anal. Calcd for C8H10N2O2 (166.17): C, 57.82; H, 6.07; N, 16.86.
Found: C, 58.02; H, 5.99; N, 17.02.
1H NMR (CDCl3): = 1.30 (s, 3 H, CH3), 1.42 (t, 3 H, J = 7.26 Hz,
CH2CH3), 1.51 (s, 3 H, CH3), 2.10 (dd, 1 H, J = 9.40, 1.29 Hz, HH-
8), 2.45 (dd, 1 H, J = 9.40, 1.23 Hz, HH-8), 3.11 (virtual s, 1 H, H-
7 or H-4), 3.28 (virtual s, 1 H, H-4 or H-7), 4.06 (dq, 2 H, J = 7.30,
5.72 Hz, CH3CH2), 4.19 (d, H, J = 5.24 Hz, H-6 or H-5), 4.27 (d, 1
H, J = 5.24 Hz, H-5 or H-6), 6.97 (s, 1 H, H-3).
( )-(exo,exo)-5,6-(Isopropylidenedioxy)-4,5,6,7-tetrahydro-4,7-
methano-2H-indazole (9)
Hydrazine hydrate (0.61 mL, 19.72 mmol) was added under argon
to a well-stirred solution of freshly prepared 7 (2.06 g, 9.86 mmol)
in anhyd EtOH (50 mL), and the mixture was refluxed for 5 h and
then concentrated to dryness. The residue was taken into toluene (50
mL), this solution was refluxed for a further 12 h and concentrated
to dryness, and purification of the resulting residue (2.68 g) on a col-
umn (silica gel; hexane–EtOAc, 1:1), followed by concentration to
dryness afforded 9.
EIMS: m/z (%) = 235 (M + 1, 1), 234 (M, 7), 205 (M – Et, 2), 148
(7), 147 (53), 134 (12), 119 (20), 92 (9), 65 (6), 59 (6), 58 (100).
Anal. Calcd for C13H18N2O2 (234.29): C, 66.64; H, 7.74; N, 11.96.
Found: C, 66.81; H, 7.92; N, 11.89.
( )-(3aR*,4R*,5R*,6S*,7R*,7aR*)-7a-Hydroxy-5,6-isopropyl-
idenedioxy-1-methyl-3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-
indazole (12)
Yield: 1.06 g (52%); white solid (that was washed with pentane);
mp 147–149 ºC.
N-Methylhydrazine (0.20 g, 4.30 mmol) was added under argon to
a well-stirred solution of freshly prepared 7 (0.48 g, 2.30 mmol) in
anhyd toluene (25 mL) in an ice bath, and the mixture was stirred
for 15 min at r.t., after which removal of the solvent under reduced
pressure left a brownish oily residue (0.70 g) that upon purification
by chromatography (silica gel; hexane–EtOAc, 15:1) afforded 12.
IR (KBr): 3250, 2984, 2934, 1462, 1446, 1379, 1263, 1212, 1160,
1068, 1052, 1026, 866, 577 cm–1.
1H NMR (CDCl3): = 1.31 (s, 3 H, CH3), 1.52 (s, 3 H, CH3), 2.13
(ddd, 1 H, J = 9.55, 6.81, 2.75 Hz, HH-8), 2.49 (ddd, 1 H, J = 9.48,
6.78, 2.60 Hz, HH-8), 3.26 (virtual s, 1 H, H-4), 3.33 (virtual s, 1 H,
H-7), 4.21 (d, 2 H, J = 5.21 Hz, H-6 or H-5), 4.28 (d, 1 H, J = 5.21
Hz, H-5 or H-6), 7.15 (s, 1 H H-3), 12.01 (br s, 1 H, D2O exch., NH).
Yield: 0.21 g (39%); lightly coloured solid that was crystallized
from EtOAc–pentane; mp 144–145 ºC.
