1. Introduction

Synthetic protocols utilizing biomass resources as an alternative feedstock devoid of fossil fuel resources are becoming more attracting these days due to the growing concern for sustainable chemistry. In this context organic synthesis is focused on the development of new synthetic methods to replace the existing starting materials made by synthetic reactions with simple synthons obtained from natural materials. The trans-4-hydroxy-L-proline is one such sustainable synthon which can replace pyrrole for synthesizing various pyrrole derivatives, since it is obtained from the renewable resource, collagen.¹ Isolation of trans-4 hydroxy-L-proline from collagen is the most economical way of production^1a and collagen is the main component of connective tissue and the most abundant protein in mammals.^1b Various advantages associated with sustainable chemistry prompted us to explore trans-4-hydroxy-L-proline for the synthesis of variety of substituted pyrroles. Pyrroles are an important class of heterocycles obtained from nature having broad spectrum of biological profiles.² They are constituents of many structural motifs showing antitumor, immunosuppressant, anti HIV, anti-inflammatory and antioxidant activities.³ Apart from this, they are also widely used as materials with versatile applications in material science.⁴ Several methods are reported for the construction of the pyrrole moiety. Amongst them, the pyrrole ring generation via a cascade reaction using trans-4-hydroxy-L-proline is of recent development.¹ As such the N-arylatedpyrroles, whichhave been shown to be potent HIV inhibitors,^3h are constructed via cross-coupling of pyrrole with aryl halides. We have envisaged the combination of the above two concepts and report the successful synthesis of novel one pot domino procedure to construct the N-arylpyrroles using aryl halides and trans-4-hydroxy-L-proline (Scheme 1).

Scheme 1. trans-4-hydroxy-L-proline as pyrrole synthon.

2. Results and Discussion

We are successful in reacting iodobenzene and trans-4- hydroxy-L-proline in the presence of Copper Oxide nano- powder and potassium carbonate using with dimethylsulfoxide as a solvent at 100℃ yielding 53% of N-phenyl- pyrroles. An attempt is made in vain to improve the yields using various solvents and bases under the optimized conditions. When the reaction tried with various bases like potassium tert-butoxide, Lithium tert- butoxide, lithium carbonate, potassiumphosphate, Lithiumbis (trimethylsilyl) amide, sodium hydroxide, potassium hydroxide yield could not be increased. Similarly various solvents such as toluene, 1,4- dioxane, tetrahydrofuran, N-Methyl-2-pyrrolidone, and acet- onitrile were tried in vain to improve the yields as shown in Table 1. Out of all these attempts the best results were obtained by using copper oxide nanoparticles in dimethylsulfoxide as solvent and cesium carbonate as a base at 100℃ stirred for 24 hours. Having achieved the optimization of the reaction by suitable catalyst, base and solvent, we further explored the N-arylation with variety of aryl bromides. The reaction of arylbromides required 115℃ for the N-arylation. We extended the same reaction with various aryl bromides having different substituents at the ortho, para and meta positions.

Table 1. Screening of solvents and base a

The aryl bromides with methoxy and methyl substitutions on the ring gave better yields as shown in the Table 2. Aromatic systems like naphthalene, anthracene, and biphenyl bromides gave the products in good yields as shown in Table 2. Various other heteroaryl bromides like quinoline, benzodioxane, and thiophenes were also explored to extend the scope of the reaction, which gave good to moderate conversions to N-arylpyrrole derivatives (Table 2, entries 10-15). The aryliodides were easily converted to N-aryl pyrroles when compared to the bromides (Table 3). Iodobenzene with the benzyloxy group in the para position gave the highest yield, whereas the presence of a nitro group reduced the yield. However, it is observed that the yields were lower when an ortho substituent is present as compared to meta and para substituents on the ring.

Further we were interested to test the recyclability of copper oxide nanoparticles. After the reaction the nanoparticles were centrifuged to separate them from the reaction mixture, and then were washed with acetone and oven dried for the next run. Likewise we were able to recycle the Copper oxide nanoparticles up to five cycles without loss of activity (Table 4). The native and the fifth cycle nanoparticles were carefully analyzed for any modification during the reaction course. The nanoparticles were intact in shape and size before and after the five cycles as evident from the TEM, XRD data (supporting information).

