Palladium-catalyzed benzannulation from alkynes and allylic compounds

Article abstract of DOI:10.1021/jo026857r

Various alkynes reacted with allyl tosylates in the presence of palladium catalysts, giving polysubstituted benzenes with good to high regioselectivity. Pentasubstituted and trisubstituted benzenes were readily prepared by reaction of internal alkynes and

Full text of DOI:10.1021/jo026857r

P a lla d iu m -Ca ta lyzed Ben za n n u la tion fr om Alk yn es a n d Allylic
Com p ou n d s
Naofumi Tsukada,* Shuichi Sugawara, Keiichiro Nakaoka, and Yoshio Inoue
Department of Materials Chemistry, Graduate School of Engineering, Tohoku University,
Sendai 980-8579, J apan
tsukada@aporg.che.tohoku.ac.jp
Received December 17, 2002
Various alkynes reacted with allyl tosylates in the presence of palladium catalysts, giving
polysubstituted benzenes with good to high regioselectivity. Pentasubstituted and trisubstituted
benzenes were readily prepared by reaction of internal alkynes and terminal alkynes, respectively.
The combination of allyl alcohols and p-toluenesulfonic anhydride could be utilized in place of
isolated allyl tosylates. The cyclization of diynes with allyl tosylate afforded bicyclic compounds
containing an aromatic ring.
In tr od u ction
three-component coupling reactions of allyl chlorides,
alkynes, and alkynylstannanes afford 1,4-pentadienyl
compounds.5 The reactions of allyl chlorides and ben-
zyne, which is a type of activated alkyne, are catalyzed
by palladium complexes to give phenanthrenes.6 During
an investigation of π-allylpalladium complexes, we re-
cently found that a cationic π-allyl complex reacted
with a simple alkyne to afford a substituted benzene. On
the basis of this finding, we have developed a novel
palladium-catalyzed benzannulation from allylic com-
pounds and alkynes.7 Herein we report the details of
the inter- and intramolecular versions of this benzannu-
lation.
Because allylmetal compounds possess a wide range
of reactivity toward various organic molecules, they
have been extensively utilized in organic syntheses. The
reaction of allylmetals containing main group metals
with alkynes normally gives 1,4-pentadienyl compounds
(allylmetalation).1 Allyl-transition metals show a unique
reactivity toward alkynes; for example, five-, six-, and
seven-membered rings are formed by incorporation of one
or two molecules of alkyne.2 In contrast to the stoichio-
metric reactions of the allyl/alkyne addition reactions
described above, a fair number of reports have been
published involving catalysis that includes reactions of
allylmetals with alkynes as a key step.3-6 Several pal-
ladium- and nickel-catalyzed intramolecular reactions of
allylic compounds and alkynes were reported by Oppolzer
et al. In some cases, these reactions were followed by
carbonylation to give cyclopentenones.4 Nickel-catalyzed
Resu lts a n d Discu ssion
Stoich iom etr ic Rea ction . In the course of our in-
vestigation into the reactivity of π-allylpalladium com-
plexes, we found that treatment of the cationic complex
[(η3-C3H5)Pd(CH3CN)2](BF4) (1) with an excess of 4-octyne
(2a ) at 80 °C in the presence of 1 equiv of triphenylphos-
phine per palladium resulted in the formation of 1-meth-
yl-2,3,4,5-tetrapropylbenzene (3a ) in 52% yield (eq 1). In
(1) Reviews: (a) Normant, J . F.; Alexakis, A. Synthesis 1981, 841.
(b) Negishi, E. Pure Appl. Chem. 1981, 53, 2333. (c) Oppolzer, W.
Angew. Chem., Int. Ed. Engl. 1989, 28, 38. (d) Knochel, P. In
Comprehensive Organometallic Chemistry II; Able, E. W., Stone, F.
G. A., Wilkinson G., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p
865. (e) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(2) (a) Lutsenko, Z. L.; Aleksandrov, G. G.; Petrovskii, P. V.;
Shubina, E. S.; Andrianov, V. G.; Struchkov, Y. Y.; Ruvezhov, A. Z. J .
