A Wittig-olefinationClaisen-rearrangement

approach to the 3-methylquinoline4-carbaldehyde synthesis

Mukund G. Kulkarni*, Mayur P. Desai, Deekshaputra R. Birhade,
Yunus B. Shaikh, Ajit N. Dhatrak and Ramesh Gannimani

Full Research Paper

Address:
Department of Chemistry, University of Pune, Ganeshkhind, Pune
411007, India; Fax: +91 (020) 25691728

Open Access
Beilstein J. Org. Chem. 2012, 8, 17251729.
doi:10.3762/bjoc.8.197

Email:
Mukund G. Kulkarni* - mgkulkarni@chem.unipune.ac.in

Received: 13 May 2012

Accepted: 06 September 2012
Published: 11 October 2012

* Corresponding author

Associate Editor: J. Aube

Keywords:
acetal; Claisen rearrangement; oxidative cleavage; ring-closure; Wittig
olefination

2012 Kulkarni et al; licensee Beilstein-Institut.

License and terms: see end of document.

Abstract
Efficient syntheses are described for the synthetically important 3-methylquinoline-4-carbaldehydes 6ah from o-nitrobenzaldehydes 1ah employing a Wittig-olefinationClaisen-rearrangement protocol. The Wittig reaction of o-nitrobenzaldehydes with
crotyloxymethylene triphenylphosphorane afforded crotyl vinyl ethers 2ah, which on heating under reflux in xylene underwent
Claisen rearrangement to give 4-pentenals 3ah. Protection of the aldehyde group of the 4-pentenals as acetals 4ah and subsequent oxidative cleavage of the terminal olefin furnished nitroaldehydes 5ah. Reductive cyclization of these nitroaldehydes
yielded the required 3-methylquinoline-4-carbaldehydes 6ah 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
the synthesis of heterocyclic compounds that are used in the
manufacturing of dyes [1] and pharmaceuticals [2,3]. 3-Substituted and 2,3-di-substituted quinoline-4-carbaldehyde derivatives are used in the synthesis of immunosuppressant KF20444
[4] and 5-HT3 receptor antagonists [5]. Quinoline mevalonolactones, prepared from 3-methylquinoline-4-carbaldehyde, act as

inhibitors of HMG-CoA reductase [6]. 3-Substituted quinoline4-carbaldehyde derivatives are used in the development of
molecular probes for the identification of extra interaction sites
in the midgorge and peripheral sites of butyrylcholinesterase
(BuChE) [7]. These derivatives are also exploited in the synthesis of DNA binders [8], macrolides [9], antitumor agents
[10] and for the treatment of viral and parasitic infections [11].

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Though there are a number of quite efficient methods for the

preparation of quinoline-4-carbaldehyde [12-24], only a few
methods [6,9] are available for the preparation of 3-methylquinoline-4-carbaldehyde derivatives. In connection with the
synthesis of camptothecin, we needed a general, high-yielding
method for the synthesis of 3-methylquinoline-4-carbaldehyde.
It was considered that a properly substituted 2-(2-nitrophenyl)pent-4-enal [25-27] could be a fitting intermediate for
this purpose. Such an intermediate is easily accessible through
the Wittig-olefinationClaisen-rearrangement protocol developed in our group [28,29].

Results and Discussion

Reaction of the o-nitrobenzaldehydes 1ah with crotyloxymethylene triphenylphosphorane under optimized reaction conditions (Scheme 1) gave crotyl vinyl ethers in good yields
(Table 1). The geometrical isomers of the crotyl vinyl ethers
2ad were well separated on TLC, and it was possible to separate them by column chromatography. In the case of other

crotyl vinyl ethers 2eh, all attempts to separate these (E)- or

(Z)-isomers were unsuccessful.
Claisen rearrangement on either (E)- or (Z)-isomers 2ad also
led to a diastereomeric mixture of 4-pentenals. However, these
diastereomers remained inseparable. The crotyl vinyl ethers
2eh, on heating under reflux in anhydrous xylene, underwent
the Claisen rearrangement smoothly to give the diastereomeric
mixture of the corresponding 4-pentenals 3eh in good yields
(Table 1).
Treatment of the 4-pentenals 3ah with ethylene glycol
furnished the corresponding acetals 4ah in good yields
(Table 1). From the NMR spectra of these acetals, it was clear
that they were also a mixture of diastereomers, although they
appeared to be homogeneous on TLC. All attempts to separate
the diastereomers at this stage were also unsuccessful.
Subjecting these acetals to oxidative cleavage in aq THF
furnished the aldehydes 5ah in good yields (Table 1). The

Scheme 1: Reagents and conditions: (i) Ph3P+CH2OCH2CH=CHCH3Cl, t-BuOK, dry THF, 0 C; (ii) xylene, reflux, 57 h; (iii) 3 equiv ethylene glycol,
cat. p-TSA, toluene, reflux, 34 h; (iv) cat. potassium osmate, 2 equiv NMO, 2 equiv NaIO4, aq THF, 34 h; (v) 5 equiv Zn, AcOH, reflux, 0.5 h.

