An expedient and new synthesis of pyrrolo[1,2-b]pyridazine derivatives

Article abstract of DOI:10.3762/bjoc.5.66

The reaction of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo- pentanoic acid phenylamide with tertiary butyl carbazate and subsequent condensation of the resulting carbamate derivative with a chalcone provided a facile new approach to pyrrolo

Full text of DOI:10.3762/bjoc.5.66

An expedient and new synthesis of
pyrrolo[1,2-b]pyridazine derivatives
Rajeshwar Reddy Sagyam1, Ravinder Buchikonda1, Jaya Prakash Pitta1,
Himabindu Vurimidi2, Pratap Reddy Padi1 and Mahesh Reddy Ghanta*3
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 66.
1Integrated Product Development, Dr. Reddy’s Laboratories Limited,
Bachupally, Qutubullapur, Ranga Reddy District-500072, Andhra
Pradesh, India, 2Institute of Science and Technology, Center for
Environmental Science, J. N. T. University, Kukatpally,
Hyderabad-500 072, Andhra Pradesh, India and 3Asha Laboratories,
Plot # 175/1, Prashanthi Nagar, Kukatpally, Hyderabad-500072,
Andhra Pradesh, India
doi:10.3762/bjoc.5.66
Received: 12 August 2009
Accepted: 08 October 2009
Published: 17 November 2009
Associate Editor: J. Aubé
Email:
© 2009 Sagyam et al; licensee Beilstein-Institut.
License and terms: see end of document.
Mahesh Reddy Ghanta* - reddyghanta@yahoo.com
* Corresponding author
Keywords:
1,4-diketone; migration and cyclization; pyrrolo[1,2-b]pyridazine;
tertiary butyl carbamate; tertiary butyl carbazate; α,β-unsaturated
ketone
Abstract
The reaction of 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide with tertiary butyl
carbazate and subsequent condensation of the resulting carbamate derivative with a chalcone provided a facile new approach to
pyrrolo[1,2-b]pyridazine derivatives.
Introduction
Pyrrolopyridazine derivatives have various biological applica- perchlorates with malononitrile, ethyl cyanoacetate and ethyl
tions [1-8], and their fluorescent properties have been investi- malonate in the presence of sodium ethoxide [15]; the conden-
gated for potential use in sensors, lasers, and semiconductor sation of 1,4,7-triketones with hydrazine followed by dehydro-
devices [9-13].
genation [16]; the condensation of cyanoacetic acid hydrazide
with 3-bromo-1,1,3-tricyano-2-phenylpropene [17]; and the
The synthesis and properties of pyrrolo[1,2-b]pyridazine deriva- reaction between 3-chloropyridazines with propargylic alcohol
tives were reviewed in 1977 by Kuhla and Lombardino [14]. in the presence of Pd(PPh3)2Cl2–CuI with diethylamine as the
Subsequently, new methods for the synthesis of these com- reaction medium [18,19]. The second approach is based on
pounds have been described, which can be classified into two cycloaddition reactions, such as the cycloaddition of dimethyl
main approaches. The first involves condensation reactions, acetylenedicarboxylate to the Reissert compound of pyridazine
such as the condensation of oxazolo[3,2-b]pyridazinium [20], the 1,3-dipolar cycloaddition of pyridazinium dichloro-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 66.
methylide generated by the carbene method [21], and the
cycloaddition of alkylidene cyclopropane derivatives to
pyridazine in the presence of Pd(PPh3)4 [22].
Pyrrolo[1,2-b]pyridazine derivatives can also be synthesized
from 1-aminopyrrole and its derivatives. This original method
was reported by Flitsch and Krämer (in 1968–9) [23,24], who
obtained a series of unsubstituted pyrrolopyridazines from
Figure 1: Unsubstituted pyrrolo[1,2-b]pyridazine.
