Structure determination of N-methyl-tetrahydro-5H-indazol-5-ones

Article abstract of DOI:10.1002/jhet.5570430328

This paper communicates the (regio) synthesis and a convenient NMR structural assignment method for N-methyl-tetrahydro-5H-indazol-5-one isomers. The cyclization reaction of 7-(hydroxymethylene)-1,4-dioxaspiro[4,5]decan-8-one (3) with methylhydrazine yiel

Full text of DOI:10.1002/jhet.5570430328

May-Jun 2006
719
Structure Determination of N-Methyl-tetrahydro-5H-indazol-5-ones
Kurt A. Josef,* Reddeppareddy Dandu, Ming Tao, and Robert L. Hudkins
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA, 19380 USA
Received September 30, 2005
O
O
O
O
O
O
O
3
1) CH3NHNH2
CH3OH
2) 2N HCl
acetone
O
O
or
N
N
N
N
1
2
This paper communicates the (regio) synthesis and a convenient NMR structural assignment method for
N-methyl-tetrahydro-5H-indazol-5-one isomers. The cyclization reaction of 7-(hydroxymethylene)-1,4-
dioxaspiro[4,5]decan-8-one (3) with methylhydrazine yields, after de-protection predominately the N-2
methyl isomer 2. Analysis of the product ratio and structural assignments are based on NMR data
including NOE difference experiments and subsequently confirmed with X-ray crystallography. These
findings are in sharp contrast with the literature. The experimental conditions used to optimize the
synthesis of the individual isomers are discussed.
J. Heterocyclic Chem., 43, 719 (2006).
N-Alkyl-tetrahydroindazoles have long been of interest
utilizes the key hydroxymethylidene ketal intermediate 3,
which is synthesized from commercially available 1,4-
cyclohexanedione monoethylene ketal (Scheme 1).
Indazolone isomer 1 was reported as the major product
after condensation of 3 with N-methylhydrazine in
methanol (0-65 ºC) and subsequent ketal removal.
Repeating the procedure exactly did give a major
isomer; in our hands we found that keeping the initial
temperature at -30 ºC was optimal to give this isomer at
about 9:1 over the minor isomer. It was found, as
reported, that the ratio of isomeric products changes to 1:1
in methanol at reflux [6]. However, after analysis of the
reaction it remained unclear as to which ketal isomer
to synthetic organic chemists since first described by von
Auwers [1]. Compounds comprised of these structures
have been used throughout industry in many applications,
ranging from anti-oxidants in rubber products [2], to
intestinal bile acid transporters [3], to inhibitors of blood
platelet aggregation [4] and thrombin [5]. Numerous
synthetic approaches to tetrahydroindazoles have been
described
which
produce
substituted
pyrazole
regioisomers. In this paper we describe the structural
characterization of the isomers of N-methyl-tetrahydro-
5H-indazol-5-one using NMR methods. The structural
assignments were confirmed using X-ray crystallography.
Scheme 1
1) CH3NHNH2
CH3OH
O
O
O
O
O
or
O
O
N
N
N
N
O
O
2) 2N HCl
acetone
3
1
2
For a medicinal chemistry lead optimization program
we required the synthesis of both the N1-methyl and N2-
methyl-tetrahydro-5H-indazol-5-ones. We initiated the
general synthesis to the presumed N1-methyl ꢀ-ketone
isomer based on a literature report [6]. The synthesis
represented the major product. The mixture of ketal
isomers was deprotected at 60 ºC in equal volumes of
acetone and 2 N HCl. The resulting keto isomers 1 and 2
were separated by silica gel chromatography. The major
isomer was the first to elute in a 9:1 ratio over the minor

