Synthesis of isoquinolines and pyridines by the palladium-catalyzed iminoannulation of internal alkynes

Article abstract of DOI:10.1021/jo0105540

A wide variety of substituted isoquinoline, tetrahydroisoquinoline, 5,6-dihydrobenz[f]isoquinoline, pyrindine, and pyridine heterocycles have been prepared in good to excellent yields via annulation of internal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst. The best results are obtained by employing 5 mol % of Pd(OAc)₂, an excess of the alkyne, 1 equiv of Na₂CO₃ as a base, and 10 mol % of PPh₃ in DMF as the solvent. This annulation methodology is particularly effective for aryl- or alkenyl-substituted alkynes. When electron-rich imines are employed, this chemistry can be extended to alkyl-substituted alkynes. Trimethylsilyl-substituted alkynes also undergo this annulation process to afford monosubstituted heterocyclic products absent the silyl group.

Full text of DOI:10.1021/jo0105540

8042
J . Org. Chem. 2001, 66, 8042-8051
Syn th esis of Isoqu in olin es a n d P yr id in es by th e
P a lla d iu m -Ca ta lyzed Im in oa n n u la tion of In ter n a l Alk yn es
Kevin R. Roesch, Haiming Zhang, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received J une 4, 2001
A wide variety of substituted isoquinoline, tetrahydroisoquinoline, 5,6-dihydrobenz[f]isoquinoline,
pyrindine, and pyridine heterocycles have been prepared in good to excellent yields via annulation
of internal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in
the presence of a palladium catalyst. The best results are obtained by employing 5 mol % of Pd-
(OAc)2, an excess of the alkyne, 1 equiv of Na2CO3 as a base, and 10 mol % of PPh3 in DMF as the
solvent. This annulation methodology is particularly effective for aryl- or alkenyl-substituted
alkynes. When electron-rich imines are employed, this chemistry can be extended to alkyl-
substituted alkynes. Trimethylsilyl-substituted alkynes also undergo this annulation process to
afford monosubstituted heterocyclic products absent the silyl group.
In tr od u ction
methods for the synthesis of this important ring system,
the Bischler-Napieralski reaction,10 the Pomeranz-
Fritsch reaction,10a,11 and the Pictet-Spengler reaction10a,12
have been frequently employed in the total synthesis of
isoquinoline alkaloids, they are all quite limited syntheti-
cally. For example, all of these methods are based on
electrophilic cyclizations of a â-phenylethylamine to form
the nitrogen-containing ring and therefore suffer the
disadvantages of employing strong acids in their ring
closure steps. The synthesis of appropriate starting
materials is also often difficult. Furthermore, all of these
reactions exhibit poor regioselectivity during ring closure.
Finally, the Bischler-Napieralski and Pictet-Spengler
reactions require dehydrogenations of dihydro- and
tetrahydroisoquinolines, respectively.
Annulation processes have found numerous applica-
tions in organic synthesis, primarily due to the ease with
which a wide variety of complicated hetero- and car-
bocycles can be rapidly constructed.1 In our own labora-
tories, it has been demonstrated that palladium-catalyzed
annulation methodology2 can be effectively employed for
the synthesis of indoles,3 isoindolo[2,1-a]indoles,4 benzo-
furans,5 benzopyrans,6 isocoumarins,5,6 R-pyrones,6,7 in-
denones,8 and polycyclic aromatic hydrocarbons9 (eq 1).
Substituted isoquinoline heterocycles have also been
synthesized by employing palladium methodology. For
instance, Widdowson reported the synthesis of isoquino-
line derivatives from cyclopalladated N-tert-butylaryl-
aldimines in yields from 10 to 56%.13 However, this
synthesis suffers from the disadvantages that stoichio-
metric amounts of palladium salts are required for the
preparation of the intermediate iminoalkenes, and the
final step involves pyrolysis at 180-200 °C.
Pfeffer has reported the formation of an isoquinolinium
salt in 14% yield, as well as a disubstituted isoquinoline
derivative in 60% yield from a cyclopalladated N,N-
dimethylbenzylamine complex.14 An entirely different
heterocycle was obtained by the thermal depalladation
of a cationic tetrafluoroborate palladium complex. These
The synthesis of isoquinoline heterocycles has received
considerable attention in the literature due to the fact
that the isoquinoline ring system is present in numerous
naturally occurring alkaloids. Although the classical
(1) (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.; Tzamari-
oudaki, M.; Li, Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635.
