Synthesis of substituted naphthalenes and carbazoles by the palladium-catalyzed annulation of internal alkynes

Article abstract of DOI:10.1021/jo034449x

An efficient synthesis of highly substituted naphthalenes has been developed by the palladium-catalyzed annulation of a variety of internal alkynes, in which two new carbon-carbon bonds are formed in a single step under relatively mild reaction conditions

Full text of DOI:10.1021/jo034449x

Syn th esis of Su bstitu ted Na p h th a len es a n d Ca r ba zoles 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
Qinhua Huang and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received April 9, 2003
An efficient synthesis of highly substituted naphthalenes has been developed by the palladium-
catalyzed annulation of a variety of internal alkynes, in which two new carbon-carbon bonds are
formed in a single step under relatively mild reaction conditions. This method has also been used
to synthesize carbazoles, although a higher reaction temperature is necessary. The process involves
arylpalladation of the alkyne, followed by intramolecular Heck olefination and double-bond
isomerization. This method accommodates a variety of functional groups and affords the anticipated
highly substituted naphthalenes and carbazoles in good to excellent yields.
In tr od u ction
demonstrated that palladium-catalyzed annulation8 can
be effectively employed for the synthesis of indoles,9
isoindolo[2,1-a]indoles,10 benzofurans,11 benzopyrans,12
isocoumarins,11,12 R-pyrones,12,13 indenones,14 isoquino-
lines,15 carbolines,16 and polycyclic aromatic hydrocar-
bons17 (eq 1). More recently, Takahashi et al. have
reported that pentasubstituted fulvene derivatives can
be prepared using the palladium-catalyzed annulation of
disubstituted alkynes (eq 2).18
Highly substituted naphthalenes are common struc-
tural units in numerous biologically significant natural
products and pharmaceuticals,1 and improved methods
for their construction are highly desirable.2-6 Among the
most important synthetic routes to such compounds are
annulation via Fischer carbenes (the Do¨tz reaction)3 and
the palladium-catalyzed cyclization of alkynes by arylsilyl
triflates via in situ generation of highly reactive ben-
zynes.4 Another method of synthesis is based on the
cyclopropane-shift reaction of diaryl(2-halogenocyclopro-
pyl)methanols.5 Very recently, substituted naphthalenes
have been prepared using the gallium-catalyzed cycliza-
tion of carbonyl compounds or epoxides with alkynes.6
Annulation processes have proven quite valuable in
organic synthesis because of the ease with which a
variety of complicated hetero- and carbocycles can be
rapidly constructed.7 In our own laboratories, it has been
Due to our continuing interest in the palladium-
catalyzed annulation of internal alkynes, we have inves-
* Corresponding author.
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J .; Fesen, M. R.; Mazumder, A.; Pommier, Y. J . Med. Chem. 1996, 39,
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Med. Chem. 1993, 36, 3015. (e) Zhao, H.; Neamati, N.; Mazumder, A.;
Sunder, S.; Pommier, Y.; Burke, T. R., J r. J . Med. Chem. 1997, 40,
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Castedo, L. J . Am. Chem. Soc. 1999, 121, 5827. (c) Radhakrishnan, K.
V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 7533.
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oudaki, M.; Li, Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635.
(8) 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)
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7652.
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Roesch, K. R.; Larock, R. C. J . Org. Chem. 2001, 66, 412.
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Chem. 1995, 60, 3270.
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10.1021/jo034449x CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/23/2003
7342
J . Org. Chem. 2003, 68, 7342-7349

Palladium-Catalyzed Annulation of Internal Alkynes
SCHEME 1
respectively (entries 2 and 3). However, the use of Pd-
(PPh3)4 as a catalyst and Na2CO3 as a base gave only a
trace of the desired product (entry 4). Our previous work
has shown that carbonate bases usually work better for
palladium-catalyzed annulation chemistry than organic
bases.9-17 However, it turned out that organic bases work
better than carbonate salts in this annulation chemistry.
