Synthesis of isoquinolines and pyridines by the palladium/copper-catalyzed coupling and cyclization of terminal acetylenes and unsaturated imines: The total synthesis of decumbenine B

Article abstract of DOI:10.1021/jo010579z

Monosubstituted isoquinolines and pyridines have been prepared in good to excellent yields via coupling of terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of the intermediate iminoalkynes. In addition, isoquinoline heterocycles have been prepared in excellent yields via copper-catalyzed cyclization of iminoalkynes. The choice of cyclization conditions is dependent upon the nature of the terminal acetylene that is employed, as only aryl and alkenyl acetylenes cyclize under the palladium-catalyzed reaction conditions that have been developed. However, aryl-, vinylic-, and alkyl-substituted acetylenes undergo palladium-catalyzed coupling and subsequent copper-catalyzed cyclization in excellent yields. The total synthesis of the isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall yield by employing this palladium-catalyzed coupling and cyclization methodology.

Full text of DOI:10.1021/jo010579z

86
J . Org. Chem. 2002, 67, 86-94
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 /
Cop p er -Ca ta lyzed Cou p lin g a n d Cycliza tion of Ter m in a l
Acetylen es a n d Un sa tu r a ted Im in es: Th e Tota l Syn th esis of
Decu m ben in e B
Kevin R. Roesch and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received J une 11, 2001
Monosubstituted isoquinolines and pyridines have been prepared in good to excellent yields via
coupling of terminal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-
alkenals in the presence of a palladium catalyst and subsequent copper-catalyzed cyclization of
the intermediate iminoalkynes. In addition, isoquinoline heterocycles have been prepared in
excellent yields via copper-catalyzed cyclization of iminoalkynes. The choice of cyclization conditions
is dependent upon the nature of the terminal acetylene that is employed, as only aryl and alkenyl
acetylenes cyclize under the palladium-catalyzed reaction conditions that have been developed.
However, aryl-, vinylic-, and alkyl-substituted acetylenes undergo palladium-catalyzed coupling
and subsequent copper-catalyzed cyclization in excellent yields. The total synthesis of the
isoquinoline natural product decumbenine B has been accomplished in seven steps and 20% overall
yield by employing this palladium-catalyzed coupling and cyclization methodology.
In tr od u ction
σ-aryl-, and σ-alkynylpalladium complexes10 have also
been shown to be extremely effective for the synthesis of
a wide variety of carbo- and heterocycles.
The palladium-catalyzed annulation of alkynes has
recently proven to be a powerful method for the construc-
tion of a variety of carbo- and heterocycles. For example,
we have employed the annulation of internal alkynes for
the synthesis of indoles,1 isoindolo[2,1-a]indoles,2 benzo-
furans,3 benzopyrans,3 isocoumarins,3,4 indenones,5 iso-
quinolines,6 R-pyrones,4,7 and polycyclic aromatic hydro-
carbons.8 In addition, the transition metal-catalyzed
cyclization of alkynes, which possess a nucleophile in
proximity to the triple bond, by in situ coupling/cycliza-
tion reactions,9 and reactions promoted by σ-vinyl-,
Isoquinoline derivatives have been synthesized via
base-catalyzed cyclization of terminal and disubstituted
alkynes. For example, Sharp has reported the synthesis
of N-sulfonylimine isoquinolines in modest yields (40-
77%) from the base-induced cyclization of o-ethynyl
hydrazones.11 The synthesis of these heterocycles is not
general, however, as only terminal acetylenes could be
cyclized under the reaction conditions employed. The
reaction of o-alkynyl oximes and K2CO3 affords modest
yields (39-78%) of isoquinoline N-oxides.12 Finally, 3-sub-
stituted isoquinolines are formed by the reaction of
o-ethynylbenzaldehydes and ammonia in modest to ex-
cellent yields (45-95%).13 Since few examples of the latter
two processes have been reported, the true synthetic
utility of this chemistry cannot be fully determined at
this time.
(1) (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.
(2) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 1551.
(3) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org.
Chem. 1995, 60, 3270.
(4) Larock, R. C.; Doty, M. J .; Han, X. J . Org. Chem. 1999, 64, 8770.
(5) Larock, R. C.; Doty, M. J .; Cacchi, S. J . J . Org. Chem. 1993, 58,
4579.
(6) Roesch, K. R.; Larock, R. C. J . Org. Chem. 1998, 63, 5306.
(7) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett. 1998, 39,
5713.
During the course of our earlier investigation of the
palladium-catalyzed iminoannulation of internal alkynes,
we observed an interesting new isoquinoline synthesis
(eq 1).6 To our surprise, 3-phenylisoquinoline, and not
(8) (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.
(9) 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 and references therein. (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 and references therein.
(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. Tetrahedron Lett. 1997,
38, 2307.
(10) For recent leading references, see: (a) Monteiro, N.; Arnold,
A.; Balme, G. Synlett 1998, 1111. (b) Cacchi, S.; Fabrizi, G.; Moro, L.
Synlett 1998, 741. (c) Cacchi, S.; Fabrizi, G.; Moro, L. J . Org. Chem.
