Asymmetric Synthesis of Fused Polycyclic Indazoles through Aminocatalyzed Aza-Michael Addition/Intramolecular Cyclization

Article abstract of DOI:10.1021/acs.joc.6b01201

The first example of an asymmetric aminocatalyzed aza-Michael addition of 1H-indazole derivatives to α,β-unsaturated aldehydes is described. The iminium/enamine cascade process lies at the heart of our strategy, leading to enantioenriched fused polycyclic indazole architectures. Variations on both the α,β-unsaturated aldehydes and the indazole-7-carbaldehyde heterocycles were studied in order to broaden the scope of the transformation in synthetically interesting directions. The fused polycyclic indazoles exhibit fluorescence properties and can undergo synthetic transformations.

Full text of DOI:10.1021/acs.joc.6b01201

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Note
Asymmetric Synthesis of Fused Polycyclic Indazoles through
Aminocatalyzed Aza-Michael Addition / Intramolecular Cyclization
Maxime Giardinetti, Jerome Marrot, Xavier Moreau, Vincent Coeffard, and Christine Greck
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01201 • Publication Date (Web): 05 Jul 2016
Downloaded from http://pubs.acs.org on July 6, 2016
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Asymmetric Synthesis of Fused Polycyclic Indazoles through
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Aminocatalyzed Aza-Michael Addition
Cyclization
/
Intramolecular
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Maxime Giardinetti, Jérôme Marrot, Xavier Moreau,* Vincent Coeffard,* Christine Greck
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles-St-Quentin-en-Yvelines, 45
Avenue des États-Unis, 78035 Versailles cedex, France.
xavier.moreau@uvsq.fr; vincent.coeffard@uvsq.fr.
TOC Graphic
Abstract
The first example of an asymmetric aminocatalyzed azaꢀMichael addition of 1Hꢀindazole
derivatives to α,βꢀunsaturated aldehydes is described. The iminium/enamine cascade process
lies at the heart of our strategy leading to enantioenriched fused polycyclic indazole
architectures. Variations both on the α,βꢀunsaturated aldehydes and the indazoleꢀ7ꢀ
carbaldehyde heterocycles were studied in order to broaden the scope of the transformation in
synthetically interesting directions. The fused polycyclic indazoles exhibit fluorescence
properties and can undergo synthetic transformations.
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The decoration of nitrogenꢀcontaining aromatic systems is of utmost importance in synthetic
chemistry due to the ubiquity of these architectures in biologically relevant compounds.
Amongst the reactions available in the chemist’s toolbox, the azaꢀMichael addition has
become an established method for the selective functionalization of the nitrogen atom.1 In
particular, the development of asymmetric organocatalysis over the past decades has fueled
the synthetic possibilities of azaꢀMichael additions by providing a vast number of
combinations between nitrogenꢀcontaining heteroaromatic systems and Michael acceptors.2 In
recent years, the field of asymmetric aminocatalyzed azaꢀMichael addition to α,βꢀunsaturated
carbonyl compounds has grown at a rapid pace to include numerous nitrogenated
heteroaromatic compounds such as benzotriazole,3 benzimidazole,3a imidazole,3a,3d,4 indole,5
purine bases,6 pyrazole,3a,7 pyrrole,8 tetrazole3 or triazole.3a,3c,9 To the best of our knowledge,
1Hꢀindazole has never been investigated in organocatalyzed asymmetric azaꢀMichael addition
with α,βꢀunsaturated carbonyl compounds while this reaction could lead to interesting motifs.
For example, Nꢀsubstituted indazoles are found in AG035029 which exhibits antidiabetic
effects10 and the tetracyclic compound KWꢀ2170, a DNA intercalating antitumor agent.11
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Figure 1. Selected examples of biorelevant N-substituted indazoles
Considering the nonꢀasymmetric version, a scant number of metalꢀfree synthetic methods
have been reported in literature for promoting azaꢀMichael addition of 1Hꢀindazoles to α,βꢀ
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unsaturated carbonyl compounds. For instance, P. Goya and coꢀworkers showed that
1Hꢀindazole derivatives undergo Nꢀalkylation with acrylamide under basic conditions.12 The
use of different bases (e.g. DBU, Cs2CO3, tBuOK) also turned out to be suitable conditions for
the azaꢀMichael addition with alkyl acrylate13 or enones.14,15 Because of the lack of an
organocatalytic method allowing the asymmetric azaꢀMichael addition of 1Hꢀindazole to α,βꢀ
unsaturated carbonyl compounds, we decided to explore an aminocatalytic strategy to tackle
this challenge. This approach will take advantage of the ability of chiral secondary amines 3
to condense with enals 2 affording chiral reactive iminium species which could undergo a
stereoselective nucleophilic addition (Scheme 1). In light of our continuing interest in the
preparation of enantioenriched polycyclic architectures,5d,16 we surmised that 1Hꢀindazoleꢀ7ꢀ
carbaldehyde motifs 1 could act as suitable starting materials to generate enantioenriched
fused polycyclic indazoles 4 through an iminiumꢀenamine process involving an azaꢀMichael
addition followed by an intramolecular cyclization / dehydration sequence.17 This strategy
will pave the way to the enantioselective preparation of functionalized 1,7ꢀannulated indazole
which is the core framework of the antiꢀtumor agent KWꢀ2170 (Figure 1).
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Scheme 1. Synthetic strategies for aza-Michael addition of 1H-indazoles
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The study started with the optimization of the reaction conditions using 1Hꢀindazoleꢀ7ꢀ
carbaldehyde 1a and transꢀcinnamaldehyde 2a as substrates. The reaction was promoted by
an aminocatalyst 3 and a base which are known to be a good combination to promote azaꢀ
Michael addition (Table 1).5d
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Table 1. Optimization of reaction conditionsa
Entry
Solvent
Time, T °C
Yield (%)
Ee (%)b
3
1
CHCl3
24 h, 55 °C
40 h, 55 °C
88 h, RT
90
98
55
55
94
85
n.r.
54
78
94
82
80
77
54
86
86
n.d.
ꢀ7
3a
3a
3a
3a
3a
3b
3c
3d
3a
3a
2
CHCl3
3
CHCl3
4
MeCN
24 h, 55 °C
24 h, 55 °C
24 h, 55 °C
24 h, 55 °C
24 h, 55 °C
24 h, 55 °C
24 h, 55 °C
5
1,2ꢀDCE
1,2ꢀDCE
1,2ꢀDCE
1,2ꢀDCE
1,2ꢀDCE
1,2ꢀDCE
6
7
8c
9d
61
72
10e
a
Reactions were performed on a 0.2 mmol scale using 1 equiv of 1a, 1.5 equiv of 2a, 1.1 equiv of AcONa, 15
b
mol% of 3 unless otherwise noted; n. r., no reaction; n.d., not determined. Enantiomeric excesses were
c
measured by chiral HPLC. In this case, the reaction was performed with 20 mol% of 3d and 20 mol% of HCl
added in the reaction mixture from a hydrogen chloride solution 4 N in dioxane.d 15 mol% of benzoic acid was
used instead of 1.1 equiv of AcONa. e No AcONa was added to the reaction mixture.
