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Phosphine Catalyzed Michael-Type Additions: Synthesis of Glutamic Acid Derivatives from Arylidene-α-Amino Esters

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15 December 2023

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18 December 2023

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Abstract
The reaction of arylidene-α-amino esters with electrophilic alkenes to yield the Michael type addition compounds is optimized using several phosphines as organocatalysts. The transformation is very complicated due to the generation of several final compounds, including those derived from the 1,3-dipolar cycloadditions. For this reason, the selection of the reaction conditions is a very complex task and the slow addition of the acrylic system is very important to complete the reaction. The study of the variation of the structural components of the starting imino ester is performed as well as the expansion of other electron-poor alkenes. The crude products have a purity higher than 90% in most cases without any purification. A plausible mechanism is detailed based on the bibliography and the experimental results. The synthesis of pyroglutamate entities, after reduction of the imino group and cyclization, is performed in high yields. In addition, the hydrolysis of the imino group, under acidic media, represents a direct access to glutamate surrogates.
Keywords: 
organocatalysis
;  
phosphines
;  
imino esters
;  
Michael addition
;  
glutamates
;  
pyroglutamates
Subject: 
Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Proteinogenic and non-proteinogenic α-amino acids (AAs) constitute one of the five most important families of essential molecules in many scientific areas. The synthesis of these compounds [[1]] obeys to several general patterns as, for example [[2]]: a) the introduction of the hydrogen atom in the appropriate carbon-carbon or carbon-nitrogen double bond structures; b) the employment of a methodology able to insert the nitrogen atom at the α-position to the ester group (electrophilic nitrogen source); c) the reactions involving the incorporation of a carboxy group; and d) the coupling of the α-side chain to the AA template. Considering this last approach, α-substituted glutamates have been mainly obtained by Michael-type additions of glycine derivatives (glycine templates) onto the corresponding α,β-unsaturated reagents. This reliable strategy employs N-arylidene-α-amino acid esters [[3]] or tert-butyl N-benzylidieneamino glycinate [[4],[5]] (Scheme 1a) and even activated N-arylideneaminomalonates [[6],[7],[8]] (Scheme 1b) as starting materials. In all cases, phase transfer catalysis (PTC) conditions or the employment of organic superbases are the most common trends to complete the reaction. An important drawback detected in the reactions regarding glycine templates is the double alkylation process at the α-position.
Having in mind the natural impact [[9]] and usefulness of glutamates (and their pyroglutamate surrogates) [[10]] as synthetic key building blocks and their presence in many biologically active molecules [[11],[12]], we have studied a novel Michael type approach to their preparation. This methodology consists in base-free reaction of alkyl N-arylidene-α-amino acid esters with conjugated alkenes [[13]]. Here, the transformation operates in the presence of a substoichiometric amount of a phosphine, which acts as organocatalyst (Scheme 1c) [[14]].

2. Results and Discussion

The reaction between imino esters 1 and Michael acceptors can be controlled to afford the pure conjugated product or the corresponding pyrrolidine via 1,3-dipolar cycloaddition (1,3-DC) [[15]]. In many examples, these two products are found in the final crude mixture. With the aim of selecting the formation of the glutamate structure, we consider the ability of phosphines to catalyze this process. Thus, the reaction of imino ester 1a (1 equiv) with methyl acrylate (1 equiv) was treated with the corresponding phosphine (10 mol% loading), using toluene as solvent, at 25 °C (Scheme 2 and Table 1). The optimization of this reaction was a very complicated task due to the presence of three identified secondary compounds (3a, 4 and 5, see experimental part and SI). Initially, the nature of the phosphine was tested. Thus, the nucleophilicity of a triarylphosphine, such as Ph3P, was not enough to promote the desired reaction (Table 1, entry 1). 1,2-Bis(diphenylphophino)ethane (dppe) did not complete the reaction after 15 h, affording 2a impurified with cycloadducts 3a and 5 (Table 1, entry 2). The consumption of the starting material 1a was achieved after 72 h of reaction, but these two impurities were detected in the entries 3 and 4 of the Table 1. The slow addition (60 min) of imino ester 1a to the reaction mixture avoided the 1,3-DC but promoted the generation of the diester 4 as a consequence of the presence of an excess of the alkene (Table 1, entry 5). Byproduct 4 was suppressed by the slow addition of the methyl acrylate (60 min), but imidazolidine 5 was observed instead after 72 h of reaction (Table 1, entry 6). A shorter reaction time avoided the completion of the reaction obtaining significant amounts of starting imino ester 1a (Table 1, entry 7). Both tri-n-butyl and tri-tert-butyl phosphines afforded exclusively compound 5 or the diester 4, even in the process involving a slow addition of the acrylate (Table 1, entries 8-10). Perhaps, the nucleophilicity of trialkyl phosphines is excessive to direct the desired process. So, the modulation of this property combining an aryl group together two alkyl substituents bonded to the phosphorous atom was next attempted. Then, Me2PhP was used as catalyst demonstrating a rapid conversion (2 h) but generating large amounts of compounds 4 and 5 (Table 1, entries 11 and 12). Longer addition times (60 min) of the methyl acrylate favored the formation of the cycloaddition products 3a and 5, whilst shorter ones increased the presence of compound 4. The optimal addition time of methyl acrylate was 30 min (Table 1, entries 11-16) furnishing a very clean reaction crude by 1H NMR, in fact, compound 2a did not require any additional purification after the work up (see experimental section). The lowering of the catalyst loading to 5 mol% did not promote efficiently the reaction (Table 1, entry 17). The effect of solvent was not significant, obtaining similar results when the reactions were performed in dichloromethane, THF or acetonitrile (results not shown in Table 1). A very important detail found in this study was that no reaction product 2a was identified in the 1H NMR spectra when dimethylphenylphosphine was substituted by the same loading of triethylamine, DABCO, or DBU as catalysts. All the product ratios detailed in Table 1 were accurately analyzed using 1H NMR integrals of these crude materials.
The plausible mechanism of all these processes is described in Scheme 3. The excess of methyl acrylate reaction media causes the 1,4-attack of the intermediate I (generated by the Michael type addition of the phosphine and the acrylate) onto another equivalent of methyl acrylate. After an acid-base equilibration, intermediate III affords the dimer 4 with the regeneration of the catalyst. The low amounts of the intermediate I, obtained after slow addition of methyl acrylate, is surrounded by a large excess of imino ester 1a, which can be deprotonated by enolate I furnishing stabilized carbanion V. The direct attack of V onto IV gives the desired Michael-type adduct 2a with the elimination of the active catalyst. The adjustment of the nucleophilicity of the phosphine in the last step is crucial and the overall mechanism is very sensitive to this feature. On the other hand, when the addition of the phosphine is very slow, or simply, do not occur, the excess of 1a can give the fleeting azomethine ylide VI after 1,2-prototropy shift at room temperature. This process is very slow, but the ylide VI is trapped immediately by methyl acrylate (which do not undergo the transformation to the corresponding intermediate I) giving access to cycloadduct 3a. This is a very fast reaction compared with the analogous Mannich type-cyclization to yield product 5. In consequence, the entry 15 of the Table 1 employs the optimal phosphine, able to generate intermediate I, which has the preference for abstracting the α-H of the imino ester 1a rather than other different reaction. The slow addition of the acrylate inhibits the route to yield dimer 4, but favors the route to generate the expected compound 2a. There is a paramount detail in this last step. The phosphine does not activate the imino group neither of the imino ester 1a nor other different intermediate species such as V or even VI. The absence of the route I→ IV→ V favors the presence of 4 allowing the generation of the ylide VI giving raise to pyrrolidine 3a (after reaction with methyl acrylate) or imidazolidine 5 (by self-addition of 1a). Products 3a and 5 are formed when the addition took 60 min and they are minimized performing the addition in 30 min (Table 1, entries 14 and 15). However, an alternative base-propagation mechanism where the enolate V promotes a Michael-type addition, and not a SN2 onto the phosphonium intermediate, cannot be discarded [[16]].
With the best reaction conditions established in the entry 14 of the Table 1, the scope of imino esters 1 and alkyl acrylates was investigated. The results of the crude yields, determined by 1H NMR spectra, using dimethyl terephthalate as internal standard [[17]], are depicted in Scheme 3 [[18]]. The variation of the aromatic moiety in glycinate derived imino esters was well tolerated (2a-l, Scheme 4), even starters containing heterocyclic units as 2-thienyl or 3-pyridyl (2j-l, Scheme 4). Methyl, n-butyl and tert-butyl acrylates were randomly employed finding satisfactory results (Scheme 4). However, when imino esters with a substituent at the α-position were tested, a 20 mol% of the catalyst loading was required to complete the transformations. Also, different slow addition times and excess of the acrylate component were adapted in these examples for obtaining the best yields and purities (see experimental part). Thus, glutamate derivatives 2m-q were obtained (and characterized without purification) in very good yields (Scheme 4). However, with functionalized α-side chain α-amino acid derived imino esters 1, such as tryptophan, O-benzylserine and methionine the conversions were good but the crude compounds 2r-t were not pure and could not be characterized (grey color in Scheme 4). These three last examples were immediately transformed into the corresponding pyroglutamate surrogates 8 (see Scheme 6b). Despite the large quantity of secondary products expected, the final compounds were obtained as crude materials with purities higher than 90 % in most cases (see experimental part) without any purification. Chromatographic separation was not possible for those of lower purity due to the formation of amines and aldehydes from the imines on SiO2.
Other acrylic system like N,N-dimethylacrylamide reacted satisfactorily under these conditions affording the glutamine derivative 2u in 90% yield. In the presence of acrylonitrile or phenyl vinyl sulfone (1 equiv) the corresponding molecules 6, originated by a double addition of the alkene, were detected as byproducts. Maintaining all the optimized parameters of the process, the full conversion of the reaction performed with acrylonitrile was achieved using a 20 mol% of the catalyst and 4 equiv of the Michael-type acceptor. After that, the α,α-disubstituted imino ester 6v was obtained in 94% yield (by 1H NMR, Scheme 5). Bulkier phenyl vinyl sulfone did not afford pure and clean compound 6w due to the presence of tantamount quantities of monoalkylated substance 2w, even working in the presence of excess of alkene and using 20 mol% of the catalyst (Scheme 5). This preference to the phenyl vinyl sulfone and acrylonitrile to generate double alkylation products 6, unlike the acrylic esters and amides, is due to the existence of a lower energy LUMO. LUMO’s energies of phenyl vinyl sulfone and acrylonitrile are -1.891 [[19]] and -2.52 eV [[20]], respectively, whilst the LUMO’s energy of the methyl acrylate is -0.08 eV [[21]].
A straightforward access to pyroglutamates, which are key units in biotechnology, biomedicine and for the treatment of neurodegenerative illnesses [[22]], is easily envisaged. Employing conventional transformations, that means, reduction with sodium borohydride, followed by a mild cyclization conditions using silica-gel in refluxing ethyl acetate, substituted pyroglutamates 8 were isolated in moderate to good yields after flash chromatography (Scheme 6a). Non isolated adducts 2r-t described in the Scheme 4, were directly submitted to these sequential reduction-cyclization conditions obtaining the pyroglutamates 8d, 8e, and 8f in 45, 46 and 42% overall yields, respectively (from imino ester 1, Scheme 6b). In addition, the easy access to glutamic ester derivative 9 was achieved in 90% yield by treatment with 2M HCl/Et2O (Scheme 7).