(2) For reviews, see: (a) Larock, R. C. J . Organomet. Chem. 1999,
576, 111. (b) Larock, R. C. Palladium-Catalyzed Annulation. In
Perspectives in Organopalladium Chemistry for the XXI Century, Tsuji,
J ., Ed.; Elsevier Press: Lausanne, Switzerland, 1999; pp 111-124. (c)
Larock, R. C. Pure Appl. Chem. 1999, 71, 1435.
(3) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J . Org. Chem. 1998, 63,
7652.
(4) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551.
(5) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org.
Chem. 1995, 60, 3270.
(6) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(7) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett. 1998, 39,
5713.
(8) Larock, R. C.; Doty, M. J .; Cacchi, S. J . J . Org. Chem. 1993, 58,
4579.
(10) (a) Kametani, T.; Fukumoto, K. In The Chemistry of Heterocyclic
Compounds, Isoquinolines; Grethe, G., Ed.; Wiley: New York, 1981;
Vol. 38, Part 1, Chapter 2, pp 139-274. (b) Whaley, W. M.; Govinda-
chari, T. R. In Organic Reactions; Adams, R., Ed.; Wiley: New York,
1951; Vol. 6, pp 151-190.
(11) Gensler, W. J . In Organic Reactions; Adams, R., Ed.; Wiley:
New York, 1951; Vol. 6, pp 191-206.
(12) Whaley, W. M.; Govindachari, T. R. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 74-150.
(13) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23,
4281.
(14) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J . Chem. Soc., Chem.
Commun. 1987, 565.
(9) (a) Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org.
Chem. 1997, 62, 7536. (b) Larock, R. C.; Tian, Q. J . Org. Chem. 1998,
63, 2002.
10.1021/jo0105540 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

Synthesis of Isoquinolines and Pyridines
J . Org. Chem., Vol. 66, No. 24, 2001 8043
Ta ble 1. Op tim iza tion of th e P a lla d iu m -Ca ta lyzed
F or m a tion of 3,4-Dip h en ylisoqu in olin e (eq 3)
syntheses also have the disadvantage that they use
stoichiometric amounts of palladium salts for the prepa-
ration of the starting cyclopalladated complexes.
Cl- source
(equiv)
10 mol % temp (°C), % isolated
entry
base
of PPh3
time (h)
yield of 2
Heck has also reported the synthesis of isoquinolinium
tetrafluoroborate salts in moderate yields from the reac-
tion of cyclopalladated arylaldimine tetrafluoroborates
and internal alkynes.15 In one instance, Heck observed
the formation of 3,4-diphenylisoquinoline in 22% yield
from the reaction of a cationic, tetrafluoroborate N-tert-
butylbenzaldimine palladium complex and diphenylacet-
ylene. These two syntheses, however, also suffer from the
use of stoichiometric amounts of palladium salts.
Our own interest in this type of annulation reaction
has prompted us to investigate a catalytic version of these
isoquinoline syntheses and we have previously reported
that excellent yields of isoquinolines and pyridines can
be obtained from the palladium-catalyzed annulation of
internal alkynes by the tert-butylimines of o-iodobenzal-
dehydes and 3-halo-2-alkenals.16 Herein, we report the
full details of this catalytic annulation chemistry for the
synthesis of a wide variety of nitrogen heterocycles,
including isoquinolines, tetrahydroisoquinolines, 5,6-
dihydrobenz[f]isoquinolines, pyrindines, and pyridines.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
LiCl (1)
LiCl (1)
LiCl (2)
Na2CO3
Na2CO3
Na2CO3
-
-
-
-
-
+
+
+
+
+
+
+
+
+
100, 53
110, 25
100, 115
100, 86
100, 23
100, 25
100, 32
100, 25
110, 88
100, 9
76
71
69
81
80
96
77
87
69
68
76
70
63
77a
n-Bu4NCl (1) Na2CO3
-
-
-
-
-
-
-
-
-
-
Na2CO3
Na2CO3
NaHCO3
NaOAc
K2CO3
i-Pr2NEt
Et3N
Na2CO3
Et3N
100, 8
80, 115
80, 21
Na2CO3
100, 96
a
Two mol % of Pd(OAc)2 and 4 mol % of PPh3 were used.
the reaction time was reduced, while the yield was
comparable to that of entry 1 (entry 2). It was also
observed that chloride salts significantly increased the
reaction times when employing Na2CO3 as a base (com-
pare entries 1-4 and entry 5). Upon removal of the
chloride salts from the reaction mixture, we were able
to isolate the desired product in a relatively short reaction
time, and in yields comparable to the reactions in which
chloride salts were employed (entry 5).