EIMS: m/z (%) = 207 (M + 1, 1.5), 206 (M, 9), 177 (9), 120 (12),
119 (100), 106 (14), 93 (7), 92 (16), 65 (8).
IR (KBr): 3512, 3187, 2996, 2954, 1646, 1571, 1466, 1447, 1380,
1338, 1303, 1268, 1238, 1220, 1208, 1182, 1161, 1021, 1071, 1043,
969, 812 cm–1.
1H NMR (CDCl3): = 1.20 (d, 1 H, J = 11.11 Hz, HH-8), 1.45 (s, 3
H, CH3), 1.32 (s, 3 H, CH3), 1.66 (dd 1 H, J = 11.12, 1.56 Hz, HH-
8), 2.13 (virtual s, 1 H), 2.33 (virtual s, 1 H), 2.46 (virtual s, 1 H),
2.51 (virtual s, 1 H), 2.93 (s, 3 H, CH3), 4.28 (d, 1 H, J = 5.37 Hz,
H-6), 4.67 (d, 1 H, J = 5.37 Hz, H-5), 6.64 (s, 1 H, H-3).
Anal. Calcd for C11H14N2O2 (206.24): C, 64.06; H, 6.84; N, 13.58.
Found: C, 64.28; H, 6.99; N, 13.67.
( )-(exo,exo)-1-Ethyl-5,6-isopropylidenedioxy-4,5,6,7-tetrahy-
dro-4,7-methano-1H-indazole (10) and ( )-(exo,exo)-2-Ethyl-
5,6-isopropylidenedioxy-4,5,6,7-tetrahydro-4,7-methano-2H-
indazole (11)
EIMS: m/z (%) = 239 (M + 1, 11), 238 (M, 72), 223 (63), 220 (9),
164 (9), 163 (81), 162 (12), 133 (25), 124 (8), 111 (15), 99 (100), 98
(37), 97 (12), 83 (12), 82 (20), 81 (8), 66 (7), 58 (19).
A solution of 9 (1.50 g, 6.0 mmol) and Et3O·BF4 (3.70 g, 19.47
mmol) in anhyd CH2Cl2 (45 mL) was stirred under argon at r.t. for
21 h, sat. aq NaHCO3 (30 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (3 × 50 mL). The organic phase was dried
(Na2SO4) and concentrated to dryness, and the resulting yellowish
oil (1.69 g) was chromatographed (silica gel; hexane–EtOAc, 2:1).
Removal of the solvents from the early and late product-containing
fractions afforded 11 (54 mg) and 10 (0.71 g), respectively, as co-
lourless oils that were crystallized when stored in the refrigerator,
while the intermediate fractions gave a mixture of 10 and 11 (0.60
g) that was partially resolved by MPLC (hexane–EtOAc, 2:1) [the
early MPLC fractions contained a mixture of 10 and 11 (0.21 g), and
the later fractions pure 10 (0.36 g)]; overall yield (10 + 11), 80%.
Anal. Calcd for C12H18N2O3 (238.28): C, 60.49; H, 7.61; N, 11.76.
Found: C, 60.65; H, 7.83; N, 11.91.
Single crystals suitable for X-ray diffractometry were obtained by
dissolving crystals of 12 in the least possible quantity of cold Et2O
in an open vial that was then placed in a larger container with a little
pentane in its bottom; the container was closed, and after a few days
in a cool, dark place free from vibrations afforded the desired single
crystals.
Synthesis 2003, No. 14, 2138–2144 © Thieme Stuttgart · New York

2142
M. D. García et al.
PAPER
( )-(exo,exo)-5,6-Isopropylidenedioxy-1-methyl-4,5,6,7-tetra-
hydro-4,7-methano-1H-indazole (13) and ( )-(exo,exo)-5,6-Iso-
propylidenedioxy-2-methyl-4,5,6,7-tetrahydro-4,7-methano-
2H-indazole (14)
phy (silica gel; CH2Cl2–MeOH, 15:1) afforded 5b from which a
small sample was taken and washed with Et2O for analysis.