1-aminopyrrole and β-dicarbonyl compounds. Benzoylacetone, Results and Discussion
on condensation with 1-aminopyrrole, forms only one isomer, 2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-
2-methyl-4-phenyl-pyrrolopyridazine, whereas benzoylacetal- pentanoic acid phenylamide 1 was reacted with tertiary butyl
dehyde yields a mixture of 2-phenyl- and 4-phenyl- carbazate 2 in toluene and cyclohexane in the presence of
pyrrolopyridazine. 3-Phenylpyrrolopyridazine is obtained from p-toluenesulfonic acid (p-TSA) at reflux and the resulting [2-(4-
phenylmalonaldehyde and 1-aminopyrrole [25]. Unsubstituted fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-
pyrrolopyridazine (Figure 1) was synthesized in 21% yield from 1-yl]-carbamic acid tert-butyl ester 3 was further condensed
1-aminopyrrole and 3-ethoxyacrolein diethylacetal [26].
with 3-(4-fluorophenyl)-1-phenyl-propenone 4a [29] in the
presence of p-TSA in the same medium. Pyrrolo[1,2-
As a part of our continued interest in the development of new b]pyridazine derivatives, i.e. 4,7-bis-(4-fluorophenyl)-4a-isop-
synthetic methods for highly substituted pyrrole and indole de- ropyl-2,6-diphenyl-4a,7-dihydropyrrolo[1,2-b]pyridazine-5-
rivatives [27,28], we have developed a new synthetic route to carboxylic acid phenylamide 5a, were expected as products in
pyrrolo[1,2-b]pyridazines through a hitherto unprecedented this synthetic sequence (Scheme 1). However, IR, mass,
approach from a BOC-protected 1-aminopyrrole derivative and HRMS, and 1H, 13C, and 2D NMR spectral data of the product
α,β-unsaturated ketones.
confirmed the structure of the product as 4,7-bis-(4-fluoro-
Scheme 1: Reagents and conditions: i) p-TSA (0.5 equiv), toluene/cyclohexane (4:15), reflux, 15–18 h; ii) p-TSA (1.5 equiv), toluene/cyclohexane
(30:20), reflux, 15–25 h.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 66.
phenyl)-5-isopropyl-2,6-diphenyl-3,4-dihydropyrrolo[1,2- C-5; C-4 to C-8, C-3; and C-3 to C-2, C-4. All these spectral
b]pyridazine 6a (Table 1).
data are in favor of 4,7-bis-(4-fluoro-phenyl)-5-isopropyl-2,6-
diphenyl-3,4-dihydropyrrolo[1,2-b]pyridazine structure 6a
In the mass spectrum of the compound, the molecular ion peak (Figure 2), but not of 4,7-bis-(4-fluorophenyl)-4a-isopropyl-2,6-
was observed at m/z 502 (M+), instead of m/z 621 (M+); HRMS diphenyl-4a,7-dihydropyrrolo[1,2-b]pyridazine-5-carboxylic
data also confirmed the m/z 502 (M+) and molecular formula as acid phenylamide 5a.
C34H28F2N2, in accord with structure 6a and not with 5a. The
IR spectrum lacked any –C=O absorption. The 1H NMR spec-
trum of 6a exhibited signals due to two methyl groups and the
–CH of an isopropyl group at δ 0.85 (d, 3H), δ 1.15 (d, 3H), and
δ 2.84–2.91 (m, 1H), respectively; –CH2 and –CH of pyridazine
ring at δ 3.1–3.26 (ddd, 2H) and δ 4.71–4.74 (d, 1H), respect-
ively; and aromatic protons at δ 6.88–7.63 (m, 18H). In the 13C
NMR, the DEPT spectrum was characterized by the presence of
signals due to 2 × CH3 and 1 × CH of isopropyl group; CH2 and
CH of pyridazine ring at δ 22.6, 23.8, and 25.3; 31.5 and 34.7
ppm, respectively. Product 5a should exhibit a –C=O signal and
no CH2 peak. In the DQCOSY spectrum, 1H–1H coupling
between 2 × CH3 groups and –CH of the isopropyl group and
Figure 2: Depiction with proprietary numbering of compound 6a.