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The reaction of 1Hꢀindazoleꢀ7ꢀcarbaldehyde 1a with transꢀcinnamaldehyde 2a in the presence
of the aminocatalyst 3a led to the product 4aa in 90% yield and 82% ee determined by chiral
HPLC (entry 1).18 Extending the reaction time to 40 h slightly improved the yield of 4aa
(98%) while the enantiomeric excess was 80% (entry 2). We surmised that decreasing the
reaction temperature could improve the enantioselectivity (entry 3). Nevertheless, the desired
compound 4aa was obtained in 55% yield and 77% ee by performing the reaction at room
temperature for 88 h. Switching from chloroform to acetonitrile as a reaction solvent resulted
in a dramatic decrease of both the yield and the enantioselection (entry 4). Better results were
obtained by running the reaction in 1,2ꢀdichloroethane (entry 5). Under these conditions, the
product 4aa was produced in 94% yield and 86% ee. The influence of the aminocatalyst
structure was then investigated (entries 6ꢀ8). The use of the catalyst 3b possessing a bulkier
silyl group led to the desired product 4aa with the same enantiomeric excess as with 3a but a
lower yield (85%, entry 6). No reaction occurred by using the (CF3)2C6H3ꢀderived catalyst 3c
and a low enantiomeric excess was obtained for 4aa using the MacMillan imidazolidinone
organocatalyst 3d (entries 7 and 8). The influence of sodium acetate was studied by
performing the reaction under acidic and neutral conditions (entries 9 and 10). The use of 15
mol% of benzoic acid in conjunction with 15 mol% of 3a had a negative impact on the level
of the enantioselection (61% ee, entry 9 compared to 86% ee, entry 5). The reaction carried
out without sodium acetate followed the same trend by producing 4aa in 94% yield but 72%
ee (entry 10).
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Having established the best reaction conditions (entry 5, Table 1), the scope and limitations of
the methodology were then explored on various 1Hꢀindazoleꢀ7ꢀcarbaldehyde analogues 1 and
α,βꢀunsaturated aldehydes 2 (Table 2).
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Table 2. Scope and limitationsa
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Entry R1, R2
R3
Yield (%) Ee (%)b
4
1
H, H (1a)
Ph (2a)
4aa
4ab
4ac
4ad
4ae
4af
94
96
91
93
90
90
62
78
92
99
88
33
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84
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86
79
69
60
73
84
71
88
79
59
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79
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2
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, H (1a)
H, I (1b)
4ꢀMeC6H4 (2b)
4ꢀClC6H4 (2c)
3ꢀClC6H4 (2d)
4ꢀMeOC6H4 (2e)
3ꢀMeOC6H4 (2f)
2ꢀMeOC6H4 (2g)
4ꢀNO2C6H4 (2h)
2ꢀNO2C6H4 (2i)
2ꢀnaphthyl (2j)
2ꢀthienyl (2k)
Me (2l)
3
4
5
6
7
4ag
4ah
4ai
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4aj
4ak
4al
Ph (2a)
4ba
4ca
4da
4dc
5ꢀCl, H (1c)
Ph (2a)
4ꢀMe, H (1d) Ph (2a)
16
4ꢀMe, H (1d) 4ꢀClC6H4 (2c)
a
Reactions were performed on a 0.2 mmol scale using 1 equiv of 1, 1.5 equiv of 2, 1.1 equiv of AcONa, 15
mol% of 3a at 55 °C for 24 h in 1,2ꢀdichloroethane. b Enantiomeric excesses were measured by chiral HPLC.
The influence of the aromatic substitution pattern of the aldehydes 2 on the levels of yields
and enantiomeric excesses was first investigated (entries 1ꢀ12). The reaction works well
regardless of the introduction of electronꢀdonating or electronꢀwithdrawing substituents on the
aromatic ring of the α,βꢀunsaturated aldehydes 2. The opposite enantiomeric form of 4 can be
obtained starting from the catalyst entꢀ3a with a R configuration. For instance, the reaction of
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1a with the aldehyde 2c catalyzed by entꢀ3a produced the product entꢀ4ac in 80% yield and
69% ee. The use of crotonaldehyde 2l had a negative impact on the yield and 4al was
produced in 33% yield and 55% ee (entry 12). It is also important to demonstrate the scope of
the methodology by testing diversely substituted 1Hꢀindazoleꢀ7ꢀcarbaldehyde analogues 1
(entries 13ꢀ16). Good results were obtained regardless of the substituents introduced on the
aromatic indazole ring. At this stage, a crystallographic structure for 4ba was obtained
confirming the structure of the final product.19
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The fused polcyclic indazoles 4 contain an aldehydic function which could undergo various
synthetic transformations paving the way towards new analogues. For instance, the reaction of
4dc with methyl (triphenylphosphoranylidene)acetate in toluene produced the ester 5 in 96%
yield while the reductive amination of 4dc in the presence of benzylamine and NaBH(OAc)3
produced the amineꢀderived compound 6 in 53% yield (Scheme 2)
Scheme 2. Transformations of the product 4dc
Like their indole cousins,5d the fused tricyclic indazoles 4 exhibit fluorescent properties
(Figure 2). For example, the compound 4dc presents a maximum of absorption at 396 nm and
the fluorescence spectrum recorded at this wavelength exhibits a maximum at 474 nm.
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Figure 2. Absorption and fluorescence spectra of 4dc in CHCl3 (1 x 10-5 M).
Based on previous works and the above results,5d a plausible catalytic cycle is depicted in
Scheme 3 to explain the asymmetric synthesis of fused polycyclic indazoles 4.
R2
OTMS
Ph
H
H2O
N
R1
N
2
N
Ph
4
3a
R3
HO
R3
E
CHO
H2O
OTMS
Ph
N
R2
N
Ph
R1
A
N
R3
1
O
R2
N
N
OTMS
Ph
R1
N
H
R2
Ph
D
CHO
N
R3
R1
N
N
R3
OTMS
CHO
N
Ph
Ph
Base
B
C
OTMS
Ph
BaseH
Ph
Scheme 3. Proposed reaction mechanism
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The enal 2 would react with the aminocatalyst 3a to produce the iminium A. AzaꢀMichael
addition of the indazole 1 onto this intermediate from the less hindered top face would afford
the intermediate B. It is worthwhile noting that no reaction takes place by reacting the indoles
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1 with α,βꢀunsaturated aldehydes 2 in the presence of AcONa for 24 h at 55 °C. Therefore,
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the iminium activated species A is required to ensure the smooth formation of 4. The
intermediate B would then undergo a deprotonation reaction in the presence of a base (HOꢀ or
AcOꢀ) to produce the
Nꢀalkylated indazole C. The intramolecular cyclization of C would
afford D through an intramolecular aldol reaction. The hydrolysis of D would release the
catalyst 3a and the aldol product E which would then undergo a dehydration reaction to give
rise to the desired target 4.