Organomet. Chem. 1985, 281, 349. (b) Nehl, H. Chem. Ber. 1993, 126,
1519. (c) Lutsenko, Z. L.; Petrovskii, P. V.; Bezrukova, A. A.; Ruvezhov,
A. Z. Bull. Acad. Sci. USSR Div. Chem. Sci. 1988, 37, 735. (d)
Schwiebert, K. E.; Stryker, J . M. J . Am. Chem. Soc. 1995, 117, 8275.
(e) Etkin, N.; Dzwiniel, T. L.; Schweibert, K. E.; Stryker, J . M. J . Am.
Chem. Soc. 1998, 120, 9702. (f) Tang, J .; Shinokubo, H.; Oshima, K.
Organometallics 1998, 17, 290. (g) Dzwiniel, T. L.; Etkin, N.; Stryker,
J . M. J . Am. Chem. Soc. 1999, 121, 10640. (h) Older, C. M.; Stryker,
J . M. Organometallics 2000, 19, 2661.
(3) Reviews and recent references: (a) Billington, D. C. In Compre-
hensive Organic Syhthesis; Trost, B. M., Fleming I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 3, p 423. (b) Chiusoli, G. P. Acc. Chem. Res.
1973, 6, 422. (c) Casser, L.; Chiusoli, G. P.; Guerrieri, F. Synthesis
1973, 509. (d) Inoue, Y.; Ohuchi, K.; Kawamata, T.; Ishiyama, J .;
Imaizumi, S. Chem. Lett. 1991, 835. (e) Montgomery, J .; Savchenko,
A. V. J . Am. Chem. Soc. 1996, 118, 2099. (f) Montgomery, J .; Oblinger,
E.; Savchenko, A. V. J . Am. Chem. Soc. 1997, 119, 4911. (g) Trost, B.
M.; Toste, F. D. J . Am. Chem. Soc. 1999, 121, 9728. (h) Yoshikawa,
E.; Radhakrishnan, K. V.; Yamamoto, Y. Tetrahedron Lett. 2000, 41,
729.
(4) (a) Oppolzer, W.; Keller, T. H.; Bedoya-Zurita, M.; Stone, C.
Tetrahedron Lett. 1989, 30, 5883. (b) Oppolzer, W. Angew. Chem., Int.
Ed. Engl. 1989, 28, 38-52. (c) Oppolzer, W. Pure Appl. Chem. 1990,
62, 1941-1948. (d) Oppolzer, W.; Xu, J .-Z.; Stone, C. Helv. Chim. Acta
1991, 74, 465-468. (e) Oppolzer, W.; Robyr, C. Tetrahedron 1994, 50,
415-424. (f) Negishi, E.; Wu, G.; Tour, J . M. Tetrahedron Lett. 1988,
29, 6745-6748. (g) Ihle, N. C.; Heathcock, C. H. J . Org. Chem. 1993,
58, 560-563.
(5) (a) Ikeda, S.; Cui, D.-M.; Sato, Y. J . Org. Chem. 1994, 59, 6877.
(b) Cui, D.-M.; Tsuzuki, T.; Miyake, K.; Ikeda, S.; Sato, Y. Tetrahedron
1998, 54, 1063. (c) Ikeda, S.; Miyashita, H.; Sato, Y. Organometallics
1998, 17, 4316.
10.1021/jo026857r CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/21/2003
J . Org. Chem. 2003, 68, 5961-5966
5961

Tsukada et al.
TABLE 1. Ben za n n u la tion Usin g Allyl Tosyla te a n d
Va r iou s In ter n a l Sym m etr ic Alk yn esa
contrast, only a trace amount of 3a was obtained without
addition of triphenylphosphine, and reaction using 2
equiv of triphenylphosphine or 1 equiv of bidentate
ligands did not afford any detectable 3a . (π-Allyl)chloro-
(triphenylphosphine)palladium also failed to yield prod-
ucts under the same conditions. These results suggest
that the present benzannulation requires 1 equiv of
triphenylphosphine and at least one weakly coordinating
ligand on palladium.8 More than two phosphorus atoms
per palladium or a firmly coordinating chloride ligand
disturbs the benzannulation. On the basis of the results
from the stoichiometric reactions, the catalytic benzan-
nulation reaction was then explored.
entry
alkyne
R
product
yieldb (%)
1
2
3
4
5
6
6
2b
2c
2d
2e
2f
Me
Et
n-Bu
3b
3c
3d
3e
3f
41 (63)
93
82
(28)
32
41
Ph
CH2OMe
CO2Me
COPh
2g
2h
3g
3h
49
a
Reaction conditions: allyl tosylate (0.5 mmol), 2 (2.0 mmol),
[Pd2(dba)3]‚CHCl3 (0.025 mmol), PPh3 (0.05 mmol), 1,2-dichloro-
b
ethane (3 mL) at 80 °C for 12 h. Isolated yields (NMR yields in
parentheses).