3. Materials and Methods

3.1. General

All commercially available reagents and solvents were used without further purification, only aldehydes were also distilled prior to use. Analytical TLC was performed on Schleicher & Schuell F1400/LS 254 silica gel plates, and the spots were visualised under UV light (λ = 254 nm). Flash chromatography was carried out on hand packed columns of Merck silica gel 60 (0.040-0.063 mm). Melting points were determined with a Reichert Thermovar hot plate apparatus and are uncorrected. The structurally most important peaks of the IR spectra (recorded using a Nicolet 510 P-FT) are listed and wavenumbers are given in cm-1. NMR spectra were obtained using a Bruker AC-300 or AC-400 and were recorded at 300 or 400 MHz for 1H NMR and 75 or 100 MHz for 13C{1H} NMR, using CDCl3 as the solvent and TMS as internal standard (0.00 ppm) unless otherwise stated. The following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, t = triplet q = quartet, m = multiplet or unresolved and br s = broad signal. All coupling constants (J) are given in Hz and chemical shifts in ppm. 13C{1H} NMR spectra were referenced to CDCl3 at 77.16 ppm. Chemical yields and purities of compounds 2 and 6 were calculated by integration of 1H NMR spectra using dimethyl terephthalate as internal standard [17].Low-resolution electron impact (EI) mass spectra were obtained at 70 eV using a Shimadzu QP-5000 by injection or DIP; fragment ions in m/z are given with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were measured on an instrument using a quadrupole time-of-flight mass spectrometer (QTOF) and also through the electron impact mode (EI) at 70 eV using a Finnigan VG Platform or a Finnigan MAT 95S.
The synthesis of the starting α-imino esters 1 was performed following the described procedure [[23],[24]].Thus, the corresponding α-amino acid alkyl ester hydrochloride (3.0 mmol), the corresponding aldehyde (2.3 mmol), and MgSO4 were dissolved in dry dichloromethane (5 mL). Then triethylamine (3.0 mmol) was slowly added and the mixture was then stirred for 18h. Later, the reaction mixture was filtered, extracted with dichloromethane (3 x 10mL), dried over MgSO4 and evaporated under reduced pressure obtaining 1, which were employed without further purification.
Compounds 3a [24,[25]],4 [[26]] and 5 [[27]] were obtained using procedures described in the literature just to compare the signals for the determination of the proportions depicted in Table 1 (see SI).

