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. 2025 Jul 8;27(28):7513–7517. doi: 10.1021/acs.orglett.5c01807

Access to 2,5-Disubstituted Thiazoles Via Cyclization of N‑Substituted α‑Amino Acids

Hajar Aledwan †, Guy Zimmermann †, Natalia Fridman ‡, Georgios Vassilikogiannakis §, Abed Saady †,*
PMCID: PMC12281621  PMID: 40628372

Abstract

We report a mild, metal-free synthesis of 2,5-disubstituted thiazoles from readily available N-substituted α-amino acids. The reaction proceeds via carboxylic acid activation with thionyl chloride, followed by intramolecular cyclization and in situ sulfoxide deoxygenation, affording the target thiazoles in excellent yields. This transition-metal-free, robust, and scalable protocol enables access to a broad range of 2,5-disubstituted thiazoles, bypassing the need for complex reagents and significantly simplifying their synthesis.

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Simplifying synthetic organic processes for the preparation of natural products, biologically active compounds, and other functional molecules remains a central challenge in modern chemistry, drawing significant research efforts worldwide. , Recently developed simplification methodologies have made various multistep organic syntheses more accessible to both academia and industry.

Thiazoles are ubiquitous and important heterocyclic scaffolds that are found in both natural products and synthetic drugs and exhibit diverse biological activities such as antimicrobial, anticancer, and antidiabetic properties. For example, synthetic drugs such as sulfasuxidine and sulfathiazole and natural products such as vitamin B1, apratoxins, and patellamide A, feature thiazole architecture. As a result of the significance of the thiazole motif, many researchers worldwide have invested significant efforts to develop synthetic strategies to build and modify this core structure, aiming to create a wide array of thiazole-containing compounds.

Moreover, 2,5-disubstituted thiazoles with aryl groups are core components in materials with interesting optical and electronic properties. However, the synthetic methods to directly construct thiazole skeletons possessing 2,5-disubstitutions from easily available simple starting substances are still limited. The Hantzsch synthesis stands as the most promising method for preparing these compounds; however, the synthesis encounters limitations when aiming for 2,5-disubstituted thiazoles (Scheme A).

1. (A) Hantzsch Synthesis of 2,5-Disubstituted Thiazoles. (B) Murakami’s Approach for the Construction of 2,5-Disubstituted Thiazoles Using Cu­(I)-Catalyzed 1,3-Diploar Cycloaddition. (C) Jiao’s Approach for the Construction of 2,5-Disubstituted Thiazoles Using Cu-Catalyzed Aerobic Oxidation. (D) The Work Reported in This Article.

1

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In recent years, several methods have been reported for the synthesis of 2,5-substituted thiazoles. − For instance, Murakami et al. have reported on two catalytic reactions based on a Cu­(I)-catalyzed 1,3-diploar cycloaddition of terminal alkynes with sulfonyl azides and a Rh­(II)-catalyzed reaction of the resulting intermediate with thionoesters targeting 2,5-substituted thiazoles (Scheme B). A few years later, Jiao et al. reported Cu-catalyzed aerobic oxidative synthesis of thiazoles from phenyl acetic aldehyde, primary amines, and elemental sulfur (Scheme C).

Despite this progress in the field, each of the current methodologies suffers from drawbacks such as complicated starting materials, air sensitivity, harsh synthetic conditions, or low efficiency, among others.

Hence, the development of alternative strategies capable of swiftly producing 2,5-disubstituted thiazole derivatives could offer valuable synthetic advantages. Here we report a simple synthetic strategy to rapidly and easily access 2,5-disubstituted thiazoles from N-substituted α-amino acid using thionyl chloride (SOCl2) and 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU) under metal-free reaction conditions. The method relies on the activation of carboxylic acid, followed by cyclization and finally sulfoxide deoxygenation to form the target products. Our results show that the reaction conditions tolerated many functional groups, were not sensitive to air, and are readily scalable (e.g., to 3-g scale). Based on the broad scope, we provide detailed mechanisms for this unique and simple reaction.

During our attempts to apply a Curtius rearrangement on a chiral 2,2′-bipyridine macrocycle bearing an l-phenylalanine amino acid analogue, 1, using thionyl chloride and diphenylphosphoryl azide (DPPA), unexpected species were observed and characterized that raise an interesting question and prompted a new hypothesis (Scheme ). When the reaction was repeated under the same conditions a few more times, the same unexpected product was observed. Spectroscopic analysis of the unexpected product indicated that a thiazolium ring, 2, was formed under these conditions. Later, single-crystal X-ray diffraction analysis confirmed that the thiazolium ring was formed as a result of this transformation (Scheme ).

2. Reaction of a Chiral 2,2′-Bipyridine Macrocycle in Curtius Rearrangement and Solid-State Structure of Macrocycle 2, Shown in Ball and Stick Mode.

