Letter pubs.acs.org/OrgLett
Divergent Reactivity of Amino Acid Alkyl Ester Hydrochlorides with 2‑Oxoaldehydes: Role of Selenium Dioxide To Promote Regioselective Synthesis of Imidazoles Anil K. Padala,†,‡ Raju Ranjith Kumar,§ S. Athimoolam,∥ and Qazi Naveed Ahmed*,†,‡ †
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (IIIM), Jammu 180001, India Academy of Scientific and Innovative Research (AcSIR-IIIM), Jammu 180001, India § Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India ∥ Department of Physics, University College of Engineering Nagercoil, Anna University of Technology Tirunelveli, Nagercoil 629 004, India ‡
S Supporting Information *
ABSTRACT: Novel amino acid substituted imidazoles engendered from amino acid alkyl ester hydrochlorides and 2-oxoaldehydes as a result of selenium dioxide promoted unconventional reaction in a basic environment is presented for the first time. Despite the nature of the 2-oxoaldehydes/amino acids used, the imidazoles generated had a functional core structure, and all of the reactions meticulously retained regioselectivity. The imperative feature of these reactions was the uniqueness of selenium dioxide in fixing two nitrogen atoms from amino acids through an in situ generated ArCOCHN1N2 system. Scheme 1. Summary of Work
2-Oxoaldehydes (OAs) have proven to be versatile building blocks for a variety of chemical transformations.1 The application of OAs toward the generation of different exigent products/ chemistry is the current interest of our group.2 The differing behavior of the aldehyde group in OA is primarily due to the presence of an electron-withdrawing ketone group.1 Although reactions through the aldehydic group of OA with different nucleophiles are well explored in diverse directions, the reactivity through the in situ generated hypothesized system (RCOCHN1N2) is not well explored. To develop applications for such a system, we recently established a novel method for the synthesis of 6-aminophenanthridines.2a Therein, benzotriazoles were used as nucleophiles against an in situ generated 2oxoiminium ion. However, with amino acid alkyl esters, the reactivity was not possible due to the tendency of 2-oxoiminium to oxidize to α-ketoamides.2h,j In an effort to develop such a system with amino acids, we designed our reaction against amino acids in the presence of selenium dioxide (Scheme 1A). In our previous observation regarding the conversion of α-carbonylimines to α-carbonylamides, we efficiently developed an oxidative amidation approach against weak nucleophilic amines (anilines, benzamides, and sulfonamides).2f However, such reactions, when tested against primary aliphatic amines, failed to produce any reaction. For these observations, we presume that, due to the low nucleophilicity of WNA, the intermediate I undergoes an elimination reaction to the 2-oxoimine II intermediate (path a) that ultimately undergoes oxidation to an amide bond. However, the behavior of such a reaction against amino acids alkyl esters bearing primary nucleophilic amine with the β-ester group was never explored. Herein, we assume that due © XXXX American Chemical Society
to moderate nucleophilicity of amino acid alkyl esters between secondary and weak nucleophilic amines it would preferably go through path b and result in the generation of an RCOCHN1N2 system III that ultimately results in the synthesis of imidazoles in a regioselective manner (Scheme 1C). Imidazole derivatives are well known for their diverse pharmacological applications.3 In addition, imidazole is part of histidine and histamine, and their derivatives are the core fragments in different natural products.4 Thus, our method could Received: November 18, 2015
A
DOI: 10.1021/acs.orglett.5b03321 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters be a novel, alternative, economical, and imperative method for their regioselective synthesis. Amino acids are always considered to be an attractive class of chiral reactants/reagents used for the generation of different complex organic compounds.5 While the reaction of amino acids with aldehydes has been successfully employed for the generation of amide bonds6 and different heterocycles through reaction of in situ generated imine with different reagents (Scheme 1B),7 they have never been directly utilized as reagents for the synthesis of different imidazoles (Scheme 1C). In this regard, our method highlights an unconventional tendency of selenium dioxide to promote the synthesis of imidazoles in a regioselective manner through a RCOCHN1N2 system in a basic environment. The beauty of the reaction lies in the fixing of two nitrogens from the amino acid in manner similar to the method of Hashemi et al. for the synthesis of imidazoles.8 In our initial investigations, we ventured to examine the nature of product obtained on reacting phenylglyoxal 1a (1 mmol) and glycine methyl ester hydrochloride 2a (1 mmol) in ACN under a basic environment (1 mmol) with selenium dioxide (1 mmol) as the reagent at 100 °C. To our delight, the reaction produced an unexpected product 3a in 33% yield (Table 1, entry 1).
