Synthesis of 4-(1-alkenyl)isoquinolines by palladium(II)-catalyzed cyclization/olefination

Article abstract of DOI:10.1021/jo0261303

A variety of 4-(1-alkenyl)-3-arylisoquinolines have been prepared in moderate to excellent yields by the Pd(II)-catalyzed cyclization of 2-(1-alkynyl)arylaldimines in the presence of various alkenes. The introduction of an o-methoxy group on the arylaldimine promotes the Pd-catalyzed cyclization and stabilizes the resulting Pd(II) intermediate, improving the yields of the isoquinoline products. Ketone-containing isoquinolines 36 and 49-51 have also been prepared by this process when unsaturated alcohols are employed as the alkenes.

Full text of DOI:10.1021/jo0261303

Syn th esis of 4-(1-Alk en yl)isoqu in olin es by P a lla d iu m (II)-Ca ta lyzed
Cycliza tion /Olefin a tion
Qinhua Huang and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received J uly 2, 2002
A variety of 4-(1-alkenyl)-3-arylisoquinolines have been prepared in moderate to excellent yields
by the Pd(II)-catalyzed cyclization of 2-(1-alkynyl)arylaldimines in the presence of various alkenes.
The introduction of an o-methoxy group on the arylaldimine promotes the Pd-catalyzed cyclization
and stabilizes the resulting Pd(II) intermediate, improving the yields of the isoquinoline products.
Ketone-containing isoquinolines 36 and 49-51 have also been prepared by this process when
unsaturated alcohols are employed as the alkenes.
In tr od u ction
The transition metal-catalyzed cyclization of alkynes,9
which possess nucleophilic centers in close proximity to
the carbon-carbon triple bond, by in situ coupling/
cyclization reactions,10 and reactions promoted by vinylic,
aryl, alkynyl, and acylpalladium complexes,11 have also
been shown to be extremely effective for the synthesis of
a wide variety of carbo- and heterocycles.
The palladium(II)-catalyzed cyclization/olefination re-
action of 2-(1-alkynyl)aniline derivatives to indoles has
been reported by Sakamoto et al.12 They report that the
reaction of N-protected 2-(1-alkynyl)anilines with electron-
deficient alkenes in the presence of PdCl2 and CuCl2 gives
2-substituted 3-(1-alkenyl)indoles (eq 1). Our interest in
The synthesis of isoquinolines has received consider-
able attention due to the fact that the isoquinoline ring
system is present in numerous naturally occurring
alkaloids.1 Although classical methods have frequently
been employed in the total synthesis of isoquinoline
alkaloids, these approaches often have drawbacks. For
example, the Bischler-Napieralski,2 Pictet-Spengler,3
and Pomeranz-Fritsch4 protocols require relatively strong
acids to cyclize â-phenethylamines. Also, the Bischler-
Napieralski2 and Pictet-Spengler3 reactions afford di-
hydro- and tetrahydroisoquinolines, respectively. An
additional step involving dehydrogenation is thus re-
quired to complete the synthesis of the isoquinoline.
Substituted isoquinoline heterocycles have also been
synthesized by employing palladium methodology. For
instance, 3,4-disubstituted isoquinolines have been
achieved by the annulation of internal alkynes by cyclo-
palladated N,N-dimethylbenzylamine complexes,5 cyclo-
palladated N-tert-butylbenzaldimine tetrafluoroborates,6
cyclopalladated N-tert-butylarylaldimines,7 and N-tert-
butyl-o-iodobenzaldimines plus a palladium catalyst.8
4-(1-alkenyl)isoquinolines has prompted us to develop a
convenient new synthesis of these isoquinolines by the
(1) (a) Huang, Q.; Hunter J . A.; Larock, R. C. Org. Lett. 2001, 3,
2973. (b) Huang, Q.; Larock, R. C. Tetrahedron Lett. 2002, 43, 3557.
(c) Buske, A.; Busemann, S.; Mu¨hlbacker, J .; Schmidt, J .; Porzel, A.;
Bringmann, G.; Adam, G. Tetrahedron 1999, 55, 1079. (d) Bringmann,
G.; Holenz, J .; Weirich, R.; Ru¨benacker, M.; Funke, C. Tetrahedron
1998, 54, 497. (e) Xu, X.-Y.; Qin, G.-W.; Xu, R.-S.; Zhu, X.-Z.
Tetrahedron 1998, 54, 14179. (f) Brossi, A. Heterocycles 1988, 12, 2905.
(g) Fitzgerald, J . J .; Michael, F. E.; Olofson, R. A. Tetrahedron Lett.
1994, 49, 9191. (h) Rozwadowska, M. D. Heterocycles 1994, 39, 903.
(i) Kohno, H.; Yamada, K. Heterocycles 1999, 51, 103. (j) Flippin, L.
A.; Muchowski, J . M. J . Org. Chem. 1993, 58, 2631. (k) Aubert, T.;
Farnier, M.; Hanquet, B.; Guilard, R. Synth. Commun. 1987, 17, 1831.
