Synthesis of 1,6-dihydropyrrolo[2,3-g]indazoles using Larock indole annulation

Article abstract of DOI:10.1016/j.tet.2011.07.029

The synthesis of 1,6-dihydropyrrolo[2,3-g]indazole derivatives is described. The indolic ring system is constructed via a Larock palladium-catalyzed annulation using terminal and internal alkynes. Additionally, when using internal alkynes for this reaction, we found that a directing effect on regioselectivity was mediated by the ester group of alkyl 3-substituted propiolate derivatives.

Full text of DOI:10.1016/j.tet.2011.07.029

Tetrahedron 67 (2011) 7330e7335
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Tetrahedron
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Synthesis of 1,6-dihydropyrrolo[2,3-g]indazoles using Larock indole annulation
,
,
b
,
a,b
Laurent Gavara a b, Fabrice Anizon a , Pascale Moreau
*
a
ꢀ
ꢀ
Clermont Universite, Universite Blaise Pascal, Laboratoire SEESIB, BP 10448, F-63000 Clermont-Ferrand, France
CNRS, UMR 6504, SEESIB, F-63177 Aubiere, France
b
ꢁ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2011
Received in revised form 8 July 2011
Accepted 12 July 2011
Available online 21 July 2011
The synthesis of 1,6-dihydropyrrolo[2,3-g]indazole derivatives is described. The indolic ring system is
constructed via a Larock palladium-catalyzed annulation using terminal and internal alkynes. Addi-
tionally, when using internal alkynes for this reaction, we found that a directing effect on regioselectivity
was mediated by the ester group of alkyl 3-substituted propiolate derivatives.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indazole
Larock indole annulation
Pyrroloindazole
Regioselectivity
1. Introduction
medicinal chemistry,10 we recently started a research program
aimed at developing new compounds containing this heterocyclic
The palladium-catalyzed annulation of internal alkynes proved
to be a useful method to access 2,3-disubstituted indole derivatives.
Thus, Larock indolization led efficiently to this ring system from 2-
iodoaniline derivatives by internal alkyne insertion to an arylpal-
ladium bond and subsequent cyclization of the vinylpalladium
intermediate.1e4 Alternatively, 2,3-disubstituted indoles were
synthesized from 2-iodotrifluoroacetanilides and terminal alkynes
by Sonogashira cross-coupling and Cacchi reaction sequence: the o-
alkynyltrifluoroacetanilide obtained after Sonogashira reaction
underwent a Pd(II)-catalyzed cyclization in the presence of an
arylpalladium(II) species, leading, after reductive elimination of the
generated aryl-(indol-3-yl)palladium intermediate, to a product
substituted at the 3-position of the indolic ring system by an aryl
group.5e8 In the absence of the catalytic arylpalladium complex, the
indol-3-ylpalladium intermediate formed by Pd(II)-catalyzed an-
nulation of o-alkynylaniline derivatives can undergo either proto-
nolysis to give 2-substituted indoles, carbonylation, C]C insertion
or C]O addition to give 2,3-disubstituted indoles.3,6,9
system.11,12 We next focused on the synthesis of new 1,6-
dihydropyrrolo[2,3-g]indazole derivatives, a heterocyclic system
which incorporates an indole subunit (Fig. 1).
There are only a few reports in the literature describing this ring
system, which was synthesized either by Fischer indolization or by
condensation of hydrazine derivatives with the appropriate 1,3-
dicarbonyl indole derivative.13 The palladium-catalyzed construc-
tion of the indole subunit is thought to be complementary and
useful to these methods. Therefore, we now report our study on the
synthesis of 1,6-dihydropyrrolo[2,3-g]indazole derivatives based
on a palladium-catalyzed annulation.
2. Results and discussion
We started our study from 5,6-dinitroindazole 2, which was
readily obtained from 6-nitroindazole in concentrated sulfuric acid
in the presence of potassium nitrate.12,14 Protection of indazole 2 at
the N-1 position by a THP group gave compound 3 in good yield
(Scheme 1).12
The indole ring system, as well as other nitrogen-containing
aromatic heterocyclic systems, plays a wide role in medicinal
chemistry, and privileged pharmacophores should be identified in
the course of the preparation of novel bioactive small organic
molecules. Due to the importance of the indazole ring system in
H
HN
N
N
1
* Corresponding author. Tel.: þ33 (0) 4 73 40 53 64; fax: þ33 (0) 4 73 40 77 17;
e-mail address: Fabrice.ANIZON@univ-bpclermont.fr (F. Anizon).
Fig. 1. 1,6-Dihydropyrrolo[2,3-g]indazole 1.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.029

L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
7331
Unfortunately, other methods examined to improve the yield of the
reaction did not afford the expected Sonogashira product.17 On the
other hand, we found that one of the methods experimented,17d
using a mixture of Pd(OAc)2, BINAP, and K2CO3 in refluxing THF,
led directly to the desired indole derivative 9 in 60% yield.18
THP
H
N
DHP
O2N
O2N
O2N
O2N
H2SO4 cat.
