Palladium-catalyzed tandem Heck and aldol reactions between 2-bromobenzaldehydes and functionalized alkenes leading to naphthalenes

Article abstract of DOI:10.1016/j.tetlet.2004.05.112

2-Bromobenzaldehydes react with an array of suitably functionalized alkenes in the presence of a catalytic amount of a palladium catalyst together with a base to afford the corresponding naphthalenes in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2004.05.112

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5653–5656
Palladium-catalyzed tandem Heck and aldol reactions between
2
-bromobenzaldehydes and functionalized alkenes leading
to naphthalenes
a,
b
b
Chan Sik Cho, Dong Kwon Lim, Jiao Qiang Zhang, Tae-Jeong Kim and
b
*
b,
*
Sang Chul Shim
a
Research Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, South Korea
Department of Applied Chemistry, College of Engineering, Kyungpook National University, Daegu 702-701, South Korea
b
Received 29 March 2004; revised 10 May 2004; accepted 21 May 2004
Available online 15 June 2004
Abstract—2-Bromobenzaldehydes react with an array of suitably functionalized alkenes in the presence of a catalytic amount of a
palladium catalyst together with a base to afford the corresponding naphthalenes in moderate to good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
It is well known that many carbo- and heterocycles play
an important role as a basic skeleton for the design of
many pharmacologically active compounds. Along with
conventional routes, palladium-catalyzed reactions for
such cyclic compounds have also been attempted as
alternative methods because of the facility and efficiency
The results of several attempted coupling and cycliza-
tions between 2-bromobenzaldehyde (1a) and dimethyl
1
2
itaconate (2a, 2: E ¼ E ¼ CO
2
Me) are listed in Table 1
(Scheme 1). When 1a was generally treated with 2a at
100 °C for 24 h in the presence of a catalytic amount of a
palladium catalyst (5 mol %) and a base (3 equiv), the
coupling and cyclized product dimethyl 2,3-naphtha-
1
of reaction and the wide availability of substrate.
During the course of our ongoing studies on palladium-
catalyzed cyclization reactions for N- and O-hetero-
1
2
1
2
lenedicarboxylate (3a, 3: R ¼ R ¼ H; E ¼ E ¼
CO Me) was produced without other identifiable prod-
2
2
;3
cycles, we have introduced 2-bromobenzaldehydes as
3
ucts. From the activity of several palladium precursors
examined under employment of NaOAc as base and
THF as solvent Pd(OAc) /2PPh is revealed to be the
2 3
a useful annulation counterpart for isobenzofuranones
4
and 1-aryl-1H-indazoles. It was also reported by other
groups that 2-halobenzaldehydes are cyclized with al-
catalyst of choice (entries 1–5). Inorganic bases such as
K CO and NaOH were not effective, but Et N was
5;6
7
kynes,
allyl or homoallyl alcohols and carbonyl
2
3
3
8
compounds in the presence of a palladium catalyst to
produce indenones (or indenols), indenes (or dihydro-
naphthalenes) and naphthols (or naphthalenes), respec-
tively. Under these circumstances, herein we report on
palladium-catalyzed synthesis of naphthalenes from
moderately effective for the formation of 3a under
Pd(OAc) /2PPh /THF (entries 6–8). The kind of solvent
2
3
was also critical for the effective formation of 3a (entries
9–11). From solvents examined acetonitrile could be
alternatively used, but the yield of 3a was slightly lower
than that when THF was used (entry 11). As a result, the
best result in terms of both yield and complete conver-
sion of 1a is accomplished by the standard set of reac-
tion conditions shown in entry 1 of Table 1.
2-bromobenzaldehydes and suitably functionalized al-
kenes via consecutive Heck and aldol reactions.
Having established reaction conditions, various func-
tionalized alkenes 2 were subjected to react with 1 in
order to investigate the reaction scope and several rep-
resentative results are summarized in Table 2. The
reaction of 1b and 1c with 2a gave the corresponding 3b
and 3c in 50% and 61% yields, respectively. With dialkyl
Keywords: 2-Bromobenzaldehydes; Functionalized alkenes; Heck–
aldol reaction; Naphthalenes; Palladium catalyst.
*
Corresponding authors. Fax: +82-53-950-6594 (C.S.C.); tel.: +82-53-
50-5586; fax: +82-53-959-5586/950-6594 (S.C.S.); e-mail addresses:
cscho@knu.ac.kr; scshim@knu.ac.kr; scshim@kyungpook.ac.kr
9
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.112

