Concise route to 3-arylisoquinoline skeleton by lewis acid catalyzed c(sp3)-h bond functionalization and its application to formal synthesis of (±)-Tetrahydropalmatine

Article abstract of DOI:10.1021/ol300180w

An expeditious route to furnish an isoquinoline skeleton via hydride shift mediated C-H bond functionalization was developed. In this process, an unusual [1,5]-H shift without the assistance of the adjacent heteroatom took place to produce tetrahydroisoquinoline derivatives in good to excellent chemical yields. The formal synthesis of (±)-tetrahydropalmatine was achieved by exploiting this new transformation.

Full text of DOI:10.1021/ol300180w

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1436–1439
Concise Route to 3-Arylisoquinoline
Skeleton by Lewis Acid Catalyzed
C(sp3)ÀH Bond Functionalization and
Its Application to Formal Synthesis of
(()-Tetrahydropalmatine
Keiji Mori, Taro Kawasaki, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro,
Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received January 22, 2012
ABSTRACT
An expeditious route to furnish an isoquinoline skeleton via hydride shift mediated CÀH bond functionalization was developed. In this process, an
unusual [1,5]-H shift without the assistance of the adjacent heteroatom took place to produce tetrahydroisoquinoline derivatives in good to
excellent chemical yields. The formal synthesis of (()-tetrahydropalmatine was achieved by exploiting this new transformation.
The development of methodology for the direct functio-
nalization of relatively unreactive CÀH bonds has become
a major topic of research.1 Recently, the C(sp3)ÀH bond
functionalization via the hydride shift/cyclization process,
namely, the “internal redox process”, has attracted much
attention for its unique features (Scheme 1).2 The key
feature of this transformation is the [1,5]-hydride shift of
the C(sp3)ÀH bond R to the heteroatom. Subsequent
6-endo cyclization to cation species affords heterocycle 2.
Although CÀH bond functionalization is promoted by a
transition metal catalyst in most cases, this type of CÀH
bond functionalization typically proceeds under thermal
conditions or Brønsted or Lewis acid catalysis.3À6
Whereas a range of related reactions of heteroatom-
containing substrates (X = NR2 or O) have been reported,
(2) For selected recent references, see: (a) Pastine, S. J.; McQuaid,
K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127, 12180. (b) Pastine, S. J.;
Sames, D. Org. Lett. 2005, 7, 5429. (c) Tobisu, M.; Chatani, N. Angew.
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Chem., Int. Ed. 2006, 45, 1683. (d) Barluenga, J.; Fananas-Mastral, M.;
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Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2008, 47, 6594. (e)
McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402. (f)
Shikanai, D.; Murase, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2009,
131, 3166. (g) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131,
16525. (h) Jurberg, I. D.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc.
2010, 132, 3543. (i) Zhou, G.; Zhang, J. Chem. Commun. 2010, 46, 6593.
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2011, 133, 2100. (k) Bolte, B.; Gagosz, F. J. Am. Chem. Soc. 2011, 133,
7696. (l) Alajarin, M.; Martin-Luna, M.; Vidal, A. Adv. Synth. Catal.
2011, 353, 557.
(3) These types of reactions are classified under the term “tert-amino
effect”. For reviews, see: (a) Meth-Cohn, O.; Suschitzky, H. Adv.
Heterocycl. Chem. 1972, 14, 211. (b) Verboom, W.; Reinhoudt, D. N.
Recl. Trav. Chim. Pays-Bas 1990, 109, 311. (c) Meth-Cohn, O. Adv.
Heterocycl. Chem. 1996, 65, 1. (d) Quintela, J. M. Recent Res. Dev. Org.
Chem. 2003, 7, 259. (e) Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-
Balint, A.; Halasz-Dajka, B. Synthesis 2006, 2625.
