Tetrahedron Letters

Tetrahedron Letters 45 (2004) 90499052

Alkylation of quinoline and isoquinoline in the presence of LiCl

Yu Mi Chang,a Young Sang Park,a Seung Hwan Leea and Cheol Min Yoonb,*
b

Graduate School of Biotechnology, Korea University, Seoul 136701, South Korea Department of New Material Chemistry, Korea University Jochiwon, Choong-nam 339-700, South Korea
Received 27 May 2004; revised 1 October 2004; accepted 7 October 2004 Available online 22 October 2004

AbstractEEDQ and EEDI generated in situ by the reaction of quinoline and isoquinoline with diethyl pyrocarbonate was treated with alkylating reagents having an activated carbon such as diethyl malonate, ethyl acetoacetate etc. in the presence of 0.5 equiv of LiCl in acetonitrile to provide the corresponding alkyl dihydroquinolines and alkyl dihydroisoquinolines in high yields. 2004 Elsevier Ltd. All rights reserved.

The quinoline and isoquinoline ring systems are important structural units in naturally occurring alkaloids and synthetic analogues with interesting biological activities. Therefore, the development of new and ecient synthetic route for the preparation of their analogues is of importance in both synthetic organic chemistry and medicinal chemistry.1 One of the methods for the preparation of quinoline and isoquinoline analogues is CC bond formation using organometallic compounds.2 Palladium catalyzed allylation reaction has been known to be very useful for the CC bond formation of benzyl halide (carbonate)3 and allyl halide (carbonate).4 On the basis that intermediates in these reactions are p-allylpalladium complex, palladium catalyzed carboncarbon bond formation of 2-ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline (EEDQ) with diethyl malonate through p-allylpalladium complex of dihydroquinoline was examined. If working, dihydroquinoline might be attacked at 2 or 4 position by diethyl malonate to give an expected products as two regioisomers (Scheme 1). Using various palladium reagents such as Pd(PPh3)4,

Pd2(dba)3, Pd(OAc)2 and PdCl2, EEDQ and diethyl malonate, coupling reactions were examined in various solvents. The reaction was found to proceed in DMF at 80 C in the presence of catalytic amount of Pd(PPh3)4 and excess amount of LiCl (2 equiv). In the blank test in the absence of Pd(PPh3)4, it was found that the real reagent for this coupling reaction was not palladium but lithium chloride. Here, we are going to report the coupling reaction of EEDQ and 1-ethoxy-2-ethoxycarbonyl-1,2-dihydroisoquinoline (EEDI) with various alkylating reagents bearing an active methylene group in the presence of lithium chloride in acetonitrile at room temperature to give the corresponding coupling products in high yields. The coupling reactions of EEDQ with 1.5 equiv of diethyl malonate in acetonitrile at room temperature were conducted using 2 equiv of various salts such as NaCl, NaBr, Na2CO3, Li2CO3, LiBr, LiBF4, LiOTf and LiCl. Lithium carbonate and all of sodium salts tested were not eective to proceed the reaction. Among

E diethyl malonate N OEt E E = COOEt EEDQ Pd(0), LiCl N E E E + N E

E Pd N E -allyl intermediate

Scheme 1. Keywords: Quinoline; Isoquinoline; EEDQ; Lithium chloride. * Corresponding author. Tel./fax: +82 2 3290 3433; e-mail: cmyoon@korea.ac.kr 0040-4039/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.10.032

9050

Y. M. Chang et al. / Tetrahedron Letters 45 (2004) 90499052

Table 1. Salt eect after 11 h reaction using 2 equiv of salt Entry 1 2 3 4 5 6 7 8 9

a

Salt NaCl, NaBr, Na2CO3, Li2CO3 LiBr LiOTf (regioselectivity) LiBF4 LiCl LiCl LiCl LiCl LiCl

Amount of salts (equiv) 2 2 2 2 2 1 0.5 0.1 0.05

Yielda (%) 0 54.7 49.8 92.6 90.3 92.4 90.5 56.9 Trace

group to give quinolinium ion and lithium ethoxide. Lithium ethoxide deprotonates diethyl malonate to give an enolate, which attacks at C-2 or C-4 of the quinolinium ion to aord nal coupling products and lithium chloride. Lithium chloride was recycled for the reaction. Under our reaction condition, reaction of EEDQ with various alkylating reagents gave the corresponding coupling products as two regioisomers in high yields as shown in Table 25 (entries 17). The reaction of EEDQ with Meldrums acid and 4,4-dimethyl-1,3-cyclohexandione showed complete conversion of EEDQ into the corresponding new compounds within 1 h according to TLC, but purication by column chromatography failed due to instability of products. The reaction of EEDQ with alkylating reagents with tertiary carbon was slow to give the corresponding coupling products in high yields in extended reaction time (entries 4 and 7). The reaction with malononitrile proceeded very slowly, which was overcome by using 1 equiv of lithium chloride, and the reaction using 1 equiv of lithium chloride gave a coupling product in 92.8% yield in 0.5 h (entry 2). The reactions show alpha selectivity in all of the reactants except for that of malononitrile, lower selectivity of which is probably due to the size of malononitrile (Scheme 2). When quinoline and isoquinoline were treated with diethyl pyrocarbonate in acetonitrile at rt, the formation of EEDQ and EEDI with quinoline and isoquinoline, respectively, was detected by TLC. On the basis of this

