Synthesis of 1,6-dihydropyrrolo[2,3-g]indazoles using Larock indole annulation
ABSTRACT 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.
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ABSTRACT: A series of 2,3-diarylindoles were synthesized from 2-iodoaniline and unsymmetrical diarylacetylenes using the Larock heteroannulation. Diarylacetylenes bearing electron-withdrawing substituents lead to 2,3-diarylindoles with substituted phenyl moieties at the 2-position as major products, while those with electron-donating groups preferably yield indole products with substituted phenyl moieties at the 3-position. The regioisomeric product ratios exhibit a clear correlation with Hammett sigma values. DFT calculations reveal the origin of this effect, displaying smaller activation energy barriers for those pathways leading to the major regioisomer.The Journal of Organic Chemistry 11/2013; · 4.64 Impact Factor
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ABSTRACT: Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.Organic Process Research & Development 10/2012; 16(11):1832–1845. · 2.55 Impact Factor
Synthesis of 1,6-dihydropyrrolo[2,3-g]indazoles using Larock indole annulation
Laurent Gavaraa,b, Fabrice Anizona,b,*, Pascale Moreaua,b
aClermont Universit? e, Universit? e Blaise Pascal, Laboratoire SEESIB, BP 10448, F-63000 Clermont-Ferrand, France
bCNRS, UMR 6504, SEESIB, F-63177 Aubi? ere, France
a r t i c l e i n f o
Received 1 June 2011
Received in revised form 8 July 2011
Accepted 12 July 2011
Available online 21 July 2011
Larock indole annulation
a b s t r a c t
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.
? 2011 Elsevier Ltd. All rights reserved.
The palladium-catalyzed annulation of internal alkynes proved
tobe a useful method toaccess 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
Alternatively, 2,3-disubstituted indoles were
synthesized from 2-iodotrifluoroacetanilides and terminal alkynes
bySonogashira 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.5e8In 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
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
medicinal chemistry,10we recently started a research program
aimed at developing new compounds containing this heterocyclic
system.11,12We 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.13The 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.12,14Protection of indazole 2 at
the N-1 position by a THP group gave compound 3 in good yield
Fig. 1. 1,6-Dihydropyrrolo[2,3-g]indazole 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).
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/tet
0040-4020/$ e see front matter ? 2011 Elsevier Ltd. All rights reserved.
Tetrahedron 67 (2011) 7330e7335
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,12both nitro groups
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
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.15Only one method fi-
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 a1He1H
NOESY spectrum. Relevant correlations werefound forcompound 6
compound 7 between the aromatic proton at 8.58 ppm and the THP
anomeric proton at 5.94 ppm.
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
Unfortunately, other methods examined to improve the yield of the
reaction did not afford the expected Sonogashira product.17On the
other hand, we found that one of the methods experimented,17d
using a mixture of Pd(OAc)2, BINAP, and K2CO3in refluxing THF,
led directly to the desired indole derivative 9 in 60% yield.18
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.18This
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.
The same regioselectivity was observed with other terminal
alkynes (entries 3e5).18However, 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 weremeasured foreach mixtureaccording
to characteristic1H 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.
To get more insight into the mechanism of formation of com-
pound9, alkynylindazole 8 was subjected tothe 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 PdCl2in acetonitrile20nor CuI
Indolization reaction with terminal alkynes
K2CO3, THF, reflux
ProductYield (regioisomeric ratio)
(56% of 14)
aAn inseparable mixture of regioisomers was isolated.
bA 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.
4 R1= NH2, R2= NO2
5 R1= NO2, R2= NH2
7 (17% from )
I2, DMSO, rt
CHD, 10% Pd/C
6 (57% from 3)
Scheme 1. Synthesis of o-iodoaniline derivatives 6 and 7.
K2CO3, THF, reflux
Scheme 2. Synthesis compounds 8 and 9.
L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
in DMF.21Therefore, we suppose that a Larock annulation is most
likely involved in the formation of compound 9, and the effect of
the silylgrouphada stronginfluence onthe 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.
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.22In 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 by1He1H 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.
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
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
functionwould be found at the 3-position of the indole ring system.
Actually, examples of such synthetic pathway are found in the lit-
erature23and might be involved in previous examples that de-
scribed the access to indole derivatives bearing the ester function at
the 3-position.22In 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.
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.
4. Experimental section
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 cm?1). 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;
compounds 14, 23e27,13C NMR spectra were recorded in the
presence of CDCl3in DMSO-d6(w1:5) to increase the solubility,
using DMSO-d6as 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, Universit? e Blaise Pascal,
Clermont-Ferrand, France). Chromatographic purifications were
0.040e0.063 mm column chromatography. Reactions were moni-
tored by TLC using fluorescent silica gel plates (60 F254from Merck).
13C: DMSO-d6, 39.52 ppm); for
Geduran SI60 (Merck)
Indolization reaction with internal alkynes
K2CO3, THF, reflux
aInseparable mixture with starting material.
25 or 26
HBr (from 25)
HCl (from 26)
28 R = Ph
29 R = n-Pr
10 or 12a
97% from 10
90% from 12
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.
L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
Melting points were measured on a Reichert microscope and are
4.2. Procedures for preparation of compounds 4e8
(4), 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (5),
(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).
