Letters in Organic Chemistry, 2008, 5, 29?6-29?9
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An Improved Synthetic Protocol and Plausible Mechanism in Forming Acetylpyridines from 2,6-Dicarbethoxypyridine Maliha Asmaa,b, Sheriff Adewuyia, Xiaofei Kuanga, Amin Badshahb and Wen-Hua Sun*,a a
Key Laboratory of Engineering Plastics and Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China; bDepartment of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan Received December 15, 2007: Revised February 22, 2008: Accepted March 02, 2008
Abstract: 2-Carbethoxy-6-acetylpyridine and 2,6-diacetylpyridine were transformed in good yields from the reaction of 2,6-dicarbethoxypyridine and EtOAc in the presence of sodium along with/without an equivalent of ethanol to sodium in toluene. The -keto esters, the intermediates in the transformation of -keto carboxylate into acetyl group, were isolated for understanding the plausible mechanism.
Keywords: 2-Carbethoxy-6-acetylpyridine, 2,6-diacetylpyridine, 2,6-dicarbethoxypyridine, Claisen Ester Condensation, antiClaisen reaction. INTRODUCTION The role of bis(imino)pyridine and mono(imino) pyridine derivatives as ligands in the field of ethylene reactivity can not be over emphasised. Following the independent discovery of 2,6-bis(imino)pyridylmetal (Fe and Co) complexes by Brookhart and Gibson, effective catalysts for the conversion of ethylene either to high density polyethylene or alpha olefins have achieved a remarkable development [1-7]. Moreover, after the pioneer work of -diimino nickel complexes as catalysts for ethylene polymerization [8], iminopyridine nickel complexes [9] and their dimeric analogues [10] were found to be active catalysts for ethylene reactivity. Worthy to be mentioned, the preparation of these imino-pyridine ligands commonly involve the use of acetyl- or formylpyridine as the starting materials. To explore alternative models of late-transition metal complexes as catalysts for ethylene reactivity [11,12], 2-carbethoxy-6-acetylpyridine (1) was first prepared through controllably transforming mono-carboxylate into acetyl group with the substance of dicarbethoxypyridine (3), which commonly transforms into 2,6-diacetylpyridine (2) [11,13]. The newly obtained 2carbethoxy-6-acetylpyridine (1) was found to be an important chemical for synthesizing some alternative new organic compounds. For example, 2-quinoxalinyl-acetylpyridine was prepared and used to form metal complexes as catalysts for ethylene reactivity [14-16]. However, the mostly encountered problem in preparing 2-carbethoxy-6-acetylpyridine (1) is observing the by-product of diacetylpyridine in numerous modified procedures [17,18], and it is difficult to maintain high selectivity in solely forming 2-carbethoxy-6acetylpyridine (1) without observing diacetylpyridine (2) [13]. Therefore, it would be necessary to understand the reaction mechanism, and find optimum condition and general procedure for forming acetyl group from carbethoxy group. *Address correspondence to this author at the Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China; Fax: +86 (10)62618239; E-mail:
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In the previous procedure [11,13], 2-carbethoxy-6-acetyl pyridine (1) was formed in the reaction of 2,6-dicarbethoxy pyridine (3) with EtOAc in presence of various amounts of EtONa. Due to its moisture sensitivity of EtONa, the manipulation technique and reaction condition easily affected its yield and by-product. During transforming carboxylate into acetyl group, the mechanism was explained as the Claisen ester condensation to form -keto esters [19], the following step was proposed as further hydrogenation to producing -keto acid, which was not stable to be decomposed as acetyl group, water and carbon dioxide [13]. However, there is no report with isolating its intermediates. In this work, the sodium with/without stoichiometric amount of ethanol in toluene has been used instead of EtONa, and solely one product either mono- or di-acetyl substituted pyridines could be formed. In addition, the intermediates of keto esters were individually isolated, and further treatments could produce the titled compounds in steps. These intermediates and products provide first-hand evidences for understanding their plausible reaction mechanism. Herein the detail results are reported along with discussion of the plausible mechanism. EXPERIMENTAL General Procedure All manipulations of air and/or moisture sensitive compounds were performed under nitrogen atmosphere using standard Schlenk techniques. 2,6-Dicarbethoxy-pyridine (3) was prepared according to the literature method [17]. Solvents were dried by standard purification procedures and used as freshly distilled. Common analyses include 1H NMR spectra on a Bruker DMX 300MHz instrument, IR spectra as KBr pellets on a Perkin-Elmer 2000 FT-IR spectrometer, EIMass spectra on a Kratos AEI MS-50 instrument and elemental analysis by HP-MOD 1106 microanalyser.
