One-pot synthesis of alkyl pyrrole-2-carboxylates starting from β-nitroacrylates and primary amines

Abstract

Herein, we present a new, efficient, one-pot synthesis of pyrrole-2-carboxylate derivatives starting from ketal-functionalized β-nitroacrylates in combination with primary amines under acidic heterogeneous conditions.

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Pyrroles constitute one of the most important classes of nitrogen-containing heterocycles and, due to their importance, several procedures for synthesizing poly-functionalized pyrroles were reported.¹ In this context, pyrrole-2-carboxylate derivatives have been largely investigated for their activities,² and exploited as strategic starting materials, or key intermediates, for the preparation of biological active molecules, such as pyrrolnitrin and porphyrins.³

Given their great importance, over the years several methodologies have been proposed in the literature for the preparation of these molecules. The first one was the pioneering Kleinspehn's method, which involves the use of diethyl α-oximinomalonate in combination with 1,3-diketones under reductive conditions,⁴ then, analogous procedures based on the use of α-oximinomalonate or its amino reduced form were successively proposed.⁵ Additional synthetic strategies were developed by Barluenga from azabutadiene,⁶ and Gupton from 2-substituted vinamidinium or 3-aryl-3-chloropropeniminium salts.⁷ Further useful syntheses were reported by Tashiro, from 1,3-diketones,⁸ and Guillard from β-arylacroleins.⁹

Although these methodologies lead to the preparation of pyrrole-2-carboxylates in efficient ways, they present important limitations such as, the need of high temperature (80–140 °C) and inert atmosphere, the use of dangerous reactants (e.g. NaH) and unsustainable solvents (e.g. DMF, pyridine, AcOH).¹⁰ Furthermore, all the reported procedures involve an articulate work-up, with evident further disadvantages from ecological point of view.

Nowadays, the sustainability of a chemical process is one of the main aspects that must be considered, and the implementation of new green methodologies is of dramatic importance.¹¹ In this sense, following our on-going research project concerning the development of new low impacting procedures,¹² we focused our attention to ketal-functionalized β-nitroacrylates type 1, an emerging class of molecules that we have recently used in our laboratory as precursor of the indole system.¹³ In fact, the structure 1 seems to be ideal for the ex-novo ring construction and, herein, we report a new application of 1 in combination with primary amines 2 to synthesize the title compounds 6 (Scheme 1).

Scheme 1 Synthesis of trisubstituted pyrroles 6.

Our approach consists in a one-pot process (Scheme 2), which involves (i) an initial Michael addition of the primary ammine 2 to β-nitroacrylate 1,¹⁴ with the formation of the intermediate 3, (ii) the in situ acidic treatment of 3 giving the opening of 1,3-dioxolane ring (4), with the successive cyclization-aromatization of the former β-nitroacrylate moiety (5) and formation of pyrrole 6.

Scheme 2 Plausible mechanism.

In order to find the best reaction conditions, we investigated the reaction between ethyl 4-(2-methyl-1,3-dioxolan-2-yl)-3-nitrobut-2-enoate 1a (R = Me, R¹ = Et) and benzylamine 2a.

Thanks to the great reactivity of β-nitroacrylates, the conjugate addition of 2a to 1a allows the Michael adduct 3aa in quantitative yield, over 2 hours, under promoter free and solvent free conditions. On the other hands, with the aim to maximize the reaction efficiency of the cleavage–cyclization–aromatization domino process, a variety of acidic species and solvents were screened (Table 1).

Table 1 Optimization studies

Acid (g mmol^−1)	Solvent	Temp (°C)	Yield^a (%) of 6aa (h)
a Yield of pure isolated product.
p-TsOH·H2O (0.19)	2-MeTHF	40	32 (6)
p-TsOH·H2O (0.19)	2-MeTHF	60	45 (6)
Amberlyst 15 (0.4)	2-MeTHF	40	39 (6)
Amberlyst 15 (0.4)	2-MeTHF	60	66 (3)
Amberlyst 15 (0.4)	2-MeTHF	75	67 (3)
Amberlyst 15 (0.6)	2-MeTHF	60	62 (3)
Amberlyst 15 (0.2)	2-MeTHF	60	68 (3)
Amberlyst 15 (0.1)	2-MeTHF	60	22 (3)
Amberlyst 15 (0.2)	CPME	60	55 (3)
Amberlyst 15 (0.2)	EtOAc	60	48 (3)
Amberlyst 15 (0.2)	DCM	60	42 (3)
Acidic Al2O3 (0.2)	2-MeTHF	60	—
Montm. K10 (0.2)	2-MeTHF	60	—
H2SO4/SiO2 (0.2)	2-MeTHF	60	36 (3)
Zeolite HSZ320 (0.2)	2-MeTHF	60	11 (3)

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As reported in the Table 1, the best result for pyrrole 6aa (overall yield = 68%) was obtained over 3 hours, using Amberlyst 15 (200 mg mmol⁻¹) in 2-MeTHF, as green solvent,¹⁵ at 60 °C.

