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Article

Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles

by
Nerea Conde
,
María Teresa Herrero
,
Garazi Urgoitia
and
Raul SanMartin
*
Department of Organic and Inorganic Chemistry, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
*
Author to whom correspondence should be addressed.
Catalysts 2022, 12(2), 127; https://doi.org/10.3390/catal12020127
Submission received: 18 December 2021 / Revised: 13 January 2022 / Accepted: 17 January 2022 / Published: 21 January 2022
(This article belongs to the Special Issue Metal-Catalyzed Processes in One-Pot Syntheses of Heterocycles)
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Abstract

:
Metal-catalyzed cascade processes based on hydrofunctionalization of alkynes are receiving much more attention because of their potential to provide advantageous approaches to otherwise synthetically challenging compounds. An alternative catalyst system has been found for the domino cycloisomerization/cyclocondensation reaction involving acetylenic acids and heterodinucleophiles. A CNN pincer palladium(II) complex, acting as a homogeneous catalyst, provides the corresponding polyheterocycles with a higher substrate/catalyst ratio. Other palladium sources were also tested and discarded, and a number of mechanistic studies including poisoning assays, kinetic plots, TEM images, XRD spectra and UPLC-MS analysis of reaction intermediates were conducted in order to shed light on the role of this pincer catalyst and the catalytic cycle involved in the cascade reaction. As a result, a more nuanced mechanism is tentatively proposed.

Graphical Abstract

1. Introduction

Metal-catalyzed cascade reactions have attracted much more attention as an expeditious access to relatively complex frameworks from readily available substrates. In this regard, the construction of cyclic or polycyclic structures by means of cascade processes involving alkynes is a rapidly emerging field on account of the increasing number of reports on this topic [1,2,3,4]. A particularly appealing cascade reaction between alkynoic acids and dinucleophiles was discovered due to the elegant works by Dixon [5,6,7], Patil [8,9], Liu-Zhao [10,11,12,13,14,15,16,17], Reddy [18,19] and Lei [20]. Au(I) (often Au(I)-Ag(I)), Cu(II), and recently, Ru(II) catalysts were the key for this transformation leading to a number of polyheterocycles, including structural analogues of quinazoline alkaloids Tryptanthrine, Batracyclin, Peganine, Vasicinone, or Mackinazoline, and the inhibitor of aldo-keto reductase AKR1C3 depicted in Figure 1 [21,22]. In most cases, a plausible reaction mechanism has been proposed, suggesting an initial cycloisomerization of the alkynoic acid followed by a nucleophilic attack at the corresponding enol lactone intermediate to form a ketonamide that under acidic (Brönsted or Lewis) conditions leads to the cyclized product via an acyliminium ion intermediate (Scheme 1). A minimum amount of 0.5 mol% of metal catalyst is required to affect the cascade process (catalyst loading ranging from 0.5 to 20 mol%) [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19].
Following our research on metal-catalyzed transformations involving alkynes [23], we had described an unprecedented amount of activity for the cycloisomerization of alkynoic acids exhibited by a palladium NNC complex (1) [24]. On this basis, we envisaged that such a more active catalyst could also promote a domino process leading to polyheterocyclic structures if reacted with suitable dinucleophiles. In addition to a new metal participating in this reaction, this approach could lead to a substantial enhancement in the catalytic efficiency, which is increasingly becoming a priority in sustainable chemistry [25,26,27]. In this regard, we wish to present an exceedingly active catalyst system for the cascade reaction between alkynoic acids and N,O- and N,N-dinucleophiles as well as an insight into the reaction mechanism.

