Palladium-catalyzed controlled carbopalladation of benzyne

Article abstract of DOI:10.1021/ja001205a

2-Trimethylsilylphenyl trifluoromethanesulfonate 1a, a benzyne precursor, reacted with the allylic chlorides 2a - f in the presence of CsF (2.0 equiv) and Pd₂(dba)₃·CHCl₃ (2.5 mol %)-dppf (5 mol %) in a 1:1 mixed solvent of CH₃CN and THF to produce the phenanthrene derivatives 3 along with their minor regioisomers 4 in good yields (i) and the reaction of 1a with 2a and the internal alkynes 15a,c - e afforded the naphthalene derivatives 16 in moderate yields (ii). The reaction of benzyne precursor 1a with the alkynes 15a - c,f - h in the presence of Pd(OAc)₂ (5 mol %)-(o-tolyl)₃P (5 mol %) catalyst and CsF (2.0 equiv) in CH₃CN gave the phenanthrene derivatives 17 (iii), whereas the reaction of 1a with the alkynes 15a,b,i in the presence of the same catalysts and CsF in CH₃CN - toluene gave the indene derivatives 18 in good yields (iv). Detailed mechanistic investigation revealed that the former two reactions i and ii proceed through carbopalladation to free benzyne, while the latter two reactions iii and iv proceed through the nonfree benzyne mechanism, in which the initial step of the catalytic cycle begins with Pd(0) insertion to the Ar - OTf bond of 1.

Full text of DOI:10.1021/ja001205a

7280
J. Am. Chem. Soc. 2000, 122, 7280-7286
Palladium-Catalyzed Controlled Carbopalladation of Benzyne
Eiji Yoshikawa, K. V. Radhakrishnan, and Yoshinori Yamamoto*
Contribution from the Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
ReceiVed April 6, 2000
Abstract: 2-Trimethylsilylphenyl trifluoromethanesulfonate 1a, a benzyne precursor, reacted with the allylic
chlorides 2a-f in the presence of CsF (2.0 equiv) and Pd2(dba)3‚CHCl3 (2.5 mol %)-dppf (5 mol %) in a 1:1
mixed solvent of CH3CN and THF to produce the phenanthrene derivatives 3 along with their minor regioisomers
4 in good yields (i) and the reaction of 1a with 2a and the internal alkynes 15a,c-e afforded the naphthalene
derivatives 16 in moderate yields (ii). The reaction of benzyne precursor 1a with the alkynes 15a-c,f-h in
the presence of Pd(OAc)2 (5 mol %)-(o-tolyl)3P (5 mol %) catalyst and CsF (2.0 equiv) in CH3CN gave the
phenanthrene derivatives 17 (iii), whereas the reaction of 1a with the alkynes 15a,b,i in the presence of the
same catalysts and CsF in CH3CN-toluene gave the indene derivatives 18 in good yields (iv). Detailed
mechanistic investigation revealed that the former two reactions i and ii proceed through carbopalladation to
free benzyne, while the latter two reactions iii and iv proceed through the nonfree benzyne mechanism, in
which the initial step of the catalytic cycle begins with Pd(0) insertion to the Ar-OTf bond of 1.
Introduction
the controlled benzyne-alkyne-alkene insertion (ii) occurred
by the three-component coupling reaction, giving naphthalene
derivatives.5a Then, we examined the co-cyclization of benzyne
with alkynes and found that phenanthrene derivatives were
obtained via benzyne-alkyne-benzyne insertion (iii).5b Con-
cerning the benzyne-alkyne-benzyne insertion, Pen˜a and co-
workers reported a similar result almost at the same time.3c We
now report the full account on the previous communications5a,b
together with new findings on the unprecedented cocyclization
reaction of aryne precursors with alkynes via benzyne-alkyne-
alkyne insertion (iv), which produces indene derivatives.
Alkynes are frequently used as a substrate for the transition
metal catalyzed inter- and intramolecular carbometalation reac-
tion.1 However, arynes have hardly been utilized in the transition
metal catalyzed organic synthesis, although stoichiometric
reactions of zirconium-benzyne and nickel-benzyne complexes
were studied.2 Quite recently, Pen˜a, and co-workers have
reported the efficient palladium-catalyzed cyclotrimerization3a,b
of arynes and cocyclization of arynes with alkynes.3c During
our continuing studies of the catalytic hydro- and/or carbopal-
ladation of allenes,4a enynes,4b methylenecyclopropanes,4e and
alkynes,4c,d it occurred to us that arynes may be utilized as a
reactive partner in catalytic carbopalladation. We first examined
the palladium-catalyzed intermolecular insertion reaction of
benzyne into the π-allylpalladium intermediates and found that
the reaction via controlled benzyne-benzyne-alkene insertion
(i) took place to give phenanthrene derivatives.5a Furthermore,
(1) (a) Hegedus, L. S. Transition Metal Organometallics in Organic
Synthesis. In ComprehensiVe Organometallic Chemistry II; Able, E. W.,
Stone, F. G. A., Willkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12,
pp 1-977. (b) Schore, N. E. Chem. ReV. 1988, 88, 1081-1119.
