Flexible Entry into 3-Arylpent-2-enedioic Acids via Heck–Matsuda Arylation of Dimethyl Glutaconate with Arenediazonium Tosylates

Key words

arylpent-2-enedioic acids - glutaconic acid - diazonium tosylate - Pd-catalyzed coupling - regiospecificity - ester hydrolysis - imide synthesis

The potential of 3-arylpent-2-enedioic acids 1 (hereafter referred to as 3-arylglutaconic acids) as building blocks for synthetic chemistry is illustrated by the synthesis of benzothiophene-fused pyranones 2,[2] 1,2-benzodiazepin­ones 3,[3] 4-aryl-2-pyridones 4,[4] and polysubstituted benz­enes 5 [5] (Scheme [1]).

Scheme 1 Illustrative uses of 3-arylglutaconic acids as building blocks in organic synthesis

In our research program directed at developing selective inhibitors of selenocycteine enzyme thioredoxin reductase (TrxR),[6] we envisioned 3-arylglutaconic imides 6 (possibly derived from (E)-1 [7]) to act as potential Michael acceptors for the reactive selenol of the Sec (selenocysteine) residue[8] whose reactivity can be tuned so as not to affect the abundant group of enzymes where cysteine (Cys, i.e., the less reactive thiol) is crucial for catalytic activity. While examples of β-alkyl,β-aryl-substituted Michael acceptors similar to 6 reacting with thiol nucleophiles are known,[9] the electrophilicity of 6 is likely to depend strongly on the nature of the Ar and R substituents. Thus, if these substituents are varied within a wide range, a situation where 6 does not react with thiols but continues to form adducts with selenols, can be identified (Scheme [2]).

Scheme 2 3-Arylglutaconic imides 6 as Michael acceptors with tunable reactivity

However, while the range of available primary amines (both aromatic and aliphatic) is distinctly wide, only seventeen 3-arylglutaconic acids 1 are registered in SciFinder as commercially available[10] and those exclusively contain electron-rich aryl groups. The known methods for the preparation of 1 are limited, on the one hand, to Fridel–Crafts-type alkylation of electron-rich aromatics with keto acid 7 (generated, in turn, from oxidation–decarboxylation of citric acid under the reaction conditions).[11] While this method is relatively straightforward (and is, therefore, reflected by the products in the commercial domain), its scope is clearly limited to the introduction of electron-rich aromatic groups. An alternative method,[12] potentially allowing for greater diversity of aromatic groups in 1, involves conjugate addition of dimethyl malonate anion to 3-arylpropiolic acid esters 8 followed by global hydrolysis and decarboxylation. Direct arylation of glutaconic acid, which would offer the level of flexibility varying the pendant aryl groups in 1 (and, ultimately, in 6), is lacking in the literature (Scheme [3]).

Scheme 3 Two approaches to 3-arylglutaconic acids 1 featured in the literature at the onset of this study, and the direct arylation approach investigated in this work

In this work, we set off to investigate the Heck[13] arylation of glutaconic acids with arenediazonium species,[14] which has been amply exemplified for a number of β-substituted acrylates.[15] Herein, we present the results of our study.

Arenediazonium salts were recognized by Matsuda and co-workers as exceptionally reactive partners for the Heck reaction.[16] This finding not only linked the Matsuda–Heck reaction to a vaster (compared to that of aryl halides and triflates) reagent space of commercially available anilines but also extended the reaction’s scope to include partners previously considered poorly reactive or altogether unreactive (such as β-substituted acrylates, vide supra).[17]

In terms of selecting a suitable counterion for the arenediazonium cations, our efforts were guided by the recently reported convenient preparation and use of arenediazonium tosylates.[18] Not only are they more stable toward chemical decomposition and explosion compared to conventionally used tetrafluoroborates, they are more cleanly prepared by diazotization of respective anilines in the presence of p-toluenesulfonic acid in a variety of polar organic solvents and even water.[19] Hence preparing various arenediazonium tosylates 9 and testing them in the Heck–Matsuda arylation of glutaconic acid dimethyl ester became our primary objective.

