A Very Mild Access to 3,4-Dihydroisoquinolines Using Triphenyl Phosphite-Bromine-Mediated Bischler-Napieralski-Type Cyclization

Abstract

Substituted β-phenylethylamides undergo smooth intramolecular cyclization to 3,4-dihydroisoquinolines in good to excellent yields when treated with bromotriphenoxyphosphonium bromide at -60 ˚C in dichloromethane in the presence of triethyl­amine. The reaction proceeds under the mildest conditions ever reported for Bischler-Napieralski-type cyclizations. When chlorotriphenoxyphosphonium choride is used, low yields are obtained instead.

Bischler-Napieralski cyclization - phosphonium halides - iminoyl halides - isoquinoline alkaloids - necatorone - triphenyl phosphite

References and Notes

<A NAME="RG23908ST-1A">1a</A> Aniszewski T. Alkaloids - Secrets of Life   Elsevier; Amsterdam: 2007. 

<A NAME="RG23908ST-1B">1b</A> Shulgin AT. Perry WE. The Simple Plant Isoquinolines   Transform Press; London: 2003. 

<A NAME="RG23908ST-1C">1c</A> Lundström J. In The Alkaloids   Vol. 21:  Brossi A. Academic Press; New York: 1983.  p.255-327  

<A NAME="RG23908ST-1D">1d</A> The Alkaloids   Vol. 7:  Manske RHF. Academic Press; New York: 1960. 

<A NAME="RG23908ST-1E">1e</A> The Alkaloids   Vol. 4:  Manske RHF. Holmes HL. Academic Press; New York: 1954. 

For recent reviews, see:

<A NAME="RG23908ST-2A">2a</A> Bentley KW. Nat. Prod. Rep.  2006,  20:  444 

<A NAME="RG23908ST-2B">2b</A> Bentley KW. Nat. Prod. Rep.  2005,  22:  249 

<A NAME="RG23908ST-2C">2c</A> Bentley KW. Nat. Prod. Rep.  2004,  21:  395 

<A NAME="RG23908ST-2D">2d</A> Bentley KW. Nat. Prod. Rep.  2003,  20:  342 

<A NAME="RG23908ST-3">3</A> Bischler A. Napieralski B. Ber. Dtsch. Chem. Ges.  1893,  26:  1903 

For reviews, see:

<A NAME="RG23908ST-4A">4a</A> Whaley WM. Govindachari TR. Org. React.  1951,  6:  74 

<A NAME="RG23908ST-4B">4b</A> Kametani T. Fukumoto K. In The Chemistry of Heterocyclic Compounds   Part 1, Vol. 38:  Grethe G. Weissberger A. Taylor EC. Wiley; New York: 1981.  p.139-274  

<A NAME="RG23908ST-4C">4c</A> Fowler FW. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.410-416  

<A NAME="RG23908ST-4D">4d</A> Jones G. In Comprehensive Heterocyclic Chemistry II   Vol. 5:  Katritzky AR. Rees CW. Scriven DFV. Elsevier; Oxford: 1996.  p.179-181  

For reviews, see:

<A NAME="RG23908ST-5A">5a</A> Larghi EL. Amongero M. Bracca ABJ. Kaufman TS. Arkivoc  2005,  (xii):  98 

<A NAME="RG23908ST-5B">5b</A> Chrzanowska M. Rozwadowska MD. Chem. Rev.  2004,  104:  3341 

<A NAME="RG23908ST-5C">5c</A> Cox ED. Cook JM. Chem. Rev.  1995,  95:  1797 

<A NAME="RG23908ST-6A">6a</A> Nagubandi S. Fodor G. J. Heterocycl. Chem.  1980,  17:  1457 

<A NAME="RG23908ST-6B">6b</A> Nagubandi S. Fodor G. Tetrahedron  1980,  36:  1279 

<A NAME="RG23908ST-6C">6c</A> Gal J. Wienkam RJ. Castagnoli N. J. Org. Chem.  1974,  39:  418 

<A NAME="RG23908ST-6D">6d</A> Fodor G. Gal J. Phillips BA. Angew. Chem., Int. Ed. Engl.  1972,  11:  919 

For selected examples, see:

<A NAME="RG23908ST-7A">7a</A> Martin SF. Garrison PJ. J. Org. Chem.  1982,  47:  1513 

<A NAME="RG23908ST-7B">7b</A> Bosch J. Domingo A. Linares A. J. Org. Chem.  1983,  48:  1075 

<A NAME="RG23908ST-7C">7c</A> Sotomayor N. Domínguez E. Lete E. J. Org. Chem.  1996,  61:  4062 

<A NAME="RG23908ST-7D">7d</A> Ishikawa T. Shimooka K. Narioka T. Noguchi S. Saito T. Ishikawa A. Yamazaki E. Harayama T. Seki H. Yamaguchi K. J. Org. Chem.  2000,  65:  9143 

<A NAME="RG23908ST-7E">7e</A> Capilla AS. Romero M. Pujol MD. Caignard DH. Renard P. Tetrahedron  2001,  57:  8297 