(l) Bobbitt, J . M.; Bourque, A. J . Heterocycles 1987, 25, 601. (m)
Diederen, J . J . H.; Sinkeldam, R. W.; Fru¨hauf, H.-W.; Hiemstra, H.;
Vrieze, K. Tetrahedron Lett. 1999, 40, 4255.
(7) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 4281.
(8) (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.
(9) For recent leading reviews, see: (a) Schore, N. E. Chem. Rev.
1988, 88, 1081. (b) Pfeffer, M. Recl. Trav. Chim. Pays-Bas 1990, 109,
567. (c) Negishi, E.; Cope´ret, C.; Ma, S.; Liou, S.; Liu, F. Chem. Rev.
1996, 96, 365. (d) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J .
Chem. Rev. 1996, 96, 635.
(10) For recent leading references, see: (a) Cacchi, S.; Fabrizi, G.;
Moro, L. Tetrahedron Lett. 1998, 39, 5101. (c) Cacchi, S.; Fabrizi, G.;
Moro, L. J . Org. Chem. 1997, 62, 5327 and references therein. (d)
Chowdhury, C.; Chaudhuri, G.; Guha, S.; Mukherjee, A. K.; Kundu,
N. G. J . Org. Chem. 1998, 63, 1863. (e) Arcadi, A.; Cacchi, S.; Del
Rosario, M.; Fabrizi, G.; Marinelli, F. J . Org. Chem. 1996, 61, 9280.
(11) For recent leading references, see: (a) Dai, G.; Larock, R. C. J .
Org. Chem. 2002, 67, 7142. (b) Dai, G.; Larock, R. C. Org. Lett. 2001,
3, 4035. (c) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000,
3, 394. (d) Monteiro, N.; Balme, G. Synlett 1998, 746. (e) Cacchi, S.;
Fabrizi, G.; Pace, P. J . Org. Chem. 1998, 63, 1001. (f) Larock, R. C.;
Pace, P.; Yang, H.; Russell, C. E.; Cacchi, S.; Fabrizi, G. Tetrahedron
1998, 54, 9961.
(2) Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 151-190.
(3) Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 74-150.
(4) Gensler, W. J . In Organic Reactions; Adams, R., Ed.; Wiley: New
York, 1951; Vol. 6, pp 191-206.
(5) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J . Chem. Soc., Chem.
Commun. 1987, 565.
(6) Wu, G.; Geib, S. J .; Rheingold, A. L.; Heck, R. F. J . Org. Chem.
1988, 53, 3238.
(12) Yasuhara, A.; Kaneko, M.; Sakamoto, T. Heterocycles 1998, 48,
1793.
10.1021/jo0261303 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002
980
J . Org. Chem. 2003, 68, 980-988

Synthesis of 4-(1-Alkenyl)isoquinoline
TABLE 1. Op tim iza tion of th e Rea ction of Ben za ld im in e 1 a n d Meth yl Acr yla te by Exa m in a tion of Differ en t Oxid izin g
Rea gen ts, Ba ses, a n d Solven ts (eq 2)a
entry
oxidant
base
solvent
time (h)
% yield of 2b
% yield of 3b
% yield of 4b
1
2
3
4
5
6
7
8
9
O2
CuCl2
CuCl2
CuCl2
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
DMSO
DMSO
DMSO
DMSO
24
20
36
36
36
24
12
12
24
24
24
33 (37c)
0
10
17
20
35
18
61
23
20
0
15
trace
trace
0
25
5
34
19
30
0
0
Et3N
trace
K2CO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
15
20
0
0
0
0
0
0
CuCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(CO3)2
Cu(NO3)2
benzoquinone
10
11
37
40
a
All reactions were run under the following reaction conditions: 0.25 mmol of benzaldimine 1, 5 equiv of methyl acrylate, 10 mol %
PdBr2, 2 equiv of the oxidant, and 3 equiv of the base were stirred in 3 mL of the indicated solvent at 70 °C for the specified period of
b
time. Isolated yields. c Yield based on 1H NMR spectroscopic analysis.
TABLE 2. Op tim iza tion of th e Rea ction of Ben za ld im in e 1 a n d n -Bu tyl Acr yla te Usin g Ca ta lytic Am ou n ts of th e
Cop p er Rea gen t (eq 3)a
entry
catalyst
oxidant
CuCl2
base
additive
time (h)
% yield of 5b
% yield of 3b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
PdCl2(PPh3)2
NaOAc
pyridine
Et3N
Cs2CO3
K2CO3
KHCO3
Na2CO3
NaHCO3
NaHCO3
NaHCO3
24
24
28
24
28
20
20
14
20
16
24
24
20
8
38
48
21
9
46
12
20
18
16
12
11
25
12
20
15
11
17
11
26
17
14
27
21
14
46
tracec
29
39
47
51
45
49
46
48
45
TBAC
PdCl2
PdI2
Pd(O2CCF3)2
Pd(OAc)2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
CuCl2
56
36
6
53d
45e
48
PPh3
20
18
19
24
24
16
CuF2
54
45
45
39
Cu(OAc)2
Cu(NO3)2
CuCO3
CuI
23
a
All reactions were run under the following reaction conditions, unless otherwise specified: 0.25 mmol of benzaldimine 1, 5 equiv of
n-butyl acrylate, 10 mol % of the indicated Pd(II) salt, 10 mol % of the indicated oxidant, and 3 equiv of the indicated base in 3 mL of
b
DMSO were stirred at 70 °C for the specified period of time under a balloon of O2. Isolated yield. c Benzaldimine 1 was recovered in 40%
d
yield. The reaction was run under 55 °C. e The reaction was run under 90 °C.
