Regioselective synthesis of novel substituted indazole-5,6-diamine derivatives

Article abstract of DOI:10.1016/j.tet.2011.01.010

The synthesis of a series of novel indazole-5,6-diamine derivatives is described. This indazole ring system was incorporated in an octahydropyrrolo[3, 4-b]phenazine scaffold and was diversely and regioselectively substituted on the nitrogen atoms at the 5- and 10-positions. Thus, the nitrogen atom at the 5-position was found to be more reactive toward electrophiles than the one at the 10-position. This difference of reactivity could be attributed to the electronic effect of the pyrazole moiety. Moreover, an unexpected tetrahydropyran protecting group migration was observed from the N-1 atom to the C-11 position of the octahydropyrrolo[3,4-b]phenazine scaffold.

Full text of DOI:10.1016/j.tet.2011.01.010

Tetrahedron 67 (2011) 1633e1639
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of novel substituted indazole-5,6-diamine derivatives
,
,
,
b
,
a,b
Laurent Gavara a b, Emmanuelle Saugues 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:
The synthesis of a series of novel indazole-5,6-diamine derivatives is described. This indazole ring system
was incorporated in an octahydropyrrolo[3,4-b]phenazine scaffold and was diversely and regioselectively
substituted on the nitrogen atoms at the 5- and 10-positions. Thus, the nitrogen atom at the 5-position
was found to be more reactive toward electrophiles than the one at the 10-position. This difference of
reactivity could be attributed to the electronic effect of the pyrazole moiety. Moreover, an unexpected
tetrahydropyran protecting group migration was observed from the N-1 atom to the C-11 position of the
octahydropyrrolo[3,4-b]phenazine scaffold.
Received 3 November 2010
Received in revised form 3 January 2011
Accepted 5 January 2011
Available online 12 January 2011
Keywords:
Indazole
Phenazine
Ó 2011 Elsevier Ltd. All rights reserved.
Regioselective alkylation
1. Introduction
introduce various substituents on the two nitrogens at the 5- and
10-positions of the pyrazolophenazine scaffold. Herein we describe
In the last decade, the extensive studies on drug-like properties
of small organic molecules allowed the identification of privileged
structures. The indazole ring system is among these bioactive
scaffolds that have retained the attention of organic and medicinal
chemists. Thus, numerous reports in the literature describe the
synthesis and biological properties of indazole derivatives.1e3
However, the discovery of new compounds containing the inda-
zole scaffold remains a challenging area of research. In this context,
we recently started to explore the synthesis of new indazole de-
rivatives as potential kinase inhibitors and anti-tumor agents. Ac-
cordingly, we reported a preliminary work in the field on the
synthesis and characterization of new pyrazolo[3,4-g]quinoxaline
derivatives. These heterocyclic systems were prepared by reaction
the synthesis of this unprecedented series of indazole derivatives
represented by the general structure A (Fig. 1).
H
N
N
N
N
1
R2
N
H
N
H
N
PG
H
H
O2N
O2N
N
N
N
N
N
N
N
R1
2
A
B
between 1H-indazole-5,6-diamine and
a-chloroketones or 1,2-
Fig. 1. Pyrazolo[3,4-b]phenazine derivative 1. Retrosynthetic approach to the prepa-
ration of compound A from indazole 2.
diketones.4 We showed that some of the prepared compounds
displayed interesting in vitro antiproliferative potency in the mi-
cromolar range toward PA1 cell line, as well as a moderate protein
kinase inhibitory activity toward the third isoform of the Pim
protein kinase family (Pim-3, provirus integration site of Moloney
murine leukemia virus-3). The results obtained in this preliminary
work have shown that compound 1 (Fig. 1) was the most potent of
the series toward Pim-3. Thus, we decided to extend our study to
the synthesis of novel derivatives of tetrahydro-1H-pyrazolo[3,4-b]
phenazine 1. More particularly, we considered that the pyrazine
ring of compound 1 could be reduced, offering the opportunity to
2. Results and discussion
A general access for the preparation of indazole derivative of
general structure A (Fig. 1) could be the hydrogenation and sub-
sequent nitrogen substitution of tetrahydro-1H-pyrazolo[3,4-b]
phenazine B. This approach implies the introduction of a protecting
group on the 1,2-diazole heterocycle, in order to prevent any
regioselectivity complication due to competing pyrazole moiety
during the substitution reactions on the nitrogen atoms at the
5- and 10-positions. In our previous study on the synthesis of
pyrazolo[3,4-g]quinoxaline derivatives, compound 1 was prepared
from 5,6-dinitroindazole 2 after reduction of the two nitro groups
and condensation with 2-chlorocyclohexanone.4 Therefore, we
* 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).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.010

1634
L. Gavara et al. / Tetrahedron 67 (2011) 1633e1639
firstly examined the protection of indazole 2 prior to nitro group
reduction. The protection reaction of the indazole ring system can
proceed at N-1 or N-2 positions as it contains two non-equivalent
nitrogen atoms. It has been shown that the regioselectivity of the
reaction is highly dependent of the conditions used.5e7 Thus, it was
reported that indazoles were unselectively protected under
strongly basic conditions. However, regioselective protection could
be accomplished taking advantage of the higher nucleophilicity of
the N-2 lone pair, by using a non-deprotonating base or by per-
forming the reaction under acidic conditions. Nevertheless, as the
reactivity of 5,6-dinitroindazole for protection reactions has never
been examined, we decided to investigate the introduction of dif-
ferent protecting groups on this scaffold. When compound 2 was
treated with acetic anhydride in the presence of sodium acetate at
100 ꢀC, GC/MS analysis of the reaction mixture showed a single
peak (m/z¼250) corresponding to a monoacetylated compound.
Nevertheless, this product was found to be too unstable for any
chromatographic purification or further transformation. Similarly,
the use of Boc2O/K2CO3 in refluxing THF or BnOCOCl/NEt3 in
refluxing CH2Cl2 led to unstable regioisomeric mixtures of mono-
substituted indazole derivatives (m/z¼308 and 342, respectively).
Conversely, the use of allyl or benzyl protecting groups yielded
stable products but the regioisomeric ratio was function of the
reaction conditions used, as it has already been observed for other
indazole series. Thus, treatment of indazole 2 with allylbromide/
K2CO3 in refluxing THF or benzylbromide/NaH in CH2Cl2 and sub-
sequent GC/MS analysis showed an approximately 1:1 mixture of
N-1 and N-2 protected regioisomers (m/z¼248 and 298, for allyl
and benzyl protecting groups, respectively). On the other hand, one
regioisomer was favored using benzyl chloride/DIPEA in refluxing
THF (GC/MS ratio: 3:1) (Scheme 1). Purification of the reaction
mixture and subsequent identification of the products by NMR
showed that the major isomer was the N-2 protected indazole 4,
obtained in 49% yield. Minor product 3 was isolated in 24% yield.
ammonium formate and 10% Pd/C, diamine 7 was isolated in 61%
yield. A similar yield was obtained when the reduction was per-
formed in the presence of Na2S2O4/NaOH in EtOH at 50 ꢀC. Ulti-
mately, nitro groups were efficiently reduced in the presence of
hydrazine hydrate and 10% Pd/C in refluxing methanol leading to
protected indazole-5,6-diamine 7 in 94% yield (Scheme 2).