Initial experiments involving preparation of 9 demonstrated that the arenediazonium salts were sufficiently pure to be used in the Heck–Matsuda arylation step without further purification. Thus, the syntheses of 1 were planned accordingly. Treatment of aniline with tert-butyl nitrite in a 1:3 mixture of THF and glacial acetic acid led to the formation of the anticipated diazonium salt 9, which was isolated by filtration. Mild, ambient-temperature coupling of the latter with commercially available dimethyl glutaconate (sold as a ~6.7:1 mixture of E- and Z-isomers according to ¹H NMR analysis of the reagent received from the vendor) yielded, after brief fractionation on silica gel, the crude Heck–Matsuda coupling product 10. The latter was analyzed by ¹H NMR spectroscopy to reveal its sufficiently high purity (so as not to necessitate further purification prior to subsequent hydrolysis), generally excellent yield (in the range 81–98%, except for 10k whose yield was estimated to be around 50%) and higher E/Z ratio (~10:1 throughout). Without further purification and characterization, esters 10 were subjected to alkaline hydrolysis to give pure 3-arylglutaconic acids 1 in moderate to excellent yields over two steps (from dimethyl glutaconate) predominantly in the E-configured form (as assigned by NOESY spectroscopy, see the experimental section), except for products 1d, 1i, and 1o containing an o-substituted aryl group, in which the E/Z isomeric ratio was lower or even reversed (Scheme [4], Table [1]). It should be noted that attempted direct arylation of glutaconic acid did not produce satisfactory results.

Scheme 4 Preparation of 3-arylglutaconic acids 1a–p

As it is evident from examples presented in Table [1], the arylation method reported herein displays a broad scope with respect to both electron-donating and electron-withdrawing groups in the aromatic portion and a good functional group tolerance with substituents such as carboxamide 1k, ketone 1n, and primary sulfonamide 1p remaining intact and not requiring protection. The fact that the arylation products 1 are obtained as a sole E-isomer (or are significantly enriched in it) is also notable as previously reported approaches have been reported to give significantly higher proportions of the Z-isomer.[20] [21]

Table 1 3-Arylglutaconic Acids 1a–p Synthesized in this Work

Compound	Ar	Yield (%)a	E/Z ratio
1a	Ph	58b	E only
1b	4-MeOC6H4	58b	E only
1c	4-F3CC6H4	85b	E only
1d	2-MeOC6H4	46b	3:1
1e	4-FC6H4	66b	E only
1f	4-O2NC6H4	45b	E only
1g	3-O2NC6H4	55b	E only
1h	4-F3COC6H4	73b	12:1
1i	2-ClC6H4	63c	1:1.3
1j		55b	E only
1k		32b	10:1
1l		90c	20:1
1m	3,5-(F3C)2C6H3	63c	20:1
1n		57c	>20:1
1o	mesityl	89c	1:1.3
1p		82c	5:1d

^a Isolated yields over 2 steps (from dimethyl glutaconate).

^b Analytically pure product obtained as a precipitate on acidification of the alkaline solution after hydrolysis of 10.

^c Analytically pure product obtained as a precipitate on acidification of the alkaline solution after hydrolysis of 10 followed by extraction.

^d Pure E-isomer was obtained in 41% yield by crystallization from MeCN.

Having gained access to a range of E-configured 3-arylglutaconic acids 1 that had not been featured in the literature, we were keen to apply some of them in the synthesis of 3-arylglutaconic imides 6. Examples of direct 1 → 6 conversion involving direct thermal[7] or mixed anhydride[22] activation have been sporadically reported in the literature. We successfully achieved the synthesis of imides 6a–c in moderate yield from 3-arylglutaconic acids 1b, 1l, and 1o, respectively, in refluxing toluene employing azeotropic removal of water. Notably, attempts to use thermal activation[7] of dicarboxylic acids 1b and 1o toward imide formation with respective amines at 180 °C under microwave irradiation in toluene resulted in a poor yield of target imides 6a(c). The formation of the latter was accompanied by the accumulation of unwanted mixtures of decarboxylation products 7a(c) and 8a(c), as observed by ¹H NMR spectroscopy. From this mixture, pure amides 7a and 7c were isolated chromatographically and characterized (Scheme [5]). Attempted preparation of compounds 6 from diacarboxylic acids 1 using acetic anhydride[22] was similarly ineffective.

