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Article

A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters

by
Khidmet Shikhaliev
1,
Artem Sabynin
1,
Valeri Sekirin
1,
Michael Krysin
1,*,
Fedor Zubkov
2 and
Kristina Yankina
2
1
Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., Voronezh 394018, Russia
2
Department of Organic Chemistry, Faculty of Physics and Mathematics and Natural Sciences, RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russia
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(11), 2035; https://doi.org/10.3390/molecules22112035
Submission received: 4 November 2017 / Revised: 16 November 2017 / Accepted: 20 November 2017 / Published: 22 November 2017
(This article belongs to the Collection Heterocyclic Compounds)
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Abstract

A new synthetic approach to polyfunctional hexahydropyrrolo[3,4-b]pyrroles was developed based on cyclization of N-arylbromomaleimides with aminocrotonic acid esters. A highly chemo- and stereoselective reaction is a Hantzsch-type domino process, involving the steps of initial nucleophilic C-addition or substitution and subsequent intramolecular nucleophilic addition without recyclyzation of imide cycle.

Graphical Abstract

1. Introduction

Bicyclic pyrrolopyrroles are the core of numerous compounds with various useful properties. For example, they are used as optoelectronic materials [1,2], pigments for varied purposes [3,4,5,6], and are characterized by a variety of biological activities [7,8]. Inhibitors of protein methyltransferases [9], glycosyltransferases [10], agonists of various serotonin 5-HT-receptors [11,12,13], antagonists of integrin VLA-4 [14], and promising structural analogs of antibacterial fluoroquinolones [15] have been found among the derivatives of hydrogenated pyrrolo[3,4-b]pyrroles, thereby causing a significant interest in the search for new synthetic approaches to this heterocyclic system.
The most common strategy for its construction from non-cyclic precursors (Scheme 1, Route A) is based on a multistage synthesis of N-alkenyl tethered aldehydes, which are further subjected to intramolecular cyclization with α-amino acids via the formation of azomethine ylides [11,12,16,17,18,19,20,21]. Hydrogenated pyrrolo[3,4-b]pyrroles are also formed as a result of intramolecular 1,3-dipolar cycloaddition in phosphorus-containing azomethine ylides generated in situ from alkene-tethered imines, acid chlorides and phosphonites [22], or transition metal promoted carbonilative [2+2+1] carbocyclization of N-allene imines [23,24].
Another direction in the synthesis of pyrrolo[3,4-b]pyrroles is the anellation of the second pyrrole ring. Examples of such reactions include intramolecular amidation [10,14], alkylation [25], condensation [26], nucleophilic addition [27], and Paal–Knorr heterocyclization [28] in appropriately substituted pyrroles (Scheme 1, Route B). Intermolecular convergent approaches to this heterocyclic system have been realized to a much lesser extent. Thus, the dipolarophilic pyrrole derivatives are anellated over the b bond as a result of the 1,3-dipolar cycloaddition of azomethine ylides, generated from silylated hemiaminals [29] or aziridines [30] (Scheme 1, Route C). Hexahydropyrrolo[3,4-b]indoles were obtained as a result of organocatalytic asymmetric anellation of N-hydroxymaleimides with nitrosobenzene [31]. Synthetic equivalents of C–C–N synthon are also 2H-azirines, which form hexahydropyrrolo[3,4-b]pyrroles in Cu-catalyzed domino-reactions with tetramic acid derivatives [32,33]. Oxidative cyclization of maleimides with amines and alkyne esters is also catalyzed by copper (I) salts [34] (Scheme 1, Route D). It should be noted that almost all of these reagents are not readily available.
In continuation of our research on the synthesis of heterocycles based on cyclic imides of unsaturated dicarboxylic acids [35,36], in the present work we report the unusual domino reaction of 1-aryl-3-bromo-1H-pyrrole-2,5-diones (bromomaleimides) (1) with N-substituted esters of β-aminocrotonic acids (2) for the metal-free preparation of a series of new hexahydropyrrolo[3,4-b]pyrroles.