N
N
N
CH2Cl2
93%
3
2
We next tried to extend the scope of the reaction to other ter-
minal alkynes but unfortunately, these conditions were only ap-
plicable for trimethylsilylacetylene. Nevertheless, by the use of
Pd(PPh3)4/XPhos instead of Pd(OAc)2/BINAP, compound 9 was
obtained in 91% yield (entry 1, Table 1). These conditions enabled
the preparation of other indole derivatives from compound 6 and
other terminal alkynes (Table 1). An excellent 97% yield was
obtained when phenylacetylene was used (entry 2). However,
a reverse regioselectivity was observed as the phenyl group was
found placed at the 3-position of the indolic ring system.18 This
regioselectivity rules out the indole annulation from an alkynyl
intermediate. Thus, the synthetic pathway to this indole derivative
would probably involve a Larock indolization of phenylacetylene,
which to our knowledge has never been reported so far.
CHD, 10% Pd/C
methanol, reflux
I
THP
H2N
O2N
N
N
THP
R1
R2
6 (57% from 3)
I2, DMSO, rt
N
+
N
THP
O2N
H2N
7 (17% from 3)
N
N
4 R1 = NH2, R2 = NO2
5 R1 = NO2, R2 = NH2
I
Table 1
Indolization reaction with terminal alkynes
Scheme 1. Synthesis of o-iodoaniline derivatives 6 and 7.
R1
R2
7
8
THP
R
HN
6
Access to the pyrroloindazole scaffold implied the selective re-
duction of one nitro group, subsequent ortho-halogenation of the
newly prepared arylamine and palladium-catalyzed annulation of
the pyrrole nucleus. As we previously reported,12 both nitro groups
of compound 3 can be efficiently reduced in the presence of 10% Pd/C
and hydrazine hydrate in refluxing methanol. We found that mono-
reduction was practicable in refluxing methanol in the presence of
1,4-cyclohexadiene (CHD) as hydrogen donor and 10% Pd/C. After
chromatography, an 8:2 inseparable mixture of compounds 4 and 5
was obtained. We next examined the introduction of an iodine atom
in ortho position to the amino group of compounds 4 and 5. Initial
iodination attempts from 4/5 mixture were unsuccessful by using
various conditions reported in the literature.15 Only one method fi-
nally gave the iodinationproducts 6 and 7, by using I2 in DMSO.16 The
products were separable by chromatography to give 6 and 7 in 57%
and 17% yields, respectively, from dinitroindazole 3 (Scheme 1). The
two regioisomers 6 and 7 were identified by analysis of a 1He1H
NOESY spectrum. Relevant correlations were found for compound 6
between thetwoaromatic protons at 8.16 ppmand 8.67 ppm, and for
compound 7 between the aromatic proton at 8.58 ppm and the THP
anomeric proton at 5.94 ppm.
N
Pd(PPh3)4, XPhos
K2CO3, THF, reflux
N
O2N
Entry
1
R1
R2
Product
Yield (regioisomeric ratio)
TMS
H
Ph
H
n-Pr
H
H
TMS
H
Ph
H
n-Pr
H
9
91%
d
d
d
10
11
12
13
14
15
16
17
18
19
20
2
3
4
5
6
7
d
97%
96%
(11/12w1:9)a
CH(OEt)2
65%b
H
CH(OEt)2
H
CH2OBn
H
CH2OH
H
CH2OAc
(56% of 14)
92%
CH2OBn
H
(15/16w3:7)a
60%
CH2OH
H
CH2OAc
H
(w55:45)a
95%
(w55:45)a
a
An inseparable mixture of regioisomers was isolated.
b
A mixture of compounds 13 and 14 was obtained. Compound 14 was the only
regioisomer which could be isolated by chromatography, a part remaining in mix-
ture with compound 13.
Having indazole 6 in our hands, we carried on the synthesis by
the introduction of an alkynyl side-chain at the 7-position using
a Sonogashira cross-coupling. From trimethylsilylacetylene as the
terminal alkyne, compound 8 was obtained in 51% yield using
Pd(PPh3)4 in acetonitrile in the presence of CuI and DIEA (Scheme 2).
The same regioselectivity was observed with other terminal
alkynes (entries 3e5).18 However, the formation of the minor 7-
substituted pyrrolo[2,3-g]indazole was also detected. Oppositely,
the annulation using propargyl alcohol or its acetyl derivative
(entries 6 and 7) was not regioselective. Compounds 15/16, 17/18,
and 19/20 were obtained as inseparable mixtures of regioisomers.
The regioisomeric ratios were measured for each mixture according
to characteristic 1H NMR peaks.19
It appeared from our results that, with the exception of trime-
thylsilylacetylene, the more sterically demanding group was posi-
tioned at the 3-position of the indole system, which is not in
accordance with the observations of Larock concerning the re-
activity of internal alkynes. If the formation of the pyrrolo[2,3-g]
indazole substituted at the 8-position cannot be explained by the
cyclization of an alkynyl intermediate, this is not the case for the
preparation of 7-TMS-substituted compound 9.
TMS
THP
H2N
TMS
Pd(PPh3)4, CuI
DIEA, acetonitrile
51%
N
6
N
O2N
TMS
HN
8
THP
TMS
Pd(OAc)2, BINAP
K2CO3, THF, reflux
60%
6
N
To get more insight into the mechanism of formation of com-
pound 9, alkynylindazole 8 was subjected to the reaction conditions
used for the formation of compound 9 from indazole 6. The for-
mation of indole 9 from compound 8 was not observed in these
conditions, neither in the presence of PdCl2 in acetonitrile20 nor CuI
N
O2N
9
Scheme 2. Synthesis compounds 8 and 9.

