Towards Greener Synthesis of Substituted 3-Aminophthalates Starting from 2H-Pyran-2-ones via Diels–Alder Reaction of Acetylenedicarboxylates

Abstract

The aim of this work was to prepare a large set of variously substituted 3-aminophthalates starting from substituted 3-acylamino-2H-pyran-2-ones acting as dienes in Diels–Alder reactions with dialkyl acetylenedicarboxylates having the role of dienophiles. These thermally allowed [4+2] cycloadditions were taking place with normal electron demand due to rather electron-deficient dienophiles and relatively electron-rich dienes; however, they still required quite harsh reaction conditions: heating in closed vessels at 190 °C for up to 17 h was sufficient in most cases (albeit for a few reactions the time needed was up to 58 h) to achieve conversions above 95%. Such conditions, unfortunately, necessitated the use of a larger excess of dienophiles (as undesired polymerization takes place concomitantly); nevertheless, the straightforward isolation procedures enabled access to the target compounds in moderate to high yields (average yield 56%). All products were characterized by standard analytical and spectroscopic methods. With the goal of changing the reaction conditions to be more environmentally friendly, we investigated the effect of various solvents (water, n-butanol, butyl acetate, xylene, para-cymene, n-nonane, etc.) and the temperature applied (130–190 °C) on the conversion. We found that higher temperatures are necessary in most cases (except for the most reactive 2H-pyran-2-ones) regardless of the solvent used. Relative reactivity was determined for both sets of reactants and the experimentally obtained data show good agreement with the computational results.

1. Introduction

2H-Pyran-2-ones [1,2] represent a versatile class of compounds, being key structural fragments in many natural compounds as well as in their synthetic analogues. 3-Acylamino-2H-pyran-2-ones have already demonstrated various reactivity patterns, the application as dienes in [4+2] cycloadditions [3] being one of their most prominent roles [4]. It was already shown that 2H-pyran-2-ones can react with a variety of alkenes acting as dienophiles, yielding oxabicyclo [2.2.2]octenes that usually undergo spontaneous elimination of CO₂, producing cyclohexadiene intermediates [5,6]; however, sometimes under suitable conditions even these CO₂-bridged systems can be isolated and characterized [7]. Cyclohexadiene systems can either be oxidized (aromatized) towards aniline derivatives or can act as novel dienes reacting with another molecule of dienophiles, producing bicyclo[2.2.2]octenes [8]. Reactions with alkynes, on the other hand, provide less diversity, as oxabicyclo[2.2.2]octadienes obtained in the first step always undergo CO₂ elimination, yielding aniline derivatives, formally identical to those obtained with the cycloaddition of corresponding alkenes with subsequent aromatization [9,10,11,12,13,14]. Some such alkyne cycloadditions have already featured in detailed computational studies [15,16], thus supplementing experimental results. Density functional theory (DFT) calculations have revealed that strain, substituent effects, and distortion energies play crucial roles in determining reaction feasibility, particularly in intramolecular variants [17].

When anilines are the desired final products, two possibilities thus arise: (i) either application of alkynes as dienophiles or (ii) application of alkenes, followed by an aromatization step [9,10]. Thus, to enable access to the 3-aminophthalates, both possibilities are viable; however, their weak and strong points are different. Approach (ii) is less favourable because an additional aromatization step is required, necessitating the application of a suitable oxidant (dehydrogenation agent); on the other hand, the availability of variously substituted fumaric and maleic acid derivatives is larger than the corresponding acetylenedicarboxylates, making approach (i) less attractive. However, 2H-pyran-2-ones are generally poorly reactive dienes due to their (at least partial) delocalization of the π electrons, thus necessitating rather harsh reaction conditions. For many cases in the literature, refluxing in solvents with boiling points above 200 °C was needed, thus complicating the isolation procedures and decreasing the yields. Therefore, we wanted to use environmentally less problematic solvents with lower boiling points (so that straightforward removal via rotatory evaporation would be possible, thus avoiding the need for chromatographic separations). To reach the necessary reaction temperatures, closed reaction vessels were used.

Substituted dialkyl 3-acylaminophtalates have alternatively been synthesized by a number of different approaches: electrocyclization of water-based 2,3-diarylmaleate salts with a subsequent photorearrangement reaction [18], Diels–Alder reaction of dimethyl acetylenedicarboxylate and 2-aryl-4H-furo[3,2-b]pyrrole with subsequent rearrangement [19], gold-catalyzed three-component reaction [20], Diels–Alder reaction of anellated 2-aminothiophenes and dimethyl acetylenedicarboxylate [21], Diels–Alder reaction of dimethyl acetylenedicarboxylate and substituted 5,5-dimethylcyclohexa-1,3-diene with 2-methylprop-1-ene as a leaving group [22], and the most widely investigated approach: Diels–Alder cycloaddition of dimethyl acetylenedicarboxylate and substituted 3-acylamino-2H-pyran-2-ones with CO₂ as a leaving group [23,24,25,26]. Conditions of these reactions varied from reflux in high-boiling-point solvents (decalin, b.p. cca. 190 °C) to microwave-assisted heating in aqueous media; on the other hand, research on these reactions in sealed high-pressure tubes is rather scarce. The advantage of the use of closed vessels is that the reaction mixture can achieve a significantly higher temperature than the boiling point of the solvent at atmospheric pressure, so a solvent with a lower boiling point can be used instead, enabling the use of a larger palette of solvents, including ones that are available from renewable sources and/or are of lesser environmental concern.

The desired dialkyl 3-acylaminophthalates represent parts of many important natural products, such as biologically active and pharmaceutically relevant compounds, including pesticides [27]. Additionally, N,N-disubstituted 3-aminophtalates have been shown to express potent inhibitory activity against metallo-β-lactamase, and substituted 3,6-diaminophtalates have shown IMP-1 inhibitory activity [28].

2. Results and Discussion

To investigate the cycloaddition between variously substituted (and fused) 3-acylamino-2H-pyran-2-ones 1 [29,30,31,32,33,34,35,36,37,38,39] and suitable dienophiles such as dialkyl acetylenedicarboxylates 2 [40,41,42,43], we initially started by screening various solvents for the preparation of the desired dialkyl 3-acylaminophthalates 4 (Scheme 1). Among the 3-acylamino-2H-pyran-2-ones 1, we selected the one presumed to be the most reactive in normal electron demand (NED) Diels–Alder reactions, i.e., one of the most electron-rich derivatives, i.e., 5-(4-methoxyphenyl)-6-methyl derivative 1l. In all cases, 0.5 mmol of 1l was mixed with 1.5 mmol of dimethyl acetylenedicarboxylate (2A) in 2 mL of solvent and heated in a closed thick-walled glass tube. Due to various boiling points, we arranged the solvents into two groups and selected the reaction temperature accordingly: 170 °C (for n-nonane, xylene, anisole, DMF and para-cymene) and 130 °C (for xylene, n-BuOH, n-BuOAc, water and dimethyl carbonate). The conversions at 130 °C (regardless of the solvent used), determined on the basis of the H-4 signal in ¹H NMR spectra of crude reaction mixtures after 60 min, were not sufficient, being only 31–37% (except for n-BuOH, where it was 43%). As 170 °C is not attainable with these solvents (due to safety reasons), we opted for the second group and again determined the conversions. The best result after 60 min at 170 °C was obtained with n-nonane (90% conversion); in xylene, anisole and para-cymene, the conversion was 77–81%, whereas in DMF it was only 62%. Thus, it can be concluded that the reaction temperature required for adequate conversions cannot be substantially decreased (even for such electron-rich dienes as 1l) in comparison with the literature data [24,26]. Also, it was evident that the effect of the solvent on the conversion is not substantial.

According to these preliminary results, we have chosen xylene as the most suitable solvent: (i) it is possible to reach temperatures of up to 190 °C and its removal is relatively easy and energy-efficient; (ii) xylene is much cheaper in comparison with n-nonane (more than 10× for small quantities); and (iii) it does not represent substantial environmental risks. Additionally, it is important to stress that this is a move towards a more acceptable solvent as we avoided the use of tetralin, which was previously employed [24,26].

The following conditions were then applied for the synthesis of a set of dialkyl 3-acylaminophthalates 4 (

Table 1. Cycloadditions of dimethyl acetylenedicarboxylate (2A) in xylene at 190 °C.

Run	Starting 2H-Pyran-2-one					t [h] a	Product	Isolation b	Yield [%]
	R1	R2	R3	R4	1
1	Me	H	H	Ph	1a [29]	6 c	4Aa [24]	I2	66
2	Ph	H	H	Ph	1b [29]	8 c,d	4Ab [23]	I2	57
3	4-Me-C6H4	H	H	Ph	1c	8 c,d	4Ac [20]	I1	62
4	4-MeO-C6H4	H	H	Ph	1d	12 c,d	4Ad [20]	I3	69
5	4-NO2-C6H4	H	H	Ph	1e	22 c,d	4Ae	I3	60 e
6	3-Cl-C6H4	H	H	Ph	1f	16 c,d	4Af	I1	70
7	4-Ph-C6H4	H	H	Ph	1g	10 c,d	4Ag	I1	81
8	Furan-2-yl	H	H	Ph	1h [29]	15 c,d	4Ah	I4	27
9	Furan-2-yl	H	H	Ph	1h [29]	25 c,f	6	I4	4
10	Thiophen-2-yl	H	H	Ph	1i [29]	12 c,d	4Ai	I3	53
11	Naphthalen-2-yl	H	H	Ph	1j [30]	10 c,d	4Aj	I2	64 e
12	Me	Ph	H	Ph	1k [31]	3 c	4Ak	I1	79
13	Me	4-MeO-C6H4	H	Ph	1l [32]	2 c	4Al [24]	I1	87
14	Me	3,4-(OMe)2-C6H3	H	Ph	1m [32]	2 c	4Am [23]	I1	87
15	Me	COOMe	H	Ph	1n	8 c,d	4An	I1	79
16	Me	COPh	H	Ph	1o [33]	7 c	4Ao [25]	I3	75
17	Me	COMe	H	Ph	1p [34]	7 c	4Ap [23,25]	I2	73
18	Me	COMe	H	4-NO2-C6H4	1q	8 c	4Aq [23]	I1	62
19	Me	COMe	H	4-MeO-C6H4	1r	7 c	4Ar [23]	I1	72
20	Me	COMe	H	3,4,5-(OMe)3-C6H2	1s	7 c	4As	I4	76 e
21	Me	COMe	H	Me	1t [35]	7 c	4At	I4	62
22	Et	Me	H	Ph	1u	1 c	4Au	I4	63
23	Ph	Ph	H	Ph	1v	21 d,g	4Av	I2	55
24	4-F-C6H4	Me	H	Ph	1w	8 c,d	4Aw	I2	79
25	4-MeO-C6H4	COOEt	H	Ph	1x	42 h	4Ax	I4	6
26	CH2COOMe	COOMe	H	Ph	1y [36]	8 c,d	4Ay [25]	I2	59
27	COOMe	4-MeO-C6H4	H	Ph	1z	40 i	4Az	I4	3
28	-(CH2)3-		H	Ph	1aa [32]	1 c	4Aaa	I2	64
29	-(CH2)4-		H	Ph	1ab [37]	5 c	4Aab	I2	78
30	-(CH2)6-		H	Ph	1ac [32]	4 c	4Aac [23]	I2	69
31					1ad [38]	2 c	4Aad	I1	58 e
32	Ph	H	Me	Ph	1ae [39]	10 c,d	4Aae	I2	58
33	Thiophen-2-yl	H	Me	Ph	1af [39]	15 d,g,j	4Aaf	I4	20

^a General reaction conditions: 1 eq. of 1 and 2 eq. of 2A (except where stated otherwise). ^b For isolations, see experimental section. ^c Conversion (>95%) estimated by ¹H NMR of crude reaction mixture. ^d With 3 eq. of 2A. ^e Yield after recrystallization. ^f With 10 eq. of 2A. ^g Conversion approx. 90% estimated by ¹H NMR of crude reaction mixture. ^h With 3 eq. of 2A, after 26 h addition of another 3 eq. of 2A (approx. conv. 70%). ⁱ With 3 eq. of 2A, after 24 h addition of another 3 eq. of 2A (approx. conv. 60%). ^j Highly complex product mixture.

,

Table 2. Cycloadditions of diethyl acetylenedicarboxylate (2B) in xylene at 190 °C.

Run	Starting 2H-Pyran-2-one					t [h] a	Product	Isolation b	Yield [%]
	R1	R2	R3	R4	1
1	Me	H	H	Ph	1a [29]	12 c	4Ba [24]	I4	47
2	Ph	H	H	Ph	1b [29]	17 c,d	4Bb	I2	62
3	4-Me-C6H4	H	H	Ph	1c	15 c,d	4Bc	I2	59
4	Furan-2-yl	H	H	Ph	1h [29]	17 c,d	4Bd	I4	13 e
5	Thiophen-2-yl	H	H	Ph	1i [29]	17 c,d	4Be	I2	55
6	Me	4-MeO-C6H4	H	Ph	1l [32]	2 c	4Bf [24]	I2	71
7	Me	3,4-(MeO)2-C6H3	H	Ph	1m [32]	2 c	4Bg [24]	I2	82
8	Me	COOMe	H	Ph	1n	12 c,d	4Bh	I1	66
9	Me	COMe	H	Ph	1p [34]	12 c	4Bi [25]	I2	46 e
10	Me	COMe	H	4-NO2-C6H4	1q	12 c	4Bj	I1	65
11	Et	Me	H	Ph	1u	1c	4Bk	I4	35 e
12	CH2COOMe	COOMe	H	Ph	1z	15 c,d	4Bl [25,26]	I2	59
13	-(CH2)3-		H	Ph	1ab [37]	1.5 c	4Bm	I4	53
14	-(CH2)4-		H	Ph	1ac [32]	11 c	4Bn	I4	63
15	-(CH2)5-		H	Ph	1ag [32]	6 c	4Bo	I4	49

^a General reaction conditions: 1 eq. of 1 and 2 eq. of 2B (except where stated otherwise). ^b For isolations, see experimental section. ^c Conversion (>95%) estimated by ¹H NMR of crude reaction mixture. ^d With 3 eq. of 2B. ^e Yield after recrystallization.

and

Table 3. Cycloadditions of acetylenedicarboxylates 2C–F in xylene at 190 °C.

Run	Starting 2H-Pyran-2-one					Dienophile		t [h] a	Product	Isolation b	Yield [%]
	R1	R2	R3	R4	1	R5	2
1	Thiophen-2-yl	H	H	Ph	1i [29]	n-Pr	2C [40,41]	58 c,d	4Ca	I4	31
2	Me	4-MeO-C6H4	H	Ph	1l [32]	n-Pr	2C [40,41]	3 c	4Cb	I4	48
3	Me	3,4-(MeO)2-C6H3	H	Ph	1m [32]	n-Pr	2C [40,41]	3 c	4Cc	I4	80
4	Me	COOMe	H	Ph	1n	n-Pr	2C [40,41]	12 c,d	4Cd	I2	51
5	Me	COMe	H	4-NO2-C6H4	1q	n-Pr	2C [40,41]	7 c	4Ce	I2	37
6	CH2COOMe	COOMe	H	Ph	1z	n-Pr	2C [40,41]	16.5 c,d	4Cf	I2	33
7	-(CH2)3-		H	Ph	1ab [37]	n-Pr	2C [40,41]	1.5 c	4Cg	I4	72
8	Me	4-MeO-C6H4	H	Ph	1l [32]	i-Pr	2D [40,42]	3 c	4Da	I1	61
9	Me	COMe	H	Ph	1p [34]	i-Pr	2D [40,42]	9 c	4Db	I4	33 e
10	Me	4-MeO-C6H4	H	Ph	1l [32]	n-Bu	2E [40,43]	3 c	4Ea	I4	27
11	Ph	H	H	Ph	1b [29]	CH2CH2OMe	2F	28 d,f	4Fa	I4	45
12	Me	4-MeO-C6H4	H	Ph	1l [32]	CH2CH2OMe	2F	6 c	4Fb	I4	32 e
13	Me	COOMe	H	Ph	1n	CH2CH2OMe	2F	28 d,f	4Fc	I4	43 e

^a General reaction conditions: 1 eq. of 1 and 2 eq. of 2 (except where stated otherwise). ^b For isolations, see experimental section. ^c Conversion (>95%) estimated by ¹H NMR of crude reaction mixture. ^d With 3 eq. of 2. ^e Yield after recrystallization. ^f Conversion approx. 85% estimated by ¹H NMR of crude reaction mixture.

