Combination of Lithium Chloride and Hexafluoroisopropanol for Friedel-Crafts Reactions

Abstract

A combination of weak Lewis acid (LiCl) and weak Brønsted acid (hexafluoroisopropanol, HFIP) promotes efficiently the Friedel-Crafts reaction of electron-rich aromatic compounds with ethyl glyoxylate.

Friedel-Crafts reaction - glyoxylate - lithium chloride - hexafluoroisopropanol - Lewis acid - Brønsted acid

References and Notes

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Selected recent references on HFIP-assisted transformations:

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Analytical Data
Compound 3b: IR (neat): 3428, 2904, 1734, 1654, 1499, 1461, 1370, 1215, 1046, 994, 931 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, 293 K): δ = 6.54 (s, 1 H), 6.26 (br s, 1 H), 5.96 (d, J = 1.1 Hz, 1 H), 5.91 (d, J = 1.1 Hz, 1 H), 5.12 (s, 1 H), 5.05 (s, 2 H), 4.23 (dq, J = 10.2, 7.2 Hz, 1 H), 4.18 (dq, J = 10.2, 7.2 Hz, 1 H), 3.49 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 173.0, 142.3, 141.5, 134.4, 132.3, 110.7, 108.3, 102.1, 97.6, 68.3, 62.2, 56.5, 14.0 ppm. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₃H₁₆O₈: 323.0743; found: 323.0745.
Compound 3c: IR (neat): 3386, 2930, 2857, 1731, 1482, 1335, 1251, 1126, 1006 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, 293 K): δ (mixture of two diastereomers) = 6.89 (2 s, 1 H), 6.55 (s, 1 H), 5.18 (d, J = 3.1 Hz, 1 H), 4.30 (dq, J = 10.7, 7.2 Hz, 1 H), 4.20 (dq, J = 10.7, 7.2 Hz, 1 H), 3.74 (s, 3 H), 3.45 (d, J = 3.1 Hz, 1 H), 2.15 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.01 (s, 9 H), 0.96 (2 t, J = 7.6 Hz, 3 H), 0.72 (m, 2 H), 0.16 (s, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 173.2, 150.4, 148.1, 142.1, 120.9, 117.7, 117.1, 72.7, 62.6, 60.1, 26.3 (3 C), 18.8, 14.1, 9.2, 7.5, 4.8, -6.5 ppm. MS (ESI⁺): m/z = 791.3 [2 M + Na]⁺, 407.1 [M + Na]⁺, 367.2 [M - H₂O + H]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₉H₃₂O₆Si: 407.1866; found: 407.1862.
Compound 3d: IR (neat): 3349, 2983, 2903, 1722, 1628, 1485, 1442, 1169, 1033, 930 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 6.64 (s, 1 H), 6.42 (s, 1 H), 5.90 (s, 1 H), 5.89 (s, 1 H), 5.19 (s, 1 H), 4.28 (dq, J = 10.8, 7.1 Hz, 1 H), 4.21 (dq, J = 10.8, 7.1 Hz, 1 H), 1.25 (t, J = 7.1 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 173.3, 150.4, 148.7, 141.5, 114.6, 107.8, 101.4, 99.8, 72.1, 62.7, 14.2 ppm. MS (ESI⁺): m/z = 263.0 [M + Na]⁺, 245.0 [M - H₂O + Na]⁺, 223.1 [M - H₂O + H]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₁H₁₂O₆: 263.0532; found: 263.0497.
Compound 3e: IR (neat): 3414, 2937, 2837, 1729, 1616, 1515, 1451, 1417, 1197, 1109, 997 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 7.21 (br s, 1 H), 6.67 (s, 1 H), 6.42 (s, 1 H), 5.22 (s, 1 H), 4.22 (dq, J = 10.8, 7.1 Hz, 1 H), 4.17 (dq, J = 10.8, 7.1 Hz, 1 H), 4.00 (s, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 173.3, 150.2, 149.3, 142.7, 113.6, 111.9, 101.9, 71.8, 62.4, 56.6, 55.9, 14.1 ppm. MS (ESI⁺): m/z = 279.1 [M + Na]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₆O₆: 279.0845; found: 279.0840.
