New synthesis of unsymmetrically-substituted 2,5-diarylpyrroles from homopropargyl sulfonamides

Abstract

Unsymmetrically-substituted 2,5-diarylpyrroles were prepared by 5-endo-dig cyclization with consecutive deprotection of homopropargyl sulfonamides. Stepwise elaboration of an aldehyde allows the introduction of a variety of functional aryl moieties at the pyrrole ring.

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Heterocyclic compounds are of great importance since they are widely distributed in nature and have shown great potential as components in the design of macromolecules.¹ The introduction of heteroatoms such as nitrogen into macromolecular systems introduces particular physical and chemical properties compared to the carbon-only systems.² Pyrrole rings are especially well known as π-conjugated aromatic heterocyclic moieties and have been used extensively as building blocks of a broad range of macrocycles including porphyrins,³ corroles,⁴ and calixpyrroles.⁵ In addition, pyrrole groups have been demonstrated to be indispensable to the functions of naturally occurring and synthetic prodigiosin and tambjamine derivatives (Fig. 1), which are known to possess substantial antimalarial, immunosuppressive and anticancer potencies due to their H⁺/Cl⁻ binding and transmembrane transport properties.⁶ Preorganization of a polarized hydrogen-bond about the pyrrole ring, forming a central binding pocket, is of great importance for the operation of macrocycles and transmembrane transporter systems.

Fig. 1 Natural compounds prodigiosin and tambjamine C.

Prior to this work, we had envisioned synthesis of a variety of anion receptors based on an oligomeric aryl-pyrrole framework. Thus, we set out to explore the potential synthetic methodologies towards pyrroles bearing aryl groups only at the 2,5-positions. Maintaining the 3,4-positions substituent-free allows for the preparation of systems with lower molecular weights (<500 Da), which is one of the requirements stipulated by the Lipinski rules for pharmaceuticals, supposed to increase membrane permeability in biological systems.⁷ Various routes for the synthesis of multi-substituted pyrrole moieties have been investigated.⁸ There also exist methods for the preparation of 2,5-diarylpyrrole derivatives usually containing an additional electrophilic substituent other than a hydrogen atom at the 3 or 4 positions.⁹ Other known methods involve azides,^10a boronic acid/esters,^10b toxic stannyl compounds,¹¹ or unstable intermediates requiring glovebox conditions are available.¹² Other useful methods involve 1,4-butanediones¹³ but these are less flexible for syntheses of unsymmetrical derivatives.

A recent development in indole synthesis describes the tetra-n-butylammonium fluoride (TBAF)-promoted cyclization of 1-acetyl-2-tosylaminophenyl derivatives leading to unprotected indole compounds.¹⁴ There are three aspects to the function of TBAF in this reaction: the strongly basic character of the fluoride ion results in deprotonation of the sulfonamide with subsequent reaction of the nitrogen at the acetylene forming an N-tosylindole ring; nucleophilic fluoride ions lead directly to detosylation giving the 1H-indole moiety; finally, tetra-n-butylammonium counterions promote the solubility of the fluoride ion in the appropriate solvent. To investigate the potency of TBAF in the synthesis of 2,5-diarylpyrroles a series of homopropargyl sulfonamides was prepared (Scheme 1). Acid-catalyzed condensation reaction on p-methoxybenzaldehyde (1) with p-toluenesulfonamide yielded the corresponding N-tosylimine 2 in 89% yield. Subsequently, Barbier reaction of the N-tosylimine 2 with excess propargylzinc bromide yielded homopropargyl sulfonamide 3 in quantitative yield. Sonogashira reactions of the terminal acetylene of sulfonamide 3 with various aryl halides gave sulfonamide derivatives 4a–e in excellent yields (65–86%; Scheme 1).

Scheme 1 Synthesis of homopropargyl sulfonamides 4a–e, 2,5-diarylpyrroles 5a–c and 2-pyrroline 6.

Treating CF₃-substituted propargyl sulfonamides 4a and 4b with an excess of TBAF·3H₂O (5 equiv.) in DMF at 80 °C for 48 h resulted in the formation of 2,5-diarylpyrroles 5a and 5b in excellent yields (74% and 68%, respectively; Scheme 1). The ease with which the CF₃-substituted aryl groups can be introduced onto the pyrrole ring is very useful for tuning the lipophilicity and acidity of molecular receptors. In addition, formation of the pyrrole ring starting from a benzaldehyde allows for the smooth introduction of an electron rich aryl-group without the formation of instable intermediates, making this methodology suitable for various applications.

Under the same reaction conditions (TBAF·3H₂O, DMF, 80 °C, 48 h) only 20% yield of pyrrole 5c was derived from sulfonamide 4c while for 4d only trace amounts of pyrrole 5d were obtained, leaving most of the starting material 4d intact (Scheme 1). A potential explanation for this lies in the lower electron withdrawing character of pyridinyl and phenyl groups relative to CF₃-substituted phenyl groups. This results in a weaker induced δ⁺ charge on the acetylene moiety making nitrogen atom insertion at the sp-hybridized carbon atom more difficult. Even at higher temperatures (stirring at 160 °C) no noteworthy changes were observed and again 18% and trace amounts of pyrrole 5c and 5d, respectively, were obtained.

Reaction of a more electron deficient pyridinyl derivative 4e, containing a methyl ester in the 6-position, resulted solely in the hydrolysis of the ester function without any cyclization. Interestingly, upon exposure of the aryl-free sulfonamide 3 to these cyclization/deprotection reaction conditions (TBAF·3H₂O, DMF, 80 °C, 48 h) the reaction terminated upon completion of the 5-endo-dig cyclization without deprotection occurring resulting in the N-tosyl protected 2-pyrroline 6 in excellent yield (69%; Scheme 1).