Scheme 5 Attempted (a) and successful (b) preparation of 3-arylglutaconic imides 6a–c. Reagents and conditions: a) toluene, reflux, Dean–Stark trap, 16 h; b) MW, 180 °C, toluene 1 h.

In conclusion, we have described a novel, flexible approach to 3-arylglutaconic acids via direct Heck–Matsuda arylation of dimethyl glutaconate with arenediazonium tosylate salts catalyzed by Pd(II) acetate. The method proved convenient and practically simple while displaying a wider scope with respect to the aromatic groups, compared to the previously reported approaches, and a tendency to yield E-configured products. The latter can be employed directly in the preparation of 3-arylglutaconic imides with independently variable elements of molecular periphery. These are intended as Michael acceptors with tunable reactivity as potential selective inhibitors of selenocysteine enzymes (such TrxR) not affecting the cell’s cysteinome.

NMR spectroscopic data were recorded on a 400 MHz (400.13 MHz for ¹H and 100.61 MHz for ¹³C) spectrometer in CDCl₃ and DMSO-d ₆ and were referenced to residual solvent signals (δ_H = 7.26 and 2.50; δ_C = 77.2 and 39.5, respectively). Coupling constants, J are reported in Hz. Mass spectra were recorded with a HRMS-ESI-qTOF spectrometer (electrospray ionization mode). Column chromatography was performed on silica gel 60 (230–400 mesh). Melting points were measured with SMP 50 and are not corrected. For TLC analysis UV254 silica gel coated plates were used (Merck). Dimethyl glutaconate (E/Z mixture) was purchased from Fluka and used as received. Microwave-assisted reactions were performed using Biotage Initiator+ reactor.

3-Arylglutaconic Acids 1a–p; General Procedure

To a stirred ice-cooled solution or suspension of the respective aniline (15.0 mmol) in THF (5 mL) was added a solution of p-TsOH·H₂O (3.04 g, 16.0 mmol) in glacial AcOH (15 mL). The resulting suspension was stirred for 5 min whereupon t-BuONO (2.44 mL, 22.5 mmol) was added in one portion. The mixture was stirred at 0 °C for 20 min, the ice bath was removed, and the stirring was continued for 50 min at r.t. The resulting solution was poured into Et₂O (150 mL) and the mixture was stirred for 30 min. The precipitate of 9 (crystalline in all cases except for 9d) was separated, washed with Et₂O, and dried in vacuo.

The crude aryl diazonium tosylate 9 thus obtained was dissolved or suspended in MeOH (30 mL). Dimethyl glutaconate (1.45 mL, 10.0 mmol) and Pd(OAc)₂ (112 mg, 0.5 mmol) were successively added while stirring. After stirring at r.t. for 15 h, the mixture was concentrated under reduced pressure and partitioned between CH₂Cl₂ (40 mL) and H₂O (25 mL). The organic layer was washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was briefly fractionated on SiO₂ using CH₂Cl₂ or CH₂Cl₂–acetone (5:1) as eluent. Fractions containing arylation product were pooled and concentrated to give compound 10 of at least 90% purity (according to ¹H NMR analysis). It was used in the next step without further purification.

To a stirred solution of the above compound 10 in THF (10 mL) was added a solution of NaOH (1.0 g, 25.0 mmol) (or an equiv amount of LiOH in case of 10k) in H₂O (15 mL) and the mixture was stirred at r.t. for 16 h (or 5 h in case of 10k). The resulting mixture was washed with Et₂O (30 mL) and the organic layer was extracted with H₂O (5 mL). The combined aqueous phases were acidified with concd HCl to pH ~2 and stirred in an ice bath for 1 h. The solid precipitates formed were collected by filtration, washed with ice-cold H₂O, and air-dried. The oil-like precipitates (1i, 1l–p) were extracted with EtOAc (2 × 30 mL), dried (Na₂SO₄), filtered, and evaporated to dryness to give analytically pure title compounds.