Isolated yields of two regioisomers, whose ratio was not determined.

lithium salts, LiCl and LiBF4 were identied to be the best salts for this coupling reactions as illustrated in Table 1. The choice of lithium salt was lithium chloride due to the price and convenient handling. The optimum amount of lithium chloride was 0.5 equiv and lithium chloride of more than 0.5 equiv were identied to give the similar results (entries 59). The reaction was attempted in various solvent systems. While the reaction in THF or dichloromethane in the presence of 0.5 equiv of lithium chloride was not working at all, trace amount of product in the reaction in ethanol or DMF was detected by TLC. The plausible mechanism of the reaction is as follows. Lithium cation is oxophilic to coordinate with two oxygens of EEDQ to make ethoxy group as a good leaving
Table 2. The reaction of EEDQ with various alkylating reagents5

CR1R2R3 + N OEt E E = COOEt H CR1R2R3 LiCl in CH3CN at rt N E CR1R2R3 + N E

Entry 1 2 3 4 5 6 7
a b

Alkylating reagents Acetylacetone Malononitrileb Diethyl malonate Diethyl methylmalonate Ethyl acetoacetate Ethyl cyanoacetate Diethyl acteamidomalonate

Time (h) 1 0.5 8 24 1 20 24

Yielda (%) 97.1 92.8 98.6 94.6 91.1 88.4 88.6 (8.5:1)c (0.95:1) (4.2:1) (2.7:1) (6.3:1) (2.1:1) (5.2:1)

Isolated yields. Lithium chloride (1 equiv) was used. c Ratio of a:c regioisomers.

LiCl N EtO O EEDQ E = COOEt E E E O E O OEt EtO N O O Li+ LiCl EtO + N ClO
-

LiOEt

EtOH

Li+ O OEt O OEt OEt OEt O

or N EtO O EtO

A Plausible mechanism

Scheme 2.

Y. M. Chang et al. / Tetrahedron Letters 45 (2004) 90499052

E R N diethyl pyrocarbonate R N E OEt diethyl malonate LiCl in CH3CN at rt N E E E E

9051

+ N E

E = COOEt

Scheme 3.

observation, carboncarbon bond formation of in situ generated EEDQ and EEDI with diethyl malonate was tried to expand our methodology. After lithium chloride and diethyl malonate were added to a solution of quinoline and diethyl pyrocarbonate in acetonitrile at room temperature, we observed the disappearance of quinoline in equilibrium with in situ generated EEDQ (Scheme 3)6 to give a coupling product in 97.6% yield after 12 h (entry 1 of Table 3). Quinoline in equilibrium with EEDQ in the reaction solution was observed to disappear slowly in progress of coupling product formation. While electron sucient quinolines under the reaction condition underwent reaction to give the corresponding coupling product in high yield (entries 35), 6nitroquinoline, electron decient quinoline, did not proceed, probably due to low nucleophilicity of nitrogen of 6-nitroquinoline (entry 2). It should be mentioned that lithium chloride in this reaction has another role, activation of formation of EEDQ from quinoline. The formation of EEDQ using diethyl pyrocarbonate in the presence of lithium chloride was observed to be faster than that in the absence of lithium chloride (Table 4).

Table 4. The reaction of isoquinoline with diethyl malonate at rt Entry 1 2 3 Substrate Isoquinoline 3-Methylisoquinoline 5-Nitroisoquinoline Time (h) 2 3.5 6 Yield (%) 94.5 90.4 96.1

Under the same reaction condition as quinoline, the reaction of EEDI generated in situ by the reaction of isoquinoline with diethyl pyrocarbonate was tried (Scheme 4)6 and in situ generated EEDI reacted with diethyl malonate to give coupling product in 94.5% yield. The reaction of EEDI bearing an electron donating group and electron withdrawing group with diethyl malonate gave the corresponding dihydroisoquinoline in 90.4% and 96.1%, respectively. For one example of the expansion, the coupling products of quinoline and isoquinoline with diethyl malonate were treated with KOH solution in ethanol followed by triethylamine in THF gave the corresponding decarboxylated product in good overall yields, respectively, which might be dicult to be obtained in the other simple ways (Scheme 5). In conclusion, EEDQ was successfully coupled with various alkylating reagents bearing active methylene group to give the corresponding coupling products in high yields. The methodology was expanded to the reaction of in situ generated EEDQ and EEDI with diethyl malonate to give the corresponding coupling product in high yield. However, the reaction of 6-nitroquinoline did not react with diethyl malonate due to poor nucleophilicity of nitrogen of 6-nitrogen.

Table 3. The reaction of quinoline with diethyl malonate at rt Entry 1 2 3 4 5

a

Substrate Quinoline 6-Nitroquinoline 6-Methylquinoline 6-t-Butylcarbonylaminoquinoline 6-t-Butylcarbonyloxyquinoline

Time (h) 12 48 21 24 24

Yield (%) 97.6 (3.7:1)a Trace 86.4 (4.3:1)a 85.9 (4.6:1)a 88.0 (4.8:1)a

Ratio of a:c regioisomers was determined by separation.