Yield: 0.08 g (24%); white solid; mp 150–151 ºC.
IR (KBr): 3358, 2977, 2932, 2876, 1444, 1176, 1078, 962 cm–1.
Method A
1H NMR (CDCl3): = 1.91 (ddd, 1 H, J = 9.08, 2.99, 1.49 Hz, HH-
8), 2.23 (ddd, 1 H, J = 8.93, 3.00, 1.50 Hz, HH-8), 2.91 (virtual s, 1
H, H-7), 3.14 (virtual s, 1 H, H-4), 3.39–3.44 (m, 2 H, H-5, H-6),
3.72 (s, 3 H, CH3), 4.88 (s, 1 H, D2O exch., OH), 5.08 (s, 1 H, D2O,
exch., OH), 7.01 (s, 1 H, H-3).
A suspension of NaH (60%, 38 mg, 1.6 mmol) and 9 (0.20 g, 0.97
mmol) in anhyd THF (5 mL) was stirred for 20 min at r.t., methyl
iodide (514 mg, 3.6 mmol) was added, stirring was continued for a
further 30 min, H2O (20 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (3 × 50 mL). The pooled organic phases were
washed with H2O (50 mL), dried (Na2SO4) and concentrated to dry-
ness, and the resulting residue (250 mg) was resolved by MPLC
(hexane–EtOAc, 3:2). The first and last fractions afforded 14 (100
mg, 47%) and 13 (50 mg, 24%), respectively, as dense colourless
oils, and the intermediate fractions a mixture of compound 13 and
14 (40 mg, 19%).
EIMS: m/z (%) = 195 (M + 1, 1), 194 (M, 10), 147 (9), 134 (100),
133 (14), 119 (41), 107 (9), 106 (67), 105 (10), 92 (12), 79 (8), 77
(9).
Anal. Calcd for C9H12N2O2 (180.20): C, 59.99; H, 6.71; N, 15.55.
Found: C, 60.18; H, 6.85; N, 15.71.
Hydrolysis of the Isopropylidene Group; General Procedure
Aq HCl (12 M; 1.5 mL) was added to a stirred solution of the pyra-
zole derivative 10, 11, 13 or 14 (3 mmol) in EtOH (25 mL) in an
ice–H2O bath. This mixture was allowed to return to r.t. and was
then refluxed for 2 h. The solvents were removed, and the residue
was dissolved in MeOH (15 mL) and passed through a column
packed with Amberlite IRA-400 (OH–) (40 mL) using MeOH (250
mL) as eluent. Evaporation of the solvent under reduced pressure
then afforded pyrazoles 5 and 6.
Compound 13
IR (film): 2925, 2855, 1732, 1458, 1379, 1271 cm–1.
1H NMR (CDCl3): = 1.32 (s, 3 H, CH3), 1.50 (s, 3 H, CH3), 2.21
(d, 1 H, J = 9.35 Hz, HH-8), 2.49 (d, 1 H, J = 9.35 Hz, HH-8), 3.25
(virtual s, 1 H), 3.20 (virtual s, 1 H), 3.80 (s, 3 H, CH3), 4.16–4.21
(m, 2 H, H-5 + H-6), 7.13 (s, 1 H, H-3).
EIMS: m/z (%) = 220 (M, 22), 205 (9), 134 (11), 133 (100), 131 (6),
120 (16), 119 (23), 118 (20), 106 (10), 92 (12), 85 (9), 77 (8), 66 (5),
65 (6).
( )-(exo,exo)-1-Ethyl-5,6-dihydroxy-4,5,6,7-tetrahydro-4,7-
methano-1H-indazole (5a)
HRMS: m/z calcd for C12H16N2O2: 220.1212; found: 220.1231.
Yield: 97%; white solid from which a small sample was taken and
washed with Et2O for analysis; mp 112–114 ºC.
