A Wittig-olefination-Claisen-rearrangement approach to the 3-methylquinoline-4-carbaldehyde synthesis

Article abstract of DOI:10.3762/bjoc.8.197

Efficient syntheses are described for the synthetically important 3-methylquinoline-4-carbaldehydes 6a-h from o-nitrobenzaldehydes 1a-h employing a Wittig-olefination-Claisen-rearrangement protocol. The Wittig reaction of o-nitrobenzaldehydes with crotyloxymethylene triphenylphosphorane afforded crotyl vinyl ethers 2a-h, which on heating under reflux in xylene underwent Claisen rearrangement to give 4-pentenals 3a-h. Protection of the aldehyde group of the 4-pentenals as acetals 4a-h and subsequent oxidative cleavage of the terminal olefin furnished nitroaldehydes 5a-h. Reductive cyclization of these nitroaldehydes yielded the required 3-methylquinoline-4-carbaldehydes 6a-h in excellent yields. Therefore, an efficient method was developed for the preparation of 3-methylquinoline-4-carbaldehydes from o-nitrobenzaldehydes in a simple five-step procedure.

Full text of DOI:10.3762/bjoc.8.197

A Wittig-olefination–Claisen-rearrangement
approach to the 3-methylquinoline-
4-carbaldehyde synthesis
Mukund G. Kulkarni*, Mayur P. Desai, Deekshaputra R. Birhade,
Yunus B. Shaikh, Ajit N. Dhatrak and Ramesh Gannimani
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1725–1729.
Department of Chemistry, University of Pune, Ganeshkhind, Pune
411007, India; Fax: +91 (020) 25691728
doi:10.3762/bjoc.8.197
Received: 13 May 2012
Email:
Accepted: 06 September 2012
Published: 11 October 2012
Mukund G. Kulkarni* - mgkulkarni@chem.unipune.ac.in
* Corresponding author
Associate Editor: J. Aube
Keywords:
© 2012 Kulkarni et al; licensee Beilstein-Institut.
License and terms: see end of document.
acetal; Claisen rearrangement; oxidative cleavage; ring-closure; Wittig
olefination
Abstract
Efficient syntheses are described for the synthetically important 3-methylquinoline-4-carbaldehydes 6a–h from o-nitrobenzalde-
hydes 1a–h employing a Wittig-olefination–Claisen-rearrangement protocol. The Wittig reaction of o-nitrobenzaldehydes with
crotyloxymethylene triphenylphosphorane afforded crotyl vinyl ethers 2a–h, which on heating under reflux in xylene underwent
Claisen rearrangement to give 4-pentenals 3a–h. Protection of the aldehyde group of the 4-pentenals as acetals 4a–h and subse-
quent oxidative cleavage of the terminal olefin furnished nitroaldehydes 5a–h. Reductive cyclization of these nitroaldehydes
yielded the required 3-methylquinoline-4-carbaldehydes 6a–h in excellent yields. Therefore, an efficient method was developed for
the preparation of 3-methylquinoline-4-carbaldehydes from o-nitrobenzaldehydes in a simple five-step procedure.
Introduction
Quinoline aldehydes are important synthetic intermediates in inhibitors of HMG-CoA reductase [6]. 3-Substituted quinoline-
the synthesis of heterocyclic compounds that are used in the 4-carbaldehyde derivatives are used in the development of
manufacturing of dyes [1] and pharmaceuticals [2,3]. 3-Substi- molecular probes for the identification of extra interaction sites
tuted and 2,3-di-substituted quinoline-4-carbaldehyde deriva- in the midgorge and peripheral sites of butyrylcholinesterase
tives are used in the synthesis of immunosuppressant KF20444 (BuChE) [7]. These derivatives are also exploited in the syn-
[4] and 5-HT3 receptor antagonists [5]. Quinoline mevalonolac- thesis of DNA binders [8], macrolides [9], antitumor agents
tones, prepared from 3-methylquinoline-4-carbaldehyde, act as [10] and for the treatment of viral and parasitic infections [11].
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Beilstein J. Org. Chem. 2012, 8, 1725–1729.