): 1.0 mmol of 1 was mixed with 2.0 mmol of dienophiles 2 in 4 mL of xylene and heated at 190 °C in a closed thick-walled glass tube. The reaction times were selected according to the substitution patterns of 1 (electron-rich versus electron-poor) and conversions were checked by ¹H NMR spectra of crude reaction mixtures. In all cases (except for the preparation of 4Av, 4Ax, 4Az and 4Aaf, as well as 4Fa and 4Fc), reaction times could be reached that enabled conversions above 95%; however, in the cases of the synthesis of 4Ax and 4Az (from 2H-pyran-2-one derivatives 1x and 1z), even after a rather long reaction time (42 and 40 h, respectively) at 190 °C, only conversion slightly below 70% was achieved; therefore, it was necessary to modify the approach: for the preparation of 4Ax, initially 3 eq. of 2A was used and, after 26 h of heating, another 3 eq. was added and heating was continued for 16 h (reaching conversion of 70%). For 4Az, initially, 3 eq. of 2A was also used and, after 24 h of heating, another 3 eq. was added, with heating prolonged for 16 h (reaching conversion of 60%). The reason for the very low reactivity of 1x and 1z is their electronic push–pull characteristic that is the consequence of a rather strong electron-donating group at position 5 or 6, respectively, and an electron-withdrawing group at the other position, thus strongly delocalizing the electrons away from the 1,3-diene system of the 2H-pyran-2-one ring and thus strongly decreasing its diene character. It also turned out that the addition of acetylene 2 in two separate portions is beneficial, as this decreases the amount of its polymerization. For the preparation of 4Av, conversion of 90% was reached after 21 h, whereas for 4Aaf after 15 h 90% conversion was achieved; however, due to the complex reaction mixture formed, the isolated yield of 4Aaf was rather low (20%). It is important to stress that (as in other cases) additional reaction time causes a larger degree of polymerization of 2 without increasing the conversion towards product 4. Similarly, the preparation of 4Fa (from 1b) and 4Fc (from 1n) required longer reaction times (28 h) and only 85% conversions were reached (the reason being analogous as in the cases mentioned above).

Thus, a large excess of dienophiles 2 needed in all cases is the consequence of their tendency toward polymerization, which is even more pronounced when poorly reactive 2H-pyran-2-ones 1 are used that require longer reaction times. This drawback can be at least partially offset by adding 2 in two portions (i.e., synthesis of 4Ax and 4Az). To unequivocally prove the problem of polymerization, we subjected acetylene 2A (3 mmol) in xylene (2 mL) to the same reaction conditions as applied for the synthesis of adducts 4 at 190 °C. After 2 h, 17.5 h and 25 h aliquots were sampled and analyzed by ¹H NMR: after 2 h, there was still a substantial amount of 2A unpolymerized, whereas after 17.5 h it was evident that the majority of 2A had already polymerized. These results suggest that the application of solvent-free conditions for these cycloadditions would not be suitable as the solvent substantially decreases the propensity for polymerization.

A combination of ¹H and ¹³C NMR alongside mass spectroscopy was sufficient to determine the structures of the final products 4. For example, the ¹H NMR spectrum of product 4Aa shows two singlets in the aliphatic range (i.e., with chemical shifts δ 2.33 and 3.91) with integrals 3H and 6H, respectively, clearly corresponding to the 6-methyl group and both methyl substituents of the carboxylate groups. The characteristic singlet at δ 11.28 corresponds to the NH group of the amide; both doublets at δ 8.87 and 7.44 (each integrated for 1H) are 4-H and 5-H on the central aromatic ring. The remaining signals (with total integral of 5H) belong to the phenyl group. The ¹³C NMR signal of 4Aa at δ 19.1 corresponds to the 6-methyl group; signals at δ 52.4 and 53.0 belong to carbons of the methyl substituents (in the carboxylate groups); all three carbonyl carbons are clearly identifiable with signals at appropriate chemical shifts (δ 165.5, 168.1, and 169.2). The other 14 signals are in the typical range of aromatic carbons and correspond to the central aromatic ring and phenyl substituent. Furthermore, the elemental composition of the product was confirmed by high-resolution mass spectroscopy. An analogous procedure was used to determine the structures of all other products 4 and, since there are no regio- or stereoselectivity issues, the structures provided are the only possibilities.

According to the reaction pathway, the only other possible product would be the intermediate CO₂-bridged system 3; however, these products would be clearly distinguishable from products 4 on the basis of their ¹³C NMR spectra (where an additional signal with chemical shift around δ 165 would be observed for the lactone carbonyl carbon) and mass spectra (where the measured mass would be higher for 44). Neither of these was observed in any case of the products obtained; therefore, we can confirm that all products isolated are of the aromatic type with structure 4.

To obtain additional insight into the reactivity, we decided to investigate the effects of various substituents on the conversions of these—presumably—NED Diels–Alder reactions. We conducted pairwise comparisons of 2H-pyran-2-ones (1) by reacting 0.5 mmol of each with dienophile 2A (2.0 mmol) in closed thick-walled glass vessels under otherwise identical conditions (at 170 °C, with 4 mL of xylene as the solvent). After 90 min, aliquots were sampled and analyzed by ¹H NMR to establish the conversions for each sample of 1 being reacted (all conversions provided in the next paragraphs were obtained in this way) providing the following reactivity ranking (in order of decreasing reactivity):

(Most reactive) 1aa > 1u > 1l, 1m, 1ad > 1k > 1a, 1ab > 1o, 1p, 1q, 1r, 1s, 1t >

1b, 1c, 1d, 1g, 1h, 1j, 1n, 1v, 1w, 1ae > 1x, 1z (least reactive)

Electron-rich 2H-pyran-2-ones 1l and 1d, both having a strong electron-donating substituent (para-methoxyphenyl) yet differing in its position, would be expected to be the most reactive; indeed, both performed well, but the position of the electron donor also had a strong influence on the reactivity: when this group is on C-5 (i.e., 1l) the reactivity is markedly higher, but when the same electron donor is on C-6 (i.e., 1d), the reactivity is strongly decreased (conversion for 1l: 80%; for 1d: only 15%). This can, however, be rationalized by the fact that groups on position 6 increase the delocalization of the electrons in the 1,3-diene system of 2H-pyran-2-one (1) more than the same groups on position 5.

Surprisingly, the highest conversions (above 90%) were achieved with 1aa and 1u, even though their substituents are only alkyl groups, which are commonly classified as poor electron donors. The most reactive among all 2H-pyran-2-ones was 1aa, having a five-membered fused ring (conversion 95%); on the other hand, 1ab, having a fused six-membered ring, was far less reactive (conversion 55%).

Comparison of conversions between 6-methyl- and 6-phenyl-2H-pyran-2-ones (1a and 1b) (45% vs. 15%) suggests that a phenyl group acts only as an electron-withdrawing group and thus decreases the reactivity. On the other hand, when the 6-phenyl group in 1b was exchanged with a stronger electron donor, such as the para-methoxyphenyl group (in 1d), which was expected to significantly increase the reactivity, the reactivity of both compounds was nearly the same (15% conversion in both cases). With 6-phenyl group compound 1b being so poorly reactive, an interesting comparison can be made with a fused tricyclic 1ad (80%), displaying an unexpectedly high conversion (approaching 6-ethyl-5-methyl 1u and surpassing 1a). Electron-withdrawing groups, such as acetyl and ester groups, should decrease the reactivity; however, conversion of 5-acetyl derivative 1p (35%) and 5-methoxycabonyl-substituted 1n (20%) surpassed the reactivity of para-methoxyphenyl derivative 1d.

Comparison between 5-methoxyphenyl-substituted 2H-pyran-2-one 1m and 5-dimethoxyphenyl analogue 1l showed that an additional electron-donating methoxy group on the phenyl substituent does not increase the reactivity (in both cases, conversions were 80%); however, conversion was slightly lower (nearly 70%) for 5-phenyl-substituted 2H-pyran-2-one 1k, but still higher than with 6-methyl derivative 1a (conversion: 45%).

The effects of the 3-acylamino group were also investigated, comparing different electron-donating or -withdrawing groups on the 3-amino group in 1; it was determined that reactivity is not influenced much by various benzoyl moieties, with a slightly lesser reactivity observed with the para-nitrobenzoyl group in 1q (28% conversion) in comparison with unsubstituted benzoyl group in 1p or para-methoxybenzoyl in 1r (both 35% conversion). No difference in reactivity was detected between 3-acetylamino derivative 1t and 3-benzoylamino 1p (both having 35% conversion).

When, instead of a phenyl group in the C-6 position (i.e., 1b), other aromatic groups were present, a nearly negligible difference in reactivity was observed; for example, para-tolyl (in 1c), furan-2-yl (in 1h), thiophen-2-yl (in 1i), naphtalen-2-yl (in 1j) and 4-fluorophenyl (in 1w) all exhibited conversion of around 15%. If the 6-phenyl derivative 1b was additionally substituted on the C-4 position with a methyl group (i.e., 1ae), no change in reactivity was detected; however, if 1b was additionally substituted with a 5-phenyl group (i.e., 1v), the conversion was somewhat decreased (from 15% to 10%).

To obtain deeper insight into the reactivity and make a comparison with literature data [9,10,11,15,25,26], eight reactions of 3-acylamino-2H-pyran-2-ones (1a,b,d,l,p,u,x,aa) with dimethyl acetylenedicarboxylate (2A) were selected to be investigated theoretically. Density functional theory (ωB97X-D4/def2-TZVP) was used to optimize the nuclear geometries of reactants (1 + 2A), bicyclic intermediate products 3 and final products (4A + CO₂), as well as of transition state geometries (TS1 for reactions 1 + 2A $\to$ 3 and TS2 for subsequent carbon dioxide elimination reactions 3 $\to$ 4A + CO₂). The method of Nudged Elastic Band with transition state optimization (NEB-TS) was used to identify the transition state structures. The solvent (xylene) was treated implicitly using the conductor-like polarizable continuum model (CPCM). DLPNO-CCSD(T)/def2-TZVPP theory was used to calculate the electronic energies of the optimized structures. Standard Gibbs free energies of reactants, products and transition states were corrected accordingly. Optimized structures and their energies are given in the Supporting Information, which also contains schematic representations of the reaction coordinates for all cases, as well as imaginary frequencies of transition states (TS1 and TS2) and their graphical representations. The activation standard Gibbs free energies for the selected eight reactions are given in

Table 4. Activation standard Gibbs free energies for the cycloaddition reactions 1 + 2A $\to$ 3 (${∆G}_{\mathrm{T}\mathrm{S}1}^{\#}$) and subsequent CO₂ elimination reactions 3 $\to$ 4A + CO₂ (${∆G}_{\mathrm{T}\mathrm{S}2}^{\#}$).

Starting 2H-Pyran-2-one 1					Product	${∆\mathit{G}}_{\mathbf{T}\mathbf{S}1}^{\#}$ [kJ mol–1] a	${∆\mathit{G}}_{\mathbf{T}\mathbf{S}2}^{\#}$ [kJ mol–1] a
R1	R2	R3	R4
-(CH2)3-		H	Ph	1aa	4Aaa	87.7	70.7
Et	Me	H	Ph	1u	4Au	90.8	73.9
Ph	H	H	Ph	1b	4Ab	96.6	62.3
Me	4-MeO-C6H4	H	Ph	1l	4Al	97.5	66.8
Me	H	H	Ph	1a	4Aa	101.3	67.6
Me	COMe	H	Ph	1p	4Ap	107.2	68.0
4-MeO-C6H4	H	H	Ph	1d	4Ad	112.7	61.4
4-MeO-C6H4	COOEt	H	Ph	1x	4Ax	142.6	53.0

^a ωB97X-D4 density functional with def2-TZVP basis set was used for geometry optimization; DLPNO-CCSD(T) method was used to correct the electronic energies; and NEB-TS was used to find the transition state geometries. Xylene was taken into account using the CPCM.

. The activation barrier for the formation of oxabicyclo[2.2.2]octa-5,7-dien-3-ones 3 from 2H-pyran-2-ones 1 and 2A, ${∆G}_{\mathrm{T}\mathrm{S}1}^{\#}$, is significantly higher than the free energy barrier for CO₂ elimination from the intermediate products 3 and subsequent formation of product 4A, ${∆G}_{\mathrm{T}\mathrm{S}2}^{\#}$. The differences, ${∆G}_{\mathrm{T}\mathrm{S}2}^{\#}-{∆G}_{\mathrm{T}\mathrm{S}1}^{\#}$, range from approximately 17 up to 90 kJ/mol for cases 4Aaa and 4Ax, respectively. This is in agreement with experimental observations, where no intermediate products 3 were found in the reaction mixtures. Comparing the activation standard Gibbs free energies of the rate-determining step, ${∆G}_{\mathrm{T}\mathrm{S}1}^{\#}$, we determine that the reactivity order is the same as the one observed experimentally (with the exception of 1b). A lower value of ${∆G}_{\mathrm{T}\mathrm{S}1}^{\#}$ implies better reactivity of the 2H-pyran-2-ones 1. The results of the calculations imply the following ranking (from the most to the least reactive): 1aa > 1u > 1b, 1l > 1a > 1p > 1d > 1x (c.f. experimental ranking above).

Figure 1a shows the relative standard Gibbs free energies of the stationary points for reactions involving dienes 1aa (most reactive) and 1x (least reactive) and the dienophile 2A (reactants, R) leading to the products 4Aaa and 4Ax and CO₂ (products, P) via bicyclic intermediate (IM) 3. If we compare these two cases, we can see that the product 4Aaa is slightly more thermodynamically stable than the product 4Ax (${∆}_{\mathrm{r}}G\left(1\mathbf{a}\mathbf{a}\to 4\mathbf{A}\mathbf{a}\mathbf{a}\right)=-336.7$ kJ/mol, ${∆}_{\mathrm{r}}G\left(1\mathbf{x}\to 4\mathbf{A}\mathbf{x}\right)=-321.3$ kJ/mol). Reaction diagrams for other cases are given in the Supporting Information.

For these two cases, the intrinsic reaction coordinate (IRC) profiles are shown in Figure 1b,c for steps R → IM via transition state TS1 and IM → P via transition state TS2, respectively. A uniform energy profile without intermediate states was observed in all cases (TS1 and TS2), indicating a concerted reaction mechanism. The bond formation was slightly asynchronous due to the asymmetry of the diene. The inset in Figure 1b shows the changes in the absolute values of the global electron density transfer (GEDT) [44] calculated from the Hirshfeld charges (the part belonging to dienophile 2A was selected as the framework). GEDT reaches a maximum at TS1 (for all other cases studied, GEDT values for TS1 are given in the Supporting Information). Our GEDT values are characteristic for moderately polar Diels–Alder reactions [45]. In all cases, the electron density flux is from the diene to the dienophile (2A), as expected for experimentally studied reactions with normal electron demand. In the case of our reactions, no zwitterionic intermediates were detected, indicated also by values of GEDT lower than 0.15e₀ [46]. The value of the GEDT at TS1 for the case involving diene 1aa is somewhat larger than in case 1x. A higher value of the GEDT implies grater TS stabilization and therefore a lower activation barrier (faster reaction). This is consistent with the activation standard Gibbs free energies for the cycloaddition reactions of these two cases (Table 4).

