Synthesis of 3,4-disubstituted isoquinolines via palladium-catalyzed cross-coupling of 2-(1-Alkynyl)benzaldimines and organic halides

Article abstract of DOI:10.1021/jo026294j

The palladium-catalyzed cross-coupling of readily available N-tert-butyl-2-(1-alkynyl)benzaldimines and aryl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, provides a valuable new route to 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substituents, respectively, in the 4-position. The reaction appears to require an aryl group on the end of the acetylene furthest from the imine functionality. The reaction conditions have been optimized, and reasonably good yields have been obtained.

Full text of DOI:10.1021/jo026294j

Syn th esis of 3,4-Disu bstitu ted Isoqu in olin es via
P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g of
2-(1-Alk yn yl)ben za ld im in es a n d Or ga n ic Ha lid es
Guangxiu Dai and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50010
larock@iastate.edu
Received August 6, 2002
The palladium-catalyzed cross-coupling of readily available N-tert-butyl-2-(1-alkynyl)benzaldimines
and aryl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, provides a valuable new
route to 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substit-
uents, respectively, in the 4-position. The reaction appears to require an aryl group on the end of
the acetylene furthest from the imine functionality. The reaction conditions have been optimized,
and reasonably good yields have been obtained.
SCHEME 1
In tr od u ction
The cyclization of alkynes containing proximate nu-
cleophilic centers promoted by organopalladium com-
plexes is currently of great interest and developing into
a most effective strategy for heterocyclic ring construc-
tion.1 This chemistry provides a straightforward ap-
proach to the synthesis of functionalized carbo- and
heterocycles through the regio- and stereoselective ad-
dition of a nucleophile and an unsaturated carbon unit
across the carbon-carbon triple bond (Scheme 1). Suc-
cessful examples of this process have been reported for
the synthesis of 2,3-disubstituted indoles,2 2,3-disubsti-
tuted benzofurans,3 and other cyclic compounds.4 How-
ever, no one has thus far employed this chemistry to
synthesize isoquinolines.
The isoquinoline ring system is present in many
natural alkaloids,5 encouraging the development of a
variety of classical approaches for isoquinoline synthesis,
including the Bischler-Napieralski, Pictet-Spengler,
and Pomeranz-Fritsch reactions.6 However, these meth-
(1) For recent leading references, see: (a) Cacchi, S.; Fabrizi, G.;
Moro, L. Tetrahedron Lett. 1998, 39, 5101 and references therein. (b)
Chaudhuri, G.; Chowdhury, C.; Kundu, N. G. Synlett 1998, 1273. (c)
Montiero, N.; Balme, G. Synlett 1998, 746. (d) Chowdhury, C.;
Chaudhuri, G.; Guha, S.; Mukherjee, A. K.; Kundu, N. G. J . Org. Chem.
1998, 63, 1863. (e) Cacchi, S.; Fabrizi, G.; Moro, L. J . Org. Chem. 1997,
62, 5327. (f) Khan, M. W.; Kundu, N. G. Synlett 1997, 1435. (g) Cacchi,
S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997, 1363. (h)
Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J . Org.
Chem. 1996, 61, 9280. (i) Chowdhury, C.; Kundu, N. G. J . Chem. Soc.,
Chem. Commun. 1996, 1067. (j) Kundu, N. G.; Pal, M. J . Chem. Soc.,
Chem. Commun. 1993, 86. (k) Candiani, I.; DeBernardinis, S.; Cabri,
W.; Marchi, M.; Bedeschi, A.; Penco, S. Synlett 1993, 269. (l) Zhang,
H.; Brumfield, K. K.; J aroskova, L.; Maryanoff, B. E. Tetrahedron Lett.
1998, 39, 4449. (m) Fancelli, D.; Fagnola, M. C.; Severino, D.; Bedeschi,
A. Tetrahedron Lett. 1997, 38, 2311. (n) Fagnola, M. C.; Candiani, I.;
Visentin, G.; Cabri, W.; Zarini, F.; Mongelli, N.; Bedeschi, A. Tetra-
hedron Lett. 1997, 38, 2307. (o) Gabriele, B.; Salerno, G.; Fazio, A.;
Bossio, M. Tetrahedron Lett. 2001, 42, 1339. (p) Monteiro, N.; Arnold,
A.; Balme, G. Synlett 1998, 1111. (q) Larock, R. C.; Pace, P.; Yang, H.;
Russell, C. E. Tetrahedron 1998, 54, 9961. (r) Cacchi, S.; Fabrizi, G.;
Moro, L. Synlett 1998, 741. (s) Cacchi, S.; Fabrizi, G.; Moro, L. J . Org.