Figure 1. ORTEP diagrams of compound 3e.
compound 3e, generated by reacting 2-(4-fluorophenyl)-2oxoacetaldehyde 1e (1 mmol) and glycine methyl ester hydrochloride 2a (1 mmol) under the above-mentioned conditions (Figure 1; for details, see the Supporting Information). Following the promising results achieved with the above method, the reaction conditions, particularly the change in concentrations, temperature, and base, were thoroughly investigated (Table 1). Under the conditions comparable to those perceived above, a survey of change in temperature (entry 1−3) intimated that there was no predominant effect of temperature on the yields (entry 3). Besides, screening of our reaction at different concentrations of pyridine was also performed (entries 3−6). We observed that better yields of desired product were observed at 1.5 equivalence of pyridine (entry 5). A further increase in the concentration of pyridine had no promising effect (entry 6). Later, screening about the change in amino acid concentration (entries 6−8) generated best results when taken at 1.2 equiv (entry 8). In addition, our reaction when tested with different concentrations of selenium dioxide (entries 8−10) indicated best results at 1.2 mmol (entry 9). Furthermore, we tested our reaction under different bases (entries 12−16). Finally, different reactions were tested against different oxidants to confirm the unanimous role of SeO2 to promote our reaction (entries 17−21). After extensive studies, we observed that the best conditions for the reaction were when 1 mmol of 1a was treated with 1.2 mmol of 2a and 1.2 mmol of SeO2 in 3 mL of ACN in the presence of 1.5 mmol of pyridine at rt (entry 9). Having observed that SeO2 catalyzed the unprecedented addition of glycine methyl ester 1a with 2-oxoaldehyde 2a under the above optimized conditions in a highly regioselective manner, we then decided to examine the substrate scope of this process. As compiled in Tables 2 and 3, a variety of amino acid alkyl esters 1 were tested against 2-oxoaldehydes 2 with diverse steric and electronic properties (entries 3a−ad). We were gratified to find that in all reactions tested the desired products 3 were produced in good yields (60−89%). In general, we classified these reactions in two different sets of experiments. In one set of experiments, different reactions were conducted between different 2oxoaldehydes 1 and glycine methyl ester hydrochloride 2a (entries 3a−h). It was observed that both electron-rich and electron-deficient OA could be smoothly transformed into the desired product. In addition, different experiments were performed between different representative amino acids 2 and phenylglyoxal 1a (entries 3i−l). In this case as well, yields were good for all the reactions conducted. Further, to check the reproducibility of our reaction against different ester protected amino acids, we conducted a few experiments against ethylprotected glycine (entries 3m−o). In all reactions, we found no effect of the change in yields to that extent. Another set of experiments was conducted between different OAs and amino acid hydrochlorides in order to check for a broad substrate scope (Table 3). In general, substituents at different positions of the arene group and their electronic nature in OA do
Table 1. Optimization of the Reactiona
entry
2a (mmol)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1 1 1 1 1 1 1.1 1.2 1.2 1.2 1.5 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
base (mmol)
SeO2/ oxident (mmol)
temp (°C)
3a (yieldb)/ time (h)
pyridine (1) pyridine (1) pyridine (1) pyridine (1.3) pyridine (1.5) pyridine (1.7) pyridine (1.5) pyridine (1.5) pyridine (1.5) pyridine (1.5) pyridine (1.5) TEA (1.5) KOH (1.5) NaOH (1.5) NaHCO3 (1.5) KHCO3 (1.5) pyridine (1.5) pyridine (1.5) pyridine (1.5) pyridine (1.5) pyridine (1.5)
1 1 1 1 1 1 1 1 1.2 1.5 1.2 1.2 1.2 1.2 1.2 1.2 MnO2 (1.2) IBX (1.2) TBHP (1.2) Oxone (1.2) DIB (1.2)
100 50 rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt
33/4 32/4 30/4 50/4 52/4 52/4 56/4 61/4 67/4 67/12 67/12 30/24 25/24 28/24 18/24 21/24 0/24 0/24 0/24 0/24 0/24
a Reaction conditions: 1a (1 mmol), 2a (1.2 mmol), pyridine (1.5 mmol), selenium dioxide (1.2 mmol), and ACN (3 mL). bIsolated yields.