© 2008 Bentham Science Publishers Ltd.
297 Letters in Organic Chemistry, 2008, Vol. 5, No. 4 Forming Acetylpyridines from Dicarbethoxypyridine The Transformation in the Presence of Ethanol The stoichiometric amounts (0.1 to 0.3 moles) of sodium and ethanol were refluxed for 6 hrs under nitrogen in 25 ml toluene. After the solution was cooled down, 0.10 mol, 2,6dicarbethoxy pyridine (3) in 30 ml freshly distilled ethyl acetate was added over half-hour under stirring. The mixture was refluxed for additional 6 hrs, and cooled down to room temperature. Excessive concentrated hydrochloric acid (25 ml, 37%) was added with stirring, the resultant mixture was further refluxed for a period of 6 hrs to complete the reaction. 100 ml of water was thereafter added to dissolve the solid mass in the mixture to form a dark solution. The aqueous phase was shaken with CH2Cl2 (4 25 ml) for extraction. The combined organic extracts were washed with 5% aqueous Na2SO4, filtered and the solvent was evaporated under reduced pressure. The obtained mixture was separated by column chromatography (Silica-gel, petroleum ether: EtOAc = 8:1). Firstly eluted potion was 2,6-diacetylpyridine (2), secondly eluted portion was 2-carbethoxy-6acetylpyridine (1). The routinely analysis approved the formation of 2,6-diacetylpyridine (2) [13] and 2-carbethoxy-6acetylpyridine (1) [11]. In a stoichiometric reaction (0.1 mol) of sodium and ethanol to 2,6-dicarbethoxypyridine (3, 0.1 mol), 2carbethoxy-6-acetylpyridine (1) was formed in 11.7 g (61% isolated) with trace of 2,6-diacetylpyridine (2, less than 0.5%). With two equivalents (0.2 mol) of sodium and ethanol to 2,6-dicarbethoxypyridine (3, 0.1 mol), the 2,6-acetylpyridine (2) was obtained as major product (10.1 g, 57.5% isolated) with 2-carbethoxy-6-acetylpyridine as minor product (1, 2.75 g, 14.2% isolate). With two and half equivalents (2.3 mol) of sodium and ethanol to 2,6-dicarbethoxypyridine(3, 0.1 mol), the 2,6acetylpyridine (2) was obtained as major product (12.5 g, 64.9% isolated) with 2-carbethoxy-6-acetylpyridine minor product (1, 1.5 g, 8.1%). With three equivalents (0.3 mol) of sodium and ethanol to 2,6-dicarbethoxypyridine (3, 0.1 mol), the 2,6acetylpyridine (2) was only obtained in 12.85 g (66.1% isolated). The Transformation in the Absence of Ethanol Sodium (0.1 or 0.25 mol) was suspended in freshly distilled toluene (25 ml), 22.3 g (0.1 mol) 2,6dicarbethoxypyridine (3) dissolved in 5 equivalents of EtOAc (30ml) was added with stirring. The mixture was then refluxed for 4h. After cooling down, excess amount of concentrated HCl (25ml, 37%) was dropwise added and refluxed for additional 6h to complete the reaction. A dark solution was obtained, then 100 ml water was added to dissolve the solid products present. The same work-up process was employed to purify its products. With two-and-half equivalents (0.25 mol) of sodium to 2,6-dicarbethoxypyridine (3, 0.1 mol) with 5 equivalents of EtOAc in 25 ml toluene, 2,6diacetylpyridine (2) was isolated as the solely white product (11.6g, 71.0% isolated).
Asma et al.