(2) (a) Buchwald, S. L.; Broene, R. D. Transition Metal Alkyne
Complexes: Zirconium-Benzyne Complexes. In ComprehensiVe Organo-
metallic Chemistry II; Able E. W., Stone, F. G. A., Willkinson, G., Eds.;
Pergamon: Oxford, 1995; Vol. 12, pp 771-784. (b) Bennett, M. A.;
Wenger, E. Chem. Ber. 1997, 130, 1029-1042.
(3) (a) Pen˜a, D.; Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2659-2661. (b) Pen˜a, D.; Pe´rez, D.; Guitia´n,
E.; Castedo, L Org. Lett. 1999, 1, 1555-1557. (c) Pen˜a, D.; Pe´rez, D.;
Guitia´n, E.; Castedo, L. J. Am. Chem. Soc. 1999, 121, 5827-5828.
(4) (a) Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am. Chem. Soc. 1994,
116, 6019-6020. (b) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya,
N.; Tando, K.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 970-971. (c)
Tsukada, N.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1997, 36, 2477-
2479. (d) Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y. J. Am.
Chem. Soc. 1998, 120, 10262-10263. (e) Tsukada, N.; Shibuya, A.;
Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 8123-8124.
(5) (a) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39,
173-175. (b) Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 7533-7535. For the reaction of arynes with
bis-π-allylpalladium intermediate, see: (c) Yoshikawa, E.; Radhakrishnan,
K. V.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 729-731.
Results and Discussion
Reaction of Benzyne with π-Allylpalladium Intermediate.
(i) Benzyne-Benzyne-Alkene Insertion. It is well-known that
10.1021/ja001205a CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/15/2000

Pd-Catalyzed Controlled Carbopalladation ofBenzyne
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7281
Table 1. Palladium-Catalyzed Reaction of 1a with 2
aryl- and vinylpalladiums easily undergo intra- and intermo-
lecular carbopalladation with alkynes via, for example, Heck-
type reaction. However, when we started this research, to the
best of our knowledge, there was no report on the intermolecular
carbopalladation of π-allylpalladium complexes to alkynes,
although several examples of the intramolecular reactions were
known.6,7 Quite recently, almost at the same time as our
commumication appeared, the intermolecular reaction of alkynes
with a π-allylpalladium complex leading to substituted benzenes
has been reported.8 We thought that, since benzyne is quite a
reactive substrate compared to ordinary alkynes, the intermo-
lecular reaction between benzyne and π-allylpalladium com-
plexes must take place rather readily. The initial experiment
revealed that the palladium-catalyzed reaction of allylic chlorides
2 with benzyne precursor 1a9,10 produces phenanthrene deriva-
tives 3, along with their minor regioisomers 4, in good yields
(eq 1).
a Isolated yield based on 2. b Ratio determined by H NMR of the
crude product.
1
The results are summarized in Table 1. After certain
optimization work on the reaction of allyl chloride 2a, we settled
on the following two best methods. Method A: Allyl chloride
(32.6 mL, 0.4 mmol) was added to a suspension of anhydrous
CsF (243 mg, 1.6 mmol), Pd2(dba)3‚CHCl3 (10.4 mg, 0.01
mmol), and dppf (11 mg, 0.02 mmol) in CH3CN (1 mL) and
THF (1 mL), and the mixture was stirred at room temperature
for a few minutes. Benzyne precursor 1a (182.8 mL, 0.8 mmol)
was added and the resulting mixture was stirred at 60 °C for 1
day. The mixture was cooled to room temperature, extracted
with ether, dried with MgSO4, and concentrated. The product
was purified by silica gel column chromatography, giving 3a
in 69% yield (53.1 mg) (entry 1). Method B (larger amounts
of 1a and CsF were used compared to Method A): Allyl
chloride (32.6 mL, 0.4 mmol) was added to a suspension of
anhydrous CsF (486 mg, 3.2 mmol) and Pd2(dba)3‚CHCl3 (10.4
mg, 0.01 mmol) in CH3CN (2 mL) and the mixture was stirred
at room temperature for 15 min. Four equivalents of 1a (365.6
mL, 1.6 mmol) was added and the mixture was stirred at 80 °C
for 3 h. The same workup procedure as above was used, and
3a was obtained in 70% yield (53.9 mg) (entry 2). The catalytic
system of Pd2(dba)3‚CHCl3 using PPh3 or dppe gave slightly
lower yields, and the other catalysts such as Pd(OAc)2 and Pd-
(PPh3)4 were not so effective. The reaction of crotyl chloride
2b with 1a under the conditions of Method A gave a 58:42
mixture of 3b and 4b in 66% combined yield (entry 3). The
ratio of 3b to 4b increased up to 70:30 under the conditions of
Method B (entry 4). The reaction of R-methylallyl chloride 2c
gave a 65:35 mixture of 3b and 4b in 70% yield (entry 5). It
should be noted that the isomer ratio of the products obtained
from the reaction of 2c is almost the same as that of 2b.