For example, when the organic bases n-Bu3N and Et3N
were employed, the reaction of halide 1 gave 71% and
76% yields of naphthalene 2, respectively, in the presence
of 10 mol % of Pd(OAc)2 (entries 5 and 6). This is probably
because the ester group can be hydrolyzed in the presence
of the carbonate bases and the resulting yield of naph-
thalene suffers. The use of pyridine afforded only a trace
of the desired product (entry 7). Further optimization
work showed that 5 mol % of Pd(OAc)2 and 2 equiv of
diphenylacetylene are necessary to achieve decent yields
of naphthalene 2 (entries 8-10). In entry 11, the addition
of 1 equiv of n-Bu4NCl gave an 80% yield, which is the
same yield as the reaction without n-Bu4NCl (entry 8).
We have also explored the effects on the yield of other
variables, such as the ligand and the amount of the base
(entries 12-15). The optimal reaction conditions thus far
developed employ 0.25 mmol of aryl halide 1, 2 equiv of
diphenylacetylene, 5 mol % of Pd(OAc)2, 10 mol % of
PPh3, and 2 equiv of Et3N as a base in 3 mL of DMF
stirred at 80 °C. This afforded an 86% yield of naphtha-
lene 2 (entry 14).
Using our optimal reaction conditions, the scope of the
annulation process has been explored using a variety of
substrates carefully selected in order to establish the
generality of the process and its applicability to com-
monly encountered synthetic problems (Table 2). While
the reaction of aryl halide 1 and diphenylacetylene
afforded naphthalene 2 in 86% yield (entry 1), only a 61%
yield of naphthalene 3 was obtained from the reaction of
aryl halide 1 and di(p-methoxyphenyl)acetylene (entry
2). The decrease in the yield of the reaction indicates that
electron-rich diarylacetylenes disfavor the annulation
chemistry. However, when an electron-deficient diaryl-
acetylene, such as di(p-ethoxycarbonylphenyl)acetylene,
was allowed to react with aryl halide 1, an 83% yield of
naphthalene 4 was obtained (entry 3), comparable to the
yield obtained from the reaction of aryl halide 1 and
diphenylacetylene (entry 1). When 4-octyne, a dialkyl-
acetylene, was allowed to react with aryl halide 1, a 60%
yield of naphthalene 5 was obtained (entry 4).
TABLE 1. Op tim iza tion of th e Syn th esis of
Na p h th a len e 2 (eq 3)a
alkyne
entry (equiv)
time
%
catalyst
ligand
base
(h) yield
1
2
2
2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(PPh3)4
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
5% Pd(OAc)2
3 NaOAc
3 Na2CO3
3 NaHCO3
3 Na2CO3
3 Bu3N
3 Et3N
3 pyridine
3 Et3N
3 Et3N
3 Et3N
3 Et3N
1.5 Et3N
2 Et3N
12 58
12 40
8
3
2
49
4
2
24 trace
10 71
12 76
24 trace
10 80
12 58
12 81
12 80b
12 70
12 79
12 86
12 78
5
2
6
2
7
2
8
2
9
1.2
5
2
2
2
10
11
12
13
14
15
2
2
10% PPh3 2 Et3N
10% PPh3 1.5 Et3N
a
All reactions were run under the following reaction conditions,
unless otherwise specified: 0.25 mmol of aryl halide 1 and the
indicated amount of diphenylacetylene were stirred in 3 mL of
DMF at 80 °C in the presence of the specified amount of the
indicated base, Pd(OAc)2, and PPh3. One equivalent of n-Bu4NCl
was added.
b
tigated the reaction of internal alkynes and o-(2-alkenyl)-
aryl halides derived from aldehydes and ylides and have
communicated that excellent yields of highly substituted
naphthalenes can be synthesized by employing this
method.19 Herein, we wish to report the full details of
this new naphthalene synthesis and its extension to the
formation of substituted carbazoles (Scheme 1).
