Letter pubs.acs.org/OrgLett
Mild Esterification of Carboxylic Acids via Continuous Flow Diazotization of Amines Clément Audubert and Hélène Lebel* Département de Chimie, Center for Green Chemistry and Catalysis, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, Québec, Canada H3C 3J7 S Supporting Information *
ABSTRACT: A new continuous flow protocol for the diazotization of methylamine with 1,3-propanedinitrite in THF is reported. The synthesis of methyl esters was achieved in high yields from a variety of carboxylic acids in 20 min at 90 °C. Additionally, this protocol was extended to other aryl and alkyl amines, namely secondary amines, to produce various substituted esters in high yield using 2-MeTHF as a solvent. The reaction conditions were compatible with many functional groups, namely nitrogen-containing heterocycles, alkynes, alkenes, alcohols, and phenols. Mechanistic investigations reveal that the reaction appears to proceed through a transient diazonium species rather than a diazo intermediate.
T
he esterification of carboxylic acids with alcohols is typically achieved under acid catalysis.1 For more challenging sterically hindered or highly functionalized substrates (namely with acid sensitive functionality), the activation of the acid or the alcohol is often necessary.2,3 An alternative strategy for the synthesis of methyl esters applies diazomethane as the methylating reagent.4 Under these mild reaction conditions, highly functionalized carboxylic acids are cleanly esterified in excellent yields. Despite all the advantages associated with this method, the toxicity and explosive nature of this reagent limit its applicability. To overcome the safety issues related to diazo compounds, alternatives strategies for their synthesis have been developed, namely using continuous flow processes.5 Over the past decade, continuous flow chemistry6 has appeared as a relevant tool for the safe generation and use of hazardous materials.7 For example, diazomethane has been produced in continuous flow from nitrosoamine derivatives such as Diazald8 or N-nitrosomethylurea (MNU).9,10 The subsequent reaction with carboxylic acids furnishes the corresponding methyl esters. Alternatively, the batch oxidation of silylated hydrazones,11 or free hydrazones,12 with respectively difluoroiodobenzene and manganese oxide, afforded the corresponding diazo compound that was reacted in situ with a carboxylic acid to synthesize the corresponding ester in high yields (eq 1). The diazotization of amines13 is another method to produce various diazo compounds that have been adapted to continuous flow processes.14 Recently we have reported the diazotization of trimethylsilylmethylamine (TMSCH2NH2) with 1,3-propanedinitrite (Pr(ONO)2) to yield trimethylsilyldiazomethane (TMSCHN2) using batch and continuous flow synthesis.15 Herein, we report the esterification of carboxylic acids via the diazotization of various amines, including methylamine (eq 2). The reaction appears to proceed via a diazonium intermediate that undergoes an SN2 or SN1 reaction, depending on the substitution of the transiently © XXXX American Chemical Society
formed diazonium. The corresponding diazo compound does not appear to be an intermediate, mitigating safety concerns and adverse side reactions associated with this class of reagents. We first investigated the reaction of 4-phenylbenzoic acid with the commercially available methylamine THF solution in the presence of a variety of nitrites at 90 °C, for various residence times.16 We were pleased to discover that methyl 4phenylbenzoate (1) was obtained in quantitative yield when the acid was reacted with 1.6 equiv of 1,3-propanedinitrite (Pr(ONO)2)17 and 2 equiv of methylamine for 10 min (eq 3). These reaction conditions were then applied to a variety of carboxylic acids (Scheme 1). In order to account for less reactive substrates, the residence time was extended to 20 min. The flow rate for the methylamine solution was adapted, in such way that the commercially available 2 M solution in THF could be used directly without any further dilution. Aliphatic methyl esters 1a−1h were isolated in excellent yields. Several functional groups, including ketones, thioethers, halides, sulfoxide, and pyridines, were tolerated under the reaction conditions. Sterically congested carboxylic acids were Received: July 20, 2017
A
DOI: 10.1021/acs.orglett.7b02231 Org. Lett. XXXX, XXX, XXX−XXX
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diazomethane. The esterification of probenecid proceeded in quantitative yields to afford ester 1i. The hindered ester 1j was isolated in 81% yield. Importantly, carboxylic acids with this substitution are known to be difficult to esterify.2b Both boronate ester and nitro groups were also tolerated (1k). Heteroaromatic carboxylic acids containing a free indole, thiophene, and thiazole unit were finally tested and produced the corresponding ester 1l−1n in excellent yields. The scope of amines was then investigated. The esterification reaction with aromatic methylamines was first explored (Scheme 2). A solution of benzylamine in 2-MeTHF was
Scheme 1. Synthesis of Methyl Esters from Carboxylic Acids by Diazotization of Methylaminea
Scheme 2. Synthesis of Benzylic Esters from Carboxylic Acids by Diazotization of Aromatic Methylaminesa
a
Isolated yields using ArCH 2 NH 2 (2 equiv) and Pr(ONO) 2 (1.6 equiv). bPerformed in batch for 16 h. cAn ArCH2NH2 and RCO2H solution was mixed with a solution of Pr(ONO)2 in THF.16 d i-AmONO (3.5 equiv) was used for 40 min (tR).
