Copper-catalyzed cascade reactions of substituted 4- iodopyrazolecarbaldehydes with 1,2-phenylenediamines and 2-aminophenols

Article abstract of DOI:10.1002/adsc.201000662

A new approach for the synthesis of novel annulated-pyrazoles is presented. This protocol includes an intermolecular condensation followed by a copper-mediated intramolecular C-N or C-O coupling reaction. The method is applied to a range of substituted 4-

Full text of DOI:10.1002/adsc.201000662

UPDATES
DOI: 10.1002/adsc.201000662
Copper-Catalyzed Cascade Reactions of Substituted
4-Iodopyrazolecarbaldehydes with 1,2-Phenylenediamines and
2-Aminophenols
Maloy Nayaka and Sanjay Batraa,*
a
Medicinal and Process Chemistry Division, Central Drug Research Institute (CSIR), PO Box 173, Lucknow 226 001,
India
Fax : (+91)-522-2623405, (+91)-522-2623938; phone: (+91)-522-2621411-18 Extn. 4234, 4368;
e-mail: batra_san@yahoo.co.uk or s_batra@cdri.res.in
Received: August 25, 2010; Revised: October 8, 2010; Published online: December 3, 2010
CDRI Communication No. 7986
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000662.
À
Abstract: A new approach for the synthesis of
novel annulated-pyrazoles is presented. This proto-
col includes an intermolecular condensation fol-
C N coupling is restricted to the Ullman reaction
leading to N-arylated pyrazoles.[4] Recently, we re-
ported the synthesis of pyrazoloACTHUNTGRNEUNG[4,3-b]pyridine-5-ones
À
lowed by a copper-mediated intramolecular C N or
via the first copper-promoted intramolecular amida-
tion in 4-iodopyrazole derivatives generated either
from Morita–Baylis–Hillman (MBH) or Horner–
Wadsworth–Emmon chemistry.[5] Although during this
À
C O coupling reaction. The method is applied to a
range of substituted 4-iodopyrazolecarbaldehydes
which react with 1,2-phenylenediamines or 2-
À
amino
dihydro
substituted-2H- or 1H-benzo[b]pyrazolo
ACHTUNGTRENNUNGoxazepines, respectively.
G
study the C N coupling with allylamides was success-
E
E
G
ful, we failed to achieve similar cross-coupling reac-
tions with allylamines accessed via MBH chemistry.
Nevertheless, we were keen to explore the copper-
promoted cross-coupling of substituted 4-iodopyra-
zoles as it would allow access to intermediates suita-
ble for generating novel annulated pyrazoles. Recent-
ly Reeves et al. reported the synthesis of several
azole-annulated quinoxalines via copper-catalyzed an-
nulation of 2-formylazoles with o-aminoiodoarenes
whereas two identical papers by Cai et al. and Zhou
N
ACHTUNGTRENNUNG
À
À
Keywords: C N coupling; C O coupling; copper;
diazepines; oxazepines; pyrazoles
Compounds containing the pyrazole motif are of sig- et al. described the synthesis of aza-fused polycyclic
nificant interest in medicinal, pharmaceutical and ag- quinolines through copper-catalyzed cascade reac-
ricultural research due to their important biological tions.[6] Based on these reports, we anticipated that
activities.[1] Beside being the core unit of commercial treating 4-iodopyrazolecarbaldehydes with 1,2-phenyl-
drugs such as zometapin, sildenafil, celebrex and ri- enediamine or 2-aminophenol in the presence of a
monabant, there are numerous pyrazoles that are as- copper catalyst may initiate a cascade reaction leading
cribed with anti-inflammatory, anticancer, anti-HIV, to the synthesis of novel annulated pyrazoles
antibacterial and cannabinoid receptor antagonist ac- (Figure 1). To the best of our knowledge such a strat-
tivities.[2] Primarily due to this reason, organic chem- egy for annulated pyrazoles has not been developed
ists are motivated to continuously develop strategies to date. In this update we disclose the results on the
for producing new pyrazole-based compounds.[3] In development of this methodology.
this context the transition metal-promoted cross-cou-