2. Results and Discussion

One of the most interesting applications of maleimides, which do not have substituents on the C=C bond, in the synthesis of heterocyclic compounds are domino-recyclization reactions with a variety of dinucleophilic reagents [37,38,39]. Despite the presence of three electrophilic centers in their structure (one of the double bond carbon atoms and two carbonyl C atoms), a fairly high regioselectivity was noted for similar reactions, in particular, with aminocrotonic acid esters as 1,3-C,N-dinucleophiles [40]. Our choice of 1-aryl-3-bromo-1H-pyrrole-2,5-diones (1a–d) is due, on the one hand, to their easy synthetic availability [41] and, on the other hand, the appearance of yet another, compared to the C-unsubstituted maleimides, electrophilic C-atom, to which a bromine atom is bound, which significantly expands the variety of possible transformations. N-substituted ethyl aminocrotonates (2a–c), also easily synthesized by known methods [42,43], were chosen for the purpose of structural diversification of the target substances (Scheme 2).
According to the well-known literature data on the reactions of maleimides with 1,3-C,N-dinucleophiles [35,37,40], we assumed that the most probable direction of interaction of bromomaleimides (1) with aminocrotonates (2) will be a Michael-type reaction, followed by intramolecular transamidation with simultaneous recyclization of the imide cycle in an intermediate (3). Depending on the carbonyl atom at which the last reaction takes place, either dihydropyrroles (4) or tetrahydropyridines (6) can form. Their dehydrobromination can lead to pyrrolinone (5) or pyridinone (7) (Scheme 3).
Monitoring of the reaction conditions for the example of 1a and 2a by TLC showed that, for their reactions, stirring in methanol without heating for 5 h is sufficient. Similar results were obtained in acetic acid, but the product yield was lower. In other solvents (chloroform, ethyl acetate, benzene, and dioxane), either reagent conversion was insignificant under the given conditions or a complex mixture of substances was observed to form when heated. In a 1a/2a molar ratio of 1:1, part of the starting bromomaleimide does not react, while the aminocrotonate reacts completely. Total conversion of bromomaleimide is achieved with a molar ratio of reactants of 1:2. The second molecule of aminocrotonate probably binds the hydrogen bromide liberated during the reaction. The reaction at a reactant molar ratio of 1:1 and the same amount of the additional base (Et3N or pyridine) resulted in the formation of tar products with a significant decrease in the yield of the target substances. Thus, only one product was formed: (3aS,6aR)-ethyl 1-benzyl-2-methyl-4,6-dioxo-5-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate (8a) instead of the expected 4–7 (Scheme 4).
Considering the simplicity of obtaining 2, we attempted multicomponent one-pot synthesis of pyrrolopyrroles (8). Preliminarily, the mixture of equimolar amounts of ethyl acetoacetate (9) and appropriate amine (10) was stirred for 24 h, after which, without isolation of the resulting aminocrotonate, a methanol solution of half the amount of corresponding brommaleimide was added to the solution. Stirring was continued for 4 to 6 h (TLC control). The yields of the target substances isolated by simple filtration proved to be comparable with the two-component variant (Table 1).
In the 1H NMR spectra of pyrrolopyrroles (8a–f), in addition to the well identifiable signals of the substituents, there are a doublet of doublets or broadened doublet of H-6a (about 4.30 ppm with the vicinal spin–spin coupling constants JH-3a-H-6a ~10.5 Hz and the long W-constant 4JH-C-N1-C-H6a ~1.0 Hz), as well as the doublet H-3a at ~4.50 ppm for N1-benzyl derivatives 8a,b,e and ~4.75 ppm for N1-phenethyl derivatives 8c,d,f (JH-3a-H-6a ~10.5 Hz). It is the multiplicity of the proton signal H-6a that proves its location. Diastereotopic are methylene protons, which are part of the benzyl, ester and phenethyl groups, causing the last two groups of complex type of appropriate signals. The absence of NH-signals excludes the formation of alternative compounds 4–7 (Scheme 3).
Conclusions on the arrangement of the substituents, based on 1H NMR data, are confirmed by the results of X-ray analysis of 8c (Figure 1; non-hydrogen atoms are represented by probabilistic ellipsoids of atomic displacements (p = 0.5)). Thus, the interaction of 1 with 2 proceeds chemo- and stereoselectively without recycling of the imide cycle and leads to the formation of hexahydropyrrolopyrroles (8) with two adjacent quaternary asymmetric centers in their structure.
The polyelectrophilic character of 1 and the dinucleophilic character of 2a (Scheme 2) cause a variety of possible variants of the initial interaction of the reagents and the direction of further transformations, both with opening and without opening the imide cycle. In our opinion, only two reasonable synthetic schemes can lead to the formation of 8a–f: (a) a Michael-type nucleophilic C-addition of amino crotonate at the C-4 maleimide atom followed by dehydrobromination of succinimide (3) and a subsequent intramolecular cyclization of the intermediate 11 as a result nucleophilic addition with the participation of the nitrogen atom of the enamine fragment (Path A); or (b) direct nucleophilic substitution of the bromine atom in the imide 1, also involving the C atom of the aminocrotonate and the subsequent analogous cyclization (Path B) (Scheme 5).
In the first direction, for example, base-catalyzed arylation of 1a by 2-naphthols occurs [44]. Direction B is essentially a new, unusual version of the synthetic realization of the C–C–dielectrophil + C–C–N–dinucleophil retrosynthetic scheme of the well-known method for the production of pyrroles by the Hantzsch reaction (interaction of α-halocarbonyl with β-enaminocarbonyl compounds [45,46]). The structural prerequisite for substantiating the possibility of using this approach for the synthesis of 8 is the high mobility of the bromine atom in bromomaleimides in reactions with nucleophilic reagents [47].