1997, 62, 5327 and references therein. (d) Arcadi, A.; Anacardio, R.;
D′Anniballe, G.; Gentile, M. Synlett 1997, 1315. (e) Arcadi, A.; Cacchi,
S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J . Org. Chem. 1996, 61,
9280 and references therein. (f) Balme, G.; Bouyssi, D. Tetrahedron
1994, 50, 403. (g) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F.
Tetrahedron 1994, 50, 437. (h) Arcadi, A.; Burini, A.; Cacchi, S.;
Delmastro, M.; Marinelli, F.; Pietroni, B. R. J . Org. Chem. 1992, 57,
976. (i) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992,
33, 3915.
(11) Anderson, P. N.; Sharp, J . T. J . Chem. Soc., Perkin Trans. 1
1980, 1331.
(12) Sakamoto, T.; Kondo, Y.; Miura, N.; Hayashi, K.; Yamanaka,
H. Heterocycles 1986, 24, 2311.
(13) (a) Sakamoto, T.; Kondo, Y.; Miura, N.; Yamanaka, H. Hetero-
cycles 1988, 27, 2225. (b) Numata, A.; Kondo, Y.; Sakamoto, T.
Synthesis 1999, 306.
10.1021/jo010579z CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/12/2001

Total Synthesis of Decumbenine B
J . Org. Chem., Vol. 67, No. 1, 2002 87
Sch em e 1
Sch em e 2
Sch em e 3
the expected disubstituted heterocycle, 4-phenyl-3-(tri-
methylsilyl)isoquinoline, was isolated in 85% yield from
the palladium-catalyzed reaction of N-(2-iodobenzylidene)-
tert-butylamine (1) and 1-phenyl-2-(trimethylsilyl)acetyl-
ene. Herein, we report a full investigation of this intrigu-
ing reaction, the development of a new isoquinoline
synthesis by the heteroannulation of terminal alkynes,
and the application of this methodology to the synthesis
of the naturally occurring isoquinoline alkaloid decum-
benine B (38).14
3-position of the isoquinoline, other mechanisms must
be operating in this system. This was confirmed by the
observation that 2-(2-phenylethynyl)benzaldehyde could
be isolated if the reactions were not allowed to proceed
to completion. Therefore, an alternative mechanistic
picture was envisioned for this transformation (Scheme
2). Specifically, oxidative addition of the aryl halide to
Pd(0) produces an organopalladium intermediate, which
then couples with a terminal acetylene or acetylide that
is formed in situ. The disubstituted alkyne that is
subsequently produced must then be cyclized by pal-
ladium catalysis, producing a tert-butylisoquinolinium
salt. As in our internal alkyne annulation chemistry, the
tert-butyl group apparently fragments to relieve the
strain resulting from interaction with the substituent
present in the 3-position.6
Resu lts a n d Discu ssion
The surprising results obtained from silyl acetylenes
(eq 1) encouraged us to examine the mechanism of this
interesting transformation and to define the scope and
limitations of this new isoquinoline synthesis. On the
basis of the regiochemical outcome of much of our other
alkyne annulation chemistry, in which the palladium
adds to the more hindered end of the alkyne (Scheme 1),
the expected products from the reaction with trimethyl-
silyl-substituted alkynes were either the 3,4-disubstitut-
ed products retaining the silyl group or the corresponding
4-substituted isoquinoline arising from desilylation of the
3,4-disubstituted isoquinoline.