720
K. A. Josef, R. Dandu, M. Tao, and R. L. Hudkins
Vol 43
isomer. Both compounds are slightly orange solids that
appear to be light and air sensitive. The mechanism for
formation of each regioisomer is consistent with methyl-
hydrazine condensation with either the hydroxymethylene
(aldehyde) [1] or the dimethylamino methylidene moiety
of cyclohexanedione [7]. The isomeric product ratio
changes depending on the conditions used. At lower tem-
peratures, the greater nucleophilicity of the methyl
bearing nitrogen of hydrazine drives the reaction. As the
temperature increases, that selectivity is lost. After
careful 1H NMR structural analysis the two N-methyl
isomers 1 and 2, the N2-methyl isomer 2 was assigned as
the major product. In a similar system of N-methyl
menthopyrazoles [8], the N2 isomer is also reported as the
major isomer.
Figure 2
technique to rapidly and accurately assign the correct
indazole isomer even when only one isomer was
available. A 1D NOE difference experiment on 2
resulted in a 5% enhancement at ꢀ 7.15 when irradiating
the N2-methyl at ꢀ 3.87. This result clearly indicates that
the methyl and the pyrazole C3-hydrogen are in close
proximity to each other. In contrast, under the same
conditions (irradiating the N1-methyl at ꢀ 3.79) an NOE
was not observed for 1. Taken together, the NMR data
described clearly supports the structural assignments
made.
The H3 proton on 1 and 2 is located at ꢀ 7.27 and ꢀ
7.15, respectively (Figure 1). An N2-methyl substituted
tetrahydroindazole would exhibit the C3 pyrazole proton
at a higher field than the corresponding N1-methyl
isomer; owing to the fact that an olefinic “like” proton is
more shielded than the C3-proton of an imine [9].
The structural assignments of the N-methyl-tetra-
hydroindazolones were further confirmed by X-ray
crystallography. Suitable crystals of ketones 1 and 2 for
defraction could not be obtained. Therefore, the toluene-
sulfonylhydrazone derivatives were prepared and
crystallized (Scheme 2). The reaction of ketone isomer 2
and p-toluenesulfonyl hydrazide gave 7 as an off-white
solid. The product was recrystallized from ethyl alcohol
to produce colorless plates, which were suitable for X-ray
structure determination [13]. Isomer 6 was obtained from
ketone 1 in a similar fashion to give colorless blocks.
Figure 1
Further verification of these structural assignments was
observed in the 13C NMR spectra of 1 and 2, where the
same pattern was exhibited (Figure 2); the N1-methyl
isomer has the lower field shift for the pyrazole C3-
carbon (136.0 ppm) compared to the N2-methyl isomer
with a C3 shift of 127.8 ppm [10]. Proton coupled 13C
spectra were also obtained in an attempt to find a three
bond splitting pattern caused by spin lattice interactions of
an N2 methyl substituent. Our results for 1 and 2 clearly
show the expected doublet for the pyrazole proton (J =
184 Hz), but no fine quartets (J = 2.5 Hz) can be observed
relating to the N2 methyl as described by Nagarajan [11].
The characterization of the two regioisomers can be
Scheme 2
O
O
S
N
N
O
N
N
N
N
CH3
CH3
1 or 2
6 or 7
The X-ray crystal structure data derived for each N-
methyl-tetrahydroindazol-5-one isomer unequivocally
confirms the NMR assignments of the methyl positions of
the two regioisomers. Hydrazone 6 is the N1-methyl
substituted product derived from isomer 1 (Figure 3),
while hydrazone 7, prepared from isomer 2, is the N2-
methyl isomer (Figure 4).
readily made by H and 13C NMR when both compounds
1
are available. Similar assignments have been reported
using 15N NMR, by directly comparing both isomers [12].
We were also interested in identifying a routine NMR