7332
L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
in DMF.21 Therefore, we suppose that a Larock annulation is most
likely involved in the formation of compound 9, and the effect of
the silyl group had a strong influence on the regioselectivity issue of
the reaction, which is opposite to the one we observed with the
other terminal alkynes used in this study (Table 1, entries 2e5).
Possibly, the observed unusual reactivity and regioselectivity of
terminal alkynes may be due in part to an effect of the bulky
electron-rich ligand XPhos used in this work.
We next investigated our reaction conditions to the palladium-
catalyzed annulation of internal alkynes (Table 2). In a first ap-
proach, we tried terminal alkynes bearing a trimethylsilyl group,
that were described by Larock to give regioselectively the indole
product substituted by the silyl group at the 2-position (entries 1
and 2). With our conditions, the formation of only one regioisomer
was observed but the reaction yielded only small quantities of
products 21 and 22. Nevertheless, despite the poor conversion of
the reaction, the obtention of compounds 21 and 22 allowed us to
check the regioselectivity issue of the annulation reaction. Thus,
crude mixtures of compounds 6/21 and 6/22 were subjected to
desilylation conditions in the presence of tetrabutylammonium
fluoride. After chromatography, compounds 10 and 12 were iso-
lated, showing that the silyl group was placed at the 7-position of
the pyrrolo[2,3-g]indazole ring system.
R
7
8
PTSA
EtOH, H2O
H
N
HBr (from 25)
HN
62%
a
25 or 26
10 or 12
N
or
97% from 10
90% from 12
O2N
28 R = Ph
HCl (from 26)
55%
29 R = n-Pr
Scheme 3. Decarboxylation of compounds 25 and 26. Deprotection of compounds 10
and 12. aAw9:1 mixture of compounds 12/11 was used. Compound 29 was obtained as
a mixture containing w10% of the 7-propyl regioisomer.
alkynes. In addition, the high regioselectivity showed with pro-
piolate ester derivatives may be due to the electronic effect of the
ester function, and/or an interaction between the ester function
and the amino group of the aniline moiety, affecting the regiose-
lectivity of the alkyne insertion step. Nevertheless, considering the
indolization reaction between an o-iodoaniline derivative and an
alkyl 3-substituted propiolate, an alternative mechanistic pathway
other than Larock indole annulation may be considered: (a) a 1,4-
addition of the aniline nitrogen atom to the propiolate ester un-
der basic condition, and (b) a palladium-catalyzed cyclization of the
generated N-vinylaniline intermediate. In this case, the ester
function would be found at the 3-position of the indole ring system.
Actually, examples of such synthetic pathway are found in the lit-
erature23 and might be involved in previous examples that de-
scribed the access to indole derivatives bearing the ester function at
the 3-position.22 In our case, the observed regioselectivity (ester
function at the 2-position of the indole ring system) showed that
this mechanism is not applicable. This could be due to the low
nucleophilicity of the aniline nitrogen of compound 6, bearing an
electron-withdrawing nitro group. Therefore, in our case, a Larock
annulation is more likely.
Table 2
Indolization reaction with internal alkynes
R1
R2
7
8
THP
internal alkyne
Pd(PPh3)4, XPhos
K2CO3, THF, reflux
HN
6
N
N
O2N
Entry
R1
R2
Product
Yield
3. Conclusion
1
2
3
TMS
TMS
Et
Ph
n-Pr
Ph
Et
Ph
21
22
23
24
25
26
27
Not isolateda
Not isolateda
67%
19%
86%
In summary, we synthesized 1,6-dihydropyrrolo[2,3-g]indazole
derivatives using a palladium-catalyzed annulation for the con-
struction of the indole ring system. The annulation was performed
by a Larock reaction in the presence of terminal or internal alkynes.
Moreover, we observed a directing effect on regioselectivity me-
diated by the ester function of the alkyl 3-substituted propiolate
derivatives used as internal alkynes.
Ph
4
5
6
CO2Et
CO2Me
CO2Et
n-Pr
Me
90%
94%
a
Inseparable mixture with starting material.
In the case of the other internal alkynes examined, the yields
were found to be much higher. In the case of 1-phenylbut-1-yne
(entry 3, Table 2), separable regioisomers 23 and 24 were
obtained in 67% and 19% yields, respectively. Astonishingly, the
major regioisomer was the one with the more sterically demanding
group at the 3-position of the indole subunit, which is in accor-
dance with our observation using terminal alkynes.
We also investigated internal alkynes bearing an ester function.
To the best of our knowledge, the use of such acetylene derivatives
for Larock indole annulation was rarely reported.22 In our condi-
tions, the reaction showed to be very efficient and highly regiose-
lective as only one regioisomer was identified (compounds 25e27,
entries 4e6). Nevertheless, the regioselectivity was opposite to the
one reported previously, the ester function being placed at the 2-
position of the indole scaffold. The structure of compounds
25e27 was unambiguously confirmed by 1He1H NOESY NMR ex-
periments. Additionally, compounds 25 and 26 were decarboxy-
lated to give deprotected pyrrolo[2,3-g]indazoles 28 and 29 in 62%
and 55% yields, respectively (Scheme 3). These two compounds
were identical to the deprotection products obtained by treatment
of compounds 10 and 12 with PTSA in EtOH/H2O.