To investigate the reactivity of acetylenes (2), the electron-rich 2H-pyran-2-one 1l (0.5 mmol) was reacted with acetylenes 2A–F (1.0 mmol) in 2 mL of xylene at 170 °C in a thick-walled glass tube. After 90 min, aliquots were sampled and conversions were determined with ¹H NMR on the basis of H-4 signals. Surprisingly, the largest conversions were obtained with acetylenes 2F and 2C (82% and 80% conversion, respectively), followed by 2D (65%) and 2E (55%), whereas 2A and 2B were the least reactive (45% and 32%, respectively). The trend observed does not correlate with the presumed steric hindrance, nor with the electronic effects of the substituents (NED Diels–Alder reaction should be accelerated when electron-deficient dienophiles are reacted). However, this reactivity order of acetylenes (2) is not automatically reflected in the reaction conditions necessary for the preparation of the final products (4), as higher reactivity of the acetylenes (2) generally causes larger degree of their undesired polymerization, thus decreasing the overall yields of 4.

When investigating the synthesis of furyl-substituted 4Ah (Scheme 2), additional signals were present in ¹H NMR spectra of crude reaction mixtures, implying the presence of possible side product(s): when 2H-pyran-2-one 1h was heated at 190 °C in xylene with 10 eq. of 2A after 2 h ¹H NMR showed the presence of the expected product 4Ah, with some unreacted starting 1h as well as an additional adduct (approximate ratio of 4Ah:1h:6 = 3:1:1). Upon prolonged heating (23 h), starting 1h was not detected any more; the ratio between 4Ah and the additional adduct 6 was found to be 0.7:1, remaining unchanged even with the addition of another 2 eq. of 2A and further heating for 3 h. The additional product 6 was separated from 4Ah and found to be the tetraester double cycloadduct 6. Intermediate 5 could not be detected as it immediately reacts either towards 6 via an irreversible retro-Diels–Alder elimination of gaseous acetylene (thus re-establishing the aromaticity) or with an analogous (though reversible) elimination of 2A yielding 4Ah. Adduct 6 is thus the predominant product when long reaction times are used (thermodynamic product), whereas 4Ah could be prepared when the reaction time was shortened to 15 h (with 3 eq. of 2A), albeit some 6 was also detected in the crude reaction mixture (4Ah:6 = 3:2).

To investigate the possible effects of the increased pressure (due to the evolution of CO₂ during the aromatization step) that might decrease the reaction progress (due to hindering the elimination of CO₂), we compared conversions of 1l (0.5 mmol) with 2A (1 mmol) in 2 mL of xylene in a closed versus open vessel (both vessels were immersed in the same oil bath at 140 °C for 2 h). We found out that the conversion in the closed vessel was even slightly larger (50%) than the one in the open vessel (43%), thus showing that the pressure build-up does not cause any detectable changes in the conversion.

To obtain a rough estimate regarding the improvement reached by changing the reaction conditions from those previously applied [26], Sheldon’s E-factor [47,48] for the synthesis of 4Bl according to our improved procedure was estimated to be around 4.18, whereas for the procedure described initially for the same compound it was around 5.19. Among all phthalates (4), the most favourable E-factor was found to be 3.75 for the synthesis of the product 4Cc, therefore clearly showing that our improved procedure represents a step (albeit small) towards greener synthesis of products 4.

3. Materials and Methods

3.1. General

Melting points were determined using an automatic OptiMelt MPA100 (Stanford Research System, Sunnyvale, CA, USA) instrument and were uncorrected. NMR spectra were recorded with a Bruker (Zürich, Switzerland) Avance III 500 spectrometer at 29 °C using TMS as the internal standard at 500 MHz for ¹H NMR and 126 MHz for ¹³C NMR. Chemical shifts are provided as ppm values on the δ scale; the coupling constants (J) are given in Hertz. ¹³C NMR spectra are referenced against the central line of the solvent signal (CDCl₃ at 77.0 ppm). IR spectra of compounds as powders were recorded on a Bruker (Zürich, Switzerland) Alpha Platinum ATR FT-IR spectrophotometer. Mass spectra were recorded using an Agilent (Santa Clara, CA, USA) 6624 Accurate Mass TOF LC/MS spectrometer via ESI ionization. Reagents and solvents were used as received from commercial suppliers with a purity of 98% or more. The xylene used was a commercially available mixture of all three isomers. Commercially available thick-walled ACE glass tubes closed by a Teflon screw-plug were used.

Starting 2H-pyran-2-ones (1) were prepared according to the published procedures [29,30,31,32,33,34,35,36,37,38,39]; briefly, 1a–p and 1u–ag were synthesized in a two-step one-pot procedure by heating appropriate ketones with 2 eq. of N,N-dimethylformamide dimethyl acetal (or N,N-dimethylacetamide dimethyl acetal in the case of 1ae and 1af) for 4 h, followed by a reaction with hippuric acid in acetic anhydride (4 h at 90 °C). Treating 5-acetyl-3-amino-6-methyl-2H-pyran-2-one [prepared from 1p via amide hydrolysis by heating in concentrated H₂SO₄] with the corresponding acyl or aryl chloride in CH₂Cl₂ with the addition of pyridine at room temperature yielded 2H-pyran-2-ones 1q–t. Dialkyl acetylenedicaboxylates 2C–F were prepared according to the published procedure [40] with modified extraction.

3.2. Synthesis of Diels–Alder Adducts 4 and 6

2H-Pyran-2-one 1 (2 mmol), acetylene 2 (4 or 6 mmol, see Table 1, Table 2 and Table 3) and xylene (4 mL) were heated in a closed thick-walled glass vial at 190 °C. After the reactions were complete (for times, see Table 1, Table 2 and Table 3), the mixture was cooled to room temperature. Those products that precipitated upon cooling in an ice bath were collected by vacuum filtration (isolation I1 for 4Ac, 4Af, 4Ag, 4Ak–n, 4Aq, 4Ar, 4Aad, 4Bh, 4Bj, 4Da). In other cases, volatile components were removed with a rotary evaporator in vacuo. The oily residue thus obtained was treated with either an ice-cold MeOH/petroleum ether mixture (isolation I2, for 4Aa, 4Ab, 4Ai, 4Aj, 4Ap, 4Av, 4Aw, 4Ay, 4Aaa–ac, 4Aae, 4Bb, 4Bc, 4Be–g, 4Bi, 4Bl, 4Cd–f) or ice-cold MeOH (isolation I3, for 4Ad, 4Ae, 4Ao), triggering the precipitation of crystalline products. In all other cases, oily residues were loaded on a chromatography column (isolation I4) packed with silica gel and eluted with various mobile phases: (i) petroleum ether/EtOAc 3:1 for 4Ah, 4As (with gradient to 1:1), 4At, 4Au, 4Az, 4Aaf, 4Ba, 4Bd, 4Bk, 4Bm–o, 4Ca–c, 4Cg, 4Db and 4Ea; (ii) petroleum ether/EtOAc 3:2 for 4Ax; and (iii) petroleum ether/EtOAc 1:1 for 4Fa–c and 6. Some of the products obtained were purified by an additional chromatography column (silica gel, mobile phase petroleum ether/EtOAc 1:1 for 4At and 4Az; petroleum ether/EtOAc 3:1 for 4Ax and 4Bk; petroleum ether/EtOAc 10:1 for 4Cb and 4Ea; petroleum ether/EtOAc 4:1 for 4Cg). Regardless of the isolation procedure, some of the products were additionally purified by recrystallization from EtOH (4Ab, 4Ac, 4Ae, 4Af, 4Ah–j, 4Am, 4An, 4Ap, 4Av, 4Aw, 4Ay, 4Aaa–ae, 4Bb–j, 4Bl), petroleum ether/Et₂O (4As), Et₂O (4Ax, 4Az, 4Fb), petroleum ether (4Bk, 4Fc) or petroleum ether/EtOAc (6).

Dimethyl 3-benzamido-6-methylphthalate (4Aa) [24]: pale yellow needles (MeOH); mp 118.3–119.3 °C (mp lit. [24] 110–113 °C (Et₂O)); IR ν_max 3256 (N–H), 2956 (H–C-sp³), 1729 (COO), 1683 (NHCO), 1669, 1569, 1519, 1443, 1396 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.28 (1H, s, NH), 8.78 (1H, d, J = 8.7 Hz, H-4 or H-5), 7.99 (2H, m, Ph), 7.57 (1H, m, Ph), 7.52 (2H, m, Ph), 7.44 (1H, d, J = 8.7 Hz, H-4 or H-5), 3.91 (6H, m, 2 × COOCH₃), 2.33 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.2 (COO), 168.1 (COO), 165.5 (NHCO), 138.5, 135.7, 135.0, 134.6, 132.1, 130.4, 128.9, 127.3, 122.2, 114.7 (10 × C_Ar), 53.0 (COOCH₃), 52.4 (COOCH₃), 19.1 (CH₃); HREIMS m/z 328.1181 (calcd for C₁₈H₁₈NO₅ (M+H)⁺, 328.1179).

Dimethyl 4-benzamido-[1,1′-biphenyl]-2,3-dicarboxylate (4Ab) [23]: off-white crystal flakes (EtOH); mp 155.8–157.7 °C (mp lit. [23] 153–155 °C (MeOH)); IR ν_max 3323 (N–H), 2947 (H–C-sp³), 1714 (COO), 1694, 1679 (NHCO), 1526, 1491 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.28 (1H, s, NH), 8.92 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.02 (2H, m), 7.56 (4H, m), 7.39 (3H, m), 7.33 (2H, m) (2×Ph and H-5 or H-6), 3.91 (3H, s, COOCH₃), 3.59 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.9 (COO), 168.1 (COO), 165.6 (NHCO), 139.4, 139.2, 135.5, 135.3, 134.8, 134.4, 132.3, 128.9, 128.4, 128.3, 127.7, 127.4, 122.2, 115.2 (14 × C_Ar), 53.1 (CH₃), 52.2 (CH₃); HREIMS m/z 390.1329 (calcd for C₂₃H₂₀NO₅ (M+H)⁺, 390.1336).

Dimethyl 4-benzamido-4′-methyl-[1,1′-biphenyl]-2,3-dicarboxylate (4Ac) [20]: pale yellow crystals (EtOH); mp 154.4–157.7 °C; IR ν_max 3346 (N–H), 2955 (H–C-sp³), 1736 (COO), 1681 (NHCO), 1438 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.27 (1H, s, NH), 8.90 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.02 (2H, m, Ph), 7.55 (4H, m, H-5 or H-6, Ph), 7.21 (4H, m, C₆H₄), 3.91 (3H, s, COOCH₃), 3.62 (3H, s, COOCH₃), 2.39 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.0 (COO), 168.1 (COO), 165.6 (NHCO), 139.2, 137.5, 136.3, 135.5, 135.3, 134.7, 134.4, 132.2, 129.0, 128.9, 128.3, 127.3, 122.2, 115.1 (14 × C_Ar), 53.1 (COOCH₃), 52.2 (COOCH₃), 21.2 (CH₃); HREIMS m/z 404.1482 (calcd for C₂₄H₂₂NO₅ (M+H)⁺, 404.1492).

Dimethyl 4-benzamido-4′-methoxy-[1,1′-biphenyl]-2,3-dicarboxylate (4Ad) [20]: pale brown powder (MeOH); mp 145.7–148.1 °C; IR ν_max 3309 (N–H), 3002, 2954 (H–C-sp³), 1751 (COO), 1676 (NHCO), 1585, 1507, 1488, 1457, 1436 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.28 (1H, s, NH), 8.89 (1H, d, J = 8.8 Hz, H-5 or H-6), 8.02 (2H, m, Ph), 7.56 (4H, m, H-5 or H-6 and Ph), 7.26 and 6.93 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 3.91 (3H, s, COOCH₃), 3.85 (3H, s, COOCH₃), 3.63 (3H, s, OCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.1 (COO), 168.1 (COO), 165.6 (NHCO), 159.2, 139.1, 135.4, 135.2, 134.7, 134.5, 132.2, 131.6, 129.6, 128.9, 127.4, 122.2, 115.1, 113.8 (14 × C_Ar), 55.3 (OCH₃), 53.1 (COOCH₃), 52.3 (COOCH₃); HREIMS m/z 420.1437 (calcd for C₂₄H₂₂NO₆ (M+H)⁺, 420.1442).

Dimethyl 4-benzamido-4′-nitro-[1,1′-biphenyl]-2,3-dicarboxylate (4Ae): pale orange powder (EtOH); mp 199.9–201.9 °C; IR ν_max 3352 (N–H), 2944 (H–C-sp³), 1730 (COO), 1706, 1673 (NHCO), 1597, 1578, 1517, 1489, 1435, 1410 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.32 (1H, s, NH), 8.99 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.28 and 7.51 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄NO₂), 8.02 (2H, m, Ph), 7.61 (1H, m, Ph), 7.56 (3H, m, H-5 or H-6 and Ph), 3.93 (3H, s, COOCH₃), 3.64 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.3 (COO), 167.7 (COO), 165.7 (NHCO), 147.4, 145.9, 140.5, 134.8, 134.7, 134.2, 132.9, 132.5, 129.5, 129.0, 127.4, 123.6, 122.5, 115.5 (14 × C_Ar), 53.3 (CH₃), 52.5 (CH₃); HREIMS m/z 435.1184 (calcd for C₂₃H₁₉N₂O₇ (M+H)⁺, 435.1187).

Dimethyl 4-benzamido-3′-chloro-[1,1′-biphenyl]-2,3-dicarboxylate (4Af): pale yellow powder (EtOH); mp 132.8–135.5 °C; IR ν_max 3361 (N–H), 2943 (H–C-sp³), 1746 (COO), 1691 (NHCO), 1519, 1434 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.31 (1H, s, NH), 8.94 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.02 (2H, m, Ph), 7.62–7.52 (4H, m, H-5 or H-6, Ph), 7.34 (3H, m, C₆H₄Cl), 7.22 (1H, m, C₆H₄Cl), 3.92 (3H, s, COOCH₃), 3.64 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.6 (COO), 167.9 (COO), 165.6 (NHCO), 141.0, 139.9, 135.0, 134.8, 134.3, 134.2, 133.9, 132.3, 129.6, 129.0, 128.6, 127.9, 127.4, 126.7, 122.3, 115.2 (16 × C_Ar), 53.2 (CH₃), 52.3 (CH₃); HREIMS m/z 424.0936 (calcd for C₂₃H₁₉NO₅ (M+H)⁺, 424.0946).

Dimethyl 4-benzamido-[1,1′:4′,1′’-terphenyl]-2,3-dicarboxylate (4Ag): white powder (xylene); mp 194.4–197.5 °C; IR ν_max 3347 (N–H), 3028, 2948 (H–C-sp³), 1702 (COO), 1672 (NHCO), 1593, 1559, 1516, 1486, 1442, 1391 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.30 (1H, s, NH), 8.94 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.02 (2H, m), 7.59 (8H, m), 7.46 (2H, m), 7.38 (3H, m) (2 × Ph, C₆H₄, H-5 or H-6), 3.92 (3H, s, COOCH₃), 3.64 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.0 (COO), 168.1 (COO), 165.6 (NHCO), 140.49, 140.46, 139.5, 138.2, 135.3, 135.1, 134.8, 134.4, 132.3, 128.94, 128.88, 128.87, 127.5, 127.4, 127.08, 127.01, 122.3, 115.3 (18 × C_Ar), 53.2 (CH₃), 52.3 (CH₃); HREIMS m/z 466.1655 (calcd for C₂₉H₂₄NO₅ (M+H)⁺, 466.1649).