(1) For recent reviews on CÀH activation, see: (a) Godula, K.;
Sames, D. Science 2006, 312, 67. (b) Bergman, R. G. Nature 2007, 446,
391. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (d) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (e)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (f) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer,
J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (g) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (h) Davies, H. M. L.; Du
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Bois, J.; Yu, J.-Q. Chem. Soc. Rev 2011, 40, 1855. (i) Bruckl, T.; Baxter,
R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2011, DOI: 10.1021/
ar200194b.
r
10.1021/ol300180w
Published on Web 03/05/2012
2012 American Chemical Society

the corresponding carbon analogue (X = CH2) had been
overlooked until quite recently.7,8 This is due to the
difficulties posed by the desired [1,5]-hydride shift of the
CÀH bond without the assistance of the adjacent heteroa-
tom. Aspart of ourrecentprogram to developnew catalytic
CÀH bond functionalization methodologies,6 we have
disclosed that the benzylic CÀH bond without an
adjacent heteroatom could also participate in this type
of transformation, giving 3-aryltetraline derivatives.7
Quite recently, several other groups also reported the
platinum-catalyzed benzylic CÀH bond functionaliza-
tion that led to indene derivatives.8 Stimulated by these
achievements, we turned our attention to the construc-
tion of another important substructure by exploiting
this type of transformation.
6-endo cyclization) occurred successively to afford isoquino-
line derivatives in good to excellent chemical yields. The
application of this methodology to the formal synthesis of
(()-tetrahydropalmatine is also demonstrated.
Scheme 1. C(sp3)ÀH Bond Functionalizaiton via Internal Re-
dox Process
We describe herein an expeditious route to an iso-
quinoline skeleton, which is frequently encountered
in numerous biologically active compounds, via the
hydride shift/cyclization sequence.9 In this reaction, three
transformations (imine formation, [1,5]-hydride shift, and
(4) (a) Reinhoudt, D. N.; Visser, G. W.; Verboom, W.; Benders,
P. H.; Pennings, M. L. M. J. Am. Chem. Soc. 1983, 105, 4775. (b)
Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org. Chem.
1984, 49, 269. (c) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N.;
Harkema, S. J. Am. Chem. Soc. 1987, 109, 3136. (d) Groenen, L. C.;
Verboom, W.; Nijhuis, W. H. N.; Reinhoudt, D. N.; Van Hummel, G. J.;
Teil, D. Tetrahedron 1988, 14, 4627. (e) Nijhuis, W. H. N.; Verboom, W.;
Abu El-Fadl, A.; Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1989, 54,
199. (f) Nijhuis, W. H. N.; Verboom, W.; Abu El-Fadl, A.; Van
Hummel, G. J.; Reinhoudt, D. N. J. Org. Chem. 1989, 54, 209. (g) De
Boeck, B.; Janousek, Z.; Viehe, H. G. Tetrahedron 1995, 51, 13239. (h)
Zhang, C.; Kanta De, C.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008,
130, 416. (i) Che, X.; Sheng, L.; Dang, Q.; Bai, X. Synlett 2008, 2373. (j)
Polonka-Balint, A.; Saraceno, C.; Ludanyi, K.; Benyei, A.; Matyus, P.
Synlett 2008, 2846. (k) Murarka, S.; Zhang, C.; Konieczynska, M. D.;
Seidel, D. Org. Lett. 2009, 11, 129. (l) Ruble, J. C.; Hurd, A. R.; Johnson,
T. A.; Sherry, D. A.; Barbachyn, M. R.; Toogood, P. L.; Bundy, G. L.;
Graber, D. R.; Kamilar, G. M. J. Am. Chem. Soc. 2009, 131, 3991. (m)
McQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009, 11, 2972. (n)
We have already reported that the internal redox reac-
tion that employed imine as an electrophilic partner could
be achieved in a one-pot process from aldehyde and amine
(without isolation of the corresponding imine).6a At the
outset, a solution of aldehyde 3a with p-methoxyphenethyl
moiety and TsNH2 in ClCH2CH2Cl was exposed to 10 mol
% of acid at reflux temperature (Table 1). Various Lewis
ꢀ
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€
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(o) Dunkel, P.; Turos, D.; Benyei, A.; Ludanyi, K.; Matyus, P. Tetra-
hedron 2010, 2331.