THP
THP
(NH2)2.H2O, 10% Pd/C
O2N
O2N
H2N
H2N
N
N
MeOH
94%
N
N
5
7
O
CH3CN
71%
O
THP
N
N
N
N
8
Scheme 2. Synthesis of tetrahydropyrazolo[3,4-b]phenazine 8.
Indazole 7 was further used to complete the preparation of
compound 8. In our preceding study,4 the synthesis of the non-
protected tetrahydropyrazolo[3,4-b]phenazine 1 (Fig. 1), was per-
formed by reaction between indazole-5,6-diamine and 2-chlor-
ocyclohexanone in the presence of p-toluenesulfonic acid. In the
current synthesis, the presence of the THP protecting group pre-
cludes the use of any acidic conditions. Moreover, the use of 2-
chlorocyclohexanone under basic conditions in the presence of
NEt3 in acetonitrile led to product 8 in low yield. Consequently, the
use of the cyclohexane-1,2-dione was preferred and the conden-
sation reaction was accomplished in refluxing acetonitrile to give
compound 8 in 71% yield (Scheme 2).
Hydrogenation of the pyrazine ring of compound 8 was a major
issue for this approach because a non-stereoselective reaction
would afford up to eight stereoisomers due to the presence of the
THP group and two newly formed carbon stereocenters. The con-
version of compounds containing a 2,3-disubstituted quinoxaline
ring system to the corresponding tetrahydroquinoxaline derivatives
has been described by a number of method including catalytic
hydrogenation,8e11 hydride reduction,8,12e15 BH3$THF,14 TiCl3,16 Na/
EtOH,17,18 or by the use of indium metal.19 Whereas methods, such as
hydrogenation preferentially give the cis product, no convenient
reduction yielding the trans isomer has been described so far. As we
needed a stereoselective method, we decided to apply simple cat-
alytic hydrogenation. Thus, compound 8 was reduced using am-
monium formate in refluxing methanol in the presence of 10% Pd/C
(Scheme 3). In these reaction conditions, product 9 was obtained in
high yield without need of chromatography. Nevertheless, 1H NMR
spectrum revealed a complex stereoisomeric mixture. Alternative
methods using BH3$THF or Wilkinson catalyst/H2 led to similar 1H
NMR spectra but they yielded lower quantities of reduced product 9.
The following alkylation and subsequent deprotection steps
were carried out starting from compound 9. Monoalkylation pro-
ceeded smoothly at room temperature with benzylbromide, allyl-
bromide or bromoacetonitrile in DMF in the presence of K2CO3,
leading to compounds 10e12. However, in the case of bromoe-
thanol, the reaction mixture needed to be heated at 120 ꢀC to
complete the reaction and to obtain the intermediate 13 after
chromatography. In all cases, the formation of the disubstituted
product was not observed. Deprotection of monosubstituted com-
pounds 10 and 11 in the presence of acetic acid in THF/H2O yielded
compounds 14e17. The expected deprotected products 14 and 16,
respectively substituted by benzyl and allyl groups, were isolated in
20% and 14% yields after three steps from starting material 8. The
H
N
R
BnCl, DIPEA,
THF, reflux
O2N
O2N
O2N
O2N
O2N
O2N
N
N
N
N R
+
N
or
DHP, H2SO4 cat.,
CH2Cl2
2
R = Bn
R = THP
3 (24%)
5 (93%)
4 (49%)
6 (4%)
Scheme 1. Protection of indazole 2.
Attempts to reduce the two nitro groups of 3 and 4 were per-
formed using various reaction conditions. Unfortunately, we never
managed to obtain the corresponding diamino products without
removing the benzyl protecting group. Therefore, we looked for
a protecting group inert in reduction conditions. Thus, indazole 2
was protected in a very regioselective fashion at the N-1 position to
give compound 5 in 93% yield, using dihydropyran in CH2Cl2 in the
presence of a catalytic amount of H2SO4 (Scheme 1). As it was found
previously by Slade et al.5, N-2 THP protected indazole 6 was
quickly formed during the course of the reaction, and this com-
pound was readily converted into the thermodynamic N-1 pro-
tected product 5. Nevertheless, complete conversion was not
observed and residual N-2 protected derivative 6 was isolated in 4%
yield after chromatography. Using the mild acidic conditions pro-
posed by Slade et al. (PPTS/DCM, room temperature), the N-2
protected isomer 6 was isolated as the major product in 91% yield
after chromatography. In these conditions, compound 5 was also
isolated in 3% yield.
As the two N-1 and N-2 THP protected regioisomers could be
isolated in good yields, we decided to carry on the synthesis
starting from the thermodynamically more stable indazole 5, and
considered the reduction of the two nitro groups. When the re-
action was achieved in refluxing methanol in the presence of

L. Gavara et al. / Tetrahedron 67 (2011) 1633e1639
1635
H
N
compound 8. Using similar alkylation conditions in the presence of
benzylbromide, dibenzylated compound 25 could not be isolated in
a pure form after deprotection and chromatography. Therefore,
dibenzylation was performed stepwise: monobenzylated in-
termediate 10 was isolated prior to the second alkylation step,
leading after benzylation and deprotection to the dibenzylated
derivative 25 in 18% yield from 8.
THP
THP
H
H
N
N
N
N
HCO2NH4, Pd/C
MeOH
N
N
N
H
8
9
R-X, K2CO3
DMF
H
N
10 R = Bn
11 R = Allyl
12 R = -CH2CN
13 R = -(CH2)2-OH
THP
N
H
H
H
THP
THP
HCO2NH4, Pd/C
MeOH
N
H
H
N
N
N
N
N
N
R
N
N
N
H
9
8
AcOH, THF, H2O
AllylBr, K2CO3
DMF, 80 °C
O
H
N
H
H
N
H
N
Allyl
N
Allyl
N
H
H
N
H
N
THP
N
N
H
H
H
H
AcOH, THF, H2O
N
+
N
N
N
R
N
R
H
H
N
Allyl
23 (43%)
N
Allyl
R = Bn
15 (10%)
17 (28%)
19 (0%)
14 (20%)
16 (14%)
18 (0%)
20 (0%)
22
R = Allyl
R = -CH2CN
R = -(CH2)2-OH 21 (38%)
1- HCO2NH4, Pd/C
MeOH
2- BnBr, K2CO3, DMF, rt
Scheme 3. Synthesis of monosubstituted derivatives 14e17 and 21.