Table 2. N-aryl pyrroles synthesis from various aryl bromidesa

Table 4. Recyclability of CuO nanoparticles a

3. Conclusions

In conclusion this is the first report of sustainable resource reaction of trans-4-hydroxy-L-proline, with various aryl halides, by a tandem one-pot cross-coupling reaction yields N-arylpyrroles via extrusion followed by redox amination.

TEM images of native Copper oxide nanoparticles

4. Experimental Section

Typical procedure for N-aryl pyrrole synthesis: A mixture of aryl halide (1 mmol), Copper oxide nanopowder (7.9 mg, 10 mol%), cesium carbonate (815 mg, 2.5 equiv), trans-4-hydroxy-L-proline ( 262 mg, 2 equiv ) were stirred in dimethylsulfoxide (2mL) under dry nitrogen atmosphere at respective temperature for 24h in a 25 mL round bottom flask equipped with a reflux condenser. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was allowed to cool to room temperature and was extracted with ethyl acetate (2 X 5 mL). The combined organic extracts were washed with water (2X5mL), dried over anhydrous sodium sulphate. The dried organic extracts were concentrated under reduced pressure and column chromatographed using hexanes/ethyl acetate as eluent to obtain the analytically pure product, which was characterized using ¹H, ¹³C-NMR and elemental analysis.

The spectral and analytical data are given for the molecules synthesized

1-phenyl-1H-pyrrole (table 2, entry 1): white solid, mp 58-61℃, 1H-NMR (300MHz, CDCl₃): δ= 6.27 (t, 2H), 7.02 (t, 2H), 7.18- 7.20 (m, 1H), 7.35-7.40 (m, 4H). ¹³C-NMR (75MHz, CDCl₃): δ = 110.4, 119.2, 120.4, 125.6, 129.3. Analitically calculated for: (C₁₀H₉N) C: 83.88, H: 6.34, N: 9.78, found C: 83.28, H: 6.26, N: 9.72.

1-(4-methoxyphenyl)-1H-pyrrole (table 2, entry 2): white solid, mp 111-113℃ , ¹H-NMR (300MHz,CDCl₃): δ= 3.81 (s, 1H), 6.22 (t, 2H) ,6.88-6.91( m,4H ),7.25-7.27 (m, 2H). ¹³C-NMR (75MHz, CDCl₃): δ = 55.4, 109.8, 114.5, 119.5, 122.1, 134.4, 157.5. Anal calcd for: (C₁₁H₁₁NO) C: 76.28, H: 6.40, N: 8.09; found C: 75.53, H: 6.33, N: 8.02.

1-(3-methoxyphenyl)-1H-pyrrole (table 2, entry 3): colorless oil, ¹H-NMR (300MHz, CDCl₃): δ=3.82 (t, 2H), 6.89-7.05 (m, 3H), 7.28 (m, 3H). ¹³C-NMR (75MHz, CDCl₃): δ= 55.39, 110.4, 110.8, 112.9, 119.4, 130.3, 141.9, 160.5. Analitically calculated: (C₁₁H₁₁NO) C: 76.28, H: 6.40, N, 8.09; found C: 75.78, H, 6.33; N, 7.98

1-(2-methoxyphenyl)-1H-pyrrole (table 2, entry 4 ): colorless oil, ¹H-NMR (300MHz,CDCl₃): δ =3.83 (s, 3H), 6.25(t, 2H), 6.90 (t, 2H), 6.97-6.99 (m, 2H), 7.18-7.27 (m, 2H) ¹³C-NMR (75MHz, CDCl₃):δ = 55.8, 108.8, 112.3, 121, 122.1, 125.8, 127.5, 130.3, 152.8 Analitically calculated for: (C₁₁H₁₁NO) C: 76.28; H: 6.40; N: 8.09; found C: 75.59; H: 6.33; N: 8.03.

1-p-tolyl-1H-pyrrole (table 2, entry 5): white solid, mp 82-85℃, ¹H-NMR (300MHz, CDCl₃): δ= 2.37 (s, 3H), 6.24 ( t, 2H), 6.97 (t, 2H), 7.15 (dd, 2H), 7.24 (dd, 2H). ¹³C-NMR (75MHz, CDCl₃): δ =20.7, 110.1, 119.3, 120.4, 129.9, 135.3, 138.4. Analitically calculated for: (C₁₁H₁₁N) C: 84.04, H: 7.05, N: 8.91; found C: 83.30, H: 6.95, N: 8.84.