2. Results and Discussion

Pentynoic acid 2a and anthranilic acid 3a were chosen as model substrates for a number of initial assays. Different palladium sources (Pd(OAc)2, PdCl2, and Pd(PPh3)4) were tested, and the results compared to those obtained from NNC palladium complex 1. The catalyst loading was set at 10−2 mol% in order to meet the aforementioned requirements of efficiency. The amounts of base and/or additive were also minimized following the same criteria. After a number of initial experiments, it became clear that the process required chloroform as a solvent and triethylamine as a base to get reasonable yields, as negligible results were obtained from other bases (KOH, NaOH, LiOH, KOtBu, K2CO3, Cs2CO3, DBU, DIPEA, pyridine and DMAP) and solvents (THF, PhMe, MeOH, CH2Cl2, DMF, DMA, DMSO and MeCN) (see Supplementary Material for further details).
Only pincer complex 1 provided target benzopyrrolo[1,3]oxazine-1,5-dione 4a even using triethylamine in chloroform (Figure 2, entries 1–4), and the presence of a Lewis acid additive proved beneficial for the reaction outcome (entries 5–9).
With a catalytic amount (0.01 mol%) of iron(II) bromide as the most favorable additive, an increase in the reaction temperature (120 °C) led to the desired product with a good yield (79%, entry 10). We hypothesized that both the iron Lewis acid and higher temperature favored the key dehydration step. Attempts to decrease the amounts of both the catalyst and the additive (entries 11,12), and to improve the yield by adding a little excess of the alkynoic acid or changing the reaction concentration (entries 13–18) were made so that an excellent 93% yield was obtained by the optimized conditions of entry 17.
Lower temperatures or shorter reaction times (entries 19,20) provided poorer results, and a series of blank experiments proved the need of all the ingredients, including Et3N as a base and FeBr2 as an additive, along with the palladium source (entries 21–23 vs. 17). In this regard, we were surprised to find that target 4a was isolated with a yield of 86% when complex 1 was replaced with Pd(OAc)2 (entry 28). Therefore, when the optimized conditions (Figure 2, entry 21) were applied to a number of commercially or readily available (Supplementary Material) alkynoic acids 2 and heterodinucleophiles 3, Pd(OAc)2 was also evaluated as a catalyst for the reaction.
benzopyrrolo[1,3]oxazine-1,5-diones and benzopyrido[1,3]oxazine-1,6-diones 4a–e were prepared in good to excellent yields from anthranilic acid 3a and several terminal and internal alkynoic acids 2 (Figure 3). In addition to the easy formation of tetracyclic 4c from o-ethynylbenzoic acid and the high diastereoselectivity with which 2-hexylbenzo[d]pyrrolo[1,3]oxazine-1,5-dione 4b was obtained, the use of internal alkyne 5-phenylpent-4-ynoic acid to generate 3a-benzyl derivative 4e, and the preparation of pyrido[1,3]oxazine-1,6-dione 4d should be pointed out on account of the reduced reactivity of 5-hexynoic acid in comparison with pentynoic acids [28,29,30]. An even more interesting observation was that Pd(OAc)2 failed to provide target products 4b–e in acceptable yields.
The same trend was observed for the formation of benzopyrrolo[1,2,4]thiadiazin-1-one- and benzopyrido[1,2,4]thiadiazinone-5,5-dioxides 4f–h, prepared in good to excellent yields only when the system 1/FeBr2/Et3N was employed (Figure 3).
Much effort has been devoted to the synthesis of benzopyrrolo[1,2,4]thiadiazine-5,5-dioxides [31,32,33,34,35] due to their nootropic, neuroprotective and cognition-enhancing properties as positive allosteric modulators of the AMPA receptor [36,37]. With regard to 4g, it is the first benzopyrido[1,2,4]thiadiazinone-5,5-dioxide synthesized so far.
Structure analysis of monocrystals of 4a and 4e revealed that both have the same crystal system and space group (orthorrombic Pbca). The presence of the C3a quaternary center (C-11) is responsible for the lack of coplanarity of oxazine and pyrrole rings, as shown by the C1-O1-C11-N1 and C7-N1-C11-C10 torsion angle values of −53.4–39.6° and 165.1–164.4°, respectively. Only the R enantiomer of sultam 4g crystallized in the monoclinic system (Cc) leaving the other C-5 isomer in an amorphous state (Figure 4).
Several diamines 5 were also reacted with alkynoic acids 2. Palladacycle 1 catalyzed cascade process on a general basis, whereas Pd(OAc)2 did not provide most of the target tri- and tetracycles 6. In fact, only quinazolinones 6a and 6c were obtained when using the latter commercially available palladium source, although with much inferior yields (Figure 5).
As in the case of derivatives 4, the reason probably lies in the inability of palladium(II) acetate to catalyze the initial cycloisomerization step at such low catalyst levels. By using remarkably active palladacycle 1, pyrrolo-, isoindolo- and pyrido[2,1-b]quinazolinones 6a–d were regio-selectively prepared from o-aminobenzylamine 5a. As in the case of anthranilic acid 3a or 2-aminobenzenesulfonamide 3b, the use of internal alkynes did not hinder the reaction, and 3a-benzyl derivative 6d was obtained in good yield. Besides, reaction of 5a with 5-hexynoic acid provided pyrido[2,1-b]quinazolin-9-one 6c. So far, this compound had been prepared in reasonable yield only from 5-oxohexanoic acid by a Meyers’ lactamization [38].
Benzo[d]pyrrolo[1,2-a]imidazol-1-one 6a and benzo[4,5]imidazo[2,1-a]isoindol-11-one 6f (akin to AKR1C3 inhibitor in Figure 1) were prepared by reaction with o-phenylene diamine 5b. Interestingly, a higher yield was obtained for new pyrroloimidazo[4,5-b]pyridin-6-one 6g from 2,3-diaminopyridine 5c. A significantly greater anticonvulsant effect than currently marketed valproate has been described for several structurally related pyrroloimidazopyridine derivatives prepared by condensation between 2,3-diaminopyridine and 3-acylpropionic acids [39,40,41]. Considering the latter result from 5c, a comparison of the reaction yields from dinucleophiles 3a,b and 5a–c with 4-pentynoic acid 2a led to the conclusion that the reaction is favored by the use of non-symmetric dinucleophiles.
Several experiments were then carried out in order to shed light on the role of complex 1 in the reaction mechanism. Taking the reaction leading to the formation of benzopyrrolo[1,3]oxazine-1,5-dione 4a as a model example, a plot of the conversion of anthranilic acid 3a vs. time showed neither sigmoidal shape nor induction time (Figure 6).
In addition, the latter reaction was also conducted in the presence of substoichiometric and overstoichiometric amounts of a number of known poisoning agents for palladium nanoparticles and other palladium(0) heterogeneous catalysts, including the mercury drop test (Table 1). Not the slightest inhibition or poisoning effect was observed in our case, as expected for a fully homogeneous catalyst system [42,43,44,45,46,47].
Moreover, transmission electron microscopy (TEM) analysis of the reaction mixture from 3a + 2a -> 4a, combined with energy dispersive X-ray microanalysis revealed the presence of some scattered iron nanoparticles (average size 8 nm) but no trace of palladium nanoparticles (Figure 7).
UPLC-ESI analysis of a sample taken from the reaction mixture (2a + 3a -> 4a) after 12 h of reaction not only provided evidence of the presence of several transient intermediates related to the ones postulated in Scheme 1, but also of the participation of a number of palladium and iron species displayed in Scheme 2 (see Supplementary Material for further details), thus supporting our hypothesis on the crucial role of such ingredients in the cascade reaction. On the basis of the detection of the above intermediates, a revised catalytic cycle was tentatively proposed (Scheme 2). Interaction of alkynoic acid 2a with cationic 1′ to form complex A activates the alkyne for the triethylamine-promoted cycloisomerization process that generates intermediate B, which upon protonation and interaction with Lewis’s acids 1′ and FeBr2 produces transient species C. Ring-opening amidation with o-amino derivative 3a leads to activated ketoamides D, which upon cyclization form hydroxypyrrolidinones E. After dehydration, the resulting N-acyliminium intermediates F undergo a final lactamization step to provide oxazinanone derivative 4a. According to the transient species detected by ESI-mass spectrometry (Supplementary Material), it seems that although the palladium catalyst is essential to initiate the cycloisomerization step and thus to promote the reaction, the iron additive facilitates several nucleophilic addition and dehydration steps via Lewis acid activation.
Finally, methylidene lactone 7 was prepared using catalyst 1, and then reacted with anthranilic acid 3a in the presence and absence of the optimized catalyst and additives. Target benzopyrrolo[1,3]oxazine-1,5-dione 4a was obtained in good yield (90%, Scheme 3) only when both complex 1 and FeBr2 were employed, whereas reactions lacking any of these ingredients led to negligible results (yield of 4a < 15%) (see Supplementary Material for further details), thus offering further support for the proposed reaction pathway.