R N

diethyl pyrocarbonate

R N OEt E = COOEt E

diethyl malonate LiCl in CH3CN at rt

R N E E E

Scheme 4.

N O

CO2Et CO2Et OEt

KOH EtOH, rt, 2h 75.5% N O

CO2Et CO2H OEt

Et3N THF, rt, 72h 90.0% Et3N THF, rt, 48h 90.6% N O OEt

CO2Et

N EtO2C

OEt

KOH EtOH, rt, 2h 79.1%

N EtO2C

OEt

N EtO2C O

OEt

O CO2Et

O CO2H

Scheme 5.

9052

Y. M. Chang et al. / Tetrahedron Letters 45 (2004) 90499052

Acknowledgements The authors wish to acknowledge the nancial support of the Korea Science and Engineering Foundation (KOSEF) made in the program year 2003.

References and notes

1. Balasubramanian, M.; Keay, J. G. Pyridines and their Benzo Derivatives: Application In Comprehensive Heterocyclic Chemistry II; Katrizky, A. P., Rees, V. W., Scriven, E. F., Eds.; Pergamon: Oxford, 1996; Vol. 5, pp 245300. 2. For a review, see: (a) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223; (b) Comins, D. L.; Sajan, P. J. Pyridines and their Benzo Derivatives: Reactivity at the Ring In Comprehensive Heterocyclic Chemistry II; Katrizky, A. P., Rees, V. W., Scriven, E. F., Eds.; Pergamon: Oxford, 1996; Vol. 5, p 37; For recent examples, see: (c) Comins, D. L.; Zhang, Y.; Joseph, S. P. Org. Lett. 1999, 1, 657, and references cited therein; (d) Nishikawa, T.; Yoshikai, M.; Obi, K.; Kawai, T.; Unno, R.; Jomori, T.; Isobe, M. Tetrahedron 1995, 51, 9339, and references cited therein; (e) Magnus, P.; Rodrguez-Lopez, J.; Mulholland, K.; Mat thews, I. J. Am. Chem. Soc. 1992, 114, 382; (f) Brana, M. F.; Moran, M.; Perez de Vega, M. J.; Pita-Romero, I. J. Org. Chem. 1996, 61, 1369; (g) Itoh, T.; Miyazaki, M.; Nagata, K.; Ohsawa, A. Tetrahedron 2000, 56, 4383. 3. (a) Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1992, 33, 2509; (b) Legros, J.-Y.; Toano, M.; Fiaud, J.-C. Tetrahedron 1995, 51, 3235; (c) Legros, J.-Y.; Toano, M.; Fiaud, J.-C. Tetrahedron: Asymmetry 1995, 6, 1899; (d) Toano,

M.; Legros, J.-Y.; Fiaud, J.-C. Tetrahedron Lett. 1997, 38, 77; (e) Legros, J.-Y.; Primault, G. l.; Toano, M.; Riviere, M.-A.; Fiaud, J.-C. Org. Lett. 2000, 2, 433; (f) Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc. 2003, 125, 12104; (g) Crawforth, C. M.; Fairlamb, I. J. S.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45, 461. 4. (a) Tsuji, J. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; Vol. 2, p 1669; (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395; (c) Kuwano, R.; Uchida, K.-i; Ito, Y. Org. Lett. 2003, 5, 2177; (d) Franzen, J.; Lofstedt, J.; Falk, J.; Backvall, J.-E. J. Am. Chem. Soc. 2003, 125, 14140; (e) Sato, Y.; Oonishi, Y.; Mori, M. J. Org. Chem. 2003, 68, 9858; (f) Wallner, O. A.; Szabo, K. J. J. Org. Chem. 2003, 68, 2934; (g) Obora, Y.; Nakanishi, M.; Tokunaga, M.; Tsuji, Y. J. Org. Chem. 2002, 67, 5835. 5. Typical procedure of EEDQ with diethyl malonate: To a solution of EEDQ (100 mg, 0.404 mmol) in acetonitrile was added diethyl malonate (97.1 mg, 1.5 equiv) and lithium chloride (8.6 mg, 0.5 equiv) at rt. After the reaction mixture was stirred for 8 h at rt, the reaction mixture was concentrated and chromatographed on silica gel using a solution of ethyl acetate and hexane (1:20) to give a coupling dihydroquinoline in 98.6% yield. 6. Typical reaction procedure of in situ generated EEDQ with diethyl malonate: To a solution of quinoline (52.2 mg, 0.404 mmol) in acetonitrile (4 ml) was added diethyl pyrocarbonate (132.1 mg, 2 equiv), diethyl malonate (97.1 mg, 1.5 equiv) and lithium chloride (8.6 mg, 0.5 equiv.) at rt. After the reaction mixture was stirred for 12 h at rt, the reaction mixture was concentrated and chromatographed on silica gel using a solution of ethyl acetate and hexane (1:20) to give a coupling dihydroquinoline in 97.6% yield.