H
N
THP
N
H
H
identity of these two products, as well as the cis stereochemistry of
the fused six-membered ring were confirmed by analysis of the 1D
and 2D NMR spectra (1H, 13C, 1He1H COSY, 1He13C HSQC, 1He13C
HMBC, 1He1H NOESY). Monoalkylation was performed in a highly
regioselective manner as only the N-5 alkylated compound was
isolated. The regioselectivity of the alkylation step can be assessed
on the basis of the electronic effect of the pyrazole moiety. It has
been shown that the nucleophilicity of the amino groups of
substituted benzene-1,2-diamines can be differentiated in function
of the electronic effects of the benzene ring substituents.20,21 Thus,
an amino group is activated by the presence of an electron donating
group at para position and/or of an electron withdrawing group at
meta position. Accordingly, the pyrazole ring system directed the
substitution reaction at the N-5 position of intermediates 9.
Unexpectedly, twosideproducts15 and17, inwhichtheTHPgroup
was found positioned at the C-11 carbon atom, were also isolated in
10% and 28% yields from compound 8, respectively (w1:1 mixture of
the two racemic cis-diastereoisomers). Regarding the 2-hydroxyethyl
substituted intermediate 13, the product of THP migration 21 was the
onlycompound isolatedafterdeprotection and chromatography(38%
yield, w1.4:1 mixture of the two racemic cis-diastereoisomers). On
the other hand, due to the degradation of the reaction mixture during
the deprotection step, neither the expected deprotected product 18
nor the THP side product at the C-11 position 19 were obtained from
the cyanomethyl derivative 12. The introduction of a THP group on
a carbon atom as found in compounds 15, 17, and 21 was already
reported by several authors during the THP protection/deprotection
of phenolic derivatives. This reaction leads to the substitution ortho to
the phenolic hydroxyl by a THP group.22e26 To the best of our
knowledge, the present report is the first one to describe this type of
THP C-alkylation for compounds other than phenolic derivatives. In
our case, the alkylation orientation at the C-11 position is probably
due to the presence of the ortho non-substituted amino group at the
10-position of intermediates 10, 11, and 13.
N
8
N
R1
10
BnBr, K2CO3
DMF, 60 °C
Bn
N
Bn
N
H
N
AcOH
THF, H2O
THP
N
N
H
H
H
H
N
N
Bn
N
Bn
25 (18%)
24
Scheme 4. Synthesis of dialkylated compounds 23 and 25.
Contrarily to what was observed for the deprotection of mon-
osubstituted derivatives 10, 11, and 13, the THP migration products
were not observed in the conditions used when the deprotection
was performed from disubstituted intermediates (e.g., 22, 24, and
disubstituted intermediates described below).
Taking advantage of the difference of nucleophilicity of the two
N-5 and N-10 nitrogen atoms, distinct substituents were also in-
troduced. The two alkylations were carried out consecutively after
purification by chromatography of the monosubstituted in-
termediates 10e12 (Scheme 5). After a four-step sequence, com-
pounds 29e31 were isolated in 23%, 31%, and 19% yields,
respectively. We also proceeded in further functionalization
through an additional hydroboration/oxidation sequence per-
formed on allyl precursors 22, 26, and 27. When hydroboration was
performed on the diallyl intermediate 22 obtained during the
preparation of compound 23, no reaction was observed with 9-BBN.
On the other hand, the use borane/THF complex led to a complex
mixture after oxidation and deprotection steps. Conversely,
hydroboration/oxidation of monoallyl intermediates 26 and 27 led
to alcohol derivatives 34 and 35 in 4% and 18% yields, respectively,
after a six-step sequence from starting material 8 (Scheme 5).
Finally, we prepared the non-alkylated analogue 36 (Scheme 6).
Firstly, we attempted to prepare compound 36 by deprotection of
compound 9 bearing a THP group at the N-1 position. Un-
fortunately, these conditions led to a mixture of degradation
products. Therefore, compound 36 was readily prepared in 98%
yield by hydrogenolysis of monobenzylated analogue 14.
We carried on the synthesis of dialkylated derivatives at the N-5
and N-10 nitrogen atoms. A similar reaction procedure as for the
preparation of monosubstituted compounds was performed from
compound 8 (Scheme 4). Diallyl derivative was obtained by heating
a solution of the hydrogenated intermediate 9 in DMF in the
presence of K2CO3 and an excess of allylbromide. After depro-
tection, diallyl derivative 23 was isolated in 43% yield from

1636
L. Gavara et al. / Tetrahedron 67 (2011) 1633e1639
to use. IR spectra were recorded on a Shimadzu FTIR-8400S spec-
H
1- HCO2NH4, Pd/C
MeOH
THP
H
H
trometer (v in cmꢁ1). NMR spectra were performed on a Bruker
N
N
AVANCE 400 (1H: 400 MHz, 13C: 100 MHz), or a Bruker AVANCE 500
N
8
2- R1-X, K2CO3, DMF
(1H: 500 MHz, 13C: 126 MHz); chemical shifts
d are indicated in
N
R1
parts per million and the following abbreviations are used: singlet
(s), doublet (d), triplet (t), doublet of doublet (dd), multiplet (m),
broad signal (br s). High resolution mass spectra (ESIþ) were de-
termined on a high-resolution Micro Q-Tof apparatus (CRMP, Uni-
10 R1 = Bn
11 R1 = Allyl
12 R1 = -CH2CN
R2-X, K2CO3
DMF
ꢀ
versite Blaise Pascal, Clermont-Ferrand, France). GC/MS analyses
were performed on an Agilent 6890N/5973N GC/MSD system using
an Agilent HP-5ms (19091S-433) capillary column (He flow:
0.9 mL/min; injector temperature: 250 ꢀC; temperature gradient:
1 min at 50 ꢀC, 50 ꢀC/min to 300 ꢀC, and 5 min at 300 ꢀC). Chro-
matographic purifications were performed by flash silica gel
Geduran SI 60 (Merck) 0.040e0.063 mm column chromatography.
Reactions were monitored by TLC using fluorescent silica gel plates
(60 F254 from Merck). Melting points were measured on a Reichert
R2
N
R2
N
H
N
AcOH
THF, H2O
THP
H
H
H
H
N
N
N
N
N
R1
R1
29 R1 = Bn, R2 = Allyl (23%)
30 R1 = Allyl, R2 = Bn (31%)
26 R1 = Bn, R2 = Allyl
27 R1 = Allyl, R2 = Bn
28 R1 = -CH2CN, R2 = Bn
31 R1 = -CH2CN, R2 = Bn (19%)
€
microscope or on a Buchi B-540 apparatus and are uncorrected.
from 26 and 27
4.2. Procedure for preparation of compounds 3e8
a) hydroboration
b) oxidation
4.2.1. 1-Benzyl-5,6-dinitro-1H-indazole (3) and 2-benzyl-5,6-dinitro-
2H-indazole (4). To a solution of 5,6-dinitroindazole 2 (500 mg,
2.40 mmol) in THF (5 mL) was added N,N-diisopropylethylamine
(0.5 mL, 2.9 mmol) and benzyl chloride (0.36 mL, 3.1 mmol). The
mixture was refluxed for 48 h. After evaporation under reduced
pressure, the residue was purified by flash chromatography (cy-
clohexane to EtOAc) to give 3 (172 mg, 0.58 mmol, 24%) and 4
(350 mg, 1.17 mmol, 49%) as yellow solids: compound 3,
R2
R2
H
AcOH
THF, H2O
THP
H
H
H
H
N
N
N
N
N
N
N
N
R1
R1
34 R1=Bn, R2=(CH2)3OH (4%)
32 R1=Bn, R2=(CH2)3OH
33 R1=(CH2)3OH, R2=Bn
35 R1=(CH2)3OH, R2=Bn (18%)
Scheme 5. Sequential regioselective alkylation. Synthesis of compounds 29e31, 34,
and 35. Hydroboration/oxidation: from 26, (a) 9-BBN, THF (b) NaBO3$4H2O; from 27,
(a) BH3$THF (b) NaBO3$4H2O.
