Easy access to isoquinolines and tetrahydroquinolines from ketoximes and alkynes via rhodium-catalyzed C-H bond activation

Article abstract of DOI:10.1021/jo902084j

(Chemical Equation Presented) Described herein is a convenient and highly regioselective synthesis of substituted isoquinoline derivatives from various aromatic ketoximes and alkynes via a one-pot, rhodium-catalyzed C-H bond activation. In addition, tetra

Full text of DOI:10.1021/jo902084j

pubs.acs.org/joc
Easy Access to Isoquinolines and Tetrahydroquinolines from Ketoximes
and Alkynes via Rhodium-Catalyzed C-H Bond Activation
Kanniyappan Parthasarathy and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received September 27, 2009
Described herein is a convenient and highly regioselective synthesis of substituted isoquinoline
derivatives from various aromatic ketoximes and alkynes via a one-pot, rhodium-catalyzed C-H
bond activation. In addition, tetrahydroquinoline derivatives are formed in good yields from
2-arylidene-1-cyclohexanone oximes possessing an exocyclic double bond and from tetrahydrox-
anthone oximes. A possible mechanism is proposed that involves chelation-assisted C-H activation
via oxidative addition of Rh(I) to an ortho-C-H bond, insertion of the alkyne, reductive elimination,
intramolecular electrocyclization, and aromatization. This mechanism is supported by isolation of
the ortho-alkenylation products 7p and 7q. Also described herein is an example of an iridium-
catalyzed activation of an sp3 C-H bond.
Introduction
carbon-carbon multiple bonds is a promising method for
the synthesis of isoquinoline derivatives. Initially, Heck4 and
co-workers reported a synthesis of an isoquinolinium salt
from cyclopalladated benzaldimines and alkynes. Larock5
developed a palladium-catalyzed iminoannulation of inter-
nal alkynes that leads to isoquinoline compounds, and other
related catalytic reactions have been described, as well.6 We
reported an efficient nickel-catalyzed isoquinoline synthesis
from alkynes and 2-iodobenzaldimines.7 Mechanistically,
this catalytic reaction proceeds via a five-membered metalla-
cycle intermediate, and these metallacycles are further con-
verted into various useful heterocyclic compounds.8 In most
Isoquinoline derivatives are an important class of hetero-
cycles and are found in many naturally occurring com-
pounds that exhibit a variety of biological activities such as
antitumor, analgesic, antihistaminic, and antifertility activ-
ities.1 Furthermore, some isoquinoline derivatives are useful
ligands in the synthesis of phosphorescent emitters for
organic light-emitting diodes (OLEDs).2 Although a number
of classical methods are available for the synthesis of iso-
quinoline derivatives, including Bischler-Napieralski, Po-
meranz-Fritsch, and Pictet-Spengler reactions,3 these
methods often suffer from tedious reaction procedures and
harsh reaction conditions.
(4) (a) Wu, G.; Rhiengold, A. L.; Geib, S. J.; Heck, R. F. Organometallics
1987, 6, 1941. (b) Wu, G.; Rhiengold, A. L.; Geib, S. J.; Heck, R. F. J. Org.
Chem. 1988, 53, 3238.
The transition-metal-catalyzed annulation reaction of
2-iodobenzaldimine or aromatic 2-iodoketimines with
(5) (a) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66,
8042. (b) Dai, G.; Larock, R. C. Org. Lett. 2002, 4, 193 and references therein
(c) Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920. (d) Roesch, K. R.; Larock,
R. C. Org. Lett. 1999, 1, 553.
(6) (a) Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994, 59, 6133.
(b) Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.; Suginome, H.
J. Org. Chem. 1999, 64, 6583. (c) Konno, T.; Chae, J.; Miyabe, T.; Ishihara,
T. J. Org. Chem. 2005, 70, 10172.
(1) (a) The Chemistry of Heterocyclic Compounds: Isoquinolines; Coppola,
G. M., Schuster, H. F., Eds.; John Wiley & Sons: New York, 1981; Vol. 38, Part 3.
(b) Timari, G.; Soos, T.; Hajos, G.; Messmer, A.; Nacsa, J.; Molnar, J. Biol. Org.
