Rh(I)-catalyzed direct ortho-alkenylation of aromatic ketimines with alkynes and its application to the synthesis of isoquinoline derivatives

Article abstract of DOI:10.1021/ol035083d

Novel synthetic methods of both ortho-alkenylated aromatic ketones and isoquinoline derivatives have been developed through the Rh(I)-catalyzed direct ortho-alkenylation of common aromatic ketimines with alkynes. Furthermore, a highly efficient one-pot sy

Full text of DOI:10.1021/ol035083d

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2759-2761
Rh(I)-Catalyzed Direct ortho-Alkenylation
of Aromatic Ketimines with Alkynes and
Its Application to the Synthesis of
Isoquinoline Derivatives
Sung-Gon Lim, Jun Hee Lee, Choong Woon Moon, Jun-Bae Hong, and
Chul-Ho Jun*
Department of Chemistry, Yonsei UniVeristy, Seoul 120-749, Korea
junch@yonsei.ac.kr
Received June 14, 2003
ABSTRACT
Novel synthetic methods of both ortho-alkenylated aromatic ketones and isoquinoline derivatives have been developed through the Rh(I)-
catalyzed direct ortho-alkenylation of common aromatic ketimines with alkynes. Furthermore, a highly efficient one-pot synthesis of isoquinoline
derivatives was achieved by simply mixing aromatic ketone, benzylamine, and alkyne under a Rh(I) catalyst.
Since the pioneering work by Murai and co-workers in 1993,1
the Ru-catalyzed ortho-alkylation of aromatic ketones and
imines with olefins via C-H activation has been considered
as one of the most useful and reliable synthetic methods for
the preparation of 2-alkyl-substituted aromatic carbonyl
compounds.2 Recently, we reported the Rh(I)-catalyzed
ortho-alkylation of aromatic ketones and imines with olefins.3
The reaction not only shows a high selectivity for monoalky-
lation with numerous 1-alkenes but can also be applied to
various problematic olefins such as 1-alkenes with an allylic
proton, R,ω-dienes, and internal olefins. However, for ortho-
alkenylation of aromatic ketones, only a few examples of
Ru-catalyzed reactions of a specific ketone such as R-tetral-
one with internal alkynes have been reported.4-6 Herein, we
report a Rh(I)-catalyzed direct ortho-alkenylation of common
aromatic ketimines with 1-alkynes as well as internal alkynes
and its application to a one-pot synthetic protocol of
isoquinoline derivatives.7
The reactions of the benzylimine of acetophenone 1a with
some terminal alkynes were examined, and the results are
summarized in Table 1. When 1a (1.0 equiv) was treated
with 1-hexyne (2f) or 1-octyne (2g) (1.2 equiv) in toluene
at 130 °C for 2 h in the presence of Rh(PPh3)3Cl (3, 2 mol
%), ortho-alkenylation of 1a took place to produce 4af or
(4) (a) Kakiuchi, F.; Yamamoto, Y.; Chatani, N.; Murai, S. Chem. Lett.
1995, 681. For the site selective vinylation of aromatic compounds, see:
(b) Kakiuchi, F.; Sato, T.; Tsujimoto, T.; Yamauchi, M.; Chatani, N.; Murai,
S. Chem. Lett. 1998, 1053. (c) Harris, P. W. R.; Rickard, C. E. F.; Woodgate,
P. D. J. Organomet. Chem. 1999, 589, 168. Also see: (d) Kakiuchi, F.;
Murai, S. Acc. Chem. Res. 2002, 35, 826.
(5) For â-vinylation of R,â-unsaturated ketone with internal alkynes,
see: Kakiuchi, F.; Uetsuhara, T.; Tanaka, Y.; Chatani, N.; Murai, S. J.
Mol. Catal. A: Chem. 2002, 182-183, 511.
(6) ortho-Arylation of aromatic ketones using arylboronates also has been
reported very recently: Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 1698.
(1) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, S. Nature 1993, 366, 529.
(2) (a) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.;
Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62. (b) Murai, S.;
Chatani, N.; Kakiuchi, F. Pure Appl. Chem. 1997, 69, 589. (c) Sonoda,
M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1997, 70,
3117. (d) Trost, B. M.; Imi, K.; Davies, I. W. J. Am. Chem. Soc. 1995,
117, 5371. (e) Grigg, R.; Savic, V. Tetrahedron Lett. 1997, 38, 5737. (f)
Du¨rr, U.; Kisch, H. Synlett 1997, 1335. (g) Busch, S.; Leitner, W. Chem.
Commun. 1999, 2305. (h) Lim, Y.-G.; Han, J.-S.; Yang, S.-S.; Chun, J. H.
Tetrahedron Lett. 2001, 42, 4853.
(3) (a) Jun, C.-H.; Moon, C. W.; Hong, J.-B.; Lim, S.-G.; Chung, K.-
Y.; Kim, Y.-H. Chem. Eur. J. 2002, 8, 485. (b) Jun, C.-H.; Hong, J.-B.;
Kim, Y.-H.; Chung, K.-Y. Angew. Chem., Int. Ed. 2000, 39, 3440.
(7) Rh(I)-catalyzed ortho-vinylation of some 2-phenylpyridine derivatives
with only internal alkynes has been reported: Lim, Y.-G.; Lee, K.-H.; Koo,
B. T.; Kang, J.-B. Tetrahedron Lett. 2001, 42, 7609.
10.1021/ol035083d CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003