Chem. 1997, 62, 527 and references therein. (t) Balme, G.; Bouyssi,
D. Tetrahedron 1994, 50, 403.
(3) (a) Monteiro, N.; Balme, G. Synlett 1998, 746. (b) Cacchi, S.;
Fabrizi, G.; Moro, L. Synlett 1998, 741. (c) Arcadi, A.; Cacchi, S.; Del
Rosario, M.; Fabrizi, G.; Marinelli, F. J . Org. Chem. 1996, 61, 9280
and references therein.
(4) (a) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. Tetra-
hedron 1985, 41, 3655. (b) Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. J . Org. Chem. 1991, 56, 5816. (c) Arcadi, A.; Burini, A.;
Cacchi, S.; Delmastro, M.; Marinelli, F.; Pietroni, B. R. J . Org. Chem.
1992, 57, 976. (d) Cacchi, S.; Fabrizi, G.; Moro, L. J . Org. Chem. 1997,
62, 5327. (e) Cavicchioli, M.; Decortiat, S.; Bouyssi, D.; Gore, J .; Balme,
G. Tetrahedron 1996, 52, 11463. (f) Bouyssi, D.; Cavicchioli, M.; Balme,
G. Synlett 1997, 944. (g) Arcadi, A. Synlett 1997, 941. (h) Arcadi, A.;
Anacardio, R.; D’Anniballe, G.; Gentile, M. Synlett 1997, 1315. (i)
Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett 1992, 33, 3915.
(j) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F. Tetrahedron Lett
1993, 34, 2813.
(2) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000,
3, 394. (b) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999,
620. (c) Cacchi, S.; Fabrizi, G.; Pace, P. J . Org. Chem. 1998, 63, 1001.
(d) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997,
1363. (e) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437. (f) Mandai, T.; Ohat, K.; Baba, N.; Kawada, M.; Tsuji,
J . Synlett, 1992, 671. (g) Tsuda, T.; Ohashi, Y.; Nagahama, M.; Sumiya,
R.; Saegusa, T. J . Org. Chem. 1988, 53, 2650.
(5) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic:
Australia, 1998; Vol 1.
(6) Organic Reactions; Wiley
Chapters 2-4.
& Sons: London, 1951; Vol. VI,
10.1021/jo026294j CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003
920
J . Org. Chem. 2003, 68, 920-928

Synthesis of 3,4-Disubstituted Isoquinolines
TABLE 1. Op tim iza tion of th e Rea ction of
N-ter t-Bu tyl-2-(p h en yleth yn yl)-ben za ld im in e (1) a n d P h I
(eq 2)a
ods employ either strong acidic conditions for the ring
closure (Bischler-Napieralski and Pomeranz-Fritsch) or
tedious preparation of appropriately substituted phen-
ethylamines as starting materials (Pictet-Spengler).
Palladium-catalyzed methodology has been employed
more and more for the synthesis of substituted isoquino-
lines in recent years. For instance, Pfeffer and co-workers
reported the formation of a disubstituted isoquinoline
derivative from a cyclopalladated N,N-dimethylbenzyl-
amine complex.7 Heck and co-workers observed the
formation of 3,4-diphenylisoquinoline in a 22% yield from
the reaction of cyclopalladated N-tert-butylbenzaldimine
tetrafluoroborate with diphenylacetylene.8 Widdowson
has also reported an isoquinoline synthesis based on
cyclopalladated N-tert-butylarylaldimines.9 These ap-
proaches to isoquinolines, however, suffer the major
disadvantage that they are stoichiometric with respect
to palladium, and a final pyrolysis step greatly limits the
synthetic utility. In our own laboratories, we have
developed the copper-catalyzed cyclization of 2-(1-alky-
nyl)arylaldimines to 3-substituted isoquinolines,10 the
palladium-catalyzed iminoannulation of internal alkynes,11
and the electrophile-promoted cyclization of 2-(1-alkynyl)-
arylaldimines12 as simple approaches to 3,4-disubstituted
isoquinolines, which proceed in excellent yields. Despite
the broad applicability of these processes, there are still
many 3,4-disubstituted isoquinolines that cannot be
prepared by these approaches.