(E)-3-Phenylpent-2-enedioic Acid (1a)

Yield: 1.40 g (58%); white solid; mp 141.5–144.1 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.35 (br s, 2 H), 7.59–7.50 (m, 2 H), 7.46–7.35 (m, 3 H), 6.23 (s, 1 H, HC=), 4.13 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.7, 167.7, 150.8, 140.7, 129.6, 129.1, 126.9, 120.3, 36.3.

HRMS: m/z [M – H]^– calcd for C₁₁H₉O₄ ^–: 205.0506; found: 205.0502.

(E)-3-(4-Methoxyphenyl)pent-2-enedioic Acid (1b)

Yield: 1.48 g (58%); beige solid; mp 161.7–163.0 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.27 (br s, 2 H), 7.51 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.19 (s, 1 H, HC=), 4.12 (s, 2 H, CH₂), 3.79 (s, 3 H, OCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.9, 167.9, 160.6, 150.4, 132.7, 128.3, 118.1, 114.5, 55.7, 36.0.

HRMS: m/z [M – H]^– calcd for C₁₂H₁₁O₅ ^–: 235.0612; found: 235.0609.

(E)-3-[4-(Trifluoromethyl)phenyl]pent-2-enedioic Acid (1c)

Yield: 2.33 g (85%); pale yellow solid; mp 174.5–176.1 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.51 (br s, 2 H), 7.83–7.69 (m, 4 H), 6.31 (s, 1 H, HC=), 4.15 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.6, 167.4, 149.3, 144.9, 129.6 (q, J = 32.0 Hz), 127.8, 125.9 (q, J = 3.8 Hz), 124.6 (q, J = 271.4 Hz), 122.4, 36.3.

HRMS: m/z [M – H]^– calcd for C₁₂H₈F₃O₄ ^–: 273.0369; found: 273.0367.

(E/Z)-3-(2-Methoxyphenyl)pent-2-enedioic Acid (1d)

Yield: 1.48 g (46%); E/Z = 3:1; beige solid.

¹H NMR (400 MHz, DMSO-d ₆): δ (major, E) = 12.19 (br s, 2 H), 7.35 (ddd, J = 8.3, 7.4, 1.8 Hz, 1 H), 7.19 (dd, J = 7.5, 1.7 Hz, 1 H), 7.04 (dd, J = 8.4, 0.9 Hz, 1 H), 6.96 (td, J = 7.5, 1.0 Hz, 1 H), 5.92 (s, 1 H, HC=), 3.95 (s, 2 H, CH₂), 3.78 (s, 3 H, OCH₃); δ (minor, Z) = 7.25 (ddd, J = 8.3, 7.4, 1.8 Hz, 1 H), 7.02 (dd, J = 7.6, 1.7 Hz, 1 H), 6.98 (dd, J = 8.3, 0.9 Hz, 1 H), 6.87 (td, J = 7.4, 1.0 Hz, 1 H), 6.00 (t, J = 1.0 Hz, 1 H, HC=), 3.73 (s, 3 H, OCH₃), 3.36 (d, J = 1.0 Hz, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ (major, E) = 171.3, 167.5, 156.6, 151.1, 130.8, 130.5, 130.0, 122.6, 121.0, 112.0, 55.9, 37.7; δ (minor, Z) = 171.5, 166.7, 156.0, 147.7, 129.8, 129.4, 128.4, 123.2, 120.2, 111.5, 55.8, 44.1.

HRMS m/z [M – H]^– calcd for C₁₂H₁₁O₅ ^–: 235.0601; found: 235.0598.

(E)-3-(4-Fluorophenyl)pent-2-enedioic Acid (1e)

Yield: 1.48 g (66%); pale yellow solid; mp 150.9–151.7 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.37 (br s, 2 H), 7.64–7.54 (m, 2 H), 7.24 (t, J = 8.8 Hz, 2 H), 6.22 (s, 1 H, HC=), 4.12 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.7, 167.6, 163.1 (d, J = 246.8 Hz), 149.8, 137.1 (d, J = 3.2 Hz), 129.2 (d, J = 8.4 Hz), 120.3, 116.0, 115.8, 36.3.