also between the –CH2 and –CH groups of pyridazine ring was
seen, but no coupling between the isopropyl group and the
–CH2 and –CH of the pyridazine ring was observed. This indi- A plausible mechanistic pathway for the formation of com-
cates that the newly formed –CH2 and –CH are connected to pounds 6a–j involves hydrolysis and decarboxylation of
each other, which is not possible in 5a. The HSQC spectrum carbamate 3, subsequent condensation with chalcone 4a–j to
exhibited 13C–1H coupling of two methyl groups at δ 23.0, 1.2 provide alkenyl imine 9, its sequential hydrolysis and
(d, 3H); δ 24.0, 0.90 (d, 3H) and –CH of isopropyl at δ 25.5, decarboxylation, followed by cyclization and migration of the
2.85 (m, 1H), and also the –CH2 and –CH groups of pyridazine isopropyl group (Scheme 2).
ring at δ 31.5, 3.1–3.3 (ddd, 2H); δ 35.0, 4.75 (d, 1H). The
newly formed –CH2 is linked to a -CH group. It is reported [30] To substantiate the proposed mechanism, the amine 8 was inde-
that the 4° carbons of the pyrrole ring resonate at 118 (C-8), 122 pendently prepared from compound 3 by treatment with 33%
(C-6), 124 (C-5), and 132 (C-7). The HMBC spectrum hydrobromic acid in acetic acid at 30 °C followed by reaction
displayed the 13C–1H correlations of 2 × CH3 with only C-5; with 4a in the presence of I2 (0.05 equiv) in refluxing ethyl
iPr-CH with 2 × CH3, C-5, C-6, and C-8; CH of pyridazine ring alcohol to provide alkenyl imine 9, which was characterized on
(C-4) with C-3, C-8, C-5 (less), C-2, C-9, and C-10; CH2 (C-3) the basis of its mass, 1H and 13C NMR, DEPT, and IR spectral
with C-4, C-2, C-8, C-5 (very small), C-13 (small), and C-9. data. Compound 9 was heated in toluene in the presence of
These data strongly support the linkage of isopropyl group to p-TSA for 10–12 h and the resulting compound was found to be
Table 1: 3,4-Dihydropyrrolo[1,2-b]pyridazines 6a–j.
Entry
Product
R
R1
Yield (%)
Time (h)
1
2
3
4
5
6
7
8
9
10
6a
6b
6c
6d
6e
6f
H
F
86
84
73
70
88
82
68
70
65
64
19
18
21
22
15
15
23
22
22
25
Cl
Cl
Br
Cl
Br
Br
Cl
H
F
CH3
CH3
Cl
F
6g
6h
6i
H
H
CH3
CH3
6j
CH3
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Beilstein Journal of Organic Chemistry 2009, 5, No. 66.
Scheme 2: Plausible mechanistic pathway.
identical to product 6a. Hydrolysis of the amide group and
subsequent decarboxylation was carried out on pyrrole deriva-
tive 15 to afford the 2,3-diaryl pyrrole derivative 16
(Scheme 3).
With a view to extending this protocol to aliphatic systems such
as α,β-unsaturated ketones, carbamate 3 was treated with
crotonaldehyde under similar conditions. However, the alkenyl
imine analogue 9 thus obtained did not undergo further reaction.
This may be due to the +I effect of alkyl groups, whereas in the
case of aryl groups (−M effect) the olefinic carbon is electron
deficient and therefore cyclization is favorable.
Scheme 3: Reagents and conditions: i) p-TSA (1.5 equiv), toluene/
cyclohexane (1:1), reflux, 10.0 h.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 66.
