INTRODUCTION:

Dipyrromethanes are compounds known for more than a century and are widely being used as important building blocks for the synthesis of porphyrins,¹ Calixpyrrols² and Corroles.³ which have recent applications as chiral catalysts, chiral sensors, synthetic receptors for small molecular devices, potential sensitizers for photodynamic cancer therapy.^4-6 In the past decades, a variety of conditions have been established for the synthesis of dipyrromethanes in the presence of various catalysts such as p-toluenesulfonic acid,⁷ TiCl₄,⁸ CF₃COOH,⁹ pyrrolidinium tetrafluoroborate.¹⁰ In the synthesis of dipyrromethanes most of the conditions are based on the acid catalyzed condensation of pyrrole with aldehyde. Recently, several methods have been developed, for the synthesis of dipyrromethanes in various catalyst such as ionic liquid [Hmim] BF₄,¹¹ HCL/water,¹² cation exchange resin,¹³ metal triflate catalysis,¹⁴ HCl,¹⁵ iodine/CH₂Cl₂,¹⁶ InCl₃.¹⁷ However, all of the synthetic protocols reported so far suffer from disadvantages such as, use of metal¹⁴ and expensive reagent,¹³ prolonged reaction time,¹⁵ use of organic solvent,¹⁶ harsh reaction condition,¹⁵ use of excess pyrrole ¹⁴and low yield.¹¹ Because of that the researcher still continuous to have a better methodology for the synthesis of dipyrromethanes in terms of simplicity, eco-friendly, economic viability, high yielding at lowest pyrrole/aldehyde ratio which is achieved by using iodine under solvent free condition. In recent years I₂ in solvent free conditions was found to be an efficient catalyst in terms of handling, temperature, reaction time and yield for various organic transformations.¹⁸

MATERIAL AND METHODS:

Purity of the compounds were checked by thin layer chromatography (TLC) on Merck silica gel 60 F254 pre-coated sheets Melting points of the synthesized compounds were determined in open-glass capillaries on a stuart-SMP10 melting point apparatus. IR absorption spectra were recorded on a Perkin Elmer 1650 FTIR using KBr pellets in the range of 4,000-450 cm^-1. ¹H-NMRs were recorded on a Bruker spectrometer operating at 400 MHz. The ¹H-NMR chemical shifts are reported as parts per million (ppm) downfield from TMS (Me₄Si) used as an internal standard. Elemental analyses for C, H, and N were performed using a EuroVector CHNS-O elemental analyzer. All compounds were known, and obtained physical and spectroscopic data were compared with literatures data.^9c,13,14

General Procedure for the synthesis of meso-substituted dipyrromethanes

A mixture of pyrrole (2 mmol), aldehyde (1 mmol) and I₂ (0.1 mmol) was crushed in a mortar with a pestle at room temperature. Progress of reaction was monitored by TLC. After completion of reaction (< 1 min) the crude product was washed with water, dried and purified by column chromatography using silica gel with petroleum ether/chloroform as the eluent. Pure products were obtained as solids.

Data

5-(4-nitrophenyl)dipyrromethane: Yellow powder; mp: 159–160 ⁰C, IR (KBr) 3395, 3362, 3100, 1597, 1517, 1348, 1120, 1024, 805, 737, 661, 565 cm^_1; ¹H NMR(400 MHz, CDCl3): d 5.57 (s, 1H, mesoH), 5.85 (br s, 2H, 2C3–H), 6.14 (dd, 2H, J = 2.8, 5.7, 2C4–H), 6.74 (dd, 2H, J = 2.8, 4.2, 2C5–H), 7.37 (d, 2H, J = 8.6, H-Ar), 8.0 (br s, 2H, N–H), 8.13 (d, 2H, J = 8.8, Ar-H).; Anal. Calcd. For C₁₅H₁₃N₃O₂: C, 67.4; H, 4.9; N, 15.7. Found: C, 67.13; H, 4.94; N, 15.4.

RESULT AND DISCUSSION:

Scheme 1. Synthesis of 5-(4-nitrophenyl)dipyrromethane.

We began our study by grinding the mixture of pyrrole and 4-nitrobenzaldehyde (Scheme 1) under the reaction conditions described in table 1. Initially the mixture of pyrrole (5 mmol), 4-nitrobenzaldehyde (1 mmol) and I₂ (0.2 mmol) was ground in mortar with a pestle at room temperature under solvent free condition. The result demonstrated that moderate yield of the product (Entry 1). Thus, in further study we reduced pyrrole/aldehyde ratio up to 2:1 the result demonstrated that the best yield of the product (Entry 2). For evaluating the minimum amount of catalyst, I₂ was employed in 0.15, 0.1 and 0.05 mmol. However, result demonstrated that excellent yield of the product at 0.1 mmol of I₂ (Entry 4).