SCHEME 1
set of reaction conditions for their formation. A variety
of Pd(II) catalysts, oxidants, bases, solvents, and tem-
peratures have been examined on the reaction of aryla-
ldimine 1 and methyl acrylate (eq 2) and only some
representative optimization reactions are summarized in
Tables 1 and 2.
Pd(II)-promoted cross coupling of a variety of alkenes and
2-(1-alkynyl)arylaldimines, which can be easily prepared
from the corresponding 2-halobenzaldehydes in two steps
(Scheme 1).
Resu lts a n d Discu ssion
Our initial studies on the synthesis of 4-(1-alkenyl)-
isoquinolines focused on the development of an optimum
The optimization reactions shown in Table 1 employed
2 equiv of the oxidant (eq 2). In entry 1 (Table 1),
J . Org. Chem, Vol. 68, No. 3, 2003 981

Huang and Larock
SCHEME 2
benzaldimine 1 has been allowed to react with 5 equiv
of methyl acrylate in the presence of 10 mol % of PdBr2
under an O2 balloon, and a 33% yield of isoquinoline 2
was isolated in the absence of a base. However, the use
of 2 equiv of CuCl2 as the oxidant afforded none of the
desired product, although all starting materials disap-
peared within 20 h (entry 2). The use of CuCl2 and the
bases Et3N, K2CO3, and NaOAc resulted in 10-20%
yields of the desired product 2 (entries 3-5). In entries
4 and 5, 4-chloro-3-phenylisoquinoline (4) was obtained
in 15% and 20% yields, respectively.
Possible mechanisms for the formation of isoquinolines
2 and 4 are shown in Scheme 2. The cyclization of
benzaldimine 1 by PdBr2 presumably forms intermediate
A, which is an electron-deficient arylpalladium bromide.
The cis addition of intermediate A to the carbon-carbon
double bond of the olefin affords an alkylpalladium(II)
intermediate, which undergoes subsequent â-hydride
elimination to afford intermediate C and Pd(0). Further
fragmentation of the tert-butyl group from intermediate
C generates the desired 4-(1-alkenyl)isoquinolines. The
Pd(0) generated can be reoxidized back to PdBr2 by the
oxidant present in the reaction mixture.
This reductive elimination is apparently promoted by the
presence of the copper salt, since arylpalladium halides
do not normally undergo this process spontaneously. The
use of Cu(OAc)2 as the oxidant increased the yield of the
desired isoquinoline 2 from 20% (entry 5) to 35% (entry
6). Obviously, the use of Cu(OAc)2 eliminates the forma-
tion of intermediate B and eventual formation of the
chloroisoquinoline 4.
When CH3CN was chosen as the solvent, an 18% yield
of isoquinoline 2 was isolated, alongside a 25% yield of
isoquinoline 3 (entry 7). However, the use of DMSO
resulted in a 61% yield of isoquinoline 2 and only a 5%
yield of 3 in 12 h (entry 8). Obviously, DMSO is a better
solvent than DMF or CH3CN for this isoquinoline olefi-
nation process, presumably due to improved oxidation of
Pd(0) to Pd(II). Thus, DMSO has been chosen as the
solvent for all subsequent optimization reactions. From
entries 9-11, other oxidants Cu(CO3)2, Cu(NO3)2, and 1,4-
benzoquinone have been employed and only 23-40%
yields of product 2 have been isolated. On the basis of
the above results, the following reaction conditions have
been chosen as the standard reaction conditions for
procedure A: 0.25 mmol of benzaldimine, 5 equiv of the
olefin, 10 mol % of PdBr2, 2 equiv of Cu(OAc)2, and 3
equiv of NaOAc are stirred in 3 mL of DMSO at 70 °C.
With the presence of excess chloride in the reaction
mixture, the intermediate A is converted into intermedi-
ate B by halide exchange, because the Pd-Cl bond is
much stronger than the Pd-Br bond.13 Isoquinoline 4 is
then generated by the reductive elimination of interme-
diate B, followed by fragmentation of the tert-butyl group.
The drawback of procedure A is the use of 2 equiv of
Cu(OAc)2. We have therefore tried to develop an alterna-
tive procedure using only catalytic amounts of the copper
reagent (eq 3). In this optimization study, it has been
found that only catalytic amounts of PdCl2(PPh3)2 in the
presence of 10 mol % of CuCl2, 3 equiv of NaOAc, and an
(13) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427.
