Orthogonal regioselective synthesis of N-alkyl-3-substituted tetrahydroindazolones

Article abstract of DOI:10.1002/ejoc.201000516

A divergent strategy for the regioselective and orthogonal synthesis of complementary regioisomers of N-alkyl-3-substituted-tetrahydroindazolones 3 and 4 was achieved from. Boc-protected alkylhydrazmes 1. The robustness and sub-strate generality of this method were validated by synthesizing 3 and. 4 through the intra- and intermolecular condensation of 1 with various 2-acylcyclohexane-l,3-diones 2 and aldehydes, respectively.

Full text of DOI:10.1002/ejoc.201000516

FULL PAPER
DOI: 10.1002/ejoc.201000516
Orthogonal Regioselective Synthesis of N-Alkyl-3-substituted
Tetrahydroindazolones
Jonghoon Kim,[a] Heebum Song,[a] and Seung Bum Park*[a,b]
Dedicated to the memory of Professor Chi Sun Hahn
Keywords: Nitrogen heterocycles / Protecting groups / Regioselectivity / Synthetic methods
A divergent strategy for the regioselective and orthogonal
synthesis of complementary regioisomers of N-alkyl-3-sub-
stituted-tetrahydroindazolones 3 and 4 was achieved from
Boc-protected alkylhydrazines 1. The robustness and sub-
strate generality of this method were validated by synthesiz-
ing 3 and 4 through the intra- and intermolecular condensa-
tion of 1 with various 2-acylcyclohexane-1,3-diones 2 and al-
dehydes, respectively.
Introduction
The efficient synthesis of privileged heterocycles is a cru-
cial issue in diversity-oriented synthesis (DOS), combinato-
rial chemistry, and medicinal chemistry, because many nat-
ural compounds and small molecules containing hetero-
cyclic units have been identified as potential drug candi-
dates with a wide range of biological activities.[1] Indazoles
and indazolones are prominent heterocycles that show vari-
ous biological activities such as anti-inflammatory, antivi-
ral, and anticancer activities (see Figure 1).[2,3] In particular,
SNX-2122, which contains a tetrahydroindazolone moiety,
has been identified as a potent heat shock protein 90
(HSP90) inhibitor and exhibits low nanomolar antiprolifer-
ative activities against multiple cancer cell lines. SNX-2122
is currently in phase III clinical trials.[4] Despite their
proven importance in biomedical research, regioselective
synthesis of N-alkyl-3-substituted tetrahydroindazolones
has not been studied extensively. A series of SNX com-
pounds have been synthesized by the simple condensation
of arylhydrazines with 2-acylcyclohexane-1,3-diones,[4,5] but
the regioselectivity of this reaction is significantly influ-
enced by the nature of the substrates, particularly by the
dinucleophiles used.
Figure 1. (a) Nitric oxide synthases (NOS) inhibitor; (b) anti-in-
flammatory agent; (c) anticancer agent; (d) highly potent inhibitors
of heat shock protein 90 (HSP 90).
As reported in the literature, a major strategy for the re-
gioselective synthesis of 1-aryltetrahydroindazolones in-
volves the condensation of the appropriate dielectrophiles
with an arylhydrazine in which the terminal and internal
amines have different nucleophilicities.[4–6] However, this
method cannot be extended to alkylhydrazines because of
the similar nucleophilicities of the two amines, which yields
[a] Department of Chemistry, College of Natural Sciences, Seoul regioisomeric mixtures of tetrahydroindazolone. There have
National University
been a few reports on regioselective syntheses involving the
151-747 Seoul, South Korea
condensation of alkylhydrazines with enaminedione[7] or
Fax: +82-2-884-4025
the formation of enehydrazone.[8a] However, the disadvan-
E-mail: sbpark@snu.ac.kr
[b] Department of Biophysics and Chemical Biology, Seoul
tage of these methods is that they have limited substrate
National University
generality.[7,8]
151-747 Seoul, South Korea
Fax: +82-2-884-4025
Synthetic chemists have also been investigating the re-
gioselective synthesis of 2-substituted tetrahydroindazol-
ones, which are the minor products obtained in most con-
E-mail: sbpark@snu.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000516.
Eur. J. Org. Chem. 2010, 3815–3822
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3815

J. Kim, H. Song, S. B. Park
FULL PAPER
densation reactions of 2-acylcyclohexane-1,3-dione. Some Table 1. Regioisomeric ratio (3/4) in the synthesis of tetrahydro-
indazolones by the conventional condensation of 2-acylcyclohex-
of the examples of such reactions that have been reported
are the condensation of the enol ether derivatives of 2-acyl-
ane-1,3-diones 2 with alkylhydrazines.[a]
cyclohexane-1,3-dione with arylhydrazine[6] and the con-
densation of a dimedone arylhydrazone with an aryl-
aldehyde.[9] However, 2-alkyl-3-substituted tetrahydroind-
azolones cannot be achieved regioselectively by these meth-
ods or by alkylation of unsubstituted tetrahydroindazol-
ones.[10] The cyclization of 1,3-cyclohexanedione alkyl-
hydrazone and N,N-dimethylformamide dimethyl acetal
is another reported method for the regioselective synthesis
of 2-alkyltetrahydroindazolones.[11] However, chromato-
graphic separation of regioisomeric mixtures of N-alkyl-3-
substituted tetrahydroindazolones is tedious or not possible
in many cases,[10] and the introduction of alkyl or aryl sub-
Ratio 3/4 when R2 =
stituents at the C-3 position is not feasible.[11]
R1
Me
Et
Ph
Cyclohexyl
Me
53:47
79:21
87:13
65:35
83:17
90:10
74:26
93:7
93:7
86:14
2-Hydroxyethyl
Propyl
2-Cyanoethyl
Benzyl
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
Results and Discussion
ϾϾ99:1 ϾϾ99:1 ϾϾ99:1
89:11 91:9 95:5
ϾϾ99:1 ϾϾ99:1 ϾϾ99:1
To address these issues, we aimed to develop a new
method to carry out orthogonal regioselective synthesis and
facile diversification to obtain complementary regioisomers
of N-alkyl-3-substituted tetrahydroindazolones, along with
our previous efforts in this field.[12] Initially, we investigated
the effect of the substituents at the R1 and R2 positions on
the regioisomeric ratio in the cyclization reaction of free
alkylhydrazines and 2-acylcyclohexane-1,3-diones 2 (see
Table 1); in this reaction, we obtained 1-alkyl-3-substituted
tetrahydroindazolones 3 as the major products with low re-
gioselectivity, as confirmed by 1D NOE experiments. Gen-
erally, regioisomers 3 and 4 cannot be separated by silica-
gel flash column chromatography; therefore, the regioisom-
Cyclopentyl
1
[a] Regioisomeric ratio was determined by H NMR spectroscopic
analysis of samples purified by silica-gel flash column chromatog-
raphy.
tary regioisomers, 2-alkyl-3-substituted tetrahydroindazol-
ones 4, could be synthesized in the following manner. En-
ehydrizines 5 were formed from the condensation of 1 with
dimedone. Deprotection of the Boc group and subsequent
cyclization with various aldehydes including alkyl, aryl, and
heteroaryl aldehydes afforded 4. In this manner, we could
efficiently synthesize complementary regioisomers by using
a divergent method.