To gain additional insight into this process, imi-
noalkyne 3 was independently synthesized by a pal-
ladium-catalyzed coupling of 2-bromobenzaldehyde and
phenylacetylene, followed by imine formation (Scheme
3). Imine 3 was then subjected to a variety of reaction
conditions in order to effect its cyclization to 3-phenyl-
isoquinoline (2) (eq 2, Table 1). Under the standard
palladium reaction conditions that were developed for our
internal alkyne isoquinoline synthesis [5 mol % Pd(OAc)2,
10 mol % PPh3, and 1 equiv of Na2CO3 in 10 mL of DMF
at 100 °C], isoquinoline 2 was isolated in 75% yield after
a 39 h reaction time (entry 1). Thus, our assumptions
about the mechanism of this process appeared to be
correct. We then were interested in optimizing the yield
However, since a product was isolated from this
reaction in which the trimethylsilyl substituent was not
incorporated and the phenyl substituent was in the
(14) For a preliminary communication, see: Roesch, K. R.; Larock,
R. C. Org. Lett. 1999, 1, 553.

88 J . Org. Chem., Vol. 67, No. 1, 2002
Roesch and Larock
Ta ble 1. Syn th esis of 3-P h en ylisoqu in olin e (2) (eq 2)a
Ta ble 2. Syn th esis of 3-P h en ylisoqu in olin e (2) by
P d -Ca ta lyzed Cou p lin g a n d Cycliza tion (eq 3)a
5 mol %
Pd catalyst
1 equiv 10 mol % temp (°C), % yield
entry
Na2CO3
PPh3
time (h)
of 2
base
entry (equiv)
5 mol %
Pd catalyst
5 mol % 10 mol % temp (°C),
%
CuI
PPh3
time (h) yield
1
2
Pd(OAc)2
+
-
-
+
+
-
-
-
-
+
+
-
-
-
-
-
-
-
-
-
100 (39)
100 (14)
100 (15)
100 (36)
100 (48)
100 (42)
100 (6)
75
78
Pd(OAc)2
1
2
Na2CO3 Pd(OAc)2
-
+
100 (58)
62
3
PdCl2
PdCl2
65
(1)
4
69
Na2CO3 Pd(OAc)2
(1)
+
+
+
-
+
-
-
-
-
+
-
+
+
+
-
-
-
+
-
-
-
+
rt (12),
100 (75)
rt (12),
100 (22)
rt (1),
100 (14)
100 (11)
68
5
PdCl2(PhCN)2
88
6
PdCl2(PhCN)2
58
3
NEt3
(2)
Pd(OAc)2
60
7
-
-
-
-
100b
77c
57
8
100 (6)
4
i-Pr2NEt Pd(OAc)2
50
9
130 (45)
130 (45)
(2)
10
63
5
Na2CO3 Pd(OAc)2
(1)
83b
59
a
All reactions were run with 0.25 mmol of the imine in 5 mL
6
NEt3
(2)
PdCl2(PPh3)2
rt (3),
100 (15)
100 (12)
of DMF. A 10 mol % quantity of CuI was added. c A 5 mol %
b
7
Na2CO3 PdCl2(PPh3)2
77b,c
78
quantity of CuI was added.
(1)
8
Na2CO3 PdCl2(PhCN)2
100 (72)
100 (30)
100 (14)
100 (12)
100 (23)
and reaction time for this process.
(1)
9
Na2CO3 PdCl2(PhCN)2
60
(1)
10
11
12
Na2CO3 PdCl2(PhCN)2
85b
75b
85b
(1)
Na2CO3 PdCl2(PhCN)2
(1)
Na2CO3 PdCl2(PhCN)2
(1)
a
Upon removal of the base and the phosphine from the
reaction, the desired product was isolated in 78% yield
in a shorter reaction time (cf. entries 1 and 2). PdCl2 was
also observed to promote the cyclization, although a
decrease in yield was observed (entries 3 and 4). Employ-
ing PdCl2(PhCN)2 as the palladium catalyst and Na2CO3
allowed the desired product to be isolated in 88% yield
after a 48 h reaction time (entry 5). Removal of the base
from the PdCl2(PhCN)2-catalyzed reaction, however,
resulted in a lower isolated yield of the desired product
(entry 6). Interestingly, employing only CuI as a catalyst
allowed the desired product to be obtained in quantitative
yield in a short reaction time (entry 7). In an effort to
reduce the amount of catalyst that was employed in the
reaction, 5 mol % of CuI was added, but a decrease in
the yield was observed (entry 8). Finally, this imi-
noalkyne can also be cyclized thermally, although the
yields are lower than either of the palladium- or copper-
catalyzed cyclizations and higher temperatures and
longer reactions times are required (entries 9 and 10).
On the basis of the mechanistic picture that has
emerged for this process, it was expected that terminal
acetylenes would also undergo this annulation. Indeed,
phenylacetylene was subsequently observed to partici-
pate in this palladium-catalyzed annulation (eq 3).
However, under the standard internal alkyne annulation
conditions, 3-phenylisoquinoline could only be obtained
in 62% isolated yield. Thus, we again were interested in
optimizing the yield and reaction time for this process.
The results of this investigation are shown in Table 2.
After optimization of the reaction conditions, we found
that employing 1 equiv of 1, 1.1 equiv of phenylacetylene,
5 mol % PdCl2(PhCN)2, and 1 equiv of Na2CO3 in DMF
at 100 °C allowed isoquinoline 2 to be isolated in 85%
yield after a 14 h reaction time (entry 10). It is interesting
to note that CuI was not required as a cocatalyst for this
annulation.
All reactions were run with 0.5 mmol of the imine and 1.0
mmol of phenylacetylene in 10 mL of DMF unless otherwise noted.
A 1.1 equiv quantity of phenylacetylene was used. c A 10 mol %
b
quantity of CuI was added.
After optimization of the reaction conditions with
phenylacetylene, we then proceeded to define the scope
and limitations of the terminal acetylene annulation. The
reaction in which 1-ethynylcyclohexene was employed
also afforded the desired isoquinoline 4 in good yield (eq
4). Unfortunately, when cyclohexyl acetylene was em-
ployed under the same conditions, none of the desired
isoquinoline 5 was obtained (eq 5). In addition, the
standard isoquinoline internal alkyne annulation condi-
tions also afforded none of the desired heterocycle.
Therefore, it again became necessary to find reaction
conditions that would increase the generality of this
annulation process.
Due to the success of the copper-catalyzed cyclization
of iminoalkyne 3 (Table 1, entry 7), the cyclization of
iminoalkynes with differing functionality was investi-
gated. All of the iminoalkynes employed in this cycliza-
tion process were synthesized in excellent yields by the

Total Synthesis of Decumbenine B
J . Org. Chem., Vol. 67, No. 1, 2002 89
Ta ble 3. Syn th esis of Isoqu in olin e Heter ocycles by th e
Cu -Ca ta lyzed Cycliza tion of Im in oa lk yn esa
Sch em e 4
same sequence of transformations used for the prepara-
tion of alkyne 3 (Scheme 4). Although limited success was
obtained from the terminal acetylene coupling/cyclization
chemistry discussed previously, the copper-catalyzed
cyclization proved to be more general with respect to the
functionality that can be introduced into the products
(Table 3). For example, iminoalkynes containing aryl,
alkenyl, and alkyl substituents afford excellent yields of
the desired monosubstituted isoquinoline heterocycles
(Table 3, entries 1-4). However, free propargylic hydroxy
groups are not tolerated in these cyclization reactions
(entries 5 and 6), nor were highly hindered iminoalkynes
(entry 7). The failure of the hydroxy alkynes is surprising
since our later synthesis of decumbenine B (see eq 8)
involves a successful coupling and cyclization of an alkyne
bearing a free hydroxy group, although the hydroxy group
in that alkyne is further removed from the carbon-
carbon triple bond and the cyclization there involves
palladium, not copper.
