Subscribe to RSS
DOI: 10.1055/s-0031-1290532
C-1 Alkynylation of N-Methyltetrahydroisoquinolines through CDC: A Direct Access to Phenethylisoquinoline Alkaloids
Publication History
Publication Date:
24 February 2012 (online)
![](https://www.thieme-connect.de/media/synlett/201205/lookinside/thumbnails/10.1055-s-0031-1290532-1.jpg)
Abstract
Direct cross-coupling between N-methyltetrahydroisoquinolines and alkynes using CuI-DEAD is presented. It affords the regioselective C-1-alkynylated products in good yield. This regioselectivity is in contrast to the results reported earlier in the reaction of N,N-dimethylbenzyl amine where the N-methyl alkynylated product was formed exclusively or predominantly. The C-1-substituted propargylic isoquinolines were easily reduced to phenethylisoquinolines with Pd/C. This reaction sequence provides a short route to synthesize methopholine, homolaudanosine and other phenethylisoquinoline alkaloids.
Key words
cross-coupling - regioselectivity - alkaloids - alkynes - amines
- Supporting Information for this article is available online:
- Supporting Information
-
1a
Ozturk T. The Alkaloids Vol. 53:Cordell GA. Academic Press; New York: 2000. p.120 -
1b
Wu W.Beal JL.Fairchild EH.Doskotch RW. J. Org. Chem. 1978, 43: 580 -
1c
Menachery MD.Lavanier GL.Wetherly ML.Guinaudeau H.Shamma M. J. Nat. Prod. 1986, 49: 745 -
1d
Bentley KW. Nat. Prod. Rep. 2005, 22: 249 -
2a
Scott JD.Williams RM. Chem. Rev. 2002, 102: 1669 -
2b
Chrzanowska M.Rozwadowska MD. Chem. Rev. 2004, 104: 3341 -
2c
Pedrosa R.Andre C. J. Org. Chem. 2001, 66: 243 ; and references therein - 3
Byrator E.Sasse BC.Stark H.Schneider G. ChemBioChem 2005, 6: 997 -
4a
Shamma M. The Isoquinoline Alkaloids Vol. 25:Blomquist AT.Wasserman H. Academic Press; New York: 1972. Chap. 24. p.458 -
4b
Battersby AR.Bradbury RB.Herbert RB.Munro MHG.Ramage R. J. Chem. Soc., Perkin Trans. 1 1974, 1394 -
4c
Kametani T.Koizumi M. The Alkaloids Vol. 14:Manske R. Academic Press; London: 1979. Chap. 7. p.265 -
5a
Cass LJ.Frederik WS. Am. J. Med. Sci. 1963, 246: 550 -
5b
Meyers AI.Dickman DA.Boes M. Tetrahedron 1987, 43: 5095 -
5c
Zbigniew C.MacLean DB.Szarek WA. J. Chem. Soc., Chem. Commun. 1987, 7: 1748 -
5d
Zbigniew C.MacLean DB. Can. J. Chem. 1987, 65: 2356 -
5e
Drenth JP.Meer JW. N. Engl. J. Med. 2001, 345: 1748 -
5f
Terkeltaub RA. N. Engl. J. Med. 2003, 349: 1647 -
5g
Tojo E.Önür MA.Freyer AJ.Shamma M. J. Nat. Prod. 1990, 53: 634 - For representative papers, see:
-
6a
Miyaura N.Suzuki A. Chem. Rev. 1995, 95: 2457 -
6b
Kotha S.Lahiri K.Kashinath D. Tetrahedron 2002, 58: 9633 -
6c
Nicolaou KC.Bulger PG.Sarlah D. Angew. Chem. Int. Ed. 2005, 44: 4442 -
6d
Dyker G. Handbook of C-H Transformation Wiley-VCH; Weinheim: 2005. -
6e
Zapf A.Beller M. Chem. Commun. 2005, 431 -
6f
Herreries C.Yao X.Li Z.Li C.-J. Chem. Rev. 2007, 107: 2546 -
6g
Alberico D.Scott ME.Lautens M. Chem. Rev. 2007, 107: 174 -
6h
Miyaura N. Bull. Chem. Soc. Jpn. 2008, 81: 1535 -