1
eric ratio was determined by H NMR spectroscopy. High
regioselectivity was achieved in the conventional condensa-
tion when arylhydrazines were used, as mentioned in pre-
vious reports. Therefore, we did not extensively examine the
condensation reaction involving arylhydrazine in this study,
as its nitrogen atoms exhibit inherently different nucleophi-
licities. We also obtained excellent regioselectivity in the
conventional condensation of alkylhydrazine with 2 having
bulky substituents (cyclopentyl at the R1 position and cy-
clohexyl at the R2 position). This indicates that the regiose-
lectivity is affected by steric factors and can be enhanced
by the introduction of sterically hindered substituents at the
R1 and R2 positions. We also observed that electron-with-
drawing substituents at the R1 position can result in high
regioselectivity. In the case of 2-cyanoethylhydrazine, the in-
ternal amine is significantly less nucleophilic because of the
cyano group at the R1 position.
Scheme 1. Synthetic strategy (paths I and II) for orthogonal synthe-
sis of complementary regioisomers 3 and 4.
However, we aimed at the development of a robust and
The proposed synthetic method was validated by ex-
orthogonal method for the synthesis of complementary re- tending it for the synthesis of 3, particularly for the case
gioisomers from Boc-protected alkylhydrazines 1, 2-acylcy- where conventional methods afforded poor regioselectivity.
clohexane-1,3-diones 2, and aldehydes. As shown in As opposed to the reaction route involving a free alkyl-
Scheme 1, we carried out the regioselective synthesis of 1- hydrazine, the proposed method afforded desired products
alkyl-3-substituted tetrahydroindazolones 3 by the forma- 3a–i as single regioisomers in good yields. The Boc-pro-
tion of intermediate C, followed by the deprotection of the tected internal amine of the alkylhydrazines is not nucleo-
Boc group and subsequent condensation. The complemen- philic, which leads to the regioselective formation of inter-
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Eur. J. Org. Chem. 2010, 3815–3822

Orthogonal Synthesis of N-Alkyl-3-substituted Tetrahydroindazolones
Table 2. Regioselective synthesis of 1-alkyl-3-substituted tetrahydroindazolones 3 by using Path I via intermediate C.
Entry
Compound
R1
R2
Ratio 3/4[b]
Ratio 3/4[c,e]
Yield [%][f]
1
2
3
4
5
6
7
8
9
10
11
12[a]
13
14
15
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
methyl
propyl
benzyl
methyl
propyl
benzyl
methyl
propyl
benzyl
benzyl
propyl
methyl
propyl
methyl
methyl
methyl
ethyl
ethyl
ethyl
phenyl
phenyl
phenyl
53:47[c]
87:13[c]
89:11[c]
65:35[c]
90:10[c]
91:9[c]
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
ϾϾ99:1
88
80
80
81
73
66
73
67
66
60
70
85
62
62
76
74:26[c]
93:7[c]
95:5[c]
4-trifluorophenyl
2-methylthioethyl
trifluoromethyl
3-pyridylmethyl
methyl
95:5[c]
90:10[c]
75:25[d]
89:11[c]
85:15[c]
90:10[c]
2-pyridylmethyl
2-amino-2-oxoethyl
methyl
[a] Intermediate C formed in AcOH at room temperature. [b] Isomeric ratio obtained by the condensation of 2 with free alkylhydrazine
in EtOH at 60 °C. [c] Isomeric ratio determined by 1H NMR spectroscopic analysis. [d] Isomeric ratio determined from the purified yields
of each regioisomer. [e] Isomeric ratio determined by our method (Path I). [f] Isolated yield of a single regioisomer 3.
mediate C through condensation of 1 with 2. The desired screening under various acidic conditions, the optimum
products were obtained by subsequent treatment of inter- yield was obtained within a short time when the reaction
mediate C with formic acid for Boc deprotection and spon- was carried out at 100 °C in AcOH under microwave irradi-
taneous intramolecular condensation (Table 2, Entries 1–9). ation. As shown in Table 1, 4 is generally formed as the
In addition, we expanded the scope of the proposed reac- minor product in the conventional condensation reaction of
tion and demonstrated its efficiency by extending the substituted hydrazines with 2 and is not obtained in reason-
method to the synthesis of 3j–o; these syntheses were car- able amounts in some cases. By optimizing the reaction
ried out by introducing various substituents at the R2 posi- conditions, we successfully obtained a series of 2-alkyl-3-
tion of 2 and the R1 position of 1 (Table 2, Entries 11–15). substituted tetrahydroindazolones 4, which was confirmed
As previously mentioned, the separation of these regioiso- by 1D NOE experiments (see the Supporting Information).
mers was difficult or not possible by silica-gel flash column We successfully synthesized 4 as a single regioisomer, which
chromatography in most cases, but we measured the re- was the minor product or not obtained at all under the
gioisomeric ratio through chromatographic separation of conditions outlined in Tables 1 and 2 (Table 3, Entries 1–9).
two regioisomers with a trifluoromethyl substituent at the For example, we carried out the regioselective synthesis of
R2 position, synthesized through the simple cyclization of 2-methyl-3-phenyltetrahydroindazolone (4a) by Path II and
methylhydrazine with 5,5-dimethyl-2-(2,2,2-trifluoroacetyl)- its complementary regioisomer, 1-methyl-3-phenyltetra-
cyclohexane-1,3-dione. However, we were able to obtain hydroindazolone (3g), by Path I (Figures 2 and 3). In fact,
successfully single regioisomer 3l by Path I (Table 2, En- the conventional condensation of free alkylhydrazine only
try 12).