Resu lts a n d Discu ssion
To test the regioselectivity of this annulation process,
1-phenylpropyne was allowed to react with aryl halide 1
and a 53:47 mixture of two regioisomers 6 and 7 was
obtained in a 75% overall yield (entry 5). According to
our previous work,9-17 the bulkiness of the substituents
on the acetylene plays a major role in determining the
regioselectivity of alkyne insertion. The aryl moiety of
the arylpalladium intermediate adds preferentially to the
less hindered end of the carbon-carbon triple bond. In
this naphthalene synthesis, the regioselectivity appears
to be significantly lower than we have normally observed
in the annulation of unsymmetrical alkynes. Similarly,
the reaction of aryl halide 1 and ethyl phenylpropiolate
afforded a 76:24 mixture of two regioisomers 8 and 9
(entry 6). In this case, the major product 8 results from
aryl addition to the 3-position of the phenylpropiolate.
Electronic effects appear to play a major role here. As in
Our initial studies focused on achieving optimal reac-
tion conditions for the palladium-catalyzed annulation
employing ethyl (E)-4-(2-iodophenyl)-2-butenoate (1). The
reaction of aryl halide 1 and diphenylacetylene was
chosen as the model system for optimization of this
process (eq 3), and the results are summarized in Table
1.
Using 10 mol % of Pd(OAc)2 and 3 equiv of NaOAc
afforded the desired naphthalene product 2 in a 58% yield
(entry 1, Table 1). Carbonate bases, such as Na2CO3 and
NaHCO3, gave naphthalene 2 in 40% and 49% yields,
(17) (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.
(18) Kotora, M.; Matsumura, H.; Gao, G.; Takahashi, T. Org. Lett.
2001, 3, 3467.
(19) Huang, Q.; Larock, R. C. Org. Lett. 2002, 4, 2505.
J . Org. Chem, Vol. 68, No. 19, 2003 7343

Huang and Larock
TABLE 2. Syn th esis of Su bstitu ted Na p h th a len es a n d Ca r ba zoles 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 esa
7344 J . Org. Chem., Vol. 68, No. 19, 2003

Palladium-Catalyzed Annulation of Internal Alkynes
Ta ble 2 (Con tin u ed )
J . Org. Chem, Vol. 68, No. 19, 2003 7345

Huang and Larock
Ta ble 2 (Con tin u ed )
a
All reactions were run under the following conditions, unless otherwise specified: 0.25 mmol of the aryl halide, 0.5 mmol of the
alkyne, 0.5 mmol of Et3N, 5 mol % of Pd(OAc)2 and 10 mol % of PPh3 were stirred in 3 mL of DMF at 80 °C under an Ar atmosphere.b The
d
products are inseparable. c Compound 34 was prepared and utilized as a 55:45 mixture of E/Z isomers. The reaction was run at 100 °C.
e The reaction was run at 120 °C. f 65% of the starting materials was recovered.
most Heck reactions, the aryl group of the initial Pd
intermediate is more likely to add to the end of the
carbon-carbon multiple bond furthest from the electron-
withdrawing ester moiety, which results in naphthalene
8 as the major product.
yields, although the reactions proceed smoothly (entries
7 and 8). The observed lower reactivity of the aryl
bromide 10 is consistent with our other annulation
chemistry.9-17 Notice that the reaction of compound 10
and ethyl 2-pentynoate gave a 60:40 mixture of regio-
isomers 11 and 12 (entry 9).
The reactions of aryl halide 1 and 2-butyne-1,4-diol or
3-phenyl-2-propyn-1-ol failed to afford any recognizable
product. It appears that the problem may be transesteri-
fication of the ester group by the acetylenic alcohols,
which is further supported by the results described later.
