Download PDF
Synlett 2006(5): 0789-0791  
DOI: 10.1055/s-2006-933132
LETTER
© Georg Thieme Verlag Stuttgart · New York

Establishing the NHBoc Functionality as ortho-Metallating Group for Furan

Peter Stanetty*, Krzystztof Kolodziejczyk, Gheorghe-Doru Roiban, Marko D. Mihovilovic
Vienna University of Technology, Institute of Applied Synthetic Chemistry, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax: +43(1)5880115499; e-Mail: peter.stanetty@tuwien.ac.at;
Further Information

Publication History

Received 8 December 2005
Publication Date:
09 March 2006 (online)

    Permissions and Reprints All articles of this category

Abstract

The ortho-lithiation of N-Boc protected 3-aminofuran was investigated. Directed lithiation followed by quenching with an appropriate electrophile led to new 2,3-disubstituted furans. Halogenated compounds obtained by this methodology represent useful intermediates for subsequent cross-coupling reactions.

Key words

ortho-lithiation - furans - metallation - ketones - Suzuki cross-coupling reaction

10

General Procedure for the Lithiation Reaction. To a cooled (-90 °C to -70 °C), stirred solution of compound 1 (1.64 mmol) in dry Et2O or preferable dry THF (25 mL) and TMEDA (4.1 mmol) under argon, a solution of t-BuLi in pentane (1.6 M, 4.1 mmol) was added dropwise. The mixture was then stirred for 1-2 h while raising the temperature from -90 °C to -40 °C. After addition of an electrophile (1.97 mmol; as solution in THF if solid) the reaction mixture was stirred for 6 h or overnight with a slow increase of the temperature to r.t. The reaction mixture was then quenched with an excess of aq sat. NaHCO3 (40 mL), and extracted with CH2Cl2 (6 × 25 mL). The collected organic layers were dried over Na2SO4 and the solvent was evaporated (not completely), under 400-500 mbar at 30-35 °C. The obtained solution was then purified by filtration through a column of silica gel, using CH2Cl2 as an eluent. First fractions containing the desired product were collected and the solvent evaporated under reduced pressure (30-35 °C, 400-500 mbar). In the case of the unstable compound 3k the solvent was not evaporated completely and its yield was calculated indirectly after the subsequent Suzuki coupling reaction.

11

N -(2-Formyl-3-furyl)carbamic Acid tert -Butyl Ester ( 3a).
Pale yellow crystals (51%); mp 58-61 °C. 1H NMR (CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 7.16 (br s, 1 H, H4), 7.39 (dd, 1 H, H5, 3 J = 2.0 Hz, 5 J = 0.6 Hz), 8.56 (br s, 1 H, NH), 9.64 (d, 1 H, CHO, 5 J = 0.8 Hz). 13C NMR (CDCl3): δ = 27.2 [q, C(CH3)3], 80.9 [q, C(CH3)3], 105.6 (d, C4), 136.0 (s, C3), 137.9 (s, C2), 147.2 (d, C5), 151.2 (s, NHCO), 178.8 (d, CHO).
N -[2-(1-Hydroxy)cyclohexyl-3-furyl]carbamic Acid tert -Butyl Ester ( 3f).
Transparent colorless oil (96%). 1H NMR (CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 1.53-1.70 (m, 6 H, H3′, H4′, H5′), 2.09-2.19 (m, 2 H, H2′), 2.24-2.34 (m, 2 H, H6′), 5.94 (br s, 1 H, OH), 6.08 (br s, 1 H, NH), 6.72 (br s, 1 H, H4), 7.11 (d, 1 H, H5, 3 J = 2.0 Hz).
N -(2-Benzoyl-3-furyl)carbamic Acid tert -Butyl Ester ( 3g).
Pale yellow oil (56%). 1H NMR (CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 7.23 (br s, 1 H, H4), 7.33-7.44 (m, 4 H, H2′, H3′, H5′, H6′), 8.00 (d, 1 H, H5, 3 J = 2.0 Hz), 8.04 (d, 1 H, H4′, 4 J = 1.6 Hz), 9.39 (br s, 1 H, NH). 13C NMR (CDCl3): δ = 26.2 [q, C(CH3)3], 79.3 [q, C(CH3)3], 104.4 (d, C4), 125.5 (d, C3′, C5′), 127.2 (d, C2′, C6′), 130.3 (d, C4′), 134.7 (s, C3), 135.6 (s, C1′), 137.1 (s, C2), 144.2 (d, C5), 150.4 (s, NHCO), 180.5 (s, CO).
N -[2-(4-Chlorobenzoyl)-3-furyl]carbamic Acid tert -Butyl Ester ( 3h).
Colorless crystals (62%); mp 52-55 °C. 1H NMR (CDCl3): δ = 1.53 [s, 9 H, C(CH3)3], 7.34 (br d, 1 H, H4, 3 J = 2.0 Hz), 7.47 (d, 2 H, H3′, H5′, 3 J = 9 Hz), 7.48 (dd, 1 H, H5, 3 J = 2.0 Hz, 5 J = 0.6 Hz), 8.10 (d, 2 H, H2′, H6′, 3 J = 9.0 Hz), 9.44 (br s, 1 H, NH). 13C NMR (CDCl3): δ = 27.1 [q, C(CH3)3], 80.5 [q, C(CH3)3], 105.5 (d, C4), 127.6 (d, C3′, C5′), 129.7 (d, C2′, C6′), 134.0 (s, C3), 136.4 (s, C1′), 137.8 (s, C2), 138.5 (s, C4′), 145.4 (d, C5), 151.3 (s, NHCO), 179.8 (s, CO).
N -(2-Chloro-3-furyl)carbamic Acid tert -Butyl Ester ( 3i).
Beige solid which decomposed on storage (65%). 1H NMR (CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 6.14 (br s, 1 H, NH), 6.82 (br s, 1 H, H4), 7.12 (d, 1 H, H5, 3 J = 2.0 Hz). 13C NMR (CDCl3): δ = 27.3 [q, C(CH3)3], 80.0 [q, C(CH3)3], 107.6 (s, C3), 118.9 (d, C4), 129.6 (s, C2), 139.5 (d, C5), 151.6 (s, NHCO).
N -(2-Bromo-3-furyl)carbamic Acid tert -Butyl Ester ( 3j). Beige solid which decomposed upon storage (96%). 1H NMR (CDCl3): δ = 1.43 [s, 9 H, C(CH3)3], 6.23 (br s, 1 H, NH), 6.83 (br s, 1 H, H4), 7.26 (d, 1 H, H5, 3 J = 2.0 Hz).