Methallyl chloride 2d did not produce phenanthrene derivatives
at all (entry 6).15 The reaction of prenyl chloride 2e under
Method A gave an 80:20 mixture of 3e and 4e in 44% yield
(entry 7), but both the isomer ratio and the chemical yield
increased up to >95:5 and 68% yield, respectively, under the
conditions of Method B (entry 8). The reaction of cinnamyl
chloride 2f afforded approximately a 7:3 mixture of 3f and 4f
under the conditions of both methods, but Method B gave a
higher chemical yield than Method A (entries 9 and 10).
A plausible mechanism for this unprecedented intermolecular
benzyne-benzyne-alkene insertion reaction is shown in Scheme
1. Initially π-allylpalladium chloride 5 would be formed from
Pd(0) and 2a. Benzyne 6, which is generated from the reaction
of CsF and 1a,13 would insert into 5 to afford the arylpalladium
intermediate 7. In the case of substituted allylic chlorides 2b-
c,e-f, two regioisomers 12 and 13 would be produced at this
(6) (a) Oppolzer, W. Transition Metal Allyl Complexes: Intermolecular
Alkene and Alkyne Insertion. In ComprehensiVe Organometallic Chemistry
II; Able, E. W., Stone F. G. A., Willkinson, G., Eds.; Pergamon: Oxford,
1995; Vol. 12, pp 905-921. (b) Oppolzer W. Angew. Chem., Int. Ed. Engl.
1989, 28, 38-52. (c) Keese, R.; Grept, R. G. G.; Herzog, B. Tetrahedron
Lett. 1992, 33, 1207-1210. (d) Larock, R. C.; Takagi, K.; Burkhart, J. P.;
Hershberger, S. S. Tetrahedron 1986, 42, 3759-3762. (e) Inoue, Y.; Ohuchi,
K.; Kawamata, T.; Ishiyama, J.; Imaizumi, S. Chem. Lett. 1991, 835-836.
(7) The intermolecular insertion reaction of alkynes into π-allyl nickel
complexes is known: (a) Camps, F.; Moreto´, J. M.; Page`s, L. Tetrahedron
1992, 48, 3147-3162. (b) Montgomery, J.; Oblinger, E.; Savchenko, A.
V. J. Am. Chem. Soc. 1997, 119, 4911-4920. (c) Go´mez, G. G.; Moreto´,
J. M. J. Am. Chem. Soc. 1999, 121, 878-879.
(8) Tsukada, N.; Sugawara, S.; Inoue, Y. Org. Lett. 2000, 2, 655-657.
(9) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211-
1214.
(10) A new hypervalent iodine-benzyne precursor, (phenyl)[2-(trim-
ethylsilyl)phenyl]iodonium triflate, was reported recently. (a) Kitamura, T.;
Yamane, M. J. Chem. Soc., Chem. Commun. 1995, 983-984. (b) Kitamura,
T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.; Meng, Z.; Fujiwara,
Y. J. Am. Chem. Soc. 1999, 121, 11674-11679. The use of this benzyne
precursor in our Pd reactions gave a complex mixture of products.
(11) An unidentified compound having M+ (282) was obtained in low
yield: this molecular weight corresponds to a molecule consisting of three
benzynes and one CH2dCH(CH3)CH2.
(12) A mixture of 2a (1.0 equiv), 1a (1.0 equiv), and 15a (2.0 equiv)
was stirred at 60 °C for 1 day in the presence of Pd2(dba)3‚CHCl3 (5 mol
%), dppf (10 mol %), and CsF (2.0 equiv) in CH3CN/THF (1/1). Then,
again CsF (2.0 equiv) was added and the resulting mixture was stirred at
60 °C for 1 day.
(13) For transition metal mediated cyclotrimerization of alkynes which
produces vinylcyclopentadienes, see: (a) Reinheimer, H.; Moffat, J.; Maitlis,
P. M. J. Am. Chem. Soc. 1970, 92, 2285-2294.(b) Inoue, Y.; Itoh, Y.;
Hashimoto, H. Chem. Lett. 1978, 633-634. (c) Inoue, Y.; Itoh, Y.; Haruo,
K.; Hashimoto, H. Bull. Chem. Soc. Jpn. 1980, 53, 3329-3333. (d) Kong,
K.-C.; Cheng, C.-H. J. Chem. Soc., Chem. Commun. 1991, 423-424. (e)
Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organometallics 1987,
6, 1941-1946.