PhI
(equiv)
base
(equiv)
temp time % yieldc
entry
Pd catalyst
(°C) (h)b
2a :2b
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(dba)2/2 PPh3
Pd(dba)2/2 PPh3
Pd(dba)2/2 PPh3
Pd(dba)2/2 PPh3
Pd(dba)2/2 PPh3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
3
5
3
5
5
5
5
5
5
5
5
5
5
5
5
Na2CO3 (3)
Na2CO3 (3)
Na2CO3 (3) 100
Na2CO3 (3) 100
Na2CO3 (3) 120
KOAc (5)
KOAc (5)
KOAc (5)
K2CO3 (5)
K2CO3 (5)
Na2CO3 (5) 100
Cs2CO3 (5) 100
Li2CO3 (5)
K2CO3 (5)
K2CO3 (5)
80
80
9
9
9
9
9
10
10
10
12
12
12
24
24
24
24
26:21
20:23
49:25
61:10
62:9
50
75
100
50
36:<2
27:5
29:49
17:0
49:<2
48:<2
22:0
28:36
36:12
24:45
100
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
100
100
100
14d Pd(PPh3)4
15e
Pd(PPh3)4
a
All reactions were carried out in 5 mL of DMF as the solvent,
using 0.25 mmol of imine 1 and 5 mol % palladium catalyst unless
b
otherwise specified. In all cases, monitoring by TLC showed that
the reaction had reached completion in less time than the time
specified. c Yields are given for isolated products and refer to single
d
runs. Reaction was run in 5 mL of CH3CN. e Reaction was run
in 5 mL of DMSO.
pling14 of the aryl halide and a terminal alkyne catalyzed
by 2 mol % PdCl2(PPh3)2 and 1 mol % CuI in Et3N at 55
°C. This step generally gives yields of the coupled product
above 90%. The second step of the sequence involves
reaction of the 2-(1-alkynyl)arenecarboxaldehyde and
excess tert-butylamine at room temperature and proceeds
in almost quantitative yields.
Op tim iza tion . Our first attempt to explore the reac-
tion of N-tert-butyl-2-(phenylethynyl)benzaldimine (1)
and 3 equiv of phenyl iodide employed 5 mol % Pd(dba)2,
10 mol % PPh3, and 3 equiv of Na2CO3 in 5 mL of DMF
at 100 °C (eq 2). Although the desired product 3,4-
diphenylisoquinoline (2a ) was formed, the generation of
another product, 3-phenylisoquinoline (2b), was also
observed. The 3-phenylisoquinoline (2b) is believed to be
formed by either the thermal or Pd(II)-catalyzed cycliza-
tion of imine 1.10
Therefore, we have examined the possibility of prepar-
ing 3,4-disubstituted isoquinolines by a more general
process involving the palladium-catalyzed cross-coupling
of N-tert-butyl-2-(1-alkynyl)benzaldimines and organic
halides (eq 1). Hopefully, this approach might avoid the
problem of regioselectivity that exists in the synthesis
of isoquinolines by the iminoannulation of internal
alkynes11 and may offer a new way to construct the
isoquinoline ring. We previously communicated this
methodology for the synthesis of 3,4-disubstituted iso-
quinolines13 and now report more recent developments.
Resu lts a n d Discu ssion
Sta r tin g Ma ter ia ls. The preparation of the starting
materials for this chemistry is quite simple and straight-
forward. The appropriate imines are readily available in
two steps from 2-bromoarenecarboxaldehydes and ter-
minal alkynes. The first step is the Sonogashira cou-
We have thus attempted to optimize the formation of
the disubstituted isoquinoline 2a (Table 1). Using Pd-
(dba)2 as the catalyst plus 2 equiv of Ph3P per palladium
as the ligand and raising the temperature from 80 to 100
°C significantly increased the yields of 3,4-diphenyliso-
quinoline (2a ) and the selectivity for 2a over 2b (Table
1, entries 1-4). Further raising the temperature from
100 to 120 °C did not help much (entry 5). Increasing
the amount of the PhI from 3 to 5 equiv favored formation
(7) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J . Chem. Soc., Chem.
Commun. 1987, 565.
(8) Wu, G.; Geib, S. J .; Rheingold, A. L.; Heck, R. F. J . Org. Chem.
1988, 53, 3288.
(9) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 4281.
(10) (a) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. (b)
Roesch, K. R.; Larock, R. C. J . Org. Chem. 2002, 67, 86.
(11) (a) Roesch, K. R.; Larock, R. C. J . Org. Chem. 1998, 63, 5306.
(b) Roesch, K. R.; Zhang, H.; Larock, R. C. J . Org. Chem. 2001, 66,
8042.