HRMS: m/z [M – H]^– calcd for C₁₁H₈FO₄ ^–: 223.0401; found: 223.0401.

(E)-3-(4-Nitrophenyl)pent-2-enedioic Acid (1f)

Yield: 1.13 g (45%); yellow solid; mp 167.3–169.9 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.57 (br s, 2 H), 8.24 (d, J = 8.8 Hz, 2 H), 7.81 (d, J = 8.9 Hz, 2 H), 6.36 (s, 1 H, HC=), 4.16 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.5, 167.3, 148.7, 147.9, 147.3, 128.4, 124.1, 123.4, 36.2.

HRMS: m/z [M – H]^– calcd for C₁₁H₈NO₆ ^–: 250.0346; found: 250.0347.

(E)-3-(3-Nitrophenyl)pent-2-enedioic Acid (1g)

Yield: 1.38 g (55%); yellow solid; mp 149.3–151.6 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.56 (br s, 2 H), 8.30 (t, J = 1.9 Hz, 1 H), 8.24 (ddd, J = 8.2, 2.2, 0.8 Hz, 1 H), 8.00 (ddd, J = 7.8, 1.8, 1.0 Hz, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 6.36 (s, 1 H, HC=), 4.18 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.6, 167.3, 148.6, 148.5, 142.5, 133.5, 130.7, 124.1, 122.7, 121.6, 36.3.

HRMS: m/z [M – H]^– calcd for C₁₁H₈NO₆ ^–: 250.0346; found; 250.0345.

(E/Z)-3-[4-(Trifluoromethoxy)phenyl]pent-2-enedioic Acid (1h)

Yield: 2.12 g (73%); E/Z = 12:1; colorless solid; mp 152.7–154.2 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.44 (br s, 2 H), 7.67 (d, J = 8.9 Hz, 2 H), 7.40 (d, J = 8.2 Hz, 2 H), 6.26 (s, 1 H, HC=), 4.13 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.6, 167.5, 149.3, 149.2 (q, J = 1.8 Hz), 139.9, 129.0, 121.4, 121.3, 120.5 (q, J = 256.8 Hz), 36.3.

HRMS: m/z [M – H]^– calcd for C₁₂H₈F₃O₅ ^–: 289.0318; found: 289.0314.

(E/Z)-3-(2-Chlorophenyl)pent-2-enedioic Acid (1i)

Yield: 1.52 g (63%); E/Z 1:1.3; beige viscous oil, slowly solidified on standing.

¹H NMR (400 MHz, DMSO-d ₆): δ (E) = 9.32 (br s, 2 H, 2 × CO₂H), 7.43–7.38 (m, 1 H), 7.35–7.31 (m, 1 H), 7.30–7.25 (m, 2 H), 6.08 (s, 1 H, HC=), 4.07 (s, 2 H, CH₂); δ (Z) = 7.43–7.38 (m, 1 H), 7.32–7.29 (m, 1 H), 7.28–7.22 (m, 1 H), 7.21–7.17 (m, 1 H), 6.20 (t, J = 1.0 Hz, 1 H, HC=), 3.52 (d, J = 1.0 Hz, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ (E) = 175.8, 171.1, 152.5, 140.3, 131.4, 130.2, 130.0, 129.9, 127.0, 123.6, 38.5; δ (Z) 175.2, 169.7, 150.2, 137.2, 130.8, 129.4, 129.35, 129.32, 126.6, 123.0, 43.7.

HRMS: m/z [M – H]^– calcd for C₁₁H₈ClO₄ ^–: 239.0106; found: 239.0103.

(E)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)pent-2-enedioic Acid (1j)

Yield: 1.45 g (55%); pale beige solid; mp 206.8–208.4 °C (dec.).