1-(biphenyl-4-yl)-1H-pyrrole (table 2, entry 6): white solid, mp 183-188℃.¹H-NMR (300MHz, CDCl₃): δ = 6.3 (s,2H), 7.1 (s, 2H), 7.24-7.45 (m, 5H), 7.54-7.62 (m, 4H); ¹³C-NMR (75MHz, CDCl₃): δ =110.5, 119.2, 120.7, 126.9, 127.4, 128.2, 128.9, 138.5, 139.5, 140.2. Analitically calculated for: (C₁₆H₁₃N) C: 87.64, H: 5.98, N: 6.39; found: C: 87.58, H: 5.91, N: 6.34.

1-(anthracen-9-yl)-1H-pyrrole (table 2, entry 7): white solid, mp 149-153℃. ¹H-NMR (300MHz, CDCl₃): δ = 6.45 (s, 2H), 6.94 (s, 2H), 7.41-7.52 (m, 6H), 7.95-8.02 (d, 2H), 8.49 (s, 1H). ¹³C-NMR (75MHz, CDCl₃): δ = 108.8, 123.4, 124.5, 125.6, 126.8, 127.2, 128.1, 129.2, 131.3, 133.4. Analitically calculated for: (C₁₈H₁₃N) C: 88.86, H: 5.39, N, 5.76; found: C: 88.79, H: 5.31, N: 5.69.

1-(naphthalen-1-yl)-1H-pyrrole (table 2, entry 8): pale yellow oil, ¹H-NMR (300MHz, CDCl₃): δ= 6.32 (t, 2H), 6.93 (t, 2H), 7.42-7.51 (m, 1H), 7.81-7.88 (m, 2H). ¹³C-NMR (75MHz, CDCl₃): δ = 108.9, 123.2, 123.3, 125.2, 126.5, 126.6, 127.8, 128,129.8, 134.2 Analitically calculated for: (C₁₄H₁₁N) C: 87.01, H: 5.74, N: 7.25; found C: 86.26, H: 5.66, N: 7.17.

1-(naphthalen-2-yl)-1H-pyrrole (table 2, entry 9): white solid, mp 78-84℃. ¹H-NMR (300MHz, CDCl₃): δ= 6.31 (t, 2H), 7.14 (t, 2H), 7.27-7.51 (m, 3H), 7.54-7.57 (m, 1H ), 7.75-7.87(m, 4H). ¹³C-NMR (75MHz, CDCl₃): δ = 110.6, 117.4, 119.5, 120.2, 125.6, 127.1, 127.6, 127.8, 129.6, 129.9, 131.4, 133.8. Analitically calculated for: (C₁₄H₁₁N) C: 87.01, H: 5.74, N: 7.25; found C: 86.12, H: 5.57, N: 7.14.

1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrrole (table 2, entry 10): white solid, mp 94-97℃ ¹H-NMR (300MHz,CDCl₃): δ = 4.26 (m, 4H), 6.24 (t, 2H), 6.83-6.86 (m, 3H). ¹³C-NMR (75MHz, CDCl₃): δ = 64.3, 64.5, 109.9, 113.8, 117.8, 135, 141.7, 143.9. Analitically calculated for: (C₁₂H₁₁NO₂) C, 71.63; H, 5.51; N, 6.96; found C, 70.95; H, 5.42; N, 6.89.

3-(1H-pyrrol-1-yl) quinoline (table 2, entry 11): off white solid, mp 69-74℃. ¹H-NMR (300MHz, CDCl₃): δ = 6.39 (t, 2H), 7.17 (t, 2H), 7.54-7.59 (t, 1H), 7.65-7.70 (t, 1H), 7.80-7.82 (d, 1H), 8.02-8.04 (m, 1H), 8.10-8.12 (d, 1H), 9.06-9.08 (d, 1H). ¹³C-NMR (75MHz, CDCl₃): δ= 111.6, 119.4, 124.6, 127.7, 128.9, 129.5, 132.7, 144.6, 146.3. Analitically calculated for: (C₁₃H₁₀N₂) C: 80.39, H: 5.19, N: 14.42; found C: 79.82, H: 5.09, N: 14.36.