Compound 3a, when examined in HRMS, surprisingly generated a mass of 321.1235 that formulated a structure formula of C19H17N2O3. This perhaps could be possible if two molecules of OA 1a reacted with two molecules of amino acid 2a in an unprecedented manner. In this regard, detailed NMR analysis was performed to reach a structure of 3 (for details, see the Supporting Information, page S14). The structure was finally fortified by single-crystal X-ray diffraction studies of the best crystallizable B
DOI: 10.1021/acs.orglett.5b03321 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Scope of the Reactiona
Scheme 2. Plausible Mechanism
entry
R
R′
R″
yieldb (%)/time (h)
3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3lc 3m 3n 3o
H H H H H H H H Me benzyl isopropyl ethyl(methyl)sulfane H H H
Me Me Me Me Me Me Me Me Me Me Me Me Et Et Et
Ph 4-MePh 3-MePh 4-MeOPh 4-FPh 4-ClPh 4-BrPh 4-HOPh Ph Ph Ph Ph 4-Me 4-F 4-Br
67/4 68/4 66/4 69/4 62/4 64/4 65/4 60/4 84/3.5 83/3 81/2.5 79/2.5 66/4 61/4 60/4
mechanism, OA reacts with the amino acid in the presence of SeO2 to generate intermediate I. Intermediate I avoids generation of 2-oxoimine II, undergoes elimination of selenonic acid on reacting with a second amino acid 2, and generates intermediate III. Intermediate III can either undergo tautomerism to IIIa that ultimately can undergo N−C bond cleavage to IIIb or can undergo addition of another OA molecule to IV. Since intermediate IIIa cannot justify regioselectivity, we propose a mechanism through IV. Intermediate IV can also tautomerize to IVa. However, different transformation through IVa could result in the generation of different product. Therefore, we presume that IV undergoes cyclization to V, ultimately through different steps eliminates SeO, and generates intermediate VIII. Intermediate VIII on aromatization generates the required product 3. The mechanism was supported by LC−ESI−MS analysis experiments performed between 1a and phenylalanine methyl ester 2. We could easily trap the mass of intermediate III “RCOCHN1N2 system” (for details, see the Supporting Information). In addition to the reaction mechanism, different control experiments were conducted to gain insight into the significance of different groups/reagents toward our reaction (Scheme 3). For example, we observed no reaction under the optimized conditions for coupling of benzaldehyde with 2a (experiment 1). This
a
Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), pyridine (1.5 mmol), selenium dioxide (1.2 mmol), and ACN (3 mL). bIsolated yields. cd-isomer.
Table 3. General Substrate Scope of the Reactiona
entry
R
R″
yieldb (%)/time (h)
3p 3q 3r 3s 3t 3u 3v 3w 3x 3y 3z 3aac 3ab 3ac 3ad
Me Me Me Me benzyl isopropyl isopropyl isopropyl isopropyl isopropyl isopropyl ethyl(methyl)sulfane H Me H
3-MePh 4-MePh 4-MeOPh 4-FPh 4-MePh 3-MePh 4-MePh 4-FPh 4-ClPh 4-BrPh 4-MeOPh 4-MePh 5-methylthiophene-2-yl 5-methylthiophene-2-yl 4-NO2Ph
85/3.5 86/3.5 88/3.5 84/3.5 82/3 85/2.5 86/2.5 81/2.5 83/2.5 82/2.5 89/2.5 82/2.5 64/4 86/3 0/24
Scheme 3. Control Experiment
a
Reaction conditions: 1(1 mmol), 2 (1.2 mmol), pyridine (1.5 mmol), selenium dioxide (1.2 mmol), and ACN (3 mL). bIsolated yields. cdisomer.
