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.

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.

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 stn class="Chemical">ructural 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 class="Chemical">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].

Scheme 1

Retrosynthetic routes to pyrrolo[3,4-b]pyrroles.

Another direction in the synthesis of pyrrolo[3,4-b]pyrroles is the anellation of the second n class="Chemical">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 n class="Chemical">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).

Scheme 2

Reaction centers in bromomaleimides (1) and aminocrotonates (2).

According to the well-known literature data on the reactions of maleimides with n class="Chemical">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).

Scheme 3

Probable direction of reclyzation of 1.

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 n class="Chemical">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).

Scheme 4

Reaction between 1 and 2.

Considering the simplicity of obtaining 2, we attempted multicomponent one-pot synthesis of pyrrolopyrroles (8). Preliminarily, the mixture of equimolar amounts of n class="Chemical">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).

Table 1

Reaction of 1 with 2.

Entry	Bromomaleimide, Ar	Aminocrotonate, R	Product	Time (h)	Yields 1 (%)
1	Ph (1a)	Ph (2a)	8a	5	46/53
2	Ph (1a)	4-MeOC6H4 (2b)	8b	5	77/69
3	4-EtC6H4 (1b)	PhCH2 (2c)	8c	4	82/74
4	4-EtOC6H4 (1c)	PhCH2 (2c)	8d	6	73/70
5	3,4-Cl2C6H3 (1d)	Ph (2a)	8e	6	70/64
6	3,4-Cl2C6H3 (1d)	PhCH2 (2c)	8f	6	69/61

1 Isolated yields; in two component reaction/in one-pot synthesis.

In the 1H NMR spectra of n class="Chemical">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-n class="Chemical">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.

Figure 1

Molecular structure of pyrrolopyrrole (8c).

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 n class="Disease">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).

Scheme 5

Possible sequences of reactions in the cascade formation of pyrrolopyrroles (8).

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 n class="Chemical">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 n class="Chemical">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 n class="Disease">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 ( with Aminocrotonates ( and Characterization Data of Pyrrolo[3,4-b]pyrroles (

Two-component reaction. A mixture of the corresponding bromomaleimide (0.002 mol) and n class="Chemical">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 n class="Chemical">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; n class="Chemical">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, CH3CHO); 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, CHPh); 4.80 (1H, d, J = 16.7 Hz, CHPh); 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; n class="Chemical">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, CH3CHO); 4.29 (1H, br. d, J = 10.5 Hz, H-6a); 4.48 (1H, d, J = 16.2 Hz, CHPh); 4.49 (1H, d, J = 10.5 Hz, H-3a); 4.73 (1H, d, J = 16.2 Hz, CHPh); 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; n class="Chemical">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; n class="Chemical">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; n class="Chemical">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; n class="Chemical">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, CH3CH); 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 n class="Chemical">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.