4-Substituted-pyridine-2,6-dicarboxylic acid derivatives were　synthesized in one pot under mild conditions via the formation of dihydropyran　derivatives from pyruvates and aldehydes catalyzed by pyrrolidine-acetic acid,　followed by the reaction with ammonium acetate.journal articl

Chouthaiwale, Pandurang V.

Lapointe, Sébastien

Tanaka, Fujie

Heterocycles

English

OIST Institutional Repository

HETEROCYCLES, Vol. 95, No. 1, 2017, pp. 587-594. © 2017 The Japan Institute of Heterocyclic ChemistryReceived, 9th August, 2016, Accepted, 6th September, 2016, Published online, 16th September, 2016DOI: 10.3987/COM-16-S(S)27SYNTHESIS OF 4-SUBSTITUTED-PYRIDINE-2,6-DICARBOXYLICACID DERIVATIVES FROM PYRUVATES AND ALDEHYDES IN ONEPOTPandurang V. Chouthaiwale, Sébastien Lapointe, and Fujie Tanaka*Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science andTechnology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495,Japan. E-mail: ftanaka@oist.jpAbstract – 4-Substituted-pyridine-2,6-dicarboxylic acid derivatives weresynthesized in one pot under mild conditions via the formation of dihydropyranderivatives from pyruvates and aldehydes catalyzed by pyrrolidine-acetic acid,followed by the reaction with ammonium acetate.Pyridine-2,6-dicarboxylic acids (or dipicolinic acids) and their derivatives are used as ligands for metals,small molecules, and biomolecules.1 They have also been used as building blocks for the synthesis ofbiofunctional molecules, probes for visualization of cells and molecules of interest, and solid-supportreagents.1 Previously reported methods for the synthesis of substituted pyridine-2,6-dicarboxylic acidderivatives often require long routes and severe conditions.1,2 Concise methods for the synthesis ofsubstituted pyridine-2,6-dicarboxylic acid derivatives under mild conditions would be beneficial. Wehave recently developed a concise method for the synthesis of 4-substituted-pyridine-2,6-dicarboxylicacid derivatives 1 (Scheme 1).3 In the method, pyruvates and aldehydes are used as the startingmaterials to firstly afford functionalized dihydropyran derivatives 2 in cascade reactions in one pot underβ-proline catalysis (Scheme 1a), which are then transformed to 4-substituted-pyridine-2,6-dicarboxylicacid derivatives 1 (Scheme 1b).3 Dihydropyran derivatives 2 were also transformed to variousmolecules including amino group-substituted dihydropyrans, amino acid derivatives, dihydrodiazepines,and quinoxalinone derivatives.3 Here we report the development of a one-pot version of the synthesis of4-substituted-pyridine-2,6-dicarboxylic acid derivatives 1 starting from pyruvates and aldehydes withpyrrolidine-acetic acid catalysis (Scheme 2).HETEROCYCLES, Vol. 95, No. 1, 2017 587R HOCO2EtO+ 2NHCO2HOROHOEtOOOEt2NH4OAc1NROEtOOOEtROOOEtCO2EtO+OREtOOHOEtOOEtOOR OOOEtO2(a)(b)Scheme 1. Our previous synthesis of 4-substituted-pyridine-2,6-dicarboxylic acid derivatives 13R HOCO2EtO+ 21) pyrrolidine-AcOH2) NH4OAc1NROEtOOOEtScheme 2. One-pot synthesis of 4-substituted-pyridine-2,6-dicarboxylic acid derivatives 1 developed inthis studyIn our previous two-pot method to synthesize 1, functionalized dihydropyran derivatives 2 weresynthesized from pyruvates and aldehydes under β-proline catalysis.3 It has been recognized thatreactions of simple pyruvates (such as ethyl pyruvate and methyl pyruvate) as nucleophiles (i.e., reactionsof enolates and enamines of pyruvates) with other electrophiles are often difficult, and examples of thesereactions have been limited.4,5 Self-condensation of simple pyruvates often occurs even in the presenceof other electrophiles.3,4 In our β-proline-catalyzed reactions of pyruvates with aldehydes, pyruvatesacted as nucleophiles to lead the dihydropyran derivatives.3 Whereas β-proline was the best catalystamong those tested for the formation of dihydropyran derivatives 2, other amino acids (such as(S)-alanine and β-alanine) and amines (such as Et3N and DBU) did not work as the catalyst for thereaction to give 2.3 When pyrrolidine-acetic acid was used as the catalyst, the desired dihydropyranderivative was formed although the yield was low under the previously tested conditions.3 Becausepyrrolidine and acetic acid are more readily accessed or obtained than β-proline, we first searched for588 HETEROCYCLES, Vol. 95, No. 1, 2017suitable conditions for the synthesis of 2a using pyrrolidine and acetic acid as