One-Pot Synthesis of Primary tert-Alkylamines by the Addition of Organometallic Reagents to Nitriles Mediated by Ti(Oi-Pr)₄

Abstract

A number of primary tert-alkylamines (18 examples, 25-72% yields) have been prepared according to a simple one-pot procedure by the addition of organometallic reagents such as Grignard reagents and organolithium compounds to nitriles in the presence of Ti(Oi-Pr)₄.

amines - nitriles - nucleophilic addition - organometallic reagents - titanium tetraisopropoxide

References and Notes

1a Ritter JJ. Kalish J. J. Am. Chem. Soc.  1948,  70:  4045 

1b Ritter JJ. Kalish J. J. Am. Chem. Soc.  1948,  70:  4048 

2 Koziara A. Osowska-Parewicka K. Zawadzki S. Zwierzak A. Synthesis  1987,  487 

3 Koziara A. Zwierzak A. Tetrahedron Lett.  1987,  28:  6513 

4a Davis FA. Mancinelli PA. J. Org. Chem.  1977,  42:  398 

4b Hirao A. Hattori I. Yamaguchi K. Nakahama S. Synthesis  1982,  461 

5a Chastrette M. Axiotis GP. Synthesis  1980,  889 

5b Amouroux R. Axiotis GP. Synthesis  1981,  270 

6a Henze HR. Allen BB. Leslie WB. J. Am. Chem. Soc.  1943,  65:  87 

6b Henze HR. Allen BB. J. Am. Chem. Soc.  1939,  61:  1790 

7 Ciganek E. J. Org. Chem.  1992,  57:  4521 

8 Chaplinski V. de Meijere A. Angew. Chem., Int. Ed. Engl.  1996,  35:  413 ; Angew. Chem. 1996, 108, 491

9

Massalov, N. V.; Sokolov, V. V., unpublished results.

10 Bertus P. Szymoniak J. J. Org. Chem.  2002,  67:  3965 

11

General Experimental Procedure for the Synthesis of Primary tert -Alkylamines 8-13: To a solution of the nitrile (10 mmol) in Et₂O (30-50 mL) was added the respective Grignard reagent as a 1-3 M Et₂O solution (3 equiv), and after stirring for 30 min Ti(Oi-Pr)₄ (1 equiv) was added successively at r.t. After the mixture had been heated under reflux for 10 h, a 10% aq solution of NaOH (40 mL) was added. Stirring was continued for 15-30 min. The solution was filtered and the filtrate was extracted with Et₂O (3 ¥ 30 mL). The combined Et₂O layers were concentrated under reduced pressure and the residue was extracted with dilute aq 5% HCl. The combined aqueous layers were washed with Et₂O (2 ¥ 30 mL), made basic by addition of aq 10% NaOH and extracted with Et₂O (3 × 30 mL). A few drops of concd HCl were added to the combined Et₂O phases and Et₂O was evaporated to dryness to leave the respective amine hydrochloride. In some cases it was necessary to purify the amine hydrochloride by recrystallization (EtOH-Et₂O).
1,1-Dibenzyl- n -propylamine Hydrochloride (11a): ¹H NMR (250 MHz, DMSO-d ₆): δ = 1.06 (t, J = 7.3 Hz, 3 H), 1.49 (q, J = 7.3 Hz, 2 H), 2.84 (d, J = 13.8 Hz, 2 H), 3.18 (d, J = 13.8 Hz, 2 H), 7.24-7.34 (m, 10 H), 8.32 (br s, 3 H). ¹³C NMR (250 MHz, DMSO-d ₆): δ = 7.6 (CH₃), 26.8 (CH₂), 41.2 (CH₂), 58.7 (C), 126.9 (CH), 128.4 (CH), 130.9 (CH), 134.9 (C). MS (ESI): m/z = 1067 (46) [4 ¥ M - Cl]⁺, 515 (18) [2 ¥ M - Cl]⁺, 479 (10) [2 ¥ M - HCl - Cl]⁺, 240 (100) [M - Cl]⁺. Anal. Calcd for C₁₇H₂₁N·HCl (275.8): C, 74.03; H, 8.04; N, 5.08. Found: C, 74.23; H, 8.14; N, 5.19.

12

Experimental Procedure for the Synthesis of 1-(2-Furyl)-1-phenyl- n -butylamine Hydrochloride ( 17f): To the solution of furan (1.7 g, 25 mmol) in THF (10 mL) was added n-BuLi (2.9 M in hexane, 25 mmol) keeping the temperature below -10 °C, and the mixture was stirred at r.t. for 4 h to provide a solution of 2-furyllithium.
To a solution of butyronitrile (0.69 g, 10 mmol) in Et₂O (30 mL) were added successively at ambient temperature PhMgBr (1.1 M in Et₂O, 10 mmol) then, after stirring for 30 min, Ti(Oi-Pr)₄ (2.84 g, 10 mmol) and finally the solution of 2-furyllithium. After heating under reflux for 10 h, the reaction mixture was worked up as described in the general procedure above. The product 17f was purified by column chromatography on silica gel (50 g), eluting with CHCl₃-MeOH (30:1). ¹H NMR (250 MHz, DMSO-d ₆): δ = 0.93 (t, J = 7.2 Hz, 3 H), 1.15-1.45 (m, 2 H), 2.25-2.42 (m, 2 H), 6.46 (m, 1 H), 6.57-6.58 (m, 1 H), 7.29-7.37 (m, 5 H), 7.55 (m, 1 H), 9.47 (br s, 3 H). ¹³C NMR (250 MHz, DMSO-d ₆): δ = 14.7 (CH₃), 17.7 (CH₂), 41.1 (CH₂), 61.6 (C), 109.9 (CH), 111.2 (CH), 127.2 (CH), 128.6 (CH), 128.9 (CH), 130.5 (C), 143.4 (CH), 153.7 (C). MS (ESI): m/z = 970 (16) [4 ¥ M - Cl]⁺, 199 (100) [M - Cl - NH₃]⁺, 157 (18). Anal. Calcd for C₁₄H₁₇NO·HCl (251.8): C, 66.79; H, 7.21; N, 5.56. Found: C, 66.69; H, 7.31; N, 5.26.