mp¼158e159 ꢀC; IR (ATR): 1538, 1373, 1343 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): 5.82 (2H, s), 7.30e7.43 (5H, m), 8.60 (1H, s),
8.90 (1H, s), 9.08 (1H, s); 13C NMR (100 MHz, DMSO-d6): 52.5 (CH2),
108.8,121.8,127.7 (2C),127.9,128.7 (2C),137.2 (CHarom),122.9,136.0,
136.3, 138.2, 141.8 (Carom); HRMS (ESIþ) calcd for C14H10N4NaO4
(MþNa)þ 321.0600, found 321.0610.
H
THP
H
H
N
N
AcOH
N
THF, H2O
N
H
Compound 4, mp¼120e122 ꢀC; IR (ATR): 1541, 1524, 1502, 1368,
H
N
H
N
H
H
1362 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 5.84 (2H, s), 7.25e7.39
;
9
(5H, m), 8.58 (1H, s), 8.87 (1H, s), 9.91 (1H, s); 13C NMR (100 MHz,
DMSO-d6): 57.3 (CH2), 116.7, 123.2, 128.26 (2C), 129.29, 128.7 (2C),
130.5 (CHarom), 120.1, 135.6, 136.4, 141.5, 145.7 (Carom); HRMS (ESIþ)
calcd for C14H10N4NaO4 (MþNa)þ 321.0600, found 321.0609.
N
N
H
H
N
H
N
H
H
36
HCO2NH4, Pd/C
N
MeOH
N
Bn
98%
4.2.2. 5,6-Dinitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5) and
5,6-dinitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (6). 3,4-Dihy-
dro-2H-pyran (2 mL, 21.9 mmol) was added to a solution of 5,6-
14
Scheme 6. Synthesis of compound 36.
3. Conclusion
dinitroindazole
2 (3.0 g, 14.4 mmol) and H2SO4 (0.1 mL) in
dichloromethane (35 mL) and the reaction mixture was stirred at
room temperature for 5 days. The solution was evaporated and the
residue was purified by flash chromatography (cyclohexane to
EtOAc) to give 5 (3.9 g, 13.3 mmol, 93%) and 6 (168 mg, 0.57 mmol,
4%) as yellow solids: compound 5, mp 97e98 ꢀC; IR (ATR): 1611,
We have developed a straightforward protocol for the preparation
of an unprecedented series of indazole-5,6-diamine derivatives of high
interest for pharmaceutical research. This ring system was in-
corporated into an octahydropyrazolo[3,4-b]phenazine scaffold and
we showed that nitrogen atoms at the 5- and 10-positions could be
regioselectively substituted. We also described the migration of the
THP protecting group, initially located at the N-1 indazole nitrogen
atom, on a carbon atom during the deprotection step of mono-
substituted derivatives. The synthetic pathway leading to the octahy-
dropyrazolo[3,4-b]phenazine scaffold provides a regio-controlled
access to N-5 and/or N-10 diversely substituted analogues with
potential biological interest.
1538, 1456, 1373, 1351, 1342 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
;
1.56e1.64 (2H, m), 1.67e1.80 (1H, m), 1.98e2.07 (2H, m), 2.30e2.42
(1H, m), 3.77e3.85 (1H, m), 3.87e3.93 (1H, m), 6.08 (1H, d, J¼9 Hz),
8.58 (1H, s), 8.78 (1H, s), 8.87 (1H, s); 13C NMR (100 MHz, DMSO-
d6): 21.9, 24.5, 28.8, 66.7 (CH2), 84.5 (CH), 109.2, 121.7, 136.9
(CHarom), 123.4, 136.3, 138.2, 141.8 (Carom); HRMS (ESIþ) calcd for
C12H12N4NaO5 (MþNa)þ 315.0705, found 315.0708.
Compound 6, mp 130e131 ꢀC; IR (ATR): 1619, 1542, 1520, 1496,
1365, 1352, 1337 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 1.57e1.66
;
4. Experimental section
4.1. General
(2H, m), 1.67e1.81 (1H, m), 1.89e2.00 (1H, m), 2.08e2.19 (2H, m),
3.72e3.82 (1H, m), 3.97e4.05 (1H, m), 5.90e5.98 (1H, m), 8.64 (1H,
s), 8.86 (1H, s), 9.04 (1H, s); 13C NMR (100 MHz, DMSO-d6): 21.2,
24.4, 30.3, 67.1 (CH2), 88.6 (CH), 117.3, 123.8, 129.1 (CHarom), 119.6,
136.7, 141.8, 145.1 (Carom); HRMS (ESIþ) calcd for C12H12N4NaO5
(MþNa)þ 315.0705, found 315.0718.
Starting materials were obtained from commercial suppliers
and used without further purification. Solvents were distilled prior

L. Gavara et al. / Tetrahedron 67 (2011) 1633e1639
1637
4.2.3. 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazole-5,6-diamine
(7). Hydrazine monohydrate (2.6 mL, 2.7 g, 54 mmol) was slowly
added to a mixture of 5 (1.6 g, 5.5 mmol) and 10% Pd/C (850 mg,
0.80 mmol) in methanol (25 mL) at 0 ꢀC. The mixture was refluxed
for 1 h and the catalyst was removed by filtration through a Celite
pad, which was subsequently washed with methanol (30 mL). The
filtrate was evaporated under reduced pressure to give 7 (1.2 g,
5.2 mmol, 94%) as a gray solid. Compound 7 was used directly for
the next step without any further purification: mp 55e56 ꢀC; IR
4.3.1. 5-Benzyl-5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo[4,3-b]
phenazine (14) and 5-benzyl-11-(tetrahydro-2H-pyran-2-yl)-
5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo[4,3-b]phenazine (15). Step
A; step B: Reduction product from step
A (200 mg), K2CO3
(0.96 mmol), BnBr (0.64 mmol), DMF (4 mL), 1 h, rt, flash chroma-
tography provided monoalkylated diastereoisomer mixture
(125 mg); step D: mixture from step B (125 mg), flash chromatog-
raphy provided 14 (42 mg, 0.13 mmol, 20% from 8) and 15 (27 mg,
0.067 mmol, 10% from 8) as green solids: compound 14,
(ATR): 3500e3125, 1640, 1608, 1506, 1489 cmꢁ1
;
1H NMR
mp¼67e68 ꢀC; IR (ATR): 1635, 1495, 1451, 1353, 1315, 1261 cmꢁ1
;
(400 MHz, DMSO-d6): 1.49e1.60 (2H, m), 1.64e1.78 (1H, m),
1.83e1.93 (1H, m),1.96e2.07 (1H, m), 2.29e2.42 (1H, m), 3.58e3.68
(1H, m), 3.82e3.91 (1H, m), 4.37 (2H, br s), 4.91 (2H, br s), 5.47 (1H,
d, J¼9 Hz), 6.66 (1H, s), 6.72 (1H, s), 7.55 (1H, s); 13C NMR (100 MHz,
DMSO-d6): 22.3, 24.9, 28.8, 66.3 (CH2), 84.2 (CH), 92.0, 101.9, 131.3
(CHarom), 116.8, 132.5, 135.5, 138.5 (Carom); HRMS (ESIþ) calcd for
C12H17N4O (MþH)þ 233.1402, found 233.1409.