pling reactions have been of great value as they pro- iodo-1,5-diphenyl-1H-pyrazole-3-carbaldehyde
Initial feasibility of the approach was tested with 4-
and
vide a robust route to install the desired substitution 1,2-phenylenediamine employing some commonly
in pyrazoles. Surprisingly however, all transition used copper sources, ligands, bases and solvents. The
metal-catalyzed cross-coupling reactions at 3-, 4- or 5- results of the optimization study are illustrated in
À
position result in C C bond formation whereas the Table 1. To our delight the use of CuI as copper
Adv. Synth. Catal. 2010, 352, 3431 – 3437
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Maloy Nayak and Sanjay Batra
UPDATES
300 mol% K3PO4 in DMSO at 908C were simultane-
ously used for further investigation.
The scope of reaction was explored by using a com-
bination of different 4-iodopyrazolecarbaldehydes
and several 1,2-phenylenediamines (Table 2). It was
satisfying to note that all substrates reacted smoothly
to afford the required products and the yields were
better in ligand-free conditions. Changing the substi-
tution from phenyl to methyl at the 1-position did not
affect the outcome of the reaction (Table 2, entry 14).
Likewise the substitution pattern in the phenyl ring
placed at C-5 or leaving it unsubstituted did not influ-
ence the formation of product. In general, the pres-
ence of a mild electron-withdrawing group on the 1,2-
phenylenediamine resulted in relatively lower yields
of the products as compared to unsubstituted 1,2-phe-
nylenediamine or the one containing a mild electron-
donating group. Thus this strategy proved to be a gen-
eral and convenient route for the synthesis of substi-
Figure 1. Cascade pathway to new annulated pyrazoles.
Table 1. Optimization of reaction conditions[a] with 1,2-phe-
nylenediamine.
Entry Catalyst Ligand
Base
Solvent Yield [%][b]
tuted-2,4 or 1,4-dihydrobenzo[b]pyrazolo
diazepines.
The second portion of this work involved the exten-
ACHUTGTNREN[NUG 4,3-e]ACHTUNGTRENNUNG[1,4]-
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
Cu2O
CuI
CuI
CuI
l-proline K3PO4 DMSO 76
DMEDA K3PO4 DMSO 24
l-proline K2CO3 DMSO 37
l-proline Cs2CO3 DMSO 28
sion of the strategy to similar copper-catalyzed cas-
cade reactions of 4-iodopyrazolecarbaldehydes with 2-
l-proline K3PO4 DMF
62
À
aminophenol involving C O coupling. It was satisfy-
l-proline K3PO4 toluene 13
l-proline K3PO4 dioxane 41
l-proline K3PO4 DMSO 32
l-proline K3PO4 DMSO 17
ing to note that reacting 4-iodo-1,5-diphenyl-1H-pyra-
zole-3-carbaldehyde and 2-aminophenol in the pres-
ence of CuI and Cs2CO3 in toluene under ligand-free
conditions successfully yielded 34% of the required
product. However introduction of 1,10-phenanthro-
line as ligand, keeping all other conditions constant,
9
10
11
12
–
–
–
K3PO4 DMSO 85
K2CO3 DMSO 65
Cs2CO3 DMSO 58
improved the yield significantly (Table 3, entry 2).[8]
A
[a]
[b]
Reaction
(1.0 mmol),
conditions:
4-iodo-3-pyrazolecarbaldehyde
brief survey of reactions with different bases and sol-
vents indicated Cs2CO3 and toluene to be superior for
the purpose. Thus the optimal conditions of CuI
(10 mol%), ligand 20 mol%, base 200 mol% in tolu-
ene at 908C for 24 h was employed for further screen-
ing.
o-phenylenediamine
(1.0 mmol),
CuI
(0.1 mmol), ligand (0.2 mmol), base (3.0 mmol), solvent
(1.0 mL), 908C, 36 h.
Isolated yields.
With the optimized conditions in hand, we studied
source, l-proline as ligand and K3PO4 as base led to the generality of this method with various 4-iodo-pyr-
the isolation of 76% of the desired product (Table 1, azolecarbaldehydes and different 2-aminophenols and
entry 1).[7] Changing the ligand to DMEDA was ob- the results are presented in Table 4. Although the
served to be detrimental leading to a significant drop nature of the 4-iodopyrazolecarbaldehydes did not