afforded inseparable regioisomeric mixtures (3g/4a = 74:26,
After demonstrating the robustness of our method for see Table 1). It is also worth mentioning that we synthesized
the regioselective synthesis of 3, we attempted to synthesize 2-cyclopentyl-3-substituted tetrahydroindazolones 4d and
complementary regioisomers 4 by the proposed synthetic 4e, which were not obtained by the conventional condensa-
route. As shown in Table 3, we could synthesize enehydraz- tion of cyclopentylhydrazine because of its preference for
ines 5, a key intermediate, by the condensation of 1 with the opposite regioisomer, resulting from steric factors. In
dimedone in excellent yields. To improve the efficiency of the case of benzaldehyde, under microwave irradiation in
our synthetic route, we pursued the formation of desired AcOH this one-pot procedure with spontaneous deprotec-
product 4 from 5 by Boc deprotection and spontaneous tion of the Boc group provided only moderate yields of the
intermolecular condensation with aldehydes. After reaction product; therefore, we removed the Boc group first with the
Eur. J. Org. Chem. 2010, 3815–3822
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3817

J. Kim, H. Song, S. B. Park
FULL PAPER
Table 3. Regioselective synthesis of 2-alkyl-3-substituted tetra- use of 50% TFA in DCM and then removed the excess
hydroindazolones 4 by path II.
amount of TFA prior to the microwave-assisted cyclization;
this improved the yield of this reaction (Table 3, Entries 1,
3, 5, 8–10). We also demonstrated the substrate generality
of the reaction by introducing various substituents at the
R2 position (Table 3, Entries 6–13). In particular, we carried
out intermolecular condensation of benzylenehydrazine 5d
and various heteroaryl aldehydes such as 2-thiophenyl, 4-
pyridyl, and 4-quinolinyl aldehydes and benzaldehyde hav-
ing electron-donating groups such as a methoxy moiety to
yield 4k, 4l, 4m, and 4j, respectively.
Entry Compd.
R1
R2
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
4a
4b
4c
4d
4e
4f
4g
4h
4i
methyl
propyl
propyl
cyclopentyl
cyclopentyl
benzyl
benzyl
benzyl
benzyl
benzyl
phenyl[a]
ethyl
60
61
70
56
48
62
60
79
73
53
63
63
58
phenyl[a]
methyl
phenyl[a]
Figure 3. Structural confirmation of both regioisomers 3g and 4a
by using 1D NOE experiment.
methyl
ethyl
phenyl[a]
4-trifluoromethylphenyl[a]
4-methoxyphenyl[a]
2-thiophenyl
4-pyridinyl
4-quinolinyl
4j
4k
4l
Conclusions
benzyl
benzyl
benzyl
In conclusion, we developed a divergent strategy for the
orthogonal regioselective synthesis of the complementary
regioisomers of N-alkyl-3-substituted-4,5,6,7-tetrahydro-
indazolones (i.e., 3 and 4) from Boc-protected alkylhydraz-
ines. The key step in this synthetic strategy is the introduc-
tion of a protecting group such as Boc at the nitrogen atom
of the internal amine in the alkylhydrazine. This causes a
significant difference in the nucleophilicities of the two reac-
tive nitrogen atoms of the alkylhydrazines. Consequently,
the reaction of Boc-protected alkylhydrazines 1 with 2-acyl-
cyclohexane-1,3-diones 2 and dimedone leads to the re-
gioselective generation of intermediate C and enehydrazine
5, respectively. We also successfully demonstrated the gener-
ality and orthogonality of this synthetic strategy by intro-
ducing alkyl or aryl substituents at the C-3 position of 3
and 4; for this purpose, we used various 2-acylcyclohexane-
1,3-diones 2 and substituted aldehydes, respectively. This re-
gioselective synthetic method is clearly better than the pre-
viously reported methods in terms of robustness and or-
thogonality and allows the systematic construction of a
small-molecule library that includes privileged tetrahydro-
indazolone regioisomers obtained in good yields and with
excellent regioselectivity. The construction of this library
and the biological evaluation of the synthesized compounds
will be reported in due course.
4m
[a] Desired product obtained under microwave irradiation after Boc
deprotection with 50% TFA in DCM at room temperature without
further purification. [b] Isolated yield of a single regioisomer of 4.
Experimental Section
General: 1H and 13C NMR spectra were obtained with a Varian
Inova-500 (Varian Assoc., Palo Alto, USA) and a Bruker DRX-
300 (Bruker Biospin, Germany). Chemical shifts are reported in
ppm from tetramethylsilane (TMS) as internal standard or the re-
sidual solvent peak (CDCl3, 1H: 7.26 ppm, 13C: 77.23 ppm;
CD3OD, 1H: 3.31 ppm, 13C: 49.00 ppm). High-resolution mass
Figure 2. 1H NMR spectroscopy data of (a) regioisomeric mixtures
3g and 4a synthesized by simple condensation of 2c with methyl-
hydrazine (Table 1), (b) 3g obtained by path I, and (c) 4a obtained
by path II.
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Eur. J. Org. Chem. 2010, 3815–3822

Orthogonal Synthesis of N-Alkyl-3-substituted Tetrahydroindazolones
spectrometric analysis was performed at the Mass Spectrometry
Laboratory of Seoul National University by using a mass spec-
trometer by direct injection for electron ionization (EI). Routine
mass analyses were performed with an LC–MS system equipped
3-Ethyl-6,6-dimethyl-1-propyl-6,7-dihydro-1H-indazol-4(5H)-one
(3e): Yield: 73%, yellowish solid. Rf = 0.27 (EtOAc/hexane, 1:2).
1H NMR (500 MHz, CDCl3): δ = 3.91 (t, J = 7.3 Hz, 2 H), 2.83
(q, J = 7.7 Hz, 2 H), 2.58 (s, 2 H), 2.29 (s, 2 H), 1.81 (sext., J =
with a reverse-phase column (C-18, 50ϫ2.1 mm, 5 µm) and photo- 7.3 Hz, 2 H), 1.21 (t, J = 7.5 Hz, 3 H), 1.08 (s, 6 H), 0.88 (t, J =
diode array detector by using electrospray ionization (ESI). Micro-
wave reactions were performed by using CEM Discover
Benchmate, and microwave reaction conditions are noted below.
