Highly efficient route to o-allylbiaryls via palladium-catalyzed three-component coupling of benzynes, allylic halides, and aryl organometallic reagents

Article abstract of DOI:10.1021/ol050859r

(Chemical Equation Presented) o-Allylbiaryl derivatives have been prepared in good to excellent yields by the palladium-catalyzed three-component reaction of allyl halides, benzynes, and aryl organometallic reagents.

Full text of DOI:10.1021/ol050859r

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2921-2924
Highly Efficient Route to o-Allylbiaryls
via Palladium-Catalyzed
Three-Component Coupling of
Benzynes, Allylic Halides, and Aryl
Organometallic Reagents
Thiruvellore Thatai Jayanth, Masilamani Jeganmohan, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu, 30013 Taiwan
chcheng@mx.nthu.edu.tw
Received April 19, 2005
ABSTRACT
o-Allylbiaryl derivatives have been prepared in good to excellent yields by the palladium-catalyzed three-component reaction of allyl halides,
benzynes, and aryl organometallic reagents.
Palladium-catalyzed three-component coupling reactions
based on an oxidative addition, insertion of the resulting
organopalladium species into multiple bonds (carbopallada-
tion), and followed by transmetalation have fundamentally
revolutionized synthetic concepts for the formation of
carbon-carbon and carbon-heteroatom bonds.1 Among
these reactions, those that involve carbopalladation of
alkynes,2 alkenes,3 and allenes4 have proven to be extraor-
dinarily versatile. A similar reaction sequence based on
carbopalladation of benzynes would be highly useful and
interesting, considering that benzynes are generally very
reactive species and that the reaction would lead to the
formation of two different C-C bonds at the ortho positions
of a benzene ring.
The development of new methods for the generation of
benzynes under mild conditions5 has led several groups to
explore the possibility of using arynes as partners for metal-
catalyzed reactions. In this context, palladium-catalyzed
[2 + 2 + 2] cyclotrimerization of benzynes6 and cocyclo-
trimerization of benzynes with alkynes and allylic halides
have been reported.7 Recently, also, we showed that benzynes
readily underwent [2 + 2 + 2] cocyclotrimerization with
(1) (a) Negishi, E.-I.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem.
ReV. 1996, 96, 365. (b) Malacria, M. Chem. ReV. 1996, 96, 289. (c)
Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (d) Tietze, L.
F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453. (e) Balme, G.; Bossharth,
E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101. (f) Tietze, L. F. Chem.
ReV. 1996, 96, 115.
(2) (a) Gevorgyan, V.; Yamamoto, Y. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons:
New York, 2002; Chapter IV.2.6, pp 1361-1367. (b) Cacchi, S.; Fabrizi,
G. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., Ed.; John Wiley & Sons: New York, 2002; Chapter IV.2.5,
1335-1359. (c) Negishi, E.-I.; Anastasia, L. Chem. ReV. 2003, 103, 1979.
(3) Kozhushkov, S.-I.; De Meijere, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons:
New York, 2002; Chapter IV.2.4, pp 1317-1334.
(4) (a) Ma, S. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons: New York, 2002; Chapter
IV.7, pp 1491-1521. (b) Chang, H.-M.; Cheng, C.-H. J. Org. Chem. 2000,
65, 1767. (c) Huang, T.-H.; Chang, H.-M.; Wu, M.-Y.; Cheng, C.-H. J.
Org. Chem. 2002, 67, 99.
(5) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211. (b) Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.;
Meng, Z.; Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674.
(6) (a) Pen˜a, D.; Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew.
Chem., Int. Ed. 1998, 37, 2659. (b) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo,
L. Org. Lett. 1999, 1, 1555. (c) Pen˜a, D.; Cobas, A.; Pe´rez, D.; Guitia´n, E.;
Castedo, L. Org. Lett. 2000, 2, 1629.
10.1021/ol050859r CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/08/2005