Scheme 4: Reagents and conditions: i) p-TSA (2.0 equiv), toluene (30.0 volumes).
To aromatize the pyrrolopyridazine ring system, the compound Milford, MA, USA). Melting points were determined by the
6a was heated in the presence of p-TSA in toluene at 110 °C for capillary method with a POLMON (Model MP-96) melting
25.0 h and the resulting compound to yield 4,7-bis-(4- point apparatus. Solvent removal was accomplished by a Buchi
fluorophenyl)-5-isopropyl-2,6-diphenylpyrrolo[1,2-b]pyridazine rotary evaporator at house vacuum (30–40 Torr). Solvents and
(17a, Scheme 4). Other pyrrolopyridazine derivatives 6a–j were reagents were used without further purification. The purity of
converted into corresponding dehydro derivatives 17a–j under compounds was checked on silica gel coated aluminium plates
similar conditions (Table 2).
(Merck).
Conclusion
(a) Procedure for compound 3: A mixture of 2-[2-(4-
In conclusion, a facile new approach has been developed for the fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic
synthesis of pyrrolo[1,2-b]pyridazine derivatives from commer- acid phenylamide (1, 5.0 g, 0.012 mol), tertiary butyl carbazate
cially available and environmentally friendly chemicals. This (2, 2.06 g, 0.0156 mol), and p-TSA (0.006 mol) in toluene (20.0
newly developed method offers quick access to building blocks mL) and cyclohexane (75.0 mL) was maintained at reflux until
for various products with pyrrolo[1,2-b]pyridazine cores.
no more water collected (reaction monitored by TLC). The
reaction mixture was cooled to 30 °C, allowed to stand for 3 h,
filtered and washed with cyclohexane (10.0 mL). The
Experimental
The 1H, 13C NMR spectra were recorded in DMSO-d6 and compound was washed again with cyclohexane (30.0 mL) and
CDCl3 at 200 or 400 MHz on a Mercury Plus/Varian Gemini dried to give a white solid. mp 191–193 °C; 1H NMR (400
2000 FT NMR spectrometer. Proton chemical shifts (δ) were MHz, DMSO-d6, δ ppm): 1.3 (d, 15H, 3CH3 of ester and 2CH3
expressed in ppm with tetramethylsilane (TMS, δ 0.00) as of iPr), 3.1 (m, 1H, CH), 6.97–7.54 (m, 14H, Ar-H), 9.9 (s, 1H,
internal standard. Spin multiplicities are given as s (singlet), d NH amide), 10.3 (s, 1H, NH ester), both –NH groups were D2O
(doublet), t (triplet), and m (multiplet). FT-IR spectra were exchangeable; IR KBr (cm−1): 3422, 3258, 1712, 1671; Anal.
recorded in KBr dispersion with a Perkin-Elmer 1650 FT-IR Calcd for C31H32FN3O3: C, 72.49; H, 6.28; N, 8.18. Found: C,
spectrometer. Mass spectra (70 eV) were recorded on HP-5989 72.33; H, 6.42; N, 8.35.
A LC-MS spectrometer. The high resolution mass spectroscopy
(HRMS) analysis was performed on the Micromass LCT (b) A typical procedure for compound 6a: A mixture of
Premier XE mass spectrometer equipped with an ESI Lack [2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-
spray source for accurate mass values (Water Corporation, pyrrol-1-yl]-carbamic acid tert-butyl ester (3, 5.0 g, 0.0097
Table 2: Yields and reaction times for compounds 17a–j.
Comp No.
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
R
H
F
Cl
F
Cl
CH3
79
Br
CH3
76
Cl
Cl
Br
F
Br
H
Cl
H
H
CH3
61
CH3
CH3
59
R1
Yield (%)
Time (h)
75
25
81
19
84
14
83
14
63
22
73
20
23
22
28
27
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Beilstein Journal of Organic Chemistry 2009, 5, No. 66.