3. Materials and Methods

3.1. General Information

Commercially available reagents were used throughout without purification unless otherwise stated. 1H and 13C NMR spectra were recorded on a Bruker AC-300 instrument (300 MHz for 1H and 75.4 MHz for 13C) at 20 °C. Chemical shifts (d) are given in ppm downfield from Me4Si and are referenced as internal standard to the residual solvent (unless indicated) CDCl3 (d = 7.26 for 1H and d = 77.00 for 13C). Coupling constants, J, are reported in hertz (Hz). Melting points were determined in a capillary tube and are uncorrected. TLC was carried out on SiO2 (silica gel 60 F254, Merck), and the spots were located with UV light. Flash chromatography was carried out on SiO2 (silica gel 60, Merck, 230–400 mesh ASTM). Drying of organic extracts during work-up of reactions was performed over anhydrous Na2SO4. Evaporation of solvents was accomplished with a Büchi rotatory evaporator. MS spectra were recorded on an Agilent 5975 mass spectrometer under electronic impact (EI) conditions or on an Acquity UPLC-Spectrometer of Mass QTOF from Waters under electrospray ionization (ESI). HRMS were recorded using a Micromass GCT spectrometer by electronic impact (EI) or electrospray ionization (ESI). Single crystal X-ray intensity data were collected on an Agilent Technologies Super-Nova diffractometer, which was equipped with monochromated Cu kα radiation (λ = 1.54184 A) and Atlas CCD detector. A measurement was carried out at 100(2) K with the help of an Oxford Cryostream 700 PLUS temperature device. Data frames were processed (united cell determination, analytical absorption correction with face indexing, intensity data integration and correction for Lorentz and polarization effects) using the Crysalis software package [48]. The structure was solved using Olex2 [49] and refined by full-matrix least-squares with SHELXL-97 [50]. Final geometrical calculations were carried out with Mercury [51] and PLATON [52] as integrated in WinGX [53].