1H NMR (400 MHz, DMSO-d6): 1.16e1.27 (1H, m), 1.29e1.38 (2H,
m), 1.47e1.59 (2H, m), 1.59e1.71 (2H, m), 1.82e1.92 (1H, m),
3.17e3.24 (1H, m), 3.72 (1H, br s), 4.37 (1H, d, J¼16.5 Hz), 4.42 (1H,
d, J¼16.5 Hz), 5.84 (1H, s), 6.28 (1H, s), 6.48 (1H, s), 7.18e7.24 (1H,
m), 7.28e7.36 (4H, m), 7.43 (1H, s), 11.97 (1H, br s); 13C NMR
(126 MHz, DMSO-d6): 19.2, 24.3, 24.4, 30.4, 53.5 (CH2), 48.4, 57.7
(CH), 89.6, 98.4, 126.5, 126.7 (2C), 128.4 (2C), 131.6 (CHarom), 115.5,
129.9, 135.7, 137.2, 139.5 (Carom); HRMS (ESIþ) calcd for C20H23N4
(MþH)þ 319.1923, found 319.1919.
4.2.4. 6,7,8,9-Tetrahydro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo
[4,3-b]phenazine (8). A solution of diamine 7 (1.6 g, 6.9 mmol) and
1,2-cyclohexanedione (1.15 g, 10.3 mmol) in acetonitrile (10 mL)
was refluxed for 2 h. After evaporation, the residue was purified by
flash chromatography (cyclohexane to EtOAc) to give 8 (1.5 g,
4.9 mmol, 71%) as a yellow solid: mp 147e148 ꢀC; IR (ATR): 1629,
1495, 1437, 1426, 1411, 1396, 1319 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6): 1.57e1.65 (2H, m), 1.73e1.86 (1H, m), 1.94e2.01 (4H, m),
2.01e2.11 (2H, m), 2.42e2.54 (1H, m), 3.05e3.14 (4H, m), 3.78e3.86
(1H, m), 3.88e3.95 (1H, m), 6.01 (1H, d, J¼9.5 Hz), 8.24 (1H, s), 8.44
(1H, s), 8.47 (1H, s); 13C NMR (100 MHz, DMSO-d6): 22.17, 22.21,
22.23, 24.8, 28.8, 32.6, 32.9, 66.5 (CH2), 84.2 (CH), 105.6, 119.3, 134.5
(CHarom), 126.4, 135.3, 138.7, 138.8, 152.9, 155.1 (Carom); HRMS (ESIþ)
calcd for C18H21N4O (MþH)þ 309.1715, found 309.1726.
Compound 15, IR (ATR): 1486, 1457, 1243 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): 1.15e2.02 (14Haþ14Hb, m), 3.15e3.25
(1Haþ1Hb, m), 3.48e3.57 (1Haþ1Hb, m), 3.73e3.82 (1Haþ1Hb, m),
4.08e4.14 (1Haþ1Hb, m), 4.31e4.45 (2Haþ2Hb, m), 4.84e4.94
(1Haþ1Hb, m), 5.23, 5.43 (1Haþ1Hb, 2br s), 6.27, 6.31 (1Haþ1Hb, 2s),
7.19e7.25 (1Haþ1Hb, m), 7.28e7.37 (4Haþ4Hb, m), 7.47 (1Haþ1Hb, s),
11.76, 11.93 (1Haþ1Hb, 2br s); 13C NMR (100 MHz, DMSO-d6): 19.4
(ꢂ2), 23.2 (ꢂ2), 24.0, 24.1 (ꢂ2), 24.3, 25.6, 25.7, 28.9, 29.3, 30.5, 31.2,
54.08, 54.11, 68.4, 68.5 (CH2), 48.6, 49.0, 56.8, 57.4, 75.4, 75.6 (CH),
98.1, 98.3,126.7e126.9 (3Cꢂ2, peaks at 126.7,126.8, and 126.9 ppm),
128.5 (2Cꢂ2), 131.7, 131.9 (CHarom), 103.6, 104.1, 115.4, 115.5, 130.4,
130.6,132.7,133.5,133.7,133.9,139.5 (ꢂ2) (Carom); HRMS (ESIþ) calcd
for C25H31N4O (MþH)þ 403.2498, found 403.2489.
4.3.2. 5-Allyl-5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo[4,3-b]phena-
zine (16) and 5-allyl-11-(tetrahydro-2H-pyran-2-yl)-5,5a,6,7,8,9,9a,
10-octahydro-1H-pyrazolo[4,3-b]phenazine (17). Step A; step B: Re-
duction product from step A (100 mg), K2CO3 (0.42 mmol), AllylBr
(0.32 mmol), DMF (2 mL), 16 h, rt, flash chromatography provided
monoalkylated diastereoisomer mixture (56 mg) and 8 (14 mg,
0.045 mmol); step D: mixture from step B (30 mg), flash chroma-
tography provided 16 (7 mg, 0.026 mmol, 14% from 8) as a black oil
and 17 (18 mg, 0.051 mmol, 28% from 8) as a yellow oil.
4.3. General procedure for preparation of compounds 14e17,
21, 23, 28e31, 34, and 35
Step A: Ammonium formate (4 g, 63 mmol) was added to
a mixture of 8 (1 g, 3.24 mmol) and 10% Pd/C (830 mg, 0.78 mmol)
in methanol (50 mL). The mixture was refluxed for 2 h and the
catalyst was removed by filtration through a Celite pad, which was
subsequently washed with methanol (30 mL). After evaporation of
the filtrate, the intermediate 9 (960 mg) was used directly for the
next step without any further purification.
Step B: To a solution of the residue from step A in DMF was added
potassium carbonate and the corresponding alkyl bromide. At the
end of the reaction time, the mixture was diluted by addition of
EtOAc (20 mL). The organic layer was washed with water
(4ꢂ30 mL), dried over MgSO4, and evaporated. The resulting dark-
brown oil was purified by flash chromatography (cyclohexane to
EtOAc).
Step C: To a solution of the monoalkylated diastereoisomer
mixture from step B in DMF (2 mL) was added potassium carbonate
and the corresponding alkyl bromide. The mixture was stirred for
16 h at 60 ꢀC and then diluted by addition of EtOAc (20 mL). The
organic layer was washed with water (4ꢂ30 mL), dried over MgSO4,
and evaporated. The resulting dark-brown oil was purified by flash
chromatography (cyclohexane to EtOAc).