Med. Chem. Lett. 1996, 23, 2831.
(2) (a) Igarashi, T.; Watanabe, K. U.S. Patent 2004053071A1, 2004. (b) Lee,
J. Y.; Choi, Y. J.; Kwon, J. H.; Chung, H. K. U.S. Patent 20050112401A1, 2005.
(c) Deaton, J. C.; Hatwar, T. K.; Kondakov, D. Y.; Brown, C. J. U.S. Patent
20050123791A1, 2005. (d) Deaton, J. C.; Hatwar, T. K.; Kondakov, D. Y. U.S.
Patent 20050112401A1, 2005.
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(8) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Kakiuchi, F.; Murai, S.
Acc. Chem. Res. 2002, 35, 826 and references therein. (c) Kakiuchi, F.; Chatani,
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(3) Comprehensive Organic Functional Group Transformations, 1st ed.;
Katritzky, A. R., Cohn, O. M., Rees, C. W., Eds.; Pergamon: Chichester,
England, 1991; Vol. 2, p 328; Vol. 3, p 419.
DOI: 10.1021/jo902084j
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Parthasarathy and Cheng
JOCArticle
of these reactions, a carbon-halogen moiety is used to
generate the reactive species. If an unreactive C-H bond
could participate in such a reaction, the overall transforma-
tion would fit well with the principles of green chemistry
since the use of a halogen would be avoided and less organic
waste would be produced.
assisted strategy.15 In the presence of a rhodium catalyst,
an aromatic ketimine reacted with an alkyne, and subsequent
intramolecular electrocyclization led to an isoquinoline com-
pound. However, the reaction was complicated by the for-
mation of two different isoquinoline derivatives (eq 1).
Recently, Ellman et al. reported the synthesis of pyridines
from imines and alkynes via C-H bond activation. How-
ever, this reaction requires two steps: the formation of
dihydropyridine (DHP) and the oxidation of the DHP using
10% Pd/C and air in acetic acid.16 Very recently, Jones and
co-workers described the formation of polycyclic isoquino-
line salts from arylaldimines or benzo[h]quinoline and al-
kynes via C-H bond activation with rhodium complexes.17
The reaction intermediates were isolated and well-character-
ized.
Our continued interest in the metal-catalyzed synthesis of
heterocycles18 via metallacycles prompted us to explore the
possibility of constructing such metallacycles by the strategy
of chelation-assisted C-H activation. Recently, we reported
a palladium-catalyzed synthesis of functionalized fluoren-9-
one derivatives from an aldoxime ether and an aryl iodide.
This reaction involved two distinct steps;C-H activation
and Heck-type cyclization;in one pot.19 We also reported a
rhodium-catalyzed chelation-assisted β-C-H bond activa-
tion of R,β-unsaturated ketoximes and the subsequent reac-
tion with alkynes to afford substituted pyridine derivatives in
good to excellent yields.20 Herein, we describe the extension
of this work to various oxime substrates, including aromatic
ketoximes and exocyclic R,β-unsaturated cyclic ketone oxi-
mes. The present catalytic reaction provides a convenient
method for the synthesis of various isoquinoline derivatives
in one step in good to excellent yields without further
dehydrogenation or oxidation. In addition, the ketoxime
substrates are readily prepared from the corresponding
ketones and hydroxyamine and are relatively stable when
compared with the corresponding ketimines.
An alternative method for constructing the metallacycle
intermediate involves the direct chelation-assisted activation
of a C-H bond.9 In these similar types of reactions, alde-
hyde, ketone, imine, alcohol, amine, carboxylic acid, and
nitrile groups have been used as directing groups to activate
an ortho aromatic or olefinic C-H bond.10 Recently, several
examples of using oxime as a directing group for the catalytic
activation of aromatic or olefinic C-H bonds for organic
synthesis catalyzed by palladium complexes were reported.