2

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The unexpected formation of a thiazolium ring prompted us to further explore and optimize the reaction parameters with the aim of enhancing the efficiency and generality of this transformation. Intriguingly, when a noncyclic analogue, namely, N,N-dibenzyl-l-phenylalanine, 3, was treated under the same conditions, 2,5-diphenyl-3-(phenylmethyl)­thiazolium, (4, Table ) was isolated in 14% yield and the assignment was confirmed by 1H NMR, LCMS, and single-crystal X-ray analysis (Table ). Intrigued by these observations, we investigated and optimized the reaction conditions, as shown in Table . Initially, the solvents were changed, avoiding the use of DPPA, and the reaction time and temperature were changed (Table ). Further experimentation revealed that DPPA is not necessary for the formation of the product, and, furthermore, avoiding adding DPPA to the reaction actually slightly improved the yield (Table , entry 2). When the reaction was conducted with triethylamine instead of potassium carbonate, 4 was isolated in 36% yield (Table , entry 3). Further investigations of the base in the reaction showed that the use of DABCO and DBU improved the reaction yield to 48% and 65%, respectively (Table , entries 4 and 5). When CH2Cl2 was used as a solvent instead of THF, there was a significant increase (82%) in the isolated yield of 4 (Table , entry 6). Various solvents were tested (1,4-dioxane, pyridine, and 1,2-dichloroethane) (Table entries 7–9), revealing that CH2Cl2 provides the best yield. Unexpectedly, conducting the reaction at room temperature resulted in a nearly quantitative isolation (99%) of 4 (Table entry 10). Investigation of the thionyl chloride and DBU equivalencies, along with the sensitivity of the reaction to air, was done thoroughly (see Supporting Information, Section S2). When the reaction was performed under the optimized conditions with N,N-dibenzyl-d-phenylalanine as the substrate, product 4 was obtained in a nearly quantitative yield, as expected.

1. Optimization of the Reaction Conditions.

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Entry Reaction conditions Yield [%]
1 SOCl2, K2CO3 (5 equiv) DPPA (2 equiv), THF,40 °C 14
2 SOCl2, K2CO3 (5 equiv), THF, 40 °C 21
3 SOCl2, TEA (5 equiv), THF, 40 °C 36
4 SOCl2, DABCO (5 equiv), THF, 40 °C 48
5 SOCl2, DBU (5 equiv), THF, 40 °C 65
6 SOCl2, DBU (5 equiv), DCM, 40 °C 82
7 SOCl2, DBU (5 equiv), 1,4-Dioxane, 40 °C 51
8 SOCl2, DBU (5 equiv), Pyridine, 40 °C 17
9 SOCl2, DBU (5 equiv), 1,2-Dichloroethane, 40, r.t 73
10 SOCl2(10 equiv), DBU (1 equiv), DCM, r.t 99
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a

Isolated yield.

With the optimal conditions in hand, we were interested in applying the reaction conditions to N-benzyl-l-phenylalanine (5a, Table ) to obtain 2,5-diphenylthiazole (6a). Pleasingly, under the optimized conditions, N-benzyl-l-phenylalanine, 5a, was completely consumed (detected by LCMS and NMR) and 2,5-diphenylthiazole, 6a was isolated in 92% yield (Table ).

2. Substrate Scope for the Direct Synthesis of Thiazoles from N-Substituted l-Phenylalanine.

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Next, the effects of N-substituted l-phenylalanine were investigated. When substrates bearing an alkyl group such as methyl in N-4-methylbenzyl l-phenylalanine, 5b, or tert-butyl in N-3,5-diterbutybenzyl l-phenylalanine, 5c were used, the corresponding thiazoles 6b and 6c were isolated in an excellent yield (89% and 93%, respectively). In addition, substrates bearing halogenbromine, 5d and fluorine, 5ewere successfully converted to products 6d and 6e in a good yield of 83% and 88%, respectively.

Furthermore, strongly electron-withdrawing groups such as trifluoromethyl-, nitro-, and trifluoromethoxy-substituted substrates 5f-5i were also well-tolerated, to give thiazoles 6f – 6i in excellent yields. Compounds 6f, 6g, and 6h were analyzed by single-crystal X-ray diffraction (SCXRD).

Pleasingly, N-4-methoxylbenzyl-l-phenylalanine, 5j, bearing an electron-donating group was well-tolerated, giving the corresponding thiazole 6j in good yield. Interestingly, N-[2]-furyl-l-phenylalanine, 5k, N-[2]-pyridyl-l-phenylalanine, 5l and N-[2]-6-bromopyridin-2-ylmethyl-l-phenylalanine, 5m were also used in the scope investigation to obtain the furyl- and pyridyl-substituted thiazoles 6k, 6l, and 6m in excellent yield. Styrene- and pyrene-substituted thiazoles, such as 6n and 6o, respectively, were also obtained in excellent yields when the corresponding phenylalanine derivatives 5n and 5o were used. Interestingly, when N-propargyl-l-phenylalanine, 5p, was tested the corresponding thiazole 6p was isolated in excellent yields.