(12) (a) Huang, Q.; Hunter, J . A.; Larock, R. C. Org. Lett. 2001, 3,
2973. (b) Huang, Q.; Hunter, J . A.; Larock, R. C. J . Org. Chem. 2002,
67, 3437.
(14) Sonogashira, K. Comprehensive Organic Synthesis; Pergamon
(13) Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035.
Press: Elmsford, NY, 1990; Vol. 3, p 251.
J . Org. Chem, Vol. 68, No. 3, 2003 921

Dai and Larock
of the desired product 2a at 100 °C (compare entries 3
and 4). The best result obtained was a 61% yield of 2a
and 10% yield of 2b acquired using 5 equiv of PhI, 5 mol
% Pd(dba)2, 10 mol % PPh3, and 3 equiv of Na2CO3 in 5
mL of DMF at 100 °C (entry 4).
the organopalladium ArPdX intermediate does affect the
outcome of the reaction.
A variety of imines have also been tested using
4-iodonitrobenzene. According to the results in Table 2,
the R1 group of the imine (eq 1) also plays an important
role in the reaction. When R1 is an aryl group, the
reactions work well with electron-deficient aryl halides.
However, when R1 is an alkyl or vinylic group, the yields
drop significantly (entries 15-17), even when using
4-iodonitrobenzene. It is important to note, however, that
the monosubsituted isoquinolines are not observed in
these reactions.
The replacement of Pd(dba)2 plus Ph3P by Pd(PPh3)4
and 3 equiv of Na2CO3 by 5 equiv of KOAc at 50 °C (entry
6) reduced the amount of side product 2b to only a trace,
but the yield of 2a was not sufficiently high to be
synthetically useful. Increasing the temperature from 50
to 75 to 100 °C only reduced the selectivity between 2a
and 2b and did not significantly improve the yield of 2a
(entries 6-8). Side product isoquinoline 2b was not
observed using K2CO3 as the base at 50 °C (entry 9), and
a higher yield of 2a and relatively low yield of 2b were
obtained when the temperature was further raised to 100
°C (entry 10). Using lithium, sodium, and cesium carbon-
ate as bases failed to improve the yield of 2a (entries 11-
13). Changing the solvent from DMF to acetonitrile or
DMSO did not enhance the yield of 2a or the selectivity
between the two isoquinoline products (entries 14 and
15).
In addition to the strong dependence of the reaction
on the aryl halides employed, the electronic nature of the
substituents attached to the aromatic rings of the imine
significantly affects the outcome of the reactions with aryl
halides. The electron-rich imine N-tert-butyl-2-[(4-meth-
oxyphenyl)ethynyl]benzaldimine (20) affords slightly
higher yields of 3,4-disubstituted isoquinoline products
than imine 1 when allowed to react with 4-iodonitroben-
zene and 4-iodoanisole (entries 18 and 19). However,
placing a methylenedioxy moiety on the imine-bearing
aryl ring (23) leads to a somewhat lower yield (entry 20).
Using an electron-deficient pyridine-containing imine 25
and 4-iodonitrobenzene leads to the 3,4-disubstituted
product 26 in only a 23% yield, and the 3-monosubsti-
tuted product was isolated in an 11% yield (entry 21).
Cr oss-Cou p lin g of N-ter t-Bu tyl-2-(1-a lk yn yl)a r yl-
a ld im in es w ith Allylic Ha lid es a n d Ester s. Allylpal-
ladium complexes have been used to promote the cycliza-
tion of alkynes containing proximate nucleophiles (N and
O) to afford 3-allylic indoles,2c,g,h 3-allylic benzo[b]-
furans,3a,b and 3-allylic furans.4a,b We here report that
π-allylpalladium complexes can be successfully employed
in the synthesis of 4-allylic 3-substituted isoquinolines.
First, we have investigated the reaction of our model
imine 1 with allyl bromide under our optimized cross-
coupling conditions. We were pleased to observe a 65%
yield of the 4-allyl-3-phenylisoquinoline (27) and none of
3-phenylisoquinoline (2b) (entry 22). This reaction took
18 h to complete, showing the lower reactivity of the
allylpalladium complex compared to the arylpalladium
complex. When allyl chloride was used in the reaction
(entry 23), it afforded a slightly higher yield, 69%, of
product 27 and no side product 2b at all. Although allylic
bromides usually possess higher reactivities than allylic
chlorides in π-allylpalladium chemistry, the stability of
the halides must be taken into account in this case where
there are 5 equiv of K2CO3 present in the reaction
mixture.
