A facile synthesis of 4-acylamino-tetrahydroindazoles via the Ritter reaction

Article abstract of DOI:10.1016/j.tet.2012.05.074

A new route toward 4-acylamino- and 4-amino-substituted tetrahydroindazoles is disclosed. The title compounds are obtained in good to excellent yields in the Ritter reaction between 4-hydroxy-tetrahydroindazoles and various nitriles. The reactivity of the tetrahydroindazole-derived carbenium ion is both sufficiently high to react with trichloroacetonitrile and sufficiently selective to resist the azide functionality within its structure. The present approach adds a method to the toolbox of tetrahydroindazole chemistry and facilitates the structural modifications of the scaffold, which has found important applications in medicinal chemistry.

Full text of DOI:10.1016/j.tet.2012.05.074

Tetrahedron 68 (2012) 6131e6140
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Tetrahedron
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A facile synthesis of 4-acylamino-tetrahydroindazoles via the Ritter reaction
a
,
a
a
b
c
*
ꢀ
Maris Turks , Inta Strakova , Kirils Gorovojs , Sergey Belyakov , Yuri A. Piven ,
Tatyana S. Khlebnicova c, Fedor A. Lakhvich c
a Faculty of Material Science and Applied Chemistry, Riga Technical University, Azenes Str. 14/24, Riga LV-1007, Latvia
b Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia
c Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, ul. Akad. Kuprievicha 5/2, Minsk 220141, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route toward 4-acylamino- and 4-amino-substituted tetrahydroindazoles is disclosed. The
title compounds are obtained in good to excellent yields in the Ritter reaction between 4-hydroxy-tet-
rahydroindazoles and various nitriles. The reactivity of the tetrahydroindazole-derived carbenium ion is
both sufficiently high to react with trichloroacetonitrile and sufficiently selective to resist the azide
functionality within its structure. The present approach adds a method to the toolbox of tetrahy-
droindazole chemistry and facilitates the structural modifications of the scaffold, which has found im-
portant applications in medicinal chemistry.
Received 13 March 2012
Received in revised form 4 May 2012
Accepted 21 May 2012
Available online 26 May 2012
Keywords:
Tetrahydroindazoles
Ritter reaction
Amides
Ó 2012 Elsevier Ltd. All rights reserved.
Nitriles
1. Introduction
4. In our hands this approach was not general. For example,
oximes derived from 1-pyridin-2-yl-THIs reacted smoothly in the
In recent years there has been considerable interest in the de-
velopment of various molecular scaffolds for medicinal chemistry.
The term Fsp3 has been suggested, which stands for the ratio of sp3
hybridized carbon atoms to the total carbon count.1 It was dem-
onstrated that for a successful drug candidate Fsp3 approaches 0.5
and that the structure probably contains at least one chiral center.
In this context tetrahydroindazoles (THIs) have proved to be par-
ticularly attractive due to the presence of both the planar pyrazole
moiety and a C4-tether, which points the substituents in distinct
spatial directions. Exploration of this concept in the tetrahy-
droindazole series has resulted in many distinct biological activi-
ties.2 Due to the fact that amino-substituted partially saturated
heterocycles are of tremendous interest in medicinal chemistry3
we4 and others5 have worked on the introduction of amino
groups into the tetrahydroindazole core.
aforementioned synthetic sequence. On the other hand, oximes of
1-phenylderivativesproducedabroadrangeofunidentifiedreduction
byproducts (transformation 1/2, Scheme 1). Moreover, structurally
related oximes are reported to undergo a Beckmann rearrangement
when treated with hydride containing reducing agents.6
R1
1) H2NOH or
AcONH4
N
2) [H]
(R3)n
N
[H]
R2
O
R1
R1
1
N
N
(R3)n
(R3)n
N
N
R2
R2
3
2
R1
NH2
OH
N
(R3)n
O
N
Ritter
previously
reported
methods
R2
2. Results and discussion
reaction
this work
NH
4
R4
Herewe reportastraightforwardsynthesisof4-acylamino-4,5,6,7-
tetrahydro-1H-indazoles 4 via the Ritter reaction. Previously known
methods toward derivatives of type 4 rely on imination or oximation
of the corresponding ketone 1 followed by reduction (Scheme 1).
Then, aplethoraofamideformingreactionswouldprovidederivatives
Scheme 1. Synthetic approaches toward 4-acylamino-tetrahydroindazoles.
In our hands reductive amination was not very successful on
either of the type 1 systems. At this point the Ritter reaction7 was
considered. We have found that 3-unsubstituted and 3-alkyl-1-
aryl-4-hydroxy-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazoles un-
dergo a Ritter reaction when treated with various nitriles in an
* Corresponding author. Tel.: þ371 67089251; fax: þ371 67615765; e-mail
address: maris_turks@ktf.rtu.lv (M. Turks).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.074

6132
M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
acidic medium. We began our investigations with 4-hydroxy-1-
phenyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (6a), which
was obtained upon reduction of the corresponding tetrahy-
droindazolone 5a with NaBH4 in ethanol at ambient temperature
(Scheme 2).5b Other 4-hydroxy-THI’s 6bed were synthesized by the
same procedure from previously reported starting materials.4,8
More labile nitriles such as ClCH2CN and Cl3CCN required higher
loading of sulfuric acid along with a larger excess of the nitrile itself
(up to 20 equiv) in order to obtain acceptable isolated yields of the
target amides (e.g., 9c, 9l). This may reflect increased reactivity of the
newly formed chloroacetate moiety, that is, predisposed to further
transformations involving nucleophilic displacement and can be
cleaved by various bifunctional nucleophiles.10 It is noteworthy that
even trichloroacetonitrile undergoes a Ritter reaction with 4-
hydroxy-THI’s. Indeed, this report represents one of the very few
examples where Cl3CCN is successfully used in the Ritter reaction.11
Table 1 lists many other combinations of pseudo benzylic alcohols 6
and nitriles that produce amides 9 in good to excellent yields. Among
others they include the synthesis of acrylamides 9d,m,v that are pro-
grammed for Michael additions of various nucleophiles. It is also shown
that substituted benzonitriles with both electron donating (Table 1,
entries 6, 24) and electron accepting groups (Table 1, entries 8, 26)
produce the corresponding amides equally well under the aforemen-
tioned conditions. Last but not least, fluorine containing products are
produced byreactingeithertetrahydroindazole 6c with nonfluorinated
nitriles or o-fluorobenzonitrile with 4-hydroxy-THI’s 6a,b,d.
Next, we briefly studied the diastereoselectivity of the Ritter re-
action on our substrates. Diastereomeric mixtures of azido (12) and
amino (13) alcohols were obtained from compounds 10 and 11 that
we reported earlier.4 Ritter reaction of 12 and 13 with MeCN gave
75:25 and 95:5 diastereoselectivity in favor of the trans-products,
respectively (Scheme 4). It is interesting to note that the azido
group of 12 survives the strongly electrophilic reaction conditions.12
The preference for trans-15,16 can be explained by the conformation
of the intermediate carbenium ion 14, the si-face attack of which is
partially hindered by the pseudo-axial methyl group at C(6). The
relative configuration of each of the isomers in the azido series was
independently established by coupling constant analysis in their 1H
NMR spectra and by positive cross-peaks in their 2D-NOESY spectra.
Diastereoisomers trans-15 and cis-15 are separable by crystallization.
The structure of trans-15 was unambiguously proved by X-ray dif-
fraction analysis (Fig. 1).13 Coupling constant (3J) analysis and 2D-
NOESY spectrum of 7-amino-THI derivative trans-16 revealed the
pattern practically identical to that of trans-15. This allows us to at-
tribute also the relative configuration of trans-16.
X
X
N
N
NaBH4
N
N
R
R
O
OH
5a: R = H; X = CH
6a: R = H; X = CH; 95%
6b: R = CH3; X = CH; 97%
6c: R = CF3; X = CH; 88%
6d: R = CH3; X = N; 92%
5b: R = CH3; X = CH
5c: R = CF3; X = CH
5d: R = CH3; X = N
Scheme 2. Synthesis of 4-hydroxy-tetrahydroindazoles.
We envisaged sulfuric acid or polyphosphoric acid in acetic acid
solution as a strongly ionizing medium for the Ritter reaction. In-
deed, under such strongly acidic conditions 6a smoothly un-
derwent the aforementioned reaction with acetonitrile and
produced amide 9a (Scheme 3, Table 1). It was observed that in the
absence of a nitrile 6,7-dihydroindazoles 7 were formed by
deprotonation. The latter intermediates produced identical Ritter
products when treated with the corresponding nitriles under
strongly acidic conditions.9 On the other hand, reaction of 6a with
MeCN or PhCN in CD3COOD in the presence of D2SO4 failed to
produce the expected deuteration at C(5) of the tetrahydroindazole.
It can be concluded that at least in the latter cases the consumption
of carbenium ion 8 by the nitrile is faster than its depro-
tonationedeuteration equilibrium. We have also demonstrated
that the transformation 6aþMeCN/9a proceeded equally well in
trifluoroacetic acid as the sole reaction medium. Nevertheless, due
to economical reasons this approach was not explored further as
trifluoroacetic acid costs at least ten times more than AcOH and
H2SO4. Optimization of the reaction conditions (6a/9a) revealed
that 5 equiv of sulfuric acid are sufficient for an effective reaction
that proceeds with full conversion in 4 h at 60 ꢀC. Other acids were
investigated, including concd phosphoric acid, concd perchloric
acid, para-toluene sulfonic acid, and camphorsulfonic acid. These
latter acids promoted amide formation sluggishly and the expected
products 9 were isolated along with 6,7-dihydroindazoles 7aed.
We have also explored the deacylation of some representative 4-
acylamino-THI’s. In the case of 9a,b deacylation was achieved by
acidic hydrolysis with HCl (Scheme 5). The corresponding amine
was isolated in good yields as the tosylate salt 17. Additionally,
amide 9b was deprotected by treatment with thiourea.10 This ap-
proach provided product 17 in 80% yield.
In summary, we have reported a convenient synthetic approach
to 4-acylamino-4,5,6,7-tetrahydroindazoles that are versatile build-
ing blocks in medicinal chemistry. The synthetic sequence includes
reduction of tetrahydroindazolones to the corresponding alcohols
and their Ritter reaction with various nitriles, including the relatively
R1
N
H
N
R2
R1
R1
OH
6a-d
R3CN
N
N
N
N
H
unreactive
trichloroacetonitrile.
Moreover,
4-amino-terahy-
R1
R2
R2
8a-d
O
NH
9a-z
droindazoles can be conveniently obtained by deprotection of the
aforementioned 4-acylamino-THI’s. Preliminary studies revealed
that good to excellent levels of diastereoselectivity can be obtained
when the Ritter reaction is performed on 7-substituted tetrahy-
droindazoles. It is worth mentioning that the azido group resists the
presence of carbenium ion under the reported conditions. The well
established reactivity of the azido and amino moieties allows the
further decoration of the 4-acylamino-tetrahydroindazole core.
N
R3
N
H
R2
7a,b,d
Scheme 3. Synthesis of target compounds 9aez via the Ritter reaction.
With optimized reaction conditions in hand, a combinatorial
library of 4-acylamino-tetrahydroindazoles was prepared. In
a typical experiment a solution of 6aed (5 mmol) and a nitrile
(1.5e20 equiv) in glacial acetic acid (5 mL) and concd H2SO4
(5e20 equiv) was heated at 60e70 ꢀC for the time indicated in Table
1. After neutralization with an aqueous solution of NaOH the pre-
cipitated products 9aez were filtered and recrystallized.