Table 1. Optimization for synthesis of 5-(4-nitrophenyl) dipyrromethane

Entry	Iodine (mmol)	Pyrrole/ aldehyde ratio	Time (min)	Yield^a (%)
1	0.2	5:1	< 1	72
2	0.2	2:1	< 1	97
3	0.15	2:1	< 1	98
4	0.1	2:1	< 1	99
5	0.05	2:1	2	68

^aIsolated yield of the product

Thus from all above data we confirmed that reaction gives excellent yield at lowest pyrrole/aldehyde ratio (2:1) and 0.1 mmol of I₂. When we compared this result with literature best result (Table 2) then it was cleared that all reported literatures were suffered from disadvantages such as expensive reagent,¹³ prolonged reaction time,^13,
15 use of organic solvent¹⁶ and use of excess pyrrole/aldehyde ratio.^9c Thus, in this article our strength is that we overcome all this disadvantages.

In order to confirm these interesting results, we applied this method to the synthesis of various meso-substituted dipyrromethanes (Scheme 2) and obtained results compared to literatures methods (Table 3).

R = 4-CH₃, 4-Br, 4-F, 2-NO₂, 4-OCH₃, 4-Cl, H, 2,6-di-Cl

Scheme 2. Synthesis of various meso-substituted dipyrromethanes

From table 3 it was cleared that there was no influence of the electronic nature of the substituent on the reaction time or yield. In the case of 5-(4-metoxyphenyl)dipyrromethane, Faugeras et al¹⁶ gave excellent yield (90 %) in short reaction time but they performed their work by using dichloromethane as a solvent and by using microwave oven, which is always harmful to the environment and having economically costlier. In the another case of 5-phenyldipyrromethane and 5-(2,6-dichlorophenyl) dipyrromethane, Rohand et al¹⁵ gave good yields (86 and 85 %) in prolonged reaction time but they performed their work by using large quantity of strong acid which is always hazardous to the environment. Thus, it is possible to affirm that this method allowed the reaction to proceed in shorter reaction time (< 1 min), furnishing excellent yield (97-99 %) by maintaining overall greenness of this reaction.

CONCLUSION:

In conclusion we have successfully developed an easy and rapid method for the quantitative synthesis of meso-substituted dipyrromethanes. The advantages such as non-toxic reagent, solvent free condition, lowest pyrrole/ aldehyde ratio, shorter reaction time, easy work up and excellent yield makes this reaction environmentally friendly and economically attractive.

Table 2. Synthesis of 5-(4-nitrophenyl)dipyrromethane comparison with well-known methods

	Rohand¹⁵	Naik¹³	Littler^9c	Faugeras¹⁶	I₂ (Grinding)
Solvent	HCl	―	―	CH₂Cl₂	―
Temperature	R. T.	R. T.	R. T.	30⁰c	R. T.
Catalyst	HCl	Cation exchange resin (T 63)	TFA	I₂	I₂
Pyrrole/aldehyde ratio	3:1	20:1	25:1	10:1	2:1
Reaction time	2 h	10 h	5 min	< 1 min	< 1 min
Yield (%)	97	61	56	84	99

Table 3. Comparison of the yields with best methods found in the literatures

Aldehydes	Isolated yield^a(%)/ Pyrrole: aldehyde ratio	Literatures best yield (%)/ Pyrrole: aldehyde ratio
4-methylbenzaldehyde	98/2:1	83/40:1^[*14]
4-bromobenzaldehyde	97/2:1	74/40:1^[*14]
4-fluorobenzaldehyde	98/2:1	77/20:1^[13]
2-nitrobenzaldehyde	98/2:1	73/20:1^[13]
4-methoxybenzaldehyde	99/2:1	90/10:1^[16]
4-chlorobenzaldehyde	97/2:1	77/20:1^[13]
Benzaldehyde	98/2:1	86/03:1^[15]
2,6-Dichlorobenzaldehyde	97/2:1	85/03:1^[15]

^aproducts were characterized by IR, ¹H·NMR, elemental analysis and coincided with literature data,^9c,13,14

*pyrrole/imine ratio instead of pyrrole/aldehyde

ACKNOWLEDGMENTS:

We would like to thank DST, New Delhi for financial assistance and Prof. Mohammed Tilawat Ali for providing necessary facilities for research work.

REFERENCES:

1. Temelli B, Unaleroglu C. Synthesis of meso-tetraphenyl porphyrins via condensation of dipyrromethanes with N-tosyl imines. Tetrahedron. 65(10); 2009: 2043-2050.

2. Gale PA, Anzenbacher PJr, Sessler JL. Calixpyrroles II. Coord. Chem. Rev. 222(1); 2001: 57-102.

3. Zhan H-Y, Liu H-Y, Chen H-J, et al. Preparation of meso-substituted trans-A₂B-corroles in ionic liquids. Tetrahedron Lett. 50(19); 2009: 2196-2199.

4. Sternberg ED, Dolphin D. Porphyrin-based Photosensitizers for Use in Photodynamic Therapy, Tetrahedron. 54(17); 1998: 4151.