Ben zan n u lation Usin g Allyl Tosylate an d Alkyn es.
The reactions of 2a with typical allylating agents such
as allyl bromide and allyl acetate were examined in the
presence of a catalytic amount of [Pd2(dba)3]‚CHCl3 and
1 equiv of triphenylphosphine per palladium (eq 2).
sponding pentasubstituted benzenes 3b-d in good to
high yields (entries 1-3). Diphenylacetylene (2e) also
afforded the sterically crowded product 3e in 28% yield
(entry 4). Alkyne 2f containing ether groups reacted with
allyl tosylate to give 3f in 32% yield (entry 5). The
benzannulation also was applicable to the electronically
poor alkynes 2g and 2h , giving the tetraester 3g and the
tetraketone 3h , respectively (entries 6 and 7). The
reaction of 2-butyne-1,4-diol and 1,4-dichloro-2-butyne
did not yield any identifiable product.
Although internal unsymmetrical alkynes also can be
used for benzannulation, the regioselectivity was gener-
ally low in the reactions involving dialkylethynes. For
example, the reaction of 2-octyne afforded an equal
mixture of four regioisomeric benzene derivatives in 51%
yield. However, the reactions of phenyl-substituted acety-
lenes showed higher regioselectivity (eq 4). The benzan-
However, no detectable 3a was obtained, which may be
ascribed to formation of inactive π-allyl complexes bear-
ing a bromide or an acetate ligand that coordinates firmly
to the palladium center.9 Therefore, we incorporated a
weakly ligating anion. Although the yield was low, the
reaction with allyl trifluoroacetate did produce 3a . Allyl
mesylate was more reactive, giving 3a in 80% yield. Allyl
tosylate was the best allyl source tested for this benzan-
nulation, affording 3a in 91% yield.
Table 1 summarizes the results of the benzannulation
using allyl tosylate and various internal and terminal
alkynes (eq 3). In all cases, the cyclotrimerization of
nulation reaction with 1-phenyl-1-propyne (4a ) and allyl
tosylate gave the desired products in modest yield, with
1,3-diphenyl-2,4,6-trimethylbenzene (5a ) as a major prod-
uct. Similarly, the reaction of 1-phenyl-1-butyne (4b)
selectively yielded the corresponding m-terphenyl deriva-
tive 5b (78% selectivity, 77% yield as a mixture of
isomers). Using P(OPh)3 instead of PPh3 as a ligand for
palladium, the regioselectivity increased slightly to 84%,
although the yield was low. No product was obtained
using 3,3-dimethyl-1-phenyl-1-butyne as an alkyne be-
cause of the bulkiness of the substituents.
Regioselectivity of the reactions of terminal alkynes
was significantly affected by the phosphines used as
ligands. Table 2 summarizes the results of benzannula-
tion from allyl tosylate and 3,3-dimethyl-1-butyne (6a )
in the presence of [Pd2(dba)3]‚CHCl3 and various phos-
phorus ligands (eq 5). The reaction using PPh3 afforded
a mixture of three isomers 7a , 8a , and 9a with low
selectivity (entry 4). Although P(o-Tol)3 improved the
excess alkynes was sufficiently suppressed (yield <6%),
although some polymerization of the alkynes occurred.
Dialkylethynes 2b-d , as well as 2a , provided the corre-
(6) (a) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000,
39, 173. (b) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J .
Am. Chem. Soc. 2000, 122, 7280.
(7) Preliminary communication: Tsukada, N.; Sugawara, S.; Inoue,
Y. Org. Lett. 2000, 2, 655.
(8) (a) Kawataka, F.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc.