3.2. General Procedure for Complex 1-Catalyzed Cascade Reaction between Alkynoic Acids and Heterodinucleophiles

Alkynoic acid 2 (0.2 mmol) and heterodinucleophile 3 or 5 (0.3 mmol) were charged in a heavy-wall pressure tube at room temperature with a magnetic stir bar under argon. Then, triethylamine (0.56 µL, 4.0 × 10−3 mmol), a solution of FeBr2 (30 µL of a 0.67 M solution in CHCl3, 2 × 10−5 mmol), a solution of NNC pincer 1 (30 µL of a 0.67 M solution in CHCl3, 2 × 10−5 mmol) and CHCl3 (0.34 mL) were added, the tube closed, and the mixture was heated in an oil bath at 120 °C for 96 h. After cooling, the mixture was concentrated in vacuo and purified by flash column chromatography using hexane/ethyl acetate as eluent to provide polycyclic compounds 4/6.
3a-Methyl-3,3a-dihydro-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazine-1,5(2H)-dione (4a). The general procedure was followed, and compound 4a was obtained as colorless prisms (40.4 mg, 93%). m.p. 143–147 °C (CHCl3)(Lit. [10] 165–167 °C); Its NMR spectra were consistent with published data [10]. 1H NMR (CDCl3) δ 8.12–8.05 (m, 2H, Harom), 7.71–7.65 (m, 1H, Harom), 7.34 (t, J = 7.7 Hz, 1H, Harom), 2.84–2.37 (m, 4H, CH2), 1.70 (s, 3H, CH3). 13C NMR (CDCl3) δ 171.6 (NCO), 161.6 (COO), 136.2 (qCarom), 135.5, 130.4, 125.8, 121.1 (Carom), 116.3 (qCarom), 95.34 (qC), 32.3 (CH2), 29.4 (CH2), 24.8 (CH3).
2-Hexyl-3a-methyl-3,3a-dihydro-1H-benzo[d]pyrrolo[2,1-b][1,3]oxazine-1,5(2H)-dione, (4b). The general procedure was followed, and compound 4b was obtained as a mixture of diasteroisomers (3:1) which were separated by flash column chromatography using Hexanes:EtOAc 8:2 as eluent. Their NMR spectra were consistent with published data [10]. Diasteroisomer 4ba, colorless oil (36.3 mg, 70%); 1H NMR (CDCl3) δ 8.15 (d, J = 8.2 Hz, 1H, Harom), 8.09 (dd, J = 7.9, 1.4 Hz, 1H, Harom), 7.67 (td, J = 8.2, 1.5 Hz, 1H, Harom), 7.38–7.20 (m, 1H, Harom), 2.75–2.52 (m, 2H, CH2), 2.19–2.27 (m, 1H, CH), 2.07–1.91 (m, 1H, CH2), 1.67 (s, 3H, CH3), 1.41–1.25 (m, 9H, Halkil), 0.87 (m, 3H, CH3); 13C NMR (CDCl3) δ 173.2 (NCO), 161.5 (COO), 136.2 (qCarom), 135.5, 130.4, 125.3, 120.3 (Carom), 115.6 (qCarom), 93.4 (qC), 40.7 (CH2), 39.2 (CH), 31.5 (CH2), 30.4 (CH2), 29.0 (CH2), 26.8 (CH2), 24.3 (CH2), 22.5 (CH3), 13.9 (CH3). Diasteroisomer 4bb, yellow oil (12.7 mg, 20%); 1H NMR (CDCl3) δ 8.10 (dd, J = 7.8, 1.3 Hz, 1H, Harom), 7.85 (d, J = 8.1 Hz, 1H, Harom), 7.69 (td, J = 8.0, 1.5 Hz, 1H, Harom), 7.35 (td, J = 7.7, 1.0 Hz, 1H, Harom), 2.88–2.71 (m, 2H, Harom), 2.09–2.08 (m, 1H, CH), 2.04–1.89 (m, 1H, CH2), 1.71 (s, 3H, CH3), 1.38–1.25 (m, 9H, Halkil), 0.90 (t, J = 6.4 Hz, 3H, CH3); 13C NMR (CDCl3) δ 175.4 (NCO), 162.0 (COO), 136.4 (qCarom), 153.2, 130.2, 126.1, 122.5 (Carom), 117.7 (qCarom), 94.6 (qC), 40.6 (CH2), 38.2 (CH), 31.8 (CH2), 31.6 (CH2), 28.9 (CH2), 27.1 (CH2), 26.2 (CH2), 22.5 (CH3), 14.0 (CH3).