(5) Examples of enantioselective internal redox reactions: (a)
Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 13226. (b) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc.
2010, 132, 11847. (c) Cao, W.; Liu, X.; Wang, W.; Lin, L.; Feng, X. Org.
Lett. 2011, 13, 600. (d) Zhou, G.; Liu, F.; Zhang, J. Chem.;Eur. J. 2011,
17, 3101.
(6) (a) Mori, K.; Ohshima, Y.; Ehara, K.; Akiyama, T. Chem. Lett.
2009, 38, 524. (b) Mori, K.; Kawasaki, T.; Sueoka, S.; Akiyama, T. Org.
Lett. 2010, 12, 1732. For an asymmetric version of internal redox
reaction catalyzed by chiral phosphoric acid, see: (c) Mori, K.; Ehara,
K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133, 6166.
(7) (a) Mori, K.; Sueoka, S.; Akiyama, T. J. Am. Chem. Soc. 2011,
133, 2424. (b) Mori, K.; Sueoka, S.; Akiyama, T. Chem. Lett. 2011, 40,
1386.
(8) (a) Tobisu, M.; Nakai, H.; Chatani, N. J. Org. Chem. 2009, 74,
5471. (b) Yang, S.; Li, Z.; Jian, X.; He, C. Angew. Chem., Int. Ed. 2009,
48, 3999. Fillion’s group found that the p-methoxyphenyl group is
important for the benzylic hydride shift/ring closure for the formation
of tetraline derivatives. See: (c) Mahoney, S. J.; Moon, D. T.; Hollinger,
J.; Fillion, E. Tetrahedron Lett. 2009, 50, 4706. For hydride shifts from
di- and/or triarylmethane, see: (d) Bajracharya, G. B.; Pahadi, N. K.;
Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 6204. (e) Alajarin,
M.; Bonillo, B.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Orenes,
R.-A. Org. Biomol. Chem. 2010, 8, 4690.
acids, such as SnCl4, TiCl4, and BF3 OEt2, were ineffec-
3
tive, and only corresponding imine 5a was obtained after
24 h (entries 1À3). Gratifyingly, FeCl3 promoted the two
desired reactions (imine formation and internal redox
reaction) to give isoquinoline 4a in moderate yield (62%,
entry 4). Further screening of the catalyst revealed that
strong Brønsted acids and lanthanoid triflates pro-
moted this transformation efficiently: on treatment with
TsOH H2O, 4awas obtained in 39% yield (entry 5). TfOH
3
was more effective, affording 4a in 78% isolated yield
(entry 6). Sc(OTf)3 was the catalyst of choice, and 4a was
obtained in excellent yield (90%, entry 8). Fortunately, the
catalyst loading of Sc(OTf)3 could be reduced to 5 mol %
without sacrificing the chemical yield (92%, entry 9).
Further examination suggested that the strong electro-
philicity of the imine moiety was crucial for this transfor-
mation: when aniline was employed in place of TsNH2, the
(9) Tietze’s group found that this type of cyclic amine formation
€
reaction occurred in steroidal compounds. See: (a) Wolfing, J.; Frank,
ꢀ
E.; Schneider, G.; Tietze, L. F. Angew. Chem., Int. Ed. 1999, 38, 200. (b)
ꢀ
Wolfing, J.; Frank, E.; Schneider, G.; Tietze, L. F. Eur. J. Org. Chem.
€
(10) Investigation of other solvent systems (toluene, benzene, cyclo-
hexane, and CH3CN) suggested that nonpolar solvents were suitable for
this reaction, and ClCH2CH2Cl was found to be the solvent of choice.
ꢀ
€
1999, 3013. (c) Wolfing, J.; Frank, E.; Schneider, G.; Tietze, L. F. Eur. J.
Org. Chem. 2004, 90.