No recognizable naphthalene products could be obtained
when bulky symmetrical or unsymmetrical alkynes, like
di-tert-butylacetylene, phenyl(trimethylsilyl)acetylene, and
4,4-dimethyl-2-pentyne, were allowed to react with aryl
halide 1. Presumably, the problem here is the difficulty
in adding the hindered vinylic palladium intermediate
across the relatively hindered internal alkene to place
three bulky substituents in contiguous positions on the
resulting carbocyclic ring.
A synthetically interesting question is whether aryl
bromides can also undergo this palladium-catalyzed
annulation chemistry. To answer this question, com-
pound 10 was prepared and employed in reactions with
various alkynes. Generally, compared to the results from
aryl iodide 1, the annulation reactions of aryl bromide
10 with alkynes result in a longer reaction time and lower
To vary the linkage between the alkene and the
iodoarene unit, substrates 13, 18, and 20 have been
prepared and employed in this annulation chemistry. The
reaction of aryl iodide 13 and diphenylacetylene afforded
a 72% yield of the expected product (entry10), a little
lower than the yield from the reaction of aryl halide 1
and diphenylacetylene (entry 1). When ethyl phenylpro-
piolate was allowed to react with compound 13, a 67:33
mixture of regioisomers 15 and 16 was obtained in an
86% overall yield (entry 11). Comparing the results from
entries 6 and 11, it is clear that the introduction of a
methyl group into the starting material decreases the
regioselectivity of the annulation chemistry. When aryl
halide 13 was allowed to react with 2-butyne-1,4-diol,
none of desired product was obtained. However, the use
of a benzyl-protected 2-butyne-1,4-diol resulted in a 56%
yield (entry 12). While compound 13 underwent the
annulation chemistry very well and gave good to excellent
yields, the annulation reaction of aryl halides 18 and 20
gave none of the desired products (entries 13 and 14). It
7346 J . Org. Chem., Vol. 68, No. 19, 2003

Palladium-Catalyzed Annulation of Internal Alkynes
SCHEME 2
ylacetylene. These results (entries 16-19) indicate that
the geometry of the carbon-carbon double bond has little
effect on this annulation process.
Since aryl halides bearing electron-deficient olefins
work very well in this annulation chemistry, it was
important to determine if the introduction of an electron-
withdrawing group on the alkene is really necessary to
achieve success. To answer this question, compound 28
was prepared and allowed to react with diphenylacetyl-
ene. Only a 32% yield of naphthalene 29 was isolated
(entry 20). It appears that the presence of an electron-
withdrawing group, which presumably makes the olefin
a better acceptor for the Heck reaction, facilitates this
chemistry. In this comparison, however, we cannot rule
out the possibility that the terminal alkene in aryl iodide
28 may be undergoing intermolecular Heck processes
resulting in a lower yield.
The reactions of aryl halide 30, bearing two methoxy
groups on the aromatic ring, with symmetrical alkynes
such as diphenylacetylene, 4-octyne, and 1,4-di(benzyl-
oxy)-2-butyne afforded the corresponding naphthalenes
31-33 in 71%, 73%, and 60% yields, respectively (entries
21-23). When aryl halide 30 was allowed to react with
ethyl phenylpropiolate, two regioisomers 34 (73%) and
35 (8% yield) were isolated (entry 24). Comparing this
result with that from the reaction of aryl halide 1 and
ethyl phenylpropiolate (entry 6), it appears that the
introduction of electron-donating substituents, like meth-
oxy groups, onto the arene moiety increases the regiose-
lectivity in this annulation process. The use of a diyne
afforded an 83:17 mixture of alkynes 36 and 37 in a 66%
overall yield (entry 25).