All reactions were performed either in oven-dried glassware or a
7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 192.9, 154.4,
149.1, 114.6, 52.7, 50.6, 35.71, 35.66, 28.7, 23.6, 21.4, 13.3,
11.3 ppm. HRMS (EI+): calcd. for C14H22N2O [M]+ 234.1732;
found 234.1733.
microwave vessel under
a dry atmosphere. Dichloromethane
1-Benzyl-3-ethyl-6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one
(3f): Yield: 66%, yellowish gel. Rf = 0.29 (EtOAc/hexane, 1:2). H
(DCM) was dried by distillation from CaH2. Other solvents and
organic reagents were purchased from commercial suppliers and
used without further purification unless otherwise mentioned. The
products were purified by flash column chromatography on silica
gel (230–400 mesh). The conversion of the starting materials was
monitored by thin-layer chromatography (TLC) by using silica-gel
plates (silica gel 60 F254, 0.25 mm), and components were visual-
ized by observation under UV light (254 and 365 nm) or by treating
the TLC plates with ninhydrin, phosphomolybdic acid, and
KMnO4 followed by heating.
1
NMR (500 MHz, CDCl3): δ = 7.33–7.27 (m, 3 H), 7.08 (d, J =
7.0 Hz, 2 H), 5.22 (s, 2 H), 2.89 (q, J = 7.5 Hz, 2 H), 2.51 (s, 2 H),
2.30 (s, 2 H), 1.26 (t, J = 7.5 Hz, 3 H), 1.04 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 192.9, 154.6, 149.7, 136.2, 129.1, 128.1,
126.9, 115.5, 53.0, 52.6, 35.7, 35.6, 28.6, 21.4, 13.3 ppm. HRMS
(EI+): calcd. for C18H22N2O [M]+ 282.1732; found 282.1730.
1,6,6-Trimethyl-3-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (3g):
Yield: 73% as white solid. Rf = 0.34 (EtOAc/hexane, 1:1). 1H NMR
(500 MHz, CDCl3): δ = 8.08 (d, J = 7.5 Hz, 2 H), 7.39 (t, J =
7.5 Hz, 2 H), 7.34–7.32 (m, 1 H), 3.78 (s, 3 H), 2.62 (s, 2 H), 2.37
(s, 2 H), 1.12 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
191.9, 150.4, 150.3, 132.2, 128.7, 128.6, 128.1, 114.6, 53.2, 36.2,
35.7, 35.0, 28.5 ppm. HRMS (EI+): calcd. for C16H18N2O [M]+
254.1419; found 254.1421.
General Procedure for the Synthesis of 1-Alkyl-3-substituted Tetra-
hydroindazolones (3): To a stirred solution of 2-acylcyclohexane-
1,3-diones 2 (1.5 equiv.) in AcOH (0.1 ) was added Boc-protected
alkylhydrazines 1 (1.0 equiv.), and the resulting mixture was stirred
at 60 °C for 3–5 h. After the complete formation of intermediate
C, as checked by TLC, formic acid (0.1 ) was added, and reaction
mixture was stirred at 80 °C. After completion of the reaction as
monitored by TLC, the remaining solvent was removed by azeo-
tropic distillation with toluene under reduced pressure, and the re-
action mixture was purified by silica-gel flash column chromatog-
raphy to provide desired products 3.
6,6-Dimethyl-3-phenyl-1-propyl-6,7-dihydro-1H-indazol-4(5H)-one
(3h): Yield: 67%, white solid. Rf = 0.31 (EtOAc/hexane, 1:2). 1H
NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 7.0 Hz, 2 H), 7.40 (t, J
= 7.5 Hz, 2 H), 7.36–7.34 (m, 1 H), 4.03 (t, J = 7.3 Hz, 2 H), 2.68
(s, 2 H), 2.41 (s, 2 H), 1.90 (sext., J = 7.2 Hz, 2 H), 1.15 (s, 6 H),
0.95 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
192.1, 150.7, 149.9, 132.4, 128.8, 128.7, 128.2, 114.5, 53.4, 51.0,
36.0, 35.2, 28.5, 23.5, 11.3 ppm. HRMS (EI+): calcd. for
C18H22N2O [M]+ 282.1732; found 282.1736.
1,3,6,6-Tetramethyl-6,7-dihydro-1H-indazol-4(5H)-one (3a): Yield:
88%, yellowish solid. Rf = 0.18 (MeOH/DCM, 1:30). 1H NMR
(500 MHz, CDCl3): δ = 3.69 (s, 3 H), 2.57 (s, 2 H), 2.40 (s, 3 H),
2.27 (s, 2 H), 1.08 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 193.2, 149.4, 148.6, 115.6, 52.4, 35.8, 35.6, 35.5, 28.7, 13.4 ppm.
HRMS (EI+): calcd. for C11H16N2O [M]+ 192.1263; found
192.1263.
1-Benzyl-6,6-dimethyl-3-phenyl-6,7-dihydro-1H-indazol-4(5H)-one
(3i): Yield: 66%, white solid. Rf = 0.35 (EtOAc/hexane, 1:2). 1H
NMR (500 MHz, CDCl3): δ = 8.16–8.14 (m, 2 H), 7.44–7.41 (m, 2
H), 7.39–7.30 (m, 4 H), 7.17 (d, J = 6.5 Hz, 2 H), 5.34 (s, 2 H),
2.59 (s, 2 H), 2.40 (s, 2 H), 1.08 (s, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 192.1, 150.8, 150.5, 135.9, 132.3, 129.1, 128.8, 128.5,
128.2, 127.1, 127.0, 115.3, 53.4, 53.3, 35.9, 35.2, 28.4 ppm. HRMS
(EI+): calcd. for C22H22N2O [M]+ 330.1732; found 330.1728.
3,6,6-Trimethyl-1-propyl-6,7-dihydro-1H-indazol-4(5H)-one
(3b):
Yield: 80%, yellowish solid. Rf = 0.43 (EtOAc/hexane, 1:1). 1H
NMR (500 MHz, CDCl3): δ = 3.89 (t, J = 7.3 Hz, 2 H), 2.57 (s, 2
H), 2.41 (s, 3 H), 2.28 (s, 2 H), 1.80 (sext., J = 7.3 Hz, 2 H), 1.07
(s, 6 H), 0.86 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 193.2, 149.0, 148.7, 115.3, 52.6, 50.6, 35.7, 35.6, 28.7,
23.5, 13.5, 11.2 ppm. HRMS (EI+): calcd. for C13H20N2O [M]+
220.1576; found 220.1575.