(14) It is reasonable to assume that the isomer ratio is not influenced
strongly by the stereoelectronic effect of the Me group at the C-4 position
of the methylbenzyne 6b (see eq 10).
(15) Winkle, M. R.; Ronald, R. C. J. Org. Chem. 1982, 47, 2101-2108.

7282 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
Yoshikawa et al.
Table 2. Palladium-Catalyzed Benzyne-Alkyne-Alkene Insertion
Scheme 1
a Isolated yield was based on 2a. b Hexaethyl mellitate was also
formed.
next examined the controlled insertion of benzyne-alkyne-
alkene. The results are summarized in Table 2. The reaction of
1a (1.0 equiv), 2a (1.0 equiv), and 4-octyne 15a (2.0 equiv)
under the slightly modified conditions12 of Method A gave 16a
in 47% yield along with small amounts (3%) of 3a (entry 1).
Other internal alkynes 15c-e reacted similarly to give the
corresponding naphthalene derivatives 16c-e, respectively,
along with small amounts of 3a (entries 2-4). As mentioned
stage. Second benzyne insertion into 7 would produce 8 and
subsequent carbopalladation to alkene would afford the cyclized
intermediate 9. â-Hydride elimination from 9 would give HPdCl
species and 10, which would undergo isomerization to 9-me-
thylphenanthrene 3a. In the case of the substituted allylic
chlorides, benzyne 6 would react predominantly at the less
substituted terminus of the π-allylpalladium complexes 11 to
produce 12 preferentially over its regioisomer 13. Accordingly,
3b,e-f were in general formed predominantly over their isomers
4b,e-f, respectively. Formation of 4e strongly supports the
â-elimination-rearrangement processes (9-10-3) in the pro-
posed mechanism; the rearrangement of the double bond of 4e
to form the phenanthrene ring is not possible. As is apparent
from the result of the experiment with 2d, the carbopalladation
step (8-9) would be hampered if there is a substituent, such as
Me, at the R3 position of 11. Even if the carbopalladation
proceeds in the reaction of 2d and a palladium intermediate
corresponding to 9 is formed, there is no proton at the â-position
of Pd in the intermediate, so there is no chance to regenerate
palladium catalyst by â-hydride elimination. Therefore, the
phenanthrene derivatives were not obtained from the reaction
of 2d.
As mentioned above, the lack of an example for the
intermolecular carbopalladation of π-allylpalladium complexes
toward alkynes was strange for us. Accordingly, the reaction
of π-allylpalladium chloride dimer 14 with 4-octyne was
examined under various reaction conditions. However, no
addition products were obtained, instead the starting materials
were recovered. On the other hand, the reaction of 14 (1.0 equiv)
with 1a (1.0 equiv) in the presence of CsF (2.0 equiv) in CH3-
CN at room temperature gave 3a in 22% yield (eq 2). This result
above, the insertion of π-allylpalladium chloride 5 into the
ordinary alkynes 15 would be very sluggish compared to the
insertion to benzyne, leading to the formation of 7 at the first
stage of carbopalladation. The second stage of carbopalladation
takes place via the Heck-type arylpalladation, so that alkynes
can participate in this step. Especially in the presence of excess
amounts of the alkynes, the alkyne insertion can take place
selectively compared to the second benzyne insertion. When a
terminal alkyne, such as phenyl acetylene, was used instead of
the internal alkynes 15, a small amount of diphenylacetylene
was obtained. Accordingly, the alkyne component of the
benzyne-alkyne-alkene insertion is limited to internal alkynes.
Reaction of Benzyne with Alkynes in the Presence of
Palladium Catalyst. (iii) Benzyne-Alkyne-Benzyne Inser-
tion. Since it became clear that alkynes could be incorporated
into the sequential insertion starting from benzyne, we next
studied the reaction of benzyne with alkynes. Optimization
experiments were carried out on the reaction of 1a with 15a.
After a number of trials, we found that the reaction in the
presence of a Pd(OAc)2/(o-tolyl)3P catalytic system at 60 °C in
CH3CN gave the best result, affording the phenanthrene
derivative 17a in 63% yield along with trace amounts of
triphenylene (entry 1). The results with several different alkynes
are summarized in Table 3. The other symmetrically substituted
alkynes 15b and 15c reacted similarly to give the corresponding
phenanthrene derivatives 17b and 17c, respectively, in good
yields (entries 2 and 3). The unsymmetrically substituted alkynes
clearly indicates the very high reactivity of benzyne triple bond,
compared to the ordinary one, toward the π-allyl-Pd bond.