catalyst components (Table1) toward the development of the one-pot methods. The use of higher loadings of acetic acid relative topyrrolidine above a certain level was favored for the formation of 2a (Table 2, entries 4-7), but furtherhigh loading of acetic acid did not improve the yield of 2a (Table 1, entry 7 versus entry 8). Withappropriate loadings of pyrrolidine and acetic acid as the catalyst, dihydropyran derivative 2a wasobtained in reasonable yields. As shown in Table 1, entry 7, the reaction of the aldehyde (1.0 equiv) andethyl pyruvate (3.0 equiv) using pyrrolidine (0.4 equiv) and acetic acid (1.0 equiv) as the catalyst resultedin the best yield of 2a among the conditions tested.Table 1. Optimizations of the pyrrolidine-acetic acid catalysis in the reaction to form 2aaCHOO2NCO2EtOOREtOOHOEtOO2a: R = C6H4-p-NO2+pyrrolidine-AcOHMeCNrt(1.0 equiv) (3.0 equiv)Entry Pyrrolidine (equiv) AcOH (equiv) Time (h) Yield (%)b1c 0.1 - 48 42c 0.1 0.1 48 273c - 0.1 48 nd4 0.2 0.2 24 375 0.2 0.4 24 386 0.2 1.0 24 497 0.4 1.0 24 618 0.4 2.0 24 609 0.5 1.0 24 5910 0.5 2.0 24 57a Reaction conditions: p-nitrobenzaldehyde (0.5 mmol, 1.0 equiv), ethyl pyruvate (1.5 mmol, 3.0 equiv),and indicated loadings of pyrrolidine and acetic acid in MeCN (0.5 mL) at 25 °C except where indicated.b Isolated yield (the cyclic form and the linear form were combined); nd = formation of 2a was notdetected by TLC analyses. c Reaction using p-nitrobenzaldehyde (1.0 mmol, 1.0 equiv) and ethylpyruvate (2.2 mmol, 2.2 equiv) in MeCN (1.0 mL); taken from our previous paper.3In the reaction using pyrrolidine and acetic acid (1:1) as the catalyst (Table 1, entries 2 and 4), pyruvateself-condensation products were observed. Slightly acidic conditions in the presence of pyrrolidine (i.e.,conditions with higher loadings of acetic acid than pyrrolidine, such as Table 1, entry 7) favored theformation of 2a over the pyruvate self-condensation.HETEROCYCLES, Vol. 95, No. 1, 2017 589In our previous study, addition of pyrrolidine to the solution of 2a in CD3CN resulted in thedecomposition of 2a and in the formation of a complex mixture.3 Treatment of 2a in CD3CN with Et3Nalso resulted in slow decomposition of 2a.3 In contrast, addition of acetic acid to the solution of 2a inCD3CN did not lead notable decomposition of 2a after 1 day.3 The slightly acidic conditions resultingfrom the higher loading of acetic acid than pyrrolidine may also prevent the decomposition of thegenerated product 2a.Table 2. Optimizations of the second-step conditions to form 1a in one pota2) NH4OAc (3.0 equiv)additivert, 24 hNROEtOOOEt1) pyrrolidine (0.4 equiv)AcOH (1.0 equiv)MeCN, rt, 30 h1a: R = C6H4-p-NO2CHOO2NCO2EtO+(1.0 equiv) (3.0 equiv)Entry Additive (equiv) Yield (%)b1 - 502 Et3N (1.0 equiv) 503 AcOH (1.0 equiv) 684c - 46a Reaction was performed using p-nitrobenzaldehyde (1.0 mmol, 1.0 equiv) and ethyl pyruvate (3.0 mmol,3.0 equiv) in the presence of pyrrolidine (0.4 mmol, 0.4 equiv) and acetic acid (1.0 mmol, 1.0 equiv) inMeCN (1.0 mL) at 25 °C for 30 h, followed by addition of NH4OAc (3.0 mmol, 3.0 equiv) except whereindicated and additive (if added) and by being stirred at the same temperature for 24 h. b Isolated yield.c NH4OH was used instead of NH4OAc.Next, we optimized the conditions to enable the synthesis of pyridine derivative 1a in one pot (Table 2)by adapting the best conditions identified to form 2a (Table 1, entry 7). We found that addition of aceticacid in the second step improved the yield of the pyridine derivative (Table 2, entry 3 versus entry 1).The use of acetic acid at the pyridine formation stage may act to retain or to provide an acidicenvironment in the presence of NH4OAc, minimizing the decomposition of 2a, activating 2a byprotonation to trigger the addition reaction of NH4OAc, and accelerating the cyclization of theintermediate and the elimination of water to lead the formation of 1a. The one-pot method yielded 1a in68% (Table 2, entry 3); this was a better result than that of our previous two-step route with the β-prolinecatalysis (Scheme 1), in which the yield of 1a was 56% from the aldehyde and pyruvate, based on thecalculation of 72% for the first pot to give 2a and 78% for the second pot to generate 1a from 2a.3 Theyield of 1a in the one-pot method (Table 2, entry 3) was also higher than the isolated yield of 2a in Table590 HETEROCYCLES, Vol. 95, No. 1, 20171, entry 