3. Experimental section
3.1. General
All reactions were carried out without a protective atmosphere
of nitrogen or argon. All commercial reagents were used as

M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
6133
Table 1
Synthesis on 4-acylamino-tetrahydroindazoles via the Ritter reaction
Entry
Starting
material 6
R1
R2
R3
Molar ratio
6:nitrile:H2SO4
Reaction
time, ha
Product
(yield, %)
Melting
point, ꢀCc
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
6c
6c
6d
6d
6d
6d
6d
6d
6d
6d
6d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
CF3
CF3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH2Cl
CCl3
CH]CH2
Ph
C6H4OCH3(m)
C6H4F(o)
C6H4NO2(p)
Me
n-Pr
CH2Cl
CCl3
CH]CH2
Ph
C6H4F(o)
Me
CH2Ph
Me
n-Pr
CH2Cl
CCl3
CH]CH2
Ph
1:5:5
4
25
36b
4
4
15
9
9a (95)
9b (69)
9c (50)
9d (71)
9e (73)
9f (54)
9g (69)
9h (72)
9i (95)
9j (83)
9k (80)
9l (67)
9m (66)
9n (80)
9o (71)
9p (86)
9q (82)
9r (95)
9s (76)
9t (76)
9u (62)
9v (81)
9w (85)
9x (78)
9y (75)
9z (74)
198e199
172e174d
145e146
189e191
159e160
139e140
68e70
1:4:10
1:20:10
1:2:5
1:3:5
1:1.5:4
1:2:5
1:1.5:5
1:2:5
1:5:5
1:4:8
1:20:10
1:2:5
9
4
4
8
167e169
196e197
195e197
156e157d
181e182
149e152
244e245
158e160
178e179
157e159
159e160
164e165
156e157d
181e182e
176e177
217e218
149e150
173e174
195e196
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
12b
4
1:3:5
1:2:5
1:5:5
1:3:5
4
4
6
4
4
8
11
20b
4
4
4
8
4
Ph
Py(2)
Py(2)
Py(2)
Py(2)
Py(2)
Py(2)
Py(2)
Py(2)
Py(2)
1:5:5
1:5:10
1:4:10
1:10:5
1:2:5
1:2:5
1:1.5:5
1:2:5
C6H4OCH3(m)
C6H4F(o)
C6H4NO2(p)
1:2:5
a
All reactions were run at 60 ꢀC if not stated otherwise.
The reaction was run at 70 ꢀC.
Products 9 were crystallized from EtOH/H2O 1:1 if not stated otherwise.
The product was crystallized from hexanes/EtOAc 2:1.
The product was crystallized from EtOH/H2O 2:1.
b
c
d
e
Scheme 4. Synthesis of 7-substituted 4-acylamino-THI’s 15 and 16 via Ritter reaction.
Fig. 1. ORTEP representation of trans-15.
purchased. 1H NMR, 13C NMR spectra were recorded in CDCl3, C6D6
3.2. General procedure for synthesis of products 6aed
(method A): 6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-
indazol-4-ol (6a)
or DMSO-d6 with solvent residual signal14 as the internal stan-
dard. 19F NMR spectra were recorded in CDCl3 and
a
,
a
,
a
-tri-
fluorotoluene was used as an external standard for these spectra;
the chemical shifts were converted from -trifluorotoluene to
NaBH4 (0.760 g, 20.1 mmol) was added to a solution of 5a
(2.40 g, 10.0 mmol) in ethanol (30 mL). The resulting reaction
mixture was stirred at ambient temperature for 12 h and concen-
trated under reduced pressure. The residue was partitioned be-
tween EtOAc (40 mL) and aqueous saturated solution of NH4Cl
a,a,a
CCl3F. Melting points were measured on Fisher Digital Melting
Point Analyzer Model 355 and Boetius apparatus and are un-
corrected. The progress of the reactions was followed by TLC
(Merck, 60 F254).

6134
M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
3J¼5.2 Hz, HeC(Py)), 4.82 (dd, 1H, 3J¼7.7 Hz, 3J¼6.1 Hz, HeC(4)),
Ph
Ph
1) HCl or
2.95 (s, 2H, HeC(7)), 2.41 (s, 3H, H3CeC(3)),1.95 (dd,1H, 2J¼13.3 Hz,
3J¼6.1 Hz, Ha-C(5)), 1.54 (dd, 1H, 2J¼13.3 Hz, 3J¼7.7 Hz, Hb-C(5)),
1.15, 0.97 (2s, 6H, H3CeC(6)).
N
N
(H2N)2C=S
N
N
2) TsOH
O
X
NH
H3N OTs
9a: X = H
9b: X = Cl
17
63% from 9a with HCl
3.3. General procedure for synthesis of products 7aed
(method B): 6,6-dimethyl-1-phenyl-6,7-dihydro-1H-indazole
(7a)
78% from 9b with HCl
80% from 9b with (H2N)2C=S
Scheme 5. Synthesis of 4-amino-THI 17 by deacylation of 9a and 9b.
A solution of 4-hydroxy-THI 6a (0.485 g, 2.00 mmol) in AcCl
(2 mL) was heated under reflux for 2 h and poured into water. The
precipitated solid was recrystallized from water/ethanol. Yield:
(30 mL). The aqueous phase was extracted with EtOAc (2ꢁ20 mL)
and the combined organic layers were dried over Na2SO4, filtered
and evaporated. The residue (white solid) was crystallized from
0.35 g (79%); mp 80e81 ꢀC (EtOH/H2O 1/3); IR (KBr) (cmꢂ1): 3034,
n
2960, 2946, 2934, 2885, 2857, 1601, 1561, 1507, 1424, 1387; 1H NMR
(300 MHz, CDCl3) (ppm): 7.52 (s, 1H, HeC(3)), 7.49e7.45 (m, 4H,
EtOH/H2O 1:1. Yield: 2.30 g (95%); mp 149e150 ꢀC; IR (KBr)
n
d
(cmꢂ1): 3270, 3190, 2934, 1600, 1506, 1407, 1308, 1047, 1025; 1H
HeC(Ph)), 7.40e7.32 (m, 1H, HeC(Ph)), 6.32, 5.44 (2d, 2H,
NMR (CDCl3, 300 MHz) d (ppm): 7.74 (s, 1H, HeC(3)), 7.49e7.42 (m,
3J¼9.6 Hz, HeC(4,5)), 2.79 (s, 2H, HeC(7)), 1.09 (s, 6H, H3CeC(6));
4H, HeC(Ph)), 7.38e7.31 (m, 1H, HeC(Ph)), 4.85 (dd, 1H, 3J¼8.5 Hz,
3J¼6.0 Hz, HeC(4)), 2.60, 2.42 (2d, AB syst., 2H, 2J¼16.0 Hz, HeC(7)),
1.96 (ddd, 1H, 2J¼13.0 Hz, 3J¼6.0 Hz, 4J¼1.3 Hz, Ha-C(5)), 1.53 (dd,
1H, 2J¼13.0 Hz, 3J¼8.5 Hz, Hb-C(5)), 1.12, 0.94 (2s, 6H, H3CeC(6));
13C NMR (300 MHz, CDCl3)
d (ppm): 139.5, 137.5, 136.3, 133.9, 129.2,
127.0, 123.2, 117.3, 117.2, 35.9, 34.4, 28.4 (2C); Anal. Calcd for
C15H16N2 (224.30): C 80.32, H 7.19, N 12.49; found C 80.11, H 7.32, N
12.54.
13C NMR (CDCl3, 75 MHz)
d (ppm): 139.7, 138.7, 138.2, 129.1, 127.1,
123.3, 120.3, 63.3, 46.5, 37.0, 33.1, 30.6, 26.2; Anal. Calcd for
C15H18N2O (242.32): C 74.35, H 7.49, N 11.56; found C 74.21, H 7.53,
N 11.55.
3.3.1. 3,6,6-Trimethyl-1-phenyl-6,7-dihydro-1H-indazole
(7b). Product 7b was synthesized by method B using starting ma-
terial 6b (0.520 g, 2.03 mmol). Product 7b (0.421 g, 87%) was
obtained as a white solid. Mp 57e59 ꢀC (EtOH/H2O 1/3); 1H NMR
3.2.1. 3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-ol
(6b). Product 6b was synthesized by method A using 5b (2.55 g,
10.0 mmol) as a starting material. Product 6b (2.49 g, 97%) was
obtained as a white solid. The spectral data of 6b are consistent
with those reported earlier.15 Mp 174e175 ꢀC (lit.15: 174e175 ꢀC); IR
(300 MHz, CDCl3) d (ppm): 7.48e7.41 (m, 4H, HeC(Ph)), 7.35e7.28
3
(m, 1H, HeC(Ph)), 6.28, 5.42 (2d, 2H, J¼9.6 Hz, HeC(4,5)), 2.75 (s,
2H, HeC(7)), 2.31 (s, 3H, H3CeC(3)), 1.09 (s, 6H, H3CeC(6)); 13C
NMR (75 MHz, CDCl3)
d (ppm): 144.9, 139.5, 138.0, 133.2, 129.1,
126.7, 123.1, 116.9, 115.9, 36.2, 34.4, 28.5 (2C), 11.6; Anal. Calcd for
C16H18N2 (238.33): C 80.63, H 7.61, N 11.75; found C 80.30, H 7.66, N
11.64.
(KBr)
n
(cmꢂ1): 3224, 3066, 2954,1601,1572,1508,1433,1384,1073;
(ppm): 7.46e7.43 (m, 4H, HeC(Ph)),
1H NMR (CDCl3, 300 MHz)
d
7.35e7.27 (m, 1H, HeC(Ph)), 4.86 (dd, 1H, 3J¼7.3 Hz, 3J¼6.0 Hz,
HeC(4)), 2.56, 2.41 (2d, AB syst., 2H, 2J¼16.4 Hz, HeC(7)), 2.40 (s,
3H, H3CeC(3)), 1.97 (ddd, 1H, 2J¼13.4 Hz, 3J¼6.0 Hz, 4J¼1.3 Hz, Ha-
C(5)), 1.58 (dd, 1H, 2J¼13.4 Hz, 3J¼7.3 Hz, Hb-C(5)), 1.11, 0.95 (2s, 6H,
H3CeC(6)); Anal. Calcd for C16H20N2O (256.34): C 74.97, H 7.86, N
10.93; found C 74.72, H 8.04, N 10.97.
3.3.2. 3,6,6-Trimethyl-1-pyridin-2-yl-6,7-dihydro-1H-indazole
(7d). Product 7d was synthesized by method B using starting ma-
terial 6d (1.60 g, 6.22 mmol). Product 7d (1.10 g, 74%) was obtained
as a white solid. Mp 73e74 ꢀC (EtOH); 1H NMR (300 MHz, CDCl3)
d
(ppm): 8.40 (ddd, 1H, J¼4.9, 1.9, 0.8 Hz, HeC(Py)), 7.87 (dt, 1H,
J¼8.3, 0.8 Hz, HeC(Py)), 7.75 (ddd, 1H, J¼8.3, 7.3, 1.9 Hz, HeC(Py)),
7.10 (ddd, 1H, J¼7.3, 4.9, 1.1 Hz, HeC(Py)), 6.22, 5.44 (2d, 2H,
3J¼9.6 Hz, HeC(4,5)), 3.26 (s, 2H, HeC(7)), 2.30 (s, 3H, H3CeC(3)),
3.2.2. 6,6-Dimethyl-1-phenyl-3-trifluoromethyl-4,5,6,7-tetrahydro-
1H-indazol-4-ol (6c). Product 6c was synthesized by method A
using 5c (1.24 g, 4.02 mmol) as a starting material. Product 6c
(1.10 g, 88%) was obtained as colorless crystals. Mp 120e122 ꢀC
1.17 (s, 6H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 153.2,
147.6, 145.9, 139.6, 138.1, 134.1, 120.4, 117.1, 116.1, 114.6, 37.6, 33.9,
28.8 (2C), 11.7. Anal. Calcd for C15H17N3 (239.32): C 75.28, H 7.16, N
17.56; found C 75.30, H 7.22, N 17.54.
(hexane/Et2O); IR (KBr)
1600, 1500, 1470, 1450, 1390, 1385, 1370, 1330, 1290, 1260, 1245,
n
(cmꢂ1): 3495, 3385, 2960, 2875, 1635,
1165,1130,1035,1015, 985, 950; 1H NMR (CDCl3, 500 MHz)
d (ppm):
7.41e7.51 (m, 5H, HeC(Ph)), 5.01 (dd, 1H, 3J¼6.0 Hz, 3J¼7.2 Hz,
HeC(4)), 2.60, 2.42 (2d, AB syst., 2H, 2J¼16.2 Hz, HeC(7)), 2.06 (br s,
1H, HOeC(4)), 1.99 (ddd, AB syst., 1H, 2J¼13.6 Hz, 3J¼6.0 Hz,
4J¼1.0 Hz, Ha-C(5)), 1.70 (dd, AB syst., 1H, 2J¼13.6 Hz, 3J¼7.2 Hz, Hb-
C(5)), 1.15, 0.97 (2s, 6H, H3CeC(6)); 13C NMR (CDCl3, 125 MHz)
3.4. General procedure I for Ritter reaction: N-(6,6-dimethyl-
1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-acetamide (9a)
Starting material 6a (0.969 g, 4.00 mmol, 1 equiv) was added to
a stirred solution of MeCN (1.00 mL, 20.0 mmol, 5 equiv) in glacial
acetic acid (4 mL) and concd H2SO4 (1.10 mL, 20 mmol, 5 equiv). The
resulting reaction mixture was stirred at 60 ꢀC for 4 h (TLC control).