(ii) Benzyne-Alkyne-Alkene Insertion. Encouraged by the
successful controlled insertion of benzyne-benzyne-alkene, we
15f-h gave the products 17f-h in good yields (entries 4-6).

Pd-Catalyzed Controlled Carbopalladation ofBenzyne
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7283
Table 3. Palladium-Catalyzed Reaction of 1a with 15 in CH3CN
Table 4. Palladium-Catalyzed Reaction of 1a with 15 in CH3CN
and Toluene
entry alkyne 15
R1
n-Pr
n-pentyl
R2
n-Pr
n-pentyl
product 17 yield, %a
1
2
3
4
5
6
15a
15b
15c
15f
17a
17b
63b
67b
59b
67
CH2OMe CH2OMe 17c
Ph
Ph
Ph
CH3
CH2CH3
COCH3
17f
17g
17h
15g
15h
63
76
a Isolated yield based on 1a. b Trace amounts of triphenylene were
also formed.
Because of the structural characteristics of phenanthrenes, even
if the carbopalladation to unsymmetric alkynes proceeds in
nonregioselective manner, regioisomeric phenanthrene products
are not obtained. When we completed this work, an article by
Pen˜a et al.3c appeared which described the synthesis of phenan-
threnes and naphthalenes by cocyclization of arynes with
alkynes. According to this report, electron deficient alkynes,
such as DMAD, gave phenanthrene derivatives in the presence
of Pd(Ph3P)4, while with Pd2(dba)3, they afforded naphthalene
derivatives in good yields. It is interesting to note that with other
alkynes studied, they did not observe any selectivity in the
formation of phenanthrenes and triphenylene. Phenanthrene
derivatives were obtained, albeit in low yields, in the case of
electron-rich alkynes. It is noteworthy that our method, utilizing
the Pd(OAc)2-(o-tolyl)3P catalyst system, afforded the phenan-
threne derivatives exclusively in good yields regardless of the
electronic nature of the alkynes.
Scheme 2
(iv) Benzyne-Alkyne-Alkyne Insertion. On the continu-
ation of this study, we found a dramatic solvent effect. As
mentioned above, all the previous reactions using 1a were
carried out in a rather polar solvent such as CH3CN. When the
reaction of benzyne precursor 1a and 4-octyne 15a in the
presence of CsF and Pd(OAc)2/(o-tolyl)3P was carried out in a
1:1 mixed solvent of CH3CN and toluene, the indene derivative
18a,13 a 1:2 adduct of benzyne and 15a, was obtained in 66%
yield along with trace amounts of the isomeric product 19a in
which the double bond of the side chain isomerized from C-1
to C-2. No trace amount of the phenanthrene product 17a was
1
detected by H NMR and capillary GC-mass analyses of the
crude reaction mixture. It should be mentioned also that the
indene derivatives were not obtained in the absence of toluene
(see Table 3). The use of Pd2(dba)3‚CHCl3/(o-tolyl)3P, instead
of Pd(OAc)2/(o-tolyl)3P, did not show high selectivity on the
product distribution and gave a mixture of the phenanthrene,
indene, and isomeric indene derivatives 17a, 18a, and 19a. The
results are summarized in Table 4. The reaction of the alkyl-
substituted internal alkynes 15a and 15b proceeded smoothly
to afford the indene derivatives 18a and 18b in 68% and 65%
yields, respectively (entries 1 and 2). However, the methyl ether
substituted alkyne 15c did not produce the indene derivative
18c but the phenanthrene derivative 17c in 50% yield (entry
3). On the other hand, 15i, which has a longer methylene chain
between the oxygen atom and the triple bond, gave the indene
derivative 18i in 58% yield along with trace amounts of 17i.
These results indicate that the oxygen atom at the propargyl
position prevents the formation of indene derivatives 18 (vide
post).
alkynes (Scheme 2). Initially, the reaction between Pd(0), the
alkyne 15, and benzyne generated from 1a and CsF would afford
the palladacycle 20. The fate of the intermediate 20 depends
on the solvent system. In the case of the CH3CN/toluene solvent
system, the reaction would proceed through path a. â-Hydride
elimination of 20 would produce the allenyl intermediate 21.
A second alkyne insertion into the aryl-Pd bond of 21 would
produce 22. Subsequent carbopalladation of the alkenyl-Pd
bond to the aryl-substituted double bond of the allenyl moiety
of 22 would give 23. The reductive elimination of Pd(0) would
give the indene derivative 18. The regioisomeric minor product
19 would arise by the isomerization of the double bond of 18
in the presence of a palladium hydride species. On the other
hand, in the case of CH3CN, the reaction would proceed through
path b. The palladacycle 20 would react with free benzyne to
give the phenanthrene derivatives 17. The reaction pathway
(either a or b) is controlled primarily by the generation rate of
benzyne. The generation rate of benzyne depends on the amount
of fluoride ion in solution, that is, it depends on the solubility
We propose the following plausible mechanism for the
observed palladium-catalyzed cocyclization of benzyne and

7284 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
Yoshikawa et al.