With the stoichiometric reaction (0.1 mol) of sodium and 2,6-dicarbethoxypyridine (3) with 5 equivalents of EtOAc in 25 ml toluene, 2-carbethoxy-6-acetylpyridine (1) was isolated as a sole product in 13.1 g (67.3% isolated). Isolation of the -Keto Esters Intermediate Sodium (0.1 or 0.25 mol) was suspended in freshly distilled toluene (25 ml), 2,6-dicarbethoxypyridine (3, 22.3 g, 0.1 mol) dissolved in 30 ml EtOAc was dropwise added under stirring. The resulting mixture was refluxed for 4h, and cooled to 0 oC in ice/water bath. Dilute HCl (1 M, 100 ml or 250 ml) was thereafter added to quench the reaction in ice/water bath. With employing the same workup process as above, the product was purified by column chromatography (Silica-gel, petroleum ether: EtOAc = 8:1). With one equivalent of sodium (0.1 mol), the ethyl 2carbethoxy-6-(-keto-carboxylate)pyridine (4) was isolated as a yellow oily product in 12.5g (47.0% isolated). IR (KBr): C=O1746.25 cm-1, 1710.65 cm-1, vC-O-C1140.91 cm-1 1 H NMR (300 MHz, CDCl3, ): 8.25 (d, 1H, Py-Hm), 8.20 (d, 1H, Py-Hm), 8.02 (m, 1H, Py-Hp), 4.46 (q, 2H,O–CH2), 4.26 (q, 2H, O–CH2), 4.20 (s, 2H, O=C(CH2), 1.41 (t, 6H, CH2(CH3). 13C NMR (75.45 MHz, CDCl3, ): 194.1, 168.0, 164.4, 152.3, 147.9, 138.2, 126.2, 124.7, 61.7, 61.9, 44.7, 14.2, 14.0. With two-and-half equivalents of sodium (0.25 mol), diethyl 2,6-bis(-keto-carboxylate)pyridine (5) was isolated as a yellow oily product in 14.1 g (46.0% isolated). IR (KBr) C=O 1743.83 cm-1, 1707.32 cm-1, vC-O-C1091.39 cm-1. 1 H NMR (300MHz, CDCl3, ): 8.14 (dd, 2H, Py-Hm), 7.98 (m, 1H, Py-Hp), 4.33 (q, 4H,O–CH2), 4.11 (s, 4H, O=C(CH2), 1.32 (t, 6H, CH2(CH3). 13C NMR (75.45 MHz, CDCl3, ): 193.2, 167.5, 151.3, 138.7, 128.9, 61.1, 44.7, 13.9. Transforming -Keto-Carboxylate Compounds into the Corresponding Acetyl Products The concentrated HCl (20 ml, 37%) was dropwisely added to ethyl 2-carbethoxy-6-(-keto-carboxylate)pyridine (4, 0.047 mol, 12.0g), the resulting solution was refluxed for 6h, then water (100 ml) was added. CH2Cl2 (4 25 ml) was used to extract organic compounds, and concentration and purification gave waxy solid 2-carbethoxy-6-acetylpyridine (1, 7.13 g, 78.6% isolated). With the same procedure, ethyl 2,6-bis(-ketocarboxylate)pyridine (5, 0.045 mol, 13.8g) was used to form 2,6-diacetylpyridine (2) in 5.88 g (80.1% isolated). RESULT AND DISCUSSION In the formation of 6-acetyl-2-carbethoxypyridine (1) and 2,6-diacetylpyridine (2) from 2,6-dicarbethoxypyridine (3), it is clear that the Claisen ester condensation takes place in forming the corresponding analogues of -keto ester [20], then the following hydrolysis in acidic aqueous solution will happen and cleave the carbethoxy group with the necessity of the elevated reaction temperature. The important issue related to conversation yield will involve the effective forming diethoxy-oxopropanolate (A or B), which then produces
Transformation of Acetyl Group from Carbethoxy Group
-keto ester anions (C or D). These imaged anionic compounds could not be directly obtained at this moment; however, the isolated -keto ester compounds (4 or 5) could prove the presence of -keto ester anions (C or D) in the basic solution. The -keto ester compounds (4 or 5) isolated could provide direct evidences in forming acetylarene compounds with newly understanding the reaction mechanism. In textbooks of organic chemistry, it is commonly to show that the formation of acetyl group from -keto ester will be occurred with hydrolyzing its ester group to form the -keto acid as intermediate, and it was a hypothesis accepted in the previous publication [13]. Following this philosophy, regarding to ethyl 2-carbethoxy-6-(-keto- carboxylate)pyridine (4) as an intermediate, its hydrolysis could have two possibilities due to two ester groups with similar chemical environment, and the 6-acetylpyridine-2-carboxylic acid would be one by-products. In fact, 2-carbethoxy-6acetylpyridine (1) was isolated as a sole product. Therefore, the isolation of ethyl 2-carbethoxy-6-(-ketocarboxylate)pyridine (4) helpfully clarify the mechanism of forming acetyl compounds from -keto ester analogues, in which the cleavage of carboxylate group is more reasonable. In routinely synthetic procedure in forming -carbanion carboxylic ester, the sodium ethanoate was commonly prepared and dried from its ethanol solution. However, some amount of ethanol could remain in the solid NaOEt, even when dried under vacuum line. Moreover, sodium hydroxide could also be the impurity compound due to the little amount of water remained in ethanol used. Those factors will affect the real amount of NaOEt, therefore it is necessary to use an excessive amounts of NaOEt [11, 