3.2. General Experimental Procedure for the Synthesis of Michael Type Addition Products 2

In a round-button flask and under argon, the corresponding iminoester 1 (0.5 mmol) in toluene (1.5 mL), and the catalyst dimethylphenylphosphine (0.05 mmol) were added. Then a solution of electrophilic alkene (1 mmol) in toluene (1 mL) was added dropwise during 30 minutes using an addition pump, then, the mixture was stirred at room temperature for 24 hours. Solvent was removed under reduced pressure, to afford the corresponding final product 2.
Dimethyl (E)-2-(benzylideneamino)pentanedioate (2a): Pale yellow oil (118.2 mg, 96%, 92% purity). IR (neat) νmax: 1735, 1643, 1438, 1253, 1199, 1164, 755, 694 cm-1. 1H NMR (400 MHz) δ 8.29 (s, 1H, HC=N), 7.82 – 7.72 (m, 2H, ArH), 7.48 – 7.37 (m, 3H, ArH), 4.07 (dd, J = 8.1, 5.0 Hz, 1H, NCHCO2Me), 3.74 (s, 3H, CO2CH3), 3.65 (s, 3H, CO2CH3), 2.43 – 2.38 (m, 2H, CH2), 2.36 – 2.23 (m, 2H, CH2). 13C NMR (101 MHz) δ 173.3, 171.9 (C=O), 164.3 (C=N), 135.5(CAr), 131.3(CHAr), 128.6 (4x CHAr), 71.8 (CH), 52.2, 51.6 (CH3), 30.2, 28.3 (CH2). MS (EI) m/z: 263 (M+, 11%), 204 (74), 203 (38), 190 (43), 144 (100), 130 (29), 117 (31), 104 (39), 90 (21). HRMS (ESI): m/z calcd for C14H17NO4 [M+] 263.1158; found: 263.1159.
5-Butyl 1-methyl (E)-2-(benzylideneamino)pentanedioate (2b): Pale yellow oil (146 mg, 96%, 91% purity). IR (neat) vmax: 1731, 1643, 1438, 1390, 1168, 1068, 732, 694 cm-1. 1H NMR (400 MHz) δ 8.26 (s, 1H, HC=N), 7.90 – 7.66 (m, 2H, ArH), 7.51 – 7.21 (m, 3H, ArH), 4.37 – 3.92 (m, 3H, NCHCO2Me, CO2CH2CH2CH2CH3 ), 3.86 – 3.55 (m, 3H, CO2CH3), 2.34 (d, J = 2.0 Hz, 2H, NCHCH2CH2), 2.33 – 1.88 (m, 2H, NCHCH2CH2), 1.70 – 1.41 (m, 2H, CO2CH2CH2CH2CH3), 1.41 – 1.19 (m, 2H, CO2CH2CH2CH2CH3), 1.07 – 0.68 (m, 3H, CO2CH2CH2CH2CH3). 13C NMR (101 MHz) δ 172.88 (C=O), 171.90 (C=O), 164.25 (C=N), 135.53 (CAr), 131.26 (CHAr), 128.59 (CHAr x4), 71.81 (CH), 64.34 (CH2), 52.19 (CH3), 30.61 (CH2), 30.41 (CH2), 28.33 (CH2), 19.09 (CH2), 13.66 (CH3). MS (EI) m/z: 305 (M+, 17%), 246 (66), 232 (38), 190 (81), 144 (100). HRMS (ESI): m/z calcd for C17H23NO4 [M+] 305.1627; found: 305.1622.
Dimethyl (E)-2-((4-methylbenzylidene)amino)pentanedioate (2c): Pale yellow oil (119.4 mg, 86%, 95% purity). IR (neat) νmax: 1735, 1643, 1438, 1253, 1199, 1168, 813 cm-1. 1H NMR (300 MHz) δ 8.25 (s, 1H, HC=N), 7.66 (d, J = 8.1 Hz, 2H, ArH), 7.22 (d, J = 7.7 Hz, 2H, ArH), 4.04 (dd, J = 8.0, 4.9 Hz, 1H, NCHCO2Me), 3.74 (s, 3H, CO2CH3), 3.64 (s, 3H, CO2CH3), 2.39 (s, 3H, CH3Ar), 2.38 – 2.22 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 173.5 (C=O), 172.3 (C=O), 164.2 (C=N), 141.7 (CAr), 132.9 (CH3CAr), 129.3 (CHAr), 128.6 (CHAr), 71.8 (CH), 52.2, 51.6 (CH3), 30.1, 28.3 (CH2), 21.5 (CH3CAr). MS (EI) m/z: 277 (M+, 17%), 218 (64), 217 (32) 204 (48), 158 (100), 144 (34), 131 (28), 130 (24), 118 (40). HRMS (ESI): m/z calcd for C15H19NO4 [M+] 277.1314; found: 277.1322.
Dimethyl (E)-2-[(naphth-2-ylmethylene)amino)]pentanedioate (2d): Pale yellow prisms (147.2 mg, 90%, 92% purity). mp: 78-79 ºC (n-hexane:AcOEt). IR (neat) νmax: 1727, 1639, 1434, 1176, 1095, 829, 752 cm-1. 1H NMR (300 MHz) δ 8.46 (s, 1H,HC=N), 8.10 (s, 1H, ArH), 8 .03 (dd, J = 8.6, 1.4 Hz, 1H, ArH), 7.94 – 7.81 (m, 3H, ArH), 7.59 – 7.47 (m, 2H, ArH), 4.15 (dd, J = 7.7, 5.0 Hz, 1H, NCHCO2Me), 3.78 (s, 3H,CO2CH3), 3.66 (s, 3H, CO2CH3), 2.49 – 2.42 (m, 2H, CH2), 2.41 – 2.28 (m, 2H,CH2). 13C NMR (101 MHz) δ 173.3 (C=O), 171.9 (C=O), 164.3 (C=N), 134.9 (C=CCH=N), 133.2, 133.0 (PhC), 130.7, 128.7, 128.5, 127.9, 127.6, 126.6, 124.0 (PhCH), 71.8 (NCH), 52.2, 51.6 (CH3), 30.2, 28.4 (CO2CH3). MS (EI) m/z: 313 (M+, 31%), 254 (100), 240 (61), 222 (28), 194 (99), 180 (69), 167 (66), 154 (57), 140 (30), 139 (51), 127 (24). HRMS (ESI): m/z calcd for C18H19NO4 [M+] 313.1314; found: 313.1331.