J pn. 1995, 68, 654. (b) Kayaki, Y.; Shimizu, I.; Yamamoto, A. Bull.
Chem. Soc. J pn. 1997, 70, 917.
(9) The acetate ligand is known to be dissociated from allylpalladium
intermediates in the presence of 2 equiv of phosphine ligands or 1 equiv
of bidentate ligands. The resulted cationic allylpalladium complexes
are key intermediates in the Tsuji-Trost allylic substitution reaction.
However, the acetate-coordinated allylpalladium complexes are ob-
tained in the presence of 1 equiv of monodentate phosphine ligands.
(a) Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997,
561. (b) Tsuji, Y.; Kusui, T.; Kojima, T.; Sugiura, Y.; Yamada, N.;
Tanaka, S.; Ebihara, M.; Kawamura, T. Organometallics 1998, 17,
4835. (c) Go´mez-Bengoa, E.; Cuerva, J . M.; Echavarren, A. M.;
Martorell, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 767.
5962 J . Org. Chem., Vol. 68, No. 15, 2003

Palladium-Catalyzed Benzannulation
TABLE 2. Ben za n n u la tion Usin g Allyl Tosyla te a n d
3,3-Dim eth yl-1-bu tyn e (6a )a
TABLE 3. Ben za n n u la tion Usin g Allyl Tosyla te a n d
Va r iou s Ter m in a l Alk yn esa
ratiob
ratioc
cone angle total yieldb
total yieldb major
entry
ligand
(deg)
(%)
7a
90
34 32 34
71 29
56 34 10
8a 9a
entry
alkyne
(%)
product major others
1
2
3
4
5
6
7
12
59
17
41
32
47
30
5
5
1
2
3
4
5
6
6b, R ) Ph
6c, R ) Bn
6d , R ) i-Bu
6e, R ) n-Bu
6f, R ) n-Hex
6g, R ) (CH2)3CN
31
42
7b
7c
7d
7e
7f
>99
70
80
73
73
<1
30
20
27
27
27
P(o-Tol)3
P(C6F5)3
PPh3
P(O-o-Tol)3
P(OPh)3
P(OEt)3
194
184
145
141
128
109
0
51
81d
66d
47d
81 18
1
0
0
>99
93
0
7
7g
73
a
Reaction conditions: allyl tosylate (0.5 mmol), 6 (2.0 mmol),
[Pd2(dba)3]‚CHCl3 (0.025 mmol), P(OPh)3 (0.05 mmol), 1,2-dichlo-
a
Reaction conditions: allyl tosylate (0.5 mmol), 6a (2.0 mmol),
[Pd2(dba)3]‚CHCl3 (0.025 mmol), a phosphine ligand (0.05 mmol),
b
1
roethane (3 mL) at 80 °C for 12 h. Determined by H NMR with
b
1,2-dichloroethane (3 mL) at 80 °C for 12 h. Yields and ratios
diphenylmethane as an internal standard. c Determined by GC
are determined by 1H NMR with diphenylmethane as an internal
standard.
and GC-MS analysis. Isolated yields of a mixture of regioisomers.
d
TABLE 4. Ben za n n u la tion Usin g Allyl Alcoh ol a n d
4-Octyn e (2a )a
entry
mmol of Ts2O
base (mmol)
yield of 3a b (%)
1
2
3
4
5
6
7
8
0
47
55
34
32
69
76
tr
0.5
1.0
2.0
0.5
0.5
0.5
0.5
pyridine (0.5)
i-Pr2NEt (0.5)
Et3N (0.5)
Et3N (1.0)
yields of the desired products, no selectivity was observed
(entry 2). All triarylphosphines exhibited unsatisfactory
regioselectivity (entries 2-4). In contrast, higher regio-
selectivity was obtained in the reactions using phosphite
ligands (entries 5-7), finally yielding 7a as the sole
product by using triphenyl phosphite (entry 6). The
reactions of other terminal alkynes were also investigated
(eq 6), and the results summarized in Table 3. Phenyl-
a
Reaction conditions: allyl alcohol (0.5 mmol), 2a (2.0 mmol),
[Pd2(dba)3]‚CHCl3 (0.025 mmol), PPh3 (0.05 mmol), 1,2-dichloro-
b
ethane (3 mL) at 80 °C for 12 h. Determined by GC analysis.