In this context, Ryabov employed an oxime as a directing
group for the activation of an ortho aromatic C-H bond
using a palladium complex,11 and Sanford described a
palladium-catalyzed O-methyl oxime-directed activation of
sp2 and sp3 C-H bonds followed by oxygenation with ozone
and PhI(OAc)2.12 In 2006, Che reported the ortho amidation
of an O-methyl oxime via a palladium-catalyzed C-H
activation and subsequent nitrene insertion.13 Recently, Yu
developed a palladium-catalyzed oxidative ethoxycarbony-
lation of O-methyl oxime benzaldehyde with DEAD.14
In 2003, Jun demonstrated the synthesis of isoquinoline
derivatives via
a transition-metal-catalyzed chelation-
(9) (a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Ritleng, V.;
Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (c) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. Chem. Rev. 2009, DOI: 10.1021/cr900005n. (d) Kakiuchi, F.;
Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698.
(e) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127,
5936. (f) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074,
and references therein. (g) Cao, C.; Li, Y.; Shi, Y.; Odom, A. L. Chem. Commun.
2004, 2002. (h) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 2685. (i) Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2001, 123, 9692. (j) Kuninobu, Y.; Kawata, A.; Takai, K.
J. Am. Chem. Soc. 2005, 127, 13498. (k) Kuninobu, Y.; Tokunaga, Y.; Kawata,
A.; Takai, K. J. Am. Chem. Soc. 2006, 128, 202. (l) Katagiri, T.; Mukai, T.; Satoh,
T.; Hirano, K.; Miura, M. Chem. Lett. 2009, 38, 118.
Results and Discussion
Treatment of acetophenone oxime (1a) with diphenylace-
tylene 2a in the presence of 3 mol % of Rh(PPh3)3Cl in
toluene at 130 °C for 12 h gave isoquinoline product 3a in
89% isolated yield. The structure of 3a was confirmed by 1H
NMR, 13C NMR, and mass spectral analysis.
(10) (a) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084. (b) Harayama, T.; Akiyama, T.; Nakano, Y.; Nishioka, H.; Abe, H.;
Takeuchi, Y. Chem. Pharm. Bull. 2002, 50, 519. (c) Lane, B. S.; Sames, D.
Org. Lett. 2004, 6, 2897. (d) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.;
Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112. (e) Ackermann, L.;
Althammer, A.; Born, R. Angew. Chem., Int. Ed. 2006, 45, 2619. (f)
Ackermann, L.; Born, R.; Bercedo, P. A. Angew. Chem., Int. Ed. 2007, 46,
6364. (g) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (h)
Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008,
47, 4019. (i) Stuart, D. R.; Laperle, M. B.; Burgess, K. M. N.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 16474. (j) Guimond, N.; Fagnou, K. J. Am.
Chem. Soc. 2009, 131, 12050.
To evaluate the effect of catalyst on the isoquinoline
formation reaction, various rhodium complexes were inves-
tigated in the reaction of 1a with 2a. First, we examined
the reaction in the absence of a metal catalyst. Compounds
1a and 2a were stirred in toluene at 130 °C for 24 h, and
no 3a was observed. Under similar reaction conditions,
(15) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, C. J.-B.; Jun, C.- H. Org.
Lett. 2003, 5, 2759.
(11) Oxime as a directing group for stoichiometric activation of C-H
bonds by palladium: Bezsoudnoba, E. Y.; Ryabov, A. D. J. Organomet.
Chem. 2001, 622, 38.
(12) Palladium-catalyzed O-methyl oxime as a directing group for activa-
tion of sp3 C-H bond followed by oxygenation with PhI(OAc)2: (a) Desai,
L. V.; Hull, K. L.; Sanford, S. M. J. Am. Chem. Soc. 2004, 126, 9542. For
activation of sp2 C-H bond, see: (b) Desai, L. V.; Malik, H. A.; Sanford,
S. M. Org. Lett. 2006, 8, 1141. (c) Desai, L. V.; Stowers, K. J.; Sanford, S. M.
J. Am. Chem. Soc. 2008, 130, 13285.
(16) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 3645.
