Synthesis of Symmetric meso-H-Dipyrrin Hydrobromides from 2-Formyl­pyrroles

Abstract

The reaction of 2-formylpyrroles in acidic methanol gives the corresponding symmetric, meso-H-4,6-dipyrrin hydrobromides. This convenient strategy involves initial deformylation under the acidic conditions, followed by immediate in situ reaction of the resulting α-free pyrrole with the remaining 2-formylpyrrole in solution to give the dipyrrin hydrobromide salt in good yield.

The conjugated π-system of dipyrrins[1] [2] consists of two pyrrolic units linked by a methine bridge. Traditionally of interest as a building block for porphyrins, the dipyrrinato unit is now appreciated as a useful chromophore by which to invoke desirable features such as energy transfer and storage by the corresponding complexes.[3,4] Beyond the established utility of F-BODIPYs, i.e. –BF₂ complexes of dipyrrins,[5] [6] [7] [8] the luminescence properties[9] of the ligand and other dipyrrinato complexes have fostered the recent use of this framework as a component of dye-sensitized solar cells.[10] [11] Furthermore, Fe and Co dipyrrinato complexes have recently been shown to catalyze the amination of C–H bonds,[12] [13] following earlier work regarding Ir and Rh dipyrrinato complexes as hydrogenation catalysts.[14] Indeed, there are numerous recent reports describing the use of dipyrrinato complexes in applications as diverse as biological stains/probes, light harvesters and anticancer agents,[15] [16] [17] [18] [19] [20] all pointing towards a promising future for this underdeveloped ligand.

The most common synthetic route to dipyrrins is the MacDonald coupling,[21] [22] an acid-catalyzed condensation of a 2-formylpyrrole with a pyrrole that is unsubstituted in the 2-position, i.e., α-free (Scheme [1]).[1,2] Upon the addition of aqueous HBr to a 2-formylpyrrole and an α-free pyrrole, a dramatic color change typically ensues, turning the solution an immediate orange/brown/brick-red color dependent upon the nature of the substrates. Rapid precipitation of the dipyrrin hydrobromide salt occurs (Scheme [1], top). Both the color change and the precipitation are delayed when the α-free pyrrole is electron-poor; the presence of electron-withdrawing substituents decreases the nucleophilicity of the pyrrole.[23] In some cases, an undesired symmetric dipyrrin forms under these conditions, resulting from competitive self-condensation of the 2-formylpyrrole (Scheme [1], bottom).[2]

Symmetrical dipyrrins are usually prepared via: a) reacting two equivalents of an α-free pyrrole with formic acid; b) acid-catalyzed hydrolysis, decarboxylation and condensation of pyrrole-2-carboxylates in formic acid; or c) a MacDonald coupling in which the α-free component and the 2-formylpyrrole have the same substitution pattern.[24] Wu and Burgess reported the preparation of symmetric F-BODIPYs from 2-formylpyrroles, eliminating the use of an α-free pyrrole.[25] BODIPYs were isolated via in situ trapping of the dipyrrin, demonstrating the one-pot synthesis of BODIPYs from 2-formylpyrroles. As such, just as α-free pyrroles can be generated via the acid-catalyzed decarboxylation of 2-carboxylate pyrroles so the precedent was demonstrated for the deformylation of 2-formylpyrroles.

We herein report the efficient synthesis and isolation of symmetric, meso-H-dipyrrins formed from 2-formylpyrroles in the presence of acids (Scheme [2]). As well as being extremely convenient, this strategy complements existing methods by enabling the high-yielding synthesis of symmetric dipyrrins where the α-free pyrrole has electron-withdrawing functional groups or may not be easily accessed.