13,17,18] for the transformation reaction. Herein instead of using NaOEt, the stoichiometric reaction of ethanol and sodium in toluene provides fresh NaOEt in effectively activating the Claisen ester condensation. With same work-up process, both desiring products, 6-acetyl-2-carbethoxypyridine (1) and 2,6diacetylpyridine (2), were obtained with highly improved yields. The 2-carbethoxy-6-acetylpyridine (1) could be prepared in 61% isolated yield with one equivalent of sodium and ethanol instead of its 45% yield previously [13], meanwhile 2,6-diacetylpyridine (2) was separated in 66.1% yield with 3.0 equivalents of sodium and ethanol comparing the literature yield of 58.8% [13]. Beyond that, the procedure herein used less amounts of substances with less consuming time and energy. In the stoichiometric amount of sodium, ethanol and 2,6dicarbethoxypyridine (3), a trace of 2,6-diacetyl pyridine (2) was observed in addition to 2-carbethoxy-6-acetylpyridine (1). Back to forming -carbanion carboxylic ester, the function of NaOEt is to remove hydride from ethyl acetate; the sodium could be expected to slowly produce -carbanion carboxylic ester. Accordingly, the high concentrated ethyl acetate solution with sodium will directly produce some keto ester. To avoid ethanol formed in the reaction, the toluene is used as solvent with good solubility of 2,6dicarbethoxypyridine (3) and products. With fixing 5 equivalents of ethyl acetate to 2,6-dicarbethoxypyridine, the formation of 6-acetyl-2-carbethoxypyridine (1) or 2,6diacetylpyridine (2) was individually improved through controlling the amounts of sodium. The 2-carbethoxy-6-
Letters in Organic Chemistry, 2008, Vol. 5, No. 4
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acetylpyridine was solely produced in 67.3% isolated yield with one equivalent of sodium, while 2,6-diacetylpyridine was isolated as the only product in 71.0% with 2.5 equivalents of sodium. Until now, the amounts of different reactants have been fully considered for forming 6-acetyl-2-carbethoxypyridine (1) or 2,6-diacetylpyridine (2). Therefore the reaction mechanism should be revised as the followings: EtO
OEt
N O 1 Eq. CH2CO2Et
1 Eq.
EtO
A
2 Eq.
CH2CO2Et
CH2CO2Et
O
CH2CO2Et
H C
EtO
OEt
N O
O
3
EtO2CH2C
N O
B
O
EtOH
EtOH
H C
EtO N O
C
H3O
4
H2 C
OEt EtO O
O
EtO
CH3
N 1
O
D
H3O
H2 C
O
H C
N O
CO2 H2O EtOH
H3O
O
H C
H2O
N O
CO2Et
EtO2C
O
EtO
CO2Et
O H2O
H2 C
N O
5
O
O
CH3
N O
OEt
CO2 H2O EtOH
H3O
H3C
CO2Et
2
O
In the reactions to form two products 1 and 2, the unstable diethoxy-oxopropanolate (A or B) and -keto ester anions (C or D) would be intermediates. Ethyl acetate reacts with sodium to form carbanion carboxylic ester, which could stepwise react with two carbethoxy group of 2,6dicarbethoxypyridine (3). The presence of NaOEt could somehow result in an unbalanced reaction to form mixtures of two products with 2,6-dicarbethoxypyridine (3) remained. However, sodium is not dissolved in toluene, and reacts stepwise 2,6-dicarbethoxypyridine (3) in two stages on the base of sodium amounts. With being neutralized by dilute HCl in ice/water bath, the intermediates of -keto carboxylates 4 and 5 were individually separated in good yields. It was in general accepted that the hydrolysis of -keto carboxylates to form the -keto carboxylic acid [13], however,
299 Letters in Organic Chemistry, 2008, Vol. 5, No. 4 there is no trace of 6-acetylpyridine-2-carboxylic acid observed in the hydrolysis of -keto carboxylates 4. Similarly, there is no analogues bearing carboxylic acid isolated in forming diacetylpyridine (2) from the hydrolysis of diethyl 2,6-bis(-keto-carboxylate)pyridine (5). In addition, it was reported that -keto carboxylic acid was stable [21]. Therefore, it would be better to considering an alternative mechanism. Instead, the cleavage reaction of -keto ester splits acetyl group and ethyl carboxylate, which is an unstable intermediate to be readily decomposed into ethanol and carbon dioxide. This phenomenon was also observed in synthesis of 1-chloro-2-alkanones [22]. The directly decomposing -keto carboxylic ester, namely anti-Claisen reaction, will proceed in the presence of proton to give acetyl group and ethyl carboxylate. In summary, the formation of mono- or di-acetyl pyridines from 2,6-dicarbethoxypyridine could be more effective with the reaction of 2,6-dicarbethoxypyridine and ethyl acetate in presence of sodium without ethanol. The plausible mechanism includes the Claisen ester condensation and direct splitting -keto ester into acetyl-group and ethyl carboxylate (anti-Claisen reaction). Moreover, this reaction procedure could be effectively extended in preparing other acetylarene derivatives.