The procedure summarized in Table 1, entry 10, is
thought to give the best result because of the distribution
of the two products and the ease with which one can
isolate pure product, although the yield of the desired
product 2a suffers compared to the results described in
Table 1, entry 4.
Cr oss-Cou p lin g of N-ter t-Bu tyl-2-(1-a lk yn yl)a r yl-
a ld im in es w ith Ar yl Ha lid es a n d Tr ifla tes. When the
optimized reaction conditions reported above in entry 10
were applied to the reaction of N-tert-butyl-2-(phenyl-
ethynyl)benzaldimine (1) and phenyl triflate, which is
assumed to form the corresponding PhPdOTf intermedi-
ate, no desired product, 3,4-diphenylisoquinoline (2a ),
was observed even after 48 h. A 40% yield of monosub-
stituted isoquinoline 2b was obtained as the only product.
Under the optimized reaction conditions above, the
reactions of imine 1 with a variety of aryl iodides afforded
reasonable yields of the corresponding 3,4-disubstituted
isoquinolines (eq 1; Table 2, entries 1-14). Aryl halides
bearing an electron-withdrawing group in the para or
meta positions usually lead to good to high yields of the
3,4-disubstituted isoquinoline products and low yields of
side product 3-phenylisoquinoline (2b) (entries 2, 4, 6,
7, and 9-11). Aryl iodides with an ortho electron-
withdrawing group, such as ethyl 2-iodobenzoate and
2-iodonitrobenzene, do not react well with imine 1
(entries 5 and 8). These two reactions afforded only the
monosubstituted isoquinoline 2b. This is apparently the
result of a steric problem with the ArPdX intermediate,
since electron-withdrawing groups elsewhere in the aryl
halides generally give good results. Reactions with aryl
halides containing electron-donating groups, like o- and
p-iodotoluene and 4-iodoanisole, only afford low yields of
the corresponding 3,4-disubstituted products and poor
ratios of di- to monosubstituted isoquinoline products
(entries 12-14). The best yield obtained with imine 1 was
75%, which was afforded by 4-iodonitrobenzene (entry 2).
The corresponding aryl bromide 4-bromonitrobenzene
affords 3,4-disubstituted isoquinoline product 3 in a 48%
yield (entry 3). The relatively low yield indicates that the
lower reactivity of an aryl bromide toward formation of
We were also interested in investigating diallyl carbon-
ate in this reaction (entry 24). In this case, only 2.5 equiv
of K2CO3 was employed, because 1 equiv of base is formed
when both allyl groups are released from each equivalent
of carbonate. This reaction proceeded well and afforded
a 68% yield of 27 after 18 h.
Then we turned to allyl acetate, another important
source of π-allylpalladium intermediates. After 120 h,
only 28% of the desired product 27 and 13% of side
product 2b were isolated, and 17% of starting material
1 was recovered (entry 25). Considering the fact that allyl
acetate might not be very stable with so much base
present in the reaction, we carried out another reaction
in which only a stoichiometric amount of K2CO3 was
922 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of 3,4-Disubstituted Isoquinolines
TABLE 2. Syn th esis of 3,4-Disu bstitu ted Isoqu in olin es by P d -Ca ta lyzed Cr oss-Cou p lin g of
N-ter t-Bu tyl-2-(1-a lk yn yl)ben za ld im in es a n d Or ga n ic Ha lid es (eq 1)a
J . Org. Chem, Vol. 68, No. 3, 2003 923

Dai and Larock
Ta ble 2 (Con tin u ed )
924 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of 3,4-Disubstituted Isoquinolines
Ta ble 2 (Con tin u ed )
a
b
Reaction conditions are specified in the text. Yields are given for isolated products and refer to single runs. Numbers in parentheses
are the yields of the corresponding 3-substituted isoquinolines. c Only 2.5 equiv of K2CO3 was used as the base. 4-Iodo-3-phenylisoquinoline
d
was isolated in an 8% yield.
J . Org. Chem, Vol. 68, No. 3, 2003 925

Dai and Larock
employed. This reaction took 30 h to reach completion
and gave only a 13% yield of 27 and 34% of side product
2b. On the basis of this observation, the extra base is
considered to play an important role in improving the
selectivity between the two competing processes.