To investigate the formation of dipyrrins via acid-catalyzed deformylation (Scheme [2]), 3,5-dimethyl-4-ethyl-2-formylpyrrole (1a) was chosen as a test substrate (Table [1]). First, a methanolic solution of 1a and 1.1 equivalents of 48% aqueous HBr were stirred at room temperature. Although analysis using TLC indicated that some dipyrrin had formed after 48 hours, significant amounts of starting material remained (entry 1). Elevating the reaction temperature to 40 °C induced a gradual color change and the precipitation of the product after five hours (entry 2). However, heating the reaction mixture at 70 °C for just two hours returned a 72% yield of the required dipyrrin hydrobromide (entry 3), and the yield was elevated to 84% after just one hour with the use of excess HBr (entry 4). The use of acetic acid, acetonitrile or dichloroethane was also somewhat effective, but longer reaction times were required and lower yields resulted (entries 5–7). The use of TFA as acid was effective (entry 8), but for convenience we decided to pursue the more crystalline hydrobromide salts. Presumably,[25] the mechanism involves (some of) the 2-formylpyrrole undergoing deformylation to give the α-free analogue which immediately undergoes rapid condensation, at 40 °C, with the remaining unreacted 2-formylpyrrole; this was supported using ¹H NMR spectroscopy to monitor a reaction in MeOD. However, the regioselective formation of 2c potentially points to some concerted character.

A variety of 2-formylpyrroles were then subjected to the optimized reaction conditions to evaluate the scope of the methodology (Table [2]). Analogues bearing alkyl (2a–e), keto (2f–h), alkanoate (2g–j) and conjugated ester (2k,l) substituents all reacted as expected to give the requisite dipyrrin salts. For the cases where yields are only moderate, the microcrystallinity of these dipyrrins hampered isolation, e.g. 2h. Furthermore, the ethoxy groups of 1g and 1h inevitably underwent exchange in acidic methanol, and gave the methyl ester-containing dipyrrins 2g and 2h, respectively.

Table 2 Dipyrrin Hydrobromide Salts from 2-Formylpyrroles

Dipyrrin	R1	R2	R3	Isolated yield (%)
2a	Me	Et	Me	84
2b	Me	Me	Me	72
2c	Me	Et	H	63a
2d	Me	(CH2)4Me	Me	79
2e	Me	(CH2)6Me	Me	75
2f	Me	Ac	Me	83
2g	Et	COCH2CH2CO2Me	Me	79
2h	Et	CO(CH2)4CO2Me	Me	50
2i	Me	CH2CO2Me	Me	65
2j	Me	CH2CH2CO2Me	Me	84
2k	Me	CO2Bu	Me	79
2l	Me	CO2Bn	Me	90

^a Ratio of symmetric:asymmetric dipyrrins = 9:1.

Overall, the synthesis of symmetric dipyrrins via the respective 2-formylpyrrole under acidic conditions in methanol, is convenient and high yielding at elevated temperatures.[26] [27]

Acknowledgment

This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC).