of CsF. Therefore, in the case of CH3CN solvent, enough
fluoride ion would exist in the reaction medium and a sufficient
amount of benzyne is supplied prior to the â-hydride elimination
of palladacycle 20. Accordingly the reaction proceeds through
path b to produce the phenanthrene derivatives 17. One may
raise a question that, if sufficient amounts of benzyne exist,
the palladacycle built via benzyne-benzyne combination may
be formed instead of the benzyne-alkyne counterpart 20. Excess
amounts of alkynes 15 exist already in the medium when
benzyne is generated, and perhaps therefore the mixed palla-
dacycle 20 is produced. The reaction conditions and catalyst
system would be too weak to form the corresponding alkyne-
alkyne combination. Actually, the reaction of 15a under the
same reaction conditions (Pd(OAc)2, (o-tolyl)3P, 60 °C, CH3-
CN/toluene) did not give any cyclization products but resulted
in recovery of 15a. On the other hand, in the case of CH3CN/
toluene, insufficient amounts of fluoride ion exist in the medium
due to low solubility of CsF, and thus palladacycle 20 would
not be able to wait further supply of benzyne but undergo
â-hydride elimination. This postulate is supported by the
experimental result of 15c (entry 3). In the case of the methyl
ether substituted alkyne 15c, presumably it is not easy to
eliminate a â-hydrogen from palladacycle 20c because of the
coordination of an oxygen of the methoxy group to palladium
(Scheme 2), so that 20c would be able to wait further supply of
benzyne and produce 17c selectively regardless of the polarity
of the solvent system. The structures of 18 were determined
unambiguously by 1H and 13C NMR analyses (decoupling, NOE,
H-C COSY, and COLOC).
Scheme 3
Reaction of Substituted Benzyne Precursors. Is Benzyne
Free? The above explanation of the marked solvent effect upon
the product distribution and the proposed reaction processes
shown in Scheme 2 seemed to be reasonable. However, with
further study of the palladium-catalyzed cocyclization of
substituted benzyne precursors with alkynes, we encountered a
very interesting and unexpected finding. The reaction of the
4-methyl-substituted benzyne precursor 1b with 4-octyne 15a
under the same reaction conditions as above (CH3CN/toluene
system) produced regioselectively the indene derivative 24a in
61% yield along with a trace amount of the regioisomer 25a
(eq 6). The reaction of 6-dodecyne 15b proceeded similarly and
produced 24b selectively in 66% yield. If the reactions proceed
via free methyl-substituted benzyne, an approximately 1:1
mixture of 24 and 25 should be obtained.14 To reveal the reason
for this high regioselectivity, the following controlled experiment
was performed. The reaction of 5-methyl-substituted benzyne
precursor 1c, which is expected to generate the same aryne as
in the case of 1b if a free benzyne is intervened, with 15a gave
regioselectively 25a in 60% yield along with a trace amount of
24a (eq 7). It is now clear that the reaction of 1b gives 24a
while that of 1c affords the regioisomeric product 25a. The
above experimental results indicate that the reactions did not
proceed via free benzyne.
alkyne complex 28. One may argue that the desilylation can
take place in the latter stage of the reaction sequences, for
example, just before the palladacycle formation. Why do we
prefer to put the desilylation step at an earlier stage? The
following experimental results support our proposal. The
benzyne precursor 1b did not react with 4-octyne 15a even in
the presence of palladium catalyst if CsF is not present in the
reaction medium. In the absence of CsF, the starting material
1a was recovered. On the other hand, it is reported that
iodobenzene reacts with 3-hexyne in the presence of palladium
catalyst to give a 1:3 addition product of iodobenzene and
3-hexyne via carbopalladation of phenylpalladium iodide to
3-hexyne.13e The difference between the previous observation
on the reaction of iodobenzene and our observation on the
reaction of 1a seems to be due to the steric hindrance of the
trimethyl silyl group present in 1a, which may prevent the
insertion of Pd(0) into C-OTf bond or prevent the carbopal-
ladation step.
Now, it is clear that the indene derivatives 18 in eq 5 are not
produced through free benzyne but through the Pd(0) insertion-
carbopalladation sequence. An important question is whether
the phenanthrene derivatives 17 in eq 4 are produced via free
benzyne or not. To help clarify this point, we carried out the
reactions of 1b and 1c with 15a under the reaction conditions
using CH3CN alone (eq 8 and 9). The reaction of 1b with 15a
gave an approximately 1:1 mixture of two phenanthrene
derivatives, assigned tentatively to 30 and 31, in 58% yield,
while the reaction of 1c afforded an approximately 1:1 mixture
of two phenanthrene derivatives, assigned to 31 and 32, in 62%
yield; it should be noted that the structural assignment is quite
tentative since the three products 30, 31, and 32 could not be
isolated in pure form. By GC-mass (15 m × 0.25 mm capillary
column cross-linked 5% phenyl methyl siloxane, SPB-5), the
A plausible mechanism for the observed regioselective
reactions is shown in Scheme 3. The insertion of Pd(0) into the
C-OTf bond of 1b gives the Pd(II) intermediate 26 (path c).