4. Experimental section
4.1. General
Starting materials were obtained from commercial suppliers
and used without further purification. Solvents were distilled prior
to use. IR spectra were recorded on a Shimadzu FTIR-8400S spec-
trometer (
n
in cmꢀ1). NMR spectra, performed on a Bruker AVANCE
400 (1H: 400 MHz, 13C: 100 MHz), or a Bruker AVANCE 500 (1H:
500 MHz, 13C: 126 MHz), are reported in parts per million using the
solvent residual peak as an internal standard (1H: DMSO-d6,
2.50 ppm or CDCl3, 7.26 ppm; 13C: DMSO-d6, 39.52 ppm); for
compounds 14, 23e27, 13C NMR spectra were recorded in the
presence of CDCl3 in DMSO-d6 (w1:5) to increase the solubility,
using DMSO-d6 as internal standard; the following abbreviations
are used: singlet (s), doublet (d), triplet (t), quartet (q), quintet
(quint), doublet of doublet (dd), multiplet (m), broad signal (br s).
High resolution mass spectra (ESIþ) were determined on a high-
ꢀ
resolution Micro Q-Tof apparatus (CRMP, Universite Blaise Pascal,
Clermont-Ferrand, France). Chromatographic purifications were
performed by flash silica gel Geduran SI 60 (Merck)
0.040e0.063 mm column chromatography. Reactions were moni-
tored by TLC using fluorescent silica gel plates (60 F254 from Merck).
As mentioned above, the use of a ligand such as XPhos may have
an effect on the regioselectivity issue of the reaction with terminal
alkynes. This should also be considered in the case of internal

L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
7333
Melting points were measured on a Reichert microscope and are
uncorrected.
(3 mg, 0.016 mmol) in acetonitrile (2 mL) were added DIEA (20 mg,
0.15 mmol), and trimethylsilylacetylene (15 mg, 0.15 mmol). The
mixture was refluxed for 5 h, and then was evaporated under re-
duced pressure. The residue was purified by flash chromatography
(cyclohexane/EtOAc, 100:0 to 0:100) to give 8 (14 mg, 0.039 mmol,
51%) as a yellow powder; mp¼112e113 ꢂC; IR (ATR): 1620, 1419,
1314, 1292, 1258, 1253, 1249, 1078, 1037 cmꢀ1; 1H NMR (400 MHz,
DMSO-d6): 0.35 (9H, s), 1.51e1.70 (3H, m), 1.96e2.09 (2H, m),
2.35e2.47 (1H, m), 3.63e3.72 (1H, m), 3.90e3.97 (1H, m), 6.41 (1H,
4.2. Procedures for preparation of compounds 4e8
4.2.1. 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine
(4), 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (5),
7-iodo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine
(6), and 4-iodo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-
amine (7). Step A: to a mixture of indazole derivative 3 (1.5 g,
5.1 mmol) and 10% Pd/C (600 mg, 0.56 mmol, 11 mol %) in methanol
(45 mL) was added the 1,4-cyclohexadiene (5.1 mL, 54 mmol). The
mixture was refluxed for 3 h and the catalyst was removed by fil-
tration through a Celite pad, which was subsequently washed with
methanol (50 mL). The filtrate was evaporated under reduced
pressure and the residue was purified by flash chromatography
(cyclohexane/EtOAc, 100:0 to 50:50) to give a mixture containing
reduced products 4 and 5 (NMR ratio w87:13) (1.2 g) as a red oil.
The separation by chromatography of the two regioisomers was
only practicable using small quantities. Therefore, the mixture was
used for the next step without any further purification. Neverthe-
less, compounds 4 and 5 were separated by chromatography for
characterization (cyclohexane/EtOAc, 100:0 to 0:100).
dd, J1¼10.5 Hz, J2¼2 Hz), 7.01 (2H, br s), 8.21 (1H, s), 8.72 (1H, s); 13
C
NMR (100 MHz, DMSO-d6): ꢀ0.1 (3CH3), 22.8, 24.6, 28.8, 66.1 (CH2),
83.3, 123.0, 137.6 (CH), 87.7, 96.6, 107.9, 116.4, 130.4, 140.9, 145.9 (C);
HRMS (ESIþ) calcd for C17H22N4NaO3Si (MþNa)þ 381.1359, found
381.1350.
4.3. General procedure for preparation of compounds 9, 10,
12, 14, 23e27
To a mixture of compound 6 (50 mg, 0.13 mmol), Pd(PPh3)4
(15 mg, 0.013 mmol), XPhos (12.5 mg, 0.026 mmol), and K2CO3
(36 mg, 0.26 mmol) under inert atmosphere in THF (2 mL) was
added the alkyne (0.39 mmol). The solution was refluxed for 16 h,
and then was evaporated under reduced pressure. The residue was
purified by flash chromatography (CH2Cl2/cyclohexane/EtOAc,
10:90:0 to 10:0:90) to give the title compounds.
Step B: a solution of mixture from step A (500 mg) and iodine
(2 g, 7.9 mmol) in DMSO (3 mL) was stirred at room temperature for
1 h. The solution was diluted in EtOAc (50 mL) and was washed
with a saturated aqueous Na2S2O3 solution (3ꢁ30 mL). The organic
layer was dried over MgSO4 and the residue obtained upon evap-
oration was purified by flash chromatography (cyclohexane/EtOAc,
100:0 to 0:100) to give 6 (472 mg, 1.22 mmol, 57%) as an orange
powder and 7 (140 mg, 0.36 mmol, 17%) as a purple powder.