The reaction mixture was cooled to 0 ꢀC and poured into a vigor-
ously stirred w10% aqueous solution of NaOH (50e60 mL) at 0 ꢀC.
The crude product 9a was filtered and thoroughly washed with
water until the filtrate became neutral. The obtained solid was
recrystallized from a mixture of EtOH/H2O (1:1). Yield: 1.07 g (95%);
d
(ppm): 141.3,140.1 (q, 2J¼37 Hz),138.7,129.4, 128.4,124.1,121.8 (q,
1J¼270 Hz), 117.9, 62.0, 45.2, 36.9, 32.6, 29.8, 27.1; 19F (CDCl3,
470 MHz)
d
(ppm): ꢂ61.3; Anal. Calcd for C16H17N2OF3 (310.31): C
61.93, H 5.52, N 9.03; found C 62.15, H 5.49, N 8.98.
3.2.3. 3,6,6-Trimethyl-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-indazol-
4-ol (6d). Product 6d was synthesized by method A using 5d
(2.56 g, 10.0 mmol) as a starting material. Product 6d (2.37 g, 92%)
was obtained as a white solid. The spectral data of 6d are consistent
with those reported earlier.5b Mp 118e119 ꢀC (lit.5b: 125e126 ꢀC);
IR (KBr)
1510, 1455, 1396, 1383, 1371, 1293, 1276, 1178, 1141, 1130, 1066, 966;
1H NMR (300 MHz, CDCl3)
(ppm): 7.60 (s, 1H, HeC(3)), 7.50e7.44
n
(cmꢂ1): 3265, 3068, 2963, 2905, 1645, 1634, 1601, 1554,
d
IR (KBr)
n
(cmꢂ1): 3455, 2987, 2948, 2924, 2866, 1585, 1474, 1444,
(m, 4H, PheN(1)), 7.39e7.31 (m, 1H, PheN(1)), 5.73 (d, 1H,
3J¼8.3 Hz, HeNeC(4)), 5.14, (ddd, 1H, 3J¼9.8 Hz, 3J¼8.3 Hz,
3J¼7.2 Hz, HeC(4)), 2.60 (d, 1H, 2J¼16.0 Hz, Ha-C(7)), 2.43 (d, 1H,
2J¼16.0 Hz, Hb-C(7)), 2.03 (s, 3H, HeC(20)), 2.01 (ddd, 1H,
1387, 1368, 1057, 1045; 1H NMR (CDCl3, 300 MHz)
d (ppm): 8.38 (d,
1H, 3J¼5.6 Hz, HeC(Py)), 7.85 (d, 1H, 3J¼8.2 Hz, HeC(Py)), 7.75 (dd,
1H, 3J¼8.2 Hz, 3J¼7.2 Hz, HeC(Py)), 7.11 (dd, 1H, 3J¼7.2 Hz,

M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
6135
2J¼13.0 Hz, 3J¼7.2 Hz, 4J¼1.1 Hz, Hb-C(5)), 1.35 (dd, 1H, 2J¼13.0 Hz,
3J¼9.8 Hz, Ha-C(5)), 1.10 (s, 3H, H3CeC(5)), 0.96 (s, 3H, H3CeC(5));
acrylnitrile (2 equiv) instead of MeCN. IR (KBr)
n
(cmꢂ1): 3277, 3065,
2962, 2908, 1657, 1623, 1600, 1504, 1453, 1411, 1396, 1383, 1259,
13C NMR (75 MHz, CDCl3)
d
(ppm): 169.7, 139.5, 139.1, 137.9, 129.1,
1240, 1067, 990, 967, 954; 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.60
127.2, 123.3, 118.1, 43.5, 41.8, 36.9, 32.6, 30.8, 25.3, 23.5; Anal. Calcd
for C17H21N3O (283.37): C 72.06, H 7.47, N 14.83; found C 72.16, H
7.38, N 14.69.
(s, 1H, HeC(3)), 7.48e7.44 (m, 4H, PheN(1)), 7.39e7.32 (m, 1H,
PheN(1)), 6.33 (dd,1H, 3J¼17.0 Hz, 2J¼1.5 Hz, Ha-C(30)), 6.12 (dd,1H,
3J¼17.0 Hz, 3J¼10.2 Hz, HeC(20)), 5.84 (d, 1H, 3J¼7.3 Hz, HeNeC(4)),
2
5.67 (dd, 1H, 3J¼10.2 Hz, J¼1.5 Hz, Hb-C(30)), 5.23 (ddd, 1H,
3.5. General procedure II for Ritter reaction: 2-chloro-N-(6,6-
dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-
acetamide (9b)
3J¼9.8 Hz, 3J¼7.3 Hz, 3J¼5.8 Hz, HeC(4)), 2.58 (d, 1H, 2J¼16.2 Hz,
Ha-C(7)), 2.45 (d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.04 (dd, 1H, 2J¼13.0 Hz,
3J¼5.8 Hz, Ha-C(5)), 1.38 (dd, 1H, 2J¼13.0 Hz, 3J¼9.8 Hz, Hb-C(5)),
1.11 (s, 3H, H3CeC(6)), 0.98 (s, 3H, H3CeC(6)); 13C NMR (75 MHz,
Starting material 6a (0.969 g, 4.00 mmol, 1 equiv) was added to
a stirred solution of ClCH2CN (1.00 mL, 16.0 mmol, 4 equiv) in
glacial acetic acid (4 mL) and concd H2SO4 (2.20 mL, 40 mmol,
10 equiv). The resulting reaction mixture was stirred at 60 ꢀC for
24 h (TLC control). The reaction mixture was cooled to 0 ꢀC and
poured into a vigorously stirred w10% aqueous solution of NaOH
(60 mL) at 0 ꢀC. The crude product 9b was filtered and thoroughly
washed with water until the filtrate became neutral. The obtained
solid was recrystallized from a mixture of hexanes/EtOAc (1:1).
CDCl3) d (ppm): 165.1, 139.6, 139.3, 138.1, 130.9, 129.2, 127.2, 126.7,
123.3, 117.9, 43.5, 41.9, 37.0, 32.7, 30.8, 25.4; Anal. Calcd for
C18H21N3O (295.38): C 73.19, H 7.17, N 14.23; found C 72.91, H 7.24,
N 14.17.
3.7.2. N-(6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-benzamide (9e). Product 9e (1.01 g, 73%) was obtained as
a white solid by general procedure I for Ritter reaction using ben-
zonitrile (3 equiv) instead of MeCN. IR (KBr)
n
(cmꢂ1): 3271, 2955,
Yield: 0.87 g (69%); IR (KBr)
1562, 1505, 1402, 1249, 1165, 968; 1H NMR (300 MHz, CDCl3)
(ppm): 7.62 (s, 1H, HeC(3)), 7.50e7.45 (m, 4H, PheN(1)),
n
(cmꢂ1): 3253, 3076, 2961, 1648,
1627, 1600, 1578, 1534, 1505, 1490, 1401, 1294, 1182, 1149, 1067, 968;
1H NMR (300 MHz, CDCl3)
d
(ppm): 7.81 (dd, 2H, 3J¼7.7 Hz,
d
4J¼0.9 Hz, PheC(10)), 7.66 (s, 1H, HeC(3)), 7.54e7.41 (m, 7H,
PheN(1), PheC(10)), 7.40e7.32 (m, 1H, PheN(1)), 6.34 (d, 1H,
3J¼8.5 Hz, HeNeC(4)), 5.37 (ddd, 1H, 3J¼9.4 Hz, 3J¼8.5 Hz,
3J¼5.8 Hz, HeC(4)), 2.62 (dd, 1H, 2J¼16.1 Hz, 4J¼1.1 Hz, Ha-C(7)),
2.48 (d, 1H, 2J¼16.1 Hz, Hb-C(7)), 2.12 (ddd, 1H, 2J¼12.8 Hz,
3J¼5.8 Hz, 4J¼1.1 Hz, Ha-C(5)), 1.49 (dd, 1H, 2J¼12.8 Hz, 3J¼9.4 Hz,
Hb-C(5)), 1.14 (s, 3H, H3CeC(5)), 1.02 (s, 3H, H3CeC(5)); 13C NMR
7.40e7.33 (m, 1H, PheN(1)), 6.75 (d, 1H, 3J¼8.1 Hz, HeNeC(4)),
5.16 (ddd, 1H, 3J¼9.6 Hz, 3J¼8.1 Hz, 3J¼5.8 Hz, HeC(4)), 4.14 (d, 1H,
2J¼15.3 Hz, Ha-C(20)), 4.08 (d, 1H, 2J¼15.3 Hz, Hb-C(20)), 2.61 (d, 1H,
2J¼16.2 Hz, Ha-C(7)), 2.46 (d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.02 (dd, 1H,
2J¼13.0 Hz, 3J¼5.8 Hz, Ha-C(5)), 1.46 (dd, 1H, 2J¼13.0 Hz, 3J¼9.6 Hz,
Hb-C(5)), 1.13 (s, 3H, H3CeC(6)), 0.99 (s, 3H, H3CeC(6)); 13C NMR
(75 MHz, CDCl3)
d
(ppm): 165.6, 139.5, 139.3, 137.9, 129.2, 127.4,
(75 MHz, CDCl3) d (ppm): 167.1, 139.7, 139.2, 138.2, 134.5, 131.6,
123.5, 117.2, 43.3, 42.7, 42.4, 36.9, 32.7, 30.6, 25.6; Anal. Calcd for
C17H20ClN3O (317.81): C 64.25, H 6.34, N 13.22; found C 64.11, H
6.27, N 13.00.
129.2, 128.6, 127.2, 126.9, 123.4, 118.0, 43.6, 42.4, 37.0, 32.8, 30.8,
25.6; Anal. Calcd for C22H23N3O (345.44): C 76.49, H 6.71, N 12.16;
found C 76.36, H 6.81, N 11.93.
3.6. General procedure III for Ritter reaction: 2,2,2-trichloro-
N-(6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-acetamide (9c)
3.7.3. N-(6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-3-methoxy-benzamide (9f). Product 9f (0.54 g, 54%) was
obtained as a white solid by general procedure I for Ritter reaction
using 3-methoxy-benzonitrile (1.5 equiv) instead of MeCN and
Starting material 6a (0.969 g, 4.00 mmol, 1 equiv) was added to
a stirred solution of Cl3CCN (8.00 mL, 80.0 mmol, 20 equiv) in
glacial acetic acid (5 mL) and concd H2SO4 (2.20 mL, 40 mmol,
10 equiv). The resulting reaction mixture was stirred at 70 ꢀC for
36 h (TLC control). The reaction mixture was cooled to 0 ꢀC and
poured into a vigorously stirred w10% aqueous solution of NaOH
(70 mL) at 0 ꢀC. The crude product 9c was filtered and thoroughly
washed with water until the filtrate became neutral. The obtained
solid was recrystallized from a mixture of EtOH/H2O (1:1). Yield:
H2SO4 (4 equiv). Reaction time: 15 h. IR (KBr)
1641, 1602, 1581, 1527, 1505, 1485, 1406, 1295, 1236, 1046; 1H NMR
(300 MHz, CDCl3) (ppm): 7.64 (s, 1H, HeC(3)), 7.48e7.45 (m, 4H,
n
(cmꢂ1): 3339, 2960,
d
PheN(1)), 7.44e7.41 (m, 1H, AreC(10)), 7.39e7.30 (m, 3H, PheN(1),
AreC(10)), 7.07e7.00 (m, 1H, AreC(10)), 6.44 (d, 1H, 3J¼8.3 Hz,
HeNeC(4)), 5.34 (ddd, 1H, 3J¼9.6 Hz, 3J¼8.3 Hz, 3J¼6.0 Hz, HeC(4)),
3.85 (s, 3H, m-CH3eO-AreC(10)), 2.60 (d, 1H, 2J¼16.2 Hz, Ha-C(7)),
2.46 (d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.09 (dd, 1H, 2J¼12.9 Hz,
3J¼6.0 Hz, Ha-C(5)), 1.44 (dd, 1H, 2J¼12.9 Hz, 3J¼9.6 Hz, Hb-C(5)),
1.12 (s, 3H, H3CeC(6)), 1.00 (s, 3H, H3CeC(6)); 13C NMR (75 MHz,
0.77 g (50%); IR (KBr)
n
(cmꢂ1): 3034, 2958, 2934, 1601, 1561, 1507,
(ppm): 7.64 (s, 1H,
1424, 1387, 896; 1H NMR (300 MHz, CDCl3)
d
CDCl3) d (ppm): 166.9, 159.8, 139.5, 139.1, 138.0, 135.9, 129.5, 129.1,
HeC(3)), 7.51e7.45 (m, 4H, PheN(1)), 7.41e7.34 (m, 1H, PheN(1)),
6.79 (d, 1H, 3J¼7.7 Hz, HeNeC(4)), 5.13 (ddd, 1H, 3J¼9.2 Hz,
3J¼7.7 Hz, 3J¼6.1 Hz, HeC(4)), 2.62 (d, 1H, 2J¼16.4 Hz, Ha-C(7)),
2.49 (d, 1H, 2J¼16.4 Hz, Hb-C(7)), 2.08 (ddd, 1H, 2J¼13.0 Hz,
127.2, 123.2, 118.6, 117.9, 117.7, 112.3, 55.4, 43.4, 42.3, 36.9, 32.7, 30.7,
25.5; Anal. Calcd for C23H25N3O2 (375.46): C 73.57, H 6.71, N 11.19;
found C 73.33, H 6.72, N 11.07.