As soon as the trimethylsilyl group is removed by CsF, the
coordination of alkyne to Pd(II) can take place to form the
alkyne complex 28. The carbopalladation of the aryl-Pd bond
to the triple bond of alkyne gives 29, which is further converted
to the palladacycle 20′. The palladacycle 20′ follows the reaction
course shown in Scheme 2 (path a) to give 24. Alternatively,
the desilylation of 1b by the reaction with CsF takes place first
to produce 27, which reacts with Pd(0) and alkyne to give the

Pd-Catalyzed Controlled Carbopalladation ofBenzyne
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7285
three products could be separated and those mass numbers
(M+) 290) corresponded to a compound made from two
molecules of the benzyne and one molecule of 15a. Further, it
was confirmed by GC-mass analysis that one of the two isomeric
products in eq 8 was also produced in eq 9. By these
observations, we assigned the structure 30-32 to the three
products. If the reaction does not proceed through the Pd(0)
insertion-carbopalladation sequence as mentioned in Scheme
3, and if the reaction proceeds through the free benzyne 6b, an
approximately 1:2:1 mixture of 30, 31, and 32 should be
obtained both from 1b and from 1c (eq 10). Accordingly, the
experimental results clearly indicate that the cocyclization does
not proceed through the all-free benzyne process.
2a. However, here also the products could not be isolated in
pure form, but were separated and analyzed only by GC-mass.
The reaction of 1b with 2a and 4-octyne 15a under the
conditions shown in eq 3 gave an approximately 1:1 mixture
of two regioisomeric naphthalene products, and the same result
was obtained from the reaction of 1c. These results suggest that
the reactions of the benzyne precursors 1 with allyl chloride 2a
under the conditions shown in eqs 1 and 3 proceed via an all-
free benzyne process.
Conclusion
(i) The phenanthrene derivatives 3 can be synthesized from
the benzyne precursor 1a and allylic chlorides 2 in the presence
of Pd catalyst; in certain cases, the isomeric phenanthrenes 4
are produced as a byproduct. (ii) The naphthalene derivatives
16 can be prepared from 1a, allyl chloride 2a, and alkynes 15.
(iii) The phenanthrene derivatives 17 can be synthesized by the
palladium-catalyzed reaction of 1a with alkynes 15 in CH3CN,
whereas (iv) the indene derivatives 18 can be obtained by the
similar reaction in CH3CN-toluene. The former reactions i and
ii proceed through the all-free benzyne process, while the latter
reactions iii and iv proceed via the Pd(0) insertion-carbopal-
ladation process,. in which the nonfree benzyne mechanism is
operative at the initial step.
The free benzyne mechanism is operative if the aryne
precursors 1 interact with the Pd(II) species, such as π-allylpal-
ladiums, arylpalladiums, and palladacycles. In Scheme 1,
presumably, Pd(0) rapidly reacts with allyl chlorides 2, instead
of reacting with 1, to be converted to Pd(II) species. However,
in Scheme 2, Pd(0) can interact with 1, leading to the nonfree
benzyne mechanism. In conclusion, the product distribution and
mechanism in the benzyne-Pd catalytic reaction are highly
dependent upon the reaction conditions and Pd species present
in the catalytic cycle.
A crucially weak point of the above conclusion was that the
isomeric phenanthrene products could not be isolated in a pure
form and thus the structural determination of the products was
quite ambiguous. Accordingly, we next examined the reaction
of 1d with 15a in CH3CN solvent. An 85:15 mixture of 33 and
34 was obtained in 45% combined yield (eq 11). The two
isomeric phenanthrenes were separated and the structural
determination of the products was carried out unambiguously
by 1H and 13C NMR, NOE experiments, GC-mass, and HRMS
analysis. If the all-free benzyne process is operative, a mixture
of 33, 34, and 35 should be obtained (eq 12). Therefore, the
experimental result clearly indicates that the reaction shown in
eq 11 proceeds through a nonfree benzyne mechanism. Most
probably, at the beginning of the cocyclization, the Pd(0)
insertion-carbopalladation mechanism takes place to give the
palladacyclopentadiene intermediate 20′′ (eq 13). Then the
second stage would be the cocyclization between 20′′ and free
benzyne 6d (eq 13). This mechanism can explain very well the
experimental result shown in eq 11. Since palladacycle 20′′ is
a Pd(II) species, it is very difficult to assume that such Pd(II)
intermediate undergoes insertion between the Ar-OTf bond of
1d. Accordingly, the second MeO-phenyl framework of 33 and
34 must come from the free benzyne species 6d (eq 13).