Dimethyl 3-benzamido-6-(furan-2-yl)phthalate (4Ah): isolated by column chromatography (petroleum ether/EtOAc = 3:1), pale yellow powder (EtOH); mp 173.0–174.8 °C; IR ν_max 3358 (N–H), 3118, 2956 (H–C-sp³), 1726 (COO), 1675 (NHCO), 1590, 1522, 1493 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.41 (1H, s, NH), 8.95 (1H, d, J = 9.0 Hz, H-4 or H-5), 8.00 (2H, m, Ph), 7.88 (1H, d, J = 9.0 Hz, H-4 or H-5), 7.59 (1H, m, Ph), 7.54 (2H, m, Ph), 7.49 (1H, m, C₄H₃O), 6.57 (1H, m, C₄H₃O), 6.48 (1H, m, C₄H₃O), 3.94 (3H, s, COOCH₃), 3.88 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.1 (COO), 167.8 (COO), 165.6 (NHCO), 150.7, 142.9, 139.9, 134.4, 132.5, 132.31, 132.28, 128.9, 127.4, 124.0, 122.2, 115.0, 111.8, 108.2 (10 × C_Ar, 4 × C_Fur), 53.2 (CH₃), 52.7 (CH₃); HREIMS m/z 380.1128 (calcd for C₂₁H₁₈NO₆ (M+H)⁺, 380.1129).

Dimethyl 3-benzamido-6-(thiophen-2-yl)phthalate (4Ai): pale brown powder (EtOH); mp 140.3–143.4 °C; IR ν_max 3311 (N–H), 2942 (H–C-sp³), 1711 (COO), 1679 (NHCO), 1580, 1519, 1437 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.44 (1H, s, NH), 8.93 (1H, d, J = 8.8 Hz, H-4 or H-5), 8.02 (2H, m, Ph), 7.68 (1H, d, J = 8.8 Hz, H-4 or H-5), 7.59 (1H, m, Ph), 7.54 (2H, m, Ph), 7.36 (1H, m, C₄H₃S), 7.06 (2H, m, C₄H₃S), 3.93 (3H, s, COOCH₃), 3.73 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.8 (COO), 167.8 (COO), 165.6 (NHCO), 140.2, 139.9, 136.0, 135.2, 134.4, 132.3, 128.9, 127.8, 127.4, 127.0, 126.5, 122.0, 114.7 (9 × C_Ar, 4 × C_Thioph), 53.2 (CH₃), 52.5 (CH₃) (one aromatic signal is hidden); HREIMS m/z 396.0892 (calcd for C₂₁H₁₈NO₅ (M+H)⁺, 396.0900).

Dimethyl 3-benzamido-6-(naphthalen-2-yl)phthalate (4Aj): off-white powder (EtOH); mp 171.0–174.1 °C; IR ν_max 3337 (N–H), 2949 (H–C-sp³), 1707 (COO), 1671 (NHCO), 1578, 1523, 1492, 1435, 1400 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.30 (1H, s, NH), 8.95 (1H, d, J = 8.7 Hz, H-4 or H-5), 8.04 (2H, m, Ph), 7.86 (3H, m), 7.81 (1H, m) (H-aromatic), 7.67 (1H, d, J = 8.7 Hz, H-4 or H-5), 7.54 (5H, m), 7.46 (1H, m) (H-aromatic), 3.92 (3H, s, COOCH₃), 3.55 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.0 (COO), 168.1 (COO), 165.6 (NHCO), 139.5, 136.7, 135.5, 135.4, 135.0, 134.4, 133.2, 132.6, 132.3, 129.0, 128.2, 128.0, 127.7, 127.5, 127.4, 126.5, 126.3, 122.3, 115.3 (19 × C_Ar), 53.1 (CH₃), 52.3 (CH₃) (one aromatic signal is hidden); HREIMS m/z 440.1503 (calcd for C₂₇H₂₂NO₅ (M+H)⁺, 440.1492).

Dimethyl 5-benzamido-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Ak): white crystals (xylene); mp 170.0–173.4 °C; IR ν_max 3329 (N–H), 2952 (H–C-sp³), 1707 (COO), 1681 (NHCO), 1576, 1519, 1492, 1437, 1404 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.46 (1H, s, NH), 8.84 (1H, s, H-6), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 7.42 (3H, m, Ph), 7.34 (2H, m, Ph), 3.95 (3H, s, COOCH₃), 3.94 (3H, s, COOCH₃), 2.18 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.7 (COO), 168.0 (COO), 165.5 (NHCO), 148.7, 140.2, 138.5, 136.4, 134.6, 132.1, 129.0, 128.9, 128.3, 127.83, 127.80, 127.3, 123.4, 113.2 (14 × C_Ar), 53.1 (COOCH₃), 52.5 (COOCH₃), 17.2 (CH₃); HREIMS m/z 404.1490 (calcd for C₂₄H₂₂NO₅ (M+H)⁺, 404.1492).

Dimethyl 5-benzamido-4′-methoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Al) [24]: white crystals (EtOH); mp 171.4–173.2 °C (mp lit. [24] 162.5–165.5 °C (MeOH)); IR ν_max 3264 (N–H), 2949 (H–C-sp³), 1714 (COO), 1694 (NHCO), 1673, 1580, 1508, 1441 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.46 (1H, s, NH), 8.83 (1H, s, H-6), 8.00 (2H, m, Ph), 7.56 (1H, m, Ph), 7.52 (2H, m, Ph), 7.28 and 6.96 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 3.94 (3H, s, COOCH₃), 3.93 (3H, s, COOCH₃), 3.86 (3H, s, OCH₃), 2.19 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.8 (COO), 168.0 (COO), 165.5 (NHCO), 159.3, 148.4, 138.5, 136.4, 134.6, 132.6, 132.1, 130.3, 128.9, 127.9, 127.3, 123.5, 113.7, 112.8 (14 × C_Ar), 55.4 (OCH₃), 53.0 (COOCH₃), 52.5 (COOCH₃), 17.3 (CH₃); HREIMS m/z 434.1579 (calcd for C₂₅H₂₄NO₆ (M+H)⁺, 434.1598).

Dimethyl 5-benzamido-3′,4′-dimethoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Am) [23]: white powder (EtOH) (mp lit. [23] 181–183 °C (MeOH)); mp 188.4–190.4 °C; IR ν_max 3308 (N–H), 2959 (H–C-sp³), 1731 (COO), 1671 (NHCO), 1571, 1508, 1489, 3308, 2959, 1731, 1671, 1571, 1508, 1489, cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.47 (1H, s, NH), 8.85 (1H, s, H-6), 8.00 (2H, m, Ph), 7.53 (3H, s, Ph), 6.92 (2H, m, C₆H₃), 6.85 (1H, m, C₆H₃), 3.95 (3H, s), 3.94 (3H, s), 3.93 (3H, s), 3.90 (3H, s) (2 × OCH₃ and 2 × COOCH₃), 2.20 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.7 (COO), 167.9 (COO), 165.5 (NHCO), 148.7, 148.6, 148.5, 138.4, 136.4, 134.6, 132.9, 132.1, 128.9, 127.9, 127.3, 123.3, 121.5, 112.9, 112.2, 111.0 (16 × C_Ar), 56.0 (OCH₃), 55.9 (OCH₃), 53.0 (COOCH₃), 52.5 (COOCH₃), 17.3 (CH₃); HREIMS m/z 464.1700 (calcd for C₂₆H₂₆NO₇ (M+H)⁺, 464.1704).

Trimethyl 6-benzamido-3-methylbenzene-1,2,4-tricarboxylate (4An): pale yellow powder (EtOH); mp 164.6–167.9 °C; IR ν_max 3323 (N–H), 2948 (H–C-sp³), 1742 (COO), 1673 (NHCO), 1578, 1436, 1396 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.26 (1H, s, NH), 9.29 (1H, s, H-5), 8.00 (2H, m, Ph), 7.58 (1H, m, Ph), 7.53 (2H, m, Ph), 3.94 (6H, s, 2 × COOCH₃), 3.93 (3H, s, COOCH₃), 2.45 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.8 (COO), 167.4 (COO), 167.0 (COO), 165.5 (NHCO), 138.2, 137.1, 136.1, 134.2, 132.3, 130.6, 128.9, 127.3, 123.3, 116.8 (10 × C_Ar), 53.3 (COOCH₃), 52.6 (COOCH₃), 52.6 (COOCH₃), 17.0 (CH₃); HREIMS m/z 386.1225 (calcd for C₂₀H₂₀NO₇ (M+H)⁺, 386.1234).

Dimethyl 6-benzamido-4-benzoyl-3-methylphthalate (4Ao) [25]: white powder (MeOH); mp 160.4–162.4 °C (mp lit. [25] 160–161 °C (EtOH)); IR ν_max 3359 (N–H), 2948 (H–C-sp³), 1708 (COO), 1692 (NHCO), 1666, 1598, 1577, 1516, 1492, 1436, 1399 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.39 (1H, s, NH), 8.88 (1H, s, H-5), 7.96 (2H, m, Ph), 7.86 (2H, m Ph), 7.62 (1H, m, Ph), 7.57 (1H, m, Ph), 7.50 (4H, m, Ph), 3.97 (3H, s, COOCH₃), 3.94 (3H, s, COOCH₃), 2.19 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 196.6 (COPh), 168.8 (COO), 167.6 (COO), 165.5 (NHCO), 145.1, 138.4, 136.8, 136.1, 134.2, 134.2, 132.3, 130.2, 128.9, 128.9, 127.7, 127.3, 120.6, 115.4 (14 × C_Ar), 53.3 (COOCH₃), 52.6 (COOCH₃), 16.4 (CH₃); HREIMS m/z 432.1433 (calcd for C₂₅H₂₂NO₆ (M+H)⁺, 432.1442).

Dimethyl 4-acetyl-6-benzamido-3-methylphthalate (4Ap) [23,25]: yellow powder (EtOH); mp 150.2–152.0 °C (mp lit. [23,25] 149–150 °C (EtOH)); IR ν_max 3335 (N–H), 2951 (H–C-sp³), 1738 (COO), 1679 (NHCO), 1579, 1432 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.40 (1H, s, NH), 9.20 (1H, s, H-5), 7.99 (2H, m, Ph), 7.59 (1H, m, Ph), 7.54 (2H, m, Ph), 3.94 (3H, s, COOCH₃), 3.93 (3H, s, COOCH₃), 2.64 (3H, s, COCH₃), 2.33 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 202.0 (COCH₃), 168.9 (COO), 167.5 (COO), 165.7 (NHCO), 144.2, 138.7, 137.4, 134.2, 132.4, 129.0, 128.2, 127.3, 121.0, 115.8 (10 × C_Ar), 53.3 (COOCH₃), 52.6 (COOCH₃), 30.4 (COCH₃), 16.6 (CH₃); HREIMS m/z 370.1284 (calcd for C₂₀H₂₀NO₆ (M+H)⁺, 370.1285).

Dimethyl 4-acetyl-3-methyl-6-(4-nitrobenzamido)phthalate (4Aq) [23]: pale brown powder (xylene); mp 205.8–208.5 °C (mp lit. [23] 209–211 °C (MeOH)); IR ν_max 3262 (N–H), 2947 (H–C-sp³), 1740 (COO), 1695 (NHCO), 1603, 1579, 1518, 1487, 1434, 1397 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.70 (1H, s, NH), 9.15 (1H, s, H-5), 8.40 and 8.17 (2H each, AA’XX’, J = 8.9 Hz, C₆H₄NO₂), 3.96 (3H, s, COOCH₃), 3.94 (3H, s, COOCH₃), 2.64 (3H, s, COCH₃), 2.34 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 201.8 (COCH₃), 168.7 (COO), 167.6 (COO), 163.5 (NHCO), 150.0, 144.6, 139.7, 138.2, 137.7, 128.9, 128.5, 124.2, 120.7, 115.6 (10 × C_Ar), 53.5 (COOCH₃), 52.7 (COOCH₃), 30.4 (COCH₃), 16.6 (CH₃); HREIMS m/z 415.1138 (calcd for C₂₀H₁₉N₂O₈ (M+H)⁺, 415.1136).

Dimethyl 4-acetyl-6-(4-methoxybenzamido)-3-methylphthalate (4Ar) [23]: yellow crystals (xylene); mp 139.3–141.2 °C (mp lit. [23] 139–141 °C (MeOH)); IR ν_max 3325 (N–H), 2953 (H–C-sp³), 2838, 1727 (COO), 1674 (NHCO), 1581, 1530, 1504, 1436, 1397 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.32 (1H, s, NH), 9.19 (1H, s, H-5), 7.96 and 7.02 (2H each, AA’XX’, J = 8.8 Hz, C₆H₄OCH₃), 3.94 (3H, s, COOCH₃), 3.92 (3H, s, COOCH₃), 3.88 (3H, s, OCH₃), 2.63 (3H, s, COCH₃), 2.33 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 202.0 (COCH₃), 168.9 (COO), 167.5 (COO), 165.3 (NHCO), 162.9, 144.1, 138.9, 137.4, 129.2, 127.9, 126.4, 121.0, 115.5, 114.2 (10 × C_Ar), 55.5 (OCH₃), 53.3 (COOCH₃), 52.5 (COOCH₃), 30.3 (COCH₃), 16.6 (CH₃); HREIMS m/z 400.1388 (calcd for C₂₁H₂₂NO₇ (M+H)⁺, 400.1391).

Dimethyl 4-acetyl-3-methyl-6-(3,4,5-trimethoxybenzamido)phthalate (4As): isolated by column chromatography (petroleum ether/EtOAc = 3:1 to 1:1), white powder (petroleum ether/Et₂O); mp 87.9–92.7 °C; IR ν_max 3325 (N–H), 2951 (H–C-sp³), 2839, 1732 (COO), 1692 (NHCO), 1671, 1580, 1497, 1435, 1415, 1396 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.43 (1H, s, NH), 9.18 (1H, s, H-5), 7.26 (2H, s, C₆H₂(OCH₃)₃), 3.98 (6H, s, 2 × OCH₃), 3.947 (3H, s), 3.945 (3H, s), 3.93 (3H, s) (2 × COOCH₃ and OCH₃), 2.64 (3H, s, COCH₃), 2.34 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 201.9 (COCH₃), 168.8 (COO), 167.5 (COO), 165.3 (NHCO), 153.4, 144.2, 141.6, 138.7, 137.5, 129.4, 128.2, 120.7, 115.6, 104.6 (10 × C_Ar), 61.0 (OCH₃), 56.3 (OCH₃), 53.3 (COOCH₃), 52.6 (COOCH₃), 30.3 (COCH₃), 16.6 (CH₃); HREIMS m/z 460.1601 (calcd for C₂₃H₂₆NO₉ (M+H)⁺, 460.1602).

Dimethyl 6-acetamido-4-acetyl-3-methylphthalate (4At): isolated by two rounds of column chromatography (first column was petroleum ether/EtOAc = 3:1, second column was petroleum ether/EtOAc = 1:1), yellow waxy solid (petroleum ether/EtOAc); IR ν_max 3328 (N–H), 2955 (H–C-sp³), 1726 (COO), 1688 (NHCO), 1571, 1505, 1430, 1396 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 10.27 (1H, s, NHCOCH₃), 8.92 (1H, s, H-5), 3.908 (3H, s, COOCH₃), 3.906 (3H, s, COOCH₃), 2.58 (3H, s, COCH₃), 2.30 (3H, s, NHCOCH₃), 2.23 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 202.0 (COCH₃), 169.1 (COO), 168.8 (COO), 167.0 (NHCO), 144.0, 138.0, 137.1, 128.0, 121.0, 115.9 (6 × C_Ar), 53.1 (COOCH₃), 52.5 (COOCH₃), 30.3 (COCH₃), 25.4 (COCH₃), 16.5 (CH₃); HREIMS m/z 308.1128 (calcd for C₁₅H₁₈NO₆ (M+H)⁺, 308.1129).