Compound 4, yellow oil; IR (ATR): 3486, 3373, 1635, 1305,
4.3.1. 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-7-(trimethylsilyl)-1,6-
dihydropyrrolo[2,3-g]indazole (9). Yellow powder, 91%; mp¼127
e128 ꢂC; IR (ATR): 3416, 1630, 1584, 1525, 1470, 1401, 1341, 1329,
1281, 1248, 1191, 1132, 1084, 1076, 1043 cmꢀ1 1H NMR (500 MHz,
;
DMSO-d6): 0.42 (9H, s), 1.58e1.69 (2H, m), 1.82e1.93 (1H, m),
2.05e2.14 (2H, m), 2.40e2.54 (1H, m), 3.82e3.88 (1H, m),
3.93e3.99 (1H, m), 6.06 (1H, dd, J1¼9.5 Hz, J2¼2 Hz), 7.15 (1H, d,
J¼2 Hz), 8.35 (1H, s), 8.64 (1H, s), 11.99 (1H, br s); 13C NMR
(100 MHz, DMSO-d6): ꢀ0.9 (3CH3), 21.8, 24.7, 28.6, 66.3 (CH2), 85.3
(CH), 110.8, 114.9, 136.9 (CHarom), 113.2, 117.0, 129.8, 130.7, 136.0,
140.0 (Carom); HRMS (ESIþ) calcd for C17H22N4NaO3Si (MþNa)þ
381.1359, found 381.1361.
1041 cmꢀ1 1H NMR (400 MHz, DMSO-d6): 1.51e1.63 (2H, m),
;
1.66e1.80 (1H, m),1.90e2.06 (2H, m), 2.25e2.37 (1H, m), 3.62e3.71
(1H, m), 3.84e3.92 (1H, m), 5.58 (1H, d, J¼9 Hz), 6.97 (1H, s), 7.00
(2H, br s), 8.09 (1H, s), 8.59 (1H, s); 13C NMR (100 MHz, DMSO-d6):
22.0, 24.7, 28.6, 66.4 (CH2), 84.3 (CH), 93.6, 121.1, 136.2 (CHarom),
116.9, 130.8, 142.6, 144.1 (Carom); HRMS (ESIþ) calcd for
C12H14N4NaO3 (MþNa)þ 285.0964, found 285.0975.
Compound 5, red oil; IR (ATR): 3501, 3393, 1635, 1520, 1483,
1451, 1295 cmꢀ1; 1H NMR (400 MHz, DMSO-d6): 1.49e1.64 (2H, m),
1.65e1.81 (1H, m), 1.91e2.06 (2H, m), 2.28e2.39 (1H, m), 3.72e3.80
(1H, m), 3.81e3.89 (1H, m), 5.87 (1H, dd, J1¼9.5 Hz, J2¼2.5 Hz), 6.55
(2H, br s), 7.26 (1H, s), 8.03 (1H, s), 8.43 (1H, s); 13C NMR (100 MHz,
DMSO-d6): 22.0, 24.8, 28.8, 66.3 (CH2), 83.8 (CH), 106.0, 107.2, 132.1
(CHarom), 129.7, 131.7, 134.0, 139.7 (Carom); HRMS (ESIþ) calcd for
C12H14N4NaO3 (MþNa)þ 285.0964, found 285.0960.
4.3.2. 5-Nitro-8-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-
dihydropyrrolo[2,3-g]indazole (10). Brown powder, 97%; mp¼179
e181 ꢂC; IR (ATR): 3500e3250, 1616, 1488, 1405, 1378, 1319, 1283,
1207, 1090, 1043 cmꢀ1 1H NMR (400 MHz, DMSO-d6): 0.71e0.86
;
(1H, m), 1.12e1.34 (2H, m), 1.61e1.76 (2H, m), 2.18e2.31 (1H, m),
2.50e2.58 (1H, m), 3.52e3.60 (1H, m), 4.99 (1H, dd, J1¼10.5 Hz,
J2¼2 Hz), 7.49 (1H, d, J¼2.5 Hz), 7.40e7.66 (5H, m), 8.46 (1H, s), 8.71
(1H, s), 12.34 (1H, br s); 13C NMR (100 MHz, DMSO-d6): 22.0, 24.2,
28.6, 66.8 (CH2), 85.8 (CH), 115.0, 126.0, 127.6 (single peak) and
128.2e130.3 (br s, chemical shift range evaluated from 1He13C
HSQC experiment) (5C), 139.2 (CHarom), 111.4, 117.7, 118.2, 127.1,
130.6, 136.5, 137.9 (Carom); HRMS (ESIþ) calcd for C20H18N4NaO3
(MþNa)þ 385.1277, found 385.1295.