May-Jun 2006
Structure Determination of N-Methyl-tetrahydro-5H-indazol-5-ones
721
Acknowledgement.
The authors wish to acknowledge Dr. Diane Gingrich
and Dr. Ed Bacon for useful discussions. The authors also
wish to thank ValueTek Inc., Princeton, NJ 08540 for
large scale support.
EXPERIMENTAL
NMR studies were performed on a 400 MHz Bruker DRX
system using TMS as an internal standard. Mass spectra data
were collected on a Bruker Esquire 2000 LC-MS system.
Melting points are uncorrected. Elemental analysis were perfor-
med by Quantitative Technologies, Inc., 291 Route 22 East,
Whitehouse, NJ 08888.
7-(Hydroxymethylene)-1,4-dioxaspiro[4,5]decan-8-one (3)
A mixture of NaH (60%, 19.2 g, 0.48 mol), ethyl formate
(59.2 g, 0.80 mol), and 100 mL EtOH in 500 mL dry THF was
charged with 1,4-cyclohexanedione monoethylene ketal (62.5 g,
0.40 mol) in 200 mL dry THF slowly over 90 minutes at 0 °C.
After 1 h at 25 °C, the mixture was refluxed 2 h and then cooled.
After dilution with ether, the mixture was extracted with 1 N
NaOH. The aqueous layer was acidified to pH 4 with conc. HCl
and then extracted with methylene chloride. After drying
(MgSO4), the solvent was removed to yield a dark oil that
crystallizes upon standing to give 66.7 g (90%) of 7-(hydroxy-
methylene)-1,4-dioxaspiro[4,5]decan-8-one (3); mp 72-74 °C;
1H nmr (deuteriochloroform): ꢀ 1.87 (dd, J = 6.9 Hz, 2H), 2.56
(m, 4H), 4.00 (s, 4H), 8.52 (s, 1H), 14.40 (bs, 1H); MS (m/e)
185 (M+).
6
Figure 3. Ortep drawing of compound 6.
1-Methyl-1,4,6,7-tetrahydro-5H-indazol-5-one (1) and 2-methyl-
2,4,6,7-tetrahydro-5H-indazol-5-one (2)
To a solution of 7-(hydroxymethylene)-1,4-dioxaspiro[4,5]-
decan-8-one (3) (10 g, 54.5 mmol) in 200 mL MeOH at -30 °C
was added methylhydrazine (3.0 mL, 56.5 mmol). The reaction
was warmed to ambient temperature and concentrated to yield
an amber oil that was dissolved in 100 mL acetone and 100 mL
2 N HCl. The solution was heated to 60 °C for 2 hours,
concentrated, then neutralized with NaHCO3. After extraction
with methylene chloride and drying (MgSO4), the isomers were
seperated on silica gel with 70% ethyl acetate/hexanes. The first
eluting isomer was triturated with diethyl ether to yield 2.94 g
(36%) of 2-methyl-2,4,6,7-tetrahydro-5H-indazol-5-one (2); mp
87-90 °C; 1H nmr (deuteriochloroform) ꢀ 2.69 (dd, J = 6.9 Hz,
2H), 3.05 (dd, J = 7.1 Hz, 2H), 3.42 (s, 2H), 3.87 (s, 3H), 7.15
(s, 1H); 13C nmr (deuteriochloroform) ꢀ 22.27, 35.91, 38.84,
39.55, 112.93, 127.80, 147.10, 209.63; MS (m/e) 151 (M+).
Anal. Calcd. for C8H10N2O·1.1H2O: C, 56.53; H, 7.23;
N, 16.48. Found: C, 56.47; H, 7.01; N, 16.17.
The second eluting isomer was also triturated with diethyl
ether to yield 0.33 g (4%) of 1-methyl-1,4,6,7-tetrahydro-5H-
indazol-5-one (1). mp 86-89 °C; 1H nmr (deuteriochloroform): ꢀ
2.71 (dd, J = 6.9 Hz, 2H), 3.00 (dd, J = 7.0 Hz, 2H), 3.41 (s,
2H), 3.79 (s, 3H), 7.27 (s, 1H); 13C nmr (deuteriochloroform) ꢀ
20.42, 36.02, 36.06, 37.99, 113.34, 136.03, 136.19, 208.64; MS
(m/e) 151 (M+).
7
Figure 4. Ortep drawing of compound 7.
In conclusion, this paper describes an NMR method to
correctly assign the individual N1/N2-methyl tetrahydro-
indazole isomers. The NMR methods described provide
efficient methods to accurately assign isomers of N-
methyl-tetrahydro-5H-indazol-5-ones when both regio-
isomers are available. An NOE difference experiment can
also reveal an N2-methyl tetrahydroindazole, while the
N1-methyl isomer is more difficult to detect. The
condensation of ketal 3 with methylhydrazine and
subsequent deprotection clearly provide a high yielding
regioselective route to the N2-methyl isomer 2.