a
Representative procedure for the cyclization of iminoalkynes:
10 mol % CuI, the imine (0.25 mmol), and DMF (5 mL) were placed
in a 2 dram vial and heated at 100 °C for the indicated time. The
amount of starting material recovered was 100%.
b
Ta ble 4. Syn th esis of Com p ou n d 5 by th e P d -Ca ta lyzed
Cou p lin g a n d Cycliza tion of Im in e 1 a n d Cycloh exyl
Acetylen ea
Although the copper-catalyzed synthesis was more
general than the palladium-catalyzed terminal acetylene
coupling/cyclization reactions with respect to the types
of functionality that could be incorporated into the
isoquinoline, this synthesis was still not as efficient as
the one-pot reaction discussed previously (eqs 3 and 4),
since three transformations (coupling, imine formation,
and copper-catalyzed cyclization) were required. Conse-
quently, we more closely examined the reaction of imine
1 and cyclohexyl acetylene with different bases and
palladium catalysts (Table 4). Employing Et3N, instead
of Na2CO3, as a base in the presence of 5 mol % Pd(OAc)2
and 2.5 mol % CuI, allowed 3-cyclohexylisoquinoline (5)
to be isolated in low yield (entry 3). Increasing the
amount of CuI to 10 mol % led to a slight increase in
yield (entry 4). All additional attempts to increase the
yield by changing bases and palladium catalysts in this
reaction, however, proved to be futile (entries 5-11).
On the basis of our work up to this point, we felt that
a reasonable mechanism had been formulated for this
annulation process (Scheme 2). Specifically, coupling of
base
5 mol %
CuI
temp (°C), % yield
entry
(equiv)
Pd catalyst
(mol %)
time (h)
of 5
1
2
3
4
5
6
7
8
9
Na2CO3 (1) Pd(OAc)2
Na2CO3 (1) Pd(OAc)2
Et3N (1)
Et3N (1)
Et3N (1)
Et3N (0.15) Pd(OAc)2
i-Pr2NEt (1) Pd(OAc)2
pyridine (1) Pd(OAc)2
Et3N (1)
Et3N (1)
Et3N (1)
0
10
2.5
10
10
10
10
10
10
10
10
100 (24)
100 (24)
100 (12)
100 (12)
100 (12)
100 (12)
100 (11)
100 (11)
100 (10)
100 (10)
100 (10)
0
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
20
26
19b
18
15
10
14
12
13
Pd(dba)2
PdCl2(CH3CN)2
PdCl2(PPh3)2
10
11
a
All reactions were run with 0.25 mmol of the imine and 1.1
mmol of cyclohexyl acetylene in 5 mL of DMF unless otherwise
noted. Quantities of 1.1 mmol of the imine and 1.0 mmol of
b
cyclohexyl acetylene were employed.
the aryl halide and terminal acetylene must first occur
to produce the intermediate iminoalkyne, followed by a
cyclization step to produce the isoquinoline. Therefore,
the reaction conditions employed for a one-pot synthesis
must be compatible with both steps in the catalytic cycle.

90 J . Org. Chem., Vol. 67, No. 1, 2002
Roesch and Larock
Since we had considerable success with the palladium-
catalyzed coupling of o-bromobenzaldehyde and terminal
acetylenes (Scheme 4), and also with the copper-catalyzed
cyclization of iminoalkynes (Table 3), we felt that by an
appropriate choice of reaction conditions, it should be
possible to efficiently synthesize the desired isoquino-
lines.
and 1 mol % of CuI in 2 mL of Et3N were heated at 55
°C until the coupling was judged to be complete by thin-
layer chromatography. The solvent and the precipitates
were subsequently removed, and DMF (5 mL) and 10 mol
% of CuI were added to the residue. The resulting
mixture was then heated at 100 °C until the cyclization
was judged to be complete by thin-layer chromatography.
Employing this reaction sequence allowed a variety of
isoquinolines to be synthesized in good to excellent yields
(Table 5).
A variety of functionalized terminal acetylenes have
been employed in this palladium/copper-catalyzed pro-
cess. For example, the reaction of imine 1 with aryl-,
alkenyl-, and alkyl-substituted acetylenes affords the
desired isoquinolines in good to excellent yields (Table
5, entries 1-7). As in our copper-catalyzed cyclization of
iminoalkynes, free hydroxy groups are not tolerated, as
the reaction of 1 with 3-butyn-1-ol afforded none of the
desired heterocycle. Protection of the free hydroxy group
as the tetrahydropyranyl ether, however, afforded the
desired isoquinoline 18 in 95% yield (entry 4). Acetal and
nitrile functional groups were also tolerated (entries 5
and 6). Using 1,6-heptadiyne as the terminal acetylene
afforded bis-isoquinoline 24 in 56% yield. Unfortunately,
when the highly hindered terminal alkyne 3,3-dimethyl-
1-butyne was employed, 2-(3,3-dimethylbut-1-ynyl)ben-
zaldehyde (imine hydrolysis occurred during purification)
was isolated in 95% yield after a 24 h cyclization time.