Compound 6, mp¼126 ꢂC; IR (ATR): 3480, 3371, 1623, 1299,
1266, 1078, 1040 cmꢀ1 1H NMR (400 MHz, DMSO-d6): 1.50e1.78
;
(3H, m), 1.97e2.07 (2H, m), 2.41e2.55 (1H, m), 3.76e3.93 (2H, m),
6.55 (1H, d, J¼9.5 Hz), 7.00 (2H, br s), 8.16 (1H, s), 8.67 (1H, s); 13C
NMR (126 MHz, DMSO-d6): 22.9, 24.6, 28.8, 66.0 (CH2), 82.7 (CH),
121.8, 136.7 (CHarom), 62.5, 118.0, 130.4, 143.0, 143.4 (Carom); HRMS
(ESIþ) calcd for C12H13IN4NaO3 (MþNa)þ 410.9930, found 410.9914.
Compound 7, mp¼107e108 ꢂC; IR (ATR): 3458, 3342, 1513, 1430,
4.3.3. 5-Nitro-8-propyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-
dihydropyrrolo[2,3-g]indazole (12). Orange powder, w1:9 mixture
of regioisomers 11 and 12, 96%; 1H NMR (500 MHz, DMSO-d6),
major regioisomer 12: 1.09 (3H, t, J¼7.5 Hz), 1.58e1.95 (5H, m),
1.97e2.03 (1H, m), 2.07e2.15 (1H, m), 2.58e2.67 (1H, m), 2.97e3.12
(2H, m), 3.69e3.76 (1H, m), 3.92e3.98 (1H, m), 6.07 (1H, dd,
J1¼9.5 Hz, J2¼2 Hz), 7.29 (1H, d, J¼2.5 Hz), 8.25 (1H, s), 8.59 (1H, s),
11.91 (1H, br s). HRMS (ESIþ) calcd for C17H20N4NaO3 (MþNa)þ
351.1433, found 351.1450.
1288, 1168, 1076, 1056, 1038 cmꢀ1 1H NMR (500 MHz, DMSO-d6):
;
1.52e1.61 (2H, m), 1.68e1.78 (1H, m), 1.93e2.05 (2H, m), 2.28e2.37
(1H, m), 3.74e3.81 (1H, m), 3.82e3.87 (1H, m), 5.94 (1H, dd,
J1¼9.5 Hz, J2¼2.5 Hz), 6.27 (2H, br s), 7.86 (1H, s), 8.58 (1H, s); 13C
NMR (100 MHz, DMSO-d6): 21.9, 24.7, 28.7, 66.3 (CH2), 84.1 (CH),
109.1, 135.1 (CHarom), 74.6, 131.0, 133.5, 134.4, 138.1 (Carom); HRMS
(ESIþ) calcd for C12H13IN4NaO3 (MþNa)þ 410.9930, found 410.9924.
4 . 2 . 2 . 5 - N i t r o - 1 - ( t e t r a h y d r o - 2 H - p y r a n - 2 - y l ) - 7 - ( 2 -
4.3.4. 8-Diethoxymethyl-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1,6-
trimethylsilylethynyl)-1H-indazol-6-amine (8). To
compound 6 (30 mg, 0.077 mmol), Pd(PPh3)4 (9 mg, 7.8
a
mixture of
mol), CuI
dihydropyrrolo[2,3-g]indazole
(14). Yellow
powder,
56%;
;
m
mp¼181e182 ꢂC; IR (ATR): 3384, 1614, 1412, 1380, 1328 cmꢀ1
1H

7334
L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
NMR (500 MHz, DMSO-d6): 1.06 (3H, t, J¼7 Hz), 1.23 (3H, t, J¼7 Hz),
1.57e1.64 (2H, m), 1.67e1.78 (1H, m), 1.93e1.99 (1H, m), 2.07e2.14
(1H, m), 2.51e2.60 (1H, m), 3.35e3.43 (1H, m), 3.46e3.54 (1H, m),
3.57e3.65 (1H, m), 3.78e3.90 (3H, m), 6.02 (1H, s), 6.77 (1H, br d,
J¼7.5 Hz), 7.59 (1H, d, J¼2.5 Hz), 8.41 (1H, s), 8.66 (1H, s), 12.19 (1H,
br s); 13C NMR (100 MHz, DMSO-d6þCDCl3): 14.9, 15.0 (CH3), 22.3,
24.8, 29.7, 57.7, 62.4, 65.9 (CH2), 83.3, 97.2 (CH), 114.8, 126.7, 137.8
(CHarom), 109.7, 114.1, 118.0, 127.6, 130.2, 136.9 (Carom); HRMS (ESIþ)
calcd for C19H24N4NaO5 (MþNa)þ 411.1644, found 411.1634.
94%; mp¼135e136 ꢂC; IR (ATR): 3447, 1707, 1309, 1232, 1083,
1040 cmꢀ1
;
1H NMR (500 MHz, DMSO-d6): 1.39 (3H, t, J¼7 Hz),
1.57e1.64 (2H, m), 1.71e1.82 (1H, m), 1.96e2.02 (1H, m), 2.04e2.11
(1H, m), 2.53e2.62 (1H, m), 3.01 (3H, s), 3.68e3.75 (1H, m),
3.86e3.92 (1H, m), 4.41 (2H, q, J¼7 Hz), 6.18 (1H, dd, J1¼9 Hz,
J2¼2 Hz), 8.48 (1H, s), 8.85 (1H, s), 10.98 (1H, br s); 13C NMR
(100 MHz, DMSO-d6þCDCl3): 11.6, 14.1 (CH3), 22.0, 24.4, 29.5, 60.7,
65.9 (CH2), 84.8 (CH), 118.8, 138.1 (CHarom), 113.7, 118.0, 119.3, 123.7,
127.6, 129.9, 137.8 (Carom), 160.5 (C]O); HRMS (ESIþ) calcd for
C18H21N4O5 (MþH)þ 373.1512, found 373.1507.