5654
C. S. Cho et al. / Tetrahedron Letters 45 (2004) 5653–5656
a
Table 1. Palladium-catalyzed coupling and cyclization between 1a and 2a under various conditions
Entry
Palladium catalysts
Bases
Solvents
GLC yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
PdCl /2PPh
Pd(dba)
Pd(PPh
PdCl (PPh
2
/2PPh
3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
THF
THF
THF
83
37
38
30
75
16
Trace
52
5
2
3
2
/2PPh
3
3
)
4
THF
2
3
)
2
THF
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
/2PPh
/2PPh
/2PPh
/2PPh
/2PPh
/2PPh
3
3
3
3
3
3
K
2
CO
NaOH
Et
3
THF
THF
THF
3
N
NaOAc
NaOAc
NaOAc
Toluene
Dioxane
MeCN
1
1
0
1
46
74
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), palladium catalyst (0.05 mmol), base (3 mmol), solvent (5 mL), 100 °C, for 24 h, under argon.
R1
R2
CHO
Br
R1
R2
E2
E1
E1
cat. [Pd]
+
E2
1
2
1
1
1
a R = R = H
2
3
1
2
b R = R = OMe
1
2
c R = F; R = H
Scheme 1.
9
itaconate (2a–c ), alkyl 3-butenoates, which have car-
boalkoxy substituents at position 3, the coupling and
cyclized products (3a, 3d and 3e) were formed in the
range of 71–74% yields with complete disappearance of
high yields. Lower reaction rate and yield were observed
with ethyl 3-butenoate 2h, which has aryl group at
12
13
position 3. In the case of allyl phenyl sulfone (2i ), the
reaction did not effectively proceed toward cyclization
under the usual reaction conditions, 3k being produced
in only 11% yield along with a considerable amount of
isomerized Heck product 5 (40%). Here again, as is the
case for the reaction with 2d, performing the reaction
1
a on TLC. In the case of propyl 3-butenoate (2d), the
corresponding naphthalene 3f was formed in only 7%
yield, whereas isomerized Heck product 4 was rather
produced as a major identifiable product (48%). Inter-
estingly, when the reaction was performed under Et
in place of NaOAc, 3f was formed as major product
53%) along with a small amount of 4 (5%). From the
3
N
3
under Et N in place of NaOAc resulted in an increased
yield of naphthalene 3k. On the other hand, the coupling
and cyclization did not take place at all between 1a and
(
14
reaction between 1a and 3-butenoic acid (2e), the cyc-
lized product 3g was also produced in an allowable yield
ethyl 3-butenoate 2j, which has acetylenic group at
position 3.
10
(
butenoates (2f and 2g ) having acyl group at position
35%). The reaction proceeds likewise with ethyl 3-
11
11
As to the reaction pathway, arylpalladium, initially
formed by oxidative addition of a carbon–bromide bond
3
to give the corresponding naphthalenes (3h and 3i) in
a
Table 2. Palladium-catalyzed synthesis of naphthalenes
1
Alkenes 2
Bases
Products and isolated yield (%)
CO Me
CO Me
2
2
1a
CO2Me
NaOAc
74
CO Me
2
a
2
3
a
MeO
CO Me
2
1
1
1
b
c
a
2a
2a
NaOAc
NaOAc
NaOAc
50
61
70
MeO
F
CO Me
2
3
b
CO Me
2
CO Me
2
3
c
CO Et
CO Et
2
2
CO Et
2
CO Et
2
b
2
3
d