Asma et al. [2] [3]
[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]
ACKNOWLEDGEMENTS The project supported by NSFC No 20674089. M.A. and A.S. are grateful to the Chinese Academy of Science (CAS) and The Academy of Science for The Developing World (TWAS) for the Postgraduate Fellowships. A. B thanks Higher Education Commission of Pakistan. REFERENCES [1]
Small, B. L; Brookhart, M.; Bennett, A.M.A J. Am. Chem. Soc., 1998,120, 4049.
[17] [18] [19] [20] [21] [22]
Small, B. L.; Brookhart, M. J. Am. Chem. Soc., 1998, 120, 7143. Britovsek, G. J. P.; Bruce, M.; Gibson, V.C.; Kimberley, B. S.; Madox, P. J.; Mastroianni, S.; McTavish, S. J.; Redshaw, C.; Solan, G. A.; Stromberg, S.; White, A.J.P.; Williams, D. J. J. Am. Chem. Soc., 1999, 121, 8728. Britovsek, G. J. P.; Gibson, V.C.; Kimberley, B. S.; Madox, P. J.; McTavish, S. J.; Solan, G. A.; White, A. J. P.; Williams, D. J. Chem. Commun., 1998, 849. Britovsek, G. J. P.; Mastroianni, S.; Solan, G. A.; Baugh, S. P. D.; Redshaw, C.; Gibson, V. C.; White, A. J. P.; Williams, D. J.; Elsegood, M. R. J. Chem. Eur. J., 2000, 6, 2221. Ma, Z.; Sun, W.-H.; Li, Z.-L.; Shao, C.-X.; Hu, Y.-L.; Li, X.-H. Polym. Int., 2002, 51, 994. Sun, W.-H.; Zhang, S.; Zuo, W. C. R. Chim., 2008, 11, 307. Johnson, L. K.; Killian, C. M.; Brookhart, M. J. Am. Chem. Soc., 1995, 117, 6414. Laine, T. V.; Piironen, U.; Lappalainen, K.; Klinga, M.; Aitola, E.; Leskelä, M. J. Organomet. Chem., 2000, 606, 112 and therein references. Jie, S.; Zhang, D.; Zhang, T.; Sun, W.-H.; Chen, J.; Ren, Q.; Liu, D.; Zheng, G.; Chen, W. J. Organomet. Chem., 2005, 690, 1739. Sun, W.-H.; Tang, X.; Gao, T.; Wu, B.; Zhang, W.; Ma, H. Organometallics, 2004, 23, 5037. Tang, X.; Sun, W.-H.; Gao, T.; Hou, J.; Chen, J.; Chen, W. J. Organometal. Chem., 2005, 690, 1570. Su, B.; Zhao, J.; Cui, Y.; Liang, Y.; Sun, W.-H. Synth. Commun., 2005, 35, 2317. Sun, W.-H.; Hao, P.; Li, G.; Zhang, S.; Wang, W.; Yi, J.; Asma, M.; Tang, N. J. Organometal. Chem., 2007, 692, 4506. Adewuyi, S.; Li, G.; Zhang, S.; Wang, W.; Hao, P.; Sun, W.-H.; Tang, N.; Yi, J. J. Organometal. Chem., 2007, 692, 3532. Chen, Y.; Zuo, W.; Hao, P.; Zhang, S.; Gao, K.; Sun, W.-H. J. Organometal. Chem., 2008, 693, 750. Singer, A.W.; McElvain, S. M. J. J. Am. Chem. Soc., 1935, 57, 1135. Barnes, R. A.; Fales, H. M. J. Am. Chem. Soc., 1953, 75, 3830 Claisen, L.; Lowman, O. Ber, 1887, 20, 651. Brich, W.; Michaelis, R. Beilstein Handbook of Organic chemistry, 5th supplementary series, Springer-Verlag, Berlin, 1990, 22, Part 4, 128. Gilmann, B.; Blatt, A. H. Org. Synth. 2nd, John Wiley and Sons, Inc., New York, 1948, P65. De Kimpe, N.; De Cock W.; Schamp, N. Synthesis, 1987, 188.