In summary, we have reported a novel approach for the asymmetric organocatalyzed
N
ꢀalkylation of 1Hꢀindazole derivatives with α,βꢀunsaturated aldehydes. Starting from readily
available 1Hꢀindazoleꢀ7ꢀcarbaldehyde substrates, an iminiumꢀenamine cascade process
enables the enantioselective formation of fused tricyclic indazole derivatives through an azaꢀ
Michael addition / intramolecular cyclization.
α,βꢀUnsaturated aldehydes bearing aromatic,
heteroaromatic or alkyl groups and variations on the indazole framework were tolerated
giving rise to 16 examples of 1,7ꢀannulated indazoles with ees of up to 88% and moderateꢀtoꢀ
excellent yields. Besides fluorescent characteristics, the products can undergo synthetic
transformations to form new analogues.
EXPERIMENTAL SECTION
1
General Experimental Methods. H NMR (200 or 300 MHz) and 13C (50 or 75 MHz)
spectra were recorded with 200 or 300 MHz spectrometers in chloroformꢀd or DMSOꢀd6 with
the residual solvent peak as an internal standard. Chemical shifts (δ) are given in parts per
million and coupling constants are given as absolute values expressed in Hertz. Electrospray
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ionization (ESI) mass spectra were collected using a QꢀTOF instrument. Samples (solubilized
in MeOH at 1mg/mL and then diluted by 1000) were introduced into the MS via an UHPLC
system whilst a Leucine Enkephalin solution was coꢀinjected via a micro pump. Infrared
spectra were recorded with a FT spectrometer. Optical rotation values were measured at room
temperature with a polarimeter. The absorption spectra were recorded on a spectrometer while
the fluorescence spectra were recorded on a spectrophotometer. Thinꢀlayer chromatography
(TLC) was carried out on aluminium sheets precoated with silica gel 60 F254. Column
chromatography separations were performed using silica gel (0.040ꢀ0.060 mm). HPLC
analyses were performed with a machine equipped with a UV/Vis detector at 30 °C
employing chiral columns. HPLC grade heptane and isopropyl alcohol were used as the
eluting solvents. HPLC traces were compared to racemic samples prepared by mixture of two
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enantiomeric final products obtained using (S) and (R) catalysts.
General Procedure to Prepare 1H-Indazole-7-Carbaldehyde 1 Through a Four-Step
Sequence: Methylation/Indazole Formation/Reduction/Oxidation.
Methylation – General Procedure: 2ꢀaminoꢀ3ꢀmethylbenzoic acid derivative (1 equiv) was
dissolved in DMF (3 mL / mmol of acid). K2CO3 (2 equiv) was added and the mixture was
stirred for 30 minutes at rt. MeI (1 equiv) was added and the resulting mixture was stirred for
24 hours at rt. The mixture was partitioned between water and EtOAc. The aqueous layer was
extracted with EtOAc and the combined organic layers were washed with brine, dried over
MgSO4 then evaporated, yielding the desired methyl ester without further purification.
Methyl 2-amino-3-methylbenzoate. According to the general procedure, 33 mmol of 2ꢀaminoꢀ
3ꢀmethylbenzoic acid (5 g) afforded 5.235 g of brown oil (95 %). Data were in accordance
with those found in the literature.20
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Methyl 2-amino-5-chloro-3-methylbenzoate. According to the general procedure, 22 mmol of
2ꢀaminoꢀ5ꢀchloroꢀ3ꢀmethylbenzoic acid (4 g) afforded 4.198 g of brown solid (97 %). M.p.:
33ꢀ35 °C. Rf: 0.75 (petroleum ether: ethyl acetate 75:25). IR (neat): 3490 cmꢀ1, 3364, 1692,
1561, 1467, 1435, 1228, 1198, 1086, 790. 1H NMR (300 MHz, CDCl3) δ 7.73 ppm (d, J = 2.5
Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 5.84 (s, 2H), 3.86 (s, 3H), 2.14 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 168.2 ppm, 147.7, 134.6, 128.3, 125.1, 120.1, 111.0, 51.9, 17.4. HRMS (ESI) calcd
for C9H11NO2Cl [M+H]+: 200.0478, found: 200.0484.
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Methyl 2-amino-3,4-dimethylbenzoate. According to the general procedure, 24 mmol of 2ꢀ
aminoꢀ3,4ꢀdimethylbenzoic acid (4 g) afforded 3.578 g of pale brown solid (82 %). M.p.: 69ꢀ
71 °C. Rf: (petroleum ether: ethyl acetate 75:25). IR (neat): 3474 cmꢀ1, 3367, 2946, 1683,
1
1595, 1436, 1236, 1199, 1080, 774. H NMR (300 MHz, CDCl3) δ 7.68 ppm (d, J = 8.2 Hz,
13
1H), 6.52 (d, J = 8.2 Hz, 1H), 5.88 (s, 2H), 3.88 (s, 3H), 2.29 (s, 3H), 2.06 (s, 3H). C NMR
(75 MHz, CDCl3) δ 169.2 ppm, 149.1, 142.4, 128.3, 120.9, 118.5, 108.6, 51.5, 21.2, 12.6.
HRMS (ESI) calcd for C10H14NO2 [M+H]+: 180.1025, found: 180.1028.
Indazole Formation – Typical Procedure: A NaNO2 (2.14 g, 31 mmol, 1 equiv) solution in
water (3.9 mL) was slowly added to a solution of methyl 2ꢀaminoꢀ3ꢀmethylbenzoate (5.1 g,
31 mmol, 1 equiv) in aqueous HBF4 (50 % w/w in water, 13.5 mL, 2.5 equiv) at 0 °C. The
mixture was stirred for 1 hour at 0 °C, and then filtered. The obtained solid was then added to
a stirred suspension of KOAc (6.09 g, 62 mmol, 2 eq.) and 18ꢀcrownꢀ6 (125 mg, 0.5 mmol,
0.016 eq.) in CHCl3 (51 mL). The resulting mixture was stirred for 1 hour at rt and then
filtered. The filtrate was dried over MgSO4 and evaporated. The crude compound was purified
by column chromatography on silica gel using a mixture of petroleum ether: ethyl acetate 7: 3
as eluent, yielding the desired indazole.
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Methyl 1H-indazole-7-carboxylate. According to the typical procedure, 31 mmol of methyl 2ꢀ
aminoꢀ3ꢀmethylbenzoate (5.1 g) afforded 2.98 g of the desired indazole as a white solid (55
%) after purification by chromatography on silica gel (petroleum ether: ethyl acetate, 7: 3).