Compound 14
IR (film): 2986, 2946, 1570, 1424, 1392, 1372, 1255, 1206, 1169,
1064, 1022, 985, 870, 811, 518 cm–1.
IR (KBr): 3394, 2980, 2934, 1416, 1335, 1179, 1162, 1076, 1015,
960 cm–1.
1H NMR (CDCl3): = 1.29 (s, 3 H, CH3), 1.50 (s, 3 H, CH3), 2.08
(dt, 1 H, J = 9.42, 1.44 Hz, HH-8), 2.43 (dt, 1 H, J = 9.42, 1.44 Hz,
HH-8), 3.20 (virtual s, 1 H), 3.26 (virtual s, 1 H), 3.77 (s, 3 H, CH3),
4.17 (d, 1 H, J = 5.28 Hz, H-6 or H-5), 4.25 (d, 1 H, J = 5.28 Hz, H-
5 or H-6), 6.92 (s, 1 H, H-3).
1H NMR (CDCl3): = 1.44 (t, 3 H, J = 7.32 Hz, CH2CH3), 2.14 (d,
1 H, J = 9.54 Hz, HH-8), 2.37 (d, 1 H, J = 9.54 Hz, HH-8), 3.12
(virtual s, 1 H, H-7), 3.23 (virtual s, 1 H, H-4), 3.64–3.65 (m, 1 H,
the residual H2O signal overlaps this signal, addition of D2O simpli-
fies both this signal and at = 3.70–3.75, H-5 and H-6), 3.70–3.72
(m, 1 H), 3.86–3.88 (m, 2 H, D2O exch., 2 OH), 4.13 (q, 2 H,
J = 7.32 Hz, CH3CH2), 7.10 (s, 1 H, H-3).
EIMS: m/z (%) = 220 (M, 1), 167 (28), 149 (100), 133 (15), 118
(41), 104 (3), 88 (4), 85 (3), 71 (8), 58 (92), 57 (18), 52 (6).
HRMS: m/z calcd for C12H16N2O2: 220.1212; found: 220.1226.
EIMS: m/z (%) = 194 (M, 10), 165 (1), 147 (9), 134 (100), 133 (14),
120 (5), 119 (41), 118 (4), 107 (9), 106 (67), 105 (10), 93 (4), 92
(12), 80 (5), 79 (7), 77 (9), 65 (5).
Method B
A solution of Me3O·BF4 (1.0 g, 6.76 mmol) in anhyd CH2Cl2 (10
mL) was added under argon to a solution of 9 (0.2 g, 0.97 mmol) in
CH2Cl2 (10 mL) at –10º C. This mixture was stirred for 24 h, and
then sat. aq NaHCO3 (10 mL) was added. The mixture was extract-
ed with CH2Cl2 (3 × 100 mL), and the organic phase was dried
(Na2SO4) and concentrated to dryness, affording a yellowish oil
(0.21 g) that was passed through a column (silica gel; hexane–
EtOAc, 1:3). Removal of the solvent from the product-containing
fractions yielded 13 with spectroscopic data identical to those of the
compound obtained by Method A.
Anal. Calcd for C10H14N2O2 (194.23): C, 61.84; H, 7.27; N, 14.42.
Found: C, 61.96; H, 7.41; N, 14.33.
( )-(exo,exo)-2-Ethyl-5,6-dihydroxy-4,5,6,7-tetrahydro-4,7-
methano-2H-indazole (6a)
Yield: 99%; white solid, from which a small sample was taken and
washed with Et2O for analysis; mp 115–116 ºC.
IR (KBr): 3497, 3189, 3003, 2983, 2942, 1570, 1458, 1428, 1395,
1358, 1333, 1277, 1174, 1154, 1140, 1069, 1017, 995, 969, 818,
759, 748 cm–1.
Yield: 0.11 g (51%); colourless oil.