TABLE 5. Ben za n n u la tion Usin g Va r iou s Allylic
Alcoh ols a n d 4-Octyn e (2a )a
entry
alcohol
R1
R2
product
yieldb (%)
1
2
3
4
5
6
7
8
12a
12b
12c
12d
13a
13b
13c
13d
Me
n-Pr
Ph
Me
Me
n-Pr
Ph
H
H
H
Me
H
H
H
Me
11a
11b
11c
11d
11a
11b
11c
11d
42
44
30c
27
53
49
38c
35
Me
a
acetylene (6b) reacted with allyl tosylate to afford 7b with
high regioselectivity (entry 1). Selectivity was modest in
the reactions of alkynes 6c-g bearing less bulky sub-
stituents; nevertheless, the yields were higher than those
produced by the reactions of 6a and 6b, and 7c-g were
obtained as the major products (entries 2-6). A nitrile
triple bond is compatible with the described benzannu-
lation (entry 6).10
Reaction conditions: 12 or 13 (0.5 mmol), 2a (2.0 mmol), Ts2O
(0.5 mmol), [Pd2(dba)3]‚CHCl3 (0.025 mmol), PPh3 (0.05 mmol),
b
1,2-dichloroethane (3 mL) at 80 °C for 12 h. Isolated yields.
c Determined by 1H NMR with diphenylmethane as an internal
standard.
cannot be used in the benzannulation because they are
not thermally stable enough for isolation at room tem-
perature.
The reactions of several substituted allyl tosylates also
were investigated. Crotyl and (E)-2-hexenyl tosylates
(10a and 10b) participated in the reaction to produce the
corresponding pentasubstituted benzenes 11a and 11b
in 61% and 30% yield, respectively, upon reaction with
2a (eq 7). No product was obtained in the reaction of
Ben za n n u la tion Usin g Allylic Alcoh ols in th e
P r esen ce of Ts2O. Since substituted allyl tosylates other
than 10a and 10b could not be prepared, in situ genera-
tion of the tosylates from allylic alcohols and p-toluene-
sulfonic anhydride (Ts2O) was investigated. First, the
reaction of allyl alcohol with 2a was optimized; the
results summarized in Table 4. The reaction of allyl
alcohol and 2a in the presence of Ts2O yielded 3a in
moderate yield (entries 2 and 3), whereas no product was
obtained in the reaction without Ts2O (entry 1). An excess
amount of Ts2O was not effective (entry 4). To neutralize
the p-toluenesufonic acid formed by reaction of allyl
(10) (a) Bo¨nnemann, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 248.
(b) Wakatsuki, Y.; Yamazaki, H. Bull. Chem. Soc. J pn. 1985, 58, 2715.
(c) Heller, B.; Oehme, G. Chem. Commun. 1995, 179.
methallyl tosylate and 2a . Other allyl tosylates, espe-
cially those bearing substituents at their allylic position,
J . Org. Chem, Vol. 68, No. 15, 2003 5963

Tsukada et al.
TABLE 6. Ben za n n u la tion Usin g Allyl Tosyla te a n d
alcohol and Ts2O, various organic and inorganic bases
were added, and trialkylamines were found to improve
the yield of 3a (entries 6-8). Using 1 equiv of triethyl-
amine per Ts2O, 3a was obtained in 76% yield (entry 7).
Unexpectedly, 2 equiv of triethylamine hindered forma-
tion of 3a (entry 8).
Diyn esa
This method was applied to the reactions of substituted
allyl alcohols 12 and 13 (eq 8, Table 5); however, all
reactions were conducted without the addition of triethyl-
amine, because the addition decreased the yield of 11.
Crotyl alcohol (12a ) and (E)-2-hexenyl alcohol (12b), as
well as the corresponding tosylates 10a and 10b, reacted
with 2a in the presence of Ts2O to give 11a and 11b as
sole products in 42% and 44% yield, respectively (entries
1 and 2). The reaction of cinnamyl alcohol (12c) also
selectively afforded the pentasubstituted benzene 11c in
30% yield (entry 3). Alcohol 12d bearing two methyl
groups on the terminal carbon was utilized for the
benzannulation to yield 11d (entry 4). The reactions of
secondary and tertiary allylic alcohols 13a -d resulted
in the formation of the same benzene derivatives 11a -d
with the corresponding primary alcohols 12a -d bearing
the same substituents as 13a -d on the terminal carbon,
respectively (entries 5-8). None of the reactions yielded
a hexasubstituted benzene isomer, indicating that the
benzannulation reactions from 12 and 13 proceed via a
common intermediate. A pentasubstituted benzene bear-
ing the same five substituents can be obtained by
selection of the appropriate allylic alcohol and an alkyne.