1-(thiophen-2-yl)-1H-pyrrole (table 2, entry 12): white solid, mp 75-78℃ ¹H-NMR(300MHz, CDCl₃): δ = 6.22 (t, 2H), 6.85 (t, 2H), 6.89-6.92 (m, 3H). ¹³C-NMR (75MHz, CDCl₃): δ = 110.4, 115.5, 119.1, 121.2, 126.1, 150.6. Analitically calculated for: (C₈H₇NS) C: 64.39, H: 4.73, N: 9.39, S: 21.49; found C: 63.67, H: 4.64, N: 9.31, S: 20.63

1-(3-methylthiophen-2-yl)-1H-pyrrole (table 2, entry 13): colorless oil, ¹H-NMR (300MHz, CDCl₃): δ = 2.15 (s, 3H), 6.22 (t, 2H), 6.75-6.77 (m, 3H), 6.98-6.99 (m, 1H). ¹³C-NMR (75MHz, CDCl₃): δ = 11.8, 109.5, 120.5, 123.2, 128.6, 135.6, 144.3. Analitically calculated for: (C₉H₉NS) C: 66.22, H: 5.56, N: 8.58; S, 19.64; found C: 65.45, H: 5.48, N: 8.51, S: 18.56.

1-(5-methylthiophen-2-yl)-1H-pyrrole (table 2, entry 14): white solid, mp 87-91℃ ¹H-NMR (300MHz,CDCl₃): δ = 2.45 (s, 3H), 6.19 (t, 2H), 6.51-6.52 (m, 1H), 6.61-6.62 (m, 1H), 6.85 (t, 2H). ¹³C-NMR (75MHz, CDCl₃): δ = 15.3, 110, 115.5, 121.2, 123.6, 133.7, 141.4. Analitically calculated for: (C₉H₉NS) C: 66.22, H: 5.56, N: 8.58, S: 19.64; found C: 65.75, H: 5.42, N: 8.47, S: 18.23.

1-(thiophen-3-yl)-1H-pyrrole (table 2, entry 15):white solid, mp 99-101℃ ¹H-NMR(300MHz,CDCl₃): δ =6.21 (t, 2H), 6.95 (t, 2H), 7.02 (m, 1H), 7.14 (m, 1H), 7.31 (m, 1H). ¹³C-NMR (75MHz, CDCl₃): δ =109.8, 119.7, 121.1, 126.2, 149.4. Analitically calculated for: (C₈H₇NS) C:64.39, H: 4.73, N: 9.39, S: 21.49; found C: 63.54, H: 4.57, N: 9.24, S: 20.16.

1-(3-chlorophenyl)-1H-pyrrole (table 3, entry 1): pale yellow oil, ¹H-NMR (300MHz, CDCl₃): δ = 6.27 (t, 2H), 7.00 (t, 2H), 7.17 (d, 1H), 7.24 (d, 1H), 7.32 (m, 1H) ,7.38 (m, 1H). ¹³C-NMR (75MHz, CDCl₃):δ110.9, 118.4, 119.2, 120.5, 125.5, 130.5, 135.1, 141.7. Analitically calculated for: (C₁₀H₈ClN) C: 67.62, H: 4.54, N: 7.89; found C: 66.93, H: 4.44, N: 7.83.

1-(4-methoxyphenyl)-1H-pyrrole (table 3, entry 2): white solid, mp 111-113℃ , ¹H-NMR (300MHz,CDCl₃): δ= 3.81 (s, 1H), 6.22 (t, 2H), 6.88-6.91 (m, 4H ),7.25-7.27 (m, 2H). ¹³C-NMR (75MHz, CDCl₃): δ = 55.4, 109.8, 114.5, 119.5, 122.1, 134.4, 157.5. Analitically calculated for: (C₁₁H₁₁NO) C: 76.28, H: 6.40, N: 8.09; found C: 75.67, H: 6.28, N: 7.95.

1-(4-nitrophenyl)-1H-pyrrole (table 3, entry 3): white solid, mp 180-183℃. ¹H-NMR (300MHz, CDCl₃): δ= 6.37(t, 2H), 7.13 (t, 2H), 7.53 (d, 2H), 8.29 (d, 2H). ¹³C-NMR (75MHz, CDCl₃): δ=112.5, 119.1, 119.4, 125.5, 144.6, 145.2. Analitically calculated for: (C₁₀H₈N₂O₂) C: 63.82, H: 4.28, N: 14.89; found: C: 63.24, H: 4.19, N: 14.83.