Table 1: Synthesis of 3-methylquinoline-4-carbaldehydes.

Aldehydes 1

2a

3b

90
(Z/E = 1:1.48)

85
(dr = 1:1.21)

91
(Z/E = 1:1.42)

92
(Z/E = 1:1.87)

% Yields of
4b

5b

92
(dr = 1:1.5)

91
(dr = 1:2.46)

85

83
(dr = 1:1.36)

91
(dr = 1:1.12)

90
(dr = 1:1.03)

84

84
(dr = 1:1.74)

90
(dr = 1:1.24)

91
(dr = 1:1.52)

85

1a

1b

1c

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Beilstein J. Org. Chem. 2012, 8, 17251729.

Table 1: Synthesis of 3-methylquinoline-4-carbaldehydes. (continued)

93
(Z/E = 1:1.93)

86
(dr = 1:1.63)

92
(dr = 1:1.66)

91
(dr = 1:1.41)

83

91c

85
(dr = 1:1.16)

91
(dr = 1:2.63)

90
(dr = 1:6)

80d

90
(only (E)-isomer)

83
(dr = 1:9.01)

92
(dr = 1:1)

91
(dr = 1:6.58)

79

92
(Z/E = 1:2.06)

83
(dr = 1:2.42)

91
(dr = 1:1.11)

90
(dr = 1:1.5)

80

91
(Z/E = 1:1.94)

85
(dr = 1:1.87)

90
(dr = 1:1.86)

91
(dr = 1:1.44)

82

1d

1e

1f

1g

1h
a2ad

are separable geometrical isomers, whereas 2e, 2g and 2h are mixtures of inseparable geometrical isomers. The Z/E ratio of the geometrical
isomers of 2gh was calculated from their NMR signals.
b3ah, 4ah and 5ah 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

diastereomers, although they appeared to be homogeneous on
TLC. Reductive cyclization of these nitroaldehydes furnished
the required 3-methylquinoline-4-carbaldehydes 6ah.

Conclusion
A new and efficient methodology for the construction of a
3-methylquinoline-4-carbaldehyde framework, with 5055%
overall yield, through a Wittig-olefinationClaisen-rearrangement protocol has been developed.

Experimental
General
Silica gel (100200 mesh) was used for column chromatography. IR spectra were recorded on a Perkin Elmer model 1600
series FTIR instrument. 1H and 13C NMR (ppm, TMS, internal
standard) in CDCl3 were recorded on a JEOL FX 90Q, Varian
Mercury 300 MHz and 75 MHz, respectively. CHN analysis
was performed on a Thermo FLASH EA model 1112 series.
TLC was checked either under UV light and/or charring after
dipping into anisaldehyde solution.

General procedure for the Wittig olefination

To a suspension of the o-nitrobenzaldehyde (20 mmol) and
crotyloxymethylenetriphenylphosphonium chloride (24 mmol,
1.2 equiv) in dry THF (40 mL) at 0 C was added t-BuOK
(24 mmol, 1.2 equiv) in small portions. After 4045 min (TLC,
ethyl acetate/petroleum ether 1:9), THF was removed under
vacuum. Water (25 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. The
crude product, i.e., crotyl vinyl ether, was purified by using
silica-gel column chromatography (mobile phase 13% ethyl
acetate in petroleum ether). Crotyl vinyl ethers (ah were
obtained in 8489% yield.

General procedure for the Claisen rearrangement

The crotyl vinyl ethers 2ah (17 mmol) obtained from the
Wittig reaction were dissolved in anhydrous xylene (35 mL)
and the solution was heated under reflux for 57 h (TLC, ethyl
acetate/petroleum ether 1:9). Then, the solvent was removed
under reduced pressure. The crude aldehyde was purified by

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Beilstein J. Org. Chem. 2012, 8, 17251729.

using silica-gel column chromatography (mobile phase 25%

ethyl acetate in pet. ether). 4-Pentenals 3ah were obtained in
8389% yield.

orated under vacuum. The crude product was obtained and purified by silica-gel column chromatography (mobile phase 23%
ethyl acetate in petroleum ether). The products 6ah were
obtained in 8487% yield.