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 Na2S2O3solution (3?30 mL). The organic
layer was dried over MgSO4and 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,
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);
C12H14N4NaO3(MþNa)þ285.0964, found 285.0975.
Compound 5, red oil; IR (ATR): 3501, 3393, 1635, 1520, 1483,
1451,1295 cm?1;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)þ285.0964, found 285.0960.
Compound 6, mp¼126?C; IR (ATR): 3480, 3371, 1623, 1299,
1266, 1078, 1040 cm?1;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)þ410.9930, found 410.9914.
Compound 7, mp¼107e108?C; IR (ATR): 3458, 3342,1513,1430,
1288, 1168, 1076, 1056, 1038 cm?1;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)þ410.9930, found 410.9924.
1H NMR (400 MHz, DMSO-d6): 1.51e1.63 (2H, m),
compound 6 (30 mg, 0.077 mmol), Pd(PPh3)4(9 mg, 7.8 mmol), CuI
(8). To a mixture of
(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?C; IR (ATR): 1620, 1419,
1314, 1292, 1258, 1253, 1249, 1078, 1037 cm?1;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,
dd, J1¼10.5 Hz, J2¼2 Hz), 7.01 (2H, br s), 8.21 (1H, s), 8.72 (1H, s);13C
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)þ381.1359, found
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.
dihydropyrrolo[2,3-g]indazole (9). Yellow powder, 91%; mp¼127
e128?C; IR (ATR): 3416, 1630, 1584, 1525, 1470, 1401, 1341, 1329,
1281, 1248, 1191, 1132, 1084, 1076, 1043 cm?1;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);
(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.
dihydropyrrolo[2,3-g]indazole (10). Brown powder, 97%; mp¼179
e181?C; IR (ATR): 3500e3250, 1616, 1488, 1405, 1378, 1319, 1283,
1207, 1090, 1043 cm?1;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 from1He13C
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)þ385.1277, found 385.1295.
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.
mp¼181e182?C; IR (ATR): 3384, 1614, 1412, 1380, 1328 cm?1;1H
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)þ411.1644, found 411.1634.
dihydropyrrolo[2,3-g]indazole (23), and 8-ethyl-5-nitro-7-phenyl-1-
(24). Compound 23, black powder, 67%; mp¼127e128?C; IR (ATR):
3372, 1615, 1492, 1401, 1315, 1276, 1261 cm?1;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);
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)þ391.1770, found 391.1773.
Compound 24, brown powder, 19%; mp¼120e121?C; IR (ATR):
3384, 1605, 1493, 1396, 1326, 1316, 1081, 1044 cm?1;
(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)þ391.1770, found
13C NMR (100 MHz, DMSO-
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?C; IR (ATR): 3453,1698,1400,1316,1300,1261,
1241 cm?1;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)þ435.1668,
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?C; IR (ATR): 3431, 1707, 1398, 1319, 1232, 1218,
1082, 1042 cm?1;
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);
C19H22N4NaO5(MþNa)þ409.1488, found 409.1488.
1H NMR (500 MHz, DMSO-d6): 1.06 (3H, t,
4.3.8. Ethyl 8-methyl-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1,6-
dihydropyrrolo[2,3-g]indazole-7-carboxylate (27). Yellow powder,
94%; mp¼135e136?C; IR (ATR): 3447, 1707, 1309, 1232, 1083,
1040 cm?1;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)þ373.1512, found 373.1507.
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 NaHCO3solution (20 mL) was added and
the solution was extracted with EtOAc (2?20 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
NaHCO3solution (10 mL) was added and the solutionwas extracted
with EtOAc (2?30 mL). The combined organic layers were dried
over MgSO4and then evaporated. Flash chromatography (cyclo-
hexane/EtOAc, 100:0 to 0:100) provided the title compounds.
(28). Procedure A: compound 25 (10 mg, 0.023 mmol), concen-
trated HCl (1 mL); 28 (4 mg, 0.014 mmol, 62%).
ProcedureB: compound 10 (130 mg, 0.36 mmol),ethanol (5 mL),
water (3 mL); 28 (97 mg, 0.35 mmol, 97%).
Yellow powder; mp¼193e194?C; IR (ATR): 3446, 3268, 1632,
1480, 1317, 1282, 1234, 1076 cm?1;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, its13C NMR spectrum could not be recorded;
HRMS (ESIþ) calcd for C15H11N4O2 (MþH)þ279.0882, found
(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
3300e3050, 1635, 1454, 1324, 1292, 1201, 1086 cm?1;
(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)þ245.1039, found 245.1033.
We are grateful for the financial support of ANR (ANR-08-JCJC-
0131-CSD 3). The authors thank Bertrand L? egeret for mass spectra
L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335
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6.01 (1H, d, J¼9 Hz), 6.94 (1H, s), 8.35 (1H, s), 8.59 (1H, s), 11.85 (1H, br s).
Compounds 19 and 20 (400 MHz, CDCl3), major regioisomer: 5.95 (1H, d, J¼8.
5 Hz), 8.20 (1H, s); minor regioisomer: 6.21 (1H, d, J¼8.5 Hz), 8.29 (1H, s).
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L. Gavara et al. / Tetrahedron 67 (2011) 7330e7335