Though there are a number of quite efficient methods for the crotyl vinyl ethers 2e–h, all attempts to separate these (E)- or
preparation of quinoline-4-carbaldehyde [12-24], only a few (Z)-isomers were unsuccessful.
methods [6,9] are available for the preparation of 3-methyl-
quinoline-4-carbaldehyde derivatives. In connection with the Claisen rearrangement on either (E)- or (Z)-isomers 2a–d also
synthesis of camptothecin, we needed a general, high-yielding led to a diastereomeric mixture of 4-pentenals. However, these
method for the synthesis of 3-methylquinoline-4-carbaldehyde. diastereomers remained inseparable. The crotyl vinyl ethers
It was considered that a properly substituted 2-(2-nitro- 2e–h, on heating under reflux in anhydrous xylene, underwent
phenyl)pent-4-enal [25-27] could be a fitting intermediate for the Claisen rearrangement smoothly to give the diastereomeric
this purpose. Such an intermediate is easily accessible through mixture of the corresponding 4-pentenals 3e–h in good yields
the Wittig-olefination–Claisen-rearrangement protocol devel- (Table 1).
oped in our group [28,29].
Treatment of the 4-pentenals 3a–h with ethylene glycol
Results and Discussion
furnished the corresponding acetals 4a–h in good yields
Reaction of the o-nitrobenzaldehydes 1a–h with crotyloxymeth- (Table 1). From the NMR spectra of these acetals, it was clear
ylene triphenylphosphorane under optimized reaction condi- that they were also a mixture of diastereomers, although they
tions (Scheme 1) gave crotyl vinyl ethers in good yields appeared to be homogeneous on TLC. All attempts to separate
(Table 1). The geometrical isomers of the crotyl vinyl ethers the diastereomers at this stage were also unsuccessful.
2a–d were well separated on TLC, and it was possible to sepa- Subjecting these acetals to oxidative cleavage in aq THF
rate them by column chromatography. In the case of other furnished the aldehydes 5a–h in good yields (Table 1). The
Scheme 1: Reagents and conditions: (i) Ph3P+CH2OCH2CH=CHCH3Cl−, t-BuOK, dry THF, 0 °C; (ii) xylene, reflux, 5–7 h; (iii) 3 equiv ethylene glycol,
cat. p-TSA, toluene, reflux, 3–4 h; (iv) cat. potassium osmate, 2 equiv NMO, 2 equiv NaIO4, aq THF, 3–4 h; (v) 5 equiv Zn, AcOH, reflux, 0.5 h.
Table 1: Synthesis of 3-methylquinoline-4-carbaldehydes.
% Yields of
Aldehydes 1
2a
3b
4b
5b
6
90
85
92
91
85
(Z/E = 1:1.48)
(dr = 1:1.21)
(dr = 1:1.5)
(dr = 1:2.46)
1a
1b
1c
91
83
91
90
84
85
(Z/E = 1:1.42)
(dr = 1:1.36)
(dr = 1:1.12)
(dr = 1:1.03)
92
84
90
91
(Z/E = 1:1.87)
(dr = 1:1.74)
(dr = 1:1.24)
(dr = 1:1.52)
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Beilstein J. Org. Chem. 2012, 8, 1725–1729.
Table 1: Synthesis of 3-methylquinoline-4-carbaldehydes. (continued)
93
86
92
91
83
(Z/E = 1:1.93)
(dr = 1:1.63)
(dr = 1:1.66)
(dr = 1:1.41)
1d
85
91
90
(dr = 1:6)
91c
80d
79
(dr = 1:1.16)
(dr = 1:2.63)
1e
90
83
92
(dr = 1:1)
91
(only (E)-isomer)
(dr = 1:9.01)
(dr = 1:6.58)
1f
92
83
91
90
80
82
(Z/E = 1:2.06)
(dr = 1:2.42)
(dr = 1:1.11)
(dr = 1:1.5)
1g
91
85
90
91
(Z/E = 1:1.94)
(dr = 1:1.87)
(dr = 1:1.86)
(dr = 1:1.44)
1h
a2a–d are separable geometrical isomers, whereas 2e, 2g and 2h are mixtures of inseparable geometrical isomers. The Z/E ratio of the geometrical
isomers of 2g–h was calculated from their NMR signals.
b3a–h, 4a–h and 5a–h are mixtures of diastereomers, and the diastereomeric ratio (dr) was calculated from their NMR signals.
cThe Z/E ratio of the geometrical isomers of 2e cannot be calculated from their NMR signals.
dKnown compound [6,9].