General procedure for the protection of aldehyde

Aldehydes 3ah 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 reaction mixture was heated under reflux for 34 h by using a
DeanStark 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 product was purified by silica-gel column chromatography (mobile
phase 13% ethyl acetate in petroleum ether). The products
4ah were obtained in 8993% yield.

General procedure for the oxidative cleavage of

alkene
Alkenes 4ah (13.5 mmol), obtained as described above, were
dissolved in aq. THF (30 mL, THF/H2O 1:1). N-Methylmorpholine-N-oxide (NMO) (27 mmol, 2 equiv) and potassium
osmate (0.027 mmol, 2 mol %) were added to this solution. The
mixture was stirred at room temperature for 23 h until the
starting compound disappeared (TLC, ethyl acetate/petroleum
ether 1:9). Then, sodium metaperiodate was added (27 mmol,
2 equiv) and stirring was continued for 1 h (TLC, ethyl acetate/
petroleum ether 1:9). THF was removed under reduced pressure. Water (20 mL) was added to the reaction mixture, and
then the aqueous layer was extracted with ethyl acetate
(3 10 mL), the combined organic layer was dried over sodium
sulfate, and ethyl acetate was evaporated under vacuum. The
crude product was obtained after removal of the solvent under
reduced pressure. The product was purified by using silica-gel
column chromatography (mobile phase 47% ethyl acetate in
petroleum ether). The products 5ah were obtained in 8995%
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 3ah, 4ah and 5ah 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.

References
1. Gross, W.; Oberkobusch, D.; Hffkes, H.; Moch, M. Hair Colourants.
W.O. Patent 2007/073923, July 5, 2007.
2. Allen, D. R.; Buckley, G. M.; Brli, R.; Davenport, R. J.; Kinsella, N.;
Lock, C. J.; Lowe, C.; Mack, S. R.; Pitt, W. R.; Ratcliffe, A. J.;
Richard, M. D.; Savin, V. M.; Sharpe, A.; Tait, L. J.; Warrelow, G. J.;
Williams, S. C. Quinoxaline and Quinoline Derivatives as Kinase
Inhibitors. W.O. Patent 2009/081105, July 2, 2009.
3. Schmitt, M.; Klotz, E.; Macher, J.-P.; Bourguignon, J.-J. Compositions
Derived from Quinoline and Quinoxaline, Preparation and Use Thereof.
W.O. Patent 2003/010146, Feb 6, 2003.
4. Chujo, I.; Masuda, Y.; Fujino, K.; Kato, S.; Ogasa, T.; Mohri, S.-i.;
Kasai, M. Bioorg. Med. Chem. 2001, 9, 32733286.
doi:10.1016/S0968-0896(01)00238-3
5. Cappelli, A.; Anzini, M.; Vomero, S.; Mennuni, L.; Markovec, F.;
Doucet, E.; Hamon, M.; Menziani, M. C.; De Benedetti, P. G.;
Giorgi, G.; Ghelardini, C.; Collina, S. Bioorg. Med. Chem. 2002, 10,
779801. doi:10.1016/S0968-0896(01)00332-7
6. Sliskovic, D. R.; Picard, J. A.; Roark, W. H.; Roth, B. D.; Ferguson, E.;
Krause, B. R.; Newton, R. S.; Sekerke, C.; Shaw, M. K. J. Med. Chem.
1991, 34, 367373. doi:10.1021/jm00105a057
7. Campiani, G.; Fattorusso, C.; Butini, S.; Gaeta, A.; Agnusdei, M.;
Gemma, S.; Persico, M.; Catalanotti, B.; Savini, L.; Nacci, V.;

General procedure for the reductive cyclization

Aldehydes 5ah (11 mmol) were dissolved in glacial acetic acid
(20 mL) and heated under reflux with zinc dust (5 equiv) for
0.5 h (TLC, ethyl acetate/petroleum ether 1:9). Acetic acid was
evaporated under vacuum, and chloroform was added to the
residue. The solution was filtered through a celite bed. CHCl3
was removed under reduced pressure. Water (25 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 evap-

Novellino, E.; Holloway, H. W.; Greig, N. H.; Belinskaya, T.;

Fedorko, J. M.; Saxena, A. J. Med. Chem. 2005, 48, 19191929.
doi:10.1021/jm049510k
8. Lyakhova, E. A.; Lyakhov, S. A.; Litvinova, L. A.; Andronati, S. A.;
Lebedyuk, M. N.; Fedchuk, V. P.; Khorokhorina, G. A. Pharm. Chem. J.
2005, 39, 183187. doi:10.1007/s11094-005-0113-0
9. Chupak, L. S.; Flanagan, M. E.; Kaneko, T.; Magee, T. V.; Noe, M. C.;
Reilly, U. Macrolides. U.S. Patent 2006/0135447, June 22, 2006.
10. Da Rocha Pitta, I.; Alves De Lima, M. d. C.; Lins Galdino, S.; Barbe, J.
Molecules with Antitumor Activity and Chemical Synthesis. W.O. Patent
2004/024058, March 25, 2004.