(17) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130,
12414.
(18) (a) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem.
2004, 7, 8445. (b) Hsieh, J.-C.; Cheng, C.-H. Chem. Commun. 2005, 2459.
(c) Chang, H. -T.; Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2005, 39,
4955. (d) Jayanth, T. T.; Cheng, C.-H. Chem. Commun. 2006, 894.
(e) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2006, 8, 5581.
(19) Thirunakkarasu, V, S.; Parthasarathy, K.; Cheng, C.-H. Angew.
Chem., Int. Ed. 2008, 47, 9462.
(13) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048.
(14) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan, A. S. C. J. Am.
Chem. Soc. 2008, 130, 3304.
(20) (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 8, 325. (b) Parthasarathy, K.; Cheng, C.-H. Synthesis 2009, 8, 1400.
9360 J. Org. Chem. Vol. 74, No. 24, 2009

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TABLE 1. Results of the Reaction of Aromatic Oximes with Alkynesa
aAll reactions were carried out using substituted acetophenone oximes 1 (1.0 mmol), alkynes 2 (1.1 mmol), Rh(PPh3)3Cl (3 mol %), and toluene
(3.0 mL) at 130 °C for 12 h. bIsolated yields. cTh=di(2-thienyl)acetylene. dReaction was carried out at 130 °C for 16 h.
[RhCl(COD)]2 was an effective catalyst for the present
reaction only when a monodentate phosphine ligand was
employed. The use of bidendate phosphines (dppm, dppe,
dppp, and dppf) or bipyridine as ligands for rhodium was
unsuccessful, as were phosphine-free conditions. Of the
catalyst systems with a monodentate phosphine ligand,
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SCHEME 1. Proposed Mechanism for the Formation of Isoquinoline Derivatives
[RhCl(COD)]2/4P(Cy)3 gave 3a in 38% yield, while [RhCl-
(COD)]2/4P(furyl)3, and [RhCl(COD)]2/4PPh3 afforded 3a
in 16 and 57% yields, respectively. Wilkinson’s catalyst
(Rh(PPh3)3Cl) proved to be the most effective, forming
isoquinoline product 3a in 89% isolated yield.
and 3m in 80 and 78% yields, respectively (entries 12 and 13).
Likewise, treatment of hex-3-yne (2c) and oct-4-yne (2d) with
1a provided the corresponding isoquinoline products 3n and
3o in 74 and 77% yields, respectively (entries 14 and 15). It is
noteworthy that the reaction of benzaldoxime with diphenyl-
acetylene in the presence of 3 mol % of Rh(PPh3)3Cl in
toluene at 130 °C for 12 h did not give the expected isoquino-
line product. Further studies are required to understand the
reaction.21
To evaluate the scope of the present catalytic isoquinoline
formation, we examined the reactions of several substituted
acetophenone oximes (1b-j) with various alkynes (2b-h)
under optimized reaction conditions (Table 1). 4-Methyla-
cetophenone oxime 1b underwent C-H activation and the
subsequent electrocyclization reaction effectively with 2a,
affording isoquinoline derivative 3b in 83% yield (entry 2).
Interestingly, electron-donating 3-methoxy- and 4-methox-
yacetophenone oximes 1c and 1d reacted nicely with 2a to
give 3c and 3d in 81 and 86% yields (entries 3 and 4). In the
reaction of 3-methoxyacetophenone oxime, there are two
possible C-H bond activation sites at C2 and C6 of 1c, but
the C-H activation occurs only at C6 likely due to the steric
effect of the methoxy group at C3. In a similar manner,
4-nitro- and 4-chloroacetophenone oximes 1e and 1f gave
isoquinoline derivatives 3e and 3f in 68 and 81% yields,
respectively (entries 5 and 6). The effect of changing the
methyl group in acetophenone oxime 1a to other substituents
on the product yield was also investigated. Thus, propiophe-
none oxime 1g and benzophenone oxime 1h reacted with 2a
to provide 3g and 3h in 87 and 84% yields, respectively
(entries 7 and 8).