NMR of these aldehydes revealed them again to be a mixture of General procedure for the Wittig olefination
diastereomers, although they appeared to be homogeneous on To a suspension of the o-nitrobenzaldehyde (20 mmol) and
TLC. Reductive cyclization of these nitroaldehydes furnished crotyloxymethylenetriphenylphosphonium chloride (24 mmol,
the required 3-methylquinoline-4-carbaldehydes 6a–h.
1.2 equiv) in dry THF (40 mL) at 0 °C was added t-BuOK
(24 mmol, 1.2 equiv) in small portions. After 40–45 min (TLC,
ethyl acetate/petroleum ether 1:9), THF was removed under
Conclusion
A new and efficient methodology for the construction of a vacuum. Water (25 mL) was added to the reaction mixture, and
3-methylquinoline-4-carbaldehyde framework, with 50–55% then the aqueous layer was extracted with ethyl acetate
overall yield, through a Wittig-olefination–Claisen-rearrange- (3 × 15 mL), the combined organic layer was dried over sodium
ment protocol has been developed.
sulfate, and ethyl acetate was evaporated under vacuum. The
crude product, i.e., crotyl vinyl ether, was purified by using
silica-gel column chromatography (mobile phase 1–3% ethyl
acetate in petroleum ether). Crotyl vinyl ethers (a–h were
Experimental
General
Silica gel (100–200 mesh) was used for column chromatog- obtained in 84–89% yield.
raphy. IR spectra were recorded on a Perkin Elmer model 1600
series FTIR instrument. 1H and 13C NMR (ppm, TMS, internal General procedure for the Claisen rearrangement
standard) in CDCl3 were recorded on a JEOL FX 90Q, Varian The crotyl vinyl ethers 2a–h (17 mmol) obtained from the
Mercury 300 MHz and 75 MHz, respectively. CHN analysis Wittig reaction were dissolved in anhydrous xylene (35 mL)
was performed on a Thermo FLASH EA model 1112 series. and the solution was heated under reflux for 5–7 h (TLC, ethyl
TLC was checked either under UV light and/or charring after acetate/petroleum ether 1:9). Then, the solvent was removed
dipping into anisaldehyde solution.
under reduced pressure. The crude aldehyde was purified by
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Beilstein J. Org. Chem. 2012, 8, 1725–1729.
using silica-gel column chromatography (mobile phase 2–5% orated under vacuum. The crude product was obtained and puri-
ethyl acetate in pet. ether). 4-Pentenals 3a–h were obtained in fied by silica-gel column chromatography (mobile phase 2–3%
83–89% yield.
ethyl acetate in petroleum ether). The products 6a–h were
obtained in 84–87% yield.
General procedure for the protection of aldehyde
Aldehydes 3a–h obtained from Claisen rearrangement
(15 mmol) were dissolved in anhydrous toluene (25 mL). To
this solution, a catalytic amount of p-TSA (1.5 mmol, 0.1 equiv)
and ethylene glycol (45 mmol, 3 equiv) were added. The reac-
tion mixture was heated under reflux for 3–4 h by using a
Dean–Stark condenser (TLC, ethyl acetate/petroleum ether 1:9).
After removal of the solvent under reduced pressure, water
(20 mL) was added to the reaction mixture, and then the
aqueous layer was extracted with ethyl acetate (3 × 15 mL), the
combined organic layer was dried over sodium sulfate, and
ethyl acetate was evaporated under vacuum. Finally, the prod-
uct was purified by silica-gel column chromatography (mobile
phase 1–3% ethyl acetate in petroleum ether). The products
4a–h were obtained in 89–93% yield.
Supporting Information
Supporting Information File 1
IR, 1H NMR, 13C NMR and CHN analysis and spectral
data of synthesized compounds.
The geometric isomeric ratios for 2g and 2h and
diastereomeric ratios for 3a–h, 4a–h and 5a–h were
calculated from their NMR signals.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-197-S1.pdf]
Acknowledgements
MPD would like to thank UGC, New Delhi and DRB, YBS, and
RG would like to thank CSIR, New Delhi for the fellowship.
General procedure for the oxidative cleavage of
alkene
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