3. Materials and Methods

3.1. General

NMR 1Н and 13С spectra were registered on Bruker DRX (500 and 125.8 MHz, respectively) spectrometer in DMSO-d6, internal standard is TMS. Mass spectra were registered on Agilent Technologies LCMS 6230B (ESI, Agilent Technologies, Santa Clara, CA, USA). Melting points were determined on Stuart SMP 30. Control of reagent and product individuality, and qualitative analysis of reaction mass, was performed by TLC on Merck TLC Silicagel 60 F254 chromatographic plate (Merck KGaA, Darmstadt, Germany); eluents: methanol, chloroform, and their mixtures in various ratios. The chromatograms were developed by UV and iodine vapor.
Purity of the products was controlled by high performance liquid chromatography with high resolution mass-spectrometric detection under electrospray ionization (HPLC-HRMS-ESI) in combination with UV detection. The device consists of liquid chromatograph—Agilent 1269 Infinity and time-of-flight high resolution mass detector—Agilent 6230 TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA). Block ionization is double electrospray, and the detection mass range is from 50 to 2000 Dalton. Capillary voltage is 4.0 kV, fragmentor +191 V, skimmer +66 V, OctRF 750 V. Column Poroshell 120 EC-C18 (4.6 × 50 mm; 2.7 mkm) was used. Gradient eluation: acetonitrile/water (0.1% formic acid); flow rate: 0.4 mL/min. Software for collection and elaboration of research results is MassHunter Workstation/Data Acquisition V.06.00. Starting bromomaleimides (1) and aminocrotonates (2) were provided by Alinda Chemical Ltd., Moscow, Russian Federation. Other reagents were purchased from commercial suppliers and used as received.

3.2. General Procedure for the Reaction of Bromomaleimides (1) with Aminocrotonates (3) and Characterization Data of Pyrrolo[3,4-b]pyrroles (8a–f)