in the yields (Table 1, entry 2). Amongst the different have any effect on the yields, the substituents present
bases, solvents and copper sources examined, K3PO4, on the 2-aminophenols influenced the formation of
DMSO and CuI, respectively, were found to be supe- the final product. For example, the 2-aminophenols
rior for this reaction. Later as a routine, we checked containing an electron-donating group such as methyl
the reaction under copper-free or ligand-free condi- gave better yields as compared to the ones having an
tions too. Although the copper-free conditions failed electron-withdrawing group such as chloro. However,
to induce a reaction, we were surprised to discover the 2-aminophenol bearing a strong electron-with-
that reaction was successful under ligand-free condi- drawing group such as nitro failed to react to yield
tions (Table 1, entrie 10–12). Indeed, the ligand-free the required product (Table 4, entry 6).
reaction using K3PO4 furnished 85% of the required
We speculate that, in the first step, a condensation
product whereas other evaluated bases although suc- reaction between the aldehyde and aniline occurs re-
cessful the furnished product in relatively lower sulting in the formation of an imine. Subsequently the
À
À
yields. Hence the two most successful conditions of copper-promoted C N or C O cross-coupling reac-
10 mol% CuI, ligand-free or 20 mol% l-proline and tion involving either the amino group of 1,2-phenyl-
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Copper-Catalyzed Cascade Reactions of Substituted 4-Iodopyrazolecarbaldehydes
Table 2. Scope and limitations.
Entry
Aldehyde
1,2-Phenylenediamine
Product
Yield [%][a]
85/76
1
2
3
60/52
55/48
4
5
6
82/68
77/66
57/50
7
56/49
8
72/61
79/65
58/52
9
10
11
56/51
Adv. Synth. Catal. 2010, 352, 3431 – 3437
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Maloy Nayak and Sanjay Batra
UPDATES
Table 2. (Continued)
Entry
12
Aldehyde
1,2-Phenylenediamine
Product
Yield [%][a]
78/65
13
14
62/56
80/68
81/67
15
[a]
Isolated yields for the product under ligand-free/l-proline-containing reaction conditions.
Table 3. Optimization of reaction conditions[a] with 2-aminophenol.
Entry
Catalyst
Ligand
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
Cu2O
CuCl
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
toluene
toluene
DMF
dioxane
toluene
toluene
toluene
toluene
34
72
18
34
0
13
54
47
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
1,10-phenanthroline
Cs2CO3
Cs2CO3
[a]
Reaction conditions: 4-iodo-3-pyrazolecarbaldehyde (1.0 mmol), 2-amino phenol (1.0 mmol), CuI (0.1 mmol), ligand
(0.2 mmol), base (2.0 mmol), solvent (1.0 mL), 908C, 24 h.
Isolated yields.
[b]
ACHTUNGTRENNUNG
À
À
clized product. In an effort to provide a rationale to lecular C N or C O coupling reactions during this
this basis in a representative reaction the formyl study were, however, unsuccessful.
group of 4-iodo-1,5-diphenyl-1H-pyrazole-3-carbalde-
hyde was transformed to acetal which was then inde- ed strategy for the construction of substituted 2,4- or
pendently reacted with 1,2-phenylenediamine and 2- 1,4-dihydrobenzo[b]pyrazolo[4,3-e][1,4]diazepines or
aminophenol. Under both circumstances the reactions substituted 2H- or 1H-benzo[b]pyrazolo[3,4-f][1,4]-
failed and the starting materials were recovered un- oxazepines via a copper-catalyzed cascade cyclization.
In conclusion, we have developed an unprecedent-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
reacted (Scheme 1). In view of this result, it is pro- We have demonstrated the scope of the strategy with
posed that the imine formed as the first step in the a variety of reactants. This approach therefore up-
process has Z-stereochemistry across the double bond dates the literature on the copper-catalyzed cross-cou-
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Adv. Synth. Catal. 2010, 352, 3431 – 3437