C. S. Cho et al. / Tetrahedron Letters 45 (2004) 5653–5656
5655
Table 2 (continued)
1
Alkenes 2
Bases
Products and isolated yield (%)
CO Me
CO Et
2
2
1a
CO Me
NaOAc
71
2
CO Et
2
c
2
3
e
CHO
H
CO2Pr
1a
CO Pr
NaOAc
N
7
53
48
5
2
CO Pr
2
Et
3
2
d
3
f
4
H
CO2H
b
1
a
a
CO H
NaOAc
NaOAc
25(35 )
2
2
e
3g
CO Me
COMe
CO Me
2
2
1
84
2
COMe
f
3
h
CO Et
COPh
2
1
1
1
a
a
a
CO Et
NaOAc
NaOAc
NaOAc
84
17
2
COPh
CO2Et
2
g
3
i
p-Tol
CO2Et
SO2Ph
p-Tol
2
h
3
j
CHO
H
SO2Ph
11
28
40
13
SO Ph
2
3
Et N
2
i
3k
5
Ph
CO Et
2
1a
NaOAc
0
CO Et
2
Ph
3l
2
j
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), Pd(OAc)
For 48 h.
2
(0.05 mmol), PPh
3
(0.1 mmol), base (3 mmol), THF (5 mL), 100 °C, for 24 h, under argon.
b
of 1a to palladium(0), adds to 2 to produce alkylpalla-
dium 6, which in turn triggers b-hydrogen elimination to
form an Heck product 7 or isomerized Heck product 8
as shown in 4 and 5 (Scheme 2). The direction of b-
hydrogen elimination toward 7 rather than 8 on 6 seems
to be due to resonance stabilization from aromatic ring
to substituent E . Intermediate 7 is followed by base-
catalyzed intramolecular aldol reaction to afford naph-
thalene 3.
Pd(OAc)2 (0.05 mmol), PPh3 (0.1 mmol) and NaOAc
(3 mmol) in dry THF (5 mL) was placed in a 50 mL
pressure vessel. After the system was flushed with argon,
the mixture was stirred at 100 °C for 24 h. The reaction
mixture was passed through a short silica gel column
(ethyl acetate–chloroform) to eliminate inorganic salts.
Removal of the solvent left a crude mixture, which was
separated by thin layer chromatography (silica gel, ethyl
acetate–hexane mixture) to give naphthalenes 3.
1
General experimental procedure: a mixture of 2-
bromobenzaldehyde (1 mmol), alkene (1 mmol),
In summary, we have demonstrated that 2-bromo-
benzaldehydes are coupled and cyclized with an array of
functionalized alkenes in the presence of a catalytic
amount of a palladium catalyst to give naphthalenes in
moderate to good yields. The present reaction is a
straightforward synthetic approach for naphthalenes via
tandem Heck and aldol reactions between 2-bromo-
benzaldehydes and functionalized alkenes.
CHO E2
PdBr
CHO E2
[
Pd]
1
a 2
+
-
HPdBr
base
1
E1
E
6
8
-
HPdBr
CHO E2
3
Acknowledgements
E1
7
This work was supported by the Brain Korea 21 Project
in 2003 and a Korea Research Foundation Grant
Scheme 2.

5656
C. S. Cho et al. / Tetrahedron Letters 45 (2004) 5653–5656
(
KRF-2002-070-C00055). C.S.C. gratefully acknowl-
edges a MOE-KRF Research Professor Program (KRF-
001-050-D00015).
4. Cho, C. S.; Lim, D. K.; Heo, N. H.; Kim, T.-J.; Shim,
S. C. Chem. Commun. 2004, 104.
5
6
7
. Larock, R. C.; Doty, M. J. J. Org. Chem. 1993, 58,
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Lett. 1999, 40, 4089.
. Dyker, G.; Grundt, P. Tetrahedron Lett. 1996, 37, 619.
2
4
References and notes
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and Catalysts; Wiley: Chichester, 1995; (b) Negishi, E.;
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10. Workup procedure is different from the usual procedure
noted. After the reaction mixture was poured into 5% aq
HCl solution, extracted with chloroform and dried over
2
1
96, 365; (c) Grigg, R.; Sridharan, V. Pure Appl. Chem.
1998, 70, 1047; (d) Larock, R. C. J. Organomet. Chem.
1999, 576, 111.
MgSO , the resulting crude mixture was subjected to the
4
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11. Ben Ayed, T.; Amri, H. Synth. Commun. 1995, 25,
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2
3
. For palladium-catalyzed synthesis of N-heterocycles: (a)
Cho, C. S.; Lee, J. W.; Lee, D. Y.; Shim, S. C.; Kim, T. J.
Chem. Commun. 1996, 2115; (b) Cho, C. S.; Shim, H. S.;
Choi, H.-J.; Kim, T.-J.; Shim, S. C.; Kim, M. C.
Tetrahedron Lett. 2000, 41, 3891, and other reports cited
therein.
. For palladium-catalyzed synthesis of O-heterocycles: Cho,
C. S.; Lim, D. K.; Kim, T.-J.; Shim, S. C. J. Chem. Res.
(S) 2002, 550, and other reports cited therein.