Dimethyl 6-benzamido-3-ethyl-4-methylphthalate (4Au): isolated by column chromatography (petroleum ether/EtOAc = 3:1), white powder (petroleum ether/EtOAc); mp 95.4–99.9 °C; IR ν_max 3290 (N–H), 2943 (H–C-sp³), 1731 (COO), 1668 (NHCO), 1577, 1507, 1441, 1404 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.44 (1H, s, NH), 8.74 (1H, s, H-5), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 3.91 (3H, s, COOCH₃), 3.90 (3H, s, COOCH₃), 2.58 (2H, q, J = 7.5 Hz, CH₂CH₃), 2.44 (3H, s, CH₃), 1,16 (3H, t, J = 7.5 Hz, CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.8 (COO), 168.0 (COO), 165.5 (NHCO), 143.9, 138.7, 135.3, 134.9, 134.7, 132.1, 128.9, 127.3, 123.8, 112.2 (10 × C_Ar), 52.9 (COOCH₃), 52.3 (COOCH₃), 23.8 (CH₂CH₃), 20.2 (CH₂CH₃), 14.5 (CH₃); HREIMS m/z 356.1487 (calcd for C₂₀H₂₂NO₅ (M+H)⁺, 356.1492).

Dimethyl 5′-benzamido-[1,1′:2′,1′’-terphenyl]-3′,4′-dicarboxylate (4Av): off-white powder (EtOH); mp 122.3–125.7 °C; IR ν_max 3308 (N–H), 2949 (H–C-sp³), 1736 (COO), 1675 (NHCO), 1565, 1485, 1438 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.51 (1H, s, NH), 9.00 (1H, s, H-6), 8.04 (2H, m), 7.59 (1H, m) 7.54 (2H, m), 7.19 (3H, m), 7.16 (3H, m), 7.12 (2H, m), 7.07 (2H, m) (3 × Ph), 3.92 (3H, s, COOCH₃), 3.48 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.9 (COO), 168.0 (COO), 165.6 (NHCO), 147.4, 139.8, 139.7, 137.5, 136.8, 134.5, 133.8, 132.2, 130.3, 129.7, 128.9, 127.8, 127.6, 127.4, 127.3, 127.2, 123.7, 113.2 (18 × C_Ar), 53.1 (COOCH₃), 52.1 (COOCH₃); HREIMS m/z 466.1635 (calcd for C₂₉H₂₄NO₅ (M+H)⁺, 466.1649).

Dimethyl 4-benzamido-4′-fluoro-6-methyl-[1,1′-biphenyl]-2,3-dicarboxylate (4Aw): white powder (EtOH); mp 172.7–175.7 °C; IR ν_max 3255 (N–H), 2958 (H–C-sp³), 1718 (COO), 1678 (NHCO), 1579, 1489, 1432 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.58 (1H, s, NH), 8.86 (1H, s, H-5), 8.04 (2H, m, Ph), 7.59 (1H, m, Ph), 7.54 (2H, m, Ph), 7.15 (2H, m, C₆H₄F), 7.09 (2H, m, C₆H₄F), 3.88 (3H, s, COOCH₃), 3.48 (3H, s, COOCH₃), 2.16 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.8 (COO), 167.9 (COO), 165.7 (NHCO), 162.2 (d, J = 247.0 Hz, C–4′), 144.1, 140.1, 136.3, 134.5, 134.0 (5 × C_Ar), 133.5 (d, J = 3.5 Hz, C–1′), 132.2 (C_Ar), 131.2 (d, J = 8.1 Hz, C–2′), 128.9, 127.4, 123.0 (3 × C_Ar), 115.2 (d, J = 21.4 Hz, C–3′), 111.6 (C_Ar), 52.9 (COOCH₃), 52.0 (COOCH₃), 21.6 (CH₃); ¹⁹F NMR (CDCl₃, 471 MHz) δ –114.3; HREIMS m/z 422.1390 (calcd for C₂₄H₂₁FNO₅ (M+H)⁺, 422.1398).

6-Ethyl 2,3-dimethyl 4-benzamido-4′-methoxy-[1,1′-biphenyl]-2,3,6-tricarboxylate (4Ax): isolated by rounds of two column chromatography (first column was petroleum ether/EtOAc = 3:2, second column was petroleum ether/EtOAc = 3:1), white powder (Et₂O); mp 165.7–169.2 °C; IR ν_max 3332 (N–H), 2955 (H–C-sp³), 1713 (COO), 1678 (NHCO), 1579, 1510, 1492, 1435 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.43 (1H, s, NH), 9.25 (1H, s, H-5), 8.02 (2H, m, Ph), 7.56 (3H, m, Ph), 7.15 and 6.89 (2H each, AA’XX’, J = 8.5 Hz, C₆H₄OCH₃), 4.09 (2H, q, J = 7.1 Hz, COOCH₂CH₃), 3.92 (3H, s, COOCH₃), 3.83 (3H, s, COOCH₃), 3.52 (3H, s, OCH₃), 1.07 (3H, t, J = 7.1 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.1 (COO), 167.5 (COO), 166.8 (COO), 165.6 (NHCO), 159.2, 139.6, 138.2, 137.4, 134.3, 133.8, 132.4, 130.4, 129.1, 129.0, 127.4, 121.9, 115.6, 113.1 (14 × C_Ar), 61.6 (OCH₃), 55.2 (CH₂CH₃), 53.3 (COOCH₃), 52.2 (COOCH₃), 13.9 (CH₂CH₃); HREIMS m/z 492.1645 (calcd for C₂₇H₂₆NO₈ (M+H)⁺, 492.1653).

Trimethyl 6-benzamido-3-(2-methoxy-2-oxoethyl)benzene-1,2,4-tricarboxylate (4Ay) [25]: off-white powder (EtOH); mp 148.6–150.1 °C (mp lit. [25] 143.5–145.8 °C (MeOH)); IR ν_max 3320 (N–H), 2954 (H–C-sp³), 1735 (COO), 1683 (NHCO), 1580, 1524, 1428, 1402 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.20 (1H, s, NH), 9.47 (1H, s, H-5), 7.99 (2H, m, Ph), 7.60 (1H, m, Ph), 7.54 (2H, m, Ph), 4.06 (2H, s, CH₂), 3.94 (3H, s, COOCH₃), 3.93 (3H, s, COOCH₃), 3.91 (3H, s, COOCH₃), 3.69 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 170.8 (COO), 168.2 (COO), 167.3 (COO), 166.5 (COO), 165.5 (NHCO), 139.3, 137.2, 135.4, 134.0, 132.5, 129.0, 127.6, 127.3, 124.4, 117.9 (10 × C_Ar), 53.4 (COOCH₃), 52.8 (COOCH₃), 52.8 (COOCH₃), 52.2 (COOCH₃), 35.6 (CH₂); HREIMS m/z 444.1287 (calcd for C₂₂H₂₂NO₉ (M+H)⁺, 444.1289).

Trimethyl 5-benzamido-4′-methoxy-[1,1′-biphenyl]-2,3,4-tricarboxylate (4Az): pale yellow powder (EtOH); mp 154.3–157.5 °C; IR ν_max 3321 (N–H), 2949 (H–C-sp³), 1721 (COO), 1681 (NHCO), 1569, 1506, 1488, 1432 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.43 (1H, s, NH), 9.29 (1H, s, H-6), 8.02 (2H, m, Ph), 7.56 (3H, m, Ph), 7.14 and 6.89 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 3.92 (3H, s, COOCH₃), 3.84 (3H, s, COOCH₃), 3.67 (3H, s), 3.52 (3H, s) (OCH₃ and COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.1 (COO), 167.4 (COO), 167.0 (COO), 165.6 (NHCO), 159.2, 139.6, 137.5, 137.4, 134.2, 134.1, 132.4, 130.3, 129.0, 128.9, 127.4, 122.1, 115.9, 113.1 (14 × C_Ar), 55.2 (OCH₃), 53.3 (COOCH₃), 52.5 (COOCH₃), 52.2 (COOCH₃); HREIMS m/z 478.1484 (calcd for C₂₆H₂₄NO₈ (M+H)⁺, 478.1496).

Dimethyl 6-benzamido-2,3-dihydro-1H-indene-4,5-dicarboxylate (4Aaa): white powder (EtOH); mp 107.7–108.9 °C; IR ν_max 3250 (N–H), 2948 (H–C-sp³), 1737 (COO), 1667 (NHCO), 1591, 1523, 1434 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.20 (1H, s, NH), 8.73 (1H, s, H-7), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 3.895 (3H, s, COOCH₃), 3.889 (3H, s, COOCH₃), 3.01 (2H, t, J = 7.5 Hz), 2.94 (2H, t, J = 7.5 Hz), 2.12 (2H, deg. dt, J = 7.5 Hz) (3 × CH₂); ¹³C NMR (CDCl₃, 126 MHz) δ 169.0 (COO), 168.6 (COO), 165.5 (NHCO), 151.6, 139.0, 138.0, 134.6, 132.1, 130.8, 128.9, 127.3, 118.7, 113.5 (10 × C_Ar), 52.8 (COOCH₃), 52.4 (COOCH₃), 33.6, 31.5, 25.0 (3 × CH₂); HREIMS m/z 354.1337 (calcd for C₂₀H₂₀NO₅ (M+H)⁺, 354.1336).

Dimethyl 3-benzamido-5,6,7,8-tetrahydronaphthalene-1,2-dicarboxylate (4Aab): off-white crystals (EtOH); mp 131.8–133.6 °C; IR ν_max 3250 (N–H), 2945 (H–C-sp³), 1727 (COO), 1671 (NHCO), 1578, 1509, 1411 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.44 (1H, s, NH), 8.66 (1H, s, H-4), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 3.90 (6H, s, 2 × COOCH₃), 2.88 (2H, m), 2.67 (2H, m), 1.79 (4H, m) (4 × CH₂); ¹³C NMR (CDCl₃, 126 MHz) δ 169.5 (COO), 168.1 (COO), 165.5 (NHCO), 145.0, 138.1, 135.7, 134.7, 132.0, 129.5, 128.8, 127.3, 122.4, 111.9 (10 × C_Ar), 52.9 (COOCH₃), 52.3 (COOCH₃), 30.5, 26.2, 22.7, 22.2 (4 × CH₂); HREIMS m/z 368.1491 (calcd for C₂₁H₂₂NO₅ (M+H)⁺, 368.1492).

Dimethyl 3-benzamido-5,6,7,8,9,10-hexahydrobenzo [8]annulene-1,2-dicarboxylate (4Aac) [23]: white crystals (EtOH); mp 130.3–133.1 °C (mp lit. [23] 128–129 °C (MeOH)); IR ν_max 3261 (N–H), 2926 (H–C-sp³), 1709 (COO), 1670 (NHCO), 1581, 1518, 1442 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.51 (1H, s, NH), 8.75 (1H, s, H-4), 8.00 (2H, m, Ph), 7.54 (3H, m, Ph), 3.91 (3H, s, COOCH₃), 3.90 (3H, s, COOCH₃), 2.86 (2H, m), 2.73 (2H, m), 1.77 (2H, m), 1.71 (2H, m) (4 × CH₂), 1.38 (4H, m, 2 × CH₂); ¹³C NMR (CDCl₃, 126 MHz) δ 169.9 (COO), 168.1 (COO), 165.5 (NHCO), 149.8, 139.1, 135.3, 134.8, 133.3, 132.0, 128.9, 127.3, 122.6, 112.3 (10 × C_Ar), 52.9 (COOCH₃), 52.3 (COOCH₃), 33.4, 31.9, 31.1, 28.4, 26.2, 25.8 (6 × CH₂); HREIMS m/z 396.1802 (calcd for C₂₃H₂₆NO₅ (M+H)⁺, 396.1805).

Dimethyl 2-benzamido-9H-fluorene-3,4-dicarboxylate (4Aad): pale yellow powder (EtOH); mp 189.5–192.5 °C; IR ν_max 3321 (N–H), 2949 (H–C-sp³), 1736, 1716 (COO), 1684 (NHCO), 1580, 1514, 1490, 1433, 1403 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.73 (1H, s, NH), 9.17 (1H, s, H-1), 8.04 (2H, m, Ph), 7.56 (5H, m), 7.35 (2H, m) (Ph, H-5, H-6, H-7, H-8), 4.06 (3H, s, COOCH₃), 4.02 (2H, s, CH₂), 3.98 (3H, s, COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.1 (COO), 168.3 (COO), 165.7 (NHCO), 150.6, 143.5, 139.7, 138.6, 134.6, 133.4, 132.2, 128.9, 127.6, 127.4, 127.2, 125.1, 121.5, 118.6, 112.7 (15 × C_Ar), 53.1 (COOCH₃), 52.7 (COOCH₃), 37.4 (CH₂) (one aromatic signal is hidden); HREIMS m/z 402.1327 (calcd for C₂₄H₂₀NO₅ (M+H)⁺, 402.1336).

Dimethyl 4-benzamido-5-methyl-[1,1′-biphenyl]-2,3-dicarboxylate (4Aae): white powder (EtOH); mp 177.0–180.7 °C; IR ν_max 3274 (N–H), 2944 (H–C-sp³), 1740, 1720 (COO), 1707 (NHCO), 1637, 1513, 1484, 1432 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 9.20 (1H, s, NH), 7.97 (2H, m, Ph), 7.58 (1H, m, Ph), 7.51 (2H, m, Ph), 7.43–7.35 (4H, m, H-6 and Ph), 7.32 (2H, m, Ph), 3.80 (3H, s, COOCH₃), 3.56 (3H, s, COOCH₃), 2.39 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.7 (COO), 167.7 (COO), 165.4 (NHCO), 139.5, 138.7, 138.3, 135.7, 134.2, 133.8, 132.2, 131.2, 128.9, 128.3, 128.3, 127.8, 127.5 (13 × C_Ar), 53.0 (COOCH₃), 52.3 (COOCH₃), 19.4 (CH₃) (one aromatic signal is hidden); HREIMS m/z 404.1485 (calcd for C₂₄H₂₂NO₅ (M+H)⁺, 404.1492).

Dimethyl 3-benzamido-4-methyl-6-(thiophen-2-yl)phthalate (4Aaf): isolated by column chromatography (petroleum ether/EtOAc = 3:1), white crystals (petroleum ether/EtOAc); mp 193.5–196.2 °C; IR ν_max 3235 (N–H), 3105, 2946 (H–C-sp³), 1715 (COO), 1643 (NHCO), 1602, 1508, 1486, 1430 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 9.28 (1H, s, NH), 7.97 (2H, m, Ph), 7.59 (1H, m, Ph), 7.52 (3H, m, Ph, H-5), 7.36 (1H, m, C₄H₃S), 7.06 (2H, m, C₄H₃S), 3.82 (3H, s, COOCH₃), 3.69 (3H, s, COOCH₃), 2.38 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.5 (COO), 167.3 (COO), 165.3 (NHCO), 140.1, 138.1, 136.2, 135.0, 133.7, 132.2, 131.7, 130.8, 128.9, 127.5, 127.4, 126.8, 126.5, 125.5 (10 × C_Ar, 4 × C_Thioph), 53.0 (COOCH₃), 52.5 (COOCH₃), 19.4 (CH₃); HREIMS m/z 410.1052 (calcd for C₂₂H₂₀NO₅S (M+H)⁺, 410.1057).

Diethyl 3-benzamido-6-methylphthalate (4Ba) [24]: isolated by column chromatography (petroleum ether/EtOAc = 3:1), yellow waxy solid (petroleum ether/EtOAc) (mp lit. [24] 54–57 °C (petroleum ether:AcOEt)); IR ν_max 3320 (N–H), 2981 (H–C-sp³), 1728 (COO), 1676 (NHCO), 1519, 1492 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.34 (1H, s, NH), 8.77 (1H, d, J = 8.7 Hz, H-4 or H-5), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 7.42 (1H, d, J = 8.7 Hz, H-4 or H-5), 4.38 (4H, q, J = 7.2 Hz, 2 × COOCH₂CH₃), 2.34 (3H, s, CH₃), 1.40 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.37 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.7 (COO), 167.8 (COO), 165.5 (NHCO), 138.4, 135.5, 135.3, 134.6, 132.0, 130.2, 128.8, 127.3, 122.1, 114.9 (10 × C_Ar), 62.3 (CH₂CH₃), 61.4 (CH₂CH₃), 19.1 (CH₃), 14.2 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 356.1492 (calcd for C₂₀H₂₂NO₅ (M+H)⁺, 356.1492).