Dimethyl (E)-2-[(4-methoxybenzylidene)amino]pentanedioate (2e): yellow oil (141.9 mg, 87%, 92% purity). IR (neat) νmax: 1735, 1249, 1164, 1025, 833 cm-1. 1H NMR (400 MHz) δ 8.21 (s, 1H, HC=N), 7.75 – 7.69 (m, 2H, ArH), 6.95 – 6.90 (m, 2H, ArH), 4.02 (dd, J = 8.1, 5.0 Hz, 1H, NCHCO2Me), 3.84 (s, 3H,CO2CH3), 3.74 (s, 3H,CO2CH3), 3.64 (s, 3H, CH3OAr), 2.45 – 2.15 (m, 4H, CH2-CH2). 13C NMR (75 MHz) δ 173.34 (C=O), 172.13 (C=O), 163.54 (C=N), 162.15 (OCH3CAr), 130.26 (2xCHAr), 128.52 (CAr), 114.00 (2xCHAr), 71.75(CH), 55.38 (OCH3CAr), 52.19, 51.58 (CO2CH3), 30.22, 28.39 (CH2). MS (EI) m/z: 293 (M+, 25%), 262 (21), 234 (69), 233 (41), 220 (62), 174 (100), 160 (29), 147 (23), 134 (40). HRMS (ESI): m/z calcd for C15H19NO4 [M+] 293.1263; found: 293.1262.
5-(Tert-butyl) 1-methyl (E)-2-[(2-bromobenzylidene)amino]pentanedioate (2f): Pale yellow oil (196.6 mg, 88%, 91% purity). IR (neat) νmax: 1727, 1149, 752, 686 cm-1. 1H NMR (300 MHz) δ 8.65 (s, 1H, HC=N), 8.08 (dd, J = 7.6, 2.0 Hz, 1H, ArH), 7.60 – 7.55 (m, 1H, ArH), 7.38 – 7.28 (m, 2H, ArH), 4.19 – 4.08 (m, 1H, NCHCO2Me), 3.76 (s, 3H, CH3), 2.37 – 2.22 (m, 4H, CH2-CH2), 1.44 (s, 9H, (CH3)3). 13C NMR (101 MHz) δ 172.02 (C=O2tBu), 171.85 (CO2Me), 163.16 (CH=N), 134.01 (CAr), 133.03 (CHAr), 132.37 (CHAr), 129.27 (CHAr), 127.63(CHAr), 125.36 (BrCAr), 80.54 (C(CH3)3), 71.83(NCHCO2Me), 52.29 (CH3), 31.49 (CH2), 28.45 (CH2), 28.11 (C(CH3)3). MS (EI) m/z: 384 (M+, 1%), 329 (47), 327 (48), 312 (38), 310 (38), 276 (93), 269 (44), 268 (100), 224 (41), 222 (37), 184 (41), 89 (50), 57 (66). HRMS (ESI): m/z calc for C17H22BrNO4 [M+] 383.073; found: 385.0694.
5-(Tert-butyl) 1-methyl (E)-2-[(3-bromobenzylidene)amino]pentanedioate (2g): Pale yellow oil (215.3 mg, 93%, 92% purity). IR (neat) νmax: 1727, 1369, 1149, 752, 682 cm-1. 1H NMR (400 MHz) δ 8.22 (s, 1H, HC=N), 7.98 (t, J = 1.8 Hz, 1H, ArH), 7.66 – 7.62 (m, 1H, ArH), 7.58 – 7.54 (m, 1H, ArH), 7.28 (t, J = 7.8 Hz, 1H, ArH), 4.09 – 4.04 (m, 1H, NCHCO2Me), 3.74 (s, 3H, CO2CH3), 2.30 – 2.15 (m, 4H, CH2-CH2), 1.43 (s, 9H, CO2(CH3)3). 13C NMR (101 MHz) δ 172.0 (C=O), 171.8 (C=O), 162.5 (CH=N), 137.4 (CAr), 134.1 (CHAr), 131.0 (CHAr), 130.1 (CHAr), 127.5 (CHAr), 122.9 (BrCAr), 80.5 (C(CH3)3), 71.7 (NCHCO2Me), 52.3 (CO2CH3), 31.5 (CH2), 28.4 (CH2), 28.1 [(CH3)3]. MS (EI) m/z: 384 (M+, 7%), 329 (43), 327 (45), 310 (38, 268 (100), 224 (43), 222 (40), 184 (42), 116 (36), 89 (50), 57 (93). HRMS (ESI): m/z calc for C17H22BrNO4 [M+] 383.073; found: 383.0737.
Dimethyl (E)-2-[(4-bromobenzylidene)amino]pentanedioate (2h): Pale yellow oil (151.3 mg, 88%, 93% purity). IR (neat) νmax: 1731, 2116, 1068, 1010, 821, 732 cm-1. 1H NMR (300 MHz) δ 8.24 (s, 1H, HC=N), 7.68 – 7.61 (m, 2H, ArH), 7.59 – 7.52 (m, 2H, ArH), 4.15 – 3.98 (m, 1H, NCHCO2Me), 3.75 (s, 3H, CO2CH3 ), 3.65 (s, 3H, CO2CH3), 2.47 – 2.14 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 173.24 (C=O), 171.69 (C=O), 163.07 (C=N), 134.39 (BrCAr), 131.9, 129.9 (CHAr), 125.8 (CAr), 71.6 (CH), 52.3, 51.6 (CH3), 30.1, 28.2 (CH2). MS (EI) m/z: 342 (M+, 4%), 282 (87), 268 (55), 222 (100), 184 (54), 143 (42), 116 (40), 89 (88). HRMS (ESI): m/z calcd for C14H16BrNO4 [M+] 341.0263; found: 341.0265.
5-(Tert-butyl) 1-methyl (E)-2-[(4-bromobenzylidene)amino]pentanedioate (2i): Pale yellow oil (139.1 mg, 93%, 93% purity). IR (neat) νmax: 1727, 1369, 1149, 825 cm-1. 1H NMR (300 MHz) δ 8.23 (s, 1H, HC=N), 7.65 (d, J = 8.5 Hz, 2H, ArH), 7.56 (d, J = 8.5 Hz, 2H, ArH), 4.10 – 4.02 (m, 1H, NCHCO2Me), 3.75 (s, 3H, CO2CH3), 2.34 – 2.15 (m, 4H, CH2-CH2), 1.43 (s, 9H, C(CH3)3). 13C NMR (101 MHz) δ 172.2 (C=O), 172.0 (C=O), 163.0 (C=N), 134.5 (BrCAr), 132.0 (CHAr), 130.1 (CHAr), 125.9 (CAr), 80.6 [C(CH3)3], 71.9 (CH), 52.4 (CO2CH3), 31.7 (CH2), 28.6 (CH2), 28.2 [CO2C(CH3)3]. MS (EI) m/z: 383(M+, 3%), 327 (49), 312 (42), 268 (100), 224 (48), 184 (40), 89 (63), 57(92). HRMS (ESI): m/z calc for C17H22BrNO4 [M+] 383.0730; found: 383.0720.