<A NAME="RG23908ST-7F">7f</A> Batra S. Sabnis YA. Rosenthal PJ. Avery MA. Bioorg. Med. Chem.  2003,  11:  2293 

For selected examples, see:

<A NAME="RG23908ST-8A">8a</A> Doi S. Shirai N. Sato Y. J. Chem. Soc., Perkin Trans. 1  1997,  2217 

<A NAME="RG23908ST-8B">8b</A> Wang X.-J. Tan J. Grozinger K. Tetrahedron Lett.  1998,  39:  6609 

<A NAME="RG23908ST-8C">8c</A> Sánchez-Sancho F. Mann E. Herradón B. Synlett  2000,  509 

<A NAME="RG23908ST-8D">8d</A> Nicoletti M. O’Hagan D. Slawin AMZ. J. Chem. Soc., Perkin Trans. 1  2002,  116 

<A NAME="RG23908ST-8E">8e</A> Chern M.-S. Li W.-R. Tetrahedron Lett.  2004,  45:  8323 

<A NAME="RG23908ST-9">9</A> Snyder HR. Werber FX. J. Am. Chem. Soc.  1950,  72:  2962 

<A NAME="RG23908ST-10A">10a</A> Itoh N. Sugasawa S. Tetrahedron  1957,  1:  45 

<A NAME="RG23908ST-10B">10b</A> Itoh N. Sugasawa S. Tetrahedron  1959,  6:  16 

<A NAME="RG23908ST-11">11</A> Kanaoka Y. Sato E. Yonemitsu O. Ban Y. Tetrahedron Lett.  1964,  5:  2419 

<A NAME="RG23908ST-12">12</A> Ramesh D. Srinivasan M. Synth. Commun.  1986,  16:  1523 

<A NAME="RG23908ST-13">13</A> Judeh ZMA. Ching CB. Bu J. McCluskey A. Tetrahedron Lett.  2002,  43:  5089 

<A NAME="RG23908ST-14">14</A> Hegedüs A. Hell Z. Potor A. Catal. Commun.  2006,  7:  1022 

<A NAME="RG23908ST-15">15</A> Saito T. Yoshida M. Ishikawa T. Heterocycles  2001,  54:  437 

<A NAME="RG23908ST-16">16</A> Larsen RD. Reamer RA. Corley EG. Davis P. Grabowski EJJ. Reider PJ. Shinkai I. J. Org. Chem.  1991,  56:  6034 

<A NAME="RG23908ST-17">17</A> Bhattacharijya A. Chattopadhyay P. Bhaumik M. Pakrashi SC. J. Chem. Res., Synop.  1989,  228 

<A NAME="RG23908ST-18A">18a</A> Banwell MG. Bissett BD. Busato S. Cowden CJ. Hockless DCR. Holman JW. Read RW. Wu AW. J. Chem. Soc., Chem. Commun.  1995,  2551 

<A NAME="RG23908ST-18B">18b</A> Wang Y.-C. Georghiou PE. Synthesis  2002,  2187 

<A NAME="RG23908ST-19">19</A> Boruah M. Konwar D. J. Org. Chem.  2002,  67:  7138 

<A NAME="RG23908ST-20">20</A> Spaggiari A. Blaszczak LC. Prati F. Org. Lett.  2004,  6:  3885 

<A NAME="RG23908ST-21">21</A> Spaggiari A. Davoli P. Blaszczak LC. Prati F. Synlett  2005,  661 

<A NAME="RG23908ST-22A">22a</A> Vaccari D. Davoli P. Bucciarelli M. Spaggiari A. Prati F. Lett. Org. Chem.  2007,  4:  319 

<A NAME="RG23908ST-22B">22b</A> Vaccari D. Davoli P. Spaggiari A. Prati F. Synlett  2008,  1317 

<A NAME="RG23908ST-23A">23a</A>

Acetamides 1a-e,h were prepared by treatment of the parent β-phenylethylamine with Ac₂O, whereas for amides 1f,g the appropriate acyl chloride was employed instead. Except for 1a and 1b, which were obtained from commercially available β-phenyl- and 4-methoxy-β-phenylethylamine, respectively, in all other cases the starting β-phenylethylamine was synthesized by condensation of the corresponding aromatic aldehyde with nitromethane in the presence of AcOH and NH₄OAc, and subsequent reduction of the resulting nitrostyrene with LAH in THF.^7f,²³b In particular, 3-methoxybenzaldehyde, piperonal, veratryl aldehyde, and 3,4,5-trimethoxybenz-aldehyde were used for 1c,d,e-g,h, respectively. In the latter case, the original procedure for the synthesis of mescaline was used.^²³c All synthesized β-phenylethylamines were used without any further purification.