The reaction of 1b with allyl chloride 2a under the conditions
shown in Table 1, Method A, gave a mixture of the regioiso-
meric phenanthrene products. The same regioisomeric products
with same isomer ratio were obtained in the reaction of 1c with
Experimental Section
Preparation of 3 (Method A): The preparation of 3a is representa-
tive. Allyl chloride (32.6 mL, 0.4 mmol) was added to a suspension of
anhydrous CsF (243 mg, 1.6 mmol), Pd2(dba)3‚CHCl3 (10.4 mg, 0.01
mmol), and dppf (11 mg, 0.02 mmol) in CH3CN (1 mL) and THF (1
mL), and the mixture was stirred at room temperature for 5 min.
Benzyne precursor 1a (182.8 mL, 0.8 mmol) was added and the
resulting mixture was stirred at 60 °C for 1 day. The mixture was cooled
to room temperature, extracted with ether, dried with MgSO4, and

7286 J. Am. Chem. Soc., Vol. 122, No. 30, 2000
Yoshikawa et al.
concentrated. The product was purified by column chromatography
(silica gel, eluent-hexane), giving 3a in 69% yield (53.1 mg)
Preparation of 3 (Method B): The preparation of 3a is representa-
tive. Allyl chloride (32.6 mL, 0.4 mmol) was added to a suspension of
anhydrous CsF (486 mg, 3.2 mmol) and Pd2(dba)3‚CHCl3 (10.4 mg,
0.01 mmol) in CH3CN (2 mL) and the mixture was stirred at room
temperature for 15 min. Four equivalents of 1a (365.6 mL, 1.6 mmol)
was added and the mixture was stirred at 80 °C for 3 h. The same
workup procedure as above was used, and 3a was obtained in 70%
yield (53.9 mg).
Preparation of 16: The preparation of 16a is representative. Allyl
chloride (32.6 mL, 0.4 mmol) and 4-octyne 15a (118.5 mL, 0.8 mmol)
were added to a suspension of anhydrous CsF (122 mg, 0.8 mmol),
Pd2(dba)3‚CHCl3 (20.8 mg, 0.02 mmol), and dppf (22 mg, 0.04 mmol)
in CH3CN (1 mL) and THF (1 mL), and the mixture was stirred at
room temperature for 5 min. Benzyne precursor 1a (91.4 mL, 0.4 mmol)
was added and the resulting mixture was stirred for 12 h at 60 °C.
Again, anhydrous CsF (122 mg, 0.8 mmol) was added to the reaction
mixture and the resulting mixture was stirred for 12 h at 60 °C. The
mixture was cooled to room temperature, extracted with ether, dried
over with MgSO4, and concentrated. The product was purified by
column chromatography (silica gel, eluent-hexane), giving 16a in 47%
yield (42.7 mg)
of anhydrous CsF (122 mg, 0.8 mmol), Pd(OAc)2 (4.4 mg, 0.02 mmol),
and (o-tolyl)3P (6 mg, 0.02 mmol) in CH3CN (2 mL). 4-Octyne 15a
(88.5 mL, 0.6 mmol) was then added and the mixture was stirred for
4 h at 60 °C. When the reaction was complete (monitored by TLC and
GC), the solvent was evaporated and the residue was purified by column
chromatography (silica gel, eluent-hexane), giving 9,10-dipropy-
lphenanthrene 17a in 63% yield (33.2 mg).
Preparation of 18, 24, and 25: The preparation of 18a is
representative. The benzyne precursor 1a (0.4 mmol) was added to a
suspension of anhydrous CsF (0.8 mmol), Pd(OAc)2 (8.8 mg, 0.04
mmol), and (o-tolyl)3P (24 mg, 0.08 mmol) in a CH3CN (1 mL)/toluene
(1 mL) solvent system. 4-Octyne 15a (118 mL, 0.8 mmol) was then
added and the mixture was stirred for 12 h at 60 °C. When the reaction
was complete (monitored by TLC and GC), the solvent was evaporated
and the product was purified by column chromatography (silica gel,
eluent-hexane), giving the indene derivative 18a in 68% yield (80.5
mg).
Supporting Information Available: 1H NMR spectra and
characterization data of 1b-c, 3a-b, 3e-f, 4b, 4e-f, 16a,
16c-e, 17a-c, 17g-h, 18a-b, 18i, 19a, 24a-b, 25a, 33, and
34 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Preparation of 17: The preparation of 17a is representative. The
benzyne precursor 1a (91.4 mL, 0.4 mmol) was added to a suspension
JA001205A