15

General Procedure for the Suzuki Cross-Coupling Reaction. To a solution of dioxane-water (4:1) in a three-necked round-bottom flask (150 mL) equipped with condenser, thermometer and argon inlet, a solution of 3k (ca. 10.0 mmol; estimated from 1) in THF was added. Boronic acids 4a-c (12.1 mmol) and K2CO3 (22.0 mmol) were added to the system. The flask was flushed with argon and then Pd(PPh3)4 (0.272 mmol) was added (2.2 mol%). The reaction mixture was heated at 70-80 °C keeping the inert atmosphere until the TLC showed complete reaction (usually 17-56 h) then the obtained mixture was quenched with aq sat. NaHCO3 (40 mL), extracted with CH2Cl2 (4 × 100 mL), and the organic layers were dried over Na2SO4. After solvent evaporation the residue was purified by flash column chromatography using PE-EtOAc (10:1) as eluent. The products 5a-c were obtained in an overall yield varying between 53-72%, calculated from compound 1.

16

N -(2-Phenyl-3-furyl)carbamic Acid tert -Butyl Ester ( 5a).
Yellow oil (68%). 1H NMR (CDCl3): δ = 1.41 [s, 9 H, C(CH3)3], 6.27 (d, 1 H, H4, 3 J = 2.0 Hz), 6.76 (br s, 1 H, NH), 7.10-7.18 (m, 1 H, H4′), 7.23 (d, 1 H, H5, 3 J = 2.0 Hz), 7.24-7.33 (m, 2 H, H3′, H5′), 7.49 (d, 2 H, H2′, H6′, 3 J = 9.0 Hz). 13C NMR (CDCl3): δ = 27.2 [q, C(CH3)3], 79.7 [q, C(CH3)3], 108.4 (d, C4), 119.7 (s, C3), 122.7 (s, C1′), 123.7 (d, C2′, C6′), 126.1 (d, C4′), 127.8 (d, C3′, C5′), 129.5 (s, C2), 139.7 (d, C5), 152.4 (s, NHCO).
N -[2-(4-Chlorophenyl)-3-furyl]carbamic Acid tert -Butyl Ester ( 5b).
Pale yellow solid (53%); mp 89-93 °C. 1H NMR (CDCl3): δ = 1.42 [s, 9 H, C(CH3)3], 6.15 (br s, 1 H, NH), 6.73 (br s, 1 H, H4), 7.26 (d, 1 H, H5), 7.25-7.32 (d, 2 H, H3′, H5′, 3 J = 9.0 Hz), 7.43-7.47 (d, 2 H, H2′, H6′, 3 J = 9.0 Hz). 13C NMR (CDCl3): δ = 27.2 [q, C(CH3)3], 79.9 [q, C(CH3)3], 108.9 (d, C4), 119.2 (s, C1′), 120.0 (s, C3), 124.8 (d, C2′, C6′), 127.9 (d, C3′, C5′), 129.0 (s, C2), 131.7 (s, C4′), 140.0 (d, C5), 152.4 (s, NHCO).
N -[2-(4-Fluorophenyl)-3-furyl]carbamic Acid tert -Butyl Ester ( 5c).
Pale yellow crystals (72%), mp 68-71 °C. 1H NMR (CDCl3): δ = 1.41 [s, 9 H, C(CH3)3], 6.18 (br s, 1 H, NH), 6.69 (br s, 1 H, H4), 7.00 (d, 2 H, H2′, H6′, 3 J = 9.0 Hz), 7.23 (d, 1 H, H5, 3 J = 2.0 Hz), 7.48 (dd, 2 H, H3′, H5′, 3 J = 9.0 Hz, 3 J H-F = 3.5 Hz). 13C NMR (CDCl3): δ = 28.2 [q, C(CH3)3], 80.8 [q, C(CH3)3], 109.8 (d, C4), 115.8 (d, C3′, C5′, 2 J C-F = 21.6 Hz), 120.2 (s, C2), 122.2 (s, C3), 126.4 (d, C2′, C6′, 3 J C-F = 13.1 Hz), 126.7 (s, C1′, 4 J C-F = 4.1 Hz), 140.6 (d, C5), 153.6 (s, NHCO), 161.8 (d, C4′, 1 J C-F = 247.4 Hz).