Data were in accordance with those found in the literature.20
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Methyl 5-chloro-1H-indazole-7-carboxylate. According to the typical procedure [a slight
modification was carried out by preparing the solution of 2ꢀaminoꢀ5ꢀchloroꢀ3ꢀmethylbenzoate
in methanol (2 mL) and HBF4 (50 % w/w in water, 6.6 mL, 2.5 equiv)], 15.3 mmol of methyl
2ꢀaminoꢀ5ꢀchloroꢀ3ꢀmethylbenzoate (3.05 g) afforded 1.4 g of the desired indazole as a white
solid (44 %) after purification by chromatography on silica gel (petroleum ether: ethyl acetate,
7: 3). M.p.: 172ꢀ174 °C. Rf: 0.36 (petroleum ether: ethyl acetate, 75:25). IR (neat): 3148 cmꢀ1,
3082, 1716, 1327, 1242, 1195, 1169, 897, 854, 774. 1H NMR (300 MHz, CDCl3) δ 10.16 ppm
(s, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 4.05 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
165.9 ppm, 129.6 (2C), 126.3 (2C), 126.0 (2C), 113.6, 52.8. HRMS (ESI) calcd for
C9H8N2O2Cl [M+H]+: 211.0274, found: 211.0273.
Methyl 4-methyl-1H-indazole-7-carboxylate. According to the typical procedure [a slight
modification was carried out by preparing the solution of methyl 2ꢀaminoꢀ3,4ꢀ
dimethylbenzoate in methanol (10 mL) and HBF4 (50 % w/w in water, 8.6 mL, 2.5 equiv)], 20
mmol of methyl 2ꢀaminoꢀ3,4ꢀdimethylbenzoate (3.58 g) afforded 1.34 g of the desired
indazole as a white solid (35%) after purification by chromatography on silica gel (petroleum
ether: ethyl acetate, 7: 3). M.p.: 145ꢀ147 °C. Rf: 0.23 (petroleum ether: ethyl acetate, 75:25).
1
IR (neat): 3322 cmꢀ1, 1701, 1599, 1437, 1304, 1287, 1268, 1201, 1130, 780. H NMR (300
MHz, CDCl3) δ 10.97 ppm (s, 1H), 8.18 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz,
1H), 4.02 (s, 3H), 2.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 166.9 ppm, 138.7, 130.3, 129.9,
127.4, 123.9, 121.0, 110.4, 52.3, 19.3. HRMS (ESI) calcd for C10H11N2O2 [M+H]+: 191.0821,
found: 191.0826.
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Reduction – General Procedure: Methyl ester (10 mmol, 1 equiv) was placed in a flask
under argon. Dry THF (120 mL) was added and the resulting solution was cooled down to 0
°C. LiAlH4 (790 mg, 21 mmol, 2.1 equiv) was carefully added. The mixture was stirred for 30
minutes at 0 °C then quenched by successive addition of water (2 mL), 5 N NaOHaq. (2 mL),
and water (6 mL). The mixture was diluted with THF (120 mL) and MgSO4 was added. The
mixture was stirred for 10 minutes at rt then filtered over a pad of Celite®. The filtrate was
evaporated, yielding clean alcohol without further purification.
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(1H-indazol-7-yl)methanol. According to the general procedure, methyl 1Hꢀindazoleꢀ7ꢀ
carboxylate (1.7 g) afforded 1.3 g of beige solid (86 %). Data were in accordance with those
in the literature.20
(5-Chloro-1H-indazol-7-yl)methanol. According to the general procedure, methyl 5ꢀchloroꢀ
1Hꢀindazoleꢀ7ꢀcarboxylate (1.9 g) afforded 1.5 g of beige solid (90 %). M.p.: 217ꢀ219 °C. Rf:
0.55 (dichloromethane: methanol, 9: 1). IR (neat): 3127 cmꢀ1, 2850, 1074, 1010, 944, 870,
760, 712, 654, 608. 1H NMR (300 MHz, DMSOꢀd6) δ 13.27 ppm (s, 1H), 8.08 (d,
J = 1.1 Hz,
1H), 7.71 (d, = 1.1 Hz, 1H), 7.32 (d, = 1.1 Hz, 1H), 5.48 (t, = 5.7 Hz, 1H), 4.83 (d, J =
J
J
J
5.7 Hz, 2H). 13C NMR (75 MHz, DMSOꢀd6) δ 136.4 ppm, 133.3, 127.2, 124.7, 123.8, 123.0,
117.9, 59.3. HRMS (ESI) calcd for C8H8N2OCl [M+H]+: 183.0325, found: 183.0331.
(4-Methyl-1H-indazol-7-yl)methanol. According to the general procedure, methyl 4ꢀmethylꢀ
1Hꢀindazoleꢀ7ꢀcarboxylate (1.3 g) afforded 1.1 g of beige solid (95 %). M.p.: 250ꢀ252 °C. Rf:
0.15 (petroleum ether: ethyl acetate,75:25). IR (neat): 3121 cmꢀ1, 2848, 1374, 1016, 938, 921,
1
855, 814, 775, 574. H NMR (300 MHz, DMSOꢀd6) δ 12.99 ppm (s, 1H), 8.10 (s, 1H), 7.18
(d, J = 7.0 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 5.20 (t, J = 5.7 Hz, 1H), 4.77 (d, J = 5.7 Hz, 2H),
2.52 (s, 3H). 13C NMR (75 MHz, DMSOꢀd6) δ 137.9 ppm, 132.5, 128.7, 123.4 (2C), 122.4,
119.9, 59.9, 18.3. HRMS (ESI) calcd for C9H10N2ONa [M+Na]+: 185.0691, found: 185.0682
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Oxidation – General Procedure: Alcohol (8 mmol, 1 eq.) was placed in a flask under argon.
Dry DCM (320 mL) and DMF (80 mL) were introduced. Activated MnO2 (6.9 g, 80 mmol, 10
eq.) was added and the resulting mixture was stirred overnight at rt. The mixture filtered over
Celite®, the filter cake was rinsed with DCM (300 mL) and the DCM was evaporated.
Compound was taken up in EtOAc (80 mL) and washed with brine (7x100 mL). The organic
layer was dried over MgSO4 and evaporated, affording the desired aldehyde 1 without further
purification.
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1H-indazole-7-carbaldehyde (1a). According to the general procedure, (1Hꢀindazolꢀ7ꢀ
yl)methanol (1.2 g) afforded 640 mg of yellow solid (55 %). Data were in accordance with
those found in the literature.20
5-chloro-1H-indazole-7-carbaldehyde (1c). According to the general procedure, (5ꢀchloroꢀ
1Hꢀindazolꢀ7ꢀyl)methanol (1.5 g) afforded 990 mg of yellow solid (67 %). M.p.: 213ꢀ215 °C.