1H NMR (CDCl3): = 1.41 (t, 3 H, J = 7.27 Hz, CH2CH3), 2.04 (d,
1 H, J = 9.54 Hz, HH-8), 2.40 (d, 1 H, J = 9.54 Hz, HH-8), 3.19 (d,
2 H, J = 1.93 Hz, H-4, H-7), 3.70 (d, 1 H, J = 5.25 Hz, H-5, H-6),
3.81 (dd, 1 H, J = 5.70, 0.94 Hz), 4.04 (q, 2 H, J = 7.27 Hz,
CH3CH2), 5.00 (br s, 2 H, D2O exch., 2 OH), 6.97 (s, 1 H, H-3).
( )-(exo,exo)-5,6-Dihydroxy-1-methyl-4,5,6,7-tetrahydro-4,7-
methano-1H-indazole (5b)
N-Methylhydrazine (0.17 g, 3.74 mmol) was added under argon in
one portion to a well-stirred solution of freshly prepared 7 (0.40 g,
1.91 mmol) in anhyd EtOH (25 mL) in an ice bath, and the mixture
was stirred for 15 min at r.t., treated with aq HCl (1 M; 1 mL), re-
fluxed for 30 min, and concentrated to dryness. The residue (0.60 g)
was dissolved in MeOH (15 mL) and passed through a column
packed with Amberlite IRA-400 (200 mL; OH–) using MeOH (200
mL) as eluent. Evaporation of the solvent under reduced pressure
left a solid residue (0.41 g) that upon purification by chromatogra-
EIMS: m/z (%) = 194 (M, 30), 165 (30), 149 (17), 135 52, 134 (70),
133 (20), 119 (100), 105 (52), 92 (28), 80 (18), 77 (16), 65 (21), 58
(62).
Anal. Calcd for C10H14N2O2 (194.23): C, 61.84; H, 7.27; N, 14.42.
Found: C, 61.65; H, 7.19; N, 14.28.
Synthesis 2003, No. 14, 2138–2144 © Thieme Stuttgart · New York

PAPER
Alkyl Derivatives of (exo,exo)-5,6-Dihydroxy-4,5,6,7-tetrahydro-4,7-methanoindazoles
2143
( )-(exo,exo)-5,6-Dihydroxy-1-methyl-4,5,6,7-tetrahydro-4,7-
methano-1H-indazole (5b)
The spectroscopic data were identical to those of the compound 5b
obtained by condensation of 7 as described previously.
EIMS: m/z (%) = 197 (M + 1, 1), 196 (M, 11), 166 (11), 165 (100),
147 (13), 137 (26), 119 (24), 109 (21), 92 (12), 80 (10), 65 (10), 58
(24), 52 (11).
Anal. Calcd for C10H16N2O2 (196.24): C, 61,20; H, 8.22; N, 14.27.
Found: C, 61.39; H, 8.34; N, 14.46.
Yield: 88%; white solid.
( )-(exo,exo)-5,6-Dihydroxy-2-methyl-4,5,6,7-tetrahydro-4,7-
methano-2H-indazole (6b)
Yield: 90%; white solid, from which a small sample was recrystal-
lized from EtOAc for analysis; mp 160–161 ºC.
( )-cis-2-Ethylcyclopenta[c]pyrazole-4,6-dimethanol (16)
Obtained from 6a in the same way as 15 from 5a. A small quantity
was washed with Et2O for analysis.
Yield: 70%; white solid; mp 59–60 ºC.
IR (KBr): 3473, 3198, 2939, 1387, 1263, 1177, 1164, 1081, 1017,
971, 803, 785, 761, 602, 502 cm–1.
1H NMR (CDCl3): = 1.78 (d, 1 H, J = 9.08 Hz, HH-8), 2.20 (d, 1
H, J = 9.08 Hz, HH-8), 2.93 (d, 2 H, J = 10.17 Hz, H-4, H-7), 3.46
(virtual s, 2 H, H-5, H-6), 3.67 (s, 3 H, CH3), 4.96–4.98 (m, 2 H,
D2O, exch., 2 × OH), 7.21 (s, 1 H, H-3).