Dimethyl (E)-2-[(pyridin-3-ylmethylene)amino]pentanedioate (2j): Pale yellow oil (214.7 mg, 93%, 90% purity). IR (neat) νmax: 1731, 1434, 1172, 806, 709 cm-1. 1H NMR (300 MHz) δ 8.86 (dd, J = 2.1, 0.7 Hz, 1H, ArH), 8.65 (dd, J = 4.8, 1.7 Hz, 1H, ArH), 8.32 (s, 1H, HC=N), 8.15 (dt, J = 7.9, 1.9 Hz, 1H, ArH), 7.34 (dd, J = 7.9, 4.8 Hz, 1H, ArH), 4.10 (dd, J = 7.7, 5.0 Hz, 1H, NHCO2Me), 3.73 (s, 3H, CH3), 3.63 (s, 3H, CH3), 2.42 – 2.19 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 173.2 (C=O), 171.5 (C=O), 161.6 (C=N), 152.1 (CHAr), 150.6 (CHAr), 134.9 (CHAr), 131.1 (CAr), 123.6 (CHAr), 71.7 (CH), 52.3 (CH3), 51.7 (CH3), 30.1 (CH2), 28.2 (CH2). MS (EI) m/z: 264 (M+, 7%), 205 (74), 204 (43), 191 (26), 145 (100), 118 (27), 105 (38). HRMS (ESI): m/z calcd for C13H16N2O4 [M+] 264.111; found: 264.1108.
5-(Tert-butyl) 1-methyl (E)-2-[(pyridin-3-ylmethylene)amino]pentanedioate (2k): Pale yellow oil (241.7 mg, 83 %, 89% purity). IR (neat) νmax: 1727, 1369, 1253, 1153, 802, 709 cm-1. 1H NMR (300 MHz) δ 8.88 – 8.86 (m, 1H, ArH), 8.66 (dd, J = 4.8, 1.7 Hz, 1H, ArH), 8.32 (s, 1H, HC=N), 8.16 (dt, J = 7.9, 1.9 Hz, 1H, ArH), 7.34 (dd, J = 7.7, 4.8 Hz, 1H, ArH), 4.13 – 4. 06 (m, 1H, NHCO2Me), 3.74 (s, 3H, CH3), 2.38 – 2.10 (m, 4H, CH2-CH2), 1.42 (s, 9H, [(CH3)3]. 13C NMR (75 MHz) δ 171.9 (C=O), 171.67(C=O), 161.3 (C=N), 152.0 (CHAr), 150.6 (CHAr), 134.9 (CHAr), 131.1 (CAr), 123.6 (CHAr), 80.5 [C(CH3)3], 71.8 (CH), 52.2 (CO2CH3), 31.4 (CH2), 28.3 (CH2), 28.0 [C(CH3)3]. MS (EI) m/z: 306 (M+, 1%), 250 (69), 233 (38), 191 (100), 145 (54), 118 (28), 105 (22), 57 (33). HRMS (ESI): m/z calcd for C16H22N2O4 [M+] 306.158; found: 306.1579.
5-(Tert-butyl) 1-methyl (E)-2-[(thien-2-ylmethylene)amino]pentanedioate (2l): Pale yellow oil (147.2 mg, 90%, 91% purity). IR (neat) νmax: 1727, 1627, 1249, 1211, 1153, 713 cm-1. 1H NMR (400 MHz) δ 8.39 (s, 1H, HC=N), 7.46 (d, J = 5.0 Hz, 1H, Thienyl-H), 7.38 (dd, J = 3.6, 1.0 Hz, 1H, Thienyl-H), 7.10 (dd, J = 4.9, 3.7 Hz, 1H, Thienyl-H), 4.04 (dd, J = 8.5, 4.1 Hz, 1H, NCHCO2Me), 3.75 (s, 3H, CO2CH3), 2.43 – 2.16 (m, 4H, CH2-CH2), 1.45 [s, 9H, C(CH3)3]. 13C NMR (101 MHz) δ 172.1, 171.9 (C=O), 157.1 (C=N), 141.6 (SCC=N), 131.6, 129.8, 127.4 (ArC), 80.4 [C(CH3)3], 71.4 (NCH), 52.2 (CH3), 31.6, 28.3 (CH2), 28.1 [C(CH3)3]. MS (EI) m/z: 311 (M+, 6%), 255 (93), 238 (64), 195 (100), 194 (95), 150 (71), 123 (35), 112 (44), 110 (29), 96 (44), 57 (51), 43 (36), 41 (23). HRMS (ESI): m/z calcd for C15H21NO4S[M+] 311.1196; found: 311.119.
5-Butyl 1-methyl (E)-2-(benzylideneamino)-2-methylpentanedioate (2m): Pale yellow oil (152 mg, 95%, 86% purity). IR (neat) vmax: 1729, 1643, 1452, 1378, 1174, 1114, 730, 694 cm-1. 1H NMR (400 MHz) δ 8.24 (s, 1H, HC=N), 7.76 – 7.71 (m, 2H, ArH), 7.40 – 7.36 (m, 3H ArH), 4.02 (m, J = 6.7, 0.8 Hz, 2H, CO2CH2CH2CH2CH3), 3.71 (s, 3H, CO2CH3), 2.45 (m, J = 9.6, 7.9, 5.7 Hz, 2H, NCH3CH2CH2), 2.33 (m, J = 13.7, 10.1, 5.6 Hz, 1H, NCH3CH2CH2), 2.19 – 2.10 (m, 1H, NCH3CH2CH2), 1.55 (m, J = 8.2, 7.0, 6.0 Hz, 2H, CO2CH2CH2CH2CH3), 1.49 (s, 3H, NCCH3), 1.39 – 1.26 (m, 2H, CO2CH2CH2CH2CH3), 0.89 (t, J = 7.4 Hz, 3H, CO2CH2CH2CH2CH3). 13C NMR (101 MHz) δ 174.14 (C=O), 173.53 (C=O), 159.81 (C=N), 136.27 (CAr), 130.97 (CHAr), 128.53 (CHAr x2), 128.35 (CHAr x2), 67.52 (CH), 64.32 (CH2), 52.21 (CH3), 35.06 (CH2), 30.64 (CH2), 29.64 (CH2), 23.40 (CH3), 19.11 (CH2), 13.69(CH3). MS (EI) m/z: 319 (M+, >1%), 260 (100), 158 (38). HRMS (ESI): m/z calcd for C17H22NO4 [M+ - CH3] 304.1549; found: 304.1545.
Dimethyl (E)-2-[(4-bromobenzylidene)amino]-2-methylpentanedioate (2n): Pale yellow oil (110.2 mg, 90%, 90% purity). IR (neat) νmax: 1731, 1438, 1245, 1172, 1114, 821 cm-1. 1H NMR (300 MHz) δ 8.22 (s, 1H, HC=N), 7.65 – 7.59 (m, 2H, ArH), 7.57 – 7.51 (m, 2H, ArH), 3.74 (s, 3H, CH3), 3.64 (s, 3H, CH3), 2.58 – 2.26 (m, 4H, CH2-CH2), 1.50 (s, 3H, CH3). 13C NMR (101 MHz) δ 173.9 (C=O), 173.8 (C=O), 158.7 (C=N), 135.1 (CAr), 131.8 (2xCHAr), 129.78 (2xCHAr), 125.4 (BrCAr), 67.5 (NCCO2Me), 52.3 (CH3), 51.6 (CH3), 35.0 (CH2), 29.4 (CH2), 23.3 (CH3CN). MS (EI) m/z: 356 (M+, <1%), 298 (97), 296 (100), 236 (27), 184 (19), 89 (32). HRMS (ESI): m/z calc for C13H15BrNO2 [M+-CO2CH3] 296.0286; found: 296.0286.