Table 1. Rh(I)-Catalyzed ortho-Vinylation of Ketimines (1)a
Figure 1. Mechanism for Rh(I)-cataxlyzed ortho-alkenylation.
entry
1 (R1, R2)
2 (R3, R4)
ratio (4/5)b
yield (%)c
unexpectedly from the reaction of 1a with 2i under more
vigorous reaction conditions.10 For example, when a mixture
of 1a (1.0 equiv) and 2i (1.2 equiv) was heated at 150 °C
for 24 h in the presence of 4 mol % of 3, a mixture of 9a
and 10a was isolated in 73% yield with a 53:47 ratio (Table
2, entry 1). We postulate that ketimine 8ai (R1 ) H, R3 )
1
2
3
4
5
6d
7
8d
9e
1a (H, Me)
2f (H; nBu) 100:0 (4a f/5a f)
2g (H; nHex) 100:0 (4a g/5a g)
86:14 (4a h /5a h )
2i (Ph; Ph) 100:0 (4a i/5a i)
88
85
96
93
95
81
92
41
72
60
2h (H; tBu)
1b (CF3, Me) 2h (H; tBu)
1c (OMe, Me)
65:35 (4bh /5bh )
82:18 (4bh /5bh )
52:48 (4ch /5ch )
76:24 (4ch /5ch )
86:14 (4d h /5d h )
100:0 (4eh /5eh )
1d (H, Et)
10e 1e (H, nPent)
Table 2. Tandem ortho-Alkenylation-Cyclization of
Ketimines (1)a
a Reagent and conditions: (1) 1 (1.0 equiv), 2 (1.2 equiv), Rh(PPh3)3Cl
(3, 2 mol %), toluene, 130 °C, 2 h. (2) 1 N HCl, room temperature, 12 h.
b Determined by GC. c Isolated yield. d Carried out at 100 °C for 30 min.
e Carried out using 4 mol % of 3.
4ag in 88% and 85% isolated yields, respectively, after
hydrolysis (Table 1, entries 1 and 2). Under the above
reaction conditions, the reaction of 1a with 3,3-dimethyl-1-
butyne (2h) gave a 86:14 mixture of monoalkenylated ketone
4ah and dialkenylated ketimine 5ah in an almost quantitative
yield (entry 3).8 An internal alkyne, diphenylacetylene 2i,
was also reacted with 1a smoothly to afford 4ai in a 93%
yield (entry 4). To compare the reactivities of aromatic
ketimines bearing different para-substituents, we examined
the reaction of 1b or 1c with 2h under mild reaction
conditions. When the reaction was carried out at 100 °C for
30 min, the electron-withdrawing group (CF3) containing
compound 1b displayed much better reactivity than the
electron-donating group (OCH3) containing compound 1c
(entries 6 and 8). This result is identical to that observed for
the ortho-alkylation of aromatic ketimines with alkenes.3
Other aromatic ketimines possessing longer alkyl chain on
the imino moiety were also examined and showed somewhat
low reactivities under similar reaction conditions (entries 9
and 10).
The proposed mechanism for the Rh(I)-catalyzed ortho-
alkenylation is as follows: (1) Precoordination of ketimine
1 to the rhodium catalyst 3 followed by the insertion of the
Rh into an ortho C-H bond affords rhodium hydride 6. (2)
Anti-Markovnikov syn-addition of the Rh-H bond into the
coordinated 2 and the prompt reductive elimination of the
resulting Rh(III) intermediate 7 generates the ortho-alkeny-
lated ketimine 8, which is transformed into 4 by hydrolysis
(Figure 1).9
entry
1 (R)
ratio (9/10)b
yield(%)c
1
2
3
1a (H)
1b (CF3)
1c (OMe)
53:47 (9a /10a )
33:67 (9b/10b)
41:59 (9c/10c)
73 (82)
55 (67)
71 (82)
a Reagent and conditions: 1 (1.0 equiv), 2i (1.2 equiv), 3 (4 mol %),
toluene, 150 °C, 24 h. b Determined by GC. c Isolated yield. GC yields are
given in parentheses.
R4 ) Ph), generated from 1a and 2i by direct ortho-
alkenylation, might be a key intermediate for this tandem
ortho-alkenylation-cyclization process. The phenethyl group
(CH2CH2Ph) of 10a seems to be introduced by the migration
of the benzyl group of 8ai into the benzylic position of
another 8ai.11 Other ketimines were also examined in this
tandem reaction, and the results are depicted in Table 2.
Next, we were intrigued by the possibility of developing
a more convenient one-pot synthetic method of isoquinoline
derivatives by simply mixing aromatic ketone, primary
amine, and alkyne under Rh(I) catalyst without the prior
preparation of the corresponding ketimines (Scheme 1). As
was expected, a mixture of two isoquinolines, 9a and 10a,
(9) The stereochemistry of 4 and 5 was deduced from the proposed
mechanism (Figure 1) and confirmed to be all-trans by measuring the
coupling constant between two olefinic protons of the products only except
for 4ai.
(10) Recently, Larock and co-workers ingeniously utilized Pd-catalyzed
tandem cross coupling of the tert-butylimine of o-iodobenzaldehyde with
alkynes-iminoannulation sequence to synthesize a variety of 3,4-disubstituted
isoquinoline derivatives: (a) Roesch, K. R.; Larock, R. C. J. Org. Chem.
1998, 63, 5306. Also see: (b) Huang, Q.; Hunter, J. A.; Larock, R. C. J.
Org. Chem. 2002, 67, 3437 and references therein.
During the course of optimization of the reaction variables,
we found that two isoquinoline derivatives were formed
(8) Attempts to hydrolyze the 2,4-dialkenylated ketimines 5 failed.
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Org. Lett., Vol. 5, No. 15, 2003