1-Benzyl-6,6-dimethyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-1H-
indazol-4(5H)-one (3j): Yield: 60%, white solid. Rf = 0.38 (EtOAc/
hexane, 1:2). 1H NMR (500 MHz, CDCl3): δ = 8.31 (d, J = 8.5 Hz,
2 H), 7.67 (d, J = 8.5 Hz, 2 H), 7.37–7.30 (m, 3 H), 7.17 (d, J =
7.0 Hz, 2 H), 5.36 (s, 2 H), 2.62 (s, 2 H), 2.42 (s, 2 H), 1.10 (s, 6
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 192.2, 150.8, 149.4,
1-Benzyl-3,6,6-trimethyl-6,7-dihydro-1H-indazol-4(5H)-one
(3c):
Yield: 80%, yellowish gel. Rf = 0.48 (EtOAc/hexane, 1:1). 1H NMR
(500 MHz, CDCl3): δ = 7.34–7.27 (m, 3 H), 7.09 (d, J = 7.0 Hz, 2
H), 5.20 (s, 2 H), 2.52 (s, 2 H), 2.47 (s, 3 H), 2.29 (s, 2 H), 1.05 (s,
6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 193.2, 149.5, 148.9,
136.1, 129.1, 128.1, 126.9, 116.1, 53.0, 52.5, 35.7, 35.6, 28.6,
13.5 ppm. HRMS (EI+): calcd. for C17H20N2O [M]+ 268.1576;
found 268.1576.
2
135.8, 135.6, 130.5 (q, JC,F = 31.9 Hz), 129.22, 129.16, 128.4,
1
127.1, 125.2 (q, 3JC,F = 3.6 Hz), 124.5 (q, JC,F = 270.3 Hz), 115.6,
53.7, 53.3, 35.9, 35.4, 28.5 ppm. HRMS (EI+): calcd. for
C23H21F3N2O [M]+ 398.1606; found 398.1608.
6,6-Dimethyl-3-[2-(methylthio)ethyl]-1-propyl-6,7-dihydro-1H-
indazol-4(5H)-one (3k): Yield: 70 %, yellowish gel. Rf = 0.43
1
3-Ethyl-1,6,6-trimethyl-6,7-dihydro-1H-indazol-4(5H)-one
(3d): (EtOAc/hexane, 1:1). H NMR (500 MHz, CDCl3): δ = 3.93 (t, J
1
Yield: 81%, white solid. Rf = 0.23 (EtOAc/hexane, 1:1). H NMR
(500 MHz, CDCl3): δ = 3.68 (s, 3 H), 2.80 (q, J = 7.5 Hz, 2 H),
2.56 (s, 2 H), 2.26 (s, 2 H), 1.19 (t, J = 7.5 Hz, 3 H), 1.07 (s, 6
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 192.8, 154.2, 149.4,
114.8, 52.5, 35.8, 35.53, 35.49, 28.7, 21.3, 13.1 ppm. HRMS (EI+):
calcd. for C12H18N2O [M]+ 206.1419; found 206.1423.
= 7.3 Hz, 2 H), 3.11 (t, J = 7.5 Hz, 2 H), 2.82 (t, J = 7.8 Hz, 2 H),
2.60 (s, 2 H), 2.31 (s, 2 H), 2.14 (s, 3 H), 1.82 (sext., J = 7.3 Hz, 2
H), 1.10 (s, 6 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 192.9, 150.9, 149.2, 115.0, 52.6, 50.7, 35.7,
35.6, 32.7, 28.6, 28.1, 23.5, 15.4, 11.2 ppm. HRMS (EI+): calcd.
for C15H24N2OS [M]+ 280.1609; found 280.1609.
Eur. J. Org. Chem. 2010, 3815–3822
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3819

J. Kim, H. Song, S. B. Park
FULL PAPER
1,6,6-Trimethyl-3-(trifluoromethyl)-6,7-dihydro-1H-indazol-4(5H)-
one (3l): Yield: 85%, white solid. Rf = 0.45 (EtOAc/hexane, 1:1).
1H NMR (500 MHz, CDCl3): δ = 3.84 (s, 3 H), 2.69 (s, 2 H), 2.38
tert-Butyl 1-Benzyl-2-(5,5-dimethyl-3-oxocyclohex-1-enyl)hydrazine-
carboxylate (5d): Yield: 94%, yellowish solid. Rf = 0.22 (MeOH/
DCM, 1:19). 1H NMR (500 MHz, CDCl3): δ = 7.35–7.28 (m, 3 H),
(s, 2 H) 1.13 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 190.0, 7.23 (d, J = 6.5 Hz, 2 H), 6.03 (s, 1 H), 5.29 (s, 1 H), 5.02 (br. s, 1
150.8, 139.1 (q, 2JC,F = 39.9 Hz), 120.6 (q, 1JC,F = 268.0 Hz), 115.3,
52.5, 36.8, 35.5, 35.4, 28.6 ppm. HRMS (EI+): calcd. for
C11H13F3N2O [M]+ 246.0980; found 246.0985.
H), 4.11 (br. s, 2 H), 2.20 (s, 2 H), 2.06 (br. s, 2 H), 2.20 (s, 2 H),
1.46 (s, 9 H), 1.05 (s, 6 H) ppm. LRMS (ESI+): calcd. for
C20H29N2O3 [M + H]+ 345.21; found 345.06.
General Procedure for the Synthesis of 1-Alkyl-3-substituted Tetra-
hydroindazolones (4): To a solution of aldehydes (1.1–5 equiv.) in
acetic acid (0.04 ) was added enehydrazines 5, and the resulting
mixture was heated in a capped microwave vessel under microwave
irradiation (150 W, 100 °C) for 25–30 min. After completion of the
reaction, as monitored by TLC, the solvent was removed by azeo-
tropic distillation with toluene under reduced pressure without
aqueous workup, and the reaction mixture was purified by silica-
gel flash column chromatography to provide the desired products.