Diethyl 4-benzamido-[1,1′-biphenyl]-2,3-dicarboxylate (4Bb): off-white powder (EtOH); mp 112.2–113.4 °C; IR ν_max 3255 (N–H), 2978 (H–C-sp³), 1731 (COO), 1690 (NHCO), 1665, 1518, 1490 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.34 (1H, s, NH), 8.90 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.02 (2H, m, Ph), 7.55 (4H, m, H-5 or H-6, Ph), 7.38 (5H, m, Ph), 4.38 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.02 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 1.34 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 0.93 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.4 (COO), 167.8 (COO), 165.6 (NHCO), 139.41, 139.36, 135.5, 135.1, 135.0, 134.5, 132.2, 128.9, 128.6, 128.2, 127.7, 127.4, 122.0, 115.3 (14 × C_Ar), 62.5 (CH₂CH₃), 61.3 (CH₂CH₃), 13.7 (CH₂CH₃), 13.5 (CH₂CH₃); HREIMS m/z 418.1639 (calcd for C₂₅H₂₄NO₅ (M+H)⁺, 418.1649).

Diethyl 4-benzamido-4′-methyl-[1,1′-biphenyl]-2,3-dicarboxylate (4Bc): yellow-brown powder (EtOH); mp 125.8–128.7 °C; IR ν_max 3335 (N–H), 2985 (H–C-sp³), 1709 (COO), 1681 (NHCO), 1584, 1508, 1489, 1364 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.32 (1H, s, NH), 8.88 (1H, d, J = 8.7 Hz, H-5 or H-6), 8.02 (2H, m, Ph), 7.55 (4H, m, Ph and H-5 or H-6), 7.21 (4H, m, C₆H₄), 4.38 (2H, q, J = 7.1 Hz, CH₂), 4.04 (2H, q, J = 7.1 Hz, CH₂), 2.39 (3H, s, CH₃), 1.34 (3H, t, J = 7.1 Hz, CH₃), 0.98 (3H, t, J = 7.1 Hz, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.5 (COO), 167.8 (COO), 165.6 (NHCO), 139.2, 137.4, 136.5, 135.6, 135.1, 135.0, 134.5, 132.2, 128.9, 128.9, 128.5, 127.4, 122.0, 115.3 (14 × C_Ar), 62.5 (CH₂CH₃), 61.3 (CH₂CH₃), 21.2 (CH₃), 13.7 (CH₂CH₃), 13.6 (CH₂CH₃); HREIMS m/z 432.1789 (calcd for C₂₆H₂₆NO₅ (M+H)⁺, 432.1805).

Diethyl 3-benzamido-6-(furan-2-yl)phthalate (4Bd): isolated by column chromatography (petroleum ether/EtOAc = 3:1), pale yellow powder (EtOH); mp 128.6–130.6 °C; IR ν_max 3255 (N–H), 2984 (H–C-sp³), 1727 (COO), 1674 (NHCO), 1575, 1523, 1484 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.41 (1H, s, NH), 8.92 (1H, d, J = 8.9 Hz, H-4 or H-5), 8.00 (2H, m, Ph), 7.84 (1H, d, J = 8.9 Hz, H-4 or H-5), 7.58 (1H, m, Ph), 7.53 (2H, m, Ph), 7.49 (1H, m, C₄H₃O), 6.56 (1H, m, C₄H₃O), 6.48 (1H, m, C₄H₃O), 4.41 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.32 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 1.38 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.28 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.5 (COO), 167.6 (COO), 165.6 (NHCO), 150.9, 142.8, 139.8, 134.5, 132.8, 132.6, 132.2, 128.9, 127.4, 124.1, 122.1, 115.4, 111.7, 108.3 (10 × C_Ar, 4 × C_Fur), 62.6 (CH₂CH₃), 61.7 (CH₂CH₃), 14.0 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 408.1437 (calcd for C₂₃H₂₂NO₆ (M+H)⁺, 408.1442).

Diethyl 3-benzamido-6-(thiophen-2-yl)phthalate (4Be): orange-brown crystals (EtOH); mp 122.8–124.8 °C; IR ν_max 3313 (N–H), 3114, 2979 (H–C-sp³), 1727 (COO), 1673 (NHCO), 1581, 1535, 1513, 1490, 1365 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.49 (1H, s, NH), 8.92 (1H, d, J = 8.8 Hz, H-4 or H-5), 8.02 (2H, m, Ph), 7.66 (1H, d, J = 8.8 Hz, H-4 or H-5), 7.58 (1H, m, Ph), 7.53 (2H, m, Ph), 7.36 (1H, m), 7.05 (2H, m) (C₄H₃S), 4.40 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.14 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 1.36 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.09 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.2 (COO), 167.5 (COO), 165.6 (NHCO), 140.2, 139.9, 135.9, 135.7, 134.4, 132.3, 128.9, 127.8, 127.4, 127.22, 127.15, 126.3, 121.8, 114.9 (10 × C_Ar, 4 × C_Thioph), 62.6 (CH₂CH₃), 61.5 (CH₂CH₃), 13.73 (CH₂CH₃), 13.68 (CH₂CH₃); HREIMS m/z 424.1203 (calcd for C₂₃H₂₂NO₅S (M+H)⁺, 424.1213).

Diethyl 5-benzamido-4′-methoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Bf) [24]: pale yellow powder (EtOH); mp 109.6–112.0 °C (mp lit. [24] 116.0–116.8 °C (MeOH)); IR ν_max 3340 (N–H), 2977 (H–C-sp³), 1720 (COO), 1701, 1668 (NHCO), 1508, 1365 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.52 (1H, s, NH), 8.82 (1H, s, H-6), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 7.28 and 6.96 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 4.41 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.40 (2H, q, J = 7.1 Hz, COOCH₂CH₃), 3.86 (3H, s, OCH₃), 2.21 (3H, s, CH₃), 1.42 (3H, t, J = 7.0 Hz, COOCH₂CH₃), 1.39 (3H, t, J = 7.0 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.2 (COO), 167.7 (COO), 165.5 (NHCO), 159.2, 148.2, 138.4, 136.5, 134.7, 132.7, 132.0, 130.3, 128.8, 127.8, 127.3, 123.3, 113.7, 113.0 (14 × C_Ar), 62.3 (CH₂CH₃), 61.4 (CH₂CH₃), 55.4 (OCH₃), 17.2 (CH₃), 14.2 (CH₂CH₃), 13.9 (CH₂CH₃); HREIMS m/z 462.1899 (calcd for C₂₇H₂₈NO₆ (M+H)⁺, 462.1911).

Diethyl 5-benzamido-3′,4′-dimethoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Bg) [24]: pale yellow powder (EtOH); mp 114.2–116.4 °C (mp lit. [24] 109.0–111.5 °C (Et₂O)); IR ν_max 3330 (N–H), 2982 (H–C-sp³), 1725 (COO), 1676 (NHCO), 1508, 1366 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.52 (1H, s, NH), 8.82 (1H, s, H-6), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 6.92 (2H, m, C₆H₃(OCH₃)₂), 6.84 (1H, m, C₆H₃(OCH₃)₂), 4.42 (2H, q, J = 7.1 Hz, COOCH₂CH₃), 4.40 (2H, q, J = 7.1 Hz, COOCH₂CH₃), 3.94 (3H, s, OCH₃), 3.90 (3H, s, OCH₃), 2.21 (3H, s, CH₃), 1.41 (3H, t, J = 7.1 Hz, COOCH₂CH₃), 1.40 (3H, t, J = 7.1 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.2 (COO), 167.7 (COO), 165.5 (NHCO), 148.7, 148.6, 148.3, 138.4, 136.5, 134.7, 133.0, 132.1, 128.9, 127.8, 127.3, 123.3, 121.5, 113.1, 112.2, 111.0 (16 × C_Ar), 62.3 (CH₂CH₃), 61.4 (CH₂CH₃), 56.00 (OCH₃), 55.98 (OCH₃), 17.3 (CH₃), 14.2 (CH₂CH₃), 13.9 (CH₂CH₃); HREIMS m/z 492.2004 (calcd for C₂₈H₃₀NO₇ (M+H)⁺, 492.2017).

1,2-Diethyl 4-methyl 6-benzamido-3-methylbenzene-1,2,4-tricarboxylate (4Bh): off-white crystals (EtOH); mp 134.6–137.9 °C; IR ν_max 3309 (N–H), 2981 (H–C-sp³), 1728 (COO), 1679 (NHCO), 1577, 1519, 1436 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.32 (1H, s, NH), 9.28 (1H, s, H-5), 8.00 (2H, m, Ph), 7.54 (3H, m, Ph), 4.40 (2H, q, J = 7.3 Hz, COOCH₂CH₃), 4.39 (2H, q, J = 7.1 Hz, COOCH₂CH₃), 3.94 (3H, s, COOCH₃), 2.47 (3H, s, CH₃), 1.40 (3H, t, J = 7.3 Hz, COOCH₂CH₃), 1.38 (3H, t, J = 7.1 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.3 (COO), 167.1 (COO), 167.1 (COO), 165.5 (NHCO), 138.1, 137.3, 136.0, 134.3, 132.3, 130.5, 128.9, 127.3, 123.2, 117.0 (10 × C_Ar), 62.8 (CH₂CH₃), 61.6 (CH₂CH₃), 52.6 (COOCH₃), 16.9 (CH₃), 14.1 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 414.1537 (calcd for C₂₂H₂₄NO₇ (M+H)⁺, 414.1547).

Diethyl 4-acetyl-6-benzamido-3-methylphthalate (4Bi) [25]: canary-yellow powder (EtOH); mp 91.9–93.9 °C (mp lit. [25] 97–99 °C (Et₂O)); IR ν_max 3259 (N–H), 2982 (H–C-sp³), 1731 (COO), 1683 (NHCO), 1578, 1517, 1491 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.46 (1H, s, NH), 9.19 (1H, s, H-5), 8.00 (2H, m, Ph), 7.55 (3H, m, Ph), 4.41 (2H, q, J = 7.3 Hz, COOCH₂CH₃), 4.38 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 2.64 (3H, s, COCH₃), 2.35 (3H, s, CH₃), 1.41 (3H, t, J = 6.9 Hz, COOCH₂CH₃), 1.38 (3H, t, J = 6.8 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 202.1 (COCH₃), 168.4 (COO), 167.1 (COO), 165.7 (NHCO), 144.1, 138.6, 137.6, 134.3, 132.3, 129.0, 128.1, 127.3, 120.9, 116.0 (10 × C_Ar), 62.8 (CH₂CH₃), 61.6 (CH₂CH₃), 30.4 (COCH₃), 16.5 (CH₃), 14.1 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 398.1585 (calcd for C₂₂H₂₄NO₆ (M+H)⁺, 398.1585).

Diethyl 4-acetyl-3-methyl-6-(4-nitrobenzamido)phthalate (4Bj): off-white powder (EtOH); mp 166.1–167.6 °C; IR ν_max 3332 (N–H), 3108, 2983 (H–C-sp³), 1727 (COO), 1699 (NHCO), 1676, 1582, 1520, 1489 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.77 (1H, s, NH), 9.13 (1H, s, H-5), 8.38 and 8.16 (2H each, AA’XX’, J = 8.5 Hz, C₆H₄NO₂), 4.43 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.41 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 2.64 (3H, s, COCH₃), 2.35 (3H, s, CH₃), 1.413 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.406 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 201.9 (COCH₃), 168.1 (COO), 167.3 (COO), 163.5 (NHCO), 150.0, 144.5, 139.7, 138.2, 137.9, 128.8, 128.5, 124.1, 120.5, 115.7 (10 × C_Ar), 63.0 (CH₂CH₃), 61.7 (CH₂CH₃), 30.4 (COCH₃), 16.5 (CH₃), 14.1 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 460.1704 (calcd for C₂₂H₂₆N₃O₈ (M+NH₄)⁺, 460.1714).

Diethyl 6-benzamido-3-ethyl-4-methylphthalate (4Bk): isolated by two rounds of column chromatography (petroleum ether/EtOAc = 3:1), white powder (petroleum ether); mp 105.0–107.3 °C; IR ν_max 3307 (N–H), 2973 (H–C-sp³), 1734 (COO), 1671 (NHCO), 1580, 1519, 1492, 1468, 1409 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.51 (1H, s, NH), 8.73 (1H, s, H-5), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 4.38 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.37 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 2.60 (2H, q, J = 7.4 Hz, CH₂CH₃), 2.44 (3H, s, CH₃), 1.40 (6H, t, J = 7.2 Hz, COOCH₂CH₃), 1.37 (3H, t, J = 7.4 Hz, CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.2 (COO), 167.8 (COO), 165.5 (NHCO), 143.7, 138.7, 135.5, 134.8, 134.8, 132.0, 128.8, 127.3, 123.7, 112.3 (10 × C_Ar), 62.2 (CH₂CH₃), 61.3 (CH₂CH₃), 23.7, 20.2, 14.5, 14.2, 13.9 (4 × CH₃, CH₂); HREIMS m/z 384.1802 (calcd for C₂₂H₂₆NO₅ (M+H)⁺, 384.1805).

1,2-Diethyl 4-methyl 6-benzamido-3-(2-methoxy-2-oxoethyl)benzene-1,2,4-tricarboxylate (4Bl) [25]: white crystals (EtOH); mp 119.4–121.2 °C (mp lit. [25] 113.1–114.6 °C (MeOH/H₂O)); IR ν_max 3257 (N–H), 2992 (H–C-sp³), 2953, 1730 (COO), 1681 (NHCO), 1579, 1521, 1491 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.28 (1H, s, NH), 9.47 (1H, s, H-5), 8.00 (2H, m, Ph), 7.59 (1H, m, Ph), 7.53 (2H, m, Ph), 4.40 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.37 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.07 (2H, s, CH₂COOCH₃), 3.93 (3H, s, COOCH₃), 3.69 (3H, s, COOCH₃), 1.38 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.37 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 170.8, 167.7, 167.0, 166.5, 165.5 (5 × CO), 139.3, 137.5, 135.2, 134.1, 132.4, 129.0, 127.5, 127.3, 124.2, 118.0 (10 × C_Ar), 62.9 (CH₂CH₃), 61.9 (CH₂CH₃), 52.8 (COOCH₃), 52.1 (COOCH₃), 35.6 (CH₂), 14.0 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 472.1592 (calcd for C₂₄H₂₆NO₉ (M+H)⁺, 472.1602).

Diethyl 6-benzamido-2,3-dihydro-1H-indene-4,5-dicarboxylate (4Bm): isolated by column chromatography (petroleum ether/EtOAc = 3:1), white waxy solid (petroleum ether/EtOAc); IR ν_max 3255 (N–H), 2957 (H–C-sp³), 1721 (COO), 1641, 1516, 1488 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.29 (1H, s, NH), 8.73 (1H, s, H-7), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 4.36 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.35 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 3.01 (2H, t, J = 7.5 Hz, CH₂), 2.95 (2H, t, J = 7.5 Hz, CH₂), 2.12 (2H, deg. tt, J = 7.5 Hz, CH₂), 1.39 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.35 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.5 (COO), 168.2 (COO), 165.5 (NHCO), 151.3, 139.1, 137.7, 134.7, 132.0, 131.2, 128.8, 127.3, 118.5, 113.5 (10 × C_Ar), 62.1 (CH₂CH₃), 61.3 (CH₂CH₃), 33.6, 31.5, 25.0 (3 × CH₂), 14.3 (CH₂CH₃), 13.8 (CH₂CH₃); HREIMS m/z 382.1642 (calcd for C₂₂H₂₄NO₅ (M+H)⁺, 382.1649).