Thus, this isoquinoline synthesis appears to be limited
to the use of relatively unhindered acetylenes. Finally,
isoquinolines 26 and 27 and naphthyridines 29 and 30
have also been synthesized in good yields from imines
25 and 28, respectively (entries 8-11).
We therefore investigated the use of the coupling
conditions employed in Scheme 4 for both the coupling
and cyclization steps (eq 6), since triethylamine was
employed for the coupling reactions and afforded the best
yield of isoquinoline 5 (Table 4, entry 4). These reactions
were run with 0.5 mmol of the haloimine 1 and 0.6 mmol
of cyclohexyl acetylene with 2 mol % PdCl2(PPh3)2 and 1
mol % CuI in 2 mL of Et3N at 50 °C for 1 h to effect the
coupling, and then at 100 °C for 48 h to promote the
cyclization of the intermediate iminoalkyne 13. Although
only a trace of isoquinoline product was observed under
these reaction conditions, it was possible to recover 95%
of the intermediate coupled product, thus indicating that
an efficient coupling step had occurred. On the basis of
this result, an additional 10 mol % of CuI was added to
the reaction mixture after the coupling step had gone to
completion in hopes of promoting the cyclization step.
Unfortunately, this also was quite inefficient, although
a 22% yield of the product was observed. Finally, two
reactions were run in which an additional 10 mol % of
CuI and 3 mL of either Et3N or DMF were added after
the coupling was complete. Unfortunately, this also
afforded only trace amounts of the desired isoquinoline.
As in our isoquinoline synthesis from internal alkynes,
pyridines can be synthesized by employing vinylic imines.
Pyridines 32 and 33 have been synthesized from cyclic
imine 31. This pyridine synthesis provides best results
using aryl- and alkenyl-substituted acetylenes. The reac-
tion of imine 31 and N-(2-bromocyclohex-1-enylmethyl-
ene)-tert-butylamine with various alkyl-substituted acetyl-
enes afforded only low yields of the desired pyridines
(∼10%). Interestingly, the reaction of 1-hexyne and imine
34 did afford pyridine 35 in 46% yield. Finally, pyridine
37 has been synthesized from the acyclic imine 36 in 57%
yield.
To demonstrate the utility of this annulation method-
ology, we have applied this coupling/cyclization process
to the synthesis of the naturally occurring isoquinoline
alkaloid decumbenine B (38). Decumbenine B has re-
cently been isolated in small amounts from the plant
tubers of Corydalis decumbens, which have been used in
Chinese folk herbal medicine for the treatment of para-
lytic stroke and rheumatic arthritis.15 One total synthesis
of this alkaloid has recently appeared.16 However, the
reported synthesis was accomplished in a low overall
yield and in 18 steps. We felt that decumbenine B could
be efficiently synthesized by employing the palladium-
catalyzed coupling and cyclization methodology developed
here.
On the basis of these results, it appeared that the
coupling of imine 1 and cyclohexyl acetylene was pro-
ceeding in high yield to produce iminoalkyne 13. How-
ever, under the reaction conditions employed, 13 was not
efficiently cyclized to isoquinoline 5. Since the coupling
reaction proceeded in high yield in Et3N, which serves
as both the solvent and the base, and we have had
considerable success with the copper-catalyzed cyclization
in DMF, modified reaction conditions were developed to
incorporate both of these transformations into a single
reaction sequence (eq 7).
A retrosynthetic analysis for the synthesis of 38 is
shown in Scheme 5. It was envisioned that decumbenine
B could be synthesized by the palladium-catalyzed cou-
pling of imine 39 and alkyne 40 and subsequent cycliza-
We thus employed the following reaction conditions for
the isoquinoline synthesis: the imine (0.5 mmol), the
terminal acetylene (0.6 mmol), 2 mol % of PdCl2(PPh3)2,
(15) Zhang, J .; Zhu, D.; Hong, S. Phytochemistry 1995, 39, 435.
(16) Xu, X.; Qin, G.; Xu, R.; Zhu, X. Tetrahedron 1998, 54, 14179.

Total Synthesis of Decumbenine B
J . Org. Chem., Vol. 67, No. 1, 2002 91
Ta ble 5. Syn th esis of Isoqu in olin es a n d P yr id in es by th e P d -Ca ta lyzed Cou p lin g a n d Cu -Ca ta lyzed Cycliza tion of
Ter m in a l Acetylen es (eq 7)a
a
All reactions were run using 2 mol % of PdCl2(PPh3)2 and 1 mol % of CuI in 2 mL of Et3N to effect the coupling step, and 10 mol %
of CuI in 5 mL of DMF to effect cyclization to the nitrogen heterocycle.