To obtain the cyclized products in a series of benzaldehydes, enehy-
drazine 5 was first treated with 50% TFA in DCM at room tem-
perature for 1 h. The excess amount of TFA was removed by azeo-
tropic evaporation with DCM under reduced pressure, and the
crude resultant was redissolved in acetic acid (0.04 ) and aldehyde
(1.1–3 equiv.) was added. The reaction mixture was irradiated un-
der microwave condition (150 W, 100 °C) for 25–30 min.
6,6-Dimethyl-1-propyl-3-(pyridin-3-ylmethyl)-6,7-dihydro-1H-
indazol-4(5H)-one (3m): Yield: 62%, yellow gel. Rf = 0.22 (EtOAc/
hexane, 1:1). H NMR (500 MHz, CDCl3): δ = 8.54 (s, 1 H), 8.37
(d, J = 3.0 Hz, 1 H), 7.66 (d, J = 7.5 Hz, 1 H), 7.13 (dd, J = 7.8,
4.8 Hz, 1 H), 4.17 (s, 2 H), 3.92 (t, J = 7.0 Hz, 2 H), 2.58 (s, 2 H),
2.27 (s, 2 H), 1.80 (sext., J = 7.3 Hz, 2 H), 1.06 (s, 6 H), 0.86 (t, J
= 7.3 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 192.8,
150.4, 150.0, 149.3, 147.5, 136.7, 135.1, 123.3, 114.8, 52.5, 50.8,
35.7, 35.6, 31.0, 28.6, 23.5, 11.2 ppm. HRMS (EI+): calcd. for
C18H23N3O [M]+ 297.1841; found 297.1842.
1
3,6,6-Trimethyl-1-(pyridin-2-ylmethyl)-6,7-dihydro-1H-indazol-
4(5H)-one (3n): Yield: 62%, white solid. Rf = 0.12 (EtOAc/hexane,
1
2:1). H NMR (500 MHz, CDCl3): δ = 8.53 (d, J = 4.0 Hz, 1 H),
7.63 (dt, J = 7.8, 1.5 Hz, 1 H), 7.19 (dd, J = 7.0, 5.5 Hz, 1 H), 6.97
(d, J = 8.0 Hz, 1 H), 5.30 (s, 2 H), 2.61 (s, 2 H), 2.45 (s, 3 H), 2.30
(s, 2 H), 1.05 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
193.4, 156.0, 150.4, 149.8, 149.3, 137.4, 123.1, 121.7, 116.2, 54.8,
52.6, 35.9, 35.6, 28.7, 13.6 ppm. HRMS (EI+): calcd. for
C16H19N3O [M]+ 269.1528; found 269.1533.
2,6,6-Trimethyl-3-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (4a):
1
Yield: 60%, white solid. Rf = 0.34 (EtOAc/hexane, 1:1). H NMR
(500 MHz, CDCl3): δ = 7.47–7.44 (m, 5 H), 3.77 (s, 3 H), 2.73 (s,
2 H), 2.35 (s, 2 H), 1.11 (s, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 193.4, 155.8, 144.1, 130.1, 129.7, 128.54, 128.49, 115.0,
53.7, 37.29, 37.26, 35.2, 28.6 ppm. HRMS (EI+): calcd. for
C16H18N2O [M]+ 254.1419; found 254.1419.
2-(3,6,6-Trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-
acetamide (3o): Yield: 76%, white solid. Rf = 0.34 (MeOH/DCM,
1
1:10). H NMR (500 MHz, CD3OD): δ = 4.79 (s, 2 H), 2.72 (s, 2
H), 2.38 (s, 3 H), 2.34 (s, 2 H), 1.11 (s, 6 H) ppm. 13C NMR
(75 MHz, CD3OD): δ = 196.0, 170.9, 153.6, 150.0, 116.6, 53.1, 51.7,
36.6, 35.7, 28.5, 13.2 ppm. HRMS (EI+): calcd. for C12H17N3O2
[M]+ 235.1321; found 235.1323.
3-Ethyl-6,6-dimethyl-2-propyl-6,7-dihydro-2H-indazol-4(5H)-one
1
(4b): Yield: 61%, yellowish gel. Rf = 0.27 (EtOAc/hexane, 1:2). H
NMR (500 MHz, CDCl3): δ = 3.95 (t, J = 7.5 Hz, 2 H), 2.93 (q, J
= 7.5 Hz, 2 H), 2.62 (s, 2 H), 2.30 (s, 2 H), 1.86 (sext., J = 7.5 Hz,
2 H), 1.20 (t, J = 7.5 Hz, 3 H), 1.06 (s, 6 H), 0.93 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 194.5, 155.6, 146.9,
114.1, 53.5, 50.3, 37.2, 35.3, 28.7, 23.8, 18.6, 13.4, 11.4 ppm.
HRMS (EI+): calcd. for C14H22N2O [M]+ 234.1732; found
234.1735.
General Procedures for the Synthesis of Enehydrazines 5: To a
stirred solution of Boc-protected alkylhydrazines 1 (1.0 equiv.) in
AcOH (0.1 ) was added dimedone (1.0 equiv.). After completion
of enehydrazines 5 formation, as monitored by TLC, the remaining
solvent was removed by azeotropic distillation with toluene under
reduced pressure, and the reaction mixture was purified by silica-
gel flash column chromatography to provide desired products 5.
6,6-Dimethyl-3-phenyl-2-propyl-6,7-dihydro-2H-indazol-4(5H)-one
(4c): Yield: 70 %, clear gel. Rf = 0.31 (EtOAc/hexane, 1:2). 1H
NMR (500 MHz, CDCl3): δ = 7.47–7.45 (m, 3 H), 7.42–7.40 (m, 2
H), 3.96 (t, J = 7.3 Hz, 2 H), 2.74 (s, 2 H), 2.34 (s, 2 H), 1.82 (sext.,
J = 7.5 Hz, 2 H), 1.11 (s, 6 H), 0.80 (t, J = 7.5 Hz, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 193.5, 155.8, 144.0, 129.9, 129.6,
128.9, 128.6, 115.0, 53.7, 50.9, 37.3, 35.2, 28.7, 23.7, 11.2 ppm.