Two-component reaction. A mixture of the corresponding bromomaleimide (0.002 mol) and aminocrotonate (0.004 mol) in 5 mL of methanol was stirred for 4 to 6 h. The precipitate which formed was filtered off and recrystallized from methanol.
One-pot sequence. A mixture of acetoacetic ester (9) (0.004 mol) and amine (10) (0.004 mol) in 3 mL of methanol was stirred for 24 h, after which, without isolation of the resulting aminocrotonate, a solution of the corresponding bromomaleimide (0.002 mol) in 5 mL of methanol was added. Stirring was continued for 4–6 h. The precipitate formed was filtered off and recrystallized from methanol. Hexahydropyrrolo[3,4-b]pyrrole (8) was obtained as colorless crystalline powders.
(3aS,6aR)-Ethyl 1-benzyl-2-methyl-4,6-dioxo-5-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate 8a. 0.36 g; yield 46%; m.p. 141–142 °С; 1H NMR (DMSO-d6), δ (ppm): 1.20 (3Н, t, J = 7.1 Hz, CH3CH2O); 2.31 (3Н, s, CH3-Het); 4.00–4.14 (2Н, m, CH3CH2O); 4.33 (1H, dd, J = 10.5 Hz, J = 0.8 Hz, H-6a); 4.53 (1H, d, J = 10.5 Hz, H-3a); 4.59 (1H, d, J = 16.7 Hz, CH2Ph); 4.80 (1H, d, J = 16.7 Hz, CH2Ph); 7.23–7.26 (4Н, m, CHarom); 7.30–7.34 (1Н, m, CHarom); 7.38–7.44 (3Н, m, CHarom); 7.47–7.51 (2Н, m, CHarom); 13C NMR (DMSO-d6), δ (ppm): 12.45, 14.90, 47.66, 48.16, 58.60, 63.24, 93.40, 127.37, 127.44, 127.86, 128.82, 129.21, 129.31, 132.63, 136.83, 161.46, 165.36, 173.83, 175.64; HRMS-ESI, m/z ([M + H]+), calcd for C23H22N2O4 + H+ 391.1654, found 391.1652.
(3aS,6aR)-Ethyl 1-methoxybenzyl-2-methyl-4,6-dioxo-5-phenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate 8b. 0.65 g; yield 77%; m.p. 152–153 °С; 1H NMR (DMSO-d6), δ (ppm): 1.20 (3Н, t, J = 7.1 Hz, CH3CH2O); 2.33 (3Н, s, CH3-Het); 3.75 (3Н, s, MeO); 3.99–4.13 (2Н, m, CH3CH2O); 4.29 (1H, br. d, J = 10.5 Hz, H-6a); 4.48 (1H, d, J = 16.2 Hz, CH2Ph); 4.49 (1H, d, J = 10.5 Hz, H-3a); 4.73 (1H, d, J = 16.2 Hz, CH2Ph); 6.96 (2H, d, J = 8.6 Hz, CHarom); 7.19 (2H, d, J = 8.6 Hz, CHarom); 7.23–7.26 (1Н, m, CHarom); 7.35–7.37 (1Н, m, CHarom); 7.40–7.44 (1Н, m, CHarom); 7.47–7.51 (2Н, m, CHarom); 13C NMR (DMSO-d6), δ (ppm): 12.48, 14.90, 47.59, 47.62, 55.48, 58.57, 62.88, 93.32, 114.60, 127.38, 128.32, 128.82, 129.07, 129.31, 132.63, 159.09, 161.35, 165.36, 173.86, 175.65; HRMS-ESI, m/z ([M + H]+), calcd for C24H24N2O5 + H+ 421.1759, found 421.1754.
(3aS,6aR)-Ethyl 5-(4-ethylphenyl)-2-methyl-4,6-dioxo-1-phenetyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate 8c. 0.70 g; yield 82%; m.p. 147–149 °С; 1H NMR (DMSO-d6), δ (ppm): 1.18 (3Н, t, J = 7.1 Hz, 4-CH3CH2C6H4); 1.20 (3Н, t, J = 7.6 Hz, CH3CH2O); 2.07 (3Н, s, CH3-Het); 2.64 (2Н, q, J = 7.1 Hz, 4-CH3CH2C6H4); 2.80–2.87 (1Н, m, CH2CH2Ph); 2.92–2.99 (1Н, m, CH2CH2Ph); 3.60–3.70 (2Н, m, CH2CH2Ph); 3.96–4.10 (2Н, m, CH3CH2O); 4.28 (1H, dd, J = 10.5 Hz, J = 1.1 Hz, H-6a); 4.75 (1H, d, J = 10.5 Hz, H-3a); 7.14–7.17 (2Н, m, CHarom); 7.21–7.26 (3Н, m, CHarom); 7.30–7.34 (4Н, m, CHarom); 13C NMR (DMSO-d6), δ (ppm): 11.98, 14.90, 15.84, 28.21, 33.53, 46.93, 47.62, 58.43, 63.67, 92.92, 126.81, 127.25, 128.63, 128.88, 129.25, 130.24, 139.14, 144.54, 161.61, 165.30, 174.33, 175.75; HRMS-ESI, m/z ([M + H]+), calcd for C26H28N2O4+H+ 433.2123, found 433.2128.