5-Butyl 1-methyl (E)-2-[(4-bromobenzylidene)amino]-2-methylpentanedioate (2o): Pale yellow oil (191 mg, 96%, 91% purity). IR (neat) Vmax: 1729, 1643, 1438, 1170, 1114, 1066, 821, 744 cm-1. 1H NMR (400 MHz) δ 8.18 (s, 1H, NH), 7.58 (ddd, J = 8.4, 5.8, 2.7 Hz, 2H, ArH), 7.49 (dt, J = 12.4, 4.7 Hz, 2H, ArH), 4.00 (td, J = 6.7, 2.9 Hz, 2H, CO2CH2CH2CH2CH3), 3.68 (s, 3H CH3), 2.41 (dqt, J = 9.1, 6.5, 3.2 Hz, 2H, CH2CO2nBu), 2.36 – 2.23 (m, 1H, NCCH2), 2.12 (dddd, J = 12.0, 8.3, 6.0, 2.3 Hz, 1H, NCCH2), 1.53 (dt, J = 12.7, 6.8 Hz, 2H, CO2CH2CH2CH2CH3), 1.45 (s, 3H, CH3), 1.39 – 1.24 (m, 2H, CO2CH2CH2CH2CH3), 0.87 (tt, J = 6.2, 3.2 Hz, 3H, CH3).13C NMR (101 MHz) δ 173.86 (C=O), 173.38 (C=O), 158.61 (HC=N), 135.16 (CAr), 131.73 (CHAr x2), 129.76 (CHAr x2), 125.37 (CAr), 67.60 (C), 64.32 (CH2), 52.24 (CH3), 35.01 (CH2), 30.62 (CH2), 29.62 (CH2), 23.36 (CH3), 19.10 (CH2), 13.68 (CH3). ). MS (EI) m/z: 398 (M+, >1%), 338 (100), 238 (31). HRMS (ESI): m/z calcd for C17H21BrNO4 [M+ - CH3] 382.0654; found: 382.0647.
5-(Tert-butyl) 1-methyl (E)-2-[(4-bromobenzylidene)amino]-2-methylpentanedioate (2p): Pale yellow oil (104.5 mg, 77%, 88% purity). IR (neat) νmax: 2981, 1727, 1643, 1589, 1249, 1153, 1114, 821 cm-1. 1H NMR (400 MHz) δ 8.20 (s, 1H, HC=N), 7.64 – 7.59 (m, 2H, ArH), 7.55 – 7.50 (m, 2H, ArH), 3.72 (s, 3H, CH3), 2.45 – 2.34 (m, 2H, CH2), 2.32 – 2.22 (m, 2H, CH2), 1.48 (s, 3H CH3), 1.42 [s, 9H, C(CH3)3]. 13C NMR (75 MHz) δ 174.0 (C=O), 172.6 (C=O), 158.5 (C=N), 135.2 (CAr), 131.7 (2xCHAr), 129.8 (2xCHAr), 125.3 (BrCAr), 80.3 (C(CH3)3), 67.6 (NCCO2Me), 52.2 (CO2CH3), 34.9 (CH2), 30.7 (CH2), 28.0 [C(CH3)3], 23.3 (CH3). MS (EI) m/z: 398 (M+, <1 %), 284 (97), 282 (100), 268 (100), 238 (20), 236 (20), 184 (20), 160 (48), 89 (35), 57 (31), 43(24). HRMS (ESI): m/z calc for C12H13BrNO2 [M+-C6H11O2] 284.0102; found: 284.0102.
Dimethyl (E)-2-benzyl-2-[(4-bromobenzylidene)amino]pentanedioate (2q): Pale yellow oil (201.2 mg, 90%, 90% purity). IR (neat) νmax: 1731, 1438, 1172, 1083, 821, 740, 701 cm-1. 1H NMR (300 MHz) δ 7.97 (s, 1H, HC=N), 7.60 – 7.51 (m, 4H, ArH), 7.24 – 7.14 (m, 5H, ArH), 3.74 (s, 3H, CH3), 3.62 (s, 3H, CH3), 3.35 – 3.10 (m, 2H, CH2Ar), 2.45 – 2.23 (m, 4H, CH2-CH2). 13C NMR (75 MHz) δ 173.7 (C=O), 172.8 (C=O), 160.5 (C=N), 135.8 (CAr), 135.1 (CArCH2), 131.8 (2xCHAr), 130.6 (2xCHAr), 129.7 (2xCHAr), 128.1 (2xCHAr), 126.9 (CHAr), 125.4 (BrCAr), 71.6 (NCCO2Me), 52.0 (CH3), 51.6 (CH3), 44.3 (PhCH2), 32.9 (CH2), 29.5 (CH2). MS (EI) m/z: 432 (M+, <1 %), 372 (18), 342 (98), 340 (100), 254 (25), 91 (45). HRMS (ESI): m/z calc for C19H19BrNO2 [M+- CO2CH3] 372.0599; found: 372.0605.
Methyl (E)-2-[(4-bromobenzylidene)amino]-5-(dimethylamino)-5-oxopentanoate (2u): Pale yellow oil (153.1 mg 90%, 86% purity). IR (neat) νmax: 1735, 1639, 1203, 1168, 1064, 821 cm-1. 1H NMR (300 MHz) δ 8.24 (s, 1H, HC=N), 7.65 – 7.59 (m, 2H, ArH), 7.55 – 7.49 (m, 2H, ArH), 4.19 – 4.13 (m, 1H, NCHCO2Me), 3.71 (s, 3H, CO2CH3), 2.93 (s, 3H, NCH3), 2.89 (s, 3H, NCH3), 2.40 – 2.29 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 172.1 (C=O), 171.9 (C=O), 162.9 (CH=N), 134.5 (CAr), 131.8 (CHAr), 129.9 (CHAr), 125.6 (BrCAr), 71.6 (NCHCO2Me), 52.2 (CO2CH3), 37.1 (NCH3), 35.9 (NCH3), 28.9 (CH2), 28.7 (CH2). MS (EI) m/z: 354 (M+, 5 %), 270 (30), 268 (32), 224 (35), 222 (31), 173 (24), 100 (26), 89 (31), 87 (100), 72 (35), 45 (25). HRMS (ESI): m/z calc for C15H19BrN2O3 [M+] 354.0579; found: 354.0565.
Methyl (E)-2-[(4-bromobenzylidene)amino]-4-cyano-2-(2-cyanoethyl)butanoate (6v): Pale yellow oil (117.0 mg, 90%, 84% purity). IR (neat) νmax: 1727, 1369, 1149, 825 cm-1. 1H NMR (300 MHz) δ 8.24 (s, 1H, HC=N), 7.65 – 7.59 (m, 2H, ArH), 7.55 – 7.49 (m, 2H, ArH), 4.19 – 4.13 (m, 1H, NCHCO2Me), 3.71 (s, 3H, CO2CH3), 2.93 (s, 3H, NCH3), 2.89 (s, 3H, NCH3), 2.40 – 2.29 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 172.1 (C=O), 171.9 (C=O), 162.9 (CH=N), 134.5 (CAr), 131.8 (CHAr), 129.9 (CHAr), 125.7 (BrCAr), 71.6 (NCHCO2Me), 52.2 (CO2CH3), 37.1 (NCH3), 35.3 (NCH3), 28.9 (CH2), 28.7 (CH2). MS (EI) m/z: 354 (M+, 5 %), 270 (30), 268 (32), 224 (35), 222 (31), 173 (24), 100 (26), 89 (31), 87 (100), 72 (35), 45 (25). HRMS (ESI): m/z calc for C15H19BrN2O3 [M+] 354.0579; found: 354.0565.