Step D: The residue from step B or from step C was solubilized in
a 4:2:1 acetic acid/THF/water mixture (7 mL) and the solution was
heated overnight at 60 ꢀC. EtOAc (30 mL) was added and then
a saturated aqueous NaHCO3 solution (40 mL) was added. The
aqueous layer was extracted with ethyl acetate (30 mL) and the
combined organic fractions were dried over MgSO4 and evaporated.
The resulting yellow oil was purified by flash chromatography
(cyclohexane to EtOAc).
Compound 16, IR (ATR): 1638, 1496, 1456, 1445 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): 1.16e1.37 (3H, m), 1.44e1.69 (4H, m),
1.81e1.89 (1H, m), 3.11e3.17 (1H, m), 3.54e3.59 (1H, m), 3.75 (1H,
dd, J¼16.5, 5.5 Hz), 3.87 (1H, dd, J¼16.5, 5 Hz), 5.14 (1H, dd, J¼10.5,
1.5 Hz), 5.26 (1H, dd, J¼17, 1.5 Hz), 5.75 (1H, s), 5.83e5.94 (1H, m),
6.45 (1H, s), 6.47 (1H, s), 7.52 (1H, s), 11.97 (1H, br s); 13C NMR
(100 MHz, DMSO-d6): 19.2, 24.2, 24.4, 30.4, 52.3 (CH2), 48.3, 56.7
(CH), 89.6, 98.2, 131.6, 135.6 (]CH), 115.7, 115.8, 129.9, 135.7, 137.2
(]CH2,Carom); HRMS (ESIþ) calcd for C16H21N4 (MþH)þ 269.1766,
found 269.1773.
Compound 17, IR (ATR): 1486, 1261 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6): 1.15e1.99 (14Haþ14Hb, m), 3.11e3.19 (1Haþ1Hb, m),
3.47e3.57 (1Haþ1Hb, m), 3.58e3.67 (1Haþ1Hb, m), 3.69e3.79
(1Haþ1Hb, m), 3.81e3.91 (1Haþ1Hb, m), 4.06e4.14 (1Haþ1Hb, m),
4.84e4.92 (1Haþ1Hb, m), 5.15 (1Haþ1Hb, d, J¼10 Hz), 5.19, 5.40
(1Haþ1Hb, 2s), 5.28 (1Haþ1Hb, d, J¼17 Hz), 5.83e5.95 (1Haþ1Hb,
m), 6.43, 6.45 (1Haþ1Hb, 2s), 7.56 (1Haþ1Hb, s), 11.77, 11.94
(1Haþ1Hb, 2br s); 13C NMR (100 MHz, DMSO-d6): 19.35, 19.39, 23.1
(2ꢂ), 23.96, 24.00, 24.1, 24.2, 25.4, 25.6, 28.9, 29.2, 30.4, 31.1, 52.6,
52.7, 68.28, 68.34 (CH2), 48.4, 48.9, 55.7, 56.2, 75.2, 75.5 (CH), 97.8,
98.0, 131.6, 131.8, 135.6, 135.7 (]CH), 103.5, 104.0, 115.5, 115.6,
115.9, 116.0, 130.3, 130.4, 132.5, 133.3, 133.5, 133.7 (]CH2, Carom);
HRMS (ESIþ) calcd for C21H29N4O (MþH)þ 353.2341, found
353.2357.

1638
L. Gavara et al. / Tetrahedron 67 (2011) 1633e1639
4.3.3. 2-[11-(Tetrahydro-2H-pyran-2-yl)-6,7,8,9,9a,10-hexahydro-
1H-pyrazolo[4,3-b]phenazin-5(5aH)-yl]ethanol (21). Step A; step B:
Reduction product from step A (70 mg), K2CO3 (0.90 mmol), 2-
bromoethanol (1.12 mmol), DMF (2 mL), 2 h, 120 ꢀC, flash chroma-
tography provided monoalkylated diastereoisomer mixture
(44 mg); step D: mixture from step B (30 mg), flash chromatogra-
phy provided 19 (22 mg, 0.062 mmol, 38% from 8) as a yellow oil: IR
(ATR): 3475, 1626, 1488, 1451 cmꢁ1; 1H NMR (400 MHz, DMSO-d6),
Ha major diastereoisomer, Hb minor diastereoisomer: 1.14e1.98
(14Haþ14Hb, m), 3.10e3.22 (2Haþ2Hb, m), 3.26e3.38 (1Haþ1Hb,
m), 3.47e3.65 (4Haþ4Hb, m), 4.06e4.14 (1Haþ1Hb, m), 4.64
(1Haþ1Hb, t, J¼5.5 Hz), 4.83e4.92 (1Haþ1Hb, m), 5.16 (1Ha, br s),
5.34 (1Hb, br s), 6.47 (1Hb, s), 6.49 (1Ha, s), 7.57 (1Haþ1Hb, s), 11.77
(1Ha, br s), 11.91 (1Hb, br s); 13C NMR (126 MHz, DMSO-d6): 19.30,
19.34, 23.1 (ꢂ2), 24.1, 24.3, 24.5 (ꢂ2), 25.4, 25.5, 28.8, 29.2, 30.3,
31.1, 53.0 (ꢂ2), 58.1 (ꢂ2), 68.28, 68.33 (CH2), 48.1, 48.5, 56.6, 57.1,
75.3, 75.4 (CH), 96.7, 96.9, 131.5, 131.8 (CHarom), 103.6, 104.0, 115.6,
115.7, 130.3, 130.5, 132.4, 133.2, 133.1e133.4 (1Cꢂ2) (Carom); HRMS
(ESIþ) calcd for C20H29N4O2 (MþH)þ 357.2291, found 357.2303.
7.19e7.24 (1H, m), 7.29e7.36 (4H, m), 7.48 (1H, s), 12.12 (1H, br s);
13C NMR (126 MHz, DMSO-d6): 21.5, 22.2, 25.9, 27.5, 51.3, 52.8
(CH2), 56.3, 56.6 (CH), 89.8, 99.4, 126.5, 126.7 (2C), 128.4 (2C),
131.6, 134.9 (]CH), 115.2, 116.1, 132.4, 136.0, 137.8, 139.5 (]CH2,
Carom); HRMS (ESIþ) calcd for C23H27N4 (MþH)þ 359.2236, found
359.2227.