X-Ray Crystallographic data for 8c. CCDC 1574386 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk). Crystal data for C26H28N2O4 (M = 432.50 g/mol): monoclinic, space group P 21/n (no. 14), a = 15.0252(9) Å, b = 8.6768(5) Å, c = 17.3436(10) Å, α = 90°, β = 97.7760(10)°, γ = 90° V = 2240.3(2) Å3, Z = 4, T =120(2) K, μ(CuKα) = 0.087 mm-1, Dcalc = 1.282 g/cm3. 20916 reflections measured (4.74° ≤ 2Θ ≤ 51.992°), 4387 unique (Rint = 0.0380, Rsigma = 0.0411) which were used in all calculations. The final R1 was 0.0483 (I > 2σ(I)) and wR2 was 0.0817 (all data).
(3aS,6aR)-Ethyl 5-(4-ethoxyphenyl)-2-methyl-4,6-dioxo-1-phenetyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate 8d. 0.66 g; yield 73%; m.p. 164–166 °С; 1H NMR (DMSO-d6), δ (ppm): 1.20 (3Н, t, J = 7.0 Hz, CH3CH2O); 1.34 (3Н, t, J = 7.0 Hz, 4-CH3CH2OC6H4); 2.06 (3Н, s, CH3-Het); 2.78–2.87 (1Н, m, CH2CH2Ph); 2.91–2.96 (1Н, m, CH2CH2Ph); 3.60–3.69 (2Н, m, CH2CH2Ph); 4.04–4.12 (4Н, m, 2CH3CH2); 4.27 (1H, br.d, J = 10.5 Hz, H-6a); 4.74 (1H, d, J = 10.5 Hz, H-3a); 7.01 (2H, d, J = 8.7 Hz, CHarom); 7.15 (2H, d, J = 8.7 Hz, CHarom); 7.23–7.26 (3Н, m, CHarom); 7.30–7.33 (2Н, m, CHarom); 13C NMR (DMSO-d6), δ (ppm): 11.97, 14.91, 14.96, 33.53, 46.91, 47.54, 58.42, 63.59, 63.70, 92.91, 114.96, 124.99, 126.81, 128.58, 128.88, 129.25, 139.15, 158.63, 161.58, 165.31, 174.42, 175.86; HRMS-ESI, m/z ([M + H]+), calcd. for C26H28N2O5 + H+ 449.2073, found 449.2067.
(3aS,6aR)-Ethyl 1-benzyl-2-methyl-4,6-dioxo-5-(3,4-dichlorophenyl)-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate 8e. 0.64 g; yield 70%; m.p. 146–147 °С; 1H NMR (DMSO-d6), δ (ppm): 1.20 (3Н, t, J = 7.1 Hz, CH3CH2O); 2.31 (3Н, s, CH3-Het); 4.00–4.14 (2Н, m, CH3CH2O); 4.33 (1H, br.d, J = 10.5 Hz, H-6a); 4.52 (1H, d, J = 10.5 Hz, H-3a); 4.59 (1H, d, J = 16.7 Hz, CH2Ph); 4.78 (1H, d, J = 16.7 Hz, CH2Ph); 7.25 (2H, d, J = 7.4 Hz, CHarom); 7.30–7.34 (2Н, m, CHarom); 7.40 (2H, t, J = 7.5 Hz, CHarom); 7.61 (1H, d, J = 2.3 Hz, CHarom); 7.79 (1H, d, J = 8.6 Hz, CHarom); 13C NMR (DMSO-d6), δ (ppm): 12.48, 14.90, 47.74, 48.12, 58.60, 63.15, 93.12, 127.49, 127.75, 127.87, 129.19, 129.27, 131.30, 131.53, 131.61, 132.52, 136.76, 161.61, 165.29, 173.27, 175.11; HRMS-ESI, m/z ([M + H]+), calcd for C23H20Cl2N2O4 + H+ 459.0874, found 459.0868.
(3aS,6aR)-Ethyl 5-(3,4-dichlorophenyl)-2-methyl-4,6-dioxo-1-phenetyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-b]pyrrole-3-carboxylate 8f. 0.65 g; yield 69%; m.p. 155–156 °С; 1H NMR (DMSO-d6), δ (ppm): 1.18 (3Н, t, J = 7.1 Hz, CH3CH2O); 2.08 (3Н, s, CH3-Het); 2.81–2.88 (1Н, m, CH2CH2Ph); 2.93–2.99 (1Н, m, CH2CH2Ph); 3.60–3.67 (2Н, m, CH2CH2Ph); 3.98–4.10 (2Н, m, CH3CH2); 4.28 (1H, dd, J = 10.6 Hz, J = 1.0 Hz, H-6a); 4.75 (1H, d, J = 10.6 Hz, H-3a); 7.22–7.27 (3Н, m, CHarom); 7.30–7.35 (3Н, m, CHarom); 7.64 (1H, d, J = 2.3 Hz, CHarom); 7.79 (1H, d, J = 8.6 Hz, CHarom); 13C NMR (DMSO-d6), δ (ppm): 12.05, 14.91, 14.96, 33.48, 46.81, 47.74, 58.45, 63.56, 92.63, 126.82, 127.83, 128.88, 129.01, 129.25, 129.32, 131.31, 131.53, 131.60, 132.58, 139.14, 161.80, 165.23, 173.69, 175.14; HRMS, m/z ([M + H]+), calcd for C24H22Cl2N2O4 + H+ 473.1031, found 473.1024.