The phenyl-substituted aryl iodide 38 has been found
to react well with 2-butyne-1,4-diol to produce naphtha-
lene 39 in a 73% yield (entry 26). This result confirms
our suspicion that the earlier problem with alkynols had
more to do with transesterification of the ester group
than any inherent problems with the alcohol functional-
ity. Surprisely, only one regioisomer 40 was isolated,
when 3-phenyl-2-propyn-1-ol was allowed to react with
aryl halide 38 (entry 27), although the yield of 31% was
not very good. The reaction of aryl iodide 38 and ethyl
phenylpropiolate afforded two regioisomers 41 (76%) and
42 (8%) with a yield and ratio of the two regioisomers
similar to those from the reaction of 30 and ethyl
phenylpropiolate (entry 24).
is not too surprising that aryl halide 18 was isomerized
to the more stable trisubstituted alkene 19 which was
isolated in a 48% yield after 8 h. Note that compound
19, which is a possible starting material for this annu-
lation chemistry, is relatively unstable under the reaction
conditions employed. If the reaction of compound 18 was
allowed to proceed for 28 h, compound 19 disappeared
and no other significant product was observed. The
readily prepared aryl halide 20 may also be undergoing
double-bond isomerization because no recognizable prod-
ucts could be isolated from its reaction with diphenyl-
acetylene.
It is interesting that the reaction of aryl halide 22 and
diphenylacetylene afforded compound 23 in a 73% yield
(entry 15). A mechanism for the formation of product 23
is shown in Scheme 2. From the intermediate A that is
formed, there are two possible pathways for palladium
â-hydride elimination to occur. Intermediate A can
eliminate Hb on the ring and eventually generate the
naphthalene product after isomerization. The other
pathway involves elimination of Ha from the methyl
group which would afford compound 23 bearing a disub-
stituted terminal alkene. The result indicates that the
elimination of Ha is much faster than that of Hb. This
may be because the methyl group has three hydrogens
increasing the chances of elimination. Alternatively,
when the vinylic palladium iodide adds cis to the alkene,
Hb is not syn to the alkylpalladium iodide generated. To
undergo â-hydride elimination, rotation of the C-C bond
is necessary before Hb and PdI are aligned cis to each
other for elimination. Thus, the elimination of Ha may
be achieved before this rotation can actually occur.
To examine whether the geometry of the carbon-
carbon double bond affects the annulation process, ni-
triles 24 and 27, which are E/Z isomers, were prepared
and allowed to react with 4-octyne and diphenylacetylene
(entries 16-19). When 4-octyne was employed, both
reactions reached completion in 7 h and afforded very
similar yields (entries 16 and 17). The reactions of nitriles
24 and 27 with diphenylacetylene also resulted in very
similar yields (entries 18 and 19), although they gave
lower yields than the reactions of 4-octyne. Notice that
the reactions of diphenylacetylene also required a longer
reaction time. This is probably because 4-octyne, which
is an electron-rich alkyne, is more reactive than diphen-
Carbazoles have attracted much attention due to their
biological activity20 and their potential as functional
materials,21 and the synthesis of carbazoles has been
extensively studied.22 Our palladium-catalyzed annula-
tion chemistry provides an alternative, very efficient
method to synthesize substituted carbazoles. Iodoindole
43 was first prepared using iodocyclization chemistry
currently under investigation in our group.23 This com-
pound was allowed to react with a variety of alkynes,
(20) For recent reviews, see: (a) Knoelker, H.-J .; Reddy, K. R. Chem.
Rev. 2002, 102, 4303. (b) Kirsch, G. H. Curr. Org. Chem. 2001, 5, 507.
(c) Knoelker, H.-J . Chem. Soc. Rev. 1999, 28, 151. (d) Knoelker, H.-J .
Synlett 1992, 371.
(21) For a recent review, see: Zhang, Y.; Wada, T.; Sasabe, H. J .
Mater. Chem. 1998, 8, 809.
(22) For recent reviews, see: (a) Pindur, U.; Lemster, T. Rec. Devel.
Org. Bioorg. Chem. 1997, 1, 33. (b) Kawasaki, T.; Sakamoto, M. J . Ind.
Chem. Soc. 1994, 71, 443.