Diethyl 3-benzamido-5,6,7,8-tetrahydronaphthalene-1,2-dicarboxylate (4Bn): isolated by column chromatography (petroleum ether/EtOAc = 3:1), white waxy solid (petroleum ether/EtOAc); IR ν_max 3252 (N–H), 2941 (H–C-sp³), 1723 (COO), 1644, 1517 1488 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.51 (1H, s, NH), 8.65 (1H, s, H-4), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 4.37 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 4.36 (2H, q, J = 7.2 Hz, COOCH₂CH₃), 2.88 (2H, t, J = 5.4 Hz), 2.69 (2H, t, J = 5.4 Hz), 1.80 (4H, m) (4 × CH₂), 1.39 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.37 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.0 (COO), 167.8 (COO), 165.5 (NHCO), 144.8, 138.1, 135.9, 134.8, 132.0, 129.3, 128.8, 127.3, 122.3, 112.1 (10 × C_Ar), 62.1 (CH₂CH₃), 61.2 (CH₂CH₃), 30.5, 26.1, 22.7, 22.2 (4 × CH₂), 14.2 (CH₂CH₃), 13.9 (CH₂CH₃); HREIMS m/z 396.1797 (calcd for C₂₃H₂₆NO₅ (M+H)⁺, 396.1805).

Diethyl 3-benzamido-6,7,8,9-tetrahydro-5H-benzo [7]annulene-1,2-dicarboxylate (4Bo): isolated by column chromatography (petroleum ether/EtOAc = 3:1), off-white waxy solid (petroleum ether/EtOAc); IR ν_max 3258 (N–H), 2970 (H–C-sp³), 2926, 2853, 1715 (COO), 1671 (NHCO), 1585, 1525, 1492 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.59 (1H, s, NH), 8.73 (1H, s, H-4), 8.00 (2H, m Ph), 7.53 (3H, m, Ph), 4.37 (4H, q, J = 7.2 Hz, 2 × COOCH₂CH₃), 2.91 (2H, m), 2.70 (2H, m), 1.83 (2H, m), 1.67 (4H, m), (2 × CH₂), 1.39 (3H, t, J = 7.2 Hz, COOCH₂CH₃), 1.37 (3H, t, J = 7.2 Hz, COOCH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.4 (COO), 167.8 (COO), 165.5 (NHCO), 151.2, 139.1, 135.4, 135.0, 134.8, 132.0, 128.8, 127.3, 122.1, 111.5 (10 × C_Ar), 62.1 (CH₂CH₃), 61.2 (CH₂CH₃), 36.8, 31.9, 31.5, 27.7, 27.5 (5 × CH₂), 14.2 (CH₂CH₃), 13.9 (CH₂CH₃); HREIMS m/z 410.1956 (calcd for C₂₄H₂₈NO₅ (M+H)⁺, 410.1962).

Dipropyl 3-benzamido-6-(thiophen-2-yl)phthalate (4Ca): isolated by column chromatography (petroleum ether/EtOAc = 3:1), off-white powder (petroleum ether/EtOAc); mp 122.5–124.1 °C; IR ν_max 3363 (N–H), 2964 (H–C-sp³), 2878, 1717 (COO), 1688 (NHCO), 1511, 1489 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.48 (1H, s, NH), 8.92 (1H, d, J = 8.8 Hz, H-4 or H-5), 8.02 (2H, m, Ph), 7.66 (1H, d, J = 8.8 Hz, H-4 or H-5), 7.55 (3H, m Ph), 7.35 (1H, m C₄H₃S), 7.05 (2H, m, C₄H₃S), 4.29 (2H, t, J = 6.9 Hz, COOCH₂CH₂CH₃), 4.01 (2H, t, J = 6.6 Hz, COOCH₂CH₂CH₃), 1.74 (2H, deg. hept, J = 6.9 Hz, COOCH₂CH₂CH₃), 1.48 (2H, deg. hept, J = 6.9 Hz, COOCH₂CH₂CH₃), 0.98 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃), 0.77 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.4 (COO), 167.7 (COO), 165.6 (NHCO), 140.2, 140.0, 135.8, 135.6, 134.5, 132.2, 128.9, 127.8, 127.4, 127.2, 127.1, 126.3, 121.9, 115.1 (10 × C_Ar, 4 × C_Thioph), 68.3, 67.4 (2 × CH₂CH₂CH₃), 21.7, 21.5 (2 × CH₂CH₂CH₃), 10.4, 10.3 (2 × CH₂CH₂CH₃); HREIMS m/z 452.1522 (calcd for C₂₅H₂₆NO₅S (M+H)⁺, 452.1526).

Dipropyl 5-benzamido-4′-methoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Cb): isolated by three rounds of column chromatography (first column was petroleum ether/EtOAc = 3:1, second and third columns were petroleum ether/EtOAc = 10:1), yellow waxy solid (petroleum ether/EtOAc); IR ν_max 3305 (N–H), 2966 (H–C-sp³), 1730 (COO), 1676 (NHCO), 1605, 1579, 1506, 1490, 1462, 1403 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.50 (1H, s, NH), 8.81 (1H, s, H-6), 8.00 (2H, m, Ph), 7.56 (1H, m, Ph), 7.51 (2H, m, Ph), 7.28 and 6.96 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 4.30 (2H, t, J = 7.4 Hz, COOCH₂CH₂CH₃), 4.27 (2H, t, J = 7.2 Hz, COOCH₂CH₂CH₃), 3.86 (3H, s, OCH₃), 2.20 (3H, s, CH₃), 1.79 (4H, m, 2 × COOCH₂CH₂CH₃), 1.02 (6H, q, J = 7.6 Hz, 2 × COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.3 (COO), 167.8 (COO), 165.5 (NHCO), 159.2, 148.1, 138.4, 136.5, 134.7, 132.7, 132.0, 130.3, 128.8, 127.9, 127.3, 123.4, 113.7, 113.2 (14 × C_Ar), 68.0, 67.2 (2 × CH₂CH₂CH₃), 55.4 (OCH₃), 21.9, 21.8 (2 × CH₂CH₂CH₃), 17.3 (CH₃), 10.7, 10.4 (2 × CH₂CH₂CH₃); HREIMS m/z 490.2221 (calcd for C₂₉H₃₂NO₆ (M+H)⁺, 490.2224).

Dipropyl 5-benzamido-3′,4′-dimethoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Cc): isolated by column chromatography (petroleum ether/EtOAc = 3:1), yellow waxy solid (petroleum ether/EtOAc); IR ν_max 3348 (N–H), 2963 (H–C-sp³), 2878, 1728 (COO), 1675 (NHCO), 1602, 1514, 1491 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.50 (1H, s, NH), 8.83 (1H, s, H-6), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 6.89 (3H, m, C₆H₃(OCH₃)₂), 4.31 (2H, t J = 7.6 Hz, COOCH₂CH₂CH₃), 4.28 (2H, t J = 7.6 Hz, COOCH₂CH₂CH₃), 3.94 (3H, s, OCH₃), 3.90 (3H, s, OCH₃), 2.21 (3H, s, CH₃), 1.79 (4H, deg. tq, J = 7.0 Hz, 2 × COOCH₂CH₂CH₃), 1.03 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃), 1.01 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.3 (COO), 167.8 (COO), 165.5 (NHCO), 148.7, 148.6, 148.3, 138.3, 136.5, 134.7, 133.0, 132.1, 128.8, 127.9, 127.3, 123.3, 121.5, 113.3, 112.3, 111.0 (16 × C_Ar), 68.0, 67.2 (2 × CH₂CH₂CH₃), 56.00, 55.98 (2 × OCH₃), 21.9, 21.8 (2 × CH₂CH₂CH₃), 17.3 (CH₃), 10.7, 10.4 (2 × CH₂CH₂CH₃); HREIMS m/z 520.2322 (calcd for C₃₀H₃₄NO₇ (M+H)⁺, 520.2330).

4-Methyl 1,2-dipropyl 6-benzamido-3-methylbenzene-1,2,4-tricarboxylate (4Cd): white powder (petroleum ether/MeOH); mp 118.2–120.7 °C; IR ν_max 3316 (N–H), 2973 (H–C-sp³), 1729 (COO), 1678 (NHCO), 1578, 1522, 1492, 1436, 1406 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.29 (1H, s, NH), 9.27 (1H, s, H-5), 8.00 (2H, m, Ph), 7.58 (1H, m, Ph), 7.53 (2H, m, Ph), 4.30 (2H, t, J = 7.1 Hz, COOCH₂CH₂CH₃), 4.27 (2H, t, J = 7.0 Hz, COOCH₂CH₂CH₃), 3.94 (3H, s, COOCH₃), 2.47 (3H, s, CH₃), 1.77 (4H, m, 2 × COOCH₂CH₂CH₃), 1.02 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃), 0.99 (3H, t, J = 7.5 Hz, COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.4 (COO), 167.3 (COO), 167.1 (COO), 165.5 (NHCO), 138.1, 137.3, 135.9, 134.3, 132.3, 130.5, 128.9, 127.3, 123.2, 117.2 (10 × C_Ar), 68.4, 67.4 (2 × CH₂CH₂CH₃), 52.6 (COOCH₃), 21.8, 21.7 (2 × CH₂CH₂CH₃), 17.0 (CH₃), 10.6, 10.4 (2 × CH₂CH₂CH₃); HREIMS m/z 442.1849 (calcd for C₂₄H₂₈NO₇ (M+H)⁺, 442.1860).

Dipropyl 4-acetyl-3-methyl-6-(4-nitrobenzamido)phthalate (4Ce): pale brown powder (petroleum ether/MeOH); mp 103.7–105.2 °C; IR ν_max 3338 (N–H), 2975 (H–C-sp³), 1728 (COO), 1701, 1677 (NHCO), 1601, 1580, 1520, 1490 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.77 (1H, s, NH), 9.13 (1H, s, H-5), 8.39 (2H, d, J = 8.4 Hz, C₆H₄NO₂), 8.17 (2H, d, J = 8.4 Hz, C₆H₄NO₂), 4.32 (2H, t, J = 6.9 Hz, COOCH₂CH₂CH₃), 4.28 (2H, t, J = 6.9 Hz, COOCH₂CH₂CH₃), 2.64 (3H, s, COCH₃), 2.35 (3H, s, CH₃), 1.78 (4H, m, 2 × COOCH₂CH₂CH₃), 1.03 (3H, t, J = 7.2 Hz, COOCH₂CH₂CH₃), 1.00 (3H, t, J = 7.3 Hz, COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 201.9 (COCH₃), 168.2 (COO), 167.4 (COO), 163.5 (NHCO), 150.0, 144.4, 139.8, 138.2, 137.9, 128.8, 128.5, 124.1, 120.6, 115.9 (10 × C_Ar), 68.7, 67.5 (2 × CH₂CH₂CH₃), 30.4 (COCH₃), 21.8, 21.7 (2 × CH₂CH₂CH₃), 16.6 (CH₃), 10.6, 10.3 (2 × CH₂CH₂CH₃); HREIMS m/z 488.2025 (calcd for C₂₄H₃₀N₃O₈ (M+NH₄)⁺, 488.2027).

4-Methyl 1,2-dipropyl 6-benzamido-3-(2-methoxy-2-oxoethyl)benzene-1,2,4-tricarboxylate (4Cf): pale brown powder (xylene); mp 130.9–134.4 °C; IR ν_max 3328 (N–H), 2953 (H–C-sp³), 1731, 1720 (COO), 1685 (NHCO), 1576, 1523, 1492 1434 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.25 (1H, s, NH), 9.46 (1H, s, H-5), 8.00 (2H, m, Ph), 7.59 (1H, m, Ph), 7.54 (2H, m, Ph), 4.29 (2H, t, J = 6.9 Hz, COOCH₂CH₂CH₃), 4.24 (2H, t, J = 6.9 Hz, COOCH₂CH₂CH₃), 4.07 (2H, s, CH₂COOCH₃), 3.93 (3H, s, COOCH₃), 3.68 (3H, s, COOCH₃), 1.75 (4H, m, 2 × COOCH₂CH₂CH₃), 0.987 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃), 0.985 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 170.8, 167.8, 167.1, 166.5, 165.5 (5 × CO), 139.2, 137.5, 135.2, 134.1, 132.4, 129.0, 127.5, 127.3, 124.3, 118.2 (10 × C_Ar), 68.6, 67.7 (2 × CH₂CH₂CH₃), 52.8, 52.1 (2 × COOCH₃), 35.6 (CH₂), 21.8, 21.7 (2 × CH₂CH₂CH₃), 10.5, 10.4 (2 × CH₂CH₂CH₃); HREIMS m/z 500.1917 (calcd for C₂₆H₃₀NO₉ (M+H)⁺, 500.1915).

Dipropyl 6-benzamido-2,3-dihydro-1H-indene-4,5-dicarboxylate (4Cg): isolated by two rounds of column chromatography (first column was petroleum ether/EtOAc = 3:1, second column was petroleum ether/EtOAc = 4:1), orange waxy solid (petroleum ether/EtOAc); IR ν_max 3330 (N–H), 2962 (H–C-sp³), 1723 (COO), 1676 (NHCO), 1589, 1525, 1491, 1454, 1433 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.26 (1H, s, NH), 8.73 (1H, s, H-7), 8.00 (2H, m, Ph), 7.56 (1H, m, Ph), 7.52 (2H, m, Ph), 4.25 (4H, t, J = 6.8 Hz, 2 × COOCH₂CH₂CH₃), 3.01 (2H, t, J = 7.5 Hz), 2.95 (2H, t, J = 7.5 Hz), 2.12 (2H, deg. dt, J = 7.5 Hz) (3 × CH₂), 1.75 (4H, m, 2 × COOCH₂CH₂CH₃), 1.02 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃), 0.98 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.5 (COO), 168.3 (COO), 165.4 (NHCO), 151.2, 139.0, 137.8, 134.6, 132.0, 131.2, 128.8, 127.3, 118.6, 113.8 (10 × C_Ar), 67.8, 67.1 (2 × CH₂CH₂CH₃), 33.6, 31.6, 25.0 (3 × CH₂), 22.0, 21.7 (2 × CH₂CH₂CH₃), 10.6, 10.4 (2 × CH₂CH₂CH₃); HREIMS m/z 410.1959 (calcd for C₂₄H₂₈NO₅ (M+H)⁺, 410.1962).

Diisopropyl 5-benzamido-4′-methoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Da): off-white powder (petroleum ether/MeOH); mp 132.2–135.3 °C; IR ν_max 3351 (N–H), 2979 (H–C-sp³), 1721 (COO), 1694, 1672 (NHCO), 1605, 1581, 1525, 1509, 1492, 1464, 1401 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.47 (1H, s, NH), 8.78 (1H, s, H-6), 7.99 (2H, m, Ph), 7.53 (3H, m, Ph), 7.27 and 6.95 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 5.33 (1H, hept, J = 6.1 Hz, COOCH(CH₃)₂), 5.26 (1H, hept, J = 6.1 Hz, COOCH(CH₃)₂), 3.86 (3H, s, OCH₃), 2.21 (3H, s, CH₃), 1.42 (6H, d, J = 6.3 Hz, COOCH(CH₃)₂), 1.39 (6H, d, J = 6.3 Hz, COOCH(CH₃)₂); ¹³C NMR (CDCl₃, 126 MHz) δ 168.6 (COO), 167.3 (COO), 165.4 (NHCO), 159.2, 147.9, 138.2, 136.7, 134.8, 132.8, 132.0, 130.3, 128.8, 127.7, 127.3, 123.3, 113.7, 113.5 (14 × C_Ar), 70.6, 69.4 (2 × CH(CH₃)₂), 55.4 (OCH₃), 21.8, 21.6 (2 × CH(CH₃)₂), 17.1 (CH₃); HREIMS m/z 490.2226 (calcd for C₂₉H₃₂NO₆ (M+H)⁺, 490.2224).