6a-Methyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-dione (4c). The general procedure was followed, and compound 4c was obtained as a yellow powder (46.1 mg, 87%); m.p. 138–142 °C (CHCl3)(Lit. [54] 145–148 °C (iPrOH)); Its NMR spectra were consistent with published data [15]. 1H NMR (CDCl3) δ 8.16 (dd, J = 7.9, 1.3 Hz, 1H, Harom), 8.12 (d, J = 8.2 Hz, 1H, Harom), 7.96 (d, J = 7.5 Hz, 1H, Harom), 7.81–7.71 (m, 3H, Harom), 7.68–7.61 (m, 1H, Harom), 7.40–7.35 (m, 1H, Harom), 1.95 (s, 3H, CH3); 13C-NMR (CDCl3) δ 164.7 (NCO), 162.0 (COO), 144.20, 136.2 (qCarom), 135.8, 133.9, 130.9, 130.6 (Carom), 130.0 (qCarom), 125.5, 124.7, 122. 5, 121.4 (Carom), 115.6 (qCarom), 92.6 (qC), 24.3 (CH3).
4a-Methyl-2,3,4,4a-tetrahydro-1H,6H-benzo[d]pyrido[2,1-b][1,3]oxazine-1,6-dione (4d). The general procedure was followed, and compound 4d was obtained as a white powder (28.8 mg, 61%); m.p. 70–72 °C (CHCl3)(Lit. [10] 66–68 °C); Its NMR spectra were consistent with published data [10]. 1H NMR (CDCl3) δ 8.06 (dd, J = 7.8, 1.5 Hz, 1H, Harom), 7.78 (dd, J = 8.0, 0.9 Hz, 1H, Harom), 7.64 (td, J = 7.8, 1.5 Hz, 1H, Harom), 7.35 (td, J = 8.0, 0.9 Hz, 1H, Harom), 2.72–2.53 (m, 2H, CH2), 2.49–2.35 (m, 1H, CH2), 2.21–2.01 (m, 2H, CH2), 1.96–1.79 (m, 1H, CH2), 1.62 (s, 3H, CH3); 13C NMR (CDCl3) δ 169.2 (NCO), 162.5 (COO), 138.6 (qCarom), 134.1, 129.3, 126.2, 126.1 (Carom), 120.3 (qCarom), 92.4 (qC), 36.0 (CH2), 33.4 (CH2), 26.7 (CH2), 16.6 (CH3).
3a-Benzyl-3,3a-dihydro-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazine-1,5(2H)-dione (4e). The general procedure was followed, and compound 4e was obtained as colorless prisms (43.9 mg, 75%); m.p. 142–146 °C (CHCl3); 1H NMR (CDCl3) δ 8.21 (d, J = 8.0 Hz, 1H, Harom), 8.14 (dd, J = 7.8, 1.4 Hz, 1H, Harom), 7.77 (td, J = 8.2, 1.5 Hz, 1H, Harom), 7.37 (td, J = 7.8, 0.9 Hz, 1H, Harom), 7.28 (dd, J = 6.6, 3.9 Hz, 3H, Harom), 7.04 (dd, J = 6.5, 2.9 Hz, 2H, Harom), 3.36 (d, J = 13.8 Hz, 1H, CH2), 3.11 (d, J = 13.7 Hz, 1H, CH2), 2.65–2.29 (m, 3H, CH2), 1.73–1.50 (m, 1H, CH2); 13C NMR (CDCl3) δ 172.0 (NCO), 161.4 (COO), 136.3 (qCarom), 135.9 (Carom), 133.0 (qCarom), 130.6, 129.9, 128.9, 127.9, 125.8, 120.7 (Carom), 116.3 (qCarom), 96.8 (qC), 42.6 (CH2), 30.2 (CH2), 29.5 (CH2); HRMS (m/z): [M + H]+ calc. for C18H16NO3: 294.1130; found: 294.1129.
3a-Methyl-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-1-one 5,5-dioxide (4f). The general procedure was followed, and compound 4f was obtained as colorless prisms (47.4 mg, 94%); m.p. 189–192 °C (CHCl3); 1H NMR (DMSO-d6) 8.55 (s, 1H, NH), 8.28 (dd, J = 8.4, 0.8 Hz, 1H, Harom), 7.81 (dd, J = 7.9, 1.4 Hz, 1H, Harom), 7.73–7.55 (m, 1H, Harom), 7.38 (td, J = 7.8, 1.0 Hz, 1H, Harom), 2.77 (dt, J = 17.2, 10.0 Hz, 1H, CH2), 2.31–2.18 (m, 3H, CH2), 1.58 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 172.3 (NCO), 133.6 (Carom), 132.9, 127.9 (qCarom), 125.6, 124.7, 122.2 (Carom), 78.1 (qC), 33.2 (CH2), 29.6 (CH2), 24.5 (CH3); HRMS (m/z): [M + H]+ calc. for C11H13N2O3S: 253.0647; found: 253.0640.