5. Halterman RL, Mei X. Synthesis of D2-symmetric 5,10,15,20-tetraarylporphyrins from C2-symmetric Benzaldehydes and Achiral Aryldipyrromethanes, Tetrahedron Lett. 37(35); 1996: 6291.

6. Furusho Y, Kimura T, Mizuno Y, et al. Chirality-Memory Molecule: A D2- Symmetric Fully Substituted Porphyrin as a Conceptually New Chirality Sensor, J Am Chem Soc. 119(22); 1997: 5267.

7. (a)Boyle RW, Xie LY, Dolphin D. meso-phenyl Substituted Porphocyanines: A New Class of Functionalized Expanded Porphyrins. Tetrahedron Lett. 35(30); 1994: 5377-5380.

(b) Mizutani T, Ema T, Tomita, T, et al. Design and Synthesis of a Trifunctional Chiral Porphyrin with C₂ Symmetry as a Chiral Recognition Host for Amino Acid Esters J. Am. Chem. Soc. 116(10); 1994: 4240-4250.

8. Setsune J-I, Hashimoto M, Shiozawa K, et al. Synthesis of Atropisomerism of meso-Tetraarylporphyrins with Mixed meso-Aryl Groups Having ortho-Substituents. Tetrahedron. 54(8); 1998: 1407-1424.

9. (a)Srinivasan A, Sridevi B, Reddy MVR, et al. Improved Synthesis of Meso substituted 21-oxa and 21-Thia Tetra Phenyl Porphyrins. Tetrahedron Lett. 38(23); 1997: 4149-4152.

(b) Lee CH, Lindsay JS. One-Flask Synthesis of meso-Substituted Dipyrromethanes and their application in the Synthesis of Trans-Substituted Porphyrin Building Blocks. Tetrahedron. 50(39); 1994: 11427.

(c) Littler BJ, Miller MA, Hung C-H, et al. Refined Synthesis of 5-Substituted Dipyrromethanes. J. Org. Chem. 64(4); 1999: 1391-1396.

10. Biaggi C, Benaglia M, Raimondi L, et al. Organocatalytic synthesis of dipyrromethanes by the addition of N-methylpyrrole to aldehydes. Tetrahedron. 62(52); 2006: 12375-12379.

11. Gao GH, Lu L, Gao JB, et al. One-step Synthesis of Dipyrromethanes in the Presence of Ionic Liquid [Hmim]BF₄. Chin. Chem. Lett. 16(7); 2005: 900-902.

12. Sobral AJFN, Rebanda NGCL, Silva MD, et al. One-step Synthesis of dipyrromethanes in water. Tetrahedron Lett. 44(20); 2003: 3971-3973.

13. Naik R, Joshi P, Kaiwar SP, et al. Facile synthesis of meso-substituted dipyrromethanes and porphyrins using cation exchange resins. Tetrahedron. 59(13); 2003: 2207-2213.

14. Tamelli B, Unaleroglu CA. novel method for the synthesis of dipyrromethanes by metal triflate catalysis. Tetrhedron. 62(43); 2006: 10130-10135.

15. Rohand T, Dolusic E, Ngo TH, et al. Efficient synthesis of aryldipyrromethanes in water and their application in the synthesis of corroles and dipyrromethanes. ARKIVOK. (x); 2007: 307-324.

16. Faugeras P-A, Boëns B, Elchinger P-H, et al. Synthesis of meso-substituted dipyrromethanes using iodine-catalysis. Tetrahedron Lett. 51(35); 2010: 4630-4632.

17. Laha JK, Dhanalekshami S, Taniguchi M, et al. A scalable synthesis of meso-substituted dipyrromethanes. Org. Process Res. Dev. 7(6); 2003: 799-812.

18. (a) Das B, Laxminarayana K, Ravikanth B, et al. Iodine catalyzed preparation of amidoalkyl naphthols in solution and under solvent-free conditions. Journal of Molecular Catalysis A: Chemical. 261(2); 2007: 180–183.

(b) Banik BK, Fernandez M, Alvarez C. Iodine-catalyzed highly efficient Michael reaction of indoles under solvent-free condition. Tetrahedron Lett. 46(14); 2005: 2479–2482.

(c) Wang HS, Zeng JE. Iodine catalyzed efficient synthesis of symmetrical diaryl sulfoxides from arenes and thionyl chloride under solvent-free conditions. Chin. Chem. Lett. 18(12); 2007: 1447–1450.

(d) Pasha MA, Jayashankara VP. Molecular iodine catalyzed synthesis of aryl-14H-dibenzo[a, j]xanthenes under solvent free condition. Bioorganic & Medicinal Chemistry Letters. 17(3); 2007: 621–623.

Received on 17.06.2011 Modified on 05.07.2011

Asian J. Research Chem. 4(9): Sept, 2011; Page 1408-1410