The effect of PPh3 on the reaction was then investi-
gated. The yield of 3,4-diphenylisoquinoline was observed
to increase upon addition of a catalytic amount of PPh3
(10 mol %) to the reaction mixture (compare entries 5
and 6). Presumably, the added phosphine disrupts coor-
dination of the neighboring imine substituent to the
palladium atom in the arylpalladium intermediate (see
the latter mechanistic discussion). Other inorganic bases
were also employed in the reaction with PPh3. However,
lower yields were observed with other bases, and in the
case of K2CO3, a significant increase in the reaction time
was observed (compare entries 7-9 with entry 6). When
tertiary organic amine bases were employed, a reduction
in the reaction time and yield of product was observed
(entries 10 and 11).
Resu lts a n d Discu ssion
Our initial studies focused on the palladium-catalyzed
iminoannulation of internal alkynes employing the meth-
yl imine of o-iodobenzaldehyde. However, this substrate
failed to produce any of the desired isoquinoline even at
elevated temperatures. Furthermore, use of the corre-
sponding isopropyl, allyl, and benzyl imines also failed
to produce the desired heterocyclic products. The reaction
of the R-methylbenzyl imine with diphenylacetylene did
produce the desired product, 3,4-diphenylisoquinoline,
albeit in low yields (6-11%). By employing the tert-
butylimine, however, we were able to obtain substantially
improved results with a variety of alkynes after optimi-
zation of the reaction conditions (eq 2).
Additional attempts to optimize this annulation pro-
cess included an investigation of two more reaction
variables. First of all, based on the success with Na2CO3
and PPh3 (entry 6), the reaction temperature was lowered
to 80 °C in order to determine the effect on the reaction
rate and yield (entry 12). Unfortunately, the reduction
in the temperature of the reaction was accompanied by
an increase in the reaction time, and a decrease in the
product yield. Furthermore, since the reaction times were
relatively short with the organic amine bases employed,
a reaction was run with Et3N at 80 °C (entry 13).
Although the reaction time with this base was relatively
short, the yield was significantly less than that of Na2-
CO3 at 100 °C (compare entries 6 and 13).
Finally, in an effort to reduce the amount of the
palladium catalyst, one reaction was run in which the
amount of Pd(OAc)2 was reduced from 5 mol % to 2 mol
% (entry 14). However, a decrease in the reaction rate,
as well as the yield, was observed. These results have
led to the development of the following general reaction
procedure for our heterocycle synthesis: 1 equiv of the
tert-butylimine, 2 equiv of the acetylene, 5 mol % of
Pd(OAc)2, 10 mol % of PPh3, 1 equiv of Na2CO3 in DMF
as the solvent at 100 °C. We then wanted to determine
The reaction of diphenylacetylene and the tert-butyl-
imine of o-iodobenzaldehyde (1) was chosen as the model
system for optimization of this annulation process (eq 3).
In the early stages of this work, the reaction conditions
that were chosen were similar to the conditions employed
in our other alkyne annulation chemistry (Table 1).2-9
For example, 0.5 mmol of the tert-butylimine, 1.0 mmol
of diphenylacetylene, 1 equiv of LiCl, with 1 equiv of Na2-
CO3 as a base in 10 mL of DMF at 100 °C afforded 3,4-
diphenylisoquinoline in 76% yield after a 53 h reaction
time (entry 1). By increasing the temperature to 110 °C,
(15) (a) Wu, G.; Rheingold, A. L.; Geib, S. J .; Heck, R. F. Organo-
metallics 1987, 6, 1941. (b) Wu, G.; Geib, S. J .; Rheingold, A. L.; Heck,
R. F. J . Org. Chem. 1988, 53, 3238.
(16) Roesch, K. R.; Larock, R. C. J . Org. Chem. 1998, 63, 5306.