4
2
3
3J¼6.1 Hz, J¼1.0 Hz, Ha-C(5)), 1.53 (ddd, 1H, J¼13.0 Hz, J¼9.2 Hz,
3.7.4. N-(6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-2-fluoro-benzamide (9g). Product 9g (1.00 g, 69%) was obtained
as a white solid by general procedure I for Ritter reaction using 2-
fluorobenzonitrile (2 equiv) instead of MeCN. Reaction time: 9 h.
Hb-C(5)), 1.15 (s, 3H, H3CeC(6)), 1.02 (s, 3H, H3CeC(6)); 13C NMR
(75 MHz, CDCl3)
d (ppm): 161.6, 139.7, 139.1, 137.5, 129.3, 127.7,
123.6, 116.4, 92.6, 44.2, 42.6, 36.7, 32.6, 30.4, 25.7; Anal. Calcd for
C17H18Cl3N3O (386.70): C 52.80, H 4.69, N 10.87; found C 52.80, H
4.56, N 10.79.
IR (KBr)
n
(cmꢂ1): 3388, 3066, 2951, 1648, 1616, 1501, 1396, 1320,
1297, 1258, 1219, 1099, 968, 924; 1H NMR (300 MHz, CDCl3)
d
(ppm): 8.15 (dt, 1H, J¼7.9 Hz, J¼1.9 Hz, o-FeC6H4eC(10)), 7.67 (s,
3.7. Synthesis of 4-acylamino-tetrahydroindazoles via the
Ritter reaction
1H, HeC(3)), 7.52e7.43 (m, 5H, o-FeC6H4eC(10), PheN(1)),
7.39e7.32 (m, 1H, PheN(1)), 7.30 (d, 1H, J¼7.7 Hz, o-FeC6H4eC(10)),
3
7.11 (dd, 1H, J¼12.2 Hz, J¼8.3 Hz, o-FeC6H4eC(10)), 6.91 (dd, 1H,
3.7.1. N-(6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-acrylamide (9d). Product 9d (0.839 g, 71%) was obtained as
a white solid by general procedure I for Ritter reaction using
JHeF¼12.2 Hz, 3J¼8.5 Hz, HeNeC(4)), 5.40 (ddd, 1H, 3J¼9.4 Hz,
3J¼8.5 Hz, 3J¼5.8 Hz, HeC(4)), 2.63 (d,1H, 2J¼15.8 Hz, Ha-C(7)), 2.49
(d, 1H, 2J¼15.8 Hz, Hb-C(7)), 2.14 (dd, 1H, 2J¼13.0 Hz, 3J¼5.8 Hz, Ha-

6136
M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
C(5)), 1.53 (dd, 1H, 2J¼13.0 Hz, 3J¼9.4 Hz, Hb-C(5)), 1.14 (s, 3H,
H3CeC(6)), 1.03 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
1507, 1383, 1253, 1152, 1040; 1H NMR (300 MHz, CDCl3)
d (ppm):
7.46e7.40 (m, 4H, PheN(1)), 7.34e7.27 (m, 1H, PheN(1)), 6.67 (d,
1H, 3J¼8.7 Hz, HeNeC(4)), 5.19 (dt, 1H, 3J¼6.0 Hz, 3J¼8.7 Hz,
HeC(4)), 4.09 (s, 2H, HeC(20)), 2.58 (d,1H, 2J¼16.2 Hz, Ha-C(7)), 2.41
(d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.24 (s, 3H, H3CeC(3)), 2.00 (dd, 1H,
2J¼13.0 Hz, 3J¼6.0 Hz, Ha-C(5)), 1.48 (dd, 1H, 2J¼13.0 Hz, 3J¼8.7 Hz,
Hb-C(5)), 1.11 (s, 3H, H3CeC(6)), 1.00 (s, 3H, H3CeC(6)); 13C NMR
d
(ppm): 163.0 (d, JCeF¼3 Hz), 160.7 (d, JCeF¼247 Hz), 139.7, 139.2,
138.1, 133.4 (d, JCeF¼9 Hz), 132.1 (d, JCeF¼2 Hz), 129.2, 127.2,
124.9 (d, JCeF¼3 Hz), 123.4, 121.1 (d, JCeF¼12 Hz), 117.8, 116.0
(d, JCeF¼25 Hz), 43.5, 42.4, 37.0, 32.7, 30.6, 25.8; Anal. Calcd for
C22H22N3OF (363.43): C 72.71, H 6.10, N 11.56; found C 72.58, H 6.29,
N 11.70.
(75 MHz, CDCl3)
d (ppm): 165.1, 147.0, 140.1, 139.4, 129.0, 126.8,
123.1, 113.9, 43.5, 42.5, 42.1, 37.0, 32.5, 30.1, 25.9, 12.4; Anal. Calcd
for C18H22ClN3O (331.84): C 65.15, H 6.68, N 12.66; found C 64.86, H
6.83, N 12.31.
3.7.5. N-(6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-4-nitro-benzamide (9h). Product 9h (1.13 g, 72%) was obtained
as a white solid by general procedure I for Ritter reaction using 4-
nitrobenzonitrile (1.5 equiv) instead of MeCN. Reaction time: 9 h.
3.7.9. 2,2,2-Trichloro-N-(3,6,6-trimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-acetamide (9l). Product 9l (1.08 g, 67%)
was obtained as a white solid by general procedure III for Ritter
reaction using starting material 6b (1.03 g, 4.02 mmol). Reaction
IR (KBr)
n
(cmꢂ1): 3392, 2960, 2920, 2864, 1645, 1599, 1527, 1504,
1486, 1476, 1454, 1402, 1349, 1191, 975; 1H NMR (300 MHz, CDCl3)
3
d
(ppm): 8.30 (d, 2H, J¼8.7 Hz, p-NO2eC6H4eC(10)), 7.98 (d, 2H,
3J¼8.7 Hz, p-NO2eC6H4eC(10)), 7.64 (s, 1H, HeC(3)), 7.49e7.45 (m,
4H, PheN(1)), 7.40e7.34 (m, 1H, PheN(1)), 6.50 (d, 1H, 3J¼8.1 Hz,
HeNeC(4)), 5.36 (ddd, 1H, 3J¼9.6 Hz, 3J¼8.1 Hz, 3J¼5.7 Hz, HeC(4)),
2.62 (d, 1H, 2J¼16.4 Hz, Ha-C(7)), 2.49 (d, 1H, 2J¼16.4 Hz, Hb-C(7)),
2.13 (dd, 1H, 2J¼12.9 Hz, 3J¼5.7 Hz, Ha-C(5)), 1.47 (dd, 1H,
2J¼12.9 Hz, 3J¼9.6 Hz, Hb-C(5)), 1.14 (s, 3H, H3CeC(6)), 1.02 (s, 3H,
time: 12 h. IR (KBr)
(300 MHz, CDCl3)
n
(cmꢂ1): 3267, 2952, 1696, 1507, 1078; 1H NMR
(ppm): 7.48e7.42 (m, 4H, PheN(1)), 7.37e7.30
d
(m, 1H, PheN(1)), 6.74 (d, 1H, 3J¼8.5 Hz, HeNeC(4)), 5.15 (ddd, 1H,
3J¼5.8 Hz, 3J¼8.1 Hz, 3J¼8.5 Hz, HeC(4)), 2.61 (d,1H, 2J¼16.2 Hz, Ha-
C(7)), 2.45 (d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.29 (s, 3H, H3CeC(3)), 2.07
(dd, 1H, 2J¼13.2 Hz, 3J¼5.8 Hz, Ha-C(5)), 1.56 (dd, 1H, 2J¼13.2 Hz,
3J¼8.1 Hz, Hb-C(5)), 1.11 (s, 3H, H3CeC(6)), 1.00 (s, 3H, H3CeC(6));
H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 165.0, 149.6, 140.0,
139.4, 139.3, 138.0, 129.3, 128.2, 127.4, 123.8, 123.2, 117.4, 43.3, 42.8,
37.0, 32.8, 30.8, 25.4; Anal. Calcd for C22H22N4O3 (390.44): C 67.68,
H 5.68, N 14.35; found C 67.80, H 5.56, N 14.53.
13C NMR (75 MHz, CDCl3)
d (ppm): 161.0, 147.1, 140.4, 139.2, 129.2,
127.1, 123.3, 113.3, 92.7, 44.1, 42.9, 37.0, 32.5, 29.8, 26.3, 12.4; Anal.
Calcd for C18H20Cl3N3O (400.73): C 53.95, H 5.03, N 10.49; found C
53.93, H 4.93, N 10.45.
3.7.6. N-(3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-acetamide (9i). Product 9i (1.14 g, 95%) was obtained as a white
solid by general procedure I for Ritter reaction using starting ma-
3.7.10. N-(3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-
4-yl)-acrylamide (9m). Product 9m (0.893 g, 66%) was obtained as
a white solid by general procedure I for Ritter reaction using
starting material 6b (1.03 g, 4.02 mmol) and acrylonitrile (2 equiv)
terial 6b (1.03 g, 4.02 mmol) and MeCN (2 equiv). IR (KBr)
3248, 3058, 2948, 2369, 1636, 1560, 1507, 1381, 1292, 1109, 1039,
1014; 1H NMR (300 MHz, CDCl3)
(ppm): 7.45e7.39 (m, 4H,
n
(cmꢂ1):
d
instead of MeCN. IR (KBr)
n
(cmꢂ1): 3434, 3050, 2956, 2370, 2345,
(ppm): 7.47e7.41 (m,
PheN(1)), 7.33e7.27 (m, 1H, PheN(1)), 5.76 (d, 1H, 3J¼8.9 Hz,
HeNeC(4)), 5.16 (dt, 1H, 3J¼8.9 Hz, 3J¼6.2 Hz, HeC(4)), 2.54 (d, 1H,
2J¼16.2 Hz, Ha-C(7)), 2.37 (d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.23 (s, 3H,
H3CeC(3)), 1.99 (s, 3H, HeC(20)), 1.95 (dd, 1H, 2J¼13.2 Hz, 3J¼6.2 Hz,
Ha-C(5)), 1.37 (dd, 1H, 2J¼13.2 Hz, 3J¼8.9 Hz, Hb-C(5)), 1.06 (s, 3H,
H3CeC(6)), 0.92 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
1656, 1558, 1251; 1H NMR (300 MHz, CDCl3)
d
4H, PheN(1)), 7.34e7.28 (m, 1H, PheN(1)), 6.32 (d, 1H, 3J¼16.8 Hz,
Ha-C(30)), 6.11 (dd, 1H, 3J¼16.8 Hz, 3J¼10.2 Hz, HeC(20)), 5.74 (d, 1H,
3J¼8.9 Hz, HeNeC(4)), 5.67 (d, 1H, 3J¼10.2 Hz, Hb-C(30)), 5.28 (ddd,
1H, 3J¼8.9 Hz, 3J¼8.7 Hz, 3J¼6.2 Hz, HeC(4)), 2.58 (d, 1H,
2J¼16.2 Hz, Ha-C(7)), 2.40 (d, 1H, 2J¼16.2 Hz, Hb-C(7)), 2.23 (s, 3H,
H3CeC(3)), 2.02 (dd, 1H, 2J¼13.3 Hz, 3J¼6.2 Hz, Ha-C(5)), 1.45 (dd,
d
(ppm): 169.3, 147.1, 140.0, 139.4, 129.2, 126.9, 123.1, 115.0, 44.0,
2
3
41.5, 37.2, 32.7, 30.4, 25.8, 23.4, 12.4; Anal. Calcd for C18H23N3O
(297.39): C 72.70, H 7.80, N 14.13; found C 72.76, H 7.86, N 14.17.