1-p-tolyl-1H-pyrrole (table 3, entry 4): white solid, mp 82-85℃, ¹H-NMR (300MHz, CDCl₃): δ= 2.37 (s, 3H), 6.24 (t, 2H), 6.97 (t, 2H), 7.15 (dd, 2H), 7.24 (dd, 2H). ¹³C-NMR (75MHz, CDCl₃): δ = 20.7, 110.1, 119.3, 120.4, 129.9, 135.3, 138.4. Analitically calculated for: (C₁₁H₁₁N) C: 84.04, H: 7.05, N: 8.91, found C: 83.30, H: 6.95, N: 8.84.

1-(4-tert-butylphenyl)-1H-pyrrole (table 3, entry 5): white solid, mp 68-72℃ ¹H-NMR(300MHz, CDCl₃): δ = 1.35 (s, 9H), 6.25 (t, 2H), 6.99 (t, 2H), 7.36-7.41 (d, 2H), 7.24-7.30 (d, 2H). ¹³C-NMR (75MHz, CDCl₃): δ = 31.3, 34.4, 110.1, 119.3, 120.2, 126.3, 138.3, 148.6. Analitically calculated for: (C₁₄H₁₇N) C: 84.37, H: 8.60, N: 7.03found C: 83.74, H: 8.51, N: 6.96.

1-(4-(benzyloxy)phenyl)-1H-pyrrole (table 3, entry 6): white solid, mp 102-105℃ ¹H-NMR(300MHz, CDCl₃): δ = 5.01 (s, 2H), 6.23 (t, 2H), 6.91 (m, 1H), 6.95 (d, 1H), 6.97 (d, 1H), 7.25-7.28 (m, 3H) , 7.32-7.40 (m, 5H). ¹³C-NMR (75MHz, CDCl₃): δ = 70.4, 109.9, 115.7, 119.6, 127.5, 128.6, 129.5, 134.7, 136.8, 156.8. Analitically calculated for: (C₁₇H₁₅NO) C: 81.24, H: 6.06, N: 5.62; found C: 80.71, H: 5.98, N: 5.54.

1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrole (table 3, entry 7): colorless oil, ¹H-NMR (300MHz, CDCl₃): δ= 6.37 (t,2H), 7.01 (t,2H), 7.72 (s,1H), 7.80 (s, 2H). ¹³C-NMR (75MHz, CDCl₃): δ= 112.3, 118.8, 119.1, 120.0, 124.6, 132.9, 141.7. Analitically calculated for: (C₁₂H₇F₆N) C: 51.63, H: 2.53, N: 5.02; found C: 50.95, H: 2.47, N: 4.95.

1-(4-ethylphenyl)-1H-pyrrole (table 3, entry 8): off white solid, mp 67-70℃. ¹H-NMR (300MHz, CDCl₃): δ= 1.25 (t, 3H), 2.64 (q, 2H), 7.00 (t, 2H), 7.19 (d, 2H), 7.26 (d, 2H). ¹³C- NMR (75MHz, CDCl₃): δ=15.8, 28.4, 110.3, 119.2, 120.7, 128.8, 138.9, 141.4. Analitically calculated for: (C₁₂H₁₃N) calculated C: 84.17, H: 7.65, N: 8.18, found C: 84.09, H: 7.55, N: 8.10.

3-(1H-pyrrol-1-yl) pyridine (table 3, entry 9): colorless oil. ¹H-NMR (300MHz, CDCl₃): δ = 6.34 (t, 2H), 7.0 (t, 2H), 7.35 (m, 1H), 7.66 (m, 1H), 8.47 (m, 1H), 8.74 (m, 1H) ¹³C-NMR (75MHz, CDCl₃): δ = 111.7, 119.1, 123.9, 127.3, 134.9, 142.2, 146.7. Analitically calculated for: (C₉H₈N₂) calculated C: 74.98, H: 5.59, N: 19.43; found C: 74.38, H: 5.51, N: 19.37.

1,4-di(1H-pyrrol-1-yl)benzene (table 3, entry 10): white solid, mp 234-238℃. ¹H-NMR (300MHz, CDCl₃): δ= 6.28 (t, 4H), 7.00 (t, 4H), 7.42 (m, 4H). ¹³C-NMR (75MHz, CDCl₃): δ=110.8, 119.3, 121.6, 138.5. Analitically calculated for: (C₁₄H₁₂N₂) C: 80.74, H: 5.81, N: 13.45; found C: 80.68, H: 5.69, N: 13.39.

ACKNOWLEDGEMENTS

Authors thank CSIR, New Delhi for the Junior Research Fellowship to Mr. N. Chandrasekhar.