(23) Yue, D.; Larock, R. C. Work in process.
J . Org. Chem, Vol. 68, No. 19, 2003 7347

Huang and Larock
SCHEME 3
including symmetrical and unsymmetrical alkynes. While
the reactions of 4-octyne, 2-butyne-1,4-diol, and 1,4-di-
(benzyloxy)-2-butyne gave moderate yields ranging from
33% to 56%, the use of diphenylacetylene gave only a
trace of the desired product (entries 29-32). The failure
of the reaction of diphenylacetylene is probably a result
of the fact that this alkyne appears to be less reactive
than most other alkynes. Notice that for the carbazole
synthesis, a higher reaction temperature is also required.
There was no reaction at 80 °C when iodoindole 43 was
employed. This may indicate that 5,6-fused ring systems
are more difficult to form than 6,6-fused ring systems
when employing this annulation chemistry. More reactive
alkynes, such as ethyl phenylpropiolate and ethyl 2-bu-
tynoate, have also been allowed to react with iodoindole
43, and better yields have been obtained (entries 33 and
34). The use of ethyl phenylpropiolate gave a 60:40
mixture of regioisomers 48 and 49 in a 91% overall yield,
which indicates that the electronic effects appear to be
more important than steric effects in this system (entry
33). Ethyl 2-butynoate, a less bulky alkyne, was allowed
to react with iodoindole 43 and a 82:18 mixture of isomers
50 and 51 was isolated in a 78% overall yield (entry 34).
The results from entries 33 and 34 indicate that both
electronic and steric effects play a role in the regioselec-
tivity of the alkyne insertion and the electronic effect
apparently outweighs the steric effect.
When compound 52 was allowed to react with two
alkynes, the reaction of the more reactive ethyl phenyl-
propiolate gave a 42% yield of compound 53 as a single
isomer, while use of the less reactive diphenylacetylene
results in none of the desired product (entries 35 and 36).
A mechanism for the reaction of aryl halide 1 and
diphenylacetylene is proposed in Scheme 3. First, Pd(0)
oxidatively inserts into the carbon-iodide bond of the
aryl iodide to generate an arylpalladium species. Addition
of the arylpalladium species to the carbon-carbon triple
bond, followed by an intramolecular cis addition to the
carbon-carbon double bond, generates an alkylpalladium
species B. Intermediate B can undergo â-hydride elimi-
nation forming intermediate C, which subsequently
isomerizes to naphthalene 2. Alternatively, the interme-
diate B may undergo reversible palladium hydride
elimination to an alkene complex D, which undergoes
readdition of the palladium hydride to the double bond
with the opposite regiochemistry. Further palladium
hydride elimination would produce the observed aromatic
product.
Con clu sion s
An efficient synthesis of highly substituted naphtha-
lenes and carbazoles has been developed in which two
new carbon-carbon bonds are formed in a single step
under relatively mild reaction conditions. Both electronic
and steric effects play a role in the regioselectivity of this
process and the electronic effect predominates over the
steric effect with certain ester-containing alkynes. The
introduction of an electron-rich group onto the aryl halide
increases the regioselectivity of this annulation process.
When this method was employed to synthesize carba-
zoles, a higher reaction temperature was necessary due
to the lower reactivity of the iodoindoles. This method
accommodates a variety of functional groups and gener-
ally affords the anticipated highly substituted naphtha-
lenes and carbazoles in good to excellent yields.