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.27 (br s, 2 H), 7.10–6.98 (m, 2 H), 6.94–6.81 (m, 1 H), 6.16 (s, 1 H, HC=), 4.34–4.20 (m, 4 H), 4.09 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.8, 167.8, 150.1, 144.9, 143.7, 133.7, 120.1, 118.6, 117.6, 115.6, 64.7, 64.5, 36.0.

HRMS: m/z [M – H]^– calcd for C₁₃H₁₁O₆ ^–: 263.0550; found: 263.0559.

(E/Z)-3-[4-(Piperidine-1-carbonyl)phenyl]pent-2-enedioic Acid (1k)

Yield: 1.02 g (32%); E/Z = 10:1; colorless solid; mp 158.6–159.6 °C (dec.).

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.41 (br s, 2 H), 7.59 (d, J = 8.3 Hz, 2 H), 7.40 (d, J = 8.3 Hz, 2 H), 6.28 (s, 1 H, HC=), 4.13 (s, 2 H, CH₂), 3.58 (br s, 2 H), 3.29 (br s, 2 H), 1.75–1.35 (m, 6 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.7, 168.8, 167.6, 150.0, 141.4, 137.5, 127.4, 126.9, 121.0, 48.4 (br s), 42.8 (br s), 36.2, 26.4 (br s), 25.7 (br s), 24.5.

HRMS: m/z [M – H]^– calcd for C₁₇H₁₈NO₅ ^–: 316.1179; found: 316.1176.

(E)-3-{4-[(3r,5r,7r)-Adamantan-1-yl]phenyl}pent-2-enedioic Acid (1l)

Yield: 3.06 g (90%); pale beige solid; mp 204.0–206.8 °C (dec.).

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.32 (br s, 2 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.39 (d, J = 8.7 Hz, 2 H), 6.23 (s, 1 H, HC=), 4.12 (s, 2 H, CH₂), 2.08–2.04 (m, 3 H), 1.88–1.85 (m, 6 H), 1.77–1.72 (m, 6 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.8, 167.8, 152.5, 150.6, 137.7, 126.7, 125.5, 119.3, 42.9, 36.6, 36.2, 36.1, 28.7.

HRMS: m/z [M – H]^– calcd for C₂₁H₂₃O₄ ^–: 339.1602; found: 339.1600.

(E/Z)-3-[3,5-Bis(trifluoromethyl)phenyl]pent-2-enedioic Acid (1m)

Yield: 2.15 g (63%); E/Z = 20:1; colorless solid; mp 164.1–165.7 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.59 (br s, 2 H), 8.18 (s, 2 H), 8.12 (s, 1 H), 6.44 (s, 1 H, HC=), 4.24 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.7, 167.2, 147.7, 143.7, 131.0 (q, J = 33.0 Hz), 128.1–127.6 (m), 124.0, 123.7 (q, J = 273.0 Hz), 123.3–122.6 (m), 36.2.

HRMS: m/z [M – H]^– calcd for C₁₃H₇F₆O₄ ^–: 341.0243; found: 341.0234.

(E)-3-(3-Acetylphenyl)pent-2-enedioic Acid (1n)

Yield: 1.41 g (57%); pale beige solid; mp 160.0–162.0 °C (dec.).

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.43 (br s, 2 H), 8.05 (t, J = 1.8 Hz, 1 H), 8.01–7.94 (m, 1 H), 7.80 (ddd, J = 7.9, 1.8, 1.0 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 6.32 (s, 1 H, HC=), 4.17 (s, 2 H, CH₂), 2.62 (s, 3 H, COCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 198.2, 171.7, 167.5, 150.1, 141.2, 137.6, 131.5, 129.6, 129.2, 126.4, 121.4, 36.3, 27.3.

HRMS: m/z [M – H]^– calcd for C₁₃H₁₁O₅ ^–: 247.0601; found: 247.0601.

(E/Z)-3-Mesitylpent-2-enedioic Acid (1o)

Yield: 2.21 g (89%); E/Z = 1:1.3; colorless solid.