The reactions of imine 1 with methallyl chloride and
cinnamyl chloride both proceeded smoothly to generate
the corresponding 4-allylic-3-phenylisoquinolines 28 and
29 in good yields and side product 2b in only 0-1% yields
(entries 26 and 27). Thus, the reactions of allylic chlorides
exhibit excellent product selectivity. However, with 3,3-
dimethylallyl bromide and 3-bromocyclohexene, two other
allylic halides with hydrogens next to the π-allylic moiety,
the reactions of imine 1 afforded none of the desired
products 30 and 31 and produced only 3-phenylisoquino-
line (2b) in the former case (entries 28 and 29).
The reactions of imine 1 and two electron-deficient
allylic bromides displayed completely different reactivi-
ties. Ethyl 4-bromo-2-butenoate did not produce any of
the desired product 32, but instead a significant amount
of cyclization product 2b was generated (entry 30). Ethyl
2-(bromomethyl)propenoate, however, did afford the de-
sired product 33 in a 59% yield, and 2b was produced in
only an 18% yield (entry 31). The reaction between imine
1 and 2,3-dichloropropene did not generate any of the
expected 4-allylic-3-phenylisoquinoine (34) for reasons
that are not obvious (entry 32).
Unlike the reactions of imines with aryl halides, the
reactions of imine 15 with R1 ) n-butyl provided good
yields when methallyl chloride and allyl chloride were
employed (entries 33 and 34). However, the reaction of
imine 17 with R1 ) 1-cyclohexenyl afforded only a 30%
yield of the desired product after 48 h (entry 35).
Since the highest yield from allylic halides was ob-
tained in the reaction of imine 1 with methallyl chloride,
other imines were all examined with this allylic chloride.
The influence of electronic factors present in the imines
on the reactions is obvious. Generally, electron-rich imine
substrates 20 and 23 result in better yields than their
electron-deficient pyridine counterpart 25 (entries 36-
38). The problem here might also be that the pyridine
moiety in imine 25 could also be reacting directly with
the allylic chloride (entry 38).
Besides the allylic halides and esters, benzyl chloride
and 4-methoxybenzyl chloride have also been successfully
employed in the isoquinoline cyclization and afford
reasonably good yields of the corresponding cross-
coupling products 41 and 42, respectively (entries 39 and
40). However, the reaction with 4-nitrobenzyl chloride
failed.
Encouraged by this preliminary result, we next exam-
ined the reactions of two different alkynyl iodides that
do not possess any electron-withdrawing groups. Both of
them produced the desired products in yields of 53 and
56% (entries 42 and 43).
Different imine substrates have been investigated in
the reactions with 1-iodo-1-decyne. While the electron-
donating group in imine substrate 20 did not affect the
yield of product 46 (entry 44), the presence of the R2
groups n-butyl in 15 and 1-cyclohexenyl in 17 both had
a very strong negative influence on the outcome. No 3,4-
disubstituted isoquinoline products were observed in
these latter two reactions (entries 45 and 46). The
possible 3-monosubstituted isoquinoline side products
were not observed either.
Cr oss-Cou p lin g of N-ter t-Bu tyl-2-(1-a lk yn yl)a r yl-
a ld im in es w ith Vin ylic Ha lid es. Several vinylic ha-
lides have been utilized in this chemistry. Only ethyl cis-
3-iodoacrylate produced the expected 4-vinylic-substituted
isoquinoline in a good yield (entry 47). Ethyl trans-3-
iodoacrylate, cis-â-iodostyrene, (iodomethylene)cyclohex-
ane, 3-iodo-2-cyclohexen-1-one, and 2-iodo-2-cyclohexen-
1-one all failed to generate the expected isoquinolines.
Mech a n ism . The present synthesis of 3,4-disubstitut-
ed isoquinolines is believed to proceed as outlined in
Scheme 2, which is similar to previously reported Pd-
catalyzed syntheses of benzofurans,1h,13a,b indoles,3c and
other heterocyclic compounds.4i,j The process consists of
the following key steps: (1) oxidative addition of the
organic halide to the Pd(0) catalyst,17 (2) coordination of
the resulting palladium intermediate A to the triple bond
of the imine forming complex B, which activates the triple
bond toward nucleophilic attack,1h (3) intramolecular
nucleophilic attack of the nitrogen atom of the imine on
the activated carbon-carbon triple bond to afford inter-
mediate C,1h (4) reductive elimination to form the carbon-
carbon bond between R2 and the carbon of the isoquin-
oline ring with simultaneous regeneration of the Pd(0)
catalytic species,18 and (5) cleavage of the tert-butyl group
from the N atom to generate the 3,4-disubstituted iso-
quinoline and also release the strain between the tert-
butyl group and the group R1.10-13
If the 2-(1-alkynyl)benzaldimine does not coordinate
well to the palladium(II) intermediate A, cyclization by
either thermal or Pd(II) catalysis to the monosubstituted
isoquinoline can occur. This latter chemistry can also be
accomplished by employing a catalytic amount of CuI.10
Therefore, the selectivity between the mono- and disub-
stituted isoquinolines is determined by whether the triple
bond of the 2-alkynyl imine coordinates the R2PdIIX
intermediate A.