The scope of the catalytic reaction was extended to
heterocyclic ketoximes 1i and 1j. Treatment of 2-acetylfuran
oxime 1i with alkyne 2a gave furo[2,3-c]pyridine derivative 3i
in 79% yield (entry 9). Similarly, reaction of 2-acetylthio-
phene oxime 1j with 2a or with 2b afforded thieno[2,3-c]-
pyridine derivatives 3j and 3k in 90 and 83% yields, respec-
tively (entries 10 and 11).
In addition to 2a, other symmetrical alkynes (2b-d) were
also tested for the C-H activation and electrocyclization
reaction. Thus, the reaction of di(2-thienyl)acetylene 2b with
1a and 1f gave 3,4-di(2-thienyl)isoquinoline derivatives 3l
This cyclization appears to be highly regioselective, and to
understand this regioselectivity, unsymmetrical alkynes were
used as substrates for the reaction with 1a. Thus, 1-phenyl-1-
propyne (2e) underwent cyclization with 1a at 130 °C for 16 h
to give 3p in 78% yield (entry 16), and no other regioisomeric
product was detected in the reaction mixture. The regio-
chemistry of product 3p was confirmed by NOE experi-
ments. Similar regioselectivity was observed in the reaction
between 1-phenyl-1-butyne (2f) and 1a, forming product 3q
in 74% yield (entry 17). Encouraged by these results, term-
inal alkyne 2g was tested in the reaction with 1a, and product
3r was isolated in 45% yield. Although the reaction gave a
relatively low yield of the expected product (due to the
competitive cyclotrimerization of 2g), we observed only the
regioisomer in which the phenyl substituent is located at C-4
of the isoquinoline moiety (entry 18). The regiochemistry of
product 3r was established by comparing its 1H NMR
spectrum with that of the other regioisomer of 3r prepared
according to a previous method.7 The observed different
regiochemistry of products 3p-r from 1a and unsymmetrical
alkynes is interesting but difficult to explain. It is likely
related to the selection of insertion of alkyne into Rh-H
or Rh-C bonds and the subsequent reductive elimination
(see Scheme 1).
On the basis of known metal-catalyzed, directing-group-
assisted C-H bond activation and cyclization reactions,1,4,7,8
(21) Park, S.; Choi, Y.-A.; Han, H.; Yang, S. H.; Chang, S. Chem.
Commun. 2003, 1936.
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SCHEME 2. Synthesis and Electrocyclization of Addition
Products 7
SCHEME 3. C-H Activation of R-Tetralone Oxime
TABLE 2. Results of the Reaction of Ketoximes Possessing an
R-Exocyclic Double Bond with Alkynesa
a plausible mechanism for the present rhodium-catalyzed
cyclization of acetophenone oxime (1a) with alkyne 2 is
outlined in Scheme 1. The first step likely involves coordina-
tion of the nitrogen atom of oxime group of 1a to the
rhodium metal center, followed by oxidative addition of an
ortho aromatic C-H bond to the metal to form hydro-
metallacycle 5. Coordinative syn insertion of alkyne 2 to the
rhodium-hydride or rhodium-carbon bond of intermediate
5 gives 6 or 60, respectively. Subsequent reductive elimination
of 6 or 60 gives the addition product 7 and regenerates the
catalyst. Compound 7 then undergoes 6π-electrocyclization
and elimination of water to give product 3.
The proposed formation of intermediate 7 is strongly
supported by the isolation of reaction intermediates 7p and
7q from the reactions of acetophenone oxime with 1-phenyl-
1-propyne and 1-phenyl-1-butyne, respectively (Scheme 2).