Rf: 0.50 (petroleum ether: ethyl acetate, 75:25). IR (neat): 3383 cmꢀ1, 1671, 1085, 1064, 947,
874, 763, 750, 693, 604. 1H NMR (300 MHz, DMSOꢀd6) δ 10.15 ppm (s, 1H), 8.22 (m, 2H),
8.06 (d,
J
= 1.3 Hz, 1H). 13C NMR (75 MHz, DMSOꢀd6) δ 191.5 ppm, 134.2, 133.9, 132.5,
127.0, 125.7, 124.4, 121.1. HRMS (ESI) calcd for C8H6N2OCl [M+H]+: 181.0169, found:
181.0160.
4-methyl-1H-indazole-7-carbaldehyde (1d). According to the general procedure, (4ꢀmethylꢀ
1Hꢀindazolꢀ7ꢀyl)methanol (1.1 g) afforded 900 mg of a brown solid (84 %). M.p.: 89ꢀ91 °C.
Rf: 0.38 (petroleum ether: ethyl acetate, 75:25). IR: 3376 cmꢀ1, 2803, 1664, 1596, 1041, 939,
773, 769, 710, 615. 1H NMR (300 MHz, CDCl3) δ 10.09 ppm (s, 1H), 8.20 (s, 1H), 7.73 (d,
J
= 7.3 Hz, 1H), 7.07 (br d, 1H), 2.69 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 191.9 ppm, 140.8,
136.8, 133.8 (2C), 124.9, 121.2, 118.8, 19.5. HRMS (ESI) calcd for C9H9N2O [M+H]+:
161.0715, found: 161.0714.
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3-iodo-1H-indazole-7-carbaldehyde (1b). Indazole 1a (184 mg, 1.26 mmol, 1 equiv) was
dissolved in DMF (3.6 mL). KOH (177 mg, 3.15 mmol, 2.5 equiv) followed by I2 (638 mg,
2.52 mmol, 2 equiv) were added. The mixture was stirred for 1 hour at rt. The reaction was
poured into 90 mL of water and 10 mL of an aqueous saturated solution of Na2S2O3. Mixture
was filtered and the solid was dried under vacuum, affording the desired compound without
purification as a beige solid (300 mg, 88% yield). M.p.: 200ꢀ202 °C. Rf: 0.13 (petroleum
ether: ethyl acetate, 75:25). IR (neat): 3288 cmꢀ1, 1668, 1591, 1170, 1079, 970, 787, 696, 621,
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607. 1H NMR (300 MHz, DMSOꢀd6) δ 10.16 ppm (s, 1H), 8.13 (d,
= 7.6 Hz, 1H). 13C NMR (75 MHz, DMSOꢀd6) δ 192.0 ppm, 136.4,
J = 7.6 Hz, 1H), 7.82 (d, J
= 7.6 Hz, 1H), 7.43 (t,
J
134.4, 128.5, 127.9, 121.2, 120.8, 95.4. HRMS (ESI) calcd for C8H6N2OI [M+H]+: 272.9525,
found: 272.9520.
General Procedure for the Organocatalytic sequence: Indazole 1 (0.2 mmol, 1 equiv),
aldehyde 2 (0.3 mmol, 1.5 equiv), catalyst 3a (9.8 mg, 0.03 mmol, 0.15 equiv), AcONa (18
mg, 0.22 mmol, 1.1 equiv) and 1,2ꢀDCE (1 mL) were introduced in a capped flask. The
mixture was stirred for 24 hours at 55 °C. The solvent was removed under reduced pressure.
The crude compound 4 was purified by column chromatography on silica gel.
(R)-8-phenyl-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4aa). Purification using a
mixture of petroleum ether: ethyl acetate ,75:25 as eluent yielded 49 mg of a yellow solid (94
%). M.p.: 145ꢀ147 °C. Rf: 0.45 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ457 (c =
1.05 in CHCl3) for 86 % ee. IR (neat): 2832 cmꢀ1, 1670, 1697, 1364, 1151, 1069, 748, 698,
1
595, 515. H NMR (300 MHz, CDCl3) δ 9.64 ppm (s, 1H), 8.01 (s, 1H), 7.75 (d,
J
= 8.2 Hz,
1H), 7.65 (s, 1H), 7.41 (d,
J
= 7.0 Hz, 1H), 7.33 – 7.10 (m, 6H), 6.85 (s, 1H). 13C NMR (75
MHz, CDCl3) δ 190.0 ppm, 140.8, 139.8, 139.4, 137.8, 135.2, 128.9 (2C), 128.7, 127.2 (2C),
125.4, 125.3, 122.4, 121.1, 116.6, 61.1. HRMS (ESI) calcd for C17H13N2O [M+H]+: 261.1028,
found: 261.1031.
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(R)-8-(4-tolyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ab). Purification using a
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mixture of petroleum ether: ethyl acetate, 8:2 yielded a yellow solid (53 mg, 96 %). M.p.:
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144ꢀ146 °C. Rf: 0.57 (petroleum ether: ethyl acetate, 75:25). [α]578 = ꢀ372 (c = 1.07 in
9
CHCl3) for 79 % ee. IR (neat): 2835 cmꢀ1, 1668, 1597, 1571, 1143, 1067, 885, 745, 729, 512.
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1H NMR (300 MHz, CDCl3) δ 9.62 ppm (s, 1H), 7.98 (s, 1H), 7.72 (d,
= 7.0 Hz, 1H), 7.21 – 7.00 (m, 5H), 6.79 (s, 1H), 2.26 (s, 3H). 13C NMR (75
J = 8.2 Hz, 1H), 7.62
(s, 1H), 7.38 (d,
J
MHz, CDCl3) δ 190.1 ppm, 139.7, 139.5, 138.5, 138.1, 137.7, 135.1, 129.6 (2C), 127.0 (2C),
125.3, 125.2, 122.3, 121.1, 116.6, 60.8, 21.3. HRMS (ESI) calcd for C18H15N2O [M+H]+:
275.1184, found: 275.1177.
(R)-8-(4-chlorophenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ac)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (54 mg, 91 %).
M.p.: 150ꢀ152 °C. Rf: 0.39 (petroleum ether: ethyl acetate 75:25). [α]57820 = ꢀ355 (c = 1.02 in
CHCl3) for 69 % ee. IR (neat): 2832 cmꢀ1, 1665, 1594, 1569, 1150, 1067, 880, 744, 595, 527.
1H NMR (300 MHz, CDCl3) δ 9.68 ppm (s, 1H), 8.05 (s, 1H), 7.80 (d,
(s, 1H), 7.46 (d,
J
= 8.2 Hz, 1H), 7.70
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J
= 7.0 Hz, 1H), 7.36 – 7.25 (m, 2H), 7.27 – 7.19 (m, 3H), 6.86 (s, 1H). C
NMR (75 MHz, CDCl3) δ 189.9 ppm, 140.1, 139.3, 138.9, 137.7, 135.4, 134.5, 129.1 (2C),
128.6 (2C), 125.6, 125.5, 122.5, 121.1, 116.3, 60.4. HRMS (ESI) calcd for C17H12N2OCl
[M+H]+: 295.0638, found: 295.0637.
(R)-8-(3-chlorophenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ad)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (55 mg, 93 %).