1H, J¼13.3 Hz, J¼8.7 Hz, Hb-C(5)), 1.08 (s, 3H, H3CeC(6)), 0.96 (s,
3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d
(ppm): 164.9, 147.3,
140.1, 139.4, 130.8, 129.2, 126.9, 126.7, 123.2, 114.8, 43.9, 41.6, 37.2,
32.7, 30.3, 25.9, 12.4; Anal. Calcd for C19H23N3O$1.5H2O
(309.41$1.5H2O): C 67.83, H 7.79, N 12.49; found C 67.58, H 7.71, N
12.59.
3.7.7. N-(3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl)-butyramide (9j). Product 9j (1.10 g, 83%) was obtained as a white
solid by general procedure I for Ritter reaction using starting ma-
terial 6b (1.03 g, 4.02 mmol) and butyronitrile (5) instead of MeCN.
IR (KBr)
n
(cmꢂ1): 3305, 2959, 2370,1638, 1530, 1507,1383,1047; 1H
3.7.11. N-(3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-
4-yl)-benzamide (9n). Product 9n (1.16 g, 80%) was obtained as
a white solid by general procedure I for Ritter reaction using
starting material 6b (1.03 g, 4.02 mmol) and benzonitrile (3 equiv)
NMR (300 MHz, CDCl3)
d
(ppm): 7.47e7.42 (m, 4H, PheN(1)),
7.35e7.29 (m,1H, PheN(1)), 5.49 (d,1H, 3J¼9.2 Hz, HeNeC(4)), 5.22
(ddd, 1H, 3J¼9.2 Hz, 3J¼8.7 Hz, 3J¼6.0 Hz, HeC(4)), 2.57 (d, 1H,
2J¼16.0 Hz, Ha-C(7)), 2.41 (d, 1H, 2J¼16.0 Hz, Hb-C(7)), 2.27 (s, 3H,
H3CeC(3)), 2.19 (t, 2H, 3J¼7.9 Hz, HeC(20)), 2.01 (dd, 1H, 2J¼13.1 Hz,
3J¼6.0 Hz, Ha-C(5)), 1.72 (sext., 2H, 3J¼7.5 Hz, HeC(30)), 1.23 (dd, 1H,
3J¼13.1 Hz, 3J¼8.7 Hz, Hb-C(5)), 1.09 (s, 3H, H3CeC(6)), 0.98 (t, 3H,
3J¼7.3 Hz, HeC(40)), 0.96 (s, 3H, H3CeC(6)); 13C NMR (75 MHz,
instead of MeCN. IR (KBr)
n
(cmꢂ1): 3299, 3057, 2949, 2926, 1630,
1531, 1507, 1375, 1291, 1177, 1024, 1045, 920; 1H NMR (300 MHz,
CDCl3)
d
(ppm): 7.79 (d, 1H, 3J¼7.3 Hz, PheC(10)), 7.54e7.44 (m, 7H,
PheN(1, 10)), 7.38e7.32 (m, 1H, PheN(1)), 6.24 (d, 1H, 3J¼8.7 Hz,
HeNeC(4)), 5.43 (dt, 1H, 3J¼6.2 Hz, 3J¼8.7 Hz, HeC(4)), 2.62 (d, 1H,
2J¼15.8 Hz, Ha-C(7)), 2.45 (d, 1H, 2J¼15.8 Hz, Hb-C(7)), 2.29 (s, 3H,
H3CeC(3)), 2.11 (dd, 1H, 2J¼13.1 Hz, 3J¼6.2 Hz, Ha-C(5)), 1.56 (dd,
1H, 2J¼13.1 Hz, 3J¼8.7 Hz, Hb-C(5)), 1.12 (s, 3H, H3CeC(6)), 1.01 (s,
CDCl3)
d (ppm): 172.1, 147.1, 140.2, 139.5, 129.1, 126.8, 123.3, 115.0,
44.1, 41.3, 38.9, 37.2, 32.6, 30.3, 25.9, 19.2, 13.8, 12.4; Anal. Calcd for
C20H27N3Oꢃ0.2H2O (325.45ꢃ0.2H2O): C 73.00, H 8.39, N 12.77;
found C 73.22, H 8.53, N 12.99.
3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 166.7, 147.2,
140.2, 139.4, 134.5, 131.5, 129.1, 128.7, 126.9, 126.8, 123.2, 114.9, 44.0,
42.0, 37.2, 32.7, 30.3, 26.0, 12.5; Anal. Calcd for C23H25N3O (359.46):
C 76.85, H 7.01, N 11.69; found C 76.53, H 7.34, N 11.54.
3.7.8. 2-Chloro-N-(3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-
indazol-4-yl)-acetamide (9k). Product 9k (1.07 g, 80%) was
obtained as a white solid by general procedure II for Ritter reaction
using starting material 6b (1.03 g, 4.02 mmol) and H2SO4 (8 equiv).
3.7.12. 2-Fluoro-N-(3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-
indazol-4-yl)-benzamide (9o). Product 9o (1.08 g, 71%) was
Reaction time: 8 h. IR (KBr)
n
(cmꢂ1): 3221, 3066, 2954, 1648, 1560,

M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
6137
obtained as a white solid by general procedure I for Ritter reaction
using starting material 6b (1.03 g, 4.02 mmol) and 2-
3J¼9.2 Hz, 3J¼9.0 Hz, 3J¼6.0 Hz, HeC(4)), 2.95 (d,1H, 2J¼17.7 Hz, Ha-
C(7)), 2.87 (d, 1H, 2J¼17.7 Hz, Hb-C(7)), 2.24 (s, 3H, HeC(20)), 2.03 (s,
2
4
fluorobenzonitrile (2 equiv) instead of MeCN. IR (KBr)
n
(cmꢂ1):
3H, H3CeC(3)), 1.89 (ddd, 1H, J¼13.0 Hz, 3J¼6.0 Hz, J¼0.9 Hz, Ha-
C(5)), 1.29 (dd, 1H, 2J¼13.0 Hz, 3J¼9.0 Hz, Hb-C(5)) 1.09 (s, 3H,
H3CeC(6)), 0.95 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
3247, 2957, 2930, 2368, 1648, 1508, 1220, 1103, 1069; 1H NMR
(300 MHz, CDCl3)
d
(ppm): 8.16 (dd, 1H, 3J¼7.7 Hz, 4J¼1.7 Hz,
HeC(Ar)), 7.51e7.43 (m, 5H, HeC(Ar)), 7.36e7.29 (m, 2H, HeC(Ar)),
7.12 (dd, 1H, 3J¼12.2 Hz, 3J¼8.3 Hz, HeC(Ar)), 6.81 (d, 1H, 3J¼9.0 Hz,
HeNeC(4)), 5.45 (ddd,1H, 3J¼9.2 Hz, 3J¼8.3 Hz, 3J¼6.0 Hz, HeC(4)),
2.62 (d, 1H, 3J¼16.3 Hz, Ha-C(7)), 2.45 (d, 1H, 2J¼16.3 Hz, Hb-C(7)),
2.29 (s, 3H, H3CeC(3)), 2.14 (dd, 1H, 2J¼13.2 Hz, 3J¼6.0 Hz, Ha-C(5)),
1.59 (dd, 1H, 3J¼13.2 Hz, 3J¼8.3 Hz, Hb-C(5)), 1.12 (s, 3H, H3CeC(6)),
d (ppm): 169.2, 153.0, 148.2, 147.5, 141.8, 138.3, 120.6, 116.3, 114.8,
43.9, 41.3, 38.8, 32.2, 30.6, 25.8, 23.4, 12.6; Anal. Calcd for
C17H22N4O (298.38): C 68.43, H 7.43, N 18.78; found C 68.44, H 7.49,
N 18.74.
3.7.16. N-(3,6,6-Trimethyl-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-in-
dazol-4-yl)-butyramide (9s). Product 9s (0.992 g, 76%) was
obtained as a white solid by general procedure I for Ritter reaction
using starting material 6d (1.03 g, 4.00 mmol), H2SO4 (10 equiv)
and butyronitrile (5 equiv) instead of MeCN. Reaction time: 8 h. IR
1.02 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 162.6 (d,
JCeF¼3 Hz), 160.5 (d, JCeF¼247 Hz), 147.3, 140.1, 139.6, 133.3 (d,
JCeF¼9 Hz), 132.1 (d, JCeF¼2 Hz), 129.1, 126.8, 124.9 (d, JCeF¼3 Hz),
123.2, 121.0 (d, JCeF¼12 Hz), 116.0 (d, JCeF¼25 Hz), 114.6, 43.9, 42.2,
37.3, 32.6, 30.1, 26.2, 12.5; Anal. Calcd for C23H24N3O (377.45): C
73.19, H 6.41, N 11.13; found C 72.94, H 6.53, N 10.90.
(KBr)
n
(cmꢂ1): 3232, 3063, 2957, 2927, 2871, 1639, 1584, 1557,
1486, 1470, 1443, 1382, 1366, 1216, 1058, 1040; 1H NMR (300 MHz,
CDCl3)
d
(ppm): 8.39 (ddd, 1H, 3J¼4.9 Hz, 4J¼1.6 Hz, 5J¼1.0 Hz,
4
5
3.7.13. N-(6,6-Dimethyl-1-phenyl-3-(trifluoromethyl)-4,5,6,7-
tetrahydro-1H-indazol-4-yl)acetamide (9p). Product 9p (1.21 g,
86%) was obtained as a white solid by general procedure I for Ritter
reaction using starting material 6c (1.24 g, 4.00 mmol). Reaction
PyeN(1)), 7.84 (ddd, 1H, 3J¼8.3 Hz, J¼1.0 Hz, J¼1.0 Hz, PyeN(1)),
7.76 (ddd, 1H, 3J¼8.3 Hz, 3J¼7.2 Hz, 4J¼1.6 Hz, PyeN(1)), 7.13 (ddd,
1H, 3J¼7.2 Hz, 3J¼4.9 Hz, 4J¼1.0 Hz, PyeN(1)), 5.67 (d, 1H,
3J¼9.0 Hz, HeNeC(4)), 5.17 (dt, 1H, 3J¼9.0 Hz, 3J¼6.0 Hz, HeC(4)),
2.93, 2.87 (2d, AB syst., 2H, 2J¼17.9 Hz, HeC(7)), 2.25 (s, 3H,
H3CeC(3)), 2.23e2.15 (m, 2H, HeC(20)), 1.90 (dd, 1H, 2J¼13.0 Hz,
time: 6 h. IR (KBr)
1600, 1540, 1500, 1470, 1450, 1395, 1375, 1285, 1260, 1235, 1170,
n
(cmꢂ1): 3450, 2960, 2930, 1655, 1650, 1645,
1130, 1015; 1H NMR (CDCl3, 500 MHz)
d
(ppm): 7.45e7.52 (m, 5H,
3J¼6.0 Hz, Ha-C(5)), 1.70 (sext., 2H, J¼7.5 Hz, HeC(30)), 1.29 (dd,
3
HeN(Ph)), 5.67 (d, 1H, 3J¼8.3 Hz, HeNeC(4)), 5.28 (ddd, 1H,
3J¼9.0 Hz, 3J¼8.3 Hz, 3J¼5.5 Hz, HeC(4)), 2.58, 2.42 (2d, AB syst.,
2H, 2J¼16.2 Hz, HeC(7)), 2.07 (dd, 1H, 2J¼13.1 Hz, 3J¼5.5 Hz, Ha-
C(5)), 2.01 (s, 3H, HeC(20)), 1.50 (dd, 1H, 2J¼13.1 Hz, 3J¼9.0 Hz, Hb-
C(5)), 1.11, 0.99 (2s, 6H, H3CeC(6)); 13C NMR (CDCl3, 125 MHz)
1H, 2J¼13.0 Hz, 3J¼9.0 Hz, Hb-C(5)), 1.08 (s, 3H, H3CeC(6)), 0.97 (t,
3H, 3J¼7.5 Hz, HeC(40)), 0.95 (s, 3H, H3CeC(6)); 13C NMR (75 MHz,
CDCl3)
d (ppm): 172.2, 152.9, 148.2, 147.5, 141.9, 138.3, 120.7, 116.4,
114.9, 43.9, 41.1, 38.8, 38.7, 32.2, 30.5, 25.9, 19.2, 13.8, 12.6; Anal.