In the reactions of imines and aryl halides R2X, we
observed a significant effect of the electronic nature of
the substituents present in R2X on the yields of 3,4-
disubstituted isoquinolines and the ratios of the di- and
monosubstituted isoquinolines. The strong dependence
Cr oss-Cou p lin g of N-ter t-Bu tyl-2-(1-a lk yn yl)a r yl-
a ld im in es w ith Alk yn yl Ha lid es. Inspired by the
success of the reactions of imines with electron-poor aryl
halides, we examined the cross-coupling of ethyl 3-iodo-
propiolate. This alkynyl halide gave a 38% yield of the
desired product 43 after only 4 h (entry 41). Although
we did not observe 3-phenylisoquinoline (2b) as a side
product this time, we isolated another side product,
4-iodo-3-phenylisoquinoline (2c), in an 8% yield. At the
same time, a significant amount of I2 appeared to be
generated during the reaction.15 The decomposition of
ethyl 3-iodopropiolate to I2 could account for the forma-
tion of the side product 2c12 and the low yield of the 4-(1-
alkynyl) 3-substituted isoquinoline 43.
(15) During the workup procedure described in the Experimental
Section, the reaction mixture in diethyl ether solution could be
decolored by the addition of Na2S2O3.
(16) Wu, G.; Rheingold, A. L.; Geib, S. J .; Heck, R. F. Organome-
tallics 1987, 6, 1941.
(17) Stille, J . K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434.
(18) Tsuji, J .; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965,
4387.
926 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of 3,4-Disubstituted Isoquinolines
SCHEME 2
of the reaction yields on the electronic nature of the aryl
halides used provides useful mechanistic data. For the
aryl iodides containing a para or meta electron-with-
drawing substituent, the more electron-deficient inter-
mediate A would be expected to coordinate more strongly
to the triple bond in the imine substrate producing
complex B. The coordination step therefore may be
crucial in formation of the 3,4-disubstituted isoquinoline,
because without it the imine substrate may cyclize by
either a thermal or Pd(II)-catalyzed process to form the
side product with no incorporation of the R2 group onto
the isoquinoline ring.10
Con clu sion s
We have developed a new, efficient, palladium-cata-
lyzed synthesis of 3,4-disubstituted isoquinolines from
readily available N-tert-butyl-2-(1-alkynyl)arylaldimines
and various organic halides. This synthetic strategy
exhibits considerable structural flexibility in both the
types of iminoalkynes and organic halides that can be
employed. The overall yields are reasonably good. Despite
some limitations, such as electron-rich and o-substituted
aryl halides giving lower yields, the process holds promise
as a useful tool for the construction of complex hetero-
cycles containing the isoquinoline unit.
This assumption is supported by the results from
electron-rich imine 20 and electron-deficient imine 25.
Imine 20 possesses a higher electron density on the
carbon-carbon triple bond than imine 1, and imine 25
has decreased electron density on the triple bond. The
experiments show that the higher electron density in
imine 20 affords a slightly improved 80% yield of the
corresponding 3,4-disubstituted isoquinoline product 21
when using 4-iodonitrobenzene, compared to the 75%
yield obtained from imine 1 and the same aryl iodide
(Table 1, entries 2 and 18). On the other hand, the
corresponding reaction of imine 25 with a lower electron
density on the triple bond results in a significant decrease
in the yield of 3,4-disubstituted isoquinoline product 26
(23%), and an 11% yield of the monosubstituted side
product was also isolated (Table 1, entry 21).
Exp er im en ta l Section
Gen er a l P r oced u r es. All 1H and 13C NMR spectra were
recorded at 300 and 400 and 75.5 and 100.7 MHz, respectively.