3. Nasir, A. I.; Gundersen, L.-L.; Rise, F.; Antonsen, Ø.; Kristensen, T.;
Langhelle, B.; Bast, A.; Custers, I.; Haenen, G. R. M. M.; Wikström, H.
Bioorg. Med. Chem. Lett. 1998, 8, 1829–1832.
mol), 3-(4-fluorophenyl)-1-phenyl-propenone (4a, 2.62 g,
0.0102 mol), and p-TSA (2.5 g, 0.0146 mol) in toluene
(150.0 mL) and cyclohexane (100.0 mL) was maintained at
reflux (azeotropic) for 19.0 h (reaction monitored by TLC). The
reaction mixture was cooled to ambient temperature; ethyl
acetate (40.0 mL) was added and washed first with water (25.0
mL) and then with 10% sodium bicarbonate solution (25.0 mL).
The resulting organic layer was concentrated under vacuum and
the crude product recrystallized from ethyl acetate (25.0 mL) to
remove unreacted 9 (~5.0%). The resulting filtrate was concen-
trated under vacuum and further recrystallized from isopropyl
alcohol (20.0 mL) to give a cream solid (Table 1). mp
203–205 °C; MS: m/z 502 (M+); HRMS data: m/z 502 (M+) and
mol. formula: C34H28F2N2; 1H NMR (400 MHz, CDCl3, δ
ppm): 0.85 (d, J = 7.2 Hz, 3H, CH3), 1.15 (d, J = 7.2 Hz, 3H,
CH3), 2.84–2.91 (m, 1H, CH), 3.1–3.26 (ddd, J = 6.8, 16.4 Hz,
2H, CH2 of ring), 4.71–4.74 (d, J = 6.8 Hz, 1H, CH of ring),
6.88–7.63 (m, 18H, Ar-H); 13C NMR (100 MHz, CDCl3, δ
ppm): 22.6, 23.8, 25.3, 31.5, 34.7, 114.0, 114.5, 115.2, 115.7,
118.4, 122.2, 124.0, 126.0, 126.2, 127.0, 127.7, 127.9, 128.3,
128.5, 129.7, 131.2, 132.50, 132.65, 136.1, 136.7, 139.5, 152.3,
159.0, 159.2, 163.8, 164.0; DEPT (200 MHz, CDCl3, δ ppm):
CH3 carbons at δ 22.6, 23.8; aliphatic-CH carbons at δ 25.3,
34.7 and aromatic-CH carbons at δ 114.0–132.6; CH2 carbon at
δ 31.5 ppm; DQCOSY (400 MHz, CDCl3, δ ppm, 1H–1H coup-
ling): δ 0.8 and 1.2 coupled with δ 2.8 and δ 3.2 coupled with δ
4.8 ppm; HSQC (400 MHz, CDCl3, δ ppm, 13C–1H coupling): δ
23.0, 1.2 (d, 3H, CH3 of iPr); δ 24.0, 0.90 (d, 3H, CH3 of iPr);
and δ 25.5, 2.85 (m, 1H, CH of iPr); δ 31.5, 3.1–3.3 (ddd, 2H,
CH2 of pyridazine ring); δ 35.0, 4.75 (d, 1H, CH of pyridazine
ring); and δ 113–134, 6.9–7.95 (m, 18H, Ar-H); the HMBC
spectrum: 13C–1H correlations of 2 × CH3 (124, C-5); iPr-CH
(2 × CH3, C-5, C-6, and C-8); CH of pyridazine ring (CH2, C-8,
C-5 (less), C-2, C-9, and C-10); CH2 (C-4, C-8, C-5 (very less),
C-13 (less), C-9, and C-2); IR KBr (cm−1): 3064, 1600, 1506,
1155; Anal. Calcd for C34H28F2N2: C, 81.25; H, 5.62; N, 5.57.
Found: C, 81.41; H, 5.51; N, 5.74.
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