Calcd for C19H26N4O (326.44): C 69.91, H 8.03, N 17.16; found C
69.89, H 8.08, N 17.24.
d
(ppm): 169.3, 142.1, 138.8 (q, 2J¼37 Hz), 138.5, 129.4, 128.5, 124.1,
121.5 (q, 1J¼270 Hz), 115.1, 43.7, 41.3, 36.9, 32.4, 30.2, 25.8, 23.3; 19
F
NMR (CDCl3, 470 MHz)
d
(ppm): ꢂ61.6; Anal. Calcd for C18H20F3N3O
3.7.17. 2-Chloro-N-(3,6,6-trimethyl-1-pyridin-2-yl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-acetamide (9t). Product 9t (1.01 g,
76%) was obtained as a white solid by general procedure II for Ritter
reaction using starting material 6d (1.03 g, 4.00 mmol). Reaction
(351.37): C 61.53, H 5.74, N 11.96; found C 61.32, H 5.39, N 11.62.
3.7.14. N-(6,6-Dimethyl-1-phenyl-3-(trifluoromethyl)-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-2-phenylacetamide (9q). Product 9q
(1.40 g, 82%) was obtained as a white solid by general procedure I
for Ritter reaction using starting material 6c (1.24 g, 4.00 mmol)
time: 11 h. IR (KBr)
n
(cmꢂ1): 3246, 3073, 2951, 2899, 2870, 1604,
1583, 1564, 1557, 1538, 1482, 1446, 1430, 1382, 1371, 1252; 1H NMR
(300 MHz, CDCl3)
d
(ppm): 8.39 (ddd, 1H, 3J¼4.9 Hz, 4J¼1.7 Hz,
and phenylacetonitrile (3 equiv) instead of MeCN. IR (KBr)
n
5J¼0.9 Hz, PyeN(1)), 7.85 (ddd, 1H, 3J¼8.3 Hz, 4J¼0.9 Hz, 5J¼0.9 Hz,
(cmꢂ1): 3425, 2960, 1685, 1670, 1650, 1645, 1600, 1560, 1540,
PyeN(1)), 7.77 (ddd, 1H, 3J¼8.3 Hz, J¼7.2 Hz, J¼1.7 Hz, PyeN(1)),
7.13 (ddd, 1H, 3J¼7.2 Hz, 3J¼4.9 Hz, 4J¼0.9 Hz, PyeN(1)), 6.63 (d, 1H,
3J¼8.9 Hz, HeNeC(4)), 5.19 (ddd, 1H, 3J¼8.9 Hz, 3J¼8.7 Hz,
3J¼6.0 Hz, HeC(4)), 4.11 (s, 2H, HeC(20)), 3.00 (d,1H, 2J¼17.7 Hz, Ha-
C(7)), 2.93 (d, 1H, 2J¼17.7 Hz, Hb-C(7)), 2.25 (s, 3H, H3CeC(3)), 1.97
(ddd, 1H, 2J¼13.0 Hz, 3J¼6.0 Hz, 4J¼0.8 Hz, Ha-C(5)), 1.47 (dd, 1H,
3J¼13.0 Hz, 3J¼8.7 Hz, Hb-C(5)), 1.13 (s, 3H, H3CeC(6)), 1.00 (s, 3H,
3
4
1500, 1455, 1395, 1385, 1340, 1260, 1235, 1170, 1130, 1015; 1H NMR
(CDCl3, 500 MHz)
d (ppm): 7.49e7.46 (m, 2H, HeC(Ph)), 7.42e7.39
(m, 3H, HeC(Ph)), 7.36e7.33 (m, 2H, HeC(Ph)), 7.29e7.25 (m, 3H,
HeC(Ph)), 5.49 (d, 1H, 3J¼8.3 Hz, HeNeC(4)), 5.28 (ddd, 1H,
3J¼9.0 Hz, 3J¼8.4 Hz, 3J¼5.9 Hz, HeC(4)), 3.65, 3.61 (2d, AB syst.,
2
2H, J¼16.4 Hz, HeC(20)), 2.50, 2.37 (2d, AB syst., 2H, 2J¼16.2 Hz,
HeC(7)), 2.01 (dd, 1H, 2J¼13.3 Hz, 3J¼5.9 Hz, Ha-C(5)), 1.40 (dd,
1H, 2J¼13.3 Hz, 3J¼8.4 Hz, Hb-C(5)), 0.98, 0.95 (2s, 6H, H3CeC(6));
H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 165.1, 153.1, 148.1,
147.5, 142.0, 138.3, 120.7, 115.5, 114.8, 43.5, 42.6, 42.0, 38.8, 32.1,
30.3, 26.2, 12.6; Anal. Calcd for C17H21ClN4O (332.83): C 61.35, H
6.36, N 16.83; found C 61.39, H 6.33, N 16.83.
13C NMR (CDCl3, 125 MHz)
d (ppm): 170.0, 142.1, 139.8 (q,
2J¼37 Hz), 138.5, 134.5, 129.7, 129.4, 129.0, 128.5, 127.4, 124.1, 121.4
(q, 1J¼270 Hz), 114.7, 43.9, 43.6, 41.3, 36.8, 32.2, 29.8, 26.1; 19F
NMR (CDCl3, 470 MHz)
d
(ppm): ꢂ61.4; Anal. Calcd for
3.7.18. 2,2,2-Trichloro-N-(3,6,6-trimethyl-1-pyridin-2-yl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-acetamide (9u). Starting material 6d
(1.03 g, 4.00 mmol, 1 equiv) was added to a stirred solution of
Cl3CCN (4.00 mL, 40.0 mmol, 10 equiv) in glacial acetic acid (5 mL)
and concd H2SO4 (1.10 mL, 20 mmol, 5 equiv). The resulting re-
action mixture was stirred at 70 ꢀC for 20 h (TLC control). The re-
action mixture was cooled to 0 ꢀC and poured into a vigorously
stirred w10% aqueous solution of NaOH (60 mL) at 0 ꢀC. The crude
product 9u was filtered and thoroughly washed with water until
the filtrate became neutral. The obtained white solid was recrys-
tallized from a mixture of EtOH/H2O (2:1). Yield: 1.00 g (62%). IR
C24H24F3N3O (427.46): C 67.43, H 5.66, N 9.83; found C 67.42, H
5.49, N 9.69.
3.7.15. N-(3,6,6-Trimethyl-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-in-
dazol-4-yl)-acetamide (9r). Product 9r (1.13 g, 95%) was obtained as
a white solid by general procedure I for Ritter reaction using
starting material 6d (1.03 g, 4.00 mmol). IR (KBr)
n
(cmꢂ1): 3307,
3279, 2952, 1659, 1639, 1595, 1563, 1557, 1486, 1471, 1445, 1378,
1090, 1042; 1H NMR (300 MHz, CDCl3)
d (ppm): 8.39 (ddd, 1H,
5
3
3J¼4.9 Hz, 4J¼1.6 Hz, J¼1.0 Hz, PyeN(1)), 7.83 (ddd, 1H, J¼8.5 Hz,
4J¼1.0 Hz, 5J¼1.0 Hz, PyeN(1)), 7.76 (ddd, 1H, 3J¼8.5 Hz, 3J¼7.2 Hz,
4J¼1.6 Hz, PyeN(1)), 7.12 (ddd, 1H, 3J¼7.2 Hz, 3J¼4.9 Hz, 4J¼1.0 Hz,
PyeN(1)), 5.64 (d, 1H, 3J¼9.2 Hz, HeNeC(4)), 5.16 (ddd, 1H,
(KBr)
n
(cmꢂ1): 3302, 2965, 2928, 2356, 2343, 1704, 1681, 1595,
1582, 1520, 1485, 1471, 1445, 1430, 1382, 1371, 1078, 1041; 1H NMR
(300 MHz, CDCl3)
d
(ppm): 8.40 (br d, 1H, 3J¼4.9 Hz, PyeN(1)), 7.85

6138
M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
3
(br d, 1H, 3J¼8.3 Hz, PyeN(1)), 7.77 (ddd, 1H, 3J¼8.3 Hz, 3J¼7.3 Hz,
4J¼1.7 Hz, PyeN(1)), 7.15 (ddd, 1H, 3J¼7.3 Hz, 3J¼4.9 Hz, 4J¼0.9 Hz,
PyeN(1)), 6.74 (d, 1H, 3J¼8.7 Hz, HeNeC(4)), 5.13 (ddd, 1H,
3J¼8.7 Hz, 3J¼8.3 Hz, 3J¼6.0 Hz, HeC(4)), 2.99 (s, 2H, HeC(7)), 2.29
(s, 3H, H3CeC(3)), 2.02 (dd, 1H, 2J¼13.0 Hz, 3J¼6.0 Hz, Ha-C(5)), 1.53
(dd, 1H, 2J¼13.0 Hz, 3J¼8.3 Hz, Hb-C(5)), 1.14 (s, 3H, H3CeC(6)), 1.02
4J¼1.0 Hz, HeC(Ar)), 6.55 (d, 1H, J¼9.0 Hz, HeNeC(4)), 5.33 (ddd,
1H, 3J¼9.2 Hz, 3J¼9.0 Hz, 3J¼6.0 Hz, HeC(4)), 3.84 (s, 3H, m-
CH3eOeC6H4eC(10)), 2.93 (s, 2H, HeC(7)), 2.21 (s, 3H, H3CeC(3)),
1.92 (dd, 1H, 2J¼13.0 Hz, 3J¼6.0 Hz, Ha-C(5)), 1.23 (dd, 1H,
2J¼13.0 Hz, J¼9.2 Hz, Hb-C(5)), 1.06 (s, 3H, H3CeC(6)), 0.95 (s, 3H,
3
H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 166.5, 159.9, 153.1,
(s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d
(ppm): 161.1, 153.1,
148.5, 147.6, 142.0, 138.4, 136.0, 129.6, 120.6, 118.7, 117.7, 116.4, 114.7,
112.4, 55.5, 43.5, 41.8, 38.8, 32.3, 30.6, 25.9, 12.8; Anal. Calcd for
C23H26N4O3 (390.48): C 70.75, H 6.71, N 14.35; found C 70.46, H
6.67, N 14.29.
148.2, 147.6, 142.2, 138.4, 120.9, 114.9, 114.8, 92.8, 44.1, 42.9, 38.7,
32.1, 30.1, 26.6, 12.7; Anal. Calcd for C17H19Cl3N4O (401.72): C 50.83,
H 4.77, N 13.95; found C 50.86, H 4.63, N 13.82.
3.7.19. N-(3,6,6-Trimethyl-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-in-
dazol-4-yl)-acrylamide (9v). Product 9v (1.00 g, 81%) was obtained
as a white solid by general procedure I for Ritter reaction using
starting material 6d (1.03 g, 4.00 mmol) and acrylonitrile (2 equiv)
3.7.22. 2-Fluoro-N-(3,6,6-trimethyl-1-pyridin-2-yl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-benzamide (9y). Product 9y (1.14 g,
75%) was obtained as a white solid by general procedure I for Ritter
reaction using starting material 6d (1.03 g, 4.00 mmol) and 2-
fluorobenzonitrile (2 equiv) instead of MeCN. Reaction time: 8 h.