3.3. General Procedure for the Synthesis of Pyroglutamate Derivatives

To a solution of NaBH4 (0.8 mmol, 2 eq) in Methanol (4 mL) at 0°C a solution of corresponding adduct 2 in Methanol (2mL) was added and the reaction was refluxed at 80 °C for 2 hours. After that, the solvent was removed and the crude was redissolved in AcEOt (4 mL) followed by the addition of SiO2 and refluxed again for 24 hours. Then, the mixture was filtered and removed the solvent under vacuum. Finally, the crude was purified by flash column chromatography on silica gel (Hexane/AcEOt, 3:1) to afford the corresponding cycloadducts 8.
Methyl 5-oxo-1-(pyridin-3-ylmethyl)pyrrolidine-2-carboxylate (8a): Pale yellow oil (93 mg, 60%). IR (neat) νmax: 1689, 1411, 1211, 1025, 794, 721 cm-1. 1H NMR (300 MHz) δ 8.48 (dd, J = 4.7, 1.2 Hz, 1H, ArH), 8.41 (d, J = 1.2 Hz, 1H, ArH), 7.54 (dt, J = 7.8, 2.0 Hz, 1H, ArH), 7.27 – 7.18 (m, 1H, ArH), 4.90 (d, J = 15.1 Hz, 1H, CH2NC=O), 4.04 (d, J =15.1 Hz, 1H, CH2NC=O), 3.94 (dd, J = 9.0, 3.2 Hz, 1H, NCHCO2Me), 3.62 (s, 3H, CH3), 2.56 – 2.45 (m, 1H, CH2), 2.43 – 2.34 (m, 1H, CH2), 2.27 – 2.17 (m, 1H, CH2), 2.11 – 1.99 (m, 1H, CH2). 13C NMR (101 MHz) δ 175.2 (NC=O), 171.9 (C=O), 149.6 (NCHAr), 149.3 (NCHAr), 136.3 (CHAr), 131.6 (CAr), 123.7 (CHAr), 58.8 (NCHCO2), 52.6 (CH3), 43.2 (CH2N), 29.3 (CH2), 22.8 (CH2). MS (EI) m/z: 234 (M+, 14%), 175 (98), 92 (100), 65(17). HRMS (ESI): m/z calc for C12H14N2O3 [M+] 234.1004; found: 234.0998.
Methyl 1-(4-bromobenzyl)-2-methyl-5-oxopyrrolidine-2-carboxylate (8b): Pale yellow oil (49.1 mg, 42%). IR (neat) νmax: 2360, 1735, 1689, 1392, 1168 cm-1. 1H NMR (400 MHz) δ 7.44 – 7.38 (m, 2H, ArH), 7.19 – 7.11 (m, 2H, ArH), 4.52 (d, J = 15.6 Hz, 1H, ArCH2N), 4.29 (d, J = 15.5 Hz, 1H, ArCH2N), 3.51 (s, 3H, CO2CH3), 2.57 (dt, J = 17.0, 9.8 Hz, 1H, NC=OCH2), 2.46 (ddd, J = 17.0, 9.7, 2.7 Hz, 1H, NC=OCH2), 2.34 (ddd, J = 12.9, 9.3, 2.7 Hz, 1H, NCCH2), 1.90 (dt, J = 13.2, 9.9 Hz, 1H, NCCH2), 1.41 (s, 3H, CH3). 13C NMR (101 MHz) δ 175.8 (C=O), 173.7 (C=O), 136.6 (CAr), 131.8 (2xCHAr), 129.9 (2xCHAr), 121.2 (BrCAr), 66.0 (NCCH3), 52.4 (CO2CH3), 43.9 (ArCH2N), 32.1 (C=OCH2), 29.5 (CCH2), 23.2 (NCCH3). MS (EI) m/z: 325 (M+, 7%), 268 (72), 266 (73), 171 (95), 169 (100), 90 (28), 89 (22). HRMS (ESI): m/z calc for C14H16BrNO3 [M+] 325.0314; found: 325.0306.
Methyl 2-benzyl-1-(4-bromobenzyl)-5-oxopyrrolidine-2-carboxylate (8c): Colorless needles (77 mg, 63%). Mp: 78-79 ºC (n-hexane/AcOEt). IR (neat) νmax: 1689, 1392, 1261, 1184, 1068, 806, 732, 701 cm-1. 1H NMR (300 MHz) δ 7.46 – 7.40 (m, 2H, ArH), 7.30 – 7.24 (m, 3H, ArH), 7.23 – 7.17 (m, 2H, ArH), 7.10 – 7.04 (m, 2H, ArH), 4.81 (d, J = 15.5 Hz, 1H, HCN), 4.40 (d, J = 15.5 Hz, 1H, HCN), 3.38 (s, 3H, CH3), 3.27 (d, J = 14.0 Hz, 1H, NCCHPh), 3.00 (d, J = 14.0 Hz, 1H, NCCHPh), 2.46 – 2.23 (m, 2H, NCOCH2), 2.10 – 1.84 (m, 2H,NCCH2). 13C NMR (75 MHz) δ 176.0 (C=O), 172.2 (C=O), 136.5 (CAr), 134.4 (CAr), 131.4 (2xCHAr), 130.0 (2xCHAr), 129.9 (2xCHAr), 128.6 (2xCHAr), 127.3 (CHAr), 121.2 (BrCAr), 69.2 (NCCO2Me), 52.2 (CH3), 44.0 (PhCH2N), 40.4 (CCH2Ph), 29.2 (CH2C=O), 27.5 (NCCH2). MS (EI) m/z: 402 (M+, 1%), 312 (67), 310 (68), 171 (97), 169 (100), 91 (22), 90 (27). HRMS (ESI): m/z calc for C20H20BrNO3 [M+] 401.0627; found: 401.0619.
Methyl 2-[(1H-indol-3-yl)methyl]-1-(4-bromobenzyl)-5-oxopyrrolidine-2-carboxylate (8d): Purple oil (105.6 mg, 45%). IR (neat) vmax: 1735, 1673, 1434, 1394, 1257, 1070, 736 cm-1. 1H NMR (400 MHz) δ 8.29 (s, 1H, NH), 7.56 (dt, J = 7.7, 1.0 Hz, 1H, ArH), 7.46 – 7.41 (m, 2H, ArH), 7.35 (dt, J = 8.1, 1.0 Hz, 1H, ArH), 7.27 – 7.11 (m, 4H, ArH), 6.77 (s, 1H, CHNH), 4.85 (d, J = 15.3 Hz, 1H, H2CN), 4.36 (d, J = 15.2 Hz, 1H, H2CN), 3.52 (d, J = 15.2 Hz, 1H, CH2CCHNH), 3.37 (s, 3H, CO2CH3), 3.18 (d, J = 15.3 Hz, 1H, CH2CCHNH), 2.44 (ddd, J = 16.2, 9.8, 5.5 Hz, 1H, NCOCH2), 2.30 – 2.20 (m, 1H, NCOCH2CH2), 2.13 – 1.97 (m, 2H, NCOCH2, NCOCH2CH2). 13C NMR (101 MHz) δ 176.76 (C=O), 173.09 (C=O), 136.39 (CAr), 135.85 (CAr), 131.60 (CHAr), 130.40 (CHAr), 128.43 (CAr), 123.19 (CHAr), 122.44 (CHAr), 121.48 (CAr), 119.95 (CHAr), 118.38 (CHAr), 111.47 (CHAr), 108.49 (CAr), 69.72 (C), 52.36 (CH3), 44.18 (CH2), 29.68 (CH2), 29.57 (CH2), 27.90 (CH2). MS (EI) m/z: 441 (M+, >1%), 310 (21), 252 (26), 168 (100), 126 (20), 90 (26). HRMS (ESI): m/z calcd for C22H21BrN2O3 [M+] 440.0736; found: 440.0712.
Methyl 2-[(benzyloxy)methyl]-1-(4-bromobenzyl)-5-oxopyrrolidine-2-carboxylate (8e): Colorless liquid (107.2 mg, 46%) IR (neat) vmax: 1739, 1693, 1432, 1392, 1166, 1070, 736, 698 cm-1. 1H NMR (400 MHz) δ 7.57 – 7.23 (m, 5H, ArH), 7.23 – 7.01 (m, 4H, ArH), 4.59 (d, J = 15.5 Hz, 1H, H2CN), 4.34 (d, J = 15.5 Hz, 1H, H2CN), 4.23 (q, J = 12.0 Hz, 2H, CCH2OCH2Ph), 3.68 (d, J = 10.0 Hz, 1H, CCH2OCH2Ph), 3.58 (s, 3H, CO2CH3), 3.46 (d, J = 10.0 Hz, 1H, CCH2OCH2Ph), 2.55 – 2.45 (m, 2H, CH2C=O), 2.20 (m, J = 13.2, 7.3, 5.8 Hz, 1H, CH2CCO2Me), 2.10 (m, J = 13.1, 9.5 Hz, 1H CH2CCO2Me). 13C NMR (101 MHz) δ 176.32 (C=O), 172.30 (C=O), 137.30 (CAr), 137.10 (CAr), 131.33 (CHAr), 129.95 (CHAr), 128.54 (CHAr), 128.00 (CHAr), 127.75 (CHAr), 121.04 (C), 73.40 (CH2), 71.29 (CH2), 69.63 (C), 52.60 (CH3), 44.71 (CH2), 29.32 (CH2), 27.11 (CH2). MS (EI) m/z: 432 (M+, 2%), 310 (66), 169 (100), 91 (73). HRMS (ESI): m/z calcd for C21H22BrNO4 [M+] 431.0732; found: 433.0723.
Methyl 1-(4-bromobenzyl)-2-[2-(methylthio)ethyl]-5-oxopyrrolidine-2-carboxylate (8f): Pale yellow oil (65.8 mg, 42%). IR (neat) vmax: 1733, 1689, 1432, 1390, 1160, 1070, 732 cm-1. 1H NMR (400 MHz) δ 7.41 (d, J = 8.4 Hz, 2H, ArH), 7.16 (d, J = 8.4 Hz, 2H ArH), 4.51 – 4.29 (m, 2H, H2CN), 3.45 (s, 3H, CO2CH3), 2.61 (dt, J = 17.0, 9.6 Hz, 1H, CCH2CH2SCH3), 2.53 – 2.36 (m, 2H, CCH2CH2SCH3, CCH2CH2SCH3), 2.35 – 2.25 (m, 2H, CCH2CH2SCH3, NCCH2CH2CO), 2.23 – 2.10 (m, 1H, NCCH2CH2CO), 2.01 (s, 3H, SCH3), 1.98 – 1.87 (m, 2H, NCCH2CH2CO, NCCH2CH2CO). 13C NMR (101 MHz) δ 176.19 (C=O), 172.80 (C=O), 136.24 (CAr), 131.68 (CHAr x2), 130.32 (CHAr x2), 121.61 (CAr), 68.58 (C), 52.56 (CH3), 44.14 (CH2), 35.00 (CH2), 29.62 (CH2), 28.06 (CH2), 27.92 (CH2), 15.75 (CH3). MS (EI) m/z: 386 (M+, 13%), 328 (64), 169 (100), 90 (23), 61 (30). HRMS (ESI): m/z calcd for C16H20BrNO3S [M+] 385.0347; found: 387.0328.