6a-Methyl-6a,7,8,9-tetrahydrobenzo[e]pyrido[2,1-c][1,2,4]thiadiazin-10(6H)-one 5,5-dioxide (4g). The general procedure was followed, and compound 4g was obtained as yellow prisms (33.5 mg, 63%); m.p. 196–199 °C (CHCl3); 1H NMR (CDCl3) δ 7.81 (d, J = 7.7 Hz, 1H, Harom), 7.58 (d, J = 3.7 Hz, 2H, Harom), 7.44–7.36 (m, 1H, Harom), 5.17 (bs, 1H, NH), 2.62 (t, J = 6.3 Hz, 2H, CH2), 2.23–2.06 (m, 3H, CH2), 1.95–1.80 (m, 1H, CH2), 1.52 (s, 3H, CH3); 13C NMR (CDCl3) δ 170.0 (NCO), 135.4 (qCarom), 134.5 (qCarom), 132.4, 129.3, 127.0, 123.4 (Carom), 76.1 (qC), 38.1, 33.3 (CH2), 27.6 (CH3), 16.2 (CH2); HRMS (m/z): [M + H]+ calc. for C12H15N2O3S: 267.0803; found: 267.0802.
3a-Benzyl-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-1-one 5,5-dioxide (4h). The general procedure was followed, and compound 4h was obtained as a white powder (47.9 mg, 73%); m.p. 194–196 °C (CHCl3); 1H NMR (CDCl3) δ 8.32 (d, J = 8.4 Hz, 1H, Harom), 7.80 (d, J = 7.9 Hz, 1H, Harom), 7.61 (t, J = 7.4 Hz, 1H, Harom), 7.26–7.30 (m, 4H, Harom), 7.04–7.07 (m, 2H, Harom), 5.77 (bs, 1H, NH), 3.54 (d, J = 14.1 Hz, 1H, CH2), 3.06 (d, J = 14.1 Hz, 1H, CH2), 2.55–2.46 (m, 1H, CH2), 2.24–1.99 (m, 2H, CH2), 1.46–1.31 (m, 1H, CH2); 13C NMR (CDCl3) δ 172.4 (NCO), 133.7 (Carom), 132.5 (qCarom), 130.1, 128.9 (Carom), 127.9 (qCarom), 127.8, 125.8, 124.7, 122.8 (Carom), 80.3 (qC), 42.1 (CH2), 31.3 (CH2), 29.6 (CH2); HRMS (m/z): [M + H]+ calc. for C17H17N2O3S: 329.0960; found: 329.0957.
3a-Methyl-3,3a,4,9-tetrahydropyrrolo[2,1-b]quinazolin-1(2H)-one (6a). The general procedure was followed, and compound 6a was obtained as yellow prisms (38.4 mg, 95%); m.p. 131–134 °C (CHCl3)(Lit. [8] 138–140 °C); Its NMR spectra were consistent with published data [8]. 1H NMR (CDCl3) δ 7.10–6.96 (m, 1H, Harom), 6.78 (t, J = 7.4 Hz, 1H, Harom), 6.56 (d, J = 8.0 Hz, 1H, Harom), 5.02 (d, J = 16.9 Hz, 1H, CH2), 4.17 (d, J = 16.8 Hz, 1H, CH2), 3.83 (bs, 1H, NH), 2.59–2.48 (m, 2H, CH2), 2.25–1.97 (m, 2H, CH2), 1.54 (s, 3H, CH3); 13C NMR (CDCl3) δ 174.2 (NCO), 141.8 (qCarom), 127.6, 126.9, 119.3 (Carom), 117.4 (qCarom), 116.4 (Carom), 71.9 (qC), 38.6 (CH2), 32.9 (CH2), 29.5 (CH2), 25.6 (CH3).
4b-Methyl-5,10-dihydroisoindolo[1,2-b]quinazolin-12(4bH)-one (6b). The general procedure was followed, and compound 6b was obtained as a brown powder (41.0 mg, 82%); m.p. 190–194 °C (CHCl3)(Lit. [8] 222–224 °C); Its NMR spectra were consistent with published data [8]. 1H NMR (CDCl3) δ 7.88 (d, J = 7.4 Hz, 2H, Harom), 7.63 (d, J = 4.0 Hz, 2H, Harom), 7.58–7.48 (m, 1H, Harom), 7.15–7.09 (m, 2H, Harom), 6.88 (t, J = 7.4 Hz, 1H, Harom), 6.69 (d, J = 8.0 Hz, 1H, Harom), 5.32 (d, J = 16.8 Hz, 1H, CH2), 4.45 (d, J = 17.1 Hz, 1H, CH2), 1.71 (s, 3H, CH3); 13C NMR (CDCl3) δ 165.7 (NCO), 147.7, 140.0 (qCarom), 132.2 (Carom), 131.3 (qCarom), 129.5, 127.8, 127.1, 124.3, 120.5, 120.3 (Carom), 118.6 (qCarom), 118.0 (Carom), 71.4 (qC), 37.9 (CH2), 23.8 (CH3).
5a-Methyl-5,5a,6,7,8,11-hexahydro-9H-pyrido[2,1-b]quinazolin-9-one (6c). The general procedure was followed, and compound 6c was obtained as a yellow powder (24.6 mg, 57%); m.p. 135–138 °C (CHCl3)(Lit. [8] 156–158 °C); Its NMR spectra were consistent with published data [8]. 1H NMR (CDCl3) δ 7.05 (d, J = 7.8 Hz, 2H, Harom), 6.79 (t, J = 7.4 Hz, 1H, Harom), 6.60 (d, J = 7.8 Hz, 1H, Harom), 5.48 (d, J = 17.3 Hz, 1H, CH2), 4.18 (d, J = 17.3 Hz, 1H, CH2), 2.60–2.29 (m, 2H, CH2), 2.09–1.86 (m, 3H, CH2), 1.84–1.68 (m, 1H, CH2), 1.53 (s, 3H, CH3); 13C NMR (CDCl3) δ 169.0 (NCO), 141.0 (qCarom), 127.4, 126.8, 119.3 (Carom), 118.9 (qCarom), 116.1 (Carom), 68.3 (qC), 39.8 (CH2), 37.4 (CH2), 32.9 (CH2), 26.9 (CH2), 16.8 (CH3).