8044 J . Org. Chem., Vol. 66, No. 24, 2001
Roesch and Zhang
Sch em e 1
spectral properties of compounds 8 and 9 with the
spectral properties of 3-phenyl-4-(phenylethynyl)iso-
quinoline, which has been isolated as a minor product
from the annulation of imine 1 by phenylacetylene. This
annulation methodology has also been extended to tri-
methylsilyl-substituted alkynes. To our surprise, 3-mono-
substituted isoquinolines were isolated in moderate yields
from these reactions (entries 10 and 11). These are rather
surprising results, since the expected products were
either the 3,4-disubstituted products retaining the silyl
group, or the corresponding 4-substituted isoquinolines
arising from desilylation of the former. On the basis of
the results from an extensive investigation of this reac-
tion, it appears that the trimethylsilyl acetylenes are
being desilylated by the base in the reaction (see Scheme
1). The terminal alkynes, which are thus produced, are
apparently undergoing palladium-catalyzed coupling and
subsequent cyclization. A preliminary account of this
investigation has been reported.18
Sch em e 2
In the case of the imine 16 bearing an electron-
withdrawing group and an unsymmetrical alkyne, only
a single regioisomer was obtained (entry 13), with hy-
drolysis of the unreacted imine presumably occurring
during the workup of the reaction.
The attempted annulation of other alkyl-substituted
alkynes, namely 4-octyne, 3-hexyne, 4,4-dimethyl-2-pen-
tyne, and 3,3-dimethyl-1-phenyl-1-butyne by imine 1
failed to produce any of the desired heterocycles. Based
on the observations of Heck,15 it is presumed that
multiple alkyne insertion products are being formed with
these alkynes, although none of these products have been
identified. Moreover, the use of alkynes bearing bulky
groups might inhibit the formation of intermediates A
or B due to the increased steric hindrance (see Scheme
2 and the latter mechanistic discussion). With simple
alkynes such as 4-octyne and 3-hexyne, the presumed
vinylpalladium intermediate (see the latter mechanistic
discussion) may be undergoing palladium beta hydride
elimination to an allene or oxidative addition of the C-H
bond of the imine moiety to the palladium to form an
indenone upon reductive elimination and hydrolysis.8
However, electron-rich imines afford good yields of
isoquinolines from a wide variety of alkynes (entries 14-
37). 4-Octyne produces the desired isoquinoline products
in good yields when an electron-rich imine is employed
(entries 17, 24, and 36). Even a very electron-deficient
alkyne, diethyl acetylenedicarboxylate, afforded the de-
sired heterocycles in moderate yields (entries 19, 34, and
37). The relatively low yields obtained when using this
alkyne can be rationalized by the fact that it can form
palladacyclopentadiene complexes with Pd(0) and the
resulting palladacyclopentadiene complex can further
react with another molecule of acetylenedicarboxylate to
generate the corresponding benzene hexacarboxylate.19
Surprisingly, when an electron-rich imine, such as 19 or
32, is employed in reactions that previously gave only
single regioisomers, mixtures of regioisomers have been
observed (compare entries 15, 16, and 23 with entries 2
and 3). Thus, the annulation of electron-rich imines gives
the scope and limitations of this methodology by annu-
lating a wide variety of acetylenes with a number of aryl
and vinylic imines. The results of this study are sum-
marized in Table 2.
The annulation of a variety of aryl-substituted alkynes
by the tert-butylimine of o-iodobenzaldehyde (1) has
afforded the desired disubstituted isoquinolines in mod-
erate to excellent yields with high regioselectivity (Table
2, entries 1-6). The regiochemistry of the products is
based on analogy with our previous alkyne annulation
chemistry2-9 and comparison of the spectral and physical
data for compounds 314 and 417 with those already in the
literature.
The annulation of a relatively unhindered diyne and
enyne by imine 1 also afforded the anticipated isoquino-
line products in good yields, although mixtures of regio-
isomers were obtained (entries 7-9). The annulation of
1,4-diphenylbutadiyne by imine 1 is observed to give an
unexpected major product bearing the more hindered
phenyl group in the 4-position (entry 7). This is in
contrast to the regiochemical outcome of much of our
other alkyne annulation chemistry in which the pal-
ladium adds to the more hindered end of the alkyne.2-9
The regiochemistry of the products from this annulation
has been confirmed by comparison of the 1H NMR
(18) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553.
(19) (a) Moseley, K.; Maitlis, P. M. J . Chem. Soc., Chem. Commun.
1971, 1604. (b) Moseley, K.; Maitlis, P. M. J . Chem. Soc., Dalton Trans.