<A NAME="RG23908ST-23B">23b</A> Sawant D. Kumar R. Maulik PR. Kundu B. Org. Lett.  2006,  8:  1525 

<A NAME="RG23908ST-23C">23c</A> Späth E. Monatsh. Chem.  1919,  40:  129 

<A NAME="RG23908ST-24">24</A>

Synthesis of 6,7-Dimethoxy-1-phenyl-3,4-dihydro-isoquinoline (2f)
Triphenyl phosphite (0.89 mL, 3.41 mmol) was dissolved in anhyd CH₂Cl₂ (20 mL) and cooled to -60 ˚C. Bromine (0.18 mL, 3.41 mmol) and anhyd Et₃N (0.51 mL, 3.69 mmol) were introduced sequentially under argon flow. N-[2-(3,4-dimeth-oxyphenyl)ethyl]benzamide (1f, 819 mg, 2.84 mmol) was then added in one portion to the bright yellow solution maintained at the same temperature under vigorous stirring. The resulting mixture was gradually warmed to r.t. over a
2 h period, and left to stir overnight. Subsequently, the dark reaction mixture was extracted with 3 M HCl (3 × 15 mL), the combined aqueous layers were basified with 10% aq NaOH until pH = 11 and extracted with CH₂Cl₂ (3 × 15 mL). The pooled organic phases were dried over MgSO₄, filtered, and evaporated under reduced pressure to afford the desired 3,4-dihydroisoquinoline 2f as a brownish liquid (692 mg, 92% yield). ^¹H NMR (200 MHz, CDCl₃): δ = 2.68 (2 H, t,
J = 7.4 Hz, CH ₂CH₂N), 3.67 (3 H, s, OMe), 3.77 (2 H, q, J = 7.4 Hz, CH₂CH ₂N), 3.86 (3 H, m, OMe), 6.75 (2 H, s, arom.), 7.36-7.59 (5 H, m, Ph). ^¹³C NMR (50 MHz, CDCl₃): δ = 26.0, 47.6, 56.0, 56.1, 110.4, 111.7, 120.0, 121.5, 128.1, 128.7, 129.2, 129.8, 132.5, 139.1, 147.5. MS: m/z = 235 [M⁺], 220, 204, 190, 177, 162,159, 146, 133, 110, 103, 91, 77, 65. Anal. Calcd for C₁₂H₁₃ClN₂: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.59; H, 6.65; N, 5.08.

<A NAME="RG23908ST-25A">25a</A> Fugmann B. Steffan B. Steglich W. Tetrahedron Lett.  1984,  25:  3575 

<A NAME="RG23908ST-25B">25b</A> Hilger CS. Fugmann B. Steglich W. Tetrahedron Lett.  1985,  26:  5975 

<A NAME="RG23908ST-26">26</A> Antkowiak R. Antkowiak WZ. In The Alkaloids   Vol. 40:  Brossi A. Academic Press; San Diego: 1991.  p.190-340  

<A NAME="RG23908ST-27">27</A> Spaggiari A. Vaccari D. Davoli P. Torre G. Prati F.
J. Org. Chem.  2007,  72:  2216 

<A NAME="RG23908ST-28">28</A> Okuda K. Kotake Y. Ohta S. Bioorg. Med. Chem. Lett.  2003,  13:  2853 

<A NAME="RG23908ST-29">29</A> Liu D. Venhuis BJ. Wikström HV. Dijkstra D. Tetrahedron  2007,  63:  7264 

<A NAME="RG23908ST-30">30</A> Moore MB. Wright HB. Vernsten M. Freifelder M. Richards RK. J. Am. Chem. Soc.  1954,  76:  3656 

<A NAME="RG23908ST-31A">31a</A> Bills JL. Noller CR. J. Am. Chem. Soc.  1948,  70:  957 

<A NAME="RG23908ST-31B">31b</A> Späth E. Polgar N. Monatsh. Chem.  1929,  51:  190 

<A NAME="RG23908ST-32A">32a</A> Brossi A. Dolan LA. Teitel S. Org. Synth.  1977,  56:  3 

<A NAME="RG23908ST-32B">32b</A> Venkov AP. Ivanov II. Tetrahedron  1996,  52:  12299 

<A NAME="RG23908ST-33A">33a</A> Cortés EC. Romero EC. Ramírez FG. J. Heterocycl. Chem.  1994,  31:  1425 

<A NAME="RG23908ST-33B">33b</A> Minor DL. Wyrick SD. Charifson PS. Watts VJ. Nichols DE. Mailman RB. J. Med. Chem.  1994,  37:  4317 

<A NAME="RG23908ST-34A">34a</A> Kuo C.-Y. Wu M.-J. J. Chin. Chem. Soc. (Taipei)  2005,  52:  965 

<A NAME="RG23908ST-34B">34b</A> von Nussbaum F. Miller B. Wild S. Hilger CS. Schumann S. Zorbas H. Beck W. Steglich W. J. Med. Chem.  1999,  42:  3478 

<A NAME="RG23908ST-35A">35a</A> Späth E. Monatsh. Chem.  1921,  42:  97 

<A NAME="RG23908ST-35B">35b</A> Leete E.
J. Am. Chem. Soc.  1966,  88:  4219