Copper-Catalyzed Cascade Reactions of Substituted 4-Iodopyrazolecarbaldehydes
Table 4. Scope and limitations.
Entry
Aldehyde
2-Aminophenol
Product
Yield [%][a]
1
72
2
59
3
4
60
57
5
70
6
7
no reaction
64
57
8
9
56
69
70
10
11
Adv. Synth. Catal. 2010, 352, 3431 – 3437
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3435

Maloy Nayak and Sanjay Batra
UPDATES
Table 4. (Continued)
Entry
12
Aldehyde
2-Aminophenol
Product
Yield [%][a]
60
13
14
57
74
15
16
61
61
63
17
[a]
Isolated yields.
Scheme 1.
(339 mg, 1.60 mmol) and CuI (10 mg, 0.053 mmol) were
added and the reaction mixture was heated at 908C for 36 h
under a nitrogen atmosphere. Thereafter, water (50 mL) and
ethyl acetate (25 mL) were added and the reaction mass was
pass through a Celite bed and the layers were separated.
The aqueous layer was further extracted with ethyl acetate
(2ꢁ20 mL) and the collected organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated under
vacuum. Column chromatography of the crude product over
silica gel furnished the pure 2,3-diphenyl-2,4-dihydro-
pling in pyrazoles and offers an opportunity to con-
struct new fused benzazepines and benzoxepines with
other heterocyclic systems too.
Experimental Section
General Procedure for Pyrazole-Annulated Benzo-
diazepines as Exemplified for the Synthesis of 2,3-
A
ACHUTGTNRNEUG[N 4,3-b]ACHTUTGNREN[NUGN 1,5]benzodiazepine as a yellow solid (ethyl
Diphenyl-2,4-dihydropyrazoloCAHUTNGTREN[NUG 4,3-b]CAHTUNTGERN[NUGN 1,5]benzo-
diazepine
N
ACHTUNGTRENNUNG
To a solution of 4-iodo-1,5-diphenyl-1H-pyrazole-3-carbal-
dehyde (200 mg, 0.53 mmol) in DMSO (4 mL), K3PO4
;
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Adv. Synth. Catal. 2010, 352, 3431 – 3437

Copper-Catalyzed Cascade Reactions of Substituted 4-Iodopyrazolecarbaldehydes
1H NMR (300 MHz, CDCl3): d=7.26–7.37 (m, 14H), 7.84 (s,
1H), 10.13 (brs, 1H); 13C NMR (50 MHz, CDCl3 +DMSO-
d6): d=106.6, 122.0, 125.2, 127.7, 128.3, 128.6, 129.4, 139.4,
144.0, 144.4, 146.3; ESI-MS: m/z=337 [M+H]+; DART-
HR-MS: m/z=337.1450, calcd. for C22H17N4 [MH]+:
337.1453.
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General Procedure for Pyrazole-Annulated Benz-
oxazepines as Exemplified for the Synthesis of 2,3-
Diphenyl-2H-pyrazoloACTHNUTRGENNG[U 4,3-b]ACHUTNGTRENN[NGU 1,5]benzoxazepine
To a solution of 4-iodo-1,5-diphenyl-1H-pyrazole-3-carbal-
dehyde (200 mg, 0.53 mmol) in toluene (10 mL), Cs2CO3
(348 mg, 1.07 mmol), CuI (10 mg, 0.053 mmol) and 1,10-phe-
nanthroline (19 mg, 0.107 mmol) were added and the reac-
tion mixture was heated at 908C for 24 h under a nitrogen
atmosphere. Thereafter, water and ethyl acetate were added
and the reaction mass was pass through a Celite bed and the
layers were separated. The aqueous layer was further ex-
tracted with ethyl acetate (2ꢁ20 mL) and the collected or-
ganic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated under vacuum. Column chroma-
tography of the crude product over silica gel furnished the
pure 2,3-diphenyl-2H-pyrazoloACHTUNTGRENNUG[4,3-b]ACHTUNGTERN[NUGN 1,5]benzoxazepine as
a white solid (ethyl acetate/hexanes, 1:20); yield: 130 mg
(72%).
2,3-Diphenyl-2H-pyrazoloACHTNUTRGENN[UG 4,3-b]HCATUNGTRENN[UGN 1,5]benzoxazepine
(Table 4, entry 1): Mp 169–1708C; Rf =0.34 (hexanes:
1
EtOAc, 90:10, v/v); H NMR (200 MHz, CDCl3): d=7.26–
7.29 (m, 13H), 7.64 (dd, J=3.2 and 5.9 Hz, 1H), 7.81 (dd,
J=3.2 and 5.9 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=
108.5, 111.1, 120.3, 124.8, 125.5, 125.8, 128.5, 128.8, 129.0,
129.2, 129.7, 139.7, 141.4, 141.9, 145.2, 150.7, 158.3; ESI-MS:
m/z=338 [M+H]+; DART-HR-MS: m/z=338.1302, calcd.
for C22H16N3O [MH]+: 338.1293.
Supporting Information
Characterization data for the remaining products and copies
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3307.
1
of H and 13C NMR spectra are available in the Supporting
Information.
Acknowledgements
One of the authors (MN) gratefully acknowledges the finan-
cial support from Council of Scientific and Industrial Re-
search, New Delhi in the form of fellowship. The Sophisticat-
ed Analytical Instrumentation Facility division, CDRI is
gratefully acknowledged for providing the spectral and ana-
lytical data.
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Adv. Synth. Catal. 2010, 352, 3431 – 3437
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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