1974, 169. (c) Brown, L. D.; Itoh, K.; Suzuki, H.; Hirai, K.; Ibers, J . A.
J . Am. Chem. Soc. 1978, 100, 8232. (d) Dieck, H. T.; Munz, C.; Mu¨ller,
C. J . Organomet. Chem. 1990, 384, 243. (e) Stephan, C.; Munz, C.;
Dieck, H. T. J . Organomet. Chem. 1993, 452, 223. (f) Pena, D.; Pe´rez,
D.; Guitia´n, E.; Castedo, L. J . Org. Chem. 2000, 65, 6944.
(17) Brooks, J . R.; Harcourt, D. N.; Waigh, R. D. J . Chem. Soc.,
Perkin Trans. 1 1973, 2588.

Synthesis of Isoquinolines and Pyridines
J . Org. Chem., Vol. 66, No. 24, 2001 8045
Ta ble 2. Syn th esis of Isoqu in olin es a n d P yr id in es by th e P a lla d iu m -Ca ta lyzed An n u la tion of In ter n a l Alk yn es (eq 2)a

8046 J . Org. Chem., Vol. 66, No. 24, 2001
Roesch and Zhang
Ta ble 2. (Con tin u ed )

Synthesis of Isoquinolines and Pyridines
J . Org. Chem., Vol. 66, No. 24, 2001 8047
Ta ble 2. (Con tin u ed )

8048 J . Org. Chem., Vol. 66, No. 24, 2001
Roesch and Zhang
Ta ble 2. (Con tin u ed )

Synthesis of Isoquinolines and Pyridines
J . Org. Chem., Vol. 66, No. 24, 2001 8049
Ta ble 2. (Con tin u ed )
a
A representative procedure for the annulation of internal acetylenes: 5 mol % of Pd(OAc)2, 10 mol % of PPh3, Na2CO3 (0.5 mmol), the
acetylene (1.0 mmol), the imine (0.5 mmol), and DMF (10 mL) were placed in a 4 dram vial and were heated at 100 °C for the indicated
b
time. Isolated in an 85:15 ratio of 10 to 11 as an inseparable mixture of isomers. c Isolated in a 95:5 ratio of 12 to 13 as an inseparable
d
mixture of isomers. Isolated as a 1:3 inseparable mixture of isomers 28 to 29. e A byproduct 6-(dimethylamino)-2,3-dipropylindenone
was isolated in a 10% yield.
relatively poor regiochemistry when unsymmetrical
alkynes are employed (entries 15, 16, 20, 21, and 23).
Interestingly, the electron-rich o-bromoimine 37 also
affords isoquinolines when allowed to react with diphe-
nylacetylene and 4-octyne, but in relatively low yields
compared to the corresponding o-iodoimine (entries 25
and 26). In the case of imines 38 and 41 bearing three
methoxy groups, the annulation chemistry proceeds with
4-octyne (entries 28 and 30) and even 2-butyne-1,4-diol
(entry 31), as expected, but in low yields. Even the
reactions of these imines with diphenylacetylene afford
low yields (entries 27 and 29). This may be due to the
extra steric hindrance expected in the intermediate
palladacycles (Figure 1).
lyzing to the benzaldehyde, which forms the indenone as
expected from prior work.8
When diphenylacetylene and diethyl acetylenedicar-
boxylate are employed in annulations involving imine 45,
the desired isoquinolines are obtained (entries 32 and 34).
This may be due to the fact that the electron density is
now delocalized into the phenyl ring or the ester group.
Therefore, no palladium carbene species is formed, and
the reaction smoothly affords the desired isoquinolines
(Figure 3).
F igu r e 3. Delocalization into the ester group of the reaction
intermediate.
It is worth noting that electronically, the electron-
donating groups on the phenyl ring increase the electron
density on the nitrogen atom of the imine and thus
increase the ability of the nitrogen to coordinate to
palladium and stabilize the reaction intermediate. This
apparently facilitates the annulation reactions of electron-
rich imines with internal alkynes.
F igu r e 1. Steric hindrance in the intermediate palladacycles
derived from imines 38 and 41.