4. Conclusions

Herein, we presented the new unusual variant of the realization of the Hantzsch-type synthetic scheme C–C + C–C–N for the synthesis of polyhydrogenated pyrrolo[3,4-b]pyrroles based on the cyclization of bromomaleimides with aminocrotonic acid esters. A domino-reaction proceeds chemo- and stereoselectively and involves the steps of intermolecular nucleophilic C-addition or substitution and intramolecular nucleophilic N-addition both in two- and multicomponent mode.

Supplementary Materials

The NMR spectra, data of HPLC-MS-ESI analysis of pyrrolopyrroles 8 and crystallographic data for 8c are available online.

Acknowledgments

This work was supported by the Ministry of Education and Science of the Russian Federation (Agreement number 02.a03.21.0008).

Author Contributions

K. Shikhaliev conceived and designed the experiments; A. Sabynin and V. Sekirin performed the experiments; K. Yankina and F. Zubkov analyzed the data; M. Krysin wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Krzeszewski, M.; Gryko, D.; Gryko, D.T. The tetraarylpyrrolo[3,2-b]pyrroles-from serendipitous discovery to promising heterocyclic optoelectronic materials. Acc. Chem. Res. 2017, 50, 2334–2345. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  2. Li, Y. Molecular design of photovoltaic materials for polymer solar sells: Toward suitable electronic energy levels and broad absorption. Acc. Chem. Res. 2012, 45, 723–733. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  3. Ghorpade, T.K.; Patri, M.; Mishra, S.P. Highly sensitive colorimetric and fluorometric anion sensors based on mono and di-calix[4]pyrrole substituted diketopyrrolopyrroles. Sens. Actuators B Chem. 2016, 225, 428–435. [Google Scholar] [CrossRef] [Scilit]
  4. Wiktorowski, S.; Christelle, R.; Winterhalder, M.; Daltrozzo, E.; Zumbusch, A. Water-soluble pyrrolopyrrole cyanine (PPCy) NIR fluorophores. Chem. Commun. 2014, 50, 4755–4758. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  5. Vala, M.; Vyňuchal, J.; Toman, P.; Weiter, M.; Luňák, S., Jr. Novel, soluble diphenyl-diketo-pyrrolopyrroles: Experimental and theoretical study. Dyes Pigments 2010, 84, 176–182. [Google Scholar] [CrossRef] [Scilit]
  6. Mizuguchi, J.; Shikamori, H. Spectral and Crystallographic Coincidence in a Mixed Crystal of Two Components and a Crystal of Their Hybrid Component in Pyrrolopyrrole Pigments. J. Phys. Chem. B 2004, 108, 2154–2161. [Google Scholar] [CrossRef] [Scilit]
  7. Cordes, J.; Harms, K.; Koert, U. Synthesis of the Isoquinocycline-Pyrrolopyrrole Substructure. Org. Lett. 2010, 12, 3808–3811. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  8. Muchowski, J.M.; Unger, S.H.; Ackrell, J.; Cheung, P.; Cooper, G.F.; Cook, J.; Gallegra, P.; Halpern, O.; Koehler, R.; Kluge, A.F. Synthesis and Antiinflammatory and Analgesic Activity of 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic Acids and Related Compounds. J. Med. Chem. 1989, 32, 1202–1207. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  9. Zhou, H.; Che, X.; Bao, G.; Wang, N.; Peng, L.; Barnash, K.D.; Frye, S.V.; James, L.I.; Bai, X. Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds. Bioorg. Med. Chem. Lett. 2016, 26, 4436–4440. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  10. Trunkfield, A.E.; Gurcha, S.S.; Gurdyal, S.B.; Timothy, D.H. Inhibition of Escherichia coli glycosyltransferase MurG and Mycobacterium tuberculosis Gal transferase by uridine-linked transition state mimics. Bioorg. Med. Chem. 2010, 18, 2651–2663. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  11. Russell, M.G.; Beer, M.S.; Stanton, J.A.; Sohal, B.; Castro, J.L. 2,7-Diazabicyclo[3.3.0]octanes as novel h5-HT1D receptor agonists. Bioorg. Med. Chem. Lett. 1999, 9, 2491–2496. [Google Scholar] [CrossRef] [Scilit]
  12. Huck, B.R.; Llamas, L.; Robarge, M.J.; Dent, T.C.; Song, J.; Hodnick, W.F.; Crumrine, C.; Stricker-Krongrad, A.; Harrington, J. The identification of pyrimidine-diazabicyclo[3.3.0]octane derivatives as 5-HT2C receptor agonists. Bioorg. Med. Chem. Lett. 2006, 16, 2891–2894. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  13. Ivashchenko, A.A.; Ivashchenko, A.V.; Tkachenko, S.E.; Okun, M.; Savchuk, N.F. Ligands for 5-HT6, Pharmaceutical Composition, Method for Their Production and Use Thereof. U.S. Patent Application No. 2011/0046368 A1, 24 February 2011. [Google Scholar]
  14. Chang, L.L.; Yang, G.X.; McCauley, E.; Mumford, R.A.; Schmidt, J.A.; Hagmann, W.K. Constraining the amide bond in N-Sulfonylated dipeptide VLA-4 antagonists. Bioorg. Med. Chem. Lett. 2008, 18, 1688–1691. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  15. Ma, Z.; Chu, D.T.W.; Cooper, C.S.; Li, Q.; Fung, A.K.L.; Wang, S.; Fung, S.W.; Shen, L.L.; Flamm, R.K.; Nilius, A.M.; et al. Synthesis and Antimicrobial Activity of 4H-4-Oxoquinolizine Derivatives: Consequences of Structural Modification at the C-8 Position. J. Med. Chem. 1999, 42, 4202–4213. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  16. Schenke, T.; Petersen, U. Preparation of 2,7-Diazabicyclo[3,3,0]octanes. U.S. Patent 5,071,999, 10 December 1991. [Google Scholar]