reacted with various carboxylic acids to afford benzyl esters 2a (derived from an amino acid), and 2b in excellent yields. When the carboxylic acid is only partially soluble in 2-MeTHF, the reaction was run in batch. For example, coumarin 2b was obtained in 79% yield after 16 h of reaction. The reaction conditions are compatible with an easily oxidizable ferrocenyl derivative, and benzyl ester 2c was produced in 67% yield. A substituted aromatic methylamine was tested and afforded 2d in excellent yields. Furfuryl amine was reacted with an alkynesubstituted nicotinic acid affording 2e in quantitative yield. No side reaction was observed with the alkyne moiety, a functionality known to react with diazo compounds. Quinoline
a
Isolated yields using MeNH2 (2 equiv) and Pr(ONO)2 (1.6 equiv). A MeNH2 and RCO2H solution was mixed with a solution of Pr(ONO)2 in THF.16 cMeNH2 (4 equiv) and Pr(ONO)2 (2 equiv) were used. dStarting from the corresponding Bpin carboxylic acid; esterification was followed by NaIO4 cleavage to produce boronic acid 1j. b
also successfully reacted to afford 1e and methyl podocarpate (1h) in high yields. We were pleased to observe that the reaction was tolerant to free alcohols (1g) and phenols (1h), as these have been reported to be problematic in the reaction with B
DOI: 10.1021/acs.orglett.7b02231 Org. Lett. XXXX, XXX, XXX−XXX
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resulting from the reaction of a sterically hindered acid and isopropylamine is quite remarkable. Good yields were also obtained for the reaction with cyclic amines producing 3h and 3i. The reaction conditions are again tolerant with many functional groups, such as alkenes, alkynes, protected amines, pyridines, and thiophenes. The reaction of N-Boc protected hexane diamine and piperazine proceeded smoothly, producing 3j and 3k in good yields. The reactions were performed in batch due to the low solubility of the starting amines. The diazotization of amines in the presence of carboxylic acids is a known process to produce diazo compounds.14 A few control experiments were performed to establish if a diazo intermediate was involved in the described process. When the reaction was performed with deuterated isopropylamine, only the deuterated product was produced with no H-incorporation (eq 4). This control experiment ruled out the formation of
derivative 2f was produced in quantitative yields on 1 mmol scale. The reaction on the 50 mmol scale afforded the desired compound 2f in a slightly lower, although acceptable, yield. The reaction could also be performed using commercially available i-AmONO with a residence time of 40 min producing 2f in 77% yield. Finally, licholic acid was reacted with 2aminomethylthiophene and 2g was isolated in 88% yield with no side reaction on the alcohol functionality. The method was then extended to aliphatic amines (Scheme 3). Ethyl- and butyl-amine were reacted with highly functionScheme 3. Synthesis of Substituted Aliphatic Esters from Carboxylic Acids by Diazotization of Aminesa
diazo intermediate A (Scheme 4). The carboxylate anion is likely not basic enough to perform the deprotonation. Instead, the formation of diazonium B is proposed to take place. This intermediate can then react via an SN2 or SN1 (via the formation of carbocation) mechanism. The reaction with Scheme 4. Proposed Mechanistic Pathways for the Esterifciation via Diazotization of Amines a
Isolated yields using RNH2 (2 equiv) and Pr(ONO)2 (1.6 equiv). Run in THF. cA RNH2 and RCO2H solution was mixed with a solution of Pr(ONO)2 in THF.16 dRNH2 (4 equiv) and Pr(ONO)2 (2 equiv) were used. eRun in CHCl3. fPerformed in batch for 16 h. b
alized carboxylic acids to produce 3a−3c. A functionalized aliphatic amine was also reacted to furnish 3d. The synthesis of sterically hindered isopropyl esters, known to be challenging to produce,2b was then investigated. Gratifyingly, the reaction of isopropylamine with various carboxylic acids produced the desired isopropyl ester in high yields and chemoselectivity (3e−3g). Namely, the formation in 94% yield, of ester 3f, C
DOI: 10.1021/acs.orglett.7b02231 Org. Lett. XXXX, XXX, XXX−XXX
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isobutylamine afforded ester 5 in 92% yield: no rearrangement product was observed, suggesting that the reaction proceeds via an SN2 pathway with primary amines (eq 5). Conversely, when chiral enantioenriched amines were used, the racemic product was isolated (eqs 6 and 7). The reaction appeared then to proceed via an SN1 pathway, involving carbocation C. To support this hypothesis, the reaction was run with amantadine: the desired adamantly ester 8 was isolated in 84% yields (eq 8). The formation of such a product can only take place, if a carbocation intermediate is formed in the process.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02231. Complete experimental and characterization data for all compounds (PDF)
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REFERENCES
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The proposed pathway involves the formation of diazonium B, which can undergo either an SN2 (presumably with primary amines, to avoid the formation of unstable primary carbocation) or an SN1 reaction with secondary and tertiary amines (Scheme 4). In conclusion, a novel method to synthesize esters via the diazotization of amines has been developed. The reaction is compatible with highly functionalized and sterically hindered carboxylic acids. Furthermore, various amines can be used, from the simple methylamine to functionalized amines, including sterically hindered amines. According to the mechanistic investigations, the reaction proceeded presumably through a diazonium intermediate (with no formation of the corresponding diazo compound) that undergoes either an SN2 or SN1 reaction.
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hélène Lebel: 0000-0001-8835-5786 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by the Natural Science and Engineering Research Council of Canada (NSERC) under the CREATE Training Program in Continuous Flow Science, a discovery grant from NSERC (Canada), the Canada Foundation for Innovation, the Université de Montréal, and the Centre in Green Chemistry and Catalysis (CGCC). We would like to thank Dr. Pauline Rulière and Dr. James J. Mousseau for fruitful discussions. D
DOI: 10.1021/acs.orglett.7b02231 Org. Lett. XXXX, XXX, XXX−XXX