1728

Beilstein J. Org. Chem. 2012, 8, 17251729.

11. Giannini, G.; Pisano, C.; Vesci, L.; Tinti, M. O.; Merlini, L.; Penco, S.;
Zunino, F. 7- Polyaminoalkyl(oxy) Iminomethylcamptothecins Bearing

License and Terms

Protective Groups. U.S. Patent 2007/0043067, Feb 22, 2007.

12. Prez-Melero, C.; Maya, A. B. S.; del Rey, B.; Pelez, R.;
Caballero, E.; Medarde, M. Bioorg. Med. Chem. Lett. 2004, 14,
37713774. doi:10.1016/j.bmcl.2004.04.098
13. Ramadas, S. R.; Krishna, M. V. Curr. Sci. 1981, 50, 120123.
14. Kwartler, C. E.; Lindwall, H. G. J. Am. Chem. Soc. 1937, 59, 524526.
doi:10.1021/ja01282a027

This is an Open Access article under the terms of the

Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

15. MacDonald, S. F. J. Am. Chem. Soc. 1947, 69, 12191220.

doi:10.1021/ja01197a511
16. Plobeck, N.; Delorme, D.; Wei, Z.-Y.; Yang, H.; Zhou, F.; Schwarz, P.;
Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.; Yue, S. Y.;
Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-Onge, S.;

The license is subject to the Beilstein Journal of Organic

Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)

Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts, E.

J. Med. Chem. 2000, 43, 38783894. doi:10.1021/jm000228x
17. Achremowicz, L. Synth. Commun. 1996, 26, 16811684.
doi:10.1080/00397919608002606

The definitive version of this article is the electronic one

which can be found at:
doi:10.3762/bjoc.8.197

18. Nishikawa, T.; Ino, A.; Isobe, M.; Goto, T. Chem. Lett. 1991, 7,
12711274. doi:10.1246/cl.1991.1271
19. Rodriguez, J. G.; Benito, Y. J. Heterocycl. Chem. 1988, 25, 819821.
doi:10.1002/jhet.5570250323
20. Mathes, W.; Sauermilch, W. Chem. Ber. 1954, 87, 11791183.
doi:10.1002/cber.19540870820
21. Ihara, M.; Noguchi, K.; Fukumoto, K.; Kametani, T. Tetrahedron 1985,
41, 21092114. doi:10.1016/S0040-4020(01)96581-0
22. Clemo, G. R.; Hoggarth, E. J. Chem. Soc. 1939, 12411244.
doi:10.1039/JR9390001241
23. Giordano, C.; Minisci, F.; Vismara, E.; Levi, S. J. Org. Chem. 1986, 51,
536537. doi:10.1021/jo00354a026
24. Vismara, E.; Francesca, F.; Francesco, M. Gazz. Chim. Ital. 1987, 117,
135136.
25. Kulkarni, M. G.; Davawala, S. I.; Dhondge, A. P.; Gaikwad, D. D.;
Borhade, A. S.; Chavhan, S. W. Tetrahedron Lett. 2006, 47,
10031005. doi:10.1016/j.tetlet.2005.11.134
26. Kulkarni, M. G.; Chavhan, S. W.; Desai, M. P.; Shaikh, Y. B.;
Gaikwad, D. D.; Dhondge, A. P.; Borhade, A. S.; Ningdale, V. B.;
Birhade, D. R.; Dhatrak, N. R. Tetrahedron Lett. 2010, 51, 44944496.
doi:10.1016/j.tetlet.2010.06.068
27. Kulkarni, M. G.; Dhondge, A. P.; Chavhan, S. W.; Borhade, A. S.;
Shaikh, Y. B.; Birhade, D. R.; Desai, M. P.; Dhatrak, M. P.
Beilstein J. Org. Chem. 2010, 6, 876879. doi:10.3762/bjoc.6.103
28. Kulkarni, M. G.; Pendharkar, D. S.; Rasne, R. M. Tetrahedron Lett.
1997, 38, 14591462. doi:10.1016/S0040-4039(97)00057-9
29. Kulkarni, M. G.; Davawala, S. I.; Doke, A. K.; Pendharkar, D. S.
Synthesis 2004, 17, 29192926. doi:10.1055/s-2004-831208

1729