Exp er im en ta l Section
P r ep a r a tion of th e o-(2-Alk en yl)a r yl Ha lid es. 2-(2-
Iod op h en yl)p r op a n a l. To a suspension of (methoxymethyl)-
triphenylphosphonium chloride (2.87 g, 8.4 mmol) in dry THF
(15 mL) was added KO-t-Bu (0.90 g, 8.0 mmol) portionwise
under an Ar atmosphere at 25 °C. The resulting red suspension
was stirred for 30 min at 25 °C, and a solution of 2-iodoac-
etophenone (0.98 g, 4.0 mmol) in dry THF (5 mL) was added
dropwise. After the reaction mixture was stirred at 25 °C for
1 h, the THF was removed under reduced pressure and hexane
(30 mL) was added to the residue. The resulting suspension
was stirred for 20 min, and the Ph3PO was removed by
filtration. The filtrate was collected, the solvent was removed
under reduced pressure, and the residue was purified by flash
chromatography (20:1 hexane/EtOAc) on silica gel to afford
1.10 g of 2-(2-iodophenyl)-1-methoxypropene (E/Z ) 90:10) in
a 100% yield as a yellow oil. To a solution of 2-(2-iodophenyl)-
1-methoxypropene (E/Z ) 90:10) (0.55 g, 2.0 mmol) in CH2Cl2
7348 J . Org. Chem., Vol. 68, No. 19, 2003

Palladium-Catalyzed Annulation of Internal Alkynes
(10 mL) was added 1.2 mL of hydroiodic acid (47%), and the
mixture was stirred under an Ar atmosphere at 25 °C for 40
min. The reaction was then diluted with 30 mL of CH2Cl2, and
the excess acid was carefully neutralized by 30 mL of satd aq
NaHCO3, during which time many bubbles were generated.
The organic layer was collected, washed with 20 mL of brine,
dried over Na2SO4, and filtered, and the solvent (CH2Cl2) was
removed under reduced pressure. The residue was purified by
flash chromatography (20:1 hexane/EtOAc) on silica gel to
afford 0.36 g of 2-(2-iodophenyl)propanal in a 69% yield as a
colorless liquid: 1H NMR (CDCl3) δ 1.40 (d, J ) 6.8 Hz, 3H),
4.08 (q, J ) 6.8 Hz, 1H), 6.99-7.03 (m, 1H), 7.06 (dd, J ) 1.6,
8.0 Hz, 1H), 7.35-7.39 (m, 1H), 7.93 (dd, J ) 1.2, 8.0 Hz, 1H),
9.73 (s, 1H); 13C NMR (CDCl3) δ 14.7, 56.9, 102.3, 128.6, 129.2,
129.5, 140.3, 141.4, 200.5.
Eth yl (E)-4-(2-Iod op h en yl)-2-p en ten oa te (13). To a sus-
pension of (carbethoxymethylene)triphenylphosphorane (0.69
g, 1.95 mmol) in 5 mL of CH2Cl2 was added dropwise a solution
of 2-(2-iodophenyl)propanal (0.34 g, 1.3 mmol) in 5 mL of CH2-
Cl2 at 0 °C under an Ar atmosphere. The resulting mixture
was stirred at 25 °C for 3 h, and the solvent (CH2Cl2) was
evaporated under reduced pressure. The solid residue was
dissolved in 20 mL of hexane, and the mixture was then stirred
at 25 °C for 0.5 h. The Ph3PO was filtered, and the solvent
was removed under reduced pressure. The oily residue was
purified by flash chromatography (20:1 hexane/EtOAc) to
afford 0.41 g of the indicated compound as a colorless oil in a
95% yield: 1H NMR (CDCl3) δ 1.28 (t, J ) 7.2 Hz, 3H), 1.39
(d, J ) 7.2 Hz, 3H), 3.97-4.04 (m, 1H), 4.19 (q, J ) 7.2 Hz,
2H), 5.84 (dd, J ) 2.0, 16.0 Hz, 1H), 6.90-6.95 (m, 1H), 9.08
(dd, J ) 5.6, 16.0 Hz, 1H), 7.15 (dd, J ) 1.6, 8.0 Hz, 1H), 7.30-
7.34 (m, 1H), 7.85 (dd, J ) 1.2, 8.0 Hz, 1H); 13C NMR (CDCl3)
δ 14.5, 19.7, 45.9, 60.6, 101.3, 121.0, 127.9, 128.8, 129.0, 140.0,
145.8, 151.3, 166.9; IR (neat, cm-1) 3058, 2976, 2933, 2902,
the reaction was complete, the reaction mixture was allowed
to cool to 25 °C, poured into brine (25 mL), and extracted with
EtOAc (3 × 10 mL). The combined organic layers were
concentrated, and the residue was purified by column chro-
matography on silica gel to afford the corresponding naph-
thalene or carbazole.