When the cyclization/deprotection reaction on a sulfonamide was neutralized after 24 h a mixture of N-tosyl-2-pyrroline and 1H-pyrrole was obtained. Therefore, the reaction sequence can be considered to commence with an initial 5-endo-dig cyclization upon deprotonation of the N-tosylamide, followed by deprotection through elimination of sulfinic acid, and finally tautomerization leads to formation of the pyrrole ring (Scheme 2).

Scheme 2 Proposed reaction sequence from sulfonamide to pyrrole.

To extend the scope of applicable aryl groups the introduction of a transition metal catalyst to promote the 5-endo-dig cyclization was investigated. Catalytic amounts of various transition metal salts including AuCl₃, AgOAc, AgNO₃, and Ag₂CO₃ have been reported to promote 5-endo-dig cyclization of terminal alkyne homopropargyl sulfonamides.^8c,d,15 Unfortunately, upon reaction of aryl substituted sulfonamide 4a with Au or Ag salts no cyclization occurred and mostly the starting material was recovered. Furthermore, the palladium-catalyzed intramolecular hydroamination of o-alkynylaniline and homopropargyl amide derivatives has proven extremely useful for the synthesis of indoles and multisubstituted pyrrole rings.^8b,16 Here, activation of the carbon–carbon triple bond towards nucleophilic attack by π-coordination to a Pd species leads to an increase in the electrophilicity of the triple bond, and is followed by 5-endo-dig cyclization with migratory insertion and consecutive elimination of the Pd species.

When sulfonamide 4c was subjected to the earlier established reaction conditions (TBAF·3H₂O, DMF, 80 °C, 48 h) with the addition of a catalytic amount of Pd(PPh₃)₂Cl₂ (10 mol%) no significant improvement of the reaction outcome was observed (23%). Therefore, we set out to investigate the use of a palladium catalyst to induce 2,5-diaryl-2-pyrroline formation. Homopropargyl sulfonamide 4c was stirred with Pd(PPh₃)₂Cl₂ as catalyst and K₂CO₃ (5 equiv.) as a base in DMF at 80 °C for 24 h leading to a 60% yield of N-tosyl-2-pyrroline 7c (Scheme 3). Consecutive addition of an excess of NaOH (20 equiv.; 80 °C, 3 h) resulted in the deprotected pyrrole 5c in 48% overall yield (2 steps; Scheme 3). From this outcome the yield for the deprotection of the pyrroline 7c can be deduced to be 80%. Interestingly, while for 4b the TBAF-assisted cyclization/deprotection reaction gave an excellent conversion to pyrrole 5b, the palladium-assisted cyclization afforded N-tosylpyrroline 7b in a modest 27%. Under the same conditions phenyl derivative 4d resulted in only traces of pyrroline 7d. Fortunately, increasing the temperature (100 °C) and extending the reaction time (48 h) resulted in an improved conversion to the N-tosyl-2-pyrroline 7d (33%). Further elevation of the temperature (120 °C) and extension of the reaction time (72 h) did not further improve the reaction outcome (30%). Deprotection of 7d by reaction with an excess of NaOH in wet DMF at 80 °C for 72 h finally yielded pyrrole 5d in a modest 18% yield (77% of the starting material 7d was recovered).

Scheme 3 Synthesis of 2,5-diarylpyrrolines 7b–d and 2,5-diarylpyrroles 5c and d.

Single crystals of 5c suitable for X-ray diffraction were grown by vapour diffusion of hexane into a CHCl₃ solution of 5c stored under a nitrogen atmosphere and shielded from light (Fig. 2). The structure appears almost completely planar with the aryl groups maintained at an angle of approximately 137°. Nitrogen atoms of both pyrrole and pyridine rings are oriented to the same side, presumably due to a weak N–H–N hydrogen bonding interaction.‡

Fig. 2 Crystal structure of 5c: (a) edge view, (b) plan view.

In conclusion, we present new approaches towards unsymmetrical-substituted 2,5-diarylpyrroles by 5-endo-dig cyclization and simultaneous deprotection of readily available homopropargyl sulfonamides. A straightforward methodology utilizing TBAF is very promising for the development of rather electron deficient derivatives while, alternatively, palladium-assisted cyclization with a consecutive deprotection step opens up the route to pyrrolopyridine derivatives. Currently, we are applying these synthetic techniques in the development of the relatively unexplored molecular receptors consisting of carefully arranged pyrrole rings forming a highly preorganized hydrogen-bonding pocket with potentially interesting supramolecular properties. Further investigation of the effect of substituents is required for a more profound understanding of the reaction involved here and will establish these new approaches towards 2,5-diarylpyrroles and N-tosyl-2,5-diaryl-2-pyrrolines allowing for the 2,5-diarylpyrrole sequence to be explored more intensively.

The authors gratefully acknowledge the Japan Society for the Promotion of Science (JSPS) for financial support and a postdoctoral fellowship for W.VR. The World Premier International (WPI) Research Center for Materials Nanoarchitectonics (MANA) and National Institute for Materials Science (NIMS) are also thanked for financial support.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures and data for all novel compounds, and CIF file for 5c. CCDC 962821. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra46579a

‡ X-ray data for 5c: Rigaku Varimax Saturn; T = 100(2) K. monoclinic, space group P21, a = 5.6181(4) Å, b = 21.2320(19) Å, c = 10.8628(9) Å, α = 90°, β = 98.103(2)°, γ = 90°, V = 1282.82(18) ų, Z = 4, ρ_calc = 1.291 g cm⁻³, μ = 0.082 mm⁻¹. 3938 reflections, 3256 independent. Final wR₂ = 0.1152, R₁ = 0.0414 and R_int = 0.0335. GoF = 1.031.

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