  17. Pedrosa, R.; Andrés, C.; Andrés, L.; Nieto, J. A Novel Synthesis of Enantiopure Octahydropyrrolo[3,4-b]pyrroles by Intramolecular [3 + 2] Dipolar Cycloaddition on Chiral Perhydro-1,3-benzoxazines. Org. Lett. 2002, 4, 2513–2516. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  18. Pedrosa, R.; Andrés, C.; Nieto, J.; Pérez-Cuadrado, C.; San Francisco, I. An Efficient and Diastereoselective Intramolecular 1,3-Dipolar Cycloaddition of Cyclic Azomethine Ylides and Nitrones. Eur. J. Org. Chem. 2006, 14, 3259–3265. [Google Scholar] [CrossRef] [Scilit]
  19. Poornachandran, M.; Raghunathan, R. A novel entry into 1-methyl- and 1-aryl-octahydropyrrolo[3,4-b]pyrroles and their N-1–C-2 fused derivatives: Stereoselective synthesis via an intramolecular azomethine ylide cycloaddition reaction. Tetrahedron Lett. 2005, 46, 7197–7200. [Google Scholar] [CrossRef] [Scilit]
  20. Poornachandran, M.; Raghunathan, R. Synthesis of pyrrolo[3,4-b]pyrroles and perhydrothiazolo-[3’,4’-2,3]pyrrolo[4,5-c]pyrroles. Tetrahedron 2008, 64, 6461–6474. [Google Scholar] [CrossRef] [Scilit]
  21. Poornachandran, M.; Raghunathan, R. Facile Synthesis of cis-Fused 1-Benzyl/-H-5-arylsulfonyl Pyrrolo[3,4-b]pyrroles. Synth. Commun. 2009, 39, 917–926. [Google Scholar] [CrossRef] [Scilit]
  22. Morin, M.S.T.; Aly, S.; Arndtsen, B.A. Phosphonite mediated 1,3-dipolar cycloaddition: A route to polycyclic 2-pyrrolines from imines, acid chlorides and alkenes. Chem. Commun. 2013, 49, 883–885. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  23. Kang, S.-K.; Kim, K.-J.; Hong, Y.-T. Synthesis of α-Methylene-γ-butyrolactones: Ru-Catalyzed Cyclocarbonylation of Allenyl Aldehydes and Allenyl Ketones. Angew. Chem. Int. Ed. 2002, 41, 1584–1586. [Google Scholar] [CrossRef] [Scilit]
  24. Kim, S.H.; Kang, E.S.; Yu, C.M. A Cyclocarbonylation for the Synthesis of Bicyclic 3-Methylene-1-phthalimidoylbutyrolactams from Allene-hydrazones Mediated by Mo(CO)6. Synlett 2007, 15, 2439–2441. [Google Scholar] [CrossRef] [Scilit]
  25. Lee, J.W.; Son, H.J.; Lee, J.H.; Yoon, G.J.; Park, M.H. Synthesis of 2,7-Diazabicyclo[3.3.0]octane Derivatives via Intramolecular Cyclization Reaction. Synth. Commun. 1996, 26, 89–94. [Google Scholar] [CrossRef] [Scilit]
  26. Lee, J.W.; Son, H.J.; Jung, Y.E.; Lee, J.H. Synthesis of 2,7-Diazabicyclo[3.3.0]octane and 2,7-Diazabicyclo[3.3.0]oct-4-ene Derivatives via Cyclization Reaction and Julia Reaction. Synth. Commun. 1996, 26, 1499–1505. [Google Scholar] [CrossRef] [Scilit]
  27. Attanasi, J.A.; Bianchi, L.; De Crescentini, L.; Favi, G.; Mantellini, F. Easy One-Pot Synthesis of Fused Heterocycles from 1,2-Diaza-1,3-dienes. Eur. J. Org. Chem. 2011, 2924–2927. [Google Scholar] [CrossRef] [Scilit]
  28. Guillaume, J.; Lubell, W.D. Synthesis of Fused Heteroarylprolines and Pyrrolopyrroles. J. Org. Chem. 2004, 69, 4656–4662. [Google Scholar]
  29. Lee, S.; Chataigner, I.; Piettre, S.R. Facile Dearomatization of Nitrobenzene Derivatives and Other Nitroarenes with N-Benzyl Azomethine Ylide. Angew. Chem. Int. Ed. 2011, 50, 472–476. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  30. Liu, H.; Zheng, C.; You, S.-L. Catalytic C6 Functionalization of 2,3-Disubstituted Indoles by Scandium Triflate. J. Org. Chem. 2014, 79, 1047–1054. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  31. Yang, Y.; Ren, H.-X.; Chen, F.; Zhang, Z.-B.; Zou, Y.; Chen, C.; Song, X.-J.; Tian, F.; Peng, L.; Wang, L.-X. Organocatalytic Asymmetric Annulation between Hydroxymaleimides and Nitrosoarenes: Stereoselective Preparation of Chiral Quaternary N-Hydroxyindolines. Org. Lett. 2017, 19, 2805–2808. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  32. Rostovskii, N.V.; Novikov, M.S.; Khlebnikov, A.F.; Korneev, S.M.; Yufit, D.S. Cu(II)-catalyzed domino reaction of 2H-azirines with diazotetramic and diazotetronic acids. Synthesis of 2-substituted 2H-1,2,3-triazoles. Org. Biomol. Chem. 2013, 11, 5535–5545. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  33. Rostovskii, N.V.; Sakharov, P.A.; Novikov, M.S.; Khlebnikov, A.F.; Starova, G.L. Cu(I)–NHC-Catalyzed (2 + 3)-Annulation of Tetramic Acids with 2H-Azirines: Stereoselective Synthesis of Functionalized Hexahydropyrrolo[3,4-b]pyrroles. Org. Lett. 2015, 17, 4148–4151. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  34. Zhu, J.-N.; Chen, L.-L.; Zhou, R.-X.; Li, B.; Shao, Z.-Y.; Zhao, S.-Y. Copper-Catalyzed Oxidative Cyclization of Maleimides with Amines and Alkyne Esters: Direct Access to Fully Substituted Dihydropyrroles and Pyrrole Derivatives. Org. Lett. 2017, 19, 6044–6047. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  35. Vandyshev, D.Y.; Shikhaliev, K.S.; Potapov, A.Y.; Krysin, M.Y. Condensation of 1,2-diamino-4-phenylimidazole and N-arylmaleimides with the formation of new tetrahydroimidazo[1,5-b]pyridazines. Chem. Heterocycl. Comp. 2015, 51, 829–833. [Google Scholar] [CrossRef] [Scilit]
  36. Vandyshev, D.Y.; Shikhaliev, K.S.; Kokonova, A.V.; Potapov, A.Y.; Kolpakova, M.G.; Sabynin, A.L.; Zubkov, F.I. A novel method for the synthesis of pyrimido[1,2-a]benzimidazoles. Chem. Heterocycl. Comp. 2016, 52, 493–497. [Google Scholar] [CrossRef] [Scilit]