7. The one-pot procedure bypasses the purification of dihydropyran derivatives 2, which isoften difficult because of the equilibrium between the cyclic form and the linear form (Scheme 1a).Table 3. Synthesis of various 4-substituted-pyridine-2,6-dicarboxylic acid derivatives from aldehydesand pyruvatea2) NH4OAc (3.0 equiv)AcOH (1.0 equiv)rt, 24 hNROEtOOOEt1) pyrrolidine (0.4 equiv)AcOH (1.0 equiv)MeCN, rt, 30 h1CO2EtO+(1.0 equiv) (3.0 equiv)NOEtOOOEt1a: R1 = NO21b: R1 = Cl1c: R1 = Br1d: R1 = F1e: R1 = CF31f: R1 = CN1g: R1 =68%(72% x 78% = 56%)b63%(64% x 69% = 44%)b57%(65% x 75% = 49%)b53%51%66%46%C CHR1NOEtOOOEtNOEtOOOEtONOEtOOOEtSNOEtOOOEtNOEtOOOEtNOEtOOOEtNOEtOOOEtMeO OMe1h 48% 1i 39%(51% x 79% = 40%)b1j 48% 1k 35%(64% x 72% = 46%)b1l 35% 1m 41% 1n 71%(88% x 67% = 59%)bRCHOa Reaction was performed using aldehyde (1.0 mmol) and ethyl pyruvate (3.0 mmol) in the presence ofpyrrolidine (0.4 mmol) and acetic acid (1.0 mmol) in MeCN (1.0 mL) at 25 °C for 30 h, followed byaddition of NH4OAc (3.0 mmol) and acetic acid (1.0 mmol) and by being stirred at the same temperaturefor 24 h. b Data of the two-pot reactions; yield of the formation of 2 using the β-proline catalysis(Scheme 1a),3 yield of 1 from 2 (Scheme 1b),3 and yield of 1 calculated from the aldehyde.With the conditions identified, various 4-substituted-pyridine-2,6-dicarboxylic acid derivatives 1a-1nwere synthesized in one pot (Table 3). Reactions using substituted benzaldehydes, naphthaldehyde, arylHETEROCYCLES, Vol. 95, No. 1, 2017 591aldehydes, α-branched alkyl aldehydes, and α,α-dimethoxyacetaldehyde all afforded the pyridinederivatives. For the pyridine derivatives that were previously synthesized using our two pot procedures,the calculated yields are also indicated. In most cases, the one-pot method yield was higher than ourprevious two-pot yield.6 The one-pot method was readily scaled: Pyridine-2,6-dicarboxylic acidderivative 1g (0.73 g) was obtained in 45% in one pot starting from 5.0 mmol aldehyde.Pyridine-2,6-dicarboxylic acid derivatives are often used as acids.1,2 The ester group of 1 is also a usefulsite to introduce an alcohol or aldehyde functional group. To demonstrate the utility of our one-potsynthesis, diesters 1k and 1m were hydrolyzed to afford the corresponding diacid derivatives 3k and 3m(Scheme 3). Pyridine derivatives 4 and 5 were also obtained by transformations of one ester group ofthe diester derivative (Scheme 4).NROEtOOOEt1) KOH/EtOHreflux, 2 hNROHOOOH12) HCl (pH 2.0~2.5)3k: R =3m: R =392%78%Scheme 3. Hydrolysis of 1 to afford 4-substituted-pyridine-2,6-dicarboxylic acids 3NOEtOOOEtNHOOOEtNOHOOEtNaBH4EtOH0 °CMnO2CH2Cl2rt1g 4 60% 5 65%Scheme 4. Transformations to lead to pyridine derivatives 4 and 5In conclusion, we have developed one pot reactions for the synthesis of4-substituted-pyridine-2,6-dicarboxylic acid derivatives from pyruvates and aldehydes under mildconditions. Various derivatives were synthesized using our concise, atom-economical method. The592 HETEROCYCLES, Vol. 95, No. 1, 2017developed reaction method should be useful for the synthesis of 4-substituted-pyridine-2,6-dicarboxylicacid derivatives that are of interest as ligands, bioactives, and their building blocks.ACKNOWLEDGEMENTSWe thank Jyunsuke Machida for technical assistance and Dr. Michael Chandro Roy, Research SupportDivision, Okinawa Institute of Science and Technology Graduate University for mass analyses. Thisstudy was supported by the Okinawa Institute of Science and Technology Graduate University, by aGrant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations byOrganocatalysts” from the MEXT (Japan), and in part by an Okinawa Intellectual Cluster Program(Okinawa, Japan).Supporting Information Available: Experimental procedures, product characterization, and NMRspectra.REFERENCES AND NOTES1. A. Picot, A. D’Aleo, P. L. Baldeck, A. Grichine, A. Duperray, C. Andraud, and O. Maury, J. Am.Chem. Soc., 2008, 130, 1532; X.-C. 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Synthesis of 4-Substituted-Pyridine-2,6-dicarboxylic Acid Derivatives from Pyruvates and Aldehydes in One Pot

Fujie Tanaka

Pandurang V. Chouthaiwale

Sébastien Lapointe

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Synthesis of 4-Substituted-Pyridine-2,6-dicarboxylic Acid Derivatives from Pyruvates and Aldehydes in One Pot

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