3.4. Procedure to Obtain the Glutamic acid 1,5-dimethyl ester Hydrochloride 9 [[28]]

To a solution of 2a (1 eq, 0.33mmol) in Et2O (0.7 ml), 2M HCl/Et2O (0.35 ml) was added and stirred until a precipitate was observed, then the solvent was removed under vacuum. The crude was purified washed with Et2O (3 times) and the supernatant was removed. The remaining solid was characterized (62 mg, 90%). Mp 91-92 ºC (89-91 ºC).28 1H NMR (300 MHz, Methanol-d4) δ 4.12 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 2.58 (td, J = 7.3, 2.1 Hz, 2H), 2.30 – 2.07 (m, 2H). 13C NMR (101 MHz, Methanol-d4) δ 172.6, 169.2, 52.3, 51.8, 51.0, 28.7, 25.1.

4. Conclusions

The 1,4-addition of imino esters, derived from condensation of amino esters and aldehydes, resulted to be a complicated task due to the formation of three secondary byproducts. The use of dimethylphenylphosphine as organocatalyst was crucial for the control of the desired reaction, circumventing all the undesired molecules, favoring the α-alkylated compound, which did not undergo the retro-Michael process. To the best or our knowledge, this is the first occasion that phosphines are involved in this particular transformation with the advantage of the minimization of the over-alkylation of the glycine template with alkyl acrylates. The reaction is very versatile because it tolerates many aromatic and heteroaromatic units bonded to the imino group, as well as substituents at the α-position of the imino ester. This methodology do not employ benzene as solvent and the crude reaction materials were not impurified with variable amounts (10-25%) of the corresponding pyrrolidines (formed by 1,3-dipolar cyclaodditions) such as occurred in a previous communication [3c].In addition, no sophisticated halogenated compounds were employed as electrophiles [3b] and the presence of strong bases was avoided [3].The access to different synthetic glutamates was ensured and the family of the corresponding pyroglutamate derivatives was successfully obtained by simple organic transformations.

Supplementary Materials

The following supporting information can be downloaded at: www.mdpi.com/xxx/s1.

Author Contributions

Conceptualization, JMS; methodology, LVR, EGM, ES, MK; validation, EGM, and MGR; formal analysis, LRF, MGM, EGM, MGR; investigation, LRF, MGM, EGM, ES, MK; resources, MGR and JMS; writing—original draft preparation, JMS; writing—review and editing, MGR and JMS; supervision, MGR and JMS; project administration, MGR and JMS; funding acquisition, MGR and JMS.
All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (RED2022-134287-T ORFEO CINQA and RED2022-134331-T CASI) the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2017-82935-P and PID2019-107268GB-I00), the Generalitat Valenciana (IDIFEDER/2021/013, GVA-COVID19/2021/079 and CIDEGENT/2020/058), Medalchemy S. L. (Medalchemy-22T) and the University of Alicante (VIGROB-068, UAUSTI21-05). LVR-F thanks Generalitat Valenciana for Grisolía´s fellowship (GRISOLIAP/2020/111).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (RED2022-134287-T ORFEO CINQA and RED2022-134331-T CASI) the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2017-82935-P and PID2019-107268GB-I00), the Generalitat Valenciana (IDIFEDER/2021/013, GVA-COVID19/2021/079 and CIDEGENT/2020/058), Medalchemy S. L. (Medalchemy-22T) and the University of Alicante (VIGROB-068, UAUSTI21-05). LVR-F thanks Generalitat Valenciana for Grisolía´s fellowship (GRISOLIAP/2020/111).

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of all of the compounds described are available from the authors.

References

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Preprints 93436 sch001
Scheme 1. a-c. Strategies for the preparation of glutamate derivatives.
Scheme 1. a-c. Strategies for the preparation of glutamate derivatives.
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Scheme 2. Optimization of the Michael type addition of imino ester 1a onto methyl acrylate (MA).
Scheme 2. Optimization of the Michael type addition of imino ester 1a onto methyl acrylate (MA).
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Scheme 3. Mechanism of the formation of products 2a, 3a, 4 and 5.
Scheme 3. Mechanism of the formation of products 2a, 3a, 4 and 5.
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Scheme 4. Scope of the Michael type addition of imino esters 1 onto alkyl acrylates.
Scheme 4. Scope of the Michael type addition of imino esters 1 onto alkyl acrylates.
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Scheme 5. Michael type addition of imino ester 1g onto AN and PVS.
Scheme 5. Michael type addition of imino ester 1g onto AN and PVS.
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Scheme 6. Synthesis of pyroglutamate derivatives 8.
Scheme 6. Synthesis of pyroglutamate derivatives 8.
Preprints 93436 sch006
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Scheme 7. Synthesis of glutamate derivative 9.
Scheme 7. Synthesis of glutamate derivative 9.
Preprints 93436 sch007
Table 1. Optimization conditions of the reaction shown in Scheme 2.
Table 1. Optimization conditions of the reaction shown in Scheme 2.
Entry PR3 (10 mol%) Slow addition (min) t (h) 2a:3a:4:5:1aa
1 PPh3 --- 15 0:9:0:0:91
2 dppe --- 15 37:22:0:4:37
3 dppe --- 48 22:32:0:30:16
4 dppe --- 72 56:39:0:5:0
5 dppe 1a (60) 72 80:0:20:0:0
6 dppe MA (60) 72 88:0:0:12:0
7 dppe MA (60) 12 71:0:0:9:20
8 Bu3P --- 72 0:0:0:100:0
9 Bu3P MA (60) 72 0:0:100:0:0
10 But3P --- 72 0:0:100:0:0
11 Me2PhP --- 12 23:0:38:38:0
12 Me2PhP --- 2 70:0:15:15:0
13 Me2PhP MA (60) 2 70:5:0:5:20
14 Me2PhP MA (60) 24 80:10:0:5:5
15 Me2PhP MA (30) 24 97:0:0:0:3
16 Me2PhP MA (5) 24 64:0:29:0:7
17 Me2PhPb MA (5) 24 50:0:0:0:50
a The ratio was estimated according to integral values in crude 1H NMR and also using dimethyl terephthalate as internal standard. b A 5 mol% of Me2PhP was added.
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