M.p.: 144ꢀ146 °C. Rf: 0.49 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ387 (c = 1.00 in
CHCl3) for 60 % ee. IR (neat): 2832 cmꢀ1, 1671, 1597, 1571, 1142, 1068, 906, 748, 727, 689.
1H NMR (300 MHz, CDCl3) δ 9.62 ppm (s, 1H), 8.00 (s, 1H), 7.74 (d,
= 7.0 Hz, 1H), 7.24 – 7.12 (m, 5H), 6.79 (s, 1H). 13C NMR (75 MHz,
J = 8.2 Hz, 1H), 7.65
(s, 1H), 7.41 (d,
J
CDCl3) δ 189.8 ppm, 142.5, 140.3, 138.5, 137.6, 135.4, 134.7, 130.1, 128.9, 127.3, 125.6,
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125.6 (3C), 121.1, 116.2, 60.5. HRMS (ESI) calcd for C17H12N2OCl [M+H]+: 295.0638,
found: 295.0639.
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(R)-8-(4-methoxyphenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ae). Purification
using a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (52 mg, 90 %).
M.p.: 167ꢀ169 °C. Rf: 0.3 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ334 (c = 1.04 in
CHCl3) for 73 % ee. IR (neat): 2832 cmꢀ1, 1666, 1512, 1243, 1177, 1146, 883, 807, 745, 589.
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1H NMR (300 MHz, CDCl3) δ 9.60 ppm (s, 1H), 7.98 (s, 1H), 7.71 (d,
J = 8.2 Hz, 1H), 7.61
(d, = 1.6 Hz, 1H), 7.36 (d, = 6.3 Hz, 1H), 7.19 – 7.10 (m, 3H), 6.82 – 6.72 (m, 3H), 3.71
J
J
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 190.1 ppm, 159.6, 139.5, 139.4, 137.6, 135.1, 133.4,
128.3 (2C), 125.2, 125.1, 122.3, 121.0, 116.5, 114.1 (2C), 60.4, 55.2. HRMS (ESI) calcd for
C18H15N2O2 [M+H]+: 291.1134, found: 291.1139.
(R)-8-(3-methoxyphenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4af). Purification
using a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (52 mg, 90 %).
M.p.: 178ꢀ180 °C. Rf: 0.39 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ294 (c = 0.98 in
CHCl3) for 84 % ee. IR (neat): 2832 cmꢀ1, 1674, 1599, 1572, 1259, 1141, 1069, 1042, 751,
695. 1H NMR (300 MHz, CDCl3) δ 9.62 ppm (s, 1H), 7.99 (s, 1H), 7.72 (d,
= 7.0 Hz, 1H), 7.22 – 7.10 (m, 2H), 6.78 (m, 4H), 3.72 (s, 3H). 13C
J = 8.2 Hz, 1H),
7.61 (s, 1H), 7.38 (d,
J
NMR (75 MHz, CDCl3) δ 190.0 ppm, 159.9, 142.2, 139.8, 139.2, 137.8, 135.2, 129.9, 125.4,
125.3, 122.4, 121.1, 119.5, 116.5, 113.8, 113.2, 60.9, 55.3. HRMS (ESI) calcd for
C18H15N2O2 [M+H]+: 291.1134, found: 291.1128.
(R)-8-(2-methoxyphenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ag). Purification
using a mixture of toluene: acetonitrile, 9:1 yielded a yellow solid (36 mg, 62 %). M.p.: 191ꢀ
193 °C. Rf: 0.39 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ314 (c = 1.09 in CHCl3) for
1
71 % ee. IR (neat): 2832 cmꢀ1, 1673, 1598, 1492, 1252, 1144, 907, 884, 747, 723. H NMR
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(300 MHz, CDCl3) δ 9.77 ppm (s, 1H), 8.12 (s, 1H), 7.92 – 7.79 (m, 2H), 7.59 – 7.49 (m, 1H),
7.46 – 7.26 (m, 4H), 7.10 – 6.97 (m, 2H), 3.83 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 190.1
ppm, 157.3, 140.1, 139.1, 138.1, 134.6, 130.0, 129.5, 129.1, 125.0, 124.6, 121.9, 120.9, 120.7,
117.0, 111.9, 56.5, 56.0. HRMS (ESI) calcd for C18H15N2O2 [M+H]+: 291.1134, found:
291.1130.
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(R)-8-(4-nitrophenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ah)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 7:3 yielded a yellow solid (48 mg, 78 %).
M.p.: 196ꢀ198 °C. Rf: 0.47 (petroleum ether: ethyl acetate 75:25). [α]57820 = ꢀ463 (c = 1.01 in
CHCl3) for 88 % ee. IR (neat): 2832 cmꢀ1, 1673, 1599, 1571, 1520, 1350, 1144, 746, 696, 668.
1H NMR (300 MHz, CDCl3) δ 9.63 ppm (s, 1H), 8.12 (d,
J = 8.7 Hz, 2H), 8.01 (s, 1H), 7.88 –
7.69 (m, 2H), 7.42 (m, 3H), 7.23 (m, 1H), 6.94 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 189.8
ppm, 147.9, 146.9, 140.9, 138.0, 137.8, 135.8, 128.3 (2C), 126.0 (2C), 124.2 (2C), 122.8,
121.2, 116.0, 60.3.HRMS (ESI) calcd for C17H12N3O3 [M+H]+: 306.0879, found: 306.0881.
(R)-8-(2-nitrophenyl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ai). Purification using
a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (56 mg, 92 %). M.p.:
20
165ꢀ167 °C. Rf: 0.31 (petroleum ether: ethyl acetate, 75:25). [α]578 = ꢀ399 (c = 1.05 in
CHCl3) for 79 % ee. IR (neat): 2832 cmꢀ1, 1671, 1599, 1527, 1350, 1147, 908, 887, 727, 684.
1H NMR (300 MHz, CDCl3) δ 9.54 ppm (s, 1H), 8.00 (s, 1H), 7.97 – 7.87 (m, 1H), 7.78 –
7.71 (m, 2H), 7.69 (s, 1H), 7.45 – 7.33 (m, 3H), 7.18 (t, J = 7.6 Hz, 1H), 7.07 (dd, J = 6.8, 2.1
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 189.7 ppm, 148.2, 140.7, 138.5, 137.8, 135.6, 134.6,
133.4, 129.6, 129.3, 125.8, 125.7, 124.8, 122.7, 121.0, 115.9, 55.5. HRMS (ESI) calcd
forC17H12N3O3 [M+H]+: 306.0879, found: 306.0879.
(R)-8-(naphtalen-2-yl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4aj)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 8:2 yielded a yellow solid (62 mg, 99 %).
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M.p.: 162ꢀ164 °C. Rf: 0.44 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ498 (c = 1.06 in
CHCl3) for 59 % ee. IR (neat): 3056 cmꢀ1, 2816, 1672, 1597, 1570, 1141, 1069, 904, 727, 478.