3a-Benzyl-3,3a,4,9-tetrahydropyrrolo[2,1-b]quinazolin-1(2H)-one (6d). The general procedure was followed, and compound 6d was obtained as an orange oil (45.0 mg, 81%); 1H NMR (CDCl3) δ 7.26–7.35 (m, 3H, Harom), 7.17–7.03 (m, 4H, Harom), 6.83 (t, J = 7.4 Hz, 1H, Harom), 6.59 (d, J = 7.8 Hz, 1H, Harom), 5.11 (d, J = 17.1 Hz, 1H, CH2), 4.34 (d, J = 17.1 Hz, 1H, CH2), 4.04 (bs, 1H, NH), 3.22 (d, J = 13.1 Hz, 1H, CH2), 2.90 (d, J = 13.1 Hz, 1H, CH2), 2.54–2.18 (m, 3H, CH2), 1.84–1.62 (m, 1H, CH2); 13C NMR (CDCl3) δ 174.6 (NCO), 141.4 (qCarom), 135.5 (qCarom), 130.1, 128.7, 127.9, 127.3, 127.1, 119.4 (Carom), 117.5 (qCarom), 116.3 (Carom), 74.1 (qC), 42.5 (CH2), 39.1 (CH2), 30.5 (CH2), 29.3 (CH2); HRMS (m/z): [M + H]+ calc. for C18H19N2O: 279.1497; found: 279.1498.
3a-Methyl-2,3,3a,4-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-1-one (6e). The general procedure was followed, and compound 6e was obtained as a brown oil (27.8 mg, 74%); Its NMR spectra were consistent with published data [40]. 1H NMR (CDCl3) δ 7.45 (dd, J = 7.6, 0.8 Hz, 1H, Harom), 6.98 (td, J = 7.7, 1.2 Hz, 1H, Harom), 6.84 (td, J = 7.6, 1.1 Hz, 1H, Harom), 6.70 (dd, J = 7.7, 0.6 Hz, 1H, Harom), 4.20 (bs, 1H, NH), 2.87–2.74 (m, 1H, CH2), 2.61–2.47 (m, 1H, CH2), 2.45–2.36 (m, 2H, CH2), 1.53 (s, 3H, CH3); 13C NMR (CDCl3) δ 173.7 (NCO), 142.7, 128.6 (qCarom), 125.2, 120.1, 115.4, 110.6 (Carom), 85.6 (qC), 37.7 (CH2), 33.6 (CH2), 26.2 (CH3).
4b-Methyl-4b,5-dihydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one (6f). The general procedure was followed, and compound 6f was obtained as a yellow powder (41.5 mg, 75%); m.p. 146–149 °C (CHCl3)(Lit. [55] 184–185 °C); Its NMR spectra were consistent with published data [55]. 1H NMR (CDCl3) δ 7.86 (d, J = 8.1 Hz, 1H, Harom), 7.63 (t, J = 7.4 Hz, 1H, Harom), 7.57–7.47 (m, 3H, Harom), 7.03–6.87 (m, 2H, Harom), 6.74 (d, J = 7.7 Hz, 1H, Harom), 4.24 (s, 1H, NH), 1.83 (s, 3H, CH3); 13C NMR (CDCl3) δ 170.6 (NCO), 149.5, 145.0 (qCarom), 133.4 (Carom), 132.1, 130.7 (qCarom), 129.6, 125.3, 125.1, 121.8, 121.1, 117.2, 111.5 (Carom), 86.0 (qC), 26.8 (CH3).
8a-Methyl-7,8,8a,9-tetrahydro-6H-pyrrolo[1′,2′:1,2]imidazo[4,5-b]pyridin-6-one (6g). The general procedure was followed, and compound 6g was obtained as a brown oil (34.0 mg, 90%); Its NMR spectra were consistent with published data [40]. 1H NMR (CDCl3) δ 7.75 (dd, J = 5.4, 1.2 Hz, 1H, Harom), 7.52 (dd, J = 7.4, 1.4 Hz, 1H, Harom), 6.66 (dd, J = 7.4, 5.5 Hz, 1H, Harom), 5.84 (bs, 1H, NH), 2.87–2.65 (m, 1H, CH2), 2.60–2.38 (m, 3H, CH2), 1.58 (s, 3H, CH3); 13C NMR (CDCl3) δ 174.9 (NCO), 156.6 (qCarom), 142.8 (Carom), 122.5 (qCarom), 120.6, 114.5 (Carom), 83.3 (qC), 38.2 (CH2), 32.5 (CH2), 26.7 (CH3).