Eth yl (1-Meth yl-3,4-d ip h en yl-2-n a p h th yl)a ceta te (14).
The reaction mixture was chromatographed using 30:1 hexane/
EtOAc to afford 68 mg of the indicated compound as a white
solid in a 72% yield: mp 80-82 °C; 1H NMR (CDCl3) δ 1.18 (t,
J ) 7.1 Hz, 3H), 2.72 (s, 1H), 3.69 (s, 2H), 4.08 (q, J ) 7.1 Hz,
2H), 7.01-7.21 (m, 10H), 7.32-7.38 (m, 1H), 7.48-7.54 (m,
2H), 8.16 (d, J ) 8.4 Hz, 1H); 13C NMR (CDCl3) δ 14.4, 15.8,
38.0, 60.8, 124.3, 125.8, 126.0, 126.4, 126.6, 127.6, 127.7, 127.7,
129.3, 130.5, 131.3, 132.1, 132.3, 133.0, 137.5, 139.9, 140.1,
141.0, 171.9; IR (CHCl3, cm-1) 3019, 1729, 1216, 1179; HRMS
calcd for C27H24O2 380.1776, found 380.1781.
Compounds 2-9, 25, 31, 34, 35, and 39 were reported in
our previous communication.19 The preparation and charac-
terization of other naphthalenes and carbazoles is described
in the Supporting Information.
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation and the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for partial support of this re-
search and J ohnson Matthey Inc. and Kawaken Fine
Chemicals Co. Ltd. for generous donations of palladium
salts.
Su p p or tin g In for m a tion Ava ila ble: Compounds 1-10,
24, 25, 27, 30, 31, 34, 35, 38, and 39 were reported in our
earlier communication.19 Compounds 2024 and 2825 were
prepared according to previous literature procedures. Prepara-
tion and characterization of the starting materials 13, 18, 22,
43 and 52; characterization data for compounds 11, 12, 14-
19, 22, 23, 26, 29, 32, 33, 36, 37, 40-42, 44-46, 48-51, and
53; copies of 1H NMR and 13C NMR spectra for compounds
11-23, 26, 29, 32, 33, 36, 37, 40-46, and 48-53. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1716, 1465; HRMS calcd for
330.0123.
C13H15IO2 330.0117, found
Compounds 1, 10, 24, 27, 30, and 38 were reported in our
earlier communication.19 The preparation and characterization
of other o-(2-alkenyl)aryl halides is reported in the Supporting
Information.
Gen er a l P r oced u r e for th e P r ep a r a tion of Na p h th a -
len es a n d Ca r ba zoles. To a mixture of the alkyne (0.50
mmol), Pd(OAc)2 (2.8 mg, 0.025 mmol), PPh3 (6.6 mg, 0.05
mmol), and Et3N (55.0 mg, 0.5 mmol) in 2 mL of DMF was
added dropwise a solution of the aryl halide (0.25 mmol) in 1
mL of DMF. The resulting mixture was then stirred under an
Ar atmosphere at the indicated temperature (see Table 2). The
reaction was monitored by TLC to establish completion. When
J O034449X
(24) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis
1990, 215.
(25) Negishi, E.; Coperet, C.; Ma, S.; Mita, T.; Sugihara, T.; Tour,
J . M. J . Am. Chem. Soc. 1996, 118, 5904.
J . Org. Chem, Vol. 68, No. 19, 2003 7349