1H NMR (300 MHz, CDCl3) δ 9.61 ppm (s, 1H), 7.97 (s, 1H), 7.82 – 7.60 (m, 6H), 7.46 –
7.36 (m, 3H), 7.27 – 7.12 (m, 2H), 6.99 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 190.0 ppm,
139.9, 139.1, 137.9, 137.7, 135.2, 133.3, 133.2, 128.9, 128.5, 127.7, 126.6, 126.4, 126.3,
125.4, 125.3, 124.5, 122.4, 121.1, 116.5, 61.2. HRMS (ESI) calcd for C21H15N2O [M+H]+:
311.1184, found: 311.1182.
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(R)-8-(thiophen-2-yl)-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ak)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 8:2 yielded a yellow solid (47 mg, 88 %).
M.p.: 115ꢀ117 °C. Rf: 0.47(petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ194 (c = 0.94 in
CHCl3) for 55 % ee. IR (neat): 2819 cmꢀ1, 2360, 1669, 1598, 1570, 1141, 1119, 1066, 725,
699. 1H NMR (300 MHz, CDCl3) δ 9.69 ppm (s, 1H), 8.04 (s, 1H), 7.74 (d,
J = 8.2 Hz, 1H),
7.65 (s, 1H), 7.41 (d,
J = 7.0 Hz, 1H), 7.20 – 7.13 (m, 3H), 7.03 (d, J = 3.4 Hz, 1H), 6.88 (dd,
J
= 5.0, 3.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 189.8 ppm, 143.7, 139.7, 138.3, 137.3,
135.5, 127.0, 126.0, 125.9, 125.6, 125.5, 122.5, 121.4, 116.2, 55.6. HRMS (ESI) calcd for
C15H9N2OS [MꢀH]+: 265.0436, found: 265.0432.
(R)-8-methyl-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4al). Purification using a
mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (13 mg, 33 %). M.p.:
48ꢀ50 °C. Rf: 0.6 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ289 (c=1.15 in CHCl3) for
55 % ee. IR (neat): 2924 cmꢀ1, 1673, 1599, 1573, 1372, 1148, 1094, 1070, 880, 748. 1H NMR
(300 MHz, CDCl3) δ 9.44 ppm (s, 1H), 7.78 (s, 1H), 7.45 (d,
J
= 8.2 Hz, 1H), 7.03 (t,
J = 3.5
Hz, 2H), 6.93 – 6.78 (m, 1H), 5.64 (q, = 6.5 Hz, 1H), 1.44 (d,
J
J
= 6.5 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 190.7 ppm, 141.0, 140.9, 137.4, 134.3, 125.0, 124.6, 122.2, 121.1, 116.9,
53.8, 23.5. HRMS (ESI) calcd for C12H11N2O [M+H]+: 199.0871, found: 199.0865.
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(R)-2-iodo-8-phenyl-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ba). Purification using
4
5
6
7
8
a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (68 mg, 88 %). M.p.:
20
161ꢀ163 °C. Rf: 0.63 (petroleum ether: ethyl acetate, 75:25). [α]578 = ꢀ296 (c = 098 in
9
CHCl3) for 60 % ee. IR (neat): 2832 cmꢀ1, 1676, 1596, 1144, 1068, 922, 748, 698, 601, 518.
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60
1H NMR (300 MHz, CDCl3) δ 9.59 ppm (s, 1H), 7.58 (s, 1H), 7.44 (t,
J = 8.4 Hz, 2H), 7.31 –
7.15 (m, 6H), 6.81 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 189.7 ppm, 140.4, 139.6, 138.8,
138.4, 128.9 (2C), 128.8, 127.2 (2C), 126.1, 126.1, 125.2, 123.0, 116.7, 92.8, 61.4. HRMS
(ESI) calcd for C17H12N2OI [M+H]+: 386.9994, found: 386.9997.
(R)-4-chloro-8-phenyl-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4ca)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 85:15 yielded a yellow solid (49 mg, 84 %).
M.p.: 196ꢀ198 °C. Rf: 0.56 (petroleum ether: ethyl acetate 75:25). [α]57820 = ꢀ309 (c = 1.02 in
CHCl3) for 60 % ee. IR (neat): 2923 cmꢀ1, 1676, 1573, 1339, 1144, 1084, 904, 771, 731, 698.
1H NMR (300 MHz, CDCl3) δ 9.64 ppm (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.38
(s, 1H), 7.27 – 7.24 (m, 3H), 7.20 – 7.16 (m, 2H), 6.80 (s, 1H). 13C NMR (75 MHz, CDCl3) δ
189.7 ppm, 140.6, 140.3, 138.1, 136.2, 134.6, 129.0, 128.9 (2C), 127.9, 127.1 (2C), 125.4,
124.0, 121.6, 117.4, 61.1. HRMS (ESI) calcd for C17H12N2OCl [M+H]+: 295.0638, found:
295.0641.
(R)-3-methyl-8-phenyl-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde (4da)
.
Purification
using a mixture of petroleum ether: ethyl acetate, 8:2 yielded a yellow solid (45 mg, 82 %).
M.p.: 211ꢀ213 °C. Rf: 0.55 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ435 (c = 0.96 in
CHCl3) for 79 % ee. IR (neat): 2841 cmꢀ1, 1673, 1598, 1142, 810, 747, 694, 630, 519, 433. 1H
NMR (300 MHz, CDCl3) δ 9.63 ppm (s, 1H), 8.03 (s, 1H), 7.64 (s, 1H), 7.37 – 7.20 (m, 6H),
6.97 (d,
J
= 7.1 Hz, 1H), 6.85 (s, 1H), 2.64 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 189.9 ppm,
141.0, 140.1, 138.3, 137.8, 137.5, 134.3, 128.8 (2C), 128.6, 127.1 (2C), 125.8, 122.5, 121.8,
114.3, 61.1, 19.5. HRMS (ESI) calcd for C18H15N2O [M+H]+: 275.1184, found: 275.1179.
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(R)-8-(4-chlorophenyl)-3-methyl-8H-pyrazolo[4,5,1-ij]quinoline-7-carbaldehyde
(4dc).
4
5
6
7
8
Purification using a mixture of petroleum ether: ethyl acetate, 75:25 yielded a yellow solid (49
mg, 80 %). M.p.: 179ꢀ181 °C. Rf: 0.34 (petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ490
9
(c = 1.13 in CHCl3) for 62 % ee. IR (neat): 2822 cmꢀ1, 1669, 1598, 1565, 1139, 1089, 1057,
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1
907, 807, 727. H NMR (300 MHz, CDCl3) δ 9.58 ppm (s, 1H), 8.00 (s, 1H), 7.59 (dd,
J =
2.9, 0.8 Hz, 1H), 7.30 (d,
J = 7.1 Hz, 1H), 7.24 – 7.18 (m, 2H), 7.18 – 7.11 (m, 2H), 6.94 (dd,
J
= 7.1, 0.8 Hz, 1H), 6.77 (s, 1H), 2.60 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 189.8 ppm,
140.3, 139.4, 137.7 (2C), 137.6, 134.4, 134.4, 129.0 (2C), 128.5 (2C), 126.0, 122.6, 121.8,
114.0, 60.3, 19.4. HRMS (ESI) calcd for C18H14N2OCl [M+H]+: 309.0795, found: 309.0803.
