Base-Catalyzed, Three-Component Coupling of Aldehydes, Terminal Aryl Acetylenes, and Amines: Application to Synthesis of Propargylamines

Abstract

Propargylamines are formed in high yield by three-component coupling reaction of aldehydes, terminal aryl acetylenes, and amines in DMSO in the presence of catalytic tetraalkylammonium hydroxide. This reaction does not require a transition-metal catalyst.

Key words

three-component coupling - aldehydes - aryl acetylenes - amines - tetraalkylammonium hydroxide

Reference and Notes

• For reviews, see:
• 1a Posner GH. Chem. Rev.  1986,  86:  831 
• 1b Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 
• 1c Bienayme H. Hulme C. Oddon G. Schmitt P. Chem. Eur. J.  2000,  6:  3321 
• 1d Multicomponent Reactions   Zhu J. Bienayme H. Wiley-VCH; Weinheim: 2005. 
• For reviews on reactions in water or under solvent-free conditions, see:
• 2a Li CJ. Chem. Rev.  1993,  93:  2023 
• 2b Metzger J. Angew. Chem. Int. Ed.  1998,  37:  2975 
• 2c Tanaka K. Toda F. Chem. Rev.  2000,  100:  1025 
• 2d Li CJ. Chem. Rev.  2005,  105:  3095 
• 2e Hobbs HR. Thomas NR. Chem. Rev.  2007,  107:  2786 
• 3a Wei C. Li Z. Li C.-J. Synlett  2004,  1472 
• 3b Wei C. Li Z. Li C.-J. Org. Lett.  2003,  5:  4473 
• 3c Li Z. Wei C. Chen L. Varma RS. Li C.-J. Tetrahedron Lett.  2004,  45:  2443 
• 3d Reddy KM. Babu NS. Suryanarayana I. Prasad PSS. Lingaiah N. Tetrahedron Lett.  2006,  47:  7563 
• 3e Zhang Y. Santos AM. Herdtweeck E. Mink J. Kühn FE. New J. Chem.  2005,  29:  366 
• 4 Li C.-J. Wei C. Chem. Commun.  2002,  268 
• 5a Wei C. Li C.-J. J. Am. Chem. Soc.  2002,  124:  5638 
• 5b Commermann N. Koradin C. Polborn K. Knochel P. Angew. Chem. Int. Ed.  2003,  42:  5763 
• 5c Shi L. Tu Y.-Q. Wang M. Zhang F.-M. Fan C.-A. Org. Lett.  2004,  6:  1001 
• 5d Li Z. Li C.-J. J. Am. Chem. Soc.  2004,  126:  11810 
• 5e Choudary BM. Sridhar C. Kantam ML. Sreedhar B. Tetrahedron Lett.  2004,  45:  7319 
• 5f Bieber LW. Silva MF. Tetrahedron Lett.  2004,  45:  8281 
• 5g Benaglia M. Negri D. Dell’Anna G. Tetrahedron Lett.  2004,  45:  8705 
• 5h Black DA. Arndtsen BA. Org. Lett.  2004,  6:  1107 
• 6a Zhang Y. Li P. Wang M. Wang L. J. Org. Chem.  2009,  74:  4364 
• 6b Samai S. Nandi GC. Singh MS. Tetrahedron Lett.  2010,  51:  5555 
• 7 Zengab T. Chena W. Cirtiua CM. Mooresa A. Song G. Li CJ. Green Chem.  2010,  12:  570 
• 8 Wei C. Li C.-J. J. Am. Chem. Soc.  2003,  125:  9584 
• 9a Khrustalev DP. Khamzina GT. Fazylov SD. Muldakhmetov ZM. Izv. Nats. Akad. Nauk Resp. Kaz., Ser. Khim.  2008,  67 
• 9b Khrustalev DP. Khamzina GT. Fazylov SD. Gazaliev AM. Russ. J. Gen. Chem.  2007,  77:  970 
• 9c Kabalka GW. Zhou L.-L. Wang L. Pagni RM. Tetrahedron  2006,  62:  857 
• 10a Nilsson B. Vargas HM. Ringdahl B. Hacksell U.
  J. Med. Chem.  1992,  35:  285 
• 10b Hattori K. Miyata M. Yamamoto H. J. Am. Chem. Soc.  1993,  115:  1151 
• 10c Jenmalm A. Berts W. Li YL. Luthman K. Csoeregh I. Hacksell U. J. Org. Chem.  1994,  59:  1139 
• 10d Miura M. Enna M. Okuro K. Nomura M. J. Org. Chem.  1995,  60:  4999 
• 11 Matthews WS. Bares JE. Bartmess JE. Bordwell FG. Cornforth FJ. Drucker GE. Margolin Z. McCallum RJ. McCollum GJ. Vanier NR. J. Am. Chem. Soc.  1975,  97:  7006 
• 12 Olmstead WN. Margolin Z. Bordwell FG. J. Org. Chem.  1980,  45:  3295 
• 13 Bordwell FG. Algrim D. Fried HE. J. Chem. Soc., Perkin Trans. 2  1979,  726 
• 14 Kwok SN. Fosting JR. Fraster RJ. Rodionov VO. Fokin VV. Org. Lett.  2010,  12:  4217 
• 15 Ishikawa T. Mizuta T. Hagiwara K. Aikawa T. Kudo T. Saito S. J. Org. Chem.  2003,  68:  3702 ; and references cited therein