not affect the efficiency of the reaction (3a−ac). However, reactions with nitro-substituted OA failed to produce any reaction (entry 3ad). In addition, we found that in the case of amino acids yields were good despite the nature of the isomer being used (d or l); however, variation in the R group in amino acids affects the overall yields to some extent. For glycine, the yields were slightly less than other amino acids. Since such reactions on amino acid alkyl esters 2 and 2oxoaldehydes 1 are possible with selenium dioxide only, we currently anticipate a plausible mechanism that can justify the generation of imidazole regioselectively (Scheme 2). In this C
DOI: 10.1021/acs.orglett.5b03321 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
P. P.; Ahmed, Q. N. J. Org. Chem. 2015, 80, 11588. (c) Battula, S.; Kumar, A.; Ahmed, Q. N. Org. Biomol. Chem. 2015, 13, 9953. (d) Battula, S.; Battini, N.; Singh, D.; Ahmed, Q. N. Org. Biomol. Chem. 2015, 13, 8637. (e) Battini, N.; Battula, S.; Kumar, R. R.; Ahmed, Q. N. Org. Lett. 2015, 17, 2992. (f) Padala, A. K.; Mupparapu, N.; Singh, D.; Vishwakarma, R. A.; Ahmed, Q. N. Eur. J. Org. Chem. 2015, 2015, 3577. (g) Mupparapu, N.; Vishwakarma, R. A.; Ahmed, Q. N. Tetrahedron 2015, 71, 3417. (h) Mupparapu, N.; Battini, N.; Battula, S.; Khan, S.; Vishwakarma, R. A.; Ahmed, Q. N. Chem. - Eur. J. 2015, 21, 2954. (i) Battini, N.; Padala, A. K.; Mupparapu, N.; Vishwakarma, R. A.; Ahmed, Q. N. RSC Adv. 2014, 4, 26258. (j) Mupparapu, N.; Khan, S.; Battula, S.; Kushwaha, M.; Gupta, A. P.; Ahmed, Q. N.; Vishwakarma, R. A. Org. Lett. 2014, 16, 1152. (3) (a) Luca, L. D. Curr. Med. Chem. 2006, 13, 1. (b) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1. (c) Takle, A. K.; Brown, M. J. B.; Davies, S.; Dean, D. K.; Francis, G.; Gaiba, A.; Hird, A. W.; King, F. D.; Lovell, P. J.; Naylor, A.; Reith, A. D.; Steadman, J. G.; Wilson, D. M. Bioorg. Med. Chem. Lett. 2006, 16, 378. (d) Koch, P.; Bauerlein, C.; Jank, H.; Laufer, S. J. Med. Chem. 2008, 51, 5630. (e) Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.; Warner, R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697. (j) Antolini, M.; Bozzoli, A.; Ghiron, C.; Kennedy, G.; Rossi, T.; Ursini, A. Bioorg. Med. Chem. Lett. 1999, 9, 1023. (k) Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. J. Med. Chem. 1979, 22, 1003. (4) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022. (5) (a) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825. (b) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243. (c) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (d) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988. (e) Borthwick, A. D. Chem. Rev. 2012, 112, 3641. (f) Huber, G. W.; Iborra, S.; Corma, A. Chem. Rev. 2006, 106, 4044. (g) Zakzeski, J.; Bruijnincx, P. C. A.; Jongerius, A. L.; Weckhuysen, B. M. Chem. Rev. 2010, 110, 3552. (h) Chheda, J. N.; Huber, G. W.; Dumesic, J. A. Angew. Chem., Int. Ed. 2007, 46, 7164. (6) (a) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128 (40), 13064− 13065. (b) Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.; Chai, C. L. L.; Chen, A. J. Org. Chem. 2012, 77, 8007. (c) Ghosh, S. C.; Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.; Dang, T. T.; Chen, A. Adv. Synth. Catal. 2012, 354, 1407. (7) (a) López-Pérez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 10084. (b) Takayama, H.; Jia, Z.-J.; Kremer, L.; Bauer, J. O.; Strohmann, C.; Ziegler, S.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2013, 52, 12404. (c) Yang, Q.-L.; Xie, M.-S.; Xia, C.; Sun, H.-L.; Zhang, D.-J.; Huang, K.-X.; Guo, Z.; Qu, G.-R.; Guo, H.-M. Chem. Commun. 2014, 50, 14809. (d) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250. (e) López-Pérez, A.; Robles-Machín, R.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 9261. (f) Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.; Carrascal, T.; Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-Vanaclocha, F.; Cossío, F. P. Angew. Chem., Int. Ed. 2005, 44, 2903. (g) López-Pérez, A.