4.3.5. 7-Ethyl-5-nitro-8-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-
dihydropyrrolo[2,3-g]indazole (23), and 8-ethyl-5-nitro-7-phenyl-1-
(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyrrolo[2,3-g]indazole
(24). Compound 23, black powder, 67%; mp¼127e128 ꢂC; IR (ATR):
4.4. Procedures for preparation of compounds 28 and 29
Procedure A: a solution of indazoles 25 or 26 in concentrated
hydrochloric or hydrobromic acid, respectively, was refluxed for
2 h. A saturated aqueous NaHCO3 solution (20 mL) was added and
the solution was extracted with EtOAc (2ꢁ20 mL). The combined
organic fractions were dried over MgSO4 and then evaporated.
Flash chromatography (cyclohexane/EtOAc, 100:0 to 0:100) pro-
vided the title compounds.
Procedure B: to a solution of indazoles 10 or 12 (w1:9 11/12
mixture) in ethanol and water was added PTSA monohydrate
(20 mol %). The mixture was refluxed for 16 h. A saturated aqueous
NaHCO3 solution (10 mL) was added and the solution was extracted
with EtOAc (2ꢁ30 mL). The combined organic layers were dried
over MgSO4 and then evaporated. Flash chromatography (cyclo-
hexane/EtOAc, 100:0 to 0:100) provided the title compounds.
3372, 1615, 1492, 1401, 1315, 1276, 1261 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6): 0.70e0.84 (1H, m), 1.14 (3H, t, J¼7.5 Hz), 1.11e1.32 (2H,
m), 1.49e1.57 (1H, m), 1.64e1.72 (1H, m), 2.15e2.28 (1H, m),
2.56e2.79 (3H, m), 3.53e3.60 (1H, m), 4.74 (1H, d, J¼10 Hz),
7.34e7.39 (1H, m), 7.50e7.58 (3H, m), 7.60e7.66 (1H, m), 8.41 (1H,
s), 8.61 (1H, s), 12.09 (1H, br s); 13C NMR (100 MHz, DMSO-
d6þCDCl3): 15.2 (CH3), 18.9, 21.9, 24.2, 28.7, 66.6 (CH2), 85.4 (CH),
113.4, 127.7, 128.8, 129.1, 130.3, 130.9, 138.8 (CHarom), 112.5, 113.3,
118.2, 125.9, 130.2, 136.6, 137.1, 140.8 (Carom); HRMS (ESIþ) calcd for
C22H23N4O3 (MþH)þ 391.1770, found 391.1773.
Compound 24, brown powder, 19%; mp¼120e121 ꢂC; IR (ATR):
3384, 1605, 1493, 1396, 1326, 1316, 1081, 1044 cmꢀ1 1H NMR
;
(500 MHz, DMSO-d6): 1.27 (3H, t, J¼7.5 Hz), 1.57e1.77 (3H, m),
2.02e2.08 (1H, m), 2.08e2.16 (1H, m), 2.58e2.68 (1H, m),
2.96e3.11 (2H, m), 3.65e3.73 (1H, m), 3.90e3.97 (1H, m), 6.08 (1H,
dd, J1¼9.5 Hz, J2¼2 Hz), 7.46 (1H, t, J¼7 Hz), 7.53 (2H, t, J¼7.5 Hz),
7.59 (2H, d, J¼7.5 Hz), 8.42 (1H, s), 8.61 (1H, s), 11.70 (1H, br s); 13C
NMR (126 MHz, DMSO-d6þCDCl3): 17.0 (CH3), 18.7, 22.5, 24.6, 29.9,
66.5 (CH2), 85.2 (CH), 114.3, 128.1, 128.2 (2C), 129.6 (2C), 138.2
(CHarom), 112.9, 114.7, 118.0, 127.0, 130.4, 131.9, 136.5, 137.5 (Carom);
HRMS (ESIþ) calcd for C22H23N4O3 (MþH)þ 391.1770, found
391.1777.
4.4.1. 5-Nitro-8-phenyl-1,6-dihydropyrrolo[2,3-g]indazole
(28). Procedure A: compound 25 (10 mg, 0.023 mmol), concen-
trated HCl (1 mL); 28 (4 mg, 0.014 mmol, 62%).
Procedure B: compound 10 (130 mg, 0.36 mmol), ethanol (5 mL),
water (3 mL); 28 (97 mg, 0.35 mmol, 97%).
Yellow powder; mp¼193e194 ꢂC; IR (ATR): 3446, 3268, 1632,
1480, 1317, 1282, 1234, 1076 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
;
7.35 (1H, t, J¼7.5 Hz), 7.50 (2H, t, J¼7.5 Hz), 7.60 (1H, d, J¼2.5 Hz),
7.76 (2H, br s), 8.50 (1H, br s), 8.73 (1H, s),12.22 (1H, br s),13.08 (1H,
br s); 1H NMR (400 MHz, CDCl3): 7.44e7.50 (2H, m), 7.58 (2H, t,
J¼7.5 Hz), 7.66 (2H, d, J¼7 Hz), 8.28 (1H, s), 8.69 (1H, s), 10.25e10.47
(2H, br s); 13C NMR: due to the low solubility of compound 28 in
organic solvents, its 13C NMR spectrum could not be recorded;
HRMS (ESIþ) calcd for C15H11N4O2 (MþH)þ 279.0882, found
279.0893.