HRMS (EI+): calcd. for C18H22N2O [M]+ 282.1732; found
282.1734.
tert-Butyl 2-(5,5-Dimethyl-3-oxocyclohex-1-enyl)-1-methyl-
hydrazinecarboxylate (5a): Yield: 99%, yellowish solid. Rf = 0.31
1
(MeOH/DCM, 1:20). H NMR (500 MHz, CDCl3): δ = 6.91 (br.
s, 1 H), 5.16 (s, 1 H), 3.06 (s, 3 H), 2.17 (s, 2 H), 2.14 (br. s, 2 H),
1.40 (s, 9 H), 1.05 (s, 6 H) ppm. LRMS (ESI+): calcd. for
C14H25N2O3 [M + H]+ 269.18; found 269.07.
tert-Butyl 2-(5,5-Dimethyl-3-oxocyclohex-1-enyl)-1-propylhydraz-
inecarboxylate (5b): Yield: 90%, yellowish solid. Rf = 0.14 (EtOAc/
hexane, 1:1). 1H NMR (500 MHz, CDCl3): δ = 6.60 (br. s, 1 H),
5.21 (s, 1 H), 3.33 (br. s, 2 H), 2.18 (s, 2 H), 2.15 (br. s, 2 H), 1.54
(sext., J = 7.5 Hz, 2 H), 1.41 (s, 9 H), 1.06 (s, 6 H), 0.86 (t, J =
7.5 Hz, 3 H) ppm. LRMS (ESI+): calcd. for C16H29N2O3 [M +
H]+ 297.21; found 297.07.
2-Cyclopentyl-3,6,6-trimethyl-6,7-dihydro-2H-indazol-4(5H)-one
(4d): Yield: 56%, white solid. Rf = 0.71 (EtOAc/hexane, 1:1). 1H
NMR (500 MHz, CDCl3): δ = 4.50 (pent., J = 7.8 Hz, 1 H), 2.61
(s, 2 H), 2.53 (s, 3 H), 2.27 (s, 2 H), 2.07–2.01 (m, 4 H), 1.96–1.88
(m, 2 H), 1.69–1.60 (m, 2 H), 1.04 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 195.0, 155.0, 140.7, 114.9, 58.7, 53.5, 37.3,
35.2, 32.4, 28.7, 24.7, 10.9 ppm. HRMS (EI+): calcd. for
C15H22N2O [M]+ 246.1732; found 246.1731.
tert-Butyl 1-Cyclopentyl-2-(5,5-dimethyl-3-oxocyclohex-1-enyl)-
hydrazinecarboxylate (5c): Yield: 94 %, white solid. Rf = 0.27
1
(EtOAc/hexane, 1:1). H NMR (500 MHz, CDCl3): δ = 6.31 (br. s, 2-Cyclopentyl-6,6-dimethyl-3-phenyl-6,7-dihydro-2H-indazol-4(5H)-
1 H), 5.28 (s, 1 H), 4.44 (pent., J = 8 Hz, 1 H), 2.22–2.13 (m, 4 H), one (4e): Yield: 48%, yellowish solid. Rf = 0.75 (EtOAc/hexane,
1
1.82–1.77 (m, 2 H), 1.63–1.61 (m, 2 H), 1.52–1.43 (m, 4 H), 1.41
(s, 9 H), 1.06 (s, 3 H), 1.05 (s, 3 H) ppm. LRMS (ESI+): calcd. for
C18H31N2O3 [M + H]+ 323.23; found 323.08.
1:2). H NMR (500 MHz, CDCl3): δ = 7.50–7.46 (m, 3 H), 7.43–
7.41 (m, 2 H), 4.52 (pent., J = 7.8 Hz, 1 H), 2.74 (s, 2 H), 2.33 (s,
2 H), 2.17–2.10 (m, 2 H), 2.00–1.90 (m, 4 H), 1.61–1.56 (m, 2 H),
3820
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3815–3822

Orthogonal Synthesis of N-Alkyl-3-substituted Tetrahydroindazolones
1.11 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 193.5, 155.7, 129.1, 128.3, 127.0, 124.3, 115.9, 53.6, 53.5, 37.2, 35.2, 28.6 ppm.
143.6, 130.0, 129.5, 129.2, 128.5, 114.8, 59.3, 53.7, 37.6, 35.2, 33.3,
28.7, 25.0 ppm. HRMS (EI+): calcd. for C20H24N2O [M]+
308.1889; found 308.1885.
HRMS (EI+): calcd. for C21H21N3O [M]+ 331.1685; found
331.1680.
2-Benzyl-6,6-dimethyl-3-(quinolin-4-yl)-6,7-dihydro-2H-indazol-
4(5H)-one (4m): Yield: 58%, dark yellow solid. Rf = 0.26 (EtOAc/
hexane, 1:1). 1H NMR (500 MHz, CDCl3): δ = 8.94 (d, J = 4.0 Hz,
1 H), 8.18 (d, J = 8.5 Hz, 1 H), 7.74 (dt, J = 7.8, 1.0 Hz, 1 H), 7.46
(dt, J = 7.8, 1.0 Hz, 1 H), 7.35–7.27 (m, 2 H), 7.23 (d, J = 4.5 Hz,
1 H), 7.18–7.14 (m, 2 H), 6.85 (d, J = 7.0 Hz, 2 H), 5.15 (d, J =
15.5 Hz, 1 H), 4.91 (d, J = 15.0 Hz, 1 H), 2.85 (s, 2 H), 2.36 (s, 2
H), 1.17 (s, 3 H), 1.16 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 193.2, 156.2, 149.8, 148.5, 139.3, 135.68, 135.66, 130.3, 130.1,
128.8, 128.2, 127.8, 127.5, 126.4, 124.8, 122.6, 117.7, 54.0, 53.3,
37.3, 35.4, 28.8, 28.6 ppm. HRMS (EI+): calcd. for C25H23N3O
[M]+ 381.1841; found 381.1843.
2-Benzyl-3,6,6-trimethyl-6,7-dihydro-2H-indazol-4(5H)-one (4f):
Yield: 62 %, yellowish solid. Rf = 0.48 (EtOAc/hexane, 1:1). 1H
NMR (500 MHz, CDCl3): δ = 7.32–7.27 (m, 3 H), 7.11 (d, J =
7.0 Hz, 2 H), 5.24 (s, 2 H), 2.67 (s, 2 H), 2.49 (s, 3 H), 2.33 (s, 2
H), 1.08 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 195.1,
155.6, 141.6, 136.0, 129.1, 128.2, 127.0, 115.6, 53.5, 52.8, 37.2, 35.3,
28.7, 11.0 ppm. HRMS (EI+): calcd. for C17H20N2O [M]+
268.1576; found 268.1571.