982 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of 4-(1-Alkenyl)isoquinoline
O2 atmosphere can cyclize benzaldimine 1, affording a
38% yield of isoquinoline 5 (entry 1, Table 2). On the basis
of this reaction, various bases have been examined and
the results are summarized in entries 1-8.
catalytic amount of Cu(II) reagent as procedure B: 0.25
mmol of arylaldimine, 5 equiv of the olefin, 10 mol % of
PdBr2, 10 mol % of CuCl2, 3 equiv of NaHCO3 in 3 mL of
DMSO at 70 °C under an O2 atmosphere.
By employing procedures A and B, a variety of 4-(1-
alkenyl)- and 4-alkyl-3-arylisoquinolines have been pre-
pared (Table 3). As mentioned above, using procedure A,
isoquinoline 2 was isolated in a 61% yield from the
reaction of benzaldimine 1 and methyl acrylate (entry 1,
Table 3). An identical yield of isoquinoline 5 was isolated
from the reaction of benzaldimine 1 and n-butyl acrylate
with use of procedure A (entry 2).
Several olefins, including electron-deficient and electron-
rich alkenes, have been allowed to react with benzaldi-
mine 1 following procedure B (entries 3-7). The use of
n-butyl acrylate and tert-butyl acrylate afforded a 56%
yield of isoquinoline 5 (entry 3) and a 50% yield of
isoquinoline 6 (entry 4), respectively. However, none of
the desired isoquinoline product was observed when
phenyl vinyl sulfone, an electron-deficient alkene, was
allowed to react with benzaldimine 1. The relatively
electron-rich olefins styrene and 2-methyl-3-buten-2-ol
have been allowed to react with benzaldimine 1. A 53%
yield of isoquinoline 7 (entry 5) and a 34% yield of 8
(entry 6) were obtained, respectively. Instead of forming
an internal alkene, the reaction of n-butyl vinyl ether
afforded isoquinoline 9 bearing a terminal double bond,
albeit in low overall yield (entry 7).15
Sakamoto et al. have reported that N-protected alkyl-
substituted o-(1-alkynyl)anilines react with electron-
deficient alkenes in the presence of PdCl2 and CuCl2
producing 2-substituted 3-(1-alkenyl)indoles.12 However,
in our chemistry, the N-tert-butyl alkyl-substituted o-(1-
alkynyl)benzaldimines 52 and 53 did not react with
either electron-deficient or electron-rich terminal alkenes
under either procedure A or B to afford isoquinoline
products. Although N-tert-butyl alkyl-substituted o-(1-
alkynyl)benzaldimines do not react with olefins, ben-
zaldimine 10, which is a N-tert-butyl alkenyl-substituted
o-(1-alkynyl)benzaldimine, did react with n-butyl acrylate
affording a 41% isolated yield of isoquinoline 11 (entry
8).
The use of 3 equiv of the organic bases pyridine or Et3N
afforded a 48% (entry 2) or a 46% (entry 3) yield of
isoquinoline 5, respectively. In entries 4-8, the carbonate
salts Cs2CO3, K2CO3, KHCO3, Na2CO3, and NaHCO3 have
been examined. The results show that the more soluble
carbonate bases, such as Cs2CO3 (entry 4), disfavor the
reaction and the less soluble carbonates, such as NaHCO3
(entry 8), favor the formation of isoquinoline 5. The
addition of n-Bu4NCl resulted in a slight decrease in the
yield of isoquinoline 5 (entrie 9). Thus, the reaction
conditions employed in entry 8, which are the best
reaction conditions shown in entries 1-9, have been
chosen for further optimization reactions employing a
variety of Pd(II) catalysts and difference reaction tem-
peratures. The results for this latter study are sum-
marized in entries 10-16 in Table 2.
When catalytic amounts of PdCl2, PdI2, Pd(O2CCF3)2,
Pd(OAc)2, or PdBr2 have been employed, the desired
product, isoquinoline 5, was isolated in 45-56% yields
with PdBr2 giving the best yield (entries 10-14). When
the reaction was carried out under 55 °C, isoquinoline 5
was observed in 53% yield after 36 h (entry 15), while
the reaction gave 45% yield in 6 h under 90 °C (entry
16). It is clear that 70 °C is a good reaction temperature
for this palladium-catalyzed cyclization process. In entry
17, the addition of PPh3 resulted in a slight decrease in
the yield of isoquinoline 5. Again, the reaction conditions
in entry 14, which have afforded the best result so far,
have been chosen for further optimization.
On the basis of the reaction conditions in entry 14, a
variety of oxidants have been examined and the results
are summarized in entries 18-22. As mentioned above,
a 56% isolated yield of isoquinoline 5 was obtained in
the presence of 10 mol % of CuCl2 (entry 14). The use of
10 mol % of CuF2 gave a 54% yield of isoquinoline 5 (entry
18). Other copper(II) reagents, such as Cu(OAc)2, Cu-
(NO3)2, and CuCO3, have also been examined and iso-
quinoline 5 was isolated in 39-45% yields (entries 19-
21). The use of CuI, a copper(I) reagent as the oxidant,
resulted in a decrease in the yield of isoquinoline 5 from
56% (entry 14) to 23%, while the side product 3 was
isolated in a 46% yield (entry 22).14
The reaction of arylaldimine 54, bearing a pyridine
moiety, and olefins gave none of the desired product.