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 340. (h) GonzalezEsguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun. 2013, 49, 4649. (i) Mahendar, V.; Oikawa, H.; Oguri, H. Chem. Commun. 2013, 49, 2299. (j) Robles-Machín, R.; López-Pérez, A.; González-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. - Eur. J. 2010, 16, 9864. (k) López-Pérez, A.; Segler, M.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2011, 76, 1945. (l) Liang, G.; Tong, M.-C.; Wang, C.-J. Adv. Synth. Catal. 2009, 351, 3101. (8) Khalili, B.; Tondro, T.; Hashemi, M. M. Tetrahedron 2009, 65, 6882. (9) (a) Martins, S. I. F. S.; Jongen, W. M. F.; van Boekel, M. A. J. S. A review of Maillard reaction in food and implications to kinetic modelling. Trends Food Sci. Technol. 2000, 11, 364. (b) Varoujan, A.; Yaylayan; Haffenden, L. J. W. Food Chem. 2003, 81, 403. (10) Sharpless, K. B.; Gordon, K. M. J. Am. Chem. Soc. 1976, 98, 300. (11) Mautino, M. R. U.S. Patent no. W02009/132238 A2, 2009. (12) Petit, S.; Fruit, C.; Bischoff, L. Org. Lett. 2010, 12, 4928.
observation clearly indicated the importance of the 2-oxo group in performing the reaction. Our reaction, when performed in the absence of pyridine, failed to produce the desired product (experiment 2). This result demonstrates that besides neutralization of amino acid alkyl ester hydrochloride, pyridine act as the catalyst as well. Failure of reaction with primary amines (experiment 3) proves the importance of the β-ester group. Experiment no. 4, obviously justifies the role of SeO2 in performing the reaction. However, experiments 5 and 6 clearly rule out the possibility of the Maillard-based mechanism10 for the generation of imidazoles. In experiment 7, the absence of 3a clearly justifies that our mechanism is not through 2-oxoacid. In addition, the reaction between 1a and 2a under optimized conditions under argon atmosphere also generated the desired product 3a in comparable yields (experiment 8). It clearly rules out the role of air assistance in our reaction. Finally, failure of valine, threonine, and isoleucine to generate desired product justifies that rearrangement of VI to VIII/elimination of SeO is difficult with sterically hindered amino acids (experiment 9). In conclusion, we revealed an efficient novel synthetic method for the generation of amino acid substituted imidazoles from amino acid alkyl esters 2 and 2-oxoaldehydes 1 via selenium dioxide promoted unconventional reaction in a basic environment. Despite variation in the nature of 2-oxoaldehydes/amino acids, the imidazoles generated had a functional core structure with fixed regioselectivity. The imperative feature of these reactions was the uniqueness of selenium dioxide in fixing two nitrogen atoms from amino acids through an in situ generated ArCOCHN1N2 system and generation of optically pure compounds. Further investigations, including detailed mechanistic studies, expansion of the substrate scope to different natural/nonprotein amino acids, and peptides, and application toward the development of novel IDO inhibitors11/peptidomemitics,12 are currently underway in our group.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03321. Experimental procedures, 1H and 13C NMR spectra, LC− ESI−MS data, and characterization of all compounds (PDF) X-ray data for 3e (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This research was supported by CSIR network project Grant No. BSC0108. A.K.P. thanks CSIR and also thanks AcSIR for registration. We are also thankful to Dr. Ajay P. Gupta and the analytical department of our institute. IIIM communication no. IIIM/1874/2015.
■
REFERENCES
(1) Eftekhari-Sis, B.; Zirak, M.; Akbari, A. Chem. Rev. 2013, 113, 2958. (2) (a) Battula, S.; Kumar, A.; Gupta, A. P.; Ahmed, Q. N. Org. Lett. 2015, 17, 5562. (b) Mupparapu, N.; Khushwaha, M.; Gupta, A. P.; Singh, D
DOI: 10.1021/acs.orglett.5b03321 Org. Lett. XXXX, XXX, XXX−XXX