2-Benzyl-3-ethyl-6,6-dimethyl-6,7-dihydro-2H-indazol-4(5H)-one
(4g): Yield: 60%, yellow gel. Rf = 0.29 (EtOAc/hexane, 1:2). 1H
NMR (500 MHz, CDCl3): δ = 7.33–7.27 (m, 3 H), 7.11 (d, J =
7.0 Hz, 2 H), 5.27 (s, 2 H), 2.90 (q, J = 7.7 Hz, 2 H), 2.67 (s, 2 H),
2.33 (s, 2 H), 1.08–1.06 (m, 9 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 194.6, 155.8, 147.5, 136.4, 129.0, 128.1, 126.9, 114.8,
53.5, 52.8, 37.2, 35.3, 28.7, 18.8, 13.1 ppm. HRMS (EI+): calcd.
for C18H22N2O [M]+ 282.1732; found 282.1734.
Supporting Information (see footnote on the first page of this arti-
cle): Representative synthetic scheme for N-alkyl-3-substituted
tetrahydroindazolones, measurement of regioisomeric ratio using
1
1H NMR and 1D NOE, H and 13C NMR spectroscopic data of
all new compounds.
2-Benzyl-6,6-dimethyl-3-phenyl-6,7-dihydro-2H-indazol-4(5H)-one
(4h): Yield: 79%, yellowish solid. Rf = 0.35 (EtOAc/hexane, 1:2).
1H NMR (500 MHz, CDCl3): δ = 7.44–7.37 (m, 5 H), 7.29–7.26
(m, 3 H), 7.05 (d, J = 7.0 Hz, 2 H), 5.23 (s, 2 H), 2.77 (s, 2 H),
2.37 (s, 2 H), 1.13 (s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 193.5, 156.2, 144.6, 136.7, 130.0, 129.8, 128.9, 128.62, 128.60,
128.0, 127.2, 115.3, 53.7, 53.1, 37.4, 35.2, 28.7 ppm. HRMS (EI+):
calcd. for C22H22N2O [M]+ 330.1732; found 330.1731.
Acknowledgments
This study was supported by the National Research Foundation of
Korea (NRF), the MarineBio Program funded by the Ministry of
Land, Transport, and Maritime Affairs (MLTM), Korea, and the
WCU program of the NRF funded by the Korean Ministry of Edu-
cation, Science, and Technology (MEST). J. K. and H. S. are grate-
ful for the fellowships awarded by the BK21 Program and the Seoul
Science Fellowship.
2-Benzyl-6,6-dimethyl-3-[4-(trifluoromethyl)phenyl]-6,7-dihydro-
2H-indazol-4(5H)-one (4i): Yield: 73%, yellowish solid. Rf = 0.38
1
(EtOAc/hexane, 1:2). H NMR (500 MHz, CDCl3): δ = 7.68 (d, J
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(d, J = 6.5 Hz, 2 H), 5.23 (s, 2 H), 2.79 (s, 2 H), 2.39 (s, 2 H), 1.14
(s, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 193.6, 156.4,
2
142.8, 136.4, 132.2, 131.7 (q, JC,F = 32.4 Hz), 130.5, 129.1, 128.2,
1
127.0, 125.6 (q, 3JC,F = 3.6 Hz), 124.0 (q, JC,F = 270.9 Hz), 115.7,
53.6, 53.3, 37.3, 35.2, 28.6 ppm. HRMS (EI+): calcd. for
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1982, 19, 1355–1361; b) V. Molteni, M. M. Hamilton, L. Mao,
C. M. Crane, A. P. Termin, D. M. Wilson, Synthesis 2002,
1669–1674.
2-Benzyl-3-(4-methoxyphenyl)-6,6-dimethyl-6,7-dihydro-2H-indazol-
4(5H)-one (4j): Yield: 53%, yellowish solid. Rf = 0.36 (EtOAc/hex-
ane, 1:2). 1H NMR (500 MHz, CDCl3): δ = 7.33–7.25 (m, 6 H),
7.07 (d, J = 7.5 Hz, 2 H), 6.94 (d, J = 9 Hz, 2 H), 5.23 (s, 2 H),
3.84 (s, 3 H), 2.75 (s, 2 H), 2.37 (s, 2 H), 1.13 (s, 6 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 193.5, 160.7, 156.2, 144.6, 136.9,
131.4, 128.9, 127.9, 127.1, 120.5, 115.0, 114.1, 55.5, 53.8, 52.9, 37.4,
35.1, 28.7 ppm. HRMS (EI+): calcd. for C23H24N2O2 [M]+
360.1838; found 360.1831.
2-Benzyl-6,6-dimethyl-3-(thiophen-2-yl)-6,7-dihydro-2H-indazol-
4(5H)-one (4k): Yield: 63%, yellowish solid. Rf = 0.39 (1:3, EtOAc/
hexane). 1H NMR (500 MHz, CDCl3): δ = 7.50 (dd, J = 5.0,
1.0 Hz, 1 H), 7.33–7.27 (m, 4 H), 7.10–7.08 (m, 3 H), 5.38 (s, 2 H),
2.76 (s, 2 H), 2.39 (s, 2 H), 1.13 (s, 6 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 193.3, 156.3, 137.5, 136.6, 130.9, 129.00, 128.97, 128.0,
127.9, 127.3, 127.0, 115.8, 53.8, 53.5, 37.4, 35.1, 28.6 ppm. HRMS
(EI+): calcd. for C20H20N2OS [M]+ 336.1296; found 336.1296.
2-Benzyl-6,6-dimethyl-3-(pyridin-4-yl)-6,7-dihydro-2H-indazol-
4(5H)-one (4l): Yield: 63%, yellowish solid. Rf = 0.13 (EtOAc/hex-
1
ane, 1:1). H NMR (500 MHz, CDCl3): δ = 8.69 (d, J = 5.5 Hz, 2
H), 7.31–7.27 (m, 5 H), 7.03 (dd, J = 7.8, 1.8 Hz, 2 H), 5.24 (s, 2
H), 2.79 (s, 2 H), 2.39 (s, 2 H), 1.14 (s, 6 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 193.5, 156.4, 150.2, 141.3, 136.6, 136.2,
Eur. J. Org. Chem. 2010, 3815–3822
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Kim, H. Song, S. B. Park
FULL PAPER
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Received: April 15, 2010
Published Online: June 8, 2010
3822
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3815–3822