8i to afford an ion pair consisting of iminium 14 and enamide
15. Nucleophilic attack on the benzylic position of 14 by 15
generates 3,4-dihydroisoquinoline 16 and imine 17. Similarly,
another 3,4-dihydroisoquinoline 18 could be formed from
17.12 Finally, both 16 and 18 can be easily oxidized into the
stable aromatic isoquinolines 9 and 10 (Figure 2).
Scheme 1. One-Pot Tandem Reaction of Aromatic Ketones
(11)a
a Reagent and conditions: 11 (1.0 equiv), 12 (3.0 equiv), 2i (3.0
b
equiv), 3 (10 mol %), toluene, 170 °C, 12 h. Isolated yield. GC
yields are given in parentheses. cThe ratio of 9:10 was determined
by GC.
was obtained in 89% isolated yield with a 54:46 ratio directly
from the reaction of acetophenone (11a, 1 equiv) with 2i
(3.0 equiv) and benzylamine 12 (3.0 equiv) at 170 °C for
12 h under 3 (10 mol %) (Scheme 1). Other substituted
acetophenones, 11b and 11c, also showed a good reactivity
in this one-pot tandem process.
To get more insight into this tandem process, the following
one-pot experiment was performed. The reaction of 1-[2-
(1,2-diphenylvinyl)phenyl]ethanone (4ai, 1.0 equiv), prepared
separately through direct ortho-alkenylation, with an excess
of 12 (3.0 equiv) was carried out in the absence of both 2i
and 3 in toluene at 170 °C. After 24 h, a mixture of 9a and
10a was obtained in a 69% isolated yield in a 36:64 ratio
(Scheme 2). This result implies that the formation of the
Figure 2. Plausible explanation for the formation of 9 and 10.
In summary, we have developed novel synthetic methods
for both ortho-alkenylated aromatic ketones and isoquinoline
derivatives under different reaction conditions through the
Rh(I)-catalyzed direct ortho-alkenylation of common aro-
matic ketimines with alkynes. Furthermore, the highly
efficient single-step synthesis of isoquinoline derivatives was
achieved by the three-component reaction of aromatic ketone
with benzylamine and alkyne without any use of ortho-
functionalized aromatic compounds. Extension of the scope
of these synthetic methods and mechanistic studies are
currently under investigation.
Scheme 2. Reaction of Enone (11) with Benzylamine (12)
Acknowledgment. This work was supported by the
National Research Laboratory (NRL) (2000-N-NL-01-C-271)
and Koren Science and Engineering Foundation (20004010).
High resolution mass spectra were provided by the Korea
Basic Science Institute.
isoquinolines 9a and 10a must be a thermal process through
the key intermediate 8ai (R1 ) H, R2 ) Me, R3 ) R4 ) Ph;
Figure 1).
At the present time the mechanism for the formation of 9
and 10 from the reaction of 1 with 2i is unclear. One
plausible explanation is shown in Figure 2. Electrocyclic
reaction of 8i might give the unstable bicyclic intermediate
13, which could abstract an acidic R-hydrogen from another
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035083D
(12) When the reaction of 1a with 2i was performed for a short period
of reaction time (e.g., for 2 h), a small amount of 16a and 18a (R ) H)
was isolated and characterized spectroscopically. See Supporting Informa-
tion.
(11) The structure of 10a has been confirmed undoubtedly by the
independent synthesis of 10a from 9a. See Supporting Information.
Org. Lett., Vol. 5, No. 15, 2003
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