However, when arylaldimine 12 with an alkynyl group
attached to C-3 of the pyridine nucleus was allowed to
react with n-butyl acrylate, naphthyridine 13 was iso-
lated in a 51% yield (entry 9).
It is known that electron-deficient aryl halides or
vinylic halides disfavor the Heck reaction.13 Thus, electron-
donating groups have been introduced into the arylaldi-
mine to increase the electron density in intermediate A
(15) (a) Vallin, K. S. A.; Larhed, M.; Hallberg, A. J . Org. Chem. 2001,
66, 4340. (b) Hallberg, A.; Westfelt, L.; Holm, B. J . Org. Chem. 1981,
46, 5414. (c) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R.
J . Org. Chem. 1992, 57, 1481. (d) Cabri, W.; Candiani, I. Acc. Chem.
Res. 1995, 28, 2.
After the above optimization work, we have adopted
the following standard reaction conditions using only a
(14) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553.
J . Org. Chem, Vol. 68, No. 3, 2003 983

Huang and Larock
TABLE 3. Syn th esis of Isoqu in olin es by P a lla d iu m (II)-Ca ta lyzed Cycliza tion /Olefin a tion a
984 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of 4-(1-Alkenyl)isoquinoline
Ta ble 3 (Con tin u ed )
a
b
See the text for the detailed reaction conditions for procedures A and B. The reaction was run at 90 °C. c The product was isolated
d
as a 73:27 mixture of E/Z isomers. The product was isolated as a 91:9 mixture of E/Z isomers.
(Scheme 1) and hopefully favor formation of the desired
isoquinoline products. However, the experimental results
indicate that the introduction of electron-donating groups
into the arylaldimine does not really favor the isoquino-
line olefination process, and instead results in a decrease
in the yields of the desired isoquinoline products in most
cases. For example, when benzaldimine 14 bearing a
methylenedioxo group on the benzylidene moiety was
allowed to react with n-butyl acrylate following proce-
dures A and B, the yield dropped from 61% (entry 2) to
43% (entry 10) or from 56% (entry 3) to 48% (entry 11),
respectively. The reaction of 16, another electron-rich
arylaldimine, and tert-butyl acrylate afforded isoquinoline
17 in a 51% yield (entry 12), comparable to the 50% yield
from the reaction of benzaldimine 1 and tert-butyl acry-
late (entry 4). When N,N-dimethylacrylamide or methyl
vinyl sulfone was allowed to react with arylaldimine 16,
a 51% yield of isoquinoline 18 (entry 13) and a 27% yield
of isoquinoline 19 (entry 14) were obtained, respectively.
The sulfone result is a bit surprising in view of our earlier
failure to obtain any isoquinoline product from benzaldi-
mine 1 and phenyl vinyl sulfone. The introduction of a
p-methoxy group on the phenyl moiety resulted in the
yield of the desired isoquinoline 21 dropping from 56%
(entry 3) to only 35% (entry 15).
The presence of electron-donating groups increases the
electron density of the carbon-carbon triple bond, which
apparently disfavors cyclization by attack of the imine
nitrogen on the activated triple bond and consequently
results in low conversion of the arylaldimine to interme-
diate A and eventual formation of the isoquinoline
(Scheme 2). Although the reactivity of intermediate A
J . Org. Chem, Vol. 68, No. 3, 2003 985

Huang and Larock
SCHEME 3
isoquinolines 30 and 31 in such high yields. The o-
methoxy group improves the conversion of the arylaldi-
mine to intermediate A and the introduction of electron-
donating groups on the arylaldimine moiety presumably
increases the reactivity of intermediate A toward ole-
fins,14 affording mostly improved yields. When methyl
vinyl sulfone was allowed to react with arylaldimine 29,
the yield of isoquinoline 32 increased to 52% (entry 25)
from the 27% obtained without the o-methoxy group
(entry 14).
Arylaldimine 33, bearing a methylenedioxo group on
the benzylidene moiety and an o-methoxy group on the
phenyl moiety, has been allowed to react with several
olefins (entries 26-29). The reactions of arylaldimine 33
with tert-butyl acrylate afforded a 61% (entry 26) or an
82% (entry 27) yield of isoquinoline 34 following proce-
dures A and B, respectively. For this specific arylaldi-
mine, procedure A is not as efficient as procedure B.
When N,N-dimethylacrylamide was allowed to react with
arylaldimine 33, an 89% yield of isoquinoline 35 was
isolated as a 73:27 E/Z mixture (entry 28). Comparing
entries 23, 24, 27, and 28, one can see that the introduc-
tion of two methoxy groups onto the benzylidene moiety
is much more efficient in promoting the Heck reaction
than the introduction of a methylenedioxo group onto the
benzaldimine moiety.