4.3.7. 5-Allyl-10-benzyl-5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo
[4,3-b]phenazine (30). Steps A and B as for the preparation of
compound 16; step C: mixture from step B (84 mg), K2CO3
(0.48 mmol), BnBr (0.71 mmol), flash chromatography provided
dialkylated diastereoisomer mixture (93 mg); step D: mixture from
step
0.084 mmol, 31% from 8) as a black oil: IR (ATR): 1636, 1495,
1451 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 1.21e1.37 (2H, m),
C (50 mg), flash chromatography provided 30 (30 mg,
;
1.44e1.60 (3H, m), 1.60e1.76 (2H, m), 1.85e1.95 (1H, m), 3.50e3.56
(2H, m), 3.71e3.79 (1H, m), 4.07e4.15 (1H, m), 4.47 (1H, d, J¼17 Hz),
4.59 (1H, d, J¼17 Hz), 5.20 (1H, d, J¼10 Hz), 5.32 (1H, d, J¼17.5 Hz),
5.89e6.00 (1H, m), 6.23 (1H, s), 6.68 (1H, s), 7.19e7.25 (1H, m),
7.29e7.37 (4H, m), 7.57 (1H, s), 12.01 (1H, br s); 13C NMR (100 MHz,
DMSO-d6): 21.2, 22.5, 26.7, 26.9, 50.6, 53.0 (CH2), 54.7, 58.0 (CH),
89.7, 99.6, 126.4 (2C), 126.5, 128.4 (2C), 131.6, 135.1 (]CH), 115.4,
116.3, 132.5, 135.9, 137.4, 138.9 (]CH2,Carom); HRMS (ESIþ) calcd for
C23H27N4 (MþH)þ 359.2236, found 359.2220.
4.3.4. 5,10-Diallyl-5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo[4,3-b]
phenazine (23). Step A; step B: Reduction product from step A
(100 mg), K2CO3 (0.67 mmol), AllylBr (1.28 mmol), DMF (2 mL),
16 h, 80 ꢀC, flash chromatography provided dialkylated di-
astereoisomer mixture (77 mg); step D: mixture from step B
(55 mg), flash chromatography provided 23 (32 mg, 0.104 mmol,
4.3.8. 10-Benzyl-6,7,8,9,9a,10-hexahydro-1H-pyrazolo[4,3-b]phena-
zin-5(5aH)-ylacetonitrile (31). Step A; step B: compound from step A
(100 mg), K2CO3 (0.48 mmol), bromoacetonitrile (1.28 mmol), DMF
(2 mL), 24 h, rt, flash chromatography provided monoalkylated
diastereoisomer mixture (83 mg); step C: mixture from step B
(60 mg), K2CO3 (0.34 mmol), BnBr (0.51 mmol), flash chromatog-
raphy provided dialkylated diastereoisomer mixture (43 mg); step
D: mixture from step C (42 mg), flash chromatography provided 31
(16 mg, 0.045 mmol, 19% from 8) as a yellow oil: IR (ATR): 1637,
1496, 1452 cmꢁ1; 1H NMR (400 MHz, DMSO-d6): 1.21e1.46 (3H, m),
1.56e1.80 (4H, m), 2.07e2.16 (1H, m), 3.40e3.45 (1H, m), 3.53e3.60
(1H, m), 4.39 (1H, d, J¼18.5 Hz), 4.56 (2H, s), 4.69 (1H, d, J¼18.5 Hz),
6.23 (1H, s), 6.99 (1H, s), 7.20e7.26 (1H, m), 7.28e7.37 (4H, m), 7.68
(1H, s), 12.14 (1H, br s); 13C NMR (100 MHz, DMSO-d6): 20.2, 23.1,
26.7, 27.0, 35.9, 52.8 (CH2), 54.2, 58.6 (CH), 89.4, 101.5, 126.3 (2C),
126.6, 128.5 (2C), 132.0 (CHarom), 114.7, 117.2, 130.2, 136.9, 137.1,
138.5 (CN, Carom); HRMS (ESIþ) calcd for C22H24N5 (MþH)þ
358.2032, found 358.2043.
43% from 8) as a yellow oil: IR (ATR): 3350e3100, 1636, 1496 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6): 1.26e1.36 (2H, m), 1.47e1.63 (4H,
m), 1.69e1.80 (2H, m), 3.35e3.40 (1H, m), 3.42e3.47 (1H, m),
3.66e3.75 (1H, m), 3.78e3.87 (1H, m), 4.08e5.98 (2H, m),
5.15e5.21 (2H, m), 5.23e5.32 (2H, m), 5.86e5.97 (2H, m), 6.41 (1H,
s), 6.62 (1H, s), 7.57 (1H, s), 12.10 (1H, br s); 13C NMR (100 MHz,
DMSO-d6): 21.6, 22.0, 26.4, 27.0, 50.8, 51.5 (CH2), 55.1, 56.7 (CH),
89.5, 99.4, 131.6, 134.8, 135.1 (]CH), 115.3, 116.0, 116.3, 132.3, 136.1,
137.5 (]CH2, Carom); HRMS (ESIþ) calcd for C19H25N4 (MþH)þ
309.2079, found 309.2068.
4.3.5. 5,10-Dibenzyl-5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo[4,3-b]
phenazine (25). Steps A and B as for the preparation of compound
14; step C: mixture from step B (200 mg), K2CO3 (1.49 mmol), BnBr
(1.24 mmol), flash chromatography provided dialkylated di-
astereoisomer mixture (220 mg); step D: mixture from step C
(220 mg), flash chromatography provided 25 (80 mg, 0.20 mmol,
18% from 8) as a white solid: mp¼77e78 ꢀC; IR (ATR): 1635, 1494,
1451 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6): 1.20e1.32 (2H, m),
4.3.9. 3-[5-Benzyl-5a,6,7,8,9,9a-hexahydro-1H-pyrazolo[4,3-b]phe-
nazin-10(5H)-yl]propanol (34). Steps A, B, and C as for the prepa-
ration of compound 29. A solution of 9-BBN in THF (0.5 M,
2.26 mL, 1.13 mmol) was added to the mixture obtained from step
1.44e1.55 (2H, m), 1.55e1.68 (2H, m), 1.75e1.89 (2H, m), 3.56e3.61
(1H, m), 3.64e3.70 (1H, m), 4.35 (1H, d, J¼17 Hz), 4.50 (1H, d,
J¼17 Hz), 4.62e4.70 (2H, m), 6.31 (1H, s), 6.51 (s, 1H), 7.19e7.26 (2H,
m), 7.31e7.40 (8H, m), 7.48 (1H, s),12.02 (1H, s); 13C NMR (100 MHz,
DMSO-d6): 21.8, 22.0, 26.5, 27.1, 52.7, 52.9 (CH2), 56.3, 57.7 (CH),
90.1, 99.7, 126.47 (3C), 126.53, 126.7 (2C), 128.38 (2C), 128.44 (2C),
131.6 (CHarom), 115.4, 132.7, 135.9, 137.7, 139.1, 139.6 (Carom); HRMS
(ESIþ) calcd for C27H29N4 (MþH)þ 409.2392, found 409.2396.