Org. Lett., Vol. 14, No. 6, 2012
1437

Table 1. Examination of Reaction Conditionsa
Table 2. Investigation of Substrate Scopea
yield (%)
entry
catalyst
SnCl4
4a
5ab
1
0
0
98
98
98
33
44
2
TiCl4
3
BF3 OEt2
0
3
4
FeCl3
62
39
78
26
90
92
0
5
TsOH H2O
3
6
TfOH
7
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
70
8
9c
10d,e
98
a Unless otherwise noted, all reactions were performed with 0.2 mmol
of aldehyde 3a and 0.22 mmol of TsNH2 and 10 mol % of catalyst in
ClCH2CH2Cl (2.0 mL) at refluxing temperature. b The combined yield of
corresponding imine 5a and 3a. c 5 mol % of catalyst loading. d Anilline
was employed instead of TsNH2. e 30 mol % of catalyst loading.
corresponding imine was solely obtained even in 30 mol %
catalyst (entry 10).10À12
The substrate scope of this transformation is illustrated
in Table 2. The position of substituents on the aromatic
ring (R1) significantly affected the reactivity. A substrate
with a methyl or methoxy group at the 3- or 5-position
(3bÀd) furnished corresponding isoquinolines 4bÀd in good
to excellent chemical yields with 5 mol % of catalyst (entries
1À3). On the other hand, substrate 3e having a 4-methyl
group dramatically lowered the reactivity, and an in-
crease of the catalyst loading (20 mol %) was required to
achieve moderate chemical yield (60%, entry 4). Whereas
30 mol % of catalyst was required for 2,3-naphthyl
substrate 3f (entry 5), 1,2-naphthyl product 4g was
obtained in an excellent chemical yield with low catalyst
loading (5 mol %, entry 6).
The electronic and steric factors of the aromatic ring of
the phenethyl moiety strongly affected the reactivity of this
transformation.7b In the case of p-tolyl substrate 3h, which
has low electron-donating ability compared with that of
the p-methoxyphenethyl moiety, desired product 4h was
obtained in as low as 14% yield even when the reaction was
conducted with 30 mol % of catalyst loading (entry 7).
Simple phenyl-substituted substrate 3i did not furnish
a Unless otherwise noted, all reactions were performed with 0.2 mmol
of aldehyde 3 and 0.22 mmol of TsNH2 and a catalytic amount of
Sc(OTf)3 in ClCH2CH2Cl (2.0 mL) at refluxing temperature. b Isolated
yield. The combined yield of 3 and corresponding imine 5 are indicated
in parentheses.
desired product 4i, and only corresponding imine 5i was
observed (entry 8). It is worthy of note that no desired
product was obtained in the case of 3j that had an electron-
rich 2,4,6-trimethoxyphenyl group (entry 9). Furthermore,
simply changing the position of the methoxy group from
para to ortho dramatically lowered the reactivity. The
chemical yield of 4k was only 16% even with 30 mol %
of catalyst loading (16%, entry 10, cf. entry 9 in Table 1).
These results clearly show that the steric factor is
(11) One of the reviewers suggested the intermolecular hydride shift
mechanism. The crossover experiment of d-3a and 3d revealed that the
hydride shift occurred intramolecularly. For more details, see Support-
ing Information. We thank the reviewer for the suggestion of this
experiment.
(12) Attempts to extend the present method to the catalyzed, en-
antioselective reaction with chiral Sc-complex (with several Py-BOX
ligands) were unsuccessful.
1438
Org. Lett., Vol. 14, No. 6, 2012

in 32% yield even though 30 mol % of catalyst loading
and a prolonged reaction time were required (entry 11).
The formal synthesis of (()-tetrahydropalmatine (6)13,14
was selected to showcase the synthetic potential of the
present transformation. Scheme 2 illustrates the details of
our synthesis. The Sonogashira coupling of triflate 7 with
acetylene 8 gave adduct 9 in 49% yield. Hydrogenation,
reduction of the ester group, and oxidation of the resulting
alcohol afforded aldehyde 10, which was ready for the key
internal redox reaction.