92 J . Org. Chem., Vol. 67, No. 1, 2002
Roesch and Larock
Sch em e 5
Sch em e 7
Sch em e 6
effectiveness of this methodology and its ability to toler-
ate functionality.
tion of the intermediate iminoalkyne. The starting ma-
terials required for the synthesis of decumbenine B were
easily prepared in a minimal number of synthetic trans-
formations from the commercially available aldehydes
piperonal and 2,3-(methylenedioxy)benzaldehyde.
The synthesis of imine 39 was accomplished in two
steps as shown in Scheme 6. The tert-butyl imine of
piperonal was synthesized in high yield and was sub-
jected to reaction conditions previously reported for the
metalation of cyclohexylimines derived from piperonal.17
Treatment of the imine with n-BuLi and subsequent
quenching with iodine afforded the desired iodoimine in
70% yield. It is interesting to note that the tert-butyl
imine served as an excellent directing group for the
lithiation reaction, with no addition products of n-BuLi
to the imine being observed. In addition, employing the
tert-butyl imine, rather than the cyclohexylimine as was
reported, allowed several steps involving imine formation
and hydrolysis to be avoided.
Con clu sion
Efficient palladium- and copper-catalyzed syntheses of
isoquinolines and pyridines have been developed. Only
aryl- and alkenyl-substituted alkynes cyclize when em-
ploying the palladium-catalyzed reaction conditions that
have been developed. However, a wide variety of func-
tionalized terminal acetylenes participate in a palladium-
catalyzed coupling and copper-catalyzed cyclization pro-
cess to afford the desired nitrogen heterocycles in moderate
to excellent yields. The effectiveness of the palladium-
catalyzed terminal acetylene annulation methodology has
been demonstrated by the total synthesis of the isoquino-
line alkaloid decumbenine B in seven steps and 20%
overall yield.
The synthesis of alkyne 40 was accomplished in four
steps by the synthetic route shown in Scheme 7. Reduc-
tion of 3,4-(methylenedioxy)benzaldehyde to the benzyl
alcohol and subsequent iodination afforded the interme-
diate iodide in 57% overall yield. Alkyne 40 was then
synthesized in 98% overall yield by a palladium-catalyzed
coupling of the aryl iodide with trimethylsilylacetylene
and subsequent desilylation with potassium carbonate.
With imine 39 and alkyne 40 in hand, we completed
the synthesis of decumbenine B in 52% yield by employ-
ing our palladium-catalyzed methodology (eq 8). Despite
the low yield for the key palladium-catalyzed reaction,
this synthesis of decumbenine B was completed in seven
steps and 20% overall yield, which demonstrates the
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded at 300
and 75.5 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 (Finnigan 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 com-
mercially unless otherwise noted. Anhydrous forms of Na2CO3,
(17) Ziegler, F. E.; Fowler, K. W. J . Org. Chem. 1976, 41, 1564.

Total Synthesis of Decumbenine B
J . Org. Chem., Vol. 67, No. 1, 2002 93
DMF, methanol, 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 Chemi-
cals Co., Ltd. PPh3 was donated by Kawaken Fine Chemicals
Co., Ltd. Compounds 4, 5, 22, 26, 30, and 33 have been
previously reported.14 2-Iodobenzaldehyde,5 2-bromopiper-
onal,18 2-bromocyclopentene-1-carboxaldehyde,19 1-bromo-3,4-
dihydronaphthalene-2-carboxaldehyde,20 (Z)-3-iodo-3-phenyl-
2-propenal,21 and 2-bromo-3-formylpyridine22 were prepared
according to previous literature procedures. The following
starting materials were prepared as indicated.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-(1-Alk y-
n yl)ben za ld eh yd es: 2-(2-P h en yleth yn yl)ben za ld eh yd e.
To a solution of 2-bromobenzaldehyde (1.85 g, 10.0 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 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 filtra-
tion. 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 the
compound as a yellow oil: 1H NMR (CDCl3) δ 7.35-7.44 (m,
4H), 7.52-7.64 (m, 4H), 7.94 (dd, J ) 0.3, 7.8 Hz, 1H), 10.65
(s, 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. Aldehydes
6-11 have been prepared using the same procedure. Details
and spectral identification are reported in Supporting Infor-
mation.
Gen er al P r epar ation of Im in es: N-(2-Iodoben zyliden 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 stirred
under a nitrogen atmosphere at room temperature for 12 h.
The excess tert-butylamine was removed under reduced pres-
sure, and the resulting mixture was extracted with ether. The
combined organic layers were 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. Imines 3, 12-17, 25,
28, 31, 34, and 36 have been prepared using the same
procedure. Details are provided in Supporting Information.
Gen er a l P r oced u r e for th e Cop p er -Ca ta lyzed Cycliza -
tion of Im in oa lk yn es: 3-P h en ylisoqu in olin e (2). DMF (5
mL), the imine (0.25 mmol), and CuI (5 mg, 0.025 mmol) were
placed in a 2 dram vial. 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 comple-
tion. The reaction mixture was cooled, diluted with 25 mL of
ether, washed with 30 mL of saturated NH4Cl, dried (Na2SO4),
and filtered. The solvent was evaporated under reduced
pressure, and the reaction mixture was chromatographed
using 15:1 hexanes/EtOAc to afford 51 mg (100%) of the
indicated compound with spectral properties identical to those
previously reported:23 mp 102-103 °C (lit.23 101-102 °C).
Isoquinolines 16-18 were prepared in an identical manner.