  37. Rudenko, R.V.; Komykhov, S.A.; Desenko, S.M.; Sen’ko, Y.V.; Shishkin, O.V.; Konovalova, I.S.; Shishkina, S.V.; Chebanov, V.A. A Comprehensive Study of the Heterocyclizations of N-Arylmaleimides and 6-Aminouracils. Synthesis 2011, 3161–3167. [Google Scholar] [CrossRef] [Scilit]
  38. Havrylyuk, D.; Zimenkovsky, B.; Lesyk, R. Synthesis and Anticancer Activity of Novel Nonfused Bicyclic Thiazolidinone Derivatives. Phosphorus Sulfur Silicon Relat. Elem. 2009, 184, 638–650. [Google Scholar] [CrossRef] [Scilit]
  39. Lesyk, R.; Vladzimirska, O.; Holota, S.; Zaprutko, L.; Gzella, A. New 5-substituted thiazolo[3,2-b][1,2,4]triazol-6-ones: Synthesis and anticancer evaluation. Eur. J. Med. Chem. 2007, 42, 641–648. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  40. Shah, K.R.; DeWitt Blanton, C. Reaction of Maleimides and Ethyl 3-Aminocrotonates, a Reinvesiation Leading to an Improved Synthesis of Pyrrolo[3,4-c] pyridines. J. Org. Chem. 1982, 47, 502–508. [Google Scholar] [CrossRef] [Scilit]
  41. Banwella, M.G.; Jonesa, M.T.; Loonga, D.T.; Luptona, D.W.; Pinkertona, D.M.; Rayb, J.K.; Willisa, A.S. A Pd[0]-catalyzed Ullmann cross-coupling/reductive cyclization approach to C-3 mono-alkylated oxindoles and related compounds. Tetrahedron 2010, 66, 9252–9262. [Google Scholar] [CrossRef] [Scilit]
  42. Kuckländer, U.; Hühnermann, W. Beobachtungen zum Mechanismus der Nenitzescu-Reaktion Synthese von 6-Hydroxy-indol-Derivaten. Arch. Pharm. 1979, 312, 515–526. [Google Scholar] [CrossRef] [Scilit]
  43. George, R.; Allen, G.R., Jr.; Pidacks, C.; Weiss, M.J. The Mitomycin Antibiotics. Synthetic Studies. XIV.1 the Nenitzescu Indole Synthesis. Formation of Isomeric Indoles and Reaction Mechanism. J. Am. Chem. Soc. 1966, 88, 2536–2544. [Google Scholar]
  44. Zhang, Y.; Chen, F.; Yang, Y.; Tang, C.-Z.; Tian, F.; Peng, L.; Wang, L.-X. An unexpected metal-free DMAP catalyzed Michael addition–elimination domino reaction between 2-naphthols and bromomaleimides for the effective construction of 3-arylmaleimides. Tetrahedron Lett. 2016, 57, 1261–1264. [Google Scholar] [CrossRef] [Scilit]
  45. Estevez, V.; Villacampa, M.; Menéndez, J.C. Recent advances in the synthesis of pyrroles by multicomponent reactions. Chem. Soc. Rev. 2014, 43, 4633–4657. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  46. Moss, T.A.; Nowak, T. Synthesis of 2,3-dicarbonylated pyrroles and furans via the three-component Hantzsch reaction. Tetrahedron Lett. 2012, 53, 3056–3060. [Google Scholar] [CrossRef] [Scilit]
  47. Li, X.; Li, H.; Yang, W.; Zhuang, J.; Wang, W. A mild and selective protecting and reversed modification of thiols. Tetrahedron Lett. 2016, 57, 2660–2663. [Google Scholar] [CrossRef] [Scilit]
Sample Availability: Samples of the compounds 8 are available from the authors.
Molecules 22 02035 sch001
Scheme 1. Retrosynthetic routes to pyrrolo[3,4-b]pyrroles.
Scheme 1. Retrosynthetic routes to pyrrolo[3,4-b]pyrroles.
Molecules 22 02035 sch001
Molecules 22 02035 sch002
Scheme 2. Reaction centers in bromomaleimides (1) and aminocrotonates (2).
Scheme 2. Reaction centers in bromomaleimides (1) and aminocrotonates (2).
Molecules 22 02035 sch002
Molecules 22 02035 sch003
Scheme 3. Probable direction of reclyzation of 1.
Scheme 3. Probable direction of reclyzation of 1.
Molecules 22 02035 sch003
Molecules 22 02035 sch004
Scheme 4. Reaction between 1 and 2.
Scheme 4. Reaction between 1 and 2.
Molecules 22 02035 sch004
Molecules 22 02035 g001
Figure 1. Molecular structure of pyrrolopyrrole (8c).
Figure 1. Molecular structure of pyrrolopyrrole (8c).
Molecules 22 02035 g001
Molecules 22 02035 sch005
Scheme 5. Possible sequences of reactions in the cascade formation of pyrrolopyrroles (8).
Scheme 5. Possible sequences of reactions in the cascade formation of pyrrolopyrroles (8).
Molecules 22 02035 sch005
Table 1. Reaction of 1 with 2.
Table 1. Reaction of 1 with 2.
EntryBromomaleimide, ArAminocrotonate, RProductTime (h)Yields 1 (%)
1Ph (1a)Ph (2a)8a546/53
2Ph (1a)4-MeOC6H4 (2b)8b577/69
34-EtC6H4 (1b)PhCH2 (2c)8c482/74
44-EtOC6H4 (1c)PhCH2 (2c)8d673/70
53,4-Cl2C6H3 (1d)Ph (2a)8e670/64
63,4-Cl2C6H3 (1d)PhCH2 (2c)8f669/61
1 Isolated yields; in two component reaction/in one-pot synthesis.

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Shikhaliev, K.; Sabynin, A.; Sekirin, V.; Krysin, M.; Zubkov, F.; Yankina, K. A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters. Molecules 2017, 22, 2035. https://doi.org/10.3390/molecules22112035

AMA Style

Shikhaliev K, Sabynin A, Sekirin V, Krysin M, Zubkov F, Yankina K. A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters. Molecules. 2017; 22(11):2035. https://doi.org/10.3390/molecules22112035

Chicago/Turabian Style

Shikhaliev, Khidmet, Artem Sabynin, Valeri Sekirin, Michael Krysin, Fedor Zubkov, and Kristina Yankina. 2017. "A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters" Molecules 22, no. 11: 2035. https://doi.org/10.3390/molecules22112035

APA Style

Shikhaliev, K., Sabynin, A., Sekirin, V., Krysin, M., Zubkov, F., & Yankina, K. (2017). A New Synthetic Route to Polyhydrogenated Pyrrolo[3,4-b]pyrroles by the Domino Reaction of 3-Bromopyrrole-2,5-Diones with Aminocrotonic Acid Esters. Molecules, 22(11), 2035. https://doi.org/10.3390/molecules22112035

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