For example, pentaethylbenzene (14) and pentabutyl-
benzene (15) are easily prepared by reaction of 12a (or
13a ) with 2c, and 12b (or 13b) with 2d , respectively (eqs
9 and 10).
a
Reaction conditions: allyl tosylate (0.5 mmol), diyne (1 mmol),
[Pd2(dba)3]‚CHCl3 (0.025 mmol), P(OPh)3 (0.05 mmol), 1,2-dichlo-
roethane (3 mL) at 80 °C, 12 h. Isolated yields.
b
contained less hindered alkyl substituents on the termi-
nal carbons, afforded products 17b and 17c, respectively,
in satisfactory yields (entries 2 and 3). Bulky substituents
on 16d and 16e decreased the yields of 17d and 17e
(entries 4 and 5). The cyclization of 1,7-diynes 18a -d
with allyl tosylate gave the tetrahydronaphthalene de-
rivatives 19a -d . Bicyclic compound 21, which contains
a seven-membered ring, also was obtained from reaction
of 1,8-diyne 20, although the yield was low. The benzan-
nulation from unsymmetrical diyne 22 proceeded regio-
selectively, giving only one indan derivative 23 in 57%
yield. Diyne 24 having an ester group also selectively
reacted with allyl tosylate to afford 25. The regioselec-
tivity is due to the difference between the reactivity of
the two alkyne groups in 22 and 24. Heteroatom-tethered
diyne 26 slowly decomposed under the present reaction
conditions, giving phthalan derivative 27 in low yield.
No product was formed from reaction of diyne 28, which
possesses a nitrogen tether. Unexpectedly, the malonate
derivative 29 did not react with allyl tosylate and was
recovered in almost quantitative yield, whereas the ester
groups in 16e and 24 did not hinder cyclization.
Ben za n n u la tion Usin g Allyl tosyla te An d d iyn es.
Bicyclic compounds were formed by reaction of allyl
tosylate with diynes. Table 6 summarizes the results of
the syntheses of the bicyclic systems. Reaction of 1,6-
diynes 16a-e selectively yielded indan derivatives 17a-e
(entries 1-5). The reaction of diynes 16b and 16c, which
5964 J . Org. Chem., Vol. 68, No. 15, 2003

Palladium-Catalyzed Benzannulation
SCHEME 2
Mech a n ism . A plausible mechanism for reaction of 12
or 13 with 2 (Scheme 1) can apply to the benzannulation
of other allylic compounds and alkynes. Oxidative addi-
tion of a substituted allyl tosylate, generated from 12 or
13 and Ts2O, yields the π-allylpalladium complex 30. The
common intermediate 30 accounts for reactions of 12 and
13 giving the same products in similar yields. Displace-
ment of the tosylate ligand on 30 with an alkyne and
insertion of the alkyne to the Pd-allyl bond of 30 would
afford 31. Ligand-displacement would be less active in
the case of acetate or bromide coordinated to palladium
instead of tosylate.11 Negishi reported that the palladium-
catalyzed reactions of 1-halo-1,4-pentadienes with alkynes
afforded polysubstituted benzenes, which might proceed
via an intermediate similar to 31.12 The consecutive
insertion of the second alkyne and intramolecular olefin
would generate 33. The â-hydrogen elimination from 33
would afford the palladium hydride complex 35 and the
cyclized product 34, which immediately isomerizes to the
benzene derivative 11. The elimination of HOTs from 35
would regenarate Pd(0).13 Another possible mechanism
is [2 + 2 + 2] cycloaddition via the palladacycles 36 or
37 (Scheme 2).14,15 If the present benzannulation proceeds
through 36 or 37, hexasubstituted benzene 39 should be
obtained in the reaction involving 10 (or 12). The actual
reaction, however, did not afford any 39. Moreover, a
control experiment showed that the treatment of 36′ with
allyl tosylate in the presence of PPh3 did not give any
cycloadduct (eq 12). These data and the above-mentioned
NMR experiment indicate that π-allylpalladium 30 is
more reasonable as the reaction intermediate than is 36
or 37, although other mechanisms16 cannot be ruled out
completely.