Intermediate 7p was isolated in 82% yield from the reaction
of 1a with 2e in the presence of 3 mol % of Rh(PPh3)3Cl in
toluene at 130 °C for 3 h. The E stereochemistry of the ortho-
alkenylation products 7p and 7q was confirmed by NOE
experiments. In addition, the structure of 7p was determined
by single-crystal X-ray diffraction. Furthermore, reaction
intermediate 7p underwent electrocyclization and elimina-
tion of water in toluene at 150 °C for 6 h to give 3p in 78%
yield (Scheme 2). In a similar manner, 7q also underwent
electrocyclization and elimination of water to afford 3q in
74% yield.
The C-H activation of R-tetralone oxime also proceeded
smoothly (Scheme 3). Thus, the reaction of R-tetralone
oxime 1k with diphenylacetylene (2a) in the presence of 3
mol % of Rh(PPh3)3Cl in toluene at 130 °C for 12 h provided
the cyclization product 3s in 94% yield.
The scope of the present rhodium-catalyzed C-H activa-
tion reaction can also be applied to ketoximes possessing
an exocyclic double bond and to tetrahydroxanthone oxi-
mes. The results are summarized in Table 2. Treatment of 2-
arylidene-1-cyclohexanone oxime (4a) with diphenylacety-
lene (2a) in the presence of 3 mol % of Rh(PPh3)3Cl in
toluene at 130 °C for 5 h afforded tetrahydroquinoline
derivative 5a in 83% yield (entry 1). Under similar reaction
conditions, 4a reacted with hex-3-yne (2c) to give tetra-
hydroquinoline 5b in 74% yield (entry 2). However, the reac-
tion of unsymmetrical alkyne 1-phenyl-1-propyne (2e) with
4a provided two regioisomeric products 5c and 5c0 in 43 and
aAll reactions were carried out using oximes 4 (1.0 mmol), alkynes 2
(1.1 mmol), Rh(PPh3)3Cl (3 mol %), and toluene (3.0 mL) at 130 °C for
6 h. bIsolated yields. cReaction was carried out at 130 °C for 8 h.
41% yield, respectively (entry 3). The result contrasts with
the high regioselectivity that is observed in the formation of
isoquinoline 3n from oxime 1a and alkyne 2e but is similar to
the regiochemistry observed in the reaction of R,β-unsatu-
rated ketoxime with alkyne 2e.20
Tetrahydroxanthone oxime 4b also undergoes C-H acti-
vation by Rh(PPh3)3Cl at the β-carbon of the exocyclic
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SCHEME 4. Result of the sp3 C-H Bond Activation of
2-Methylcyclohexanone Oxime (4d)
noline derivatives via a sequence that involves rhodium-
catalyzed C-H activation followed by 6π-electrocyclization
and aromatization in one pot. The catalytic reaction is highly
regioselective with unsymmetrical alkynes. The approach
was also used for the sp3 C-H activation and cyclization
catalyzed by an iridium complex. Further studies toward the
sp3 C-H activation and the formation of different carbon-
heteroatom bonds are in progress as is application of this
methodology in the context of total synthesis.
double bond. Oxime 4b reacted with alkynes 2c and 2d in the
presence of Rh(PPh3)3Cl to give the expected cyclization
products 5d and 5e in 76 and 72% yields, respectively (entries
4 and 5). Similarly, tetrahydroxanthone oxime 4c, which
bears a methoxy group on the aromatic ring, reacted
smoothly with 2c to afford 5f in 70% yield (entry 6).