2-Carbonyl-5-phenylthiazoles can be synthesized under the reported reaction conditions. For example, when N-(carboxymethyl)­phenylalanine, 5q, was used as the substrate and the reaction was quenched with methanol, the corresponding methyl ester, methyl 5-phenylthiazole-2-carboxylate 6q, was isolated in 77% yield.

Next, we were interested in evaluating whether 5-phenylthiazole, 6r, or 2-alkyl-5-phenylthiazole such as 6s and 6t could be obtained using the reported methodology. Therefore, N-methyl-l-phenylalanine, 5r and N-ethyl-l-phenylalanine, 5s were used as a substrate. Unfortunately, neither of the desired thiazoles was detected by either NMR or MS spectra (see Supporting Information, Section S2).

Although when phenethyl-l-phenylalanine, 5t, was used as a substrate, thiazole 6t was detected only in minor amounts by LCMS. The results indicate that the preparation of 2-alkyl-5-phenylthiazoles is currently a limitation of the reported methodology.

Based on the broad scope of the N-substituted-phenylalanine method, we were interested in evaluating the tolerance of the amino acid tyrosine in our methodology. For this purpose, we synthesized the corresponding N-substituted tyrosine using reductive amination with suitable benzaldehyde derivatives. Our focus was mainly on three different substitutions: N-benzyl, 5u, N-4-methyxobenzyl, 5v, and N-4-nitrobenzyl, 5w. Pleasingly, the amino acid tyrosine was tolerated by our methodology, and thiazoles 6u–w were isolated in moderate to good yields as shown in Table . Furthermore, when N,N-dibenzyl-l-tyrosine, 5x, was used as a substrate, corresponding thiazolium 6x was isolated in 88% yield and the assignment was confirmed by 1H NMR, LCMS, and SCXRD. The slight decrease in reaction efficiency observed upon switching to tyrosine can be attributed to its electron-donating hydroxy group, which may hinder the elimination step by destabilizing the intermediate of the reaction (Scheme ).

3. Plausible Mechanistic Sequence.

3

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Our attempts to use other aromatic amino acids such as tryptophan and histidine did not lead to the desired products (see Supporting Information, Section S2). Our hypothesis attributes this fact to the potential reactivity of the NH group in the indole and imidazole side chains in tryptophan and histidine, respectively. To the best of our knowledge, there is no reported procedure in the literature for 5-imadazoyl-2-phenylthiazoles and only one example of 5-indolyl-2-phenylthiazole. Further investigation of NH-protected derivatives is currently underway and will be reported in due course.

A plausible mechanism for the production of the 2,5-disubstituted thiazolium/thiazoles is depicted in Scheme . Initially, an activation of carboxylic acid using 1 equiv of SOCl2 takes place to form the corresponding acid chloride, compound A. The latter undergoes β-elimination, followed by DBU-assisted deprotonation, resulting in an enamine intermediate (compound C).

The enamine intermediate C reacts with one more equivalent of SOCl2 to form intermediate D. Deprotonation of intermediate D following by cyclization leads to 3-thiazoline S-oxide (intermediate E), that can react with one more equivalent of SOCl2 followed by sulfoxide deoxygenation using DBU to give the corresponding 2,5-disubstitiued thiazolium/thiazoles.

To support our suggested mechanism, intermediate C1 was synthesized using phenylacetaldehyde and dibenzyl amine. Pleasingly, when compound C1 was treated with SOCl2 and DBU in CH2Cl2, 2,5-diphenyl-3-(phenylmethyl)­thiazolium, 4, was the sole product detected by LCMS and NMR (see Supporting Information, Section S2).

In conclusion, we have developed a one-pot synthetic procedure for the synthesis of 2,5-disubstituted thiazoles in excellent yields, wherein an N-substituted-α-amino acid is treated with SOCl2 and DBU in DCM at room temperature. Salient features of the reaction are its tolerance to many functional groups, resulting in a broad reaction scope, availability of the starting materials, and its insensitivity to air. Notably, SOCl2 played multiple roles; it was used as an activating reagent, the source of the sulfur atom in the thiazole ring, and it facilitates the sulfoxide deoxygenation step. This protocol should be very useful in organic synthesis due to its ease of operation, the mild reaction conditions, and the use of cheap reagents. We anticipate this protocol may facilitate the production of useful thiazoles.

Supplementary Material

ol5c01807_si_001.pdf (6.8MB, pdf)

Acknowledgments

This study was supported by Ministry of Regional Cooperation of Israel, Grant 590934 (Abed Saady and Georgios Vassilikogiannakis). Abed Saady thanks Bar-Ilan University (Start-up grant) and the Council for Higher Education (MAOF scholarship). The authors thank Dr. Yulia Shenberger (BIU) for recording the HRMS for all the reported compounds. The authors thank Dr. Graham J. Tizzard (University of Southampton) for his assistance in partly solving the SCXRD for compound 2.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c01807.

  • Procedures and full characterization data (NMR, MS, SCXRD as appropriate) for all new compounds and supplementary discussion (PDF)

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This work was published earlier and appeared on ChemRxiv prior to submission.

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

ol5c01807_si_001.pdf (6.8MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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