Thin-layer chromatography was performed using commercially
prepared 60-mesh silica gel plates, and visualization was
effected with short-wavelength UV light (254 nm) and a basic
KMnO4 solution [3 g of KMnO4 + 20 g of K2CO3 + 5 mL of
NaOH (5%) + 300 mL of H2O]. All melting points are
uncorrected. Compounds 1, 15, 17, 20, 23, and 25 have been
previously reported.13 For characterization of compounds 3, 4,
6, 7, 14, 16, 18, 21, 26-28, 35, 37, 41, and 44, see ref 13. For
characterization of the rest of the 3,4-disubstituted isoquino-
lines, see Supporting Information.
Typ ica l P r oced u r e for Syn th esis of th e N-ter t-Bu tyl-
2-(1-a lk yn yl)a r yla ld im in es: N-ter t-Bu tyl-2-(p h en yleth y-
n yl)ben za ld im in e (1). To a solution of 2-bromo-benzaldehyde
J . Org. Chem, Vol. 68, No. 3, 2003 927

Dai and Larock
(1.85 g, 10 mmol) and phenylacetylene (1.23 g, 12.0 mmol) in
Et3N (40 mL) was added PdCl2(PPh3)2 (140 mg, 2 mol %). The
mixture was stirred for 5 min, and CuI (20 mg, 1 mol %) was
mg, 0.0125 mmol), K2CO3 (0.1725 g, 1.25 mmol), N-tert-butyl-
o-(phenylethynyl)benzaldimine (1) (0.0653 g, 0.25 mmol), and
phenyl iodide (0.2551 g, 1.25 mmol) was flushed with Ar at
room temperature for 5 min and then heated to 100 °C with
stirring for 12 h. The reaction mixture was then cooled to room
temperature, diluted with diethyl ether (30 mL), and washed
with brine (30 mL). The aqueous layer was re-extracted with
diethyl ether (15 mL). The organic layers were combined, dried
(MgSO4), and filtered, and the solvent was removed under
reduced pressure. The residue was purified by column chro-
matography on a silica gel column using 10:1 hexanes/EtOAc
to afford 34 mg (49%) of the indicated compound: mp 154-
155 °C (lit.11a,16 154-155 °C). The spectral properties were
identical to those previously reported.11a,16 Complete charac-
terization of the isoquinolines prepared by this process can
be found in Supporting Information.
added. The resulting mixture was then heated under
a
nitrogen atmosphere at 50 °C for 4 h. The reaction was
monitored by TLC to establish completion. The reaction
mixture was allowed to cool to room temperature, and the
ammonium salt was removed by filtration. The solvent was
removed under reduced pressure, and the residue was purified
by column chromatography on silica gel using 20:1 hexanes/
EtOAc to afford 1.88 g (91%) of 2-(phenylethynyl)benzaldehyde
as a yellow oil: 1H NMR (CDCl3) δ 7.37-7.40 (m, 3H), 7.45 (t,
J ) 7.2 Hz, 1H), 7.54-7.65 (m, 4H), 7.95 (dd, J ) 0.8, 7.6 Hz,
1H), 10.65 (d, J ) 0.8 Hz, 1H); 13C NMR (CDCl3) δ 85.1, 96.5,
122.4, 126.9, 127.3, 128.6, 128.7, 129.2, 131.8, 133.3, 133.9,
135.9, 191.7. To a mixture of the prepared 2-(phenylethynyl)-
benzaldehyde (0.80 g, 3.88 mmol) and H2O (0.25 mL/mmol)
was added tert-butylamine (11.64 mmol, 3 equiv). The mixture
Ack n ow led gm en t. We thank the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for partial support of this re-
search and Kawaken Fine Chemicals Co., Ltd., for
donation of the palladium catalysts.
was then stirred under
a nitrogen atmosphere at room
temperature for 12 h. The excess tert-butylamine was removed
under reduced pressure, and the resulting mixture was
extracted with ether. The combined organic layers were dried
(Na2SO4) and filtered. Removal of the solvent afforded 1.00 g
(97%) of the indicated compound 1 with spectral properties
identical to those previously reported:10,12,13 mp 52-53 °C
(lit.10,12 52-53 °C).
Typ ica l P r oced u r e for th e P a lla d iu m -Ca ta lyzed F or -
m a tion of 3,4-Disu bstitu ted Isoqu in olin es: 3,4-Dip h en yl-
isoqu in olin e (2a ). A mixture of DMF (5 mL), Pd(PPh3)4 (14.4
Su p p or tin g In for m a tion Ava ila ble: Product character-
1
ization data for the isoquinoline products and H and 13C NMR
spectra for all new compounds prepared. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026294J
928 J . Org. Chem., Vol. 68, No. 3, 2003