Experimental details and spectral characterization are pro-
vided in Supporting Information.
Gen er a l P r oced u r e for th e P a lla d iu m /Cop p er -Ca ta -
lyzed F or m a tion of Isoqu in olin es a n d P yr id in es fr om
Ter m in a l Acetylen es: 3-P h en ylisoqu in olin e (2). Et3N (2
mL), PdCl2(PPh3)2 (7 mg, 0.01 mmol), the imine (0.5 mmol),
the terminal acetylene (0.6 mmol), and CuI (1 mg, 0.005 mmol)
were placed in a 2 dram vial. The vial was flushed with
nitrogen and heated in an oil bath at 55 °C for the indicated
period of time. The reaction was monitored by TLC to establish
completion. For the reactions with imine 7, the reaction
mixture was cooled, the precipitates were filtered off and
washed with ether, and the solvent was removed under
reduced pressure. For the reactions with imines 32, 35, 37,
and 39, the reaction mixture was cooled, the solvent was
removed under reduced pressure, the precipitates were filtered
off and washed with ether, and the solvent was removed under
reduced pressure. The residue obtained was transferred to a
2 dram vial, and DMF (5 mL) and CuI (10 mg, 0.05 mmol)
were added. The vial was flushed with nitrogen and heated
in an oil bath at 100 °C for the indicated period of time. The
reaction mixture was cooled, diluted with 25 mL of ether,
washed with 30 mL of saturated aqueous NH4Cl, dried (Na2-
SO4), and filtered. The solvent was evaporated under reduced
pressure, and the reaction mixture was chromatographed
using 15:1 hexanes/EtOAc to afford 94 mg (91%) of the
indicated compound 2, whose spectral data were identical with
that reported above.
Tota l Syn th esis of Decu m ben in e B. N-(Ben zo[1,3]-
d ioxol-5-ylm eth ylen e)-ter t-bu tyla m in e. To a mixture of
piperonal (2.00 g, 13.3 mmol) and H2O (2 mL) was added tert-
butylamine (26.6 mmol, 2 equiv). The mixture was then stirred
under a nitrogen atmosphere at room temperature for 12 h.
The excess tert-butylamine was removed under reduced pres-
sure, and the resulting mixture was extracted with ether. The
combined organic layers were dried (Na2SO4) and filtered.
Removal of the solvent afforded 2.65 g (97%) of the imine as a
white solid: mp 44-45 °C; 1H NMR (CDCl3) δ 1.27 (s, 9H),
5.97 (s, 2H), 6.81 (d, J ) 8.4 Hz, 1H), 7.10 (dd, J ) 1.5, 8.1
Hz, 1H), 7.38 (d, J ) 1.5 Hz, 1H), 8.15 (s, 1H); 13C NMR
(CDCl3) δ 29.9, 57.0, 101.4, 106.6, 108.0, 123.9, 132.2, 148.3,
149.5, 154.3; IR (CHCl3, cm-1) 3060, 2214, 1637; HRMS calcd
for C12H15NO2 205.1100, found 205.1103.
N-(4-Iod ob en zo[1,3]d ioxol-5-ylm et h ylen e)-ter t-b u t yl-
a m in e (39). N-(4-Iodo-benzo[1,3]dioxol-5-ylmethylene)-tert-
butylamine was prepared according to a modified literature
procedure.17 To a solution of N-(benzo[1,3]dioxol-5-ylmethyl-
ene)-tert-butylamine (1.03 g, 5.00 mmol) in 40 mL of THF at
-78 °C was added 5.25 mmol of n-BuLi (2.5 M in hexanes)
dropwise over a five minute period. The solution was stirred
for 30 min at -78 °C, and a solution of I2 (2.68 g, 7.5 mmol) in
15 mL of THF was added dropwise. The resulting solution was
warmed to room temperature and stirred for 2 h. The reaction
was quenched with water, and the mixture was extracted with
ether, washed with saturated aqueous Na2S2O3, dried (MgSO4),
and filtered; the solvent was removed under reduced pressure.
Recrystallization from hexanes/EtOAc afforded 0.77 g (70%)
of the desired compound as an off-white solid: mp 126-127
1
°C; H NMR (CDCl3) δ 1.29 (s, 9H), 6.05 (s, 2H), 6.61 (d, J )
8.1 Hz, 1H), 7.53 (d, J ) 8.1 Hz, 1H), 8.32 (s, 1H); 13C NMR
(CDCl3) δ 29.9, 57.8, 77.1, 100.9, 108.6, 122.7, 131.2, 147.6,
149.4, 157.4; IR (CHCl3, cm-1) 3062, 2965, 1596; HRMS calcd
for C12H14INO2 331.0069, found 331.0064.
(5-Iod oben zo[1,3]d ioxol-4-yl)m eth a n ol. To a solution of
2,3-(methylenedioxy)benzaldehyde (1.50 g, 10.0 mmol) in 5 mL
CH2Cl2 was added NaBH4 (0.47 g, 12.5 mmol) in MeOH (5 mL).