Diisopropyl 4-acetyl-6-benzamido-3-methylphthalate (4Db): isolated by column chromatography (petroleum ether/EtOAc = 3:1), pale yellow powder (petroleum ether); mp 117.3–118.9 °C; IR ν_max 3350 (N–H), 2981 (H–C-sp³), 1724 (COO), 1702, 1674 (NHCO), 1604, 1580, 1528, 1494, 1439, 1403 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.40 (1H, s, NH), 9.15 (1H, s, H-5), 7.99 (2H, m, Ph), 7.59 (1H, m, Ph), 7.53 (2H, m, Ph), 5.32 (1H, hept, J = 6.3 Hz, COOCH(CH₃)₂), 5.24 (1H, hept, J = 6.2 Hz, COOCH(CH₃)₂), 2.63 (3H, s, COCH₃), 2.36 (3H, s, CH₃), 1.41 (6H, d, J = 6.3 Hz, COOCH(CH₃)₂), 1.38 (6H, d, J = 6.3 Hz, COOCH(CH₃)₂); ¹³C NMR (CDCl₃, 126 MHz) δ 202.2 (COCH₃), 167.8 (COO), 166.7 (COO), 165.7 (NHCO), 143.9, 138.3, 137.7, 134.4, 132.3, 128.9, 128.1, 127.3, 120.8, 116.6 (10 × C_Ar), 71.2, 69.7 (2 × CH(CH₃)₂), 30.4 (COCH₃), 21.8, 21.5 (2 × CH(CH₃)₂), 16.4 (CH₃); HREIMS m/z 426.1912 (calcd for C₂₄H₂₈NO₆ (M+H)⁺, 426.1911).

Dibutyl 5-benzamido-4′-methoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Ea): isolated by two rounds of column chromatography (first column was petroleum ether/EtOAc = 3:1, second column was petroleum ether/EtOAc = 10:1), orange oil (petroleum ether/EtOAc); IR ν_max 3297 (N–H), 2959 (H–C-sp³), 2873, 1730 (COO), 1676 (NHCO), 1579, 1507, 1491, 1462, 1403 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.49 (1H, s, NH), 8.81 (1H, s, H-6), 8.00 (2H, m, Ph), 7.53 (3H, m, Ph), 7.28 and 6.96 (2H each, AA’XX’, J = 8.6 Hz, C₆H₄OCH₃), 4.34 (2H, t, J = 6.9 Hz, COOCH₂CH₂CH₂CH₃), 4.31 (2H, t, J = 6.7 Hz, COOCH₂CH₂CH₂CH₃), 3.86 (3H, s, OCH₃), 2.20 (3H, s, CH₃), 1.74 (4H, m, 2 × COOCH₂CH₂CH₂CH₃), 1.45 (4H, m, 2 × COOCH₂CH₂CH₂CH₃), 0.973 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₂CH₃), 0.965 (3H, t, J = 7.4 Hz, COOCH₂CH₂CH₂CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.3 (COO), 167.8 (COO), 165.5 (NHCO), 159.2, 148.1, 138.3, 136.6, 134.7, 132.7, 132.0, 130.3, 128.8, 127.8, 127.3, 123.4, 113.7, 113.2 (14 × C_Ar), 66.3, 65.5 (2 × CH₂CH₂CH₂CH₃), 55.4 (OCH₃), 30.6, 30.4 (2 × CH₂CH₂CH₂CH₃), 19.4, 19.1 (2 × CH₂CH₂CH₂CH₃), 17.3 (CH₃), 13.8, 13.7 (2 × CH₂CH₂CH₂CH₃); HREIMS m/z 518.2530 (calcd for C₃₁H₃₆NO₆ (M+H)⁺, 518.2537).

Bis(2-methoxyethyl) 4-benzamido-[1,1′-biphenyl]-2,3-dicarboxylate (4Fa): isolated by column chromatography (petroleum ether/EtOAc = 1:1), yellow oil (petroleum ether/EtOAc); IR ν_max 3334 (N–H), 2284 (H–C-sp³), 1725 (COO), 1681 (NHCO), 1584, 1515, 1488, 1447, 1396 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.19 (1H, s, NH), 8.90 (1H, d, J = 8.8 Hz, H-5 or H-6), 8.02 (2H, m), 7.55 (4H, m), 7.38 (5H, m) (2 × Ph and H-5 or H-6), 4.47 (2H, m, COOCH₂CH₂OCH₃), 4.15 (2H, m, COOCH₂CH₂OCH₃), 3.63 (2H, m, COOCH₂CH₂OCH₃), 3.31 (3H, s, COOCH₂CH₂OCH₃), 3.26 (2H, m, COOCH₂CH₂OCH₃), 3.23 (3H, s, COOCH₂CH₂OCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.2 (COO), 167.6 (COO), 165.6 (NHCO), 139.4, 139.3, 135.6, 135.1, 134.7, 134.5, 132.2, 128.9, 128.7, 128.2, 127.7, 127.4, 122.2, 115.4 (14 × C_Ar), 69.74, 69.70, 65.4, 64.4 (2 × OCH₂CH₂O), 58.9, 58.8 (2 × OCH₃); HREIMS m/z 478.1855 (calcd for C₂₇H₂₈NO₇ (M+H)⁺, 478.1860).

Bis(2-methoxyethyl) 5-benzamido-4′-methoxy-2-methyl-[1,1′-biphenyl]-3,4-dicarboxylate (4Fb): isolated by column chromatography (petroleum ether/EtOAc = 1:1), white powder (Et₂O); mp 86.9–88.8 °C; IR ν_max 3362 (N–H), 2886 (H–C-sp³), 1722 (COO), 1671 (NHCO), 1603, 1579, 1525, 1508, 1493, 1454, 1403 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.34 (1H, s, NH), 8.80 (1H, s, H-6), 7.99 (2H, m, Ph), 7.56 (1H, m, Ph), 7.51 (2H, m, Ph), 7.27 and 6.96 (2H each, AA’XX’, J = 8.7 Hz, C₆H₄OCH₃), 4.50 (4H, m, 2 × COOCH₂CH₂OCH₃), 3.86 (3H, s, OCH₃), 3.71 (2H, m, COOCH₂CH₂OCH₃), 3.68 (2H, m, COOCH₂CH₂OCH₃), 3.39 (3H, s, COOCH₂CH₂OCH₃), 3.37 (3H, s, COOCH₂CH₂OCH₃), 2.22 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 169.1 (COO), 167.5 (COO), 165.5 (NHCO), 159.2, 148.3, 138.3, 136.3, 134.7, 132.7, 132.0, 130.3, 128.8, 128.2, 127.3, 123.5, 113.7, 113.1 (14 × C_Ar), 70.2, 69.9, 65.3, 64.6 (2 × OCH₂CH₂O), 59.0, 58.9 (2 × OCH₃), 55.4 (ArOCH₃), 17.2 (CH₃); HREIMS m/z 522.2115 (calcd for C₂₉H₃₂NO₈ (M+H)⁺, 522.2122).

1,2-Bis(2-methoxyethyl) 4-methyl 6-benzamido-3-methylbenzene-1,2,4-tricarboxylate (4Fc): isolated by column chromatography (petroleum ether/EtOAc = 1:1), off-white powder (petroleum ether); mp 84.8–86.3 °C; IR ν_max 3259 (N–H), 2883 (H–C-sp³), 1737, 1722 (COO), 1677 (NHCO), 1601, 1579, 1521, 1492, 1435, 1400 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 11.11 (1H, s, NH), 9.25 (1H, s, H-5), 7.99 (2H, m, Ph), 7.58 (1H, m, Ph), 7.52 (2H, m, Ph), 4.50 (4H, m, 2 × COOCH₂CH₂OCH₃), 3.94 (3H, s, COOCH₃), 3.70 (2H, m, COOCH₂CH₂OCH₃), 3.66 (2H, m, COOCH₂CH₂OCH₃), 3.39 (3H, s, COOCH₂CH₂OCH₃), 3.34 (3H, s, COOCH₂CH₂OCH₃), 2.49 (3H, s, CH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 168.1, 167.1, 167.0, 165.6 (3 × COO, NHCO), 137.9, 137.0, 136.0, 134.3, 132.3, 130.9, 128.9, 127.4, 123.4, 117.3 (10 × C_Ar), 70.1, 69.7, 65.7, 64.8 (2 × OCH₂CH₂O), 59.0, 58.9 (2 × OCH₃), 52.6 (COOCH₃), 16.9 (CH₃); HREIMS m/z 474.1748 (calcd for C₂₄H₂₈NO₉ (M+H)⁺, 474.1759).

Dimethyl 2-(4-benzamido-2,3-bis(methoxycarbonyl)phenyl)furan-3,4-dicarboxylate (6): isolated by column chromatography (petroleum ether/EtOAc = 1:1), light yellow powder (CDCl₃); mp 166.0–169.4 °C; IR ν_max 3323 (N–H), 3151, 2949 (H–C-sp³), 1730 (COO), 1710, 1677 (NHCO), 1616, 1586, 1549, 1516 cm^–1; ¹H NMR (CDCl₃, 500 MHz) δ 11.21 (1H, s, NH), 8.97 (1H, d, J = 8.9 Hz, H-5′ or H-6′), 8.00 (2H, m, Ph), 7.95 (1H, s, H-5), 7.77 (1H, s, J = 8.9 Hz, H-5′ or H-6′), 7.60 (1H, m, Ph), 7.54 (3H, m, Ph), 3.91 (3H s), 3.87 (3H, s), 3.78 (3H, s), 3.76 (3H, s) (4 × COOCH₃); ¹³C NMR (CDCl₃, 126 MHz) δ 167.7, 167.6, 165.6, 162.9, 162.0 (4 × COO, NHCO), 153.7, 147.1, 141.2, 135.5, 135.3, 134.1, 132.5, 129.0, 127.4, 122.2, 122.0, 119.6, 116.1, 115.8 (10 × C_Ar, 4 × C_Fur), 53.3, 52.9, 52.4, 52.1 (4 × COOCH₃); HREIMS m/z 496.1232 (calcd for C₂₅H₂₂NO₁₀ (M+H)⁺, 496.1238).

3.3. Theoretical Calculations

Quantum–chemical calculations were carried out using ORCA 6.0 software [49]. We used the ωB97X-D4 range-separated hybrid functional [50] with DFT-D4 dispersion correction for van der Waals interactions [51] and the def2-TZVP basis set [52] along with the def2/J auxiliary basis set [53] for the RIJCOSX approximation for geometry optimization. The ωB97X functional is accurate for modelling systems with π stacking, van der Waals interactions, and dispersion effects. Due to its good cost/accuracy ratio, it is a recommended choice for the determination of geometry optimized structures and frequencies [54]. It has also been evaluated in Diels–Alder reactions [55]. The self-consistent field (SCF) energy convergence threshold was set to $1·{10}^{-8}$ Ha. Solvation effects were accounted for using a conductor-like polarizable continuum model (CPCM) [56] with a dielectric constant and refractive index of xylene of 2.399 and 1.4995, respectively. Thermodynamic functions were calculated at 298.15 K and 1.00 atm assuming ideal gas behaviour and treating all vibrations as harmonic. The standard Gibbs free energy was corrected for electronic energy; a domain-based local-pair natural orbital coupled cluster theory with single, double, and perturbative triple excitations (DLPNO-CCSD(T)) [57] with the def2-TZVPP [52] basis set and def2-TZVPP/C auxiliary basis set [58] was used to determine the electronic energies of the optimized structures. A method of Nudged Elastic Band with transition state optimization (TS-NEB) [59] was used to find the transition state structures. Vibrational frequencies were calculated for all nuclear geometry optimizations in order to check whether they were stable minima or transition states. The ground-state molecular geometries were characterized by the absence of imaginary (negative) frequencies, while the transition states were characterized by a single imaginary frequency. For all transition states, the values of the imaginary frequency are given in the Supporting Information. The number of intermediate images and images free to move was set to 8. Images were calculated using the limited-memory BFGS (L-BFGS) optimizer. The maximum allowed step size was set to 0.10 Bohr and a maximum force of $2·{10}^{-3}$ Ha/Bohr was set as the convergence parameter for climbing image. The highest-energy image from the NEB calculation was used to optimize the transition state. An intrinsic reaction coordinate (IRC) path was calculated using Morokuma et al.’s method implemented in ORCA. The global electron density transfer (GEDT) [44,46] at the transition structure was calculated from the sum of the Hirshfeld charges of the atoms belonging to the dienophile part. The absolute values and the electron density flux are given in the figures in the Supporting Information.

4. Conclusions

We have shown that the cycloadditions between various 3-acylamino-2H-pyran-2-one derivatives 1a–ag and dialkyl acetylenedicarboxylates 2 acting as dienophiles yield substituted dialkyl 3-acylaminophthalic esters 4 (61 examples, 43 novel compounds, yields 3–87%, average yield 56%, median yield 60%). The reactions take place in two steps: initial [4+2] cycloaddition yields the oxabicyclo[2.2.2]octadiene intermediates 3 (that are not isolated, corroborated by the results of the computational study as well), and the second step being an irreversible elimination of carbon dioxide via retro-hetero-Diels–Alder reaction, providing 4. However, the reaction conditions to achieve appropriate conversions (above 95% in most cases) are rather harsh: heating at 190 °C in xylene for prolonged reaction times (up to 58 h, average time 9.4 h, median time 8 h). However, in some cases, even this was insufficient (for 4Ax and 4Az, 42 and 40 h, respectively, with only 60–70% conversion; for 4Fa and 4Fc, 28 h with only 85% conversion).

To elucidate the reactivity of various 2H-pyran-2-ones 1, the reactions (at 170 °C) were stopped after 90 min: conversions above 90% were reached only by two 2H-pyran-2-one derivatives (1u and 1aa); slightly lower conversions (75–85%) were achieved by 1l, 1m and 1ad. These observations are somewhat unexpected, as those 2H-pyran-2-ones 1 that were presumably the most electron-rich (such as 1l having a 4-methoxyphenyl substituent) were not the most reactive. Additionally, the position of the electron-donating group on the 2H-pyran-2-one ring strongly influenced their reactivity: in the case of 1d having the same electron-donating group as 1l, the change in its position from C-4 (in 1l) to C-5 (in 1d) decreased the conversion from 75–85% to only 15–25%, making 1d even less reactive than electron-deficient examples, such as 1p (having a 4-acetyl substituent), where the conversions were 25–35%. However, these reactivity differences, observed experimentally, were also confirmed by computational calculations and explained by the electron delocalization that disturbs the 1,3-diene character of these 2H-pyran-2-ones 1. This effect is most important in 6-substituted 2H-pyran-2-ones (for example, extremely low reactivity of 1d). The perturbing effects are even more pronounced in those 2H-pyran-2-ones 1 that contain substituents on positions 5 and 6, where one is electron-donating and the other electron-withdrawing, thus exerting electronic push–pull effects (such as 1x).

A special case was observed with furyl-substituted 2H-pyran-2-one 1h, where cycloaddition of dimethyl acetylenedicarboxylate (2A) produced two different products: not only the 2H-pyran-2-one system was reacting as a diene (thus yielding 4Ah), but also the furan ring reacted with acetylenedicarboxylate 2A; however, intermediate 5 extruded a molecule of acetylene (via an irreversible retro-Diels–Alder reaction) thus yielding 6 as the other final product. We were able to fine-tune the necessary reaction conditions to be able to prepare and isolate either of the two products (4Ah and 6), albeit in low yields due to the complications with isolation and purification. It is of interest to note that the reactivity of the furan ring in 1h with diethyl acetylenedicarboxylate (2B) was not sufficient to be able to isolate product type 6; additionally, the cycloadducts on the thiophene ring (in 1i and 1af) with any of the acetylenes (2A–C) could also not be detected.