Then, we tested the generality of our protocol to a plethora of β-nitroacrylates 1 and amines 2 (Table 2). In all cases, pyrroles 6 were isolated in good overall yields (53–75%) with both aliphatic and aromatic amines, independently from the nature of substituents present on β-nitroacrylates.

Table 2 One-pot synthesis of pyrroles 6

	R	R^1		R^2	Time1 (h)	Time2 (h)	Yield^a (%) of 6
a Yield of pure isolated product.b The first step was performed in presence of 300 μL mmol^−1 of 2-MeTHF.
1a	Me	Et	2a	Bn	2	3	6aa	68
1a	Me	Et	2b	CH3(CH2)4	2	3	6ab	72
1a	Me	Et	2c	CH≡CCH2	2	3	6ac	68
1b	CH3(CH2)7	Et	2a	Bn	2	3	6ba	70
1c	p-Tol	Et	2d	4-MeOC6H4	3^b	20	6cd	60
1c	p-Tol	Et	2e	CH2 = CHCH2	2	3	6ce	70
1d	Me	i-Pr	2f	Ph	3	16	6df	75
1e	CH3(CH2)5	i-Bu	2g	i-Bu	2	3	6eg	73
1f	H	i-Bu	2h	i-Pr	2	15	6fh	64
1f	H	i-Bu	2f	Ph	3	16	6ff	63
1g	Me	Me	2c	CH≡CCH2	2	3	6gc	53
1g	Me	Me	2i	2-BnOC6H4	7	7	6gi	63

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Moreover, by the appropriate selection of the amines 2, even a variety of protecting groups at N-position (benzyl: 6aa and 6ba, allyl: 6ce and PMP: 6cd), and reactive functionalities such as double (6ce) and triple (6ac and 6gc) bonds were introduced. Successively, we applied our method to synthesize pyrrolebenzoxoazinone derivatives 7 (Fig. 1), a valuable class of biologically active molecules,¹⁶ starting from 1 and aminophenols (2k–l).

Fig. 1 Pyrrolebenzoxoazinone derivatives 7.

As reported in the Scheme 3, the synthesis was tested studying the reaction of 1g with 2j. Applying our reaction conditions the reaction gives the pyrrole 6gj (57% yield after purification), which in turn, was cyclized into the target compound 7gj, in quantitative yield, by treatment with p-toluensulfonic acid under refluxing toluene. Alternatively, the crude intermediate 6gj can be directly converted into 7gj (54% overall yield) avoiding the purification of the intermediate and minimizing the waste production.

Scheme 3 Synthesis of compounds 7.

The synthetic process was then applied to prepare the additional derivatives 7gk, 7fl, and 7hk.

Finally, in order to automate the process, we explored the reactivity of the starting materials 1a and 2b under flow chemical conditions (Scheme 4). A preliminary screening was carried out with the aim to optimize the reaction conditions in terms of concentration, residence time and stoichiometry. The best result was achieved using 0.2 M solution of 1a and 2b in 2-MeTHF, a flow rate of 0.05 ml min⁻¹ for each pumps, a coil reactor R₁ (PTFE, i.d. = 0.5 mm) having and internal volume of 10 mL (residence time, 100 minutes), an Omnifit column reactor R₂ heated at 60 °C and packed with Amberlyst 15 (1.5 g mmol⁻¹), and a back pressure regulator (BPR) set at ∼2 atm.

Scheme 4 Flow chemical synthesis of pyrrole 6ab.

Working under these reaction conditions, the pyrrole 6ab was synthesized in 70% of yield (vs. 72% in batch). The same conditions were extended to substrate 1a and 2c for synthesizing 6ac, which was isolated in 71% of yield (vs. 68% in batch). In particular the flow chemical synthesis of 6ac is of valuable interest, since it could be potentially submitted to further clickable manipulations.¹⁷

Conclusions

In conclusion, by our methodology it has been possible to synthesize several pyrroles introducing a variety of protecting group at N-position, as well as an assortment of both aliphatic and aromatics substituents at C-5. Furthermore, we demonstrated the applicability of our synthetic approach preparing benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-one derivatives, and we extended our methodology to flow chemical conditions demonstrating the easy process-automation.

Finally, by the choices of 2-MeTHF as solvent, and the use of Amberlyst A15 as solid acid, we could avoid any complicate aqueous work-up, saving resources and energy with evident advantages from sustainable point of view.

Acknowledgements

The authors thank the University of Camerino and MIUR-Italy (FIRB National Project “Metodologie di nuova generazione nella formazione di legami carbonio-carbonio e carbonio-eteroatomo in condizioni eco-sostenibili”) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13094d

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