The reaction mixture was stirred for 2 h at room temperature,
and the reaction was quenched with water. The mixture was
then extracted with CH2Cl2, dried (Na2SO4), and filtered, and
the solvent was removed under reduced pressure to afford 1.52
g of the desired alcohol as a colorless oil: 1H NMR (CDCl3) δ
2.36 (br s, 1H), 4.64 (s, 2H), 5.93 (s, 2H), 6.73-6.85 (m, 3H);
13C NMR (CDCl3) δ 60.0, 101.1, 108.2, 121.2, 121.8, 122.4,
145.1, 147.4. To a mixture of this alcohol and AgO2CCF3 (2.21
g, 10.0 mmol) in 15 mL of CHCl3 was added a solution of iodine
(2.54 g, 10.0 mmol) in 80 mL of CHCl3. The reaction mixture
was stirred for 24 h and then filtered. The filtrate was washed
(18) Conrad, P. C.; Kwiatkowski, P. L.; Fuchs, P. L. J . Org. Chem.
1987, 52, 586.
(19) Gilchrist, T. L.; Kemmitt, P. D. Tetrahedron 1995, 51, 9119.
(20) Gilchrist, T. L.; Summersell, R. J . J . Chem. Soc., Perkin Trans.
1 1988, 2595.
(21) Han, X. Ph.D. Dissertation, Iowa State University, Ames, IA,
1998.
(22) Melnyk, P.; Gasche, J .; Thal, C. Synth. Commun. 1993, 23,
2727.
(23) Sard, H. J . Heterocycl. Chem. 1994, 31, 1085.

94 J . Org. Chem., Vol. 67, No. 1, 2002
Roesch and Larock
with saturated aqueous NaHCO3, brine, dried (MgSO4), and
filtered. Removal of the solvent afforded a yellow oil, which
was dissolved in ether. Addition of hexanes precipitated 1.58
g (57%) of the desired alcohol as a yellow solid: mp 96-97 °C;
1H NMR (CDCl3) δ 2.20 (br s, 1H), 4.69 (s, 2H), 5.99 (s, 2H),
6.53 (d, J ) 8.1 Hz, 1H), 7.28 (d, J ) 8.1 Hz, 1H); 13C NMR
(CDCl3) δ 63.4, 88.3, 101.8, 110.2, 124.3, 132.1, 146.6, 148.2;
IR (CHCl3, cm-1) 3358, 2891, 1460; HRMS calcd for C8H7IO3
277.9444, found 277.9442.
(5-Eth yn ylben zo[1,3]d ioxol-4-yl)m eth a n ol (40). To a
solution of (5-iodobenzo[1,3]dioxol-4-yl)methanol (0.56 g, 2.0
mmol) and (trimethylsilyl)acetylene (0.24 g, 2.4 mmol) in Et2-
NH (10 mL) was added PdCl2(PPh3)2 (28 mg, 2 mol %). The
mixture was stirred for 5 min, and CuI (4 mg, 1 mol %) was
dioxol-5-ylmethylene)-tert-butylamine (0.083 g, 0.25 mmol)
were placed in a 2 dram vial. The contents were then stirred
for 1 min, and (5-ethynylbenzo[1,3]dioxol-4-yl)methanol (42
mg, 0.28 mmol) was added. The vial was flushed with nitrogen
and heated in an oil bath at 100 °C for 48 h. The reaction was
monitored by TLC to establish completion. The reaction
mixture was cooled, diluted with 25 mL of ether, washed with
30 mL of saturated aqueous NH4Cl, dried (Na2SO4), and
filtered. The solvent was evaporated under reduced pressure,
and the product was isolated by chromatography on a silica
gel column using 1:1 hexanes/EtOAc to afford 42 mg (52%) of
the indicated compound with spectral properties identical to
those previously reported:15,16 mp 221-222 °C (lit.15,16 222-
224 °C).
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 crude silyl
acetylene was dissolved in 30 mL of MeOH, and K2CO3 (0.55
g, 4 mmol) was added. The mixture was then stirred for 1 h
at room temperature. The mixture was washed with saturated
aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4), and
filtered. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica
gel using 2:1 hexanes/EtOAc to afford 0.30 g (98%) of the
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 the donation of the
palladium salts; and Merck and Co., Inc., for an
Academic Development Award in Chemistry.
1
desired compound as a brown solid: mp 64-65 °C; H NMR
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of aldehydes 6-11; imines 3, 12-17,
25, 28, 31, 34, and 36; isoquinolines 4, 5, 18, 22-24, 26, 27,
29, 30, 32, 33, and 35; and pyridine 37; and spectral charac-
terization. This material is available free of charge via the
Internet at http://pubs.acs.org.
(CDCl3) δ 2.50 (br t, J ) 5.7 Hz, 1H), 3.20 (s, 1H), 4.77 (d, J )
5.4 Hz, 2H), 5.98 (s, 2H), 6.68 (d, J ) 8.1 Hz, 1H), 7.03 (d, J
) 8.1 Hz, 1H); 13C NMR (CDCl3) δ 58.1, 79.9, 81.4, 101.7, 108.0,
114.7, 124.1, 127.6, 146.0, 148.3; IR (CHCl3, cm-1) 3401, 3286,
2099, 1466; HRMS calcd for C10H8O3 176.0474, found 176.0474.
Decu m ben in e B (38). DMF (5 mL), Pd(OAc)2 (3 mg, 0.013
mmol), Na2CO3 (26 mg, 0.25 mmol), and N-(4-iodobenzo[1,3]-
J O010579Z