In addition to the oxime-assisted sp2 C-H bond activation
by rhodium complexes, we also investigated the activation of
sp3 C-H bonds by rhodium and iridium complexes. How-
ever, when 2-methylcyclohexanone oxime (4d) was treated
with diphenylacetylene (2a) in the presence of Rh(PPh3)3Cl
(3 mol %) in toluene at 150 °C for 20 h, only a trace amount
of cyclization product 5g was observed. After extensive
optimization studies that examined different metal com-
plexes (see the Supporting Information), we identified
[IrCl(COD)]2/P(Cy)3 as an effective catalyst for the sp3
C-H activation of 4d under the same reaction conditions
(toluene at 150 °C for 20 h) used above. The tetrahydropyr-
idine derivative 5g was obtained in 52% yield by 1H NMR
and was isolated in 38% yield (Scheme 4). While the mechan-
ism for the formation of 5g is not clear, it is likely that oxime-
group-assisted sp3 C-H activation by the iridium complex
is involved, followed by dehydrogenation and other cata-
lytic steps similar to those shown in Scheme 1. It should be
noted that examples of sp3 C-H activation by metal com-
plexes are abundant,22 but the application of such methodo-
logies to give useful organic compounds catalytically is less
common.
Experimental Section
A few representative experimental procedures are listed
below. Full experimental procedures and spectroscopic data
for all compounds can be found in the Supporting Information.
General Procedure for the Synthesis of Isoquinoline Deriva-
tives. A sealed tube containing Rh(PPh3)3Cl (0.030 mmol,
3.0 mol %) was evacuated and purged with nitrogen gas three
times. Freshly distilled toluene (2.0 mL), ketoxime (1.00 mmol),
and alkyne (1.10 mmol) were sequentially added to the system,
and the reaction mixture was allowed to stir at 130 °C for 12 h.
The mixture was filtered through a short Celite pad and washed
with dichloromethane several times. The filtrate was concen-
trated, and the residue was purified on a neutral silica gel column
using hexanes/ethyl acetate as eluent to afford the isoquinoline
derivative 3.
1-Methyl-3,4-diphenylisoquinoline (3a):. White solid; mp
1
174-176 °C; H NMR (400 MHz, CDCl3) δ 8.20-8.18 (m, 1
H), 7.65-7.56 (m, 3 H), 7.37-7.16 (m, 10 H), 3.06 (s, 3 H); 13
C
NMR (100 MHz, CDCl3) δ 157.7, 149.4, 141.0, 137.5, 136.0,
131.3, 130.2, 129.9, 129.1, 128.1, 127.5, 127.0, 126.9, 126.5,
126.2, 126.1 125.5, 22.7; HRMS calcd for C22H17N 295.1361,
found 295.1355.
1,6-Dimethyl-3,4-diphenylisoquinoline (3b):. Pale yellow solid;
mp 158-160 °C; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 9.0
Hz, 1 H), 7.41 (s, 1 H), 7.39 (d, J = 9.0 Hz, 1 H), 7.33-7.31 (m,
5 H), 7.20-7.14 (m, 5 H), 3.03 (s, 3 H), 2.41 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 157.3, 149.3, 140.8, 140.3, 137.6, 136.2,
131.4, 130.2, 128.7, 128.1, 127.5, 127.0, 126.8, 125.5, 125.0,
124.5, 22.5, 22.1; HRMS calcd for C23H19N 309.1517, found
309.1520.
1-Methyl-4-phenylisoquinoline (3r):. Brownish viscous oil; 1H
NMR (400 MHz, CDCl3) δ 8.33 (s, 1 H), 8.17 (d, J = 7.6 Hz,
1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.64-7.59 (m, 2 H), 7.52-7.44
(m, 5 H), 3.00 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 158.0,
141.5, 137.3, 134.3, 131.9, 130.1, 130.0, 128.5, 127.7, 126.8,
125.8, 125.4, 22.5; HRMS calcd for C16H13N 219.1048, found
219.1042.
Conclusion
We have successfully developed a novel and convenient
method for the synthesis of isoquinoline and tetrahydroqui-
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Acknowledgment. We thank the National Science Council
of Republic of China (NSC 95-2119-M-007-005) for support
of this research.
Supporting Information Available: General experimental
procedure and characterization details. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
9364 J. Org. Chem. Vol. 74, No. 24, 2009