Unsaturated alcohols undergo reaction to afford ketone-
containing products. Thus, 3-buten-2-ol has been allowed
to react with arylaldimine 33 (entry 29). The correspond-
ing ketone 36 was isolated in a 48% yield. The formation
of ketone 36 can be explained by the mechanism shown
in Scheme 4. The cyclization of arylaldimine 33 by PdBr2
affords an arylpalladium(II) intermediate D, which is
stabilized by the o-methoxy group. The cis addition of
intermediate D to 3-buten-2-ol results in an alkylpalla-
dium bromide intermediate, which undergoes â-hydride
elimination to form enol E.16 Subsequent tautomerization
and fragmentation of intermediate E affords the desired
ketone 36.
To further test the electronic effects of substituents on
the isoquinoline olefination process, arylaldimines 37 and
40 have been prepared and allowed to react with tert-
butyl acrylate and N,N-dimethylacrylamide. The reaction
of arylaldimine 37, bearing a dimethylamino group meta
to the alkynyl group, and tert-butyl acrylate at 70 °C was
complete in 16 h and afforded isoquinoline 38 in a 69%
yield (entry 30). When the reaction was run at 90 °C, it
was complete in 2 h and gave isoquinoline 38 in a 67%
yield (entry 31). By employing N,N-dimethylacrylamide
at 90 °C, the reaction was complete in 1.5 h and a 70%
yield of isoquinoline 39 was isolated as a 91:9 E/Z mixture
(entry 32). While the introduction of a m-dimethylamino
group shortens the reaction time, the introduction of a
dimethylamino group para to the alkynyl moiety slows
the reaction down. Thus, arylaldimine 40 has been
allowed to react with tert-butyl acrylate and N,N-dim-
ethylacrylamide at 90 °C affording a 71% yield of iso-
quinoline 41 in 12 h (entry 33) and a 70% yield of
isoquinoline 42 in 16 h (entry 34). The reason for the slow
reactions is apparently because the dimethylamino group
para to the alkynyl group in arylaldimine 40 significantly
toward olefins is presumably improved by introducing
electron-donating groups, the low conversion of arylaldi-
mine to intermediate A results in a decrease in the
overall yield of isoquinoline products.
The position of the electron-donating methoxy group
in the arylaldimine is critical to the success of this
process. Thus, the introduction of an o-methoxy group
on the phenyl moiety facilitates isoquinoline formation.
When benzaldimine 22 was allowed to react with n-butyl
acrylate following procedures A and B, the yields in-
creased to 65% (entry 16) and 64% (entry 17) from 61%
(entry 2) and 56% (entry 3), respectively. Employing
procedure B, a variety of olefins have been allowed to
react with arylaldimine 22 (entries 18-22). The reactions
of 22 with tert-butyl acrylate and styrene afforded a 68%
yield of isoquinoline 24 (entry 18) and a 64% yield of
isoquinoline 25 (entry 19), respectively. These yields are
much better than the yields of 50% and 53% from the
corresponding reactions of benzaldimine 1 (entries 4 and
5). As mentioned above, the reaction of benzaldimine 1
and phenyl vinyl sulfone gave none of the desired
product. However, a 20% yield of isoquinoline 26 was
observed when benzaldimine 22 was allowed to react
with phenyl vinyl sulfone (entry 20). When N,N-dim-
ethylacrylamide was allowed to react with arylaldimine
22, isoquinoline 27 was isolated in a 65% yield (entry
21), much better than the yield of 51% from the reaction
of benzaldimine 16 and N,N-dimethylacrylamide (entry
13). The reaction of arylaldimine 22 and 2-methyl-3-
buten-2-ol afforded isoquinoline 28 in a 25% yield (entry
22). For some reason, this yield is lower than the 35%
yield obtained with benzaldimine 1 (entry 6).
The beneficial effects of an o-methoxy group can be
explained by Scheme 3. Basically, the introduction of an
o-methoxy group helps direct the PdBr2 to the vicinity of
the triple bond where attack by the imine nitrogen on
the activated triple bond takes place generating an
arylpalladium intermediate, which is stabilized by che-
lation with the o-methoxy group. Subsequent Heck
olefination and fragmentation of the tert-butyl group
affords the desired isoquinoline olefin.
The reactions of benzaldimine 29 and tert-butyl acry-
late or N,N-dimethylacrylamide are very slow at 70 °C.
These reactions were thus run at 90 °C and the corre-
sponding isoquinolines 30 and 31 have been obtained in
92% and 97% yields, respectively (entries 23 and 24).
Comparing the results from entries 12, 13, 18, 21, 23,
and 24, one can see that both electronic effects and
facilitation by the o-methoxy group play a role in forming
(16) (a) Chalk, A. J .; Magennis, S. A. J . Org. Chem. 1976, 41, 273.
(b) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Tetrahedron Lett. 1978, 919.