instead of MeCN. IR (KBr)
n
(cmꢂ1): 3237, 3066, 2950, 2932, 1651,
1621, 1593, 1583, 1549, 1486, 1470, 1446, 1427, 1382, 1366, 1320,
IR (KBr)
n
(cmꢂ1): 3238, 2949, 1638, 1616, 1583, 1552, 1536, 1484,
(ppm): 8.41 (br
1307, 1249, 1147, 1134, 1088, 1069, 1053, 1042, 988, 971; 1H NMR
1448, 1382, 1322, 1225; 1H NMR (300 MHz, CDCl3)
d
(300 MHz, CDCl3)
d
(ppm): 8.39 (ddd, 1H, 3J¼4.9 Hz, 4J¼1.7 Hz,
s,1H, HeC(Ar)), 8.14 (td,1H, J¼8.0 Hz, J¼1.9 Hz, HeC(Ar)), 7.89 (br d,
1H, J¼7.7 Hz, HeC(Ar)), 7.78 (t, 1H, J¼8.0 Hz, HeC(Ar)), 7.51e7.44
(m, 1H, HeC(Ar)), 7.30 (d, 1H, J¼8.0 Hz, HeC(Ar)), 7.16e7.08 (m, 2H,
HeC(Ar)), 6.78 (dd, 1H, JH-F¼12.2 Hz, 3J¼9.0 Hz, HeNeC(4)), 5.45
(ddd, 1H, 3J¼9.0 Hz, 3J¼8.7 Hz, 3J¼6.0 Hz, HeC(4)), 2.99 (s, 2H,
HeC(7)), 2.29 (s, 3H, H3CeC(3)), 2.09 (dd, 1H, 3J¼13.2 Hz, 3J¼6.0 Hz,
Ha-C(5)), 1.57 (dd, 1H, 3J¼13.2 Hz, 3J¼8.7 Hz, Hb-C(5)), 1.15 (s, 3H,
H3CeC(6)), 1.05 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
5J¼0.9 Hz, PyeN(1)), 7.82 (ddd, 1H, 3J¼8.3 Hz, 4J¼0.9 Hz, 5J¼0.9 Hz,
PyeN(1)), 7.75 (ddd, 1H, 3J¼8.3 Hz, J¼7.2 Hz, J¼1.7 Hz, PyeN(1)),
3
4
7.12 (ddd, 1H, 3J¼7.2 Hz, 3J¼4.9 Hz, 4J¼0.9 Hz, PyeN(1)), 6.33 (dd,
2
1H, 3J¼17.0 Hz, J¼1.9 Hz, Ha-C(30)), 6.19 (dd, 1H, 3J¼17.0 Hz,
3J¼10.0 Hz, HeC(20)), 6.10 (d, 1H, 3J¼9.4 Hz, HeNeC(4)), 5.67 (dd,
1H, 3J¼10.0 Hz, 2J¼1.9 Hz, Hb-C(30)), 5.18 (dt, 1H, 3J¼9.4 Hz,
3J¼6.2 Hz, HeC(4)), 2.89 (s, 2H, HeC(7)), 2.19 (s, 3H, H3CeC(3)), 1.83
(dd, 1H, 2J¼13.0 Hz, 3J¼6.2 Hz, Ha-C(5)), 1.11 (dd, 1H, 2J¼13.0 Hz,
3J¼9.4 Hz, Hb-C(5)), 1.03 (s, 3H, H3CeC(6)), 0.91 (s, 3H, H3CeC(6));
d
(ppm): 162.6 (d, JCeF¼3 Hz), 160.5 (d, JCeF¼247 Hz), 153.1, 148.2,
147.5, 141.9, 138.1, 133.3 (d, JCeF¼9 Hz), 132.1 (d, JCeF¼2 Hz), 126.8,
124.9 (d, JCeF¼3 Hz), 121.0 (d, JCeF¼11 Hz), 120.6, 116.0 (d,
JCeF¼25 Hz), 114.9, 43.5, 41.7, 38.6, 32.0, 30.1, 26.2, 12.3; Anal. Calcd
for C22H23N4OF (378.44): C 69.82, H 6.13, N 14.80; found C 69.79, H
6.18, N 14.86.
13C NMR (75 MHz, CDCl3)
d (ppm): 164.9, 153.0, 148.5, 147.6, 142.0,
138.4, 130.9, 126.6, 120.7, 116.2, 114.7, 43.5, 41.2, 38.8, 32.3, 30.6,
25.7, 12.7. Anal. Calcd for C18H22N4O (310.18): C 69.65, H 7.14, N
18.05; found C 69.77, H 7.15, N 18.15.
3.7.20. N-(3,6,6-Trimethyl-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-in-
dazol-4-yl)-benzamide (9w). Product 9w (1.23 g, 85%) was obtained
as a white solid by general procedure I for Ritter reaction using
starting material 6d (1.03 g, 4.00 mmol) and benzonitrile (2 equiv)
3.7.23. 4-Nitro-N-(3,6,6-trimethyl-1-pyridin-2-yl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-benzamide (9z). Product 9z (1.20 g,
74%) was obtained as a white solid by general procedure I for Ritter
reaction using starting material 6d (1.03 g, 4.00 mmol) and 4-
instead of MeCN. IR (KBr)
n
(cmꢂ1): 3291, 3060, 2946, 2927, 2914,
nitrobenzonitrile (2 equiv) instead of MeCN. IR (KBr)
3216, 2956, 2926, 1633, 1598, 1583, 1529, 1484, 1447, 1390, 1382,
1368, 1346, 1321, 1047; 1H NMR (300 MHz, CDCl3)
(ppm): 8.42 (br
n
(cmꢂ1):
1629, 1582, 1530, 1487, 1470, 1445, 1429, 1382, 1268, 1319, 1301,
1286, 1178, 1148, 1075, 1042; 1H NMR (300 MHz, CDCl3)
d
(ppm):
d
8.41 (br d, 1H, 3J¼4.9 Hz, PyeN(1)), 7.85e7.82 (m, 3H, PyeN(1),
d, 1H, 3J¼4.7 Hz, PyeN(1)), 8.29, 8.04 (2d, 4H, 3J¼8.7 Hz, p-
O2NeC6H4eC(10)), 7.79 (br d,1H, 3J¼8.3 Hz, PyeN(1)), 7.76 (ddd,1H,
3J¼6.5 Hz, 3J¼8.3 Hz, 4J¼1.7 Hz, PyeN(1)), 7.15 (dd, 1H, 3J¼6.5 Hz,
3J¼4.7 Hz, 4J¼1.0 Hz, PyeN(1)), 6.68 (d,1H, 3J¼9.0 Hz, HeN(4)), 5.34
(ddd, 1H, 3J¼9.4 Hz, 3J¼9.0 Hz, 3J¼6.2 Hz, HeC(4)), 2.94 (s, 2H,
HeC(7)), 2.19 (s, 3H, H3CeC(3)), 1.95 (dd, 1H, 2J¼13.0 Hz, 3J¼6.2 Hz,
Ha-C(5)), 1.26 (dd, 1H, 2J¼13.0 Hz, 3J¼9.4 Hz, Hb-C(5)), 1.09 (s, 3H,
H3CeC(6)), 0.96 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
3
3
4
HeC(Ph)), 7.75 (ddd, 1H, J¼8.3 Hz, J¼7.2 Hz, J¼1.7 Hz, PyeN(1)),
7.53e7.41 (m, 3H, HeC(Ar)), 7.13 (ddd, 1H, 3J¼7.2 Hz, 3J¼4.9 Hz,
3
4J¼1.0 Hz, PyeN(1)), 6.39 (d, 1H, J¼8.9 Hz, HeNeC(4)), 5.38 (ddd,
1H, 3J¼9.0 Hz, 3J¼8.9 Hz, 3J¼6.0 Hz, HeC(4)), 2.96 (s, 2H, HeC(7)),
2.24 (s, 3H, H3CeC(3)), 1.99 (dd, 1H, 2J¼13.0 Hz, 3J¼6.0 Hz, Ha-C(5)),
1.37 (dd, 1H, 2J¼13.0 Hz, 3J¼9.0 Hz, Hb-C(5)), 1.10 (s, 3H, H3CeC(6)),
0.99 (s, 3H, H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 166.7,
153.1,148.3,147.5,141.9,138.3,134.5,131.5,128.6,126.8,120.6,116.4,
114.8, 43.7, 41.8, 38.8, 32.2, 30.5, 26.0, 12.7; Anal. Calcd for
C22H24N4O (360.45): C 73.31, H 6.71, N 15.54; found C 73.37, H 6.73,
N 15.59.
d (ppm): 164.6, 152.9, 149.6, 148.2, 147.7, 142.2, 140.0, 138.5, 128.2,
123.9, 120.9, 115.8, 114.8, 43.5, 42.3, 38.7, 32.3, 30.6, 25.8, 12.8; Anal.
Calcd for C22H23N5O3 (405.45): C 65.17, H 5.72, N 17.27; found C
65.10, H 5.68, N 17.23.
3.7.21. 3-Methoxy-N-(3,6,6-trimethyl-1-pyridin-2-yl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-benzamide (9x). Product 9x (1.22 g,
78%) was obtained as a white solid by general procedure I for Ritter
reaction using starting material 6d (1.03 g, 4.00 mmol) and 3-
3.8. Synthesis of a 3:1 mixture of ( )-(4RS,7RS)-(trans-15) and
( )-(4SR,7RS)-N-(7-azido-6,6-dimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-acetamide (cis-15)
methoxy-benzonitrile (1.5 equiv) instead of MeCN. IR (KBr)
n
NaBH4 (0.760 g, 20.0 mmol) was added to a solution of 10
(2.81 g, 10.0 mmol) in ethanol (30 mL) and water (5 mL). The
resulting reaction mixture was stirred at ambient temperature for
60 h. Then it was diluted with water (100 mL) and extracted with
EtOAc (3ꢁ30 mL). The combined organic layers were washed with
brine, dried over Na2SO4, filtered and evaporated. Product 12 was
obtained as a 1:1 mixture of diastereoisomers and was used in the
next step without purification. Yield of crude 12 (oil): 2.38 g (84%).
MeCN (1.31 mL, 25 mmol, 5 equiv) was added to a solution of crude
(cmꢂ1): 3278, 2959, 2929, 2869, 2835, 1637, 1609, 1583, 1550, 1487,
1445, 1390, 1381, 1369, 1323, 1301, 1243, 1142, 1133, 1088, 1059,
1039, 989; 1H NMR (300 MHz, CDCl3)
d (ppm): 8.39 (br d, 1H,
3J¼4.9 Hz, PyeN(1)), 7.81 (br d, 1H, 3J¼8.1 Hz, PyeN(1)), 7.72 (ddd,
1H, 3J¼8.3 Hz, 3J¼7.2 Hz, 4J¼1.7 Hz, PyeN(1)), 7.46 (dd, 1H,
4J¼2.5 Hz, 4J¼1.0 Hz, HeC(Ar)), 7.39 (dt, 1H, 3J¼7.7 Hz, 3J¼1.0 Hz,
HeC(Ar)), 7.31 (t, 1H, 3J¼7.7 Hz, HeC(Ar)), 7.11 (ddd, 1H, J¼7.2 Hz,
3
4
3
4
3J¼4.9 Hz, J¼1.0 Hz, PyeN(1)), 7.03 (ddd, 1H, J¼7.9 Hz, J¼2.5 Hz,

M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
6139
azido alcohol 12 (1.42 g, 5.01 mmol, 1 equiv) in glacial acetic acid
(5 mL) and concd H2SO4 (1.40 mL, 25.0 mmol, 5 equiv). The
resulting reaction mixture was stirred at 65e70 ꢀC for 8 h (TLC
control). The reaction mixture was cooled to 0 ꢀC and poured into
a vigorously stirred w10% aqueous solution of NaOH (50e60 mL) at
control). The reaction mixture was cooled to 0 ꢀC and poured into
a vigorously stirred w10% aqueous solution of NaOH (40e50 mL) at
0 ꢀC. The resulting suspension was adjusted to pH 12 and extracted
with EtOAc (3ꢁ20 mL). The combined organic layers were washed
with brine, dried over Na2SO4, filtered and evaporated. Yield of
crude 16 (solid): 1.00 g (96%). The crude product revealed dr 95:5
by 1H NMR spectroscopic analysis. The crude product was recrys-
tallized from a mixture of EtOAc (10 mL) and DCM (15 mL). Yield of
16: 0.92 g (88%) as a 95:5 mixture of trans-16 and cis-16. Mp
0
ꢀC. The precipitate was filtered and thoroughly washed with
water until the filtrate became neutral. Drying in the air provided
1.19 g (73%) of a 3:1 mixture of trans-15 and cis-15 as a solid ma-
terial. In order to separate the diastereoisomers the mixture was
crystallized from a mixture of EtOAc (30 mL) and hexanes (30 mL).
The first precipitate after 2 h at ambient temperature followed by
2 h at 4 ꢀC provided pure diastereoisomer trans-15 (0.67 g). The
filtrate was precipitated with hexanes and kept for 24 h at 4 ꢀC. It
gave a mixture of disasteroisomers, which was filtered (100 mg).