¹H NMR (400 MHz, DMSO-d ₆): δ (E) = 12.27 (br s, 2 H, 2 × CO₂H), 6.85 (s, 2 H), 5.72 (s, 1 H, HC=), 3.73 (s, 2 H, CH₂), 2.21 (s, 3 H), 2.18 (s, 6 H); δ (Z) = 12.27 (br s, 2 H, 2 × CO₂H), 6.80 (s, 2 H), 6.14 (t, J = 1.3 Hz, 1 H, HC=), 3.18 (d, J = 1.3 Hz, 2 H, CH₂), 2.21 (s, 3 H), 2.09 (s, 6 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ (E) = 171.0, 167.3, 151.3, 139.1, 136.9, 136.7, 128.7, 123.8, 39.8, 20.9, 20.1; δ (Z) = 171.2, 166.3, 150.0, 135.9, 134.5, 133.6, 128.2, 122.4, 44.3, 21.0, 19.6.

HRMS: m/z [M – H]^– calcd for C₁₄H₁₅O₄ ^–: 247.0965; found: 247.0968.

(E)-3-(4-Sulfamoylphenyl)pent-2-enedioic Acid (1p)

Yield: 2.34 g (82%); E/Z = 5:1; colorless solid; pure E-diastereomer was isolated after recrystallization of diastereomeric mixture from MeCN; yield: 1.17 g (41%), colorless solid; mp 275.2–280.0 °C (dec.).

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.47 (br s, 2 H), 7.84 (d, J = 8.6 Hz, 2 H), 7.72 (d, J = 8.6 Hz, 2 H), 7.41 (s, 2 H, SO₂NH₂), 6.30 (s, 1 H, HC=), 4.15 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.6, 167.4, 149.5, 144.7, 144.0, 127.6, 126.4, 122.1, 36.2.

HRMS: m/z [M – H]^– calcd for C₁₁H₁₀NO₆S^–: 284.0223; found: 284.0221.

3-Arylglutaconic Imides 6a–c; General Procedure

To a solution of amine (1.1 mmol) in toluene (30 mL) was added diacid 1b, 1l, or 1o (1 mmol) and the mixture was heated at reflux with a Dean–Stark trap for 16 h. Upon cooling to r.t., the mixture was concentrated and the respective title compound was isolated using flash column chromatography on silica gel eluting with CHCl₃.

1-(Furan-2-ylmethyl)-4-(4-methoxyphenyl)pyridine-2,6(1H,3H)-dione (6a)

Yield: 127 mg (43%); orange foam.

¹H NMR (400 MHz, CDCl₃): δ = 7.62–7.42 (m, 2 H), 7.34 (dd, J = 2.0, 0.9 Hz, 1 H), 7.10–6.77 (m, 2 H), 6.58 (t, J = 1.5 Hz, 1 H), 6.37 (dd, J = 3.2, 0.8 Hz, 1 H), 6.32 (dd, J = 3.3, 1.8 Hz, 1 H), 5.11 (s, 2 H), 3.87 (s, 3 H), 3.82 (d, J = 1.4 Hz, 2 H).

¹³C NMR (101 MHz, CDCl₃): δ = 169.5, 165.2, 161.9, 150.2, 148.5, 142.0, 127.4, 127.2, 114.7, 114.6, 110.4, 109.0, 55.5, 36.0, 35.3.

HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₆NO₄: 298.1074; found: 298.1064.

4-[4-(Adamantan-1-yl)phenyl]-1-(4-methoxybenzyl)pyridine-2,6(1H,3H)-dione (6b)

Yield: 197 mg (45%); light yellow foam.

¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.38 (m, 6 H), 6.86 (d, J = 8.7 Hz, 2 H), 6.62 (d, J = 1.5 Hz, 1 H), 5.04 (s, 2 H), 3.82 (d, J = 1.6 Hz, 2 H), 3.80 (s, 3 H), 2.14 (pent, J = 3.1 Hz, 3 H), 1.94 (d, J = 2.9 Hz, 6 H), 1.87–1.74 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃) δ = 169.9, 165.7, 159.0, 154.7, 148.9, 132.1, 130.7, 129.3, 125.7, 125.6, 116.2, 113.7, 55.2, 42.9, 41.9, 36.7, 36.5, 36.1, 28.8.