986 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of 4-(1-Alkenyl)isoquinoline
SCHEME 4
SCHEME 5
prepared and allowed to react with olefins. The reaction
of arylaldimine 48 and styrene afforded none of the
desired product for reasons which are not obvious. When
3-buten-2-ol and 1-phenyl-2-propen-1-ol have been al-
lowed to react with arylaldimine 48, a 50% yield of ketone
49 (entry 39) and a 36% yield of ketone 50 were obtained,
respectively. Using procedure B, the reaction of aryla-
ldimine 48 and 5-hexen-2-ol afforded compound 51 by
palladium migration, albeit in a low yield (entry 41).17
Con clu sion s
An efficient and straightforward route to synthesize
4-(1-alkenyl)isoquinolines and 4-alkyl-3-arylisoquinolines
containing a ketone group has been developed with use
of a palladium(II)-catalyzed cyclization, followed by ole-
fination (Heck reaction). A wide variety of olefins undergo
this process in moderate to excellent yields with high
regioselectivity being observed. The introduction of an
o-methoxy group on the benzaldimine moiety promotes
the Pd-catalyzed cyclization and stabilizes the resulting
Pd(II) intermediate, improving the yields of the desired
isoquinoline products. Moreover, the introduction of an
o-methoxy group onto the phenyl moiety has been shown
to promote this isoquinoline olefination more efficiently
than the introduction of an o-methoxy group onto the
benzylidene moiety. To form isoquinolines in high yields,
both electronic effects and facilitation by an o-methoxy
group are necessary.
increases the electron density on the carbon-carbon
triple bond and has little influence on the electron density
of the imine nitrogen, disfavoring attack of the imine
nitrogen on the triple bond. However, the dimethylamino
group in arylaldimine 37 significantly increases the
electron density on the imine nitrogen, favoring attack
of the imine nitrogen on the carbon-carbon triple bond.
Thus, the reactions of arylaldimine 37 reach completion
in shorter reaction times.
The reactions of arylaldimine 43 with n-butyl acrylate,
tert-butyl acrylate, N,N-dimethylacrylamide, and styrene
gave the corresponding isoquinolines 44-47 in 51-78%
yields (entries 35-38). Similar to the reactions of aryla-
ldimine 29, the reactions of arylaldimine 43 with olefins
also involve electronic effects and facilitation by the
o-methoxy group (Scheme 5). However, the reactions of
arylaldimine 43, having an o-methoxy group on the
benzylidene moiety are very slow. For example, when
benzaldimine 43 was allowed to react with n-butyl
acrylate or N,N-dimethylacrylamide, the reactions are
not complete even in 48 h at 90 °C (entries 35 and 37).
The reason is probably because the intermediate F
(Scheme 4) is quite hindered, preventing approach of the
olefins. Comparing the results from arylaldimine 29
(entries 23 and 24) with those of arylaldimine 43 (entries
36 and 37), we conclude that the introduction of an
o-methoxy group onto the phenyl moiety promotes this
isoquinoline olefination better than the introduction of
an o-methoxy group onto the benzylidene moiety.
To further test the effect of oxygen substituents in this
isoquinoline olefination process, arylaldimine 48 has been
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded at 300
and 75 MHz or 400 and 100 MHz, respectively. Thin-layer
chromatography was performed with use of commercially
prepared 60-mesh silica gel plates (Whatman K6F), and
visualization was effected with short-wavelength UV light (254
nm) and a basic KMnO4 solution [3 g of KMnO4 + 20 g of K2-
CO3 + 5 mL of NaOH (5%) + 300 mL of H2O].
Rea gen ts. All reagents were used directly as obtained
commercially unless otherwise noted. All palladium salts were
donated by J ohnson Matthey Inc. and Kawaken Fine Chemi-
cals Co. Ltd. Compounds 1,1a 10,1a 12,1a 14,1a 20,1a 52,1a 53,12
54,1a 4-(dimethylamino)-2-iodobenzaldehyde,8b 5-(dimethylami-
(17) Larock, R. C.; Leung, W.; Stolz-Dunn, S. Tetrahedron Lett. 1989,
30, 6629.
J . Org. Chem, Vol. 68, No. 3, 2003 987

Huang and Larock
no)-2-iodobenzaldehyde,8b 2-iodo-3,4,5-trimethoxybenzaldehyde,8b
and N-(benzo[1,3]dioxol-5-ylmethylene)-tert-butylamine14 were
prepared according to previous literature procedures. The
preparation and characterization of the other starting materi-
als can be found in the Supporting Information.
(6.7 mg, 0.025 mmol), CuCl2 (3.4 mg, 0.025 mmol), NaHCO3
(0.063 g, 0.75 mmol), and the arylaldimine (0.25 mmol) were
placed in a 4-dram vial. The contents were then stirred for 1
min and the appropriate olefin (1.25 mmol) was added. The
vial was flushed with O2 and heated in an oil bath at 70 or 90
°C under an O2 balloon for the indicated period of time. The
reaction was monitored by TLC to establish completion. The
reaction mixture was cooled to 25 °C, diluted with 20 mL of
EtOAc, washed with 20 mL of brine, dried (Na2SO4), and
filtered. The solvent was evaporated under reduced pressure,
and the product was isolated by chromatography on a silica
gel column.
n -Bu t yl (E)-3-(3-P h en ylisoq u in olin -4-yl)a cr yla t e (5).