Compound 3f: IR (neat): 3418, 2961, 2871, 1724, 1625, 1460, 1368, 1222, 1059, 1024, 935 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 7.63 (br s, 1 H), 6.77 (d, J = 8.2 Hz, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 5.72 (br s, 1 H), 5.30 (s, 1 H), 4.33 (dq, J = 10.7, 7.1 Hz, 1 H), 4.24 (dq, J = 10.7, 7.1 Hz, 1 H), 3.39 (br s, 1 H), 3.27 (hept, J = 7.0 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.23 (t, J = 7.0 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 173.4, 143.0, 141.8, 135.5, 119.9, 118.8, 118.0, 72.7, 62.9, 27.3, 22.5, 22.4, 14.1 ppm. MS (ESI⁺): m/z = 277.1 [M + Na]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₃H₁₈O₅: 277.1052; found: 277.1034.
Compound 3g: IR (neat): 3482, 2939, 2839, 1731, 1612, 1589, 1507, 1207, 1157, 1065, 1030 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 7.15 (d, J = 8.5 Hz, 1 H), 6.45 (m, 2 H), 5.19 (d, J = 5.8 Hz, 1 H), 4.19 (dq, J = 10.8, 7.1 Hz,
1 H), 4.18 (dq, J = 10.8, 7.1 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.53 (d, J = 5.8 Hz, 1 H), 1.19 (t, J = 7.1 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 174.0, 161.2, 158.3, 130.2, 119.9, 104.4, 99.0, 69.8, 61.7, 55.5, 55.4, 14.1 ppm. MS (ESI⁺): m/z = 263.1 [M + Na]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₆O₅: 263.0895; found: 263.0893.
Compound 3h: IR (neat): 3442, 2891, 1727, 1614, 1523, 1354, 1180, 1074, 1012, 800 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 7.25 (d, J = 8.7 Hz, 2 H), 6.70 (d, J = 8.7 Hz, 2 H), 5.06 (s, 1 H), 4.26 (dq, J = 10.9, 7.0 Hz, 1 H), 4.16 (dq, J = 10.9, 7.0 Hz, 1 H), 3.27 (br s, 1 H), 2.95 (s, 6 H), 1.23 (t, J = 7.0 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 174.3, 150.8, 127.7 (2 C), 126.3, 112.5 (2 C), 72.9, 62.0, 40.6 (2 C), 14.2 ppm. MS (ESI⁺): m/z = 246.1
[M + Na]⁺, 224.1 [M + H]⁺, 206.1 [M - H₂O + H]⁺. HRMS (ESI⁺): m/z [M + H]⁺ calcd for C₁₂H₁₇NO₃: 224.1287; found: 224.1270.
Compound 3i: IR (neat): 3399, 2981, 1724, 1548, 1457, 1423, 1198, 1077, 1037, 743 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 8.40 (br s, 1 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 7.20 (ddd, J = 8.2, 7.0, 1.0 Hz, 1 H), 7.14 (ddd, J = 8.2, 7.0, 0.9 Hz, 1 H), 7.08 (d, J = 2.3 Hz, 1 H), 5.46 (d, J = 5.5 Hz, 1 H), 4.28 (dq, J = 10.8, 7.0 Hz, 1 H), 4.16 (dq, J = 10.8, 7.0 Hz, 1 H), 3.51 (m, 1 H), 1.20 (t, J = 7.0 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 174.1, 136.5, 125.4, 123.5, 122.5, 120.1, 119.4, 113.6, 111.6, 67.4, 62.1, 14.1 ppm. MS (ESI⁺): m/z = 242.1 [M + Na]⁺, 202.1 [M - H₂O + H]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₃NO₃: 242.0793; found: 242.0805.
Compound 3j: IR (neat): 3369, 2981, 1730, 1492, 1368, 1299, 1203, 1052, 1018, 714 cm^-¹. ^¹H NMR (500 MHz, CDCl₃, 293 K): δ = 6.61 (t, J = 2.1 Hz, 1 H), 6.05 (d, J = 2.1 Hz, 2 H), 5.20 (d, J = 7.0 Hz, 1 H), 4.31 (dq, J = 10.9, 7.0 Hz, 1 H), 4.27 (dq, J = 10.9, 7.0 Hz, 1 H), 3.66 (s, 3 H), 3.15 (d, J = 7.0 Hz, 1 H), 1.29 (t, J = 7.0 Hz, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃, 293 K): δ = 172.9, 129.2, 124.1, 108.5, 107.0, 66.4, 62.1, 34.1, 14.2 ppm. MS (ESI⁺): m/z = 206.1 [M + Na]⁺, 166.1 [M - H₂O + H]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₉H₁₃NO₃: 206.0793; found: 206.0791.

Formation of bisindolylalkanes, see for examples:

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14 Schadt FL. Bentley TW. Schleyer P.v.R.. J. Am. Chem. Soc.  1976,  98:  7667 

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16

We thank one of the referees for bringing up this important point.