(E)-methyl 3-(8-(4-chlorophenyl)-3-methyl-8H-pyrazolo[4,5,1-ij]quinolin-7-yl)acrylate
(5). The aldehyde 4dc (31 mg, 0.1 mmol, 1 equiv) was introduced in a flask under argon. Dry
toluene (1 mL) was added, followed by methyl (triphenylphosphoranylidene)acetate (43 mg,
0.12 mmol, 1.2 equiv). The mixture was stirred for 24 hours at rt, and then the toluene was
removed under reduced pressure. The crude compound was purified by preparative
chromatography on silica gel using a mixture of dichloromethane: diethyl ether, 9:1 as eluent,
yielding the desired compound 5 as a yellow solid (35 mg, 96 %). M.p.: 178ꢀ180 °C. Rf:
(petroleum ether: ethyl acetate, 75:25). [α]57820 = ꢀ490 (c = 1.13 in CHCl3) for 62 % ee. IR
(neat): 2942 cmꢀ1, 1702, 1595, 1316, 1273, 1192, 1089, 907, 854, 728. H NMR (300 MHz,
1
CDCl3) δ 7.92 ppm (s, 1H), 7.46 (d,
J
= 16.0 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.30 – 7.20 (m,
= 7.1, 0.7 Hz, 1H), 6.64 (s, 1H), 5.79 (d, = 16.0
3H), 7.14 (d, = 7.1 Hz, 1H), 6.86 (dd,
J
J
J
Hz, 1H), 3.72 (s, 3H), 2.55 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.1 ppm, 143.2, 138.7,
136.2, 134.9, 134.7, 134.2, 132.9, 131.3, 129.4 (2C), 128.9 (2C), 124.0, 122.4, 121.5, 118.5,
115.4, 62.2, 51.8, 19.2. HRMS (ESI) calcd for C21H18N2O2Cl [M+H]+: 365.1057, found:
365.1063.
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N-benzyl-1-(8-(4-chlorophenyl)-3-methyl-8H-pyrazolo[4,5,1-ij]quinolin-7-
4
5
6
7
8
yl)methanamine (6). Benzylamine (21 µL, 0.2 mmol, 2 equiv) and benzoic acid (61 mg, 0.5
mmol, 5 equiv) were suspended in 1,2ꢀDCE (0.5 mL). The suspension was cooled down to 0
°C. Aldehyde 4dc (36.5 mg, 0.1 mmol, 1 equiv) then NaBH(OAc)3 (42.4 mg, 0.2 mmol, 2
equiv) were added. The mixture was stirred for 7 hours being allowed to come back to rt. The
reaction was quenched upon addition of saturated NaHCO3 (15 mL). The mixture was diluted
with ethyl acetate (20 mL). The organic layer was washed with brine (15 mL), dried over
MgSO4 and evaporated. The crude compound was purified by preparative chromatography on
silica gel using a mixture of petroleum ether: ethyl acetate 6:4 as eluent, yielding 21 mg of 6
as a viscous yellow oil (53 %). Rf: 0.32 (petroleum ether: ethyl acetate 75:25). IR (neat): ν
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1
2907 cmꢀ1, 1488, 1088, 1014, 907, 880, 906, 728, 697, 579. H NMR (300 MHz, CDCl3) δ
7.90 ppm (d,
Hz, 1H), 6.79 (d,
(d,
J = 8.3 Hz, 1H), 7.35 – 7.22 (m, 8H), 7.12 (d, J = 7.7 Hz, 2H), 6.95 (d, J = 6.9
J
= 6.9 Hz, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 3.83 (d,
J = 13.3 Hz, 1H), 3.69
J
= 13.3 Hz, 1H), 3.26 (d, J = 14.2 Hz, 1H), 3.18 (d, J
= 14.2 Hz, 1H), 2.53 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 139.7 ppm, 139.5, 137.7, 136.9, 134.3, 133.7, 131.8, 129.2 (2C),
128.9 (2C), 128.6 (2C), 128.4 (2C), 127.3, 121.8, 121.3, 121.0, 120.3, 116.0, 63.7, 53.1, 51.7,
19.0. HRMS (ESI) calcd for C25H23N3Cl [M+H]+: 400.1581, found: 400.1578.
ASSOCIATED CONTENT
Supporting Information
1
Copies of H, 13C NMR, HPLC traces and crystallographic data for 4ba are provided. This
material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgements
The authors thank University of VersaillesꢀStꢀQuentinꢀenꢀYvelines for a Ph.D. grant (M.G.)
and CNRS.
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S. A.; Bouchard, P. J.; Forsythe, M .S.; Harlow, P. P.; Barbera, F. A.; Spitz, S. M.; Wexler, R.
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(15) For other examples, see: (a) Lone, S. H.; Bhat, K. A.; Rehman, S.ꢀU.; Majeed, R.;
Hamid, A.; Khuroo, M. A. Bioorg. Med. Chem. Lett. 2013, 23, 4931ꢀ4934. (b) Choi, I. Y.;
Lee, K. C.; Lee, H. W. Bull. Korean Chem. Soc. 2012, 33, 3535ꢀ3536. (c) Moran, J.; Dornan,
P.; Beauchemin, A. M. Org. Lett. 2007,
Tetrahedron Lett. 2000, 41, 4363ꢀ4366.
9, 3893ꢀ3896. (d) Collot, V.; Varlet, D.; Rault, S.
(16) (a) Pantaine, L.; Coeffard, V.; Moreau, X.; Greck, C. Org. Lett. 2015, 17, 3674ꢀ3677.
(b) Pantaine, L.; Coeffard, V.; Moreau, X.; Greck, C. Eur. J. Org. Chem. 2015, 2005ꢀ2011.
(c) Portalier, F.; Bourdreux, F.; Marrot, J.; Moreau, X.; Coeffard, V.; Greck, C. Org. Lett.
2013, 15, 5642ꢀ5645.
(17) For seminal reports on iminiumꢀenamine asymmetric catalysis, see: (a) Marigo, M.;
Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964ꢀ
6965; (b) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am. Chem. Soc. 2005, 127
,
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(18) The absolute configurations of the compounds 4 have been determined in comparison
with our previous work dealing with asymmetric organocatalytic Nꢀalkylation of indoles with
enals 2. See ref. 5d.
(19) See supporting information for details.
(20) Hansen, M.; Jacobsen, S. E.; Plunkett, S.; Liebscher, G. E.; McCorvy, J. D.; Bräunerꢀ
Osborne, H.; Kristensen, J. L. Bioorg. Med. Chem. 2015, 23, 3933ꢀ3937.
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