6i
Martin R.Buchwald SL. Acc. Chem. Res. 2008, 41: 1461 -
6j
Chen X.Engle K.-M.Wang D.-H.Yu J.-Q. Angew. Chem. Int. Ed. 2009, 48: 5094 -
6k
Bellina F.Rossi R. Chem. Rev. 2010, 110: 1082 -
6l
Liu C.Zhang H.Shi W.Lei A. Chem. Rev. 2011, 111: 1780 -
7a
Li C.-J. Acc. Chem. Res. 2009, 42: 335 -
7b
Scheuermann C.-J. Chem. Asian J. 2010, 5: 436 -
7c
Yeung CS.Dong VM. Chem. Rev. 2011, 111: 1215 -
8a
Li Z.-P.Li C.-J. J. Am. Chem. Soc. 2004, 126: 11810 -
8b
Li Z.-P.Li C.-J. Org. Lett. 2004, 6: 4997 -
8c
Li Z.-P.Li C.-J. J. Am. Chem. Soc. 2005, 127: 3672 -
8d
Li Z.-P.Li C.-J. J. Am. Chem. Soc. 2005, 127: 6968 -
8e
Zhang Y.Li C.-J. J. Am. Chem. Soc. 2006, 128: 4242 -
8f
Murahashi S.-I.Nakae T.Terai H.Komiya N. J. Am. Chem. Soc. 2008, 130: 11005 -
8g
Li Z.Li C.-J. Angew. Chem. Int. Ed. 2008, 47: 7075 -
8h
Sud D.Sureshkumar D.Klussmann M. Chem. Commun. 2009, 3169 -
8i
Shen Y.-M.Li M.Wang S.-Z.Zhan T.-G.Tan Z.Guo C.-C. Chem. Commun. 2009, 953 -
8j
Condie A.-G.Gonzalez-Gomez J.-C.Stephenson C.-R.-J. J. Am. Chem. Soc. 2010, 132: 1464 -
8k
Liu P.Zhou C.-Y.Xiang S.Che C.-M. Chem. Commun. 2010, 2739 -
9a
Ghobrial M.Harhammer K.Mihovilovic MD.Schnurch M. Chem. Commun. 2010, 46: 8836 -
9b
Tsang S.-K.Todd MH. Tetrahedron Lett. 2009, 50: 1199 - 10
Weinberg NL.Brown EA. J. Org. Chem. 1966, 31: 4058 -
11a
Xu X.Li X. Org. Lett. 2009, 11: 1027 -
11b
Xu X.Li X.Ma L.Ye N. J. Am. Chem. Soc. 2008, 130: 14048 -
12a
Lewis FD.Ho T.-I.Simpson JT. J. Am. Chem. Soc. 1982, 104: 1924 -
12b
Dumbrowski GW.Dinnocenzo JP.Farid S.Goodman JL.Gould IR. J. Org. Chem. 1999, 64: 427 -
12c
Barry JE.Finkelstein M.Mayeda EA.Ross SD. J. Org. Chem. 1974, 39: 2695 - DDQ-promoted cyanation and VO(acac)2-MCPBA-promoted coupling of nucleophiles like nitroalkanes, ketones and heteroaromatics such as indole and pyrrole with N-alkyltetrahydroisoquinolines have been reported earlier:
-
13a
Sundberg RJ.Theret M.-H.Wright L. Org. Prep. Proced. Int. 1994, 26: 386 -
13b
Jones KM.Karier P.Klussmann M. ChemCatChem 2012, 4: 51 -
15a
Hershberg EB.Oliveto EP.Gerold C.Johnson L. J. Am. Chem. Soc. 1951, 73: 5073 -
15b
Taylor AM.Schreiber SL. Org. Lett. 2006, 8: 143 -
17a
Brossi A.Besendrof H.Pellmont B.Walter M.Schinder O. Helv. Chim. Acta 1960, 43: 1459 -
17b
Brossi A.Besendrof H.Pirk LA.Rheiner A. Med. Chem. 1965, 5: 281 -
17c
Ito K.Furukawa H.Tanaka H.Kato S. J. Pharm. Soc. Jpn. 1970, 90: 1169
References and Notes
General Procedure:
To a solution of appropriate N-methyltetrahydroisoquinoline
(1 mmol) in THF (2 mL), taken in 10-mL two-necked round bottom flask,
was added DEAD (1.1 mmol) dropwise in 1-2 min at 0-5 ˚C
and the reaction mixture was allowed to reach r.t. and stirred for
1 h. After re-cooling the reaction mixture to 0-5 ˚C,
CuI (0.05 mmol) was added followed by dropwise addition of the alkyne
(1.5 mmol). The resulting mixture was stirred for 5-6 h
at r.t. and then the solvent was evaporated under reduced pressure.