4. Conclusions

To sum up, an alternative catalyst system for the cascade reaction between alkynoic acids and heterodinucleophiles is presented. This palladium-based system is based on the use of very small amounts of a NNC pincer complex, thus providing a more efficient approach to polycyclic structures of interest. Good to excellent yields are obtained in all cases by this particularly active system, which according to a number of mechanistic studies participates as a fully homogenous catalyst. A more nuanced mechanism describing the role of the metal species and transient intermediates detected by UPLC-ESI is also proposed.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/catal12020127/s1, synthesis of 5-phenylpent-4-ynoic acid, structure factor tables, additional experiments, ESI-MS results and scans of NMR spectra (PDF).

Author Contributions

Co-authors M.T.H., N.C. and G.U. contributed to searching and collating of the relevant literature and the proof-reading of the document. Investigation, experiments and analysis were carried out by N.C. Corresponding author R.S. conceptualized and supervised the study and wrote the body of the article. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Basque Government (IT1405-19) and the Spanish Ministry of Economy and Competitiveness (CTQ2017-86630-P).

Acknowledgments

Technical and human support provided by SGIker of UPV/EHU is gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 00127 g001 550
Figure 1. Structure of quinazoline alkaloids and reductase inhibitor pyrrolobenzimidazolone.
Figure 1. Structure of quinazoline alkaloids and reductase inhibitor pyrrolobenzimidazolone.
Catalysts 12 00127 g001
Catalysts 12 00127 sch001 550
Scheme 1. Postulated catalytic cycle and reported metal catalysts for the cascade reaction between alkynoic acids and dinucleophiles.
Scheme 1. Postulated catalytic cycle and reported metal catalysts for the cascade reaction between alkynoic acids and dinucleophiles.
Catalysts 12 00127 sch001
Catalysts 12 00127 g002 550
Figure 2. Palladium-catalyzed formation of benzo[d]pyrrolo [2,1-b]oxazine-1,5-dione 4a. Selected optimization experiments a.
Figure 2. Palladium-catalyzed formation of benzo[d]pyrrolo [2,1-b]oxazine-1,5-dione 4a. Selected optimization experiments a.
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Catalysts 12 00127 g003 550
Figure 3. Palladium-catalyzed cascade reaction between alkynoic acids and o-aminobenzoic acid or o-aminobenzenesulfonamide.
Figure 3. Palladium-catalyzed cascade reaction between alkynoic acids and o-aminobenzoic acid or o-aminobenzenesulfonamide.
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Catalysts 12 00127 g004 550
Figure 4. Molecular structure of benzopyrrolo[1,3]oxazine-1,5-diones 4a and 4e and benzopyrido[1,2,4]thiadiazinone-5,5-dioxide 4g with the atomic numbering scheme. Thermal ellipsoids are given at the 50% probability level.
Figure 4. Molecular structure of benzopyrrolo[1,3]oxazine-1,5-diones 4a and 4e and benzopyrido[1,2,4]thiadiazinone-5,5-dioxide 4g with the atomic numbering scheme. Thermal ellipsoids are given at the 50% probability level.
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Catalysts 12 00127 g005 550
Figure 5. Palladium-catalyzed cascade reaction between alkynoic acids and diamines.
Figure 5. Palladium-catalyzed cascade reaction between alkynoic acids and diamines.
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Catalysts 12 00127 g006 550
Figure 6. Conversion rate of anthranilic acid 3a versus time.
Figure 6. Conversion rate of anthranilic acid 3a versus time.
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Catalysts 12 00127 g007 550
Figure 7. TEM images and EDX spectra of the crude. Note: The presence of copper is due to the grid supporting the sample.
Figure 7. TEM images and EDX spectra of the crude. Note: The presence of copper is due to the grid supporting the sample.
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Catalysts 12 00127 sch002 550
Scheme 2. Revised catalytic cycle for the cascade reaction catalyzed by the 1/FeBr3/Et3N system.
Scheme 2. Revised catalytic cycle for the cascade reaction catalyzed by the 1/FeBr3/Et3N system.
Catalysts 12 00127 sch002
Catalysts 12 00127 sch003 550
Scheme 3. Reaction of methylene lactone 7 with anthranilic acid 3a under optimized conditions.
Scheme 3. Reaction of methylene lactone 7 with anthranilic acid 3a under optimized conditions.
Catalysts 12 00127 sch003
Table
Table 1. Summary of poisoning experiments a.
Table 1. Summary of poisoning experiments a.
EntryPoisoning Additive4a (%) b
1Hg (one drop)99
2CS2 (0.5 equiv. per metal atom)99
3CS2 (2.0 equiv. per metal atom)98
4PPh3 (0.03 equiv. per metal atom)99
5PPh3 (0.3 equiv. per metal atom)99
6PPh3 (4.0 equiv. per metal atom)99
7Py (150 equiv. per metal atom) c98
8PVPy (300 equiv. per metal atom) d99
a Reaction conditions: 3a (0.2 mmol), 2a (1.5 equiv.), 1 (10−2 mol%), FeBr2 (10−2 mol%), Et3N (2 mol%), CHCl3 (0.4 mL per mmol of 2), 120 °C, 96 h. b NMR yields determined using 3,4,5-trichloropyridine as an internal standard. c Py: Pyridine. d PVPy: Polyvinylpyridine.
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Conde, N.; Herrero, M.T.; Urgoitia, G.; SanMartin, R. Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles. Catalysts 2022, 12, 127. https://doi.org/10.3390/catal12020127

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Conde N, Herrero MT, Urgoitia G, SanMartin R. Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles. Catalysts. 2022; 12(2):127. https://doi.org/10.3390/catal12020127

Chicago/Turabian Style

Conde, Nerea, María Teresa Herrero, Garazi Urgoitia, and Raul SanMartin. 2022. "Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles" Catalysts 12, no. 2: 127. https://doi.org/10.3390/catal12020127

APA Style

Conde, N., Herrero, M. T., Urgoitia, G., & SanMartin, R. (2022). Palladium-Catalyzed Domino Cycloisomerization/Double Condensation of Acetylenic Acids with Dinucleophiles. Catalysts, 12(2), 127. https://doi.org/10.3390/catal12020127

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