Finally, the dimethylamino-substituted imines 45 and
49 have also been prepared and employed in this annu-
lation process (entries 32-37). The desired isoquinoline
products are obtained in good yields (entries 32, 35 and
36) in some cases, but not all cases. It is interesting to
note that the annulation of imine 45 with 4-octyne did
not afford the desired isoquinoline. Instead, the reaction
was quite messy and about a 10% yield of 6-(dimethy-
lamino)-2,3-di-n-propylindenone was isolated. It is pos-
sible that the anticipated palladium intermediate might
be a zwitterionic palladium carbene species,20 which
undergoes a series of side reactions (Figure 2). The
This annulation chemistry has also been extended to
vinylic imines. For example, the tetrahydroisoquinoline
derivatives 54-57 have been synthesized by annulation
with the cyclic vinylic imine 53 (entries 38-41). In
addition, the pyrindine derivatives 59-61 and the dihy-
drobenzoisoquinoline derivatives 63 and 64 have been
synthesized from vinylic imines 58 and 62, respectively
(entries 42-46). Finally, the acyclic vinylic imines 65 and
69 have also been successfully employed in this annula-
tion process to produce highly substituted pyridine
derivatives (entries 47-51). It is interesting to note that
the compounds derived from the vinylic imines were all
isolated as single regioisomers. Surprisingly, the imine
69 works quite well in this pyridine synthesis, whereas
the corresponding ethyl ester (Z-PhCIdCHCO2Et) fails
to undergo annulation of this same alkyne to produce the
corresponding R-pyrone, a process with which we have
recently had considerable success.7
We propose a mechanism for this process which is
similar to our other alkyne annulation chemistry (Scheme
2). Specifically, oxidative addition of the aryl or vinylic
halide to Pd(0) produces an organopalladium intermedi-
ate, which then inserts the acetylene, producing a vinylic
palladium intermediate, which then reacts with the
neighboring imine substituent to form a seven-membered
palladacyclic ammonium salt A. Subsequent reductive
F igu r e 2. A possible zwitterionic palladium carbene species.
by-product 6-(dimethylamino)-2,3-di-n-propylindenone
could be the product of a typical carbene C-H insertion
into the imine moiety, followed by hydrolysis during the
workup. Alternatively, the imine may simply be hydro-
(20) For palladium carbene intermediates, see: (a) Tsuji, J .; Wa-
tanabe, H.; Minami, I.; Shimizu, I. J . Am. Chem. Soc. 1985, 107, 2196.
(b) Trost, B. M.; Hashmi, A. S. K. J . Am. Chem. Soc. 1994, 116, 2183.
(c) Sierra, M. A.; Mancheno, M. J .; Saez, E.; del Amo, J . C. J . Am.
Chem. Soc. 1998, 120, 6812. (d) Balme, G.; Monteiro N. J . Org. Chem.
2000, 65, 3223.

8050 J . Org. Chem., Vol. 66, No. 24, 2001
Roesch and Zhang
benzaldehyde,27 and 2-iodo-4-dimethylaminobenzaldehyde28
were prepared according to previous literature procedures. The
preparation and characterization of the starting materials 1-(1-
butynyl)cyclohexene, 2-iodopiperonal, 2-iodobenzene-1,4-dicar-
baldehyde, and 2-iodo-5-(dimethylamino)benzaldehyde can be
found in the Supporting Information.
elimination produces a tert-butylisoquinolinium salt B
and regenerates Pd(0). As previously suggested by Heck,15
the tert-butyl group apparently fragments to relieve the
strain resulting from interaction with the substituent
present in the 3-position. It is also easy to understand
why when an extremely bulky alkyne like 3,3-dimethyl-
1-phenyl-1-butyne is employed in this annulation process,
none of the desired heterocyclic product is produced. In
this case, the reaction intermediate A might form either
A with R1 ) t-Bu and R2 ) Ph or A with R1 ) Ph and R2
) t-Bu. Generally, an intermediate, such as the former
is difficult to generate due to the steric hindrance
between the bulky tert-butyl group and the neighboring
arene. Although the latter might be formed as an
intermediate, it is unable to undergo palladium reductive
elimination to generate B, because of steric hindrance
between the two bulky tert-butyl groups in the 2 and 3
positions of B.
P r ep a r a tion of th e Im in es. The following procedures are
representative of those used to prepare the imines.