The residue was purified by column chromatog-raphy over silica gel
using hexane-EtOAc mixture (9:1-6:4) as the eluent
to give the pure products 8a-j.
Spectral data of selected compounds:
1-(4-Chlorophenylethynyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
(8f): yellow viscous liquid. ¹H NMR (300
MHz, CDCl3): δ = 7.23-7.27
(m, 2 H), 7.15-7.18 (m, 2 H), 6.97 (s, 1 H), 6.49 (s, 1
H), 4.53 (s, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 2.86-2.96
(m, 2 H), 2.78-2.83 (m, 1 H), 2.70-2.73 (m, 1
H), 2.51 (s, 3 H). ¹³C NMR (75 MHz, CDCl3-CCl4): δ = 148.35,
147.54, 134.15, 132.96, 128.54, 126.73, 125.48, 121.62, 111.35,
110.37, 88.59, 85.21, 56.42, 55.96, 55.80, 48.53, 43.58, 28.33.
MS (ESI): m/z = 342.1 [M + H]+.
6,7-Dimethoxy-1-(3,4-dimethoxyphenylethynyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline
(8h): yellow viscous liquid. ¹H NMR (300
MHz, CDCl3): δ = 6.90 (dd, J = 8.1, 1.8
Hz, 1 H), 6.80 (d, J = 1.8 Hz,
1 H), 6.72 (s, 1 H), 6.65 (d, J = 8.4
Hz, 1 H), 6.49 (s, 1 H), 4.50 (s, 1 H), 3.78 (s, 6 H), 3.77 (s,
6 H), 2.73-2.94 (m, 3 H), 2.58-2.62 (m, 1 H), 2.52
(s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 149.39, 148.59,
148.21, 147.45, 127.18, 125.43, 125.00, 115.38, 114.61, 111.27,
110.93, 110.48, 86.14, 85.90, 56.57, 56.52, 55.92, 55.89, 55.74,
48.66, 43.66, 28.39. MS (ESI): m/z = 368.1 [M + H]+.
Spectral data of selected phenethylisoquinolines:
1-(4-Methoxyphenethyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline
(10): light yellow oil. ¹H NMR (300 MHz, CDCl3): δ = 7.07-7.14
(m, 6 H), 6.79-6.82 (m, 2 H), 3.77 (s, 3 H), 3.46 (t, J = 5.4 Hz, 1 H), 3.12-3.18
(m, 1 H), 2.64-2.84 (m, 4 H), 2.42-2.47 (m, 1
H), 2.44 (s, 3 H), 2.00-2.09 (m, 2 H). ¹³C
NMR (75 MHz, CDCl3): δ = 157.60, 138.18,
134.94, 129.29, 128.71, 127.06, 125.80, 125.74, 113.70, 63.03, 55.22,
48.31, 42.82, 36.93, 30.59, 26.14. Anal. Calcd for C19H23NO:
C, 81.10; H, 8.24; N, 4.98. Found: C, 81.19; H, 8.33; N, 4.89.
6,7-Dimethoxy-2-methyl-1-phenethyl-1,2,3,4-tetra-hydroisoquinoline
(12):¹7 yellow pasty mass. ¹H
NMR (300 MHz, CDCl3): δ = 7.16-7.21
(m, 2 H), 7.09-7.12 (m, 3 H), 6.50 (s, 1 H), 6.44 (s, 1
H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.44 (t, J = 4.8
Hz, 1 H), 3.11-3.19 (m, 1 H), 2.66-2.87 (m, 4
H), 2.50-2.59 (m, 1 H), 2.44 (s, 3 H), 1.94-2.10
(m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 147.46,
147.33, 142.43, 128.74, 128.39, 128.29, 125.85, 125.65, 111.26,
110.06, 62.59, 55.93, 55.76, 47.41, 42.03, 36.64, 31.76, 24.82.
MS (ESI): m/z = 308.1 [M + H]+.