IR (KBr): 3356, 2935, 1654, 1560, 1400, 1154, 1035 cm–1.
1H NMR (CDCl3): = 1.45 (t, 3 H, J = 7.33 Hz, CH3), 1.88 (dt, 1 H,
J = 13.52, 6.02 Hz, HH-5), 2.19 (br s, 2 H, D2O exch., 2´OH), 2.71
(dt, 1 H, J = 13.52, 8.66 Hz, HH-5), 3.20–3.34 (m, 2 H), 3.60 (dd, 1
H, J = 10.31, 6.56 Hz), 3.64–3.76 (m 2 H), 3.84 (dd, 1 H, J = 10.59,
5.50 Hz), 4.10 (dq, 2 H, J = 7.35, 7.18 Hz, CH3CH2), 7.12 (s, 1 H,
H-3).
13C NMR (CDCl3): = 161.54 (C3a), 125.94 (C6a), 123.45 (C3),
67.18 and 66.12 (2 CH2OH), 47.58 (CH3CH2), 40.60 (C6), 39.40
(C5), 36.81 (C4), 16.23 (CH3).
EIMS: m/z (%) = 181 (M + 1, 5), 180 (M, 36), 151 (36), 149 (12),
135 (24), 133 (18), 123 (15), 120 (100), 119 (81), 105 (33), 93 (25)
92 (13), 77 (10), 58 (17).
Anal. Calcd for C9H12N2O2 (180.20): C, 59.99; H, 6.71; N, 15.55.
Found: C, 60.34; H, 6.83; N, 15.67.
EIMS: m/z (%) = 197 (M + 1, 4), 196 (M, 15), 166 (31), 165 (100),
147 (59), 137 (22), 135 (15), 134 (11), 119 (43), 109 (14), 92 (10).
( )-cis-1-Ethylcyclopenta[c]pyrazole-4,6-dimethanol (15)
An aq solution of NaIO4 (0.65 M; 6.25 mL, 4.0 mmol) was added
dropwise to a vigorously stirred suspension of chromatography
grade silica gel (6.25 g) in CH2Cl2 (50 mL). After addition of com-
pound 5a (0.56 g, 2.88 mmol) in CH2Cl2 (5 mL) to the resulting
flaky solution, stirring was continued for other 15 min and then
passed through a filter pad onto a small quantity of Na2SO4; the re-
tained silica gel was washed with CH2Cl2 (10 mL) and the washings
were pooled with the filtrate. Removal of the solvent left the dialde-
hyde as an oily reddish residue, which was dissolved in MeOH (25
mL). NaBH4 (0.7 g, 15.31 mmol) was added in a single portion and
stirring was continued for 10 min. After cooling with an ice bath,
H2O (10 mL) was added. The MeOH was removed under reduced
pressure. The aq solution was neutralized (pH 7) with aq HCl (2 M),
and concentrated to dryness. The resulting solid residue was ex-
tracted with hot EtOAc (4 × 100 mL), and removal of the solvent
from the pooled extracts under reduced pressure afforded 15 (0.36
g, 64%) as a dense oil that crystallized upon treatment with Et2O.
Single crystals suitable for X-ray diffractometry were obtained by
dissolving a sample of 15 in the least possible quantity of cold
EtOAc in an open vial that was then placed in a larger container
with a little hexane in its bottom; the container was closed, and after
a few days in a cool, dark place free from vibrations afforded the de-
sired single crystals, one of which was analysed by X-ray diffracto-
metry.
HRMS: m/z calcd for C10H16N2O2: 196.1212; found: 196.1236.
Acknowledgments
The authors thank the Xunta de Galicia for financial support under
project PGIDT01PXI20302PR.
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IR (KBr): 3418, 1639, 1552, 1205, 742 cm–1.
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Synthesis 2003, No. 14, 2138–2144 © Thieme Stuttgart · New York