Scheme 2. Formal Synthesis of (()-Tetrahydropalmatine
Gratifyingly, the planned reaction worked well and
desired product 11 was obtained in excellent chemical yield
with low catalyst loading (93% with 5 mol %).15 The
selective cleavage of isopropyl ether in preference to the
methyl ether by BCl316 and subsequent monobromination
by means of chiral phosphoric acid 1617 provided mono-
bromide 12 in excellent yield (92%).18
After the methylation of the phenolic hydroxy group,
the introduction of an oxygen function via aryl boronic
ester19 followed by methylation of the resulting phenol
afforded 14,20 thereby setting the same oxygen function
of the target compound. Finally, treatment of 14 with
LiAlH4 furnished free secondary amine 15, which is
the synthetic intermediate reported by Boudou and
Enders.14c The NMR spectra of 15 coincided with those
of the literature. We have achieved the formal synthesis
of (()-6.
Insummary, a concise approach to 3-arylisoquinolines
by Lewis acid catalyzed C(sp3)ÀH bond functionaliza-
tion was developed. Various substrates could be em-
ployed in this transformation, and the desired quinoline
derivatives were obtained in good to excellent chemical
yields. The application of this methodology to the for-
mal synthesis of (()-tetrahydropalmatine was also de-
monstrated. We hope this method will draw much
attention as a new entry for the expeditious construction
of the isoquinoline skeleton.
overwhelmingly important compared with the electronic
factor in this reaction.
Another interesting feature of this reaction is that the
reaction proceeds even in the absence of the electronic
assistance of the adjacent aromatic ring, as in the case of
tetraline formation:7a aliphatic product 4l was obtained
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan.
€
(13) (a) Heyl, G. Arch. Pharm. 1903, 241, 318. (b) Spath, E.; Mosettig,
€
E.; Trothandl, O. Chem. Ber. 1923, 56, 875. (c) Miyazawa, M.; Yoshio,
K.; Ishikawa, Y.; Kameoka, H. J. Agric. Food Chem. 1998, 46, 1914. (d)
Ito, C.; Itoigawa, M.; Tokuda, H.; Kuchide, M.; Nishino, H.; Furukawa,
H. Planta Med. 2001, 67, 473.
Supporting Information Available. Experimental pro-
cedures, analytical and spectroscopic data for new com-
pounds, copies of NMR spectra, and crystallographic
data for 4a and 14 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) For selected references for the total synthesis of tetrahydropal-
matine, see: (a) Pyne, S. G.; Dikic, B. J. Org. Chem. 1990, 55, 1932. (b)
Matulenko, M. A.; Meyers, A. I. J. Org. Chem. 1996, 61, 573. (c) Boudou,
M.; Enders, D. J. Org. Chem. 2005, 70, 9486 and references cited therein.
(15) Attempts with most suitable substrate 17 failed. Treatment of 17
with 10 mol % of Sc(OTf)3 at refluxing ClCH2CH2Cl for 24 h afforded
seven-membered ring adduct 18 rather than desired isoquinoline 14.
This kind of side reaction was also observed in the formation of tetraline
derivatives reported by Fillion. See ref 8c.
(17) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356.
(18) Treatment with simple Brønsted acids (such as AcOH, PPTS,
etc.) led to the moderate chemical yield of monobromide 12 and a sub-
stantial amount of the dibrominated adduct was obtained (20À30%).
For more details, see Supporting Information.
(19) Nicolaou, K. C.; Sasmal, P. K.; Xu, H.; Namoto, K.; Ritzen, A.
Angew. Chem., Int. Ed. 2003, 42, 4225.
(20) The structure of 14 was unambiguously established by single-
(16) Selected references for the selective removal of isopropyl group
in preference to methyl ether: (a) Hughes, A. B.; Sargent, M. V. J. Chem.
Soc., Perkin Trans. 1 1989, 1787. (b) Wang, Y.-C.; Geprghiou, P. E. Org.
Lett. 2002, 4, 2675.
crystal X-ray analysis.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1439