The reaction mixtures were chromatographed with use of 3:1
hexane/EtOAc to afford 51 mg (Table 3, entry 2) or 46 mg
(entry 3) of the indicated compound as a yellow oil in a 61%
or a 56% yield following procedure A or B, respectively: 1H
NMR (CDCl3) δ 0.96 (t, J ) 7.2 Hz, 3H), 1.37-1.46 (m, 2H),
1.64-1.72 (m, 2H), 4.23 (t, J ) 6.8 Hz, 2H), 6.32 (d, J ) 16.4
Hz, 1H), 7.42-7.49 (m, 3H), 7.63 (d, J ) 7.2 Hz, 2H), 7.67 (d,
J ) 7.2 Hz, 1H), 7.78 (t, J ) 7.6 Hz, 1H), 7.99 (d, J ) 16.4 Hz,
1H), 8.05 (d, J ) 8.4 Hz, 1H), 8.26 (d, J ) 8.8 Hz, 1H), 9.31 (s,
1H); 13C NMR (CDCl3) δ 13.9, 19.4, 30.9, 64.8, 123.9, 124.4,
126.6, 127.4, 127.6, 128.4, 128.5, 128.5, 130.6, 131.5, 134.4,
140.2, 141.3, 152.0, 152.8, 166.4; IR (neat, cm-1) 3412, 3058,
2958, 2872, 1716, 1636, 1570; HRMS calcd for C22H21O2N
331.1572, found 331.1577.
P r ep a r a tion of Ar yla ld im in es: N-[4,5-Dim eth oxy-2-
(p h en yleth yn yl)ben zylid en e]-ter t-bu tyla m in e (16). To a
solution of 2-bromo-4,5-dimethoxybenzaldehyde (1.23 g, 5.0
mmol) and phenylacetylene (0.62 g, 6.0 mmol) in Et3N (20 mL)
were added PdCl2(PPh3)2 (70 mg, 2 mol %) and CuI (10 mg, 1
mol %). The resulting mixture was then heated under an Ar
atmosphere at 55 °C. The reaction was monitored by TLC to
establish completion. When the reaction was complete, the
reaction mixture was allowed to cool to 25 °C, 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 to afford the corre-
sponding arylalkyne. To the purified arylalkyne in a 4-dram
vial was added t-BuNH2 (12 equiv). The mixture was then
stirred under an Ar atmosphere at 25 °C for 24 h. The resulting
mixture was extracted with ether. The combined organic layers
were dried (Na2SO4) and filtered. Removal of the solvent
afforded 1.32 g of the indicated arylaldimine in an 82% overall
1
yield as a yellow solid: mp 137-140 °C; H NMR (CDCl3) δ
1.35 (s, 9H), 3.95 (s, 3H), 4.00 (s, 3H), 7.01 (s, 1H), 7.36-7.38
(m, 3H), 7.52-7.55 (m, 2H), 7.63 (s, 1H), 8.86 (s, 1H); 13C NMR
(CDCl3) δ 30.1, 56.2, 56.3, 57.8, 86.9, 93.8, 107.9, 113.9, 117.1,
123.5, 128.5, 128.7, 131.5, 132.1, 149.9, 150.5, 153.9; IR
(CHCl3, cm-1) 3019, 2969, 1681, 1593, 1507; HRMS calcd for
Characterization of all other isoquinolines prepared in this
study can be found in the Supporting Information.
C
21H23O2N 321.1729, found 321.1735.
The preparation and characterization of other arylaldimines
employed in this study can be found in the Supporting
Information.
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research and J ohnson Matthey Inc. and Kawaken
Fine Chemicals Co. Ltd. for generous donations of
palladium catalysts.
Gen er a l P r oced u r e A for th e P a lla d iu m -Ca ta lyzed
F or m a tion of Isoqu in olin es. Dried DMSO (3 mL), PdBr2
(6.7 mg, 0.025 mmol), Cu(OAc)2 (0.091 g, 0.50 mmol), NaOAc
(0.062 g, 0.75 mmol), and the arylaldimine (0.25 mmol) were
placed in a 4-dram vial. The contents were then stirred for 1
min, and the appropriate olefin (1.25 mmol) was added. The
vial was sealed carefully and heated in an oil bath at 70 °C
for the indicated period of time. The reaction was monitored
by TLC to establish completion. The reaction mixture was
cooled to 25 °C, diluted with 20 mL of EtOAc, washed with 20
mL of brine, dried (Na2SO4), and filtered. The solvent was
evaporated under reduced pressure, and the product was
isolated by chromatography on a silica gel column.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of the starting materials 16, 22, 29, 33, 37,
40, 43, and 48; characterization data for compounds 2, 5-9,
11, 13, 15, 17-19, 21, 23-28, 30-32, 34-36, 38, 39, 41, 42,
1
44-47 and 49-51; copies of H NMR and 13C NMR spectra
for compounds 2, 5-9, 11, 13, 16-19, and 21-51. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Gen er a l P r oced u r e B for th e P a lla d iu m -Ca ta lyzed
F or m a tion of Isoqu in olin es. Dried DMSO (3 mL), PdBr2
J O0261303
988 J . Org. Chem., Vol. 68, No. 3, 2003