4.3.6. Ethyl 5-nitro-8-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-
dihydropyrrolo[2,3-g]indazole-7-carboxylate (25). Yellow powder,
86%; mp¼151e152 ꢂC; IR (ATR): 3453, 1698, 1400, 1316, 1300, 1261,
1241 cmꢀ1; 1H NMR (500 MHz, DMSO-d6): 0.76e0.87 (1H, m), 1.03
(3H, t, J¼7 Hz), 1.14e1.32 (2H, m), 1.47e1.53 (1H, m), 1.64e1.71 (1H,
m), 2.16e2.25 (1H, m), 2.67e2.73 (1H, m), 3.55e3.60 (1H, m),
4.07e4.19 (2H, m), 4.58 (1H, d, J¼10 Hz), 7.41 (1H, d, J¼7.5 Hz),
7.51e7.63 (4H, m), 8.49 (1H, s), 8.88 (1H, s),11.26 (1H, br s); 13C NMR
(100 MHz, DMSO-d6þCDCl3): 13.4 (CH3), 21.6, 24.0, 28.7, 60.5, 66.5
(CH2), 85.4 (CH), 118.9, 128.18, 128.25, 128.33, 129.7, 130.6, 139.2
(CHarom), 112.7, 118.5, 122.5, 124.7, 127.3, 130.0, 135.0, 137.5 (Carom),
159.9 (C]O); HRMS (ESIþ) calcd for C23H23N4O5 (MþH)þ 435.1668,
found 435.1689.
4.4.2. 5-Nitro-8-propyl-1,6-dihydropyrrolo[2,3-g]indazole
(29). Procedure A: compound 26 (20 mg, 0.052 mmol), concen-
trated HBr (2 mL); 29 (7 mg, 0.029 mmol, 55%).
Procedure B: mixture of compounds 11 and 12 (w1:9) (84 mg,
0.26 mmol), ethanol (3 mL), water (3 mL); compound 29 (56 mg,
0.23 mmol, 90%) was obtained as a mixture containing w10% of the
7-propyl regioisomer.
4.3.7. Methyl 5-nitro-8-propyl-1-(tetrahydro-2H-pyran-2-yl)-1,6-
dihydropyrrolo[2,3-g]indazole-7-carboxylate (26). Yellow powder,
90%; mp¼135e136 ꢂC; IR (ATR): 3431, 1707, 1398, 1319, 1232, 1218,
Orange powder; mp >250 ꢂC; IR (ATR): 3450e3300,
3300e3050, 1635, 1454, 1324, 1292, 1201, 1086 cmꢀ1 1H NMR
;
(500 MHz, DMSO-d6): 0.98 (3H, t, J¼7.5 Hz), 1.68 (2H, quint,
J¼7.5 Hz), 2.96 (2H, t, J¼7.5 Hz), 7.23 (1H, s), 8.37 (1H, s), 8.61 (1H, s),
11.78 (1H, br s),13.62 (1H, br s); 13C NMR (126 MHz, DMSO-d6): 13.5
(CH3), 23.7, 27.2 (CH2), 114.2, 123.0, 137.4 (CHarom), 112.3, 116.2,
116.4, 125.7, 130.2, 136.6 (Carom); HRMS (ESIþ) calcd for C12H13N4O2
(MþH)þ 245.1039, found 245.1033.
1082, 1042 cmꢀ1 1H NMR (500 MHz, DMSO-d6): 1.06 (3H, t,
;
J¼7.5 Hz), 1.56e1.83 (5H, m), 2.07e2.17 (2H, m), 2.56e2.65 (1H, m),
3.09e3.17 (1H, m), 3.45e3.53 (1H, m), 3.70e3.77 (1H, m),
3.89e3.94 (1H, m), 3.95 (3H, s), 6.83 (1H, dd, J1¼9 Hz, J2¼2.5 Hz),
8.51 (1H, s), 8.86 (1H, s), 11.13 (1H, br s); 13C NMR (100 MHz, DMSO-
d6þCDCl3): 13.6, 51.9 (CH3), 22.1, 24.4, 24.8, 26.8, 29.6, 66.0 (CH2),
85.0 (CH), 119.0, 138.5 (CHarom), 112.7, 118.4, 123.5, 124.5, 127.7,
130.0, 137.7 (Carom), 160.6 (C]O); HRMS (ESIþ) calcd for
C19H22N4NaO5 (MþNa)þ 409.1488, found 409.1488.
Acknowledgements
We are grateful for the financial support of ANR (ANR-08-JCJC-
ꢀ
4.3.8. Ethyl 8-methyl-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1,6-
0131-CSD 3). The authors thank Bertrand Legeret for mass spectra
dihydropyrrolo[2,3-g]indazole-7-carboxylate (27). Yellow powder,
analysis.

L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
7335
Appl. SU685664 A1, 1979. (f) McEvoy, F.; Smith, J.; Allen, D. Pat. Appl.
NL6600752, 1966.
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