16

General Procedure for the Synthesis of Propargylamines A 25 mL round-bottom flask was charged with DMSO (3 mL), aldehyde (1.0 mmol), amine (1.3 mmol), alkyne (1.3 mmol), and TBAOH (0.1 mmol). The resulting solution was stirred at r.t., for the time indicated in Table  [¹] . The reaction mixture was poured into H₂O (60 mL), and the suspension was stirred for 30 min. Then, it was extracted with EtOAc (2 × 25 mL), and the combined organic extracts were dried over anhyd Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude products. Purification by silica gel column chromatography (hexane-EtOAc) gave pure materials. Representative Spectroscopic Data N -(1,3-Diphenyl-2-propynyl)piperidine (3a) ^¹H NMR (400 MHz, CDCl₃): δ = 7.62-7.60 (m, 2 H), 7.53-7.50 (m, 2 H), 7.37-7.27 (m, 6 H), 4.79 (s, 1 H), 2.56 (m, 4 H), 1.61-1.56 (m, 4 H), 1.45-1.44 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 138.3, 131.6, 128.5, 128.2, 128.0, 127.4, 123.2, 87.6, 86.0, 62.3, 26.8, 26.1, 24.4. MS: m/z (%) = 275 (20) [M⁺], 198 (81), 191 (100), 115 (14).
N -[1-(4-Methoxyphenyl)-3-phenyl-2-propynyl]-piperidine (3b)
^¹H NMR (400 MHz, CDCl₃): δ = 7.55-7.50 (m, 4 H), 7.33-7.30 (m, 3 H), 6.90-6.87 (m, 2 H), 4.74 (s, 1 H), 3.80 (s, 3 H), 2.56-2.54 (m, 4 H), 1.64-1.53 (m, 4 H), 1.46-1.42 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 158.9, 131.7, 130.6, 129.6, 128.2, 128.0, 123.3, 113.3, 87.6, 86.3, 61.7, 55.2, 50.6, 26.1, 24.4. MS: m/z (%) = 307 (4) [M⁺], 221 (38), 135 (30), 87 (100), 43 (73).
N -(1,3-Diphenyl-2-propynyl)pyrrolidine (3h) ^¹H NMR (400 MHz, CDCl₃): δ = 7.68-7.66 (m, 2 H), 7.56-7.53 (m, 2 H), 7.37-7.30 (m, 6 H), 4.90 (s, 1 H), 2.72 (m, 4 H), 1.81 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 138.3, 131.5, 128.2, 128.1, 127.5, 123.1, 86.8, 86.6, 59.0, 50.2, 23.4. MS: m/z (%) = 261 (8) [M⁺], 184 (61), 115 (13).
N -1[(4-Cyclohexyl-3-phenyl-2-propynyl)]morpholine (3l) ^¹H NMR (400 MHz, CDCl₃): δ = 7.45-7.44 (m, 2 H), 7.29-7.28 (m, 3 H), 3.79-3.74 (m, 4 H), 3.13 (d, J = 9.9 Hz, 1 H), 2.70-2.69 (m, 2 H), 2.53-2.50 (m, 2 H), 2.14-2.04 (m, 2 H), 1.77-1.59 (m, 4 H), 1.32-0.96 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 131.6, 128.1, 127.7, 123.3, 86.7, 86.5, 67.0, 63.8, 49.8, 38.9, 30.9, 30.2, 26.6, 26.1, 25.9. MS: m/z (%) = 283 (5) [M⁺], 200(100), 115 (20), 77 (2), 55 (9), 41 (10).