722
K. A. Josef, R. Dandu, M. Tao, and R. L. Hudkins
Vol 43
8.0 Hz, 2H), 7.46 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 10.20 (s,
1H); MS (m/e) 319 (M+).
4-Methyl-N'-(1-methyl-1,4,6,7-tetrahydro-5H-indazol-5-yl-
idene)benzenesulfonohydrazide (6).
Anal. Calcd. for C15H18N4O2S: C, 56.58; H, 5.70; N, 17.60.
An oven dried flask was charged with 1-methyl-1,4,6,7-
tetrahydro-5H-indazol-5-one (1) (0.3 g, 2 mmol) and p-toluene-
sulfonyl hydrazide (0.39 g, 2.09 mmol) followed by MeOH (10
mL). The resulting mixture was stirred at ambient temperature
for 1 hr then filtered, washed with MeOH, ether and dried
to furnish 0.4 g (63%) of 4-Methyl-N'-(1-methyl-1,4,6,7-
tetrahydro-5H-indazol-5-ylidene)benzenesulfonohydrazide (6).
Recrystallized from ethyl alcohol to afford quality crystals; mp
Found: C, 56.03; H, 5.47; N, 17.50.
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Chem. Abstr., 138, 238335 (2003).
1
168.3 °C; H nmr (dimethyl sulfoxide -d6) ꢀ 2.38 (s, 3H), 2.46
(dd, J = 6.6 Hz, 2H), 2.72 (dd, J = 6.6 Hz, 2H), 3.35 (s, 2H),
3.64 (s, 3H), 7.19 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.75 (d, J =
8.2 Hz, 2H), 10.24 (s, 1H); MS (m/e) 319 (M+).
[4] T. Kuroita, M. Bogauchi, M. Fujio, H. Nakagawa, JP 1171865
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Ammon, Dept. of Chemistry, University of Maryland. Coordinates
available in Cambridge database.
Anal. Calcd. for C15H18N4O2S: C, 56.58; H, 5.70; N, 17.60.
Found: C, 56.38; H, 5.60; N, 17.54.
4-Methyl-N'-(2-methyl-2,4,6,7-tetrahydro-5H-indazol-5-ylidene)-
benzenesulfonohydrazide (7).
An oven dried flask was charged with 2-methyl-2,4,6,7-tetra-
hydro-5H-indazol-5-one (1) (1.5 g, 10 mmol) and p-toluene-
sulfonyl hydrazide (1.95 g, 10.48 mmol) followed by MeOH (60
mL). The resulting mixture was stirred at ambient temperature for
1 hr then filtered, washed with MeOH, ether and dried to give 2.8
g (88%) of 4-Methyl-N'-(2-methyl-2,4,6,7-tetrahydro-5H-indazol-
5-ylidene)benzenesulfonohydrazide (7). Recrystallized from
1
ethyl alcohol to afford quality crystals; mp 165.2 °C; H nmr
(dimethyl sulfoxide-d6) ꢀ 2.38 (s, 3H), 2.43 (dd, J = 6.6 Hz, 2H),
2.62 (dd, J = 6.6 Hz, 2H), 3.39 (s, 2H), 3.73 (s, 3H), 7.39 (d, J =