A mechanism involving reaction of π-allylnickels with
alkynes has been proposed for the Chiusoli reaction.3b-c,17
After studying the reaction widely and systematically,18
SCHEME 1
(11) Sulfonates such as tosylate and triflate exhibit weaker coordi-
nation ability than carboxylates and are often used as counteranions
for cationic complexes. Although the tosylate-coordinated complex 30
was observed in CDCl3 (see ref 7), the tosylate is predicted to be
partially replaced with alkynes under the reaction conditions. (a)
Carina, R. F.; Williams, A. F. Inorg. Chem. 2001, 40, 1826. (b) Milani,
B.; Anzilutti, A.; Vicentini, L.; o Santi, A. S.; Zangrando, E.; Geremia,
S.; Mestroni, G. Organometallics 1997, 16, 5064. (c) Gusev, O. V.;
Kalsin, A. M.; Peterleitner, M. G.; Petrovskii, P. V.; Lyssenko, K. A.;
Akhmedov, N.; Bianchini, C.; Meli, A.; Oberhauser, W. Organometallics
2002, 21, 3637.
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J . Org. Chem, Vol. 68, No. 15, 2003 5965

Tsukada et al.
SCHEME 3
alcohol and p-toluenesulfonic anhydride makes the reac-
tion possible. The cyclization of diynes with allyl tosylate
affords bicyclic compounds containing an aromatic ring.
All of the reaction results described in this study can be
rationalized by a mechanism involving a π-allylpalladium
intermediate.
Exp er im en ta l Section
Ma ter ia ls. Commercially available chemicals were used as
received except for the solvents, which were distilled by the
usual method. Palladium complexes 121 and 36′14a were
synthesized according to literature procedures. Tosylates
10a ,b22 were prepared by reaction of the corresponding allylic
alcohols with excess tosyl chloride and potassium hydroxide
in THF and were used without purification. Diynes 16a -c,
18a -c, and 20 were prepared by alkylation of commercially
available terminal alkynes according to the published method.23
Diynes 16d ,24 16e,25 18d ,24 and 2626 were prepared according
to literature procedures. Diynes 22 and 24 were obtained by
Sonogashira coupling24 and carbonylation,25 respectively, of
1,6-nonadiyne.27
Gen er a l P r oced u r e for Ben za n n u la tion fr om Alk yn es
a n d Allyl Tosyla te. To a solution of Pd2(dba)3‚CHCl3 (26 mg,
0.025 mmol) and a phosphorus ligand (0.05 mmol) in 1,2-
dichloroethane (3 mL) was added allyl tosylate (0.5 mmol)
under nitrogen atmosphere in a pressure vial. After 0.5 h of
stirring at room temperature, an alkyne (2.0 mmol) or diyne
(1.0 mmol) was added to the solution. After heating at 80 °C
for 12 h, the mixture was filtered through a short silica gel
column using ether as an eluent. Solvents and excess alkyne
were removed under reduced pressure, and the benzene
derivative was purified by silica gel column chromatography.
Gen er a l P r oced u r e for Ben za n n u la tion fr om Alk yn es
a n d Allylic Alcoh ols in th e P r esen ce of Ts2O. To a solution
of Pd2(dba)3‚CHCl3 (26 mg, 0.025 mmol), PPh3 (13 mg, 0.05
mmol), and Ts2O (163 mg, 0.5 mmol) in 1,2-dichloroethane (3
mL) was added an allylic alcohol (0.5 mmol) under nitrogen
atmosphere in a pressure vial. After 1 h of stirring at room
temperature, an alkyne (2.0 mmol) was added to the solution.
After heating at 80 °C for 12 h, the mixture was filtered
through a short silica gel column using ether as an eluent.
Solvents and excess alkyne were removed under reduced
pressure, and the benzene derivative was purified by silica gel
column chromatography.