HRMS: m/z [M + H]⁺ calcd for C₂₉H₃₂NO₃: 442.2377; found: 442.2373.

1-Isopentyl-4-mesitylpyridine-2,6(1H,3H)-dione (6c)

Yield: 146 mg (49%); beige foam.

¹H NMR (400 MHz, CDCl₃): δ = 6.93 (s, 2 H), 6.10 (t, J = 1.7 Hz, 1 H), 4.00–3.76 (m, 2 H), 3.48 (d, J = 1.7 Hz, 2 H), 2.32 (s, 3 H), 2.20 (s, 6 H), 1.76–1.58 (m, 1 H), 1.58–1.43 (m, 2 H), 1.00 (d, J = 6.6 Hz, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 170.0, 165.2, 152.9, 138.2, 133.9, 133.8, 128.6, 122.0, 38.5, 38.1, 36.7, 26.4, 22.5, 21.0, 19.6.

HRMS: m/z [M + H]⁺ calcd for C₁₉H₂₆NO₂: 300.1958; found: 300.1968.

Microwave-Assisted Reaction of Dicarboxylic Acids 1b and 1o with Amines

A mixture dicaboxylic acid 1b or 1o (1 mmol) and amine (see below) (1 mmol) in toluene (3 mL) was heated at 180 °C for 1 h in a microwave reactor. Upon cooling to r.t., the reaction mixture was concentrated and subjected to column chromatography on silica eluting with CHCl₃.

Reaction of 1b with 2-furylmethaneamine afforded 37 mg (12%) of 6a and 77 mg (28%) of compounds 7a and 8a as 6.4:1 mixture (by ¹H NMR analysis). The latter was further purified by column chromatography using CHCl₃ as eluent to give 44 mg (16%) of pure 7a.

(E)-N-(Furan-2-ylmethyl)-3-(4-methoxyphenyl)but-2-enamide (7a)

Yield: 44 mg (16%); light yellow foam.

¹H NMR (400 MHz, CDCl₃): δ = 7.47–7.34 (m, 3 H), 7.02–6.61 (m, 2 H), 6.34 (dd, J = 3.3, 1.9 Hz, 1 H), 6.27 (dd, J = 3.2, 0.8 Hz, 1 H), 6.00 (q, J = 1.3 Hz, 1 H), 5.97 (br s, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 3.83 (s, 3 H), 2.57 (d, J = 1.2 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.7, 160.01, 151.6, 151.0, 142.1, 134.8, 127.4, 117.7, 113.8, 110.5, 107.4, 55.3, 36.3, 17.5.

For NOESY spectrum, see Supporting Information.

HRMS: m/z [M + Na]⁺ calcd for C₁₆H₁₇NO₃Na: 294.1101; found: 294.1127.

Reaction of 1o with isopentylamine afforded 45 mg (15%) of 6c and 108 mg (40%) of compounds 7c and 8c as 5.7:1 mixture (by ¹H NMR analysis). The latter was further purified by column chromatography using CHCl₃ as eluent to give 62 mg (23%) of pure 7c.

(E)-N-Isopentyl-3-mesitylbut-2-enamide (7c)

Yield: 62 mg (23%); light brown oil.

¹H NMR (400 MHz, CDCl₃): δ = 6.87 (s, 2 H), 5.54 (q, J = 1.5 Hz, 1 H), 5.41 (s, 1 H), 3.53–3.22 (m, 2 H), 2.39 (d, J = 1.5 Hz, 3 H), 2.29 (s, 3 H), 2.20 (s, 6 H), 1.74–1.57 (m, 1 H), 1.52–1.36 (m, 2 H), 0.96 (d, J = 6.6 Hz, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 166.5, 153.1, 140.9, 136.3, 133.9, 128.2, 121.8, 38.6, 37.7, 26.0, 22.5, 20.9, 19.6, 19.5.

For NOESY spectrum, see Supporting Information.

HRMS: m/z [M + H]⁺ calcd for C₁₈H₂₈NO: 274.2165; found: 274.2180.

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