N-(2-Iod oben zylid en e)-ter t-bu tyla m in e (1). To a mixture
of 2-iodobenzaldehyde (1.00 g, 4.3 mmol) and H2O (0.25 mL/
mmol) was added tert-butylamine (12.9 mmol, 3 equiv). The
mixture 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 then
dried (Na2SO4) and filtered. Removal of the solvent afforded
1.18 g (95%) of the imine as a yellow oil: 1H NMR (CDCl3) δ
1.33 (s, 9H), 7.07 (td, J ) 1.5, 7.2 Hz, 1H), 7.36 (tt, J ) 0.6,
7.2 Hz, 1H), 7.83 (dd, J ) 0.9, 7.8 Hz, 1H), 7.94 (dd, J ) 1.8,
7.8 Hz, 1H), 8.41 (s, 1H); 13C NMR (CDCl3) δ 29.8, 58.0, 100.4,
128.5, 128.7, 131.6, 137.9, 139.4, 159.2; IR (neat, cm-1) 3059,
2966, 1633; HRMS Calcd for C11H14IN: 287.0170. Found:
287.0173.
Con clu sion
N -(2-Iod o-3,4,5-t r im e t h oxyb e n zylid e n e )-t er t -b u t yl
a m in e (38). To 2-iodo-3,4,5-trimethoxybenzaldehyde (0.966 g,
3.0 mmol) was added tert-butylamine (6 mL, 2 mL/mmol). The
tube was carefully sealed, and the mixture was then stirred
under a nitrogen atmosphere at 100 °C for 24 h. The mixture
was then cooled, diluted with ether, and dried with Na2SO4.
The excess tert-butylamine was removed to afford 1.13 g (99%)
of the imine 38 as a yellow oil: 1H NMR (CDCl3) δ 1.32 (s,
9H), 3.88 (s, 1H), 3.90 (s, 1H), 3.94 (s, 1H), 7.41 (s, 1H), 8.44
(s, 1H); 13C NMR (CDCl3) δ 30.1, 56.4, 58.0, 61.1, 61.3, 89.5,
107.5, 133.7, 144.2, 152.9, 154.1, 159.2; IR (neat, cm-1) 3011,
2968, 1475; HRMS Calcd for C14H20INO3: 377.0488. Found:
377.0494.
An efficient, palladium-catalyzed synthesis of nitrogen
heterocycles, including isoquinolines, tetrahydroisoquino-
lines, 5,6-dihydrobenz[f]isoquinolines, pyrindines, and
pyridines has been developed. A wide variety of acety-
lenes undergo this process in moderate to excellent yields,
with high regioselectivity being observed in most cases.
When a relatively unhindered diyne and enyne or an
electron-rich imine are employed, mixtures of regioiso-
mers are observed. By employing trimethylsilyl-contain-
ing acetylenes, we have been able to synthesize mono-
substituted heterocyclic products.
Characterization of all other imines prepared in this study
can be found in the Supporting Information.
Exp er im en ta l Section
Gen er a 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 Isoqu in olin es a n d P yr id in es. DMF (10 mL), Pd-
(OAc)2 (6.0 mg, 0.027 mmol), PPh3 (13 mg, 0.05 mmol), Na2CO3
(53 mg, 0.5 mmol), and the alkyne (1.0 mmol) were placed in
a 4 dram vial. The contents were then stirred for 1 min, and
the appropriate imine (0.5 mmol) was added. The vial was
flushed with nitrogen and heated in an oil bath at 100 °C for
the indicated period of time. The reaction was monitored by
TLC to establish completion. The reaction mixture (except
entries 18, 21 and 31 in Table 2, which afford fairly water
soluble isoquinoline derivatives) was cooled, diluted with 30
mL of ether, washed with 45 mL of saturated NH4Cl, dried
(Na2SO4), and filtered. The solvent was evaporated under
reduced pressure, and the product was isolated by chroma-
tography on a silica gel column. The reaction mixtures of
entries 18, 21, and 31 in Table 2 were filtered, the solvent was
removed directly under reduced pressure, and the residue was
purified by chromatography on a silica gel column.