The second filtrate was concentrated to a volume of 5 mL and kept
for 12 h at 4 ꢀC. This provided the minor diastereoisomer cis-15
(50 mg). Data for (ꢄ)-(4RS,7RS)-N-(7-azido-6,6-dimethyl-1-
phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-acetamide (trans-15):
207e209 ꢀC; IR (KBr)
1507, 1400, 1370, 1300. Signals of trans-16 are described form the
n
(cmꢂ1): 3400, 3247, 3067, 2965, 1637, 1560,
spectrum of the mixture: 1H NMR (300 MHz, CDCl3)
d (ppm): 7.61
(d, 2H, 3J¼8.4 Hz, HeC(Ph)), 7.57 (s, 1H, HeC(3)), 7.48 (t, 2H,
3J¼8.4 Hz, HeC(Ph)), 7.39 (t, 1H, 3J¼7.4 Hz, HeC(Ph)), 5.59 (br d, 1H,
3J¼8.3 Hz, HeNeC(4)), 5.18 (ddd, 1H, 3J¼8.3 Hz, 3J¼7.0 Hz,
3J¼6.0 Hz, HeC(4)), 3.76 (s, 1H, HeC(7)), 2.11 (dd, 1H, AB syst.,
3
2J¼13.8 Hz, J¼6.0 Hz, Ha-C(5)), 2.02 (s, 3H, HeC(20)), 1.53 (dd, 1H,
AB syst., 2J¼13.8 Hz, 3J¼7.0 Hz, Hb-C(5)), 1.08, 0.98 (2s, 6H,
mp 210e212 ꢀC. IR (KBr)
n
(cmꢂ1): 3238, 3069, 2964, 2939, 2870,
H3CeC(6)); 13C NMR (75 MHz, CDCl3)
d (ppm): 169.5, 142.3, 140.4,
2100, 1638, 1566, 1504, 1407, 1323; 1H NMR (300 MHz, CDCl3)
137.8, 129.3, 127.7, 124.1, 118.3, 53.6, 42.0, 41.1, 36.5, 27.4, 23.3, 21.9;
Anal. Calcd for C17H22N4O (298.38): C 68.43, H 7.43, N 18.78; found
C 68.19, H 7.62, N 19.11.
d
(ppm): 7.62 (s, 1H, HeC(3)), 7.53e7.40 (m, 5H, HeC(Ph)), 5.75 (br
d, 1H, 3J¼8.1 Hz, HeNeC(4)), 5.19 (dt, 1H, 3J¼8.1 Hz, 3J¼6.0 Hz,
HeC(4)), 4.21 (s, 1H, HeC(7)), 2.13 (dd, 1H, 2J¼14.1 Hz, 3J¼6.0 Hz,
Ha-C(5)), 1.99 (s, 3H, HeC(20)), 1.58 (dd, 1H, 2J¼14.1 Hz, 3J¼6.0 Hz,
Hb-C(5)), 1.10, 1.08 (2s, 6H, H3CeC(6)); 1H NMR (300 MHz, C6D6)
3.10. 6,6-Dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-
yl-ammonium toluene-4-sulfonate (17)
d
(ppm): 7.58 (s, 1H, HeC(3)), 7.52 (d, 2H, 3J¼8.5 Hz, HeC(Ph)), 7.13
(t, 2H, 3J¼8.5 Hz, HeC(Ph)), 7.01 (t, 1H, 3J¼8.5 Hz, HeC(Ph)), 5.23
(ddd, 1H, 3J¼7.5 Hz, 3J¼6.8 Hz, 3J¼6.0 Hz, HeC(4)), 4.59 (br d, 1H,
3J¼7.5 Hz, HeNeC(4)), 3.97 (s, 1H, HeC(7)), 1.85 (dd,1H, 2J¼13.9 Hz,
3J¼6.0 Hz, Ha-C(5)), 1.55 (s, 3H, HeC(20)), 1.16 (dd, 1H, 2J¼13.9 Hz,
3J¼6.8 Hz, Hb-C(5)), 0.76, 0.65 (2s, 6H, H3CeC(6)); 13C NMR
Method A. A solution of 9a (1.00 g, 3.53 mmol) in EtOH (6 mL)
and 36% aqueous solution of HCl (6 mL) was heated under reflux for
11 h. The reaction mixture was poured onto ice (20 g) and neu-
tralized with a 10% aqueous solution of NaOH until pH 10. The
aqueous phase was extracted with EtOAc (3ꢁ20 mL). The combined
organic layers were washed with brine, dried over Na2SO4, filtered
and evaporated under reduced pressure. The residue (0.80 g) was
redissolved in EtOAc (20 mL) and mixed with a solution of para-
toluene sulfonic acid monohydrate (0.630 g, 3.31 mmol) in EtOAc
(6 mL) at ambient temperature. The resulting turbid solution was
kept for 4 h at 4 ꢀC and the precipitate was filtered and dried in the
air. Yield: 0.92 g (63%).
(75 MHz, CDCl3)
d (ppm): 169.4, 139.4, 138.0, 136.7, 129.4, 128.3,
124.5, 119.4, 62.9, 41.2, 40.8, 38.2, 27.4, 23.4 (2C); Anal. Calcd for
C17H20N6O (324.38): C 62.95, H 6.21, N 25.91; found C 62.71, H 6.42,
N 26.14. Data for (ꢄ)-(4SR,7RS)-N-(7-azido-6,6-dimethyl-1-phenyl-
4,5,6,7-tetrahydro-1H-indazol-4-yl)-acetamide
(cis-15):
mp
167e168 ꢀC. IR (KBr)
n
(cmꢂ1): 3241, 3068, 2959, 2926, 2877, 2093,
(ppm):
1634, 1557, 1504, 1406, 1236. 1H NMR (300 MHz, CDCl3)
d
7.65 (br s, 1H, HeC(3)), 7.53e7.48 (m, 4H, HeC(Ph)), 7.48e7.41 (m,
1H, HeC(Ph)), 5.73 (br d, 1H, 3J¼7.9 Hz, HeNeC(4)), 5.15 (ddd, 1H,
3J¼10.7 Hz, 3J¼7.9 Hz, 3J¼6.6 Hz, HeC(4)), 4.00 (s, 1H, HeC(7)), 2.05
(s, 3H, HeC(20)), 1.93 (dd, 1H, 2J¼13.6 Hz, 3J¼6.6 Hz, Ha-C(5)), 1.54
(dd, 1H, 2J¼13.6 Hz, 3J¼10.7 Hz, Hb-C(5)), 1.17, 1.01 (2s, 6H,
Method B. Equivalent to Method A, but starting material 9b was
used. Final precipitation of tosylate salt for 48 h at 4 ꢀC provides
78% yield of product 17.
Method C. Thiourea (0.250 g, 3.28 mmol, 1.3 equiv) was added to
a solution of 9b (0.790 g, 2.49 mmol) in ethanol (20 mL). The
resulting reaction mixture was heated under reflux for 23 h and
then cooled to 4 ꢀC and kept at this temperature over a weekend.
The precipitated 2-amino-thiazol-4-ol (0.22 g) was filtered and
discarded. The filtrate was evaporated under reduced pressure and
the residue was partitioned between water (10 mL), which was
adjusted to pH 10 with 10% aqueous solution of NaOH and EtOAc.
The layers were separated and the aqueous phase was extracted
with EtOAc (2ꢁ10 mL). The combined organic layers were washed
with brine, dried over Na2SO4, filtered and evaporated under re-
duced pressure. The residue (0.60 g) was redissolved in EtOAc
(10 mL) and mixed with solution of para-toluene sulfonic acid
monohydrate (0.480 g, 2.52 mmol) in EtOAc (6 mL) at ambient
temperature. The resulting turbid solution was kept for 12 h at 4 ꢀC
and the white precipitate was filtered and dried in the air. Yield:
H3CeC(6)). 13C NMR (75 MHz, DMSO-d6)
d (ppm): 169.2, 139.1,
137.8,136.5,129.6,128.1,124.1,120.8, 60.5, 40.1, 37.8, 37.6, 26.6, 23.5,
22.6. Anal. Calcd for C17H20N6O (324.38): C 62.95, H 6.21, N 25.91;
found C 62.66, H 6.50, N 25.99.
3.9. Synthesis of a 95:5 mixture of ( )-(4RS,7RS)-(trans-16)
and ( )-(4SR,7RS)-N-(7-amino-6,6-dimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-yl)-acetamide (cis-16)
NaBH4 (0.31 g, 8.19 mmol) was added to a solution of 11 (1.02 g,
3.96 mmol) in ethanol (30 mL) and THF (10 mL). The resulting re-
action mixture was stirred at ambient temperature for 72 h. Then it
was evaporated under reduced pressure and the residue was par-
titioned between aqueous solution of K2CO3 (20 mL, pH 12) and
EtOAc (15 mL). The aqueous phase was extracted additionally with
EtOAc (2ꢁ10 mL). The combined organic layers were washed with
brine, dried over Na2SO4, filtered and evaporated. Product 13 was
obtained as a 1:1 mixture of diastereoisomers and was used in the
next step without purification. Yield of crude 13 (oil): 0.90 g (88%).
MeCN (0.91 mL, 17.5 mmol, 5 equiv) was added to a solution of
crude amino alcohol 13 (0.90 g, 3.5 mmol, 1 equiv) in glacial acetic
acid (4 mL) and concd H2SO4 (0.93 mL, 17.5 mmol, 5 equiv). The
resulting reaction mixture was stirred at 60e70 ꢀC for 6 h (TLC
0.83 g (80%). Mp 202e204 ꢀC; IR (KBr)
n
(cmꢂ1): 3441, 3024, 2955,
2709, 2619, 1600, 1505, 1392, 1236, 1164, 1123, 1029, 1005; 1H NMR
(300 MHz, CDCl3)
d (ppm): 8.04 (s, 1H, HeC(3)), 7.67 (s, 2H,
3J¼8.3 Hz, HeC(Ar)), 7.46e7.31 (m, 5H, HeC(Ph)), 7.08 (d, 2H,
3J¼8.3 Hz, HeC(Ar)), 4.28 (dd, 1H, 3J¼10.7 Hz, 3J¼6.2 Hz, HeC(4)),
2.54, 2.27 (2 d, AB syst., 2H, 2J¼16.6 Hz, HeC(7)), 2.25 (s, 3H,
H3CeC(Ar)), 1.85 (dd, 1H, J¼13.2 Hz, 3J¼6.2 Hz, Ha-C(5)), 1.68 (dd,
2
1H, 2J¼13.2 Hz, 3J¼10.7 Hz, Hb-C(5)), 1.00, 0.72 (2s, 6H, H3CeC(6));
13C NMR (75 MHz, DMSO-d6)
d (ppm): 145.5, 139.5, 139.1, 137.9,

6140
M. Turks et al. / Tetrahedron 68 (2012) 6131e6140
Fuller, R. W.; Wong, D. T.; Mason, N. R. J. Med. Chem. 1989, 32, 2388e2396; (d)
Avenell, K. Y.; Boyfield, I.; Hadley, M. S.; Johnson, C. N.; Nash, D. J.; Riley, G. J.;
Stemp, G. Bioorg. Med. Chem. Lett. 1999, 9, 2715e2720; (e) Massaroli, G. G.; Del
Corona, L.; Signorelli, G. Boll. Chim. Farm. 1969, 108, 706e722; (f) Scuri, R.
Farmaco Prat. 1970, 25, 568e579.
137.8, 129.5, 128.2, 127.4, 125.5, 123.0, 114.1, 42.8, 40.6, 35.8, 32.2,
30.6, 24.3, 20.8; Anal. Calcd for C22H27N3O3S (413.53): C 63.90, H
6.58, N 10.16; found C 63.73, H 6.77, N 10.01.
6. Cho, H.; Iwama, Y.; Sugimoto, K.; Mori, S.; Tokuyama, H. J. Org. Chem. 2010, 75,
627e636.
Acknowledgements
7. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045e4048; (b) Ritter, J. J.;
Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048e4050; (c) Krimen, L. I.; Cota, D. J. Org.
React. 1969, 17, 213e325; (d) Gridnev, I. D.; Gridneva, N. A. Russ. Chem. Rev. 1995,
64, 1021e1034.
8. (a) Khlebnicova, T. S.; Isakova, V. G.; Lakhvich, F. A. Doklady NAS Belarus 2007,
51, 55e58; (b) Strakova, I.; Turks, M.; Strakovs, A. Tetrahedron Lett. 2009, 50,
3046e3049.
9. N-(3,6,6-Trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-acetamide
(9i) (1.16 g, 78%) was obtained upon treatment of 3,6,6-trimethyl-1-phenyl-6,7-
dihydro-1H-indazole (7b) (1.19 g, 5 mmol) and MeCN (1.30 mL, 25 mmol,
5 equiv) in the mixture consisting of glacial AcOH (5 mL) and concd H2SO4 (1.
33 mL, 25 mmol, 5 equiv) at 60 ꢀC for 9 h.
This work was supported by the Latvian-Belarus joint project
IZM10-0501/18 e L7630, Latvian Council of Science grant 09.1557,
and Riga Technical University grant ZP-2010/18. Authors thank
Professor E. Vedejs for helpful discussions and JSC ‘Grindeks’ for
a kind donation of organic solvents. Analytical support by Syntagon
Baltic Ltd and Bapeks Ltd is kindly acknowledged.
Supplementary data
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Supplementary data related to this article can be found online at
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