• References and Notes

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• 2 Wood TE, Uddin IM, Thompson A In Handbook of Porphyrin Science . Kadish KM, Smith K, Guilard R. World Scientific; New Jersey: 2010: 235
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• 3 Khan TK, Bröring M, Mathur S, Ravikanth M. Coord. Chem. Rev. 2013; 257 (15–16) (15) 2348
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• 4 Mondal P, Chaudharya A, Rath SP. Dalton Trans. 2013; 42: 12381
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• 5 Benstead M, Mehl GH, Boyle RW. Tetrahedron 2011; 67: 3573
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• 6 Boens N, Leen V, Dehaen W. Chem. Soc. Rev. 2012; 41: 1130
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• 7 Loudet A, Burgess K. Chem. Rev. 2007; 107: 4891
  CrossrefPubMedSearch in Google Scholar
• 8 Ziessel R, Ulrich G, Harriman A. New J. Chem. 2007; 31: 496
  CrossrefSearch in Google Scholar
• 9 Baudron SA. Dalton Trans. 2013; 42: 7498
  CrossrefPubMedSearch in Google Scholar
• 10 Li G, Bomben PG, Robson KC. D, Gorelsky SI, Berlinguette CP, Shatruk M. Chem. Commun. 2012; 48: 8790
  CrossrefSearch in Google Scholar
• 11 Li G, Hu K, Yi C, Knappenberger KL, Meyer GJ, Gorelsky SI, Shatruk M. J. Phys. Chem. C 2013; 117: 17399
  CrossrefSearch in Google Scholar
• 12 Hennessy ET, Betley TA. Science 2013; 340: 591
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• 13 King ER, Hennessy ET, Betley TA. J. Am. Chem. Soc. 2011; 133: 4917
  CrossrefSearch in Google Scholar
• 14 Yadav M, Singh AK, Pandey DS. Organometallics 2009; 28: 4713
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• 15 Ding Y, Li X, Li T, Zhu W, Xie Y. J. Org. Chem. 2013; 78: 5328
  CrossrefSearch in Google Scholar
• 16 Gupta RK, Pandey R, Sharma G, Prasad R, Koch B, Srikrishna S, Li P.-Z, Xu Q, Pandey DS. Inorg. Chem. 2013; 52: 3687
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• 17 Gupta RK, Sharma G, Pandey R, Kumar A, Koch B, Li P.-Z, Xu Q, Pandey DS. Inorg. Chem. 2013; 52: 13984
  CrossrefSearch in Google Scholar
• 18 Hall JD, McLean TM, Smalley SJ, Waterland MR, Telfer SG. Dalton Trans. 2010; 39: 437
  CrossrefSearch in Google Scholar
• 19 Klein JH, Sunderland TL, Kaufmann C, Holzapfel M, Schmiedel A, Lambert C. Phys. Chem. Chem. Phys. 2013; 15: 16024
  CrossrefSearch in Google Scholar
• 20 McLean TM, Moody JL, Waterland MR, Telfer SG. Inorg. Chem. 2012; 51: 446
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• 21 MacDonald SF. J. Chem. Soc. C 1952; 4176
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• 23 Paine JB. III In The Porphyrins . Vol. I. Dolphin D. Chap. 4 Academic Press; New York: 1978: 101
  CrossrefSearch in Google Scholar
• 24 Tu B, Wang C, Ma J. Org. Prep. Proced. Int. 1999; 31: 349
  CrossrefSearch in Google Scholar
• 25 Wu L, Burgess K. Chem. Commun. 2008; 4933
• 26 General Procedure for the Synthesis of meso-H-4,6-Dipyrrin Hydrobromides: Aqueous HBr (48%, 1 mL) was added to a solution of 2-formylpyrrole (100 mg, 1 equiv) in MeOH (2 mL). The reaction mixture was then heated at reflux temperature, with stirring, for 1 h or until all starting material was consumed, monitored using thin layer chromatography (30% EtOAc–hexanes). The precipitated product was collected using suction filtration and the residue was washed with Et₂O to yield the respective meso-H-4,6-dipyrrin hydrobromide.
• 27 1,3,7,9-Tetramethyl-2,8-diethyl-4,6-dipyrrin Hydrobromide (2a): The title compound was isolated as a red solid (93 mg, 84% yield); mp 225 °C (dec.). ¹H NMR (300 MHz, CDCl₃): δ = 12.90 (br s, 2 H), 7.01 (s, 1 H), 2.65 (s, 6 H), 2.41 (q, 4 H), 2.25 (s, 6 H), 1.06 (t, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.9, 141.4, 130.7, 126.3, 118.8, 17.4, 14.6, 13.0, 10.2. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₅N₂: 257.2012; found: 257.2018.