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 using commercially prepared
60-mesh silica gel plates (Whatman K6F), and visualization
was effected with short wavelength UV light (254 nm) and
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. Low resolution mass spectra were recorded on a
Finnigan TSQ700 triple quadrupole mass spectrometer (Finni-
gan MAT, San J ose, CA). High resolution mass spectra were
recorded on a Kratos MS50TC double focusing magnetic sector
mass spectrometer using EI at 70 eV. Elemental analyses were
performed at Iowa State University on a Perkin-Elmer 2400
CHNS/O Series II Analyzer. All reagents were used directly
as obtained commercially unless otherwise noted. Anhydrous
forms of Na2CO3, K2CO3, NaOAc, NaHCO3, LiCl, DMF, THF,
ethyl ether, hexanes, and ethyl acetate were purchased from
Fisher Scientific Co. All palladium salts were donated by
J ohnson Matthey Inc. and Kawaken Fine Chemicals Co. Ltd.
PPh3 was donated by Kawaken Fine Chemicals Co. Ltd.
Compounds 2, 3, 4, 7, 8, 9, 10, 11, 18, 34, 35, 54, 60, 68, and
71 have been previously reported.16 2-Iodobenzaldehyde,8
2-bromopiperonal,21 2-bromocyclohexene-1-carboxaldehyde,22
4-Eth yl-3-p h en ylisoqu in olin e (5). The reaction mixture
was chromatographed using 5:1 hexanes/EtOAc to afford 109
mg (93%) of the indicated compound as a white solid: mp 117-
118 °C; 1H NMR (CDCl3) δ 1.30 (t, J ) 7.5 Hz, 3H), 3.07 (q, J
) 7.5 Hz, 2H), 7.39-7.56 (m, 5H), 7.62 (ddd J ) 1.2, 6.9, 8.4
Hz, 1H), 7.77 (ddd, J ) 1.2, 6.9, 8.1 Hz, 1H), 8.02 (d, J ) 8.1
Hz, 1H), 8.10 (d, J ) 8.4 Hz, 1H), 9.19 (s, 1H); 13C NMR
(CDCl3) δ 15.7, 21.9, 123.7, 126.6, 127.6, 127.9, 128.2, 128.5,
2-bromocyclopentene-1-carboxaldehyde,23
1-bromo-3,4-di-
hydronaphthalene-2-carboxaldehyde,24 (Z)-3-iodo-2-methyl-
3-phenyl-2-propenal,25 (Z)-3-iodo-3-phenyl-2-propenal,25 2-
iodo-3,4,5-trimethoxybenzaldehyde,26 2-iodo-4,5,6-trimethoxy-
129.3, 130.4, 130.5, 135.3, 141.6, 150.2, 151.9; IR (CHCl3, cm-1
)
3027, 2976, 1653, 1559; MS m/z (rel intensity) 233 (76, M+),
232 (100), 217 (44). Anal. Calcd for C17H15N: C, 87.52; H, 6.48;
N, 6.00. Found: C, 87.48; H, 6.68; N, 5.91.
(21) Conrad, P. C.; Kwiatkowski, P. L.; Fuchs, P. L. J . Org. Chem.
1987, 52, 586.
(22) Coates, R. M.; Senter, P. D.; Baker, W. R. J . Org. Chem. 1982,
47, 3597.
(23) Gilchrist, T. L.; Kemmitt, P. D. Tetrahedron 1995, 51, 9119.
(24) Gilchrist, T. L.; Summersell, R. J . J . Chem. Soc., Perkin Trans.
1 1988, 2595.
(26) Bradley, A.; Motherwell, W. B.; Ujjainwalla, F. J . Chem. Soc.,
Chem. Commun. 1999, 917.
(27) Cherkaoui, M. Z.; Scherowsky, G. New J . Chem. 1997, 21, 1203.
(28) Raeppel, S.; Toussaint, D.; Suffert, J . Synlett 1998, 537.
(25) Han, X. Ph.D. Dissertation, Iowa State University, 1998.

Synthesis of Isoquinolines and Pyridines
J . Org. Chem., Vol. 66, No. 24, 2001 8051
Characterization of all other isoquinolines prepared in this
study can be found in the Supporting Information.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of the starting materials; characterization
data for compounds 6, 12-17, 19-33, 36, 37, 39-46, 48-53,
55-67, 69, and 70, copies of 1H and 13C spectra for compounds
1, 12, 13, 16, 19, 21, 24-27, 30-33, 36, 38, 41-46, 48-53,
57, 58, 62-67, and 69. This material is available free of charge
via the Internet at http://pubs.acs.org.
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, J ohnson Matthey, Inc. and Kawaken
Fine Chemicals Co., Ltd. for donation of the palladium
acetate, and Merck and Co., Inc. for an Academic
Development Award in Chemistry.
J O0105540