C
(100 mg). The solution was refluxed for 3 h and then
NaBO3$4H2O (185 mg, 1.20 mmol) was added. After 4 h at room
temperature, the mixture was evaporated under reduced pres-
sure, water (10 mL) was added and, the mixture was extracted
with EtOAc (2ꢂ20 mL). The combined organic fractions were dried
over MgSO4 and evaporated. The residue was purified by flash
chromatography (cyclohexane to EtOAc) to give the intermediate
mixture (28 mg) as an oil; step D: mixture from hydroboration/
oxidation step (28 mg), flash chromatography provided 34 (12 mg,
0.032 mmol, 4% from 8) as a green oil: IR (ATR): 3450e3125, 1610,
4.3.6. 10-Allyl-5-benzyl-5,5a,6,7,8,9,9a,10-octahydro-1H-pyrazolo
[4,3-b]phenazine (29). Steps A and B as for the preparation of
compound 14; step C: mixture from step B (100 mg), K2CO3
(0.50 mmol), AllylBr (0.75 mmol), flash chromatography provided
dialkylated diastereoisomer mixture (68 mg); step D: mixture
from step C (60 mg), flash chromatography provided 29 (40 mg,
0.11 mmol, 23% from 8) as a green oil: IR (ATR): 3350e3100, 1636,
1496, 1451 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 1.19e1.29 (1H,
;
m), 1.29e1.40 (1H, m), 1.43e1.62 (4H, m), 1.62e1.72 (1H, m),
1.72e1.81 (2H, m), 1.85e1.94 (1H, m), 3.22e3.56 (6H, m), 4.29 (1H,
d, J¼17 Hz), 4.57 (1H, d, J¼17 Hz), 4.61 (1H, t, J¼5 Hz), 6.44 (1H, s),
6.51 (1H, s), 7.18e7.24 (1H, m), 7.29e7.36 (4H, m), 7.47 (1H, s),
12.09 (1H, br s); 13C NMR (100 MHz, DMSO-d6): 21.7, 21.9, 26.3,
27.1, 29.0, 45.0, 52.8, 58.6 (CH2), 56.0, 56.2 (CH), 88.8, 99.4, 126.4,
126.7 (2C), 128.3 (2C), 131.6 (CHarom), 114.9, 132.6, 136.2, 137.3,
1494, 1451 cmꢁ1 1H NMR (500 MHz, DMSO-d6): 1.20e1.35 (2H,
;
m), 1.46e1.71 (5H, m), 1.84e1.93 (1H, m), 3.40e3.45 (1H, m),
3.56e3.61 (1H, m), 3.82e3.88 (1H, m), 4.06e4.13 (1H, m), 4.30
(1H, d, J¼17 Hz), 4.57 (1H, d, J¼17 Hz), 5.22 (1H, d, J¼10.5 Hz), 5.30
(1H, d, J¼17 Hz), 5.90e6.00 (1H, m), 6.44 (1H, s), 6.47 (1H, s),

L. Gavara et al. / Tetrahedron 67 (2011) 1633e1639
1639
139.6 (Carom); HRMS (ESIþ) calcd for C23H29N4O (MþH)þ 377.2341,
(Carom); HRMS (ESIþ) calcd for C13H17N4 (MþH)þ 229.1453, found
found 377.2339.
229.1456.
4.3.10. 3-[10-Benzyl-6,7,8,9,9a,10-hexahydro-1H-pyrazolo[4,3-b]
phenazin-5(5aH)-yl]propanol (35). Steps A, B, and C as for the
preparation of compound 30. A solution of BH3 in THF (1 M, 1.0 mL,
1.0 mmol) was added to the mixture obtained from step C (30 mg).
The solution was stirred at room temperature for 1 h and a solution
of NaBO3$4H2O (209 mg, 1.36 mmol) in water (1 mL) was added.
After 4 h at room temperature, the mixture was evaporated under
reduced pressure, water (10 mL) was added, and the mixture was
extracted with EtOAc (2ꢂ20 mL). The combined organic fractions
were dried over MgSO4 and evaporated. The residue was purified
by flash chromatography (cyclohexane to EtOAc) to give the in-
termediate mixture (22 mg) as an oil; step D: mixture from
hydroboration/oxidation step (22 mg), flash chromatography pro-
vided 35 (11 mg, 0.029 mmol, 18% from 8) as a green oil: IR (ATR):
Acknowledgements
ꢁ
ꢀ
The French Ministere de l’Enseignement Superieur et de la
Recherche (E.S.), the ANR (ANR-08-JCJC-0131-CSD 3) (L.G.) are
greatly acknowledged for financial support. The authors are
ꢀ
grateful to Bertrand Legeret for mass spectra analysis.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.01.010.
References and notes
3500e3000, 1506, 1496, 1490, 1261 cmꢁ1 1H NMR (500 MHz,
;
1. Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem. 2008, 4073.
2. Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; de Ocariz, C. O. Mini-Rev. Med.
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3. Henderson, J. L.; Buchwald, S. L. Org. Lett. 2010, 12, 4442.
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Chem. 2010, 45, 5520.
ꢀ
ꢀ
DMSO-d6): 1.21e1.29 (1H, m), 1.32e1.39 (1H, m), 1.44e1.58 (3H, m),
1.58e1.79 (4H, m), 1.87e1.95 (1H, m), 3.17e3.23 (1H, m), 3.43e3.55
(5H, m), 4.46 (1H, d, J¼17.5 Hz), 4.57 (1H, t, J¼5 Hz), 4.58 (1H, d,
J¼17.5 Hz), 6.22 (1H, s), 6.71 (1H, s), 7.19e7.24 (1H, m), 7.29e7.35
(4H, m), 7.57 (1H, s), 11.99 (1H, br s); 13C NMR (100 MHz, DMSO-d6):
21.4, 22.3, 26.6, 26.9, 28.3, 44.5, 53.0, 58.8 (CH2), 54.6, 57.7 (CH),
89.7, 98.7, 126.4 (2C), 126.5, 128.4 (2C), 131.6 (CHarom), 115.5, 132.2,
135.7, 137.6, 139.0 (Carom); HRMS (ESIþ) calcd for C23H29N4O
(MþH)þ 377.2341, found 377.2350.
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4.4.1. 5,5a,6,7,8,9,9a,10-Octahydro-1H-pyrazolo[4,3-b]phenazine
(36). Ammonium formate (117 mg, 1.86 mmol) was added to
a mixture of 14 (40 mg, 0.126 mmol) and 10% Pd/C (16 mg, 15 mmol)
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in methanol (5 mL). The mixture was refluxed for 1 h and the cat-
alyst was removed by filtration through a Celite pad, which was
subsequently washed with methanol (20 mL). After evaporation of
the filtrate, the residue was purified by flash chromatography (cy-
clohexane to EtOAc) to give 36 (28 mg, 0.123 mmol, 98%) as a gray
solid: mp 215e217 ꢀC; IR (ATR): 3400e3050, 1639, 1497, 1442,
1425 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 1.21e1.37 (2H, m),
;
1.46e1.73 (6H, m), 3.24 (1H, br s), 3.30e3.35 (1H, br s), 5.16 (1H, br
s), 5.76 (1H, br s), 6.36 (1H, s), 6.51 (1H, s), 7.47 (1H, s), 11.91 (1H, br
s); 13C NMR (100 MHz, DMSO-d6): 21.7, 21.8, 29.6, 30.0 (CH2), 48.8,
49.3 (CH), 89.5, 99.4, 131.1 (CHarom), 115.3, 130.3, 135.9, 136.1
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25. Kometani, T.; Kondo, H.; Fujimori, Y. Synthesis 1988, 1005.
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