• References and Notes

• 1 Wood TE, Thompson A. Chem. Rev. 2007; 107: 1831
  CrossrefPubMedSearch in Google Scholar
• 2 Wood TE, Uddin IM, Thompson A In Handbook of Porphyrin Science . Kadish KM, Smith K, Guilard R. World Scientific; New Jersey: 2010: 235
  Search in Google Scholar
• 3 Khan TK, Bröring M, Mathur S, Ravikanth M. Coord. Chem. Rev. 2013; 257 (15–16) (15) 2348
  CrossrefSearch in Google Scholar
• 4 Mondal P, Chaudharya A, Rath SP. Dalton Trans. 2013; 42: 12381
  CrossrefSearch in Google Scholar
• 5 Benstead M, Mehl GH, Boyle RW. Tetrahedron 2011; 67: 3573
  CrossrefSearch in Google Scholar
• 6 Boens N, Leen V, Dehaen W. Chem. Soc. Rev. 2012; 41: 1130
  CrossrefPubMedSearch in Google Scholar
• 7 Loudet A, Burgess K. Chem. Rev. 2007; 107: 4891
  CrossrefPubMedSearch in Google Scholar
• 8 Ziessel R, Ulrich G, Harriman A. New J. Chem. 2007; 31: 496
  CrossrefSearch in Google Scholar
• 9 Baudron SA. Dalton Trans. 2013; 42: 7498
  CrossrefPubMedSearch in Google Scholar
• 10 Li G, Bomben PG, Robson KC. D, Gorelsky SI, Berlinguette CP, Shatruk M. Chem. Commun. 2012; 48: 8790
  CrossrefSearch in Google Scholar
• 11 Li G, Hu K, Yi C, Knappenberger KL, Meyer GJ, Gorelsky SI, Shatruk M. J. Phys. Chem. C 2013; 117: 17399
  CrossrefSearch in Google Scholar
• 12 Hennessy ET, Betley TA. Science 2013; 340: 591
  CrossrefPubMedSearch in Google Scholar
• 13 King ER, Hennessy ET, Betley TA. J. Am. Chem. Soc. 2011; 133: 4917
  CrossrefSearch in Google Scholar
• 14 Yadav M, Singh AK, Pandey DS. Organometallics 2009; 28: 4713
  CrossrefSearch in Google Scholar
• 15 Ding Y, Li X, Li T, Zhu W, Xie Y. J. Org. Chem. 2013; 78: 5328
  CrossrefSearch in Google Scholar
• 16 Gupta RK, Pandey R, Sharma G, Prasad R, Koch B, Srikrishna S, Li P.-Z, Xu Q, Pandey DS. Inorg. Chem. 2013; 52: 3687
  CrossrefSearch in Google Scholar
• 17 Gupta RK, Sharma G, Pandey R, Kumar A, Koch B, Li P.-Z, Xu Q, Pandey DS. Inorg. Chem. 2013; 52: 13984
  CrossrefSearch in Google Scholar
• 18 Hall JD, McLean TM, Smalley SJ, Waterland MR, Telfer SG. Dalton Trans. 2010; 39: 437
  CrossrefSearch in Google Scholar
• 19 Klein JH, Sunderland TL, Kaufmann C, Holzapfel M, Schmiedel A, Lambert C. Phys. Chem. Chem. Phys. 2013; 15: 16024
  CrossrefSearch in Google Scholar
• 20 McLean TM, Moody JL, Waterland MR, Telfer SG. Inorg. Chem. 2012; 51: 446
  CrossrefSearch in Google Scholar
• 21 MacDonald SF. J. Chem. Soc. C 1952; 4176
• 22 Shanmugathasan S, Edwards C, Boyle RW. Tetrahedron 2000; 56: 1025
  CrossrefSearch in Google Scholar
• 23 Paine JB. III In The Porphyrins . Vol. I. Dolphin D. Chap. 4 Academic Press; New York: 1978: 101
  CrossrefSearch in Google Scholar
• 24 Tu B, Wang C, Ma J. Org. Prep. Proced. Int. 1999; 31: 349
  CrossrefSearch in Google Scholar
• 25 Wu L, Burgess K. Chem. Commun. 2008; 4933
• 26 General Procedure for the Synthesis of meso-H-4,6-Dipyrrin Hydrobromides: Aqueous HBr (48%, 1 mL) was added to a solution of 2-formylpyrrole (100 mg, 1 equiv) in MeOH (2 mL). The reaction mixture was then heated at reflux temperature, with stirring, for 1 h or until all starting material was consumed, monitored using thin layer chromatography (30% EtOAc–hexanes). The precipitated product was collected using suction filtration and the residue was washed with Et₂O to yield the respective meso-H-4,6-dipyrrin hydrobromide.
• 27 1,3,7,9-Tetramethyl-2,8-diethyl-4,6-dipyrrin Hydrobromide (2a): The title compound was isolated as a red solid (93 mg, 84% yield); mp 225 °C (dec.). ¹H NMR (300 MHz, CDCl₃): δ = 12.90 (br s, 2 H), 7.01 (s, 1 H), 2.65 (s, 6 H), 2.41 (q, 4 H), 2.25 (s, 6 H), 1.06 (t, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.9, 141.4, 130.7, 126.3, 118.8, 17.4, 14.6, 13.0, 10.2. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₅N₂: 257.2012; found: 257.2018.

• Supplementary Material