Moreto´ et al. reported that the regioselectivity depends
on alkyne triple-bond polarization if steric effects are not
very demanding.19 The regioselectivity of the present
palladium-catalyzed benzannulation using terminal al-
kynes can be similarly explained (Scheme 3). The elec-
trophilic allyl moiety of the π-allypalladium intermediate
A adds to the more electron-rich carbon atom of the al-
kyne, leading to the preferred formation of 7 via inter-
mediate C. Because alkynes bearing bulky substituents
exhibit higher regioselectivity than other alkynes, steric
effects must also be considered. The bulky R groups can
interrupt approach of the alkyne to the allylic moiety in
intermediate B. Thus, formation of the regioisomers 8
and 9 is unfavorable as a result of electronic and steric
effects.
Both steric and electronic factors of phosphine ligands
affect regioselectivity. The results summarized in Table
2 show that triaryl and trialkyl phosphites, having
smaller cone angles,20 exhibit regioselectivities higher
than those of triarylphosphines. The reversals of P(OPh)3
and P(OEt)3, or PPh3 and P(C6F5)3, are due to their
electronic factors. In conclusion, the less hindered phos-
phorus ligand having a lower basicity showed higher
regioselectivity in the reactions of terminal alkynes. The
low basicity might increase the electrophilicity of the
π-allyl terminal carbon at the trans position in A, and
the small cone angles might decrease steric repulsion
between PR′3 and R in A.
Ack n ow led gm en t. This work was financially sup-
ported by the Ministry of Education, Science, Sport, and
Culture, J apan (13650909).
High regioselectivities also were observed in the reac-
tions involving unsymmetrical diynes 22 and 24. The
cyclization of 22 begins with reaction of the π-allylpal-
ladium intermediate 30 with the less hindered ethyl-
subsitituted alkyne rather than the phenyl-substituted
one, leading to formation of 23. In the case of 24, the
polarized alkyne is more reactive than the normal alkyne
to afford 25 selectively.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for benzene derivatives 3, 5, 7, 11, 14, 15, 17, 19, 21, 23,
25, and 27. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O026857R
(19) (a) Camps, F.; Coll, J .; Moreto´, J . M.; Torras, J . J . Org. Chem.
1989, 54, 1969. (b) Camps, F.; Moreto´, J . M.; Page`s, L. Tetrahedron
1992, 48, 3147. (c) Carbo´, J . J .; Bo, C.; Poblet, J . M.; Moreto´, J . M.
Organometallics 2000, 19, 3516.
Con clu sion
(20) Tolman, C. A. Chem. Rev. 1977, 77, 313.
(21) Sen, A.; Lai, T. W. Organometallics 1983, 2, 1059.
(22) Barta, N. S.; Cook, G. R.; Landis, M. S.; Stille, J . R. J . Org.
Chem. 1992, 57, 7188.
(23) (a) Tsuda, T.; Morikawa, S.; Sumiya, R.; Saegusa, T. J . Org.
Chem. 1988, 53, 3140. (b) Schwartz, M.; Waters, R. M. Synthesis 1972,
567.
(24) Lucht, B. L.; Mao, S. S. H.; Tilley, T. D. J . Am. Chem. Soc. 1998,
120, 4354.
(25) Sha, C.-K.; Zhan, Z.-P.; Wang, F.-S. Org. Lett. 2000, 2, 2011.
(26) Scheller, A.; Winter, W.; Mu¨ller, E. J ustus Liebigs Ann. Chem.
1976, 1448.
In summary, we have developed a palladium-catalyzed
regioselective synthesis of polysubstituted benzenes from
one molecule of allyl tosylate and two molecules of alkyne.
Pentasubstituted and trisubstituted benzenes were easily
prepared by reaction of internal alkynes and terminal
alkynes, respectively. Triphenyl phosphite, having a
small cone angle and low basicity, showed the highest
regioselectivity with terminal alkynes. Although a sub-
stituted allyl tosylate cannot be prepared because of its
low stability, the combination of the corresponding allylic
(27) Pabon, H. J . J .; Van Drop, D. A. J . Am. Oil Chem. Soc. 1969,
46, 269.
5966 J . Org. Chem., Vol. 68, No. 15, 2003