bicyclic alkenes, allenes, and diynes.8 Further, we found that
a benzyne carbopalladated by a π-allylpalladium intermediate
can be terminated efficiently with alkynyltin reagents to yield
1-allyl-2-alkynylbenzene derivatives.9 Given the importance
of substituted biaryl compounds in drugs,10 natural products,11
and material science,12 we envisaged that termination of a
carbopalladation sequence involving benzyne with an aryl
nucleophile would lead to o-substituted biaryl derivatives.
Herein, we report a highly efficient route for the synthesis
of o-allyl-substituted biaryl derivatives from allyl chlorides,
benzynes, and areneboronic acids catalyzed by palladium
complexes under mild conditions. It is noteworthy that o-allyl
biphenyl derivatives were found in clusiparalicolines, isolated
from the roots of Clusia paralicola, and used as DNA strand-
scission active compounds.13
The presence of 4 equiv of CsF relative to benzyne
precursor 1a was necessary to ensure a high product yield.
When only 2 equiv of CsF was employed, the reaction gave
product 4a in 46% yield with 41% benzyne precursor 1a
unreacted. In the reaction, CsF is used to react with
trimethylsilyl group in 1a for the generation of benzyne and
also for the activation of phenylboronic acid (3a). The
method for the benzyne generation is also important for the
success of the present catalytic three-component coupling
reaction. Product 4a was not obtained when KF/18-crown-6
in THF was used instead of CsF in acetonitrile as in Table
1. Other methods of generating benzyne, including 1,2-
dibromobenzene with n-BuLi, and o-aminobenzoic acid with
isoamylnitrite are not compatible with the present catalytic
reaction.
Under the optimized reaction conditions, substituted allylic
chlorides underwent the three-component reaction with 1 and
3a to afford the corresponding 2-allylbiphenyl derivatives
in good yields (Table 1). Thus, methallyl chloride (2b)
afforded 4b in 76% yield (entry 2), while both 1-chloro-
but-2-ene (2c) and 3-chloro-but-1-ene (2d) on treatment with
1b and 3a gave regioisomeric products 4c,d in 75 and 74%
combined yields, respectively (entries 3 and 4). The regio-
isomeric ratios in both cases were approximately 85:15,
favoring the linear product 4c.
Treatment of 2-(trimethylsilyl)phenyl triflate (1a) with allyl
chloride (2a) and phenylboronic acid (3a), in the presence
of Pd(dba)2/dppb (5 mol %) and CsF in acetonitrile at
ambient temperature for 8 h, afforded 2-allylbiphenyl (4a)
in 88% isolated yield (Table 1). Product 4a was thoroughly
1
characterized by its H NMR, 13C NMR, and mass data.
Control experiments revealed that in the absence of either
palladium catalyst or CsF, no 4a was obtained.
The phosphine ligand was crucial for the success of the
foregoing catalytic reaction. Phosphine-free palladium com-
plexes Pd(dba)2, Pd(OAc)2, and PdCl2(CH3CN)2 in acetoni-
trile were totally ineffective for mediating the reaction.
Monodentate phosphine complexes such as Pd(PPh3)4, PdCl2-
(PPh3)2, and PdCl2(PCy3)2 were active but gave 4a in low
yields (31-38%). It appears that a proper bidendate phos-
phine ligand is required for the reaction to proceed with high
yield. Pd(dba)2 with an equivalent of dppb afforded 4a in
excellent yield. Other bidendate phosphine ligands such as
dppm, dppe, dppp, dpppentane, dpphexane, and dppf are less
effective, giving 4a in only 22-55% yields. On the basis of
these optimization studies, we chose Pd(dba)2/dppb as the
catalyst for this palladium-catalyzed three-component reac-
tion.
The reaction of 3-chlorocyclohexene (2e) with 1a and 3a
under the optimized reaction conditions proceeded smoothly
to give the corresponding product 4e in 77% yield (entry
5). In a similar manner, cinnamyl chloride (2f) reacted with
3c and 1b to provide 4f in 66% yield (entry 6). It is
noteworthy that the allylation of benzyne by 2f is highly
regioselective, giving exclusively the cinnamyl-substituted
product (entry 6).
In addition to 1a, various benzyne precursors were
successfully used for the three-component reaction with 2a
and 3a. Thus, 1b with two methyl groups on the phenyl ring
furnished product 4g in 87% yield (entry 7), and indene
derivative 1c afforded 4h in 85% yield (entry 8). 4-Methyl-
substituted benzyne precursor 1d gave a mixture of regioi-
somers (entry 9) as expected for a reaction using 4-methyl-
benzyne as a substrate.
(7) (a) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am. Chem. Soc.
1999, 121, 5827. (b) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Org.
Chem. 2000, 65, 6944. (c) Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto,
Y. Tetrahedron Lett. 1999, 40, 7533. (d) Yoshikawa, E.; Radhakrishnan,
K. V.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 729. (e) Yoshikawa, E.;
Radhakrishnan, K. V.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 7280.
(f) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000, 39, 173.
(8) Jayanth T. T.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem. 2004,
69, 8445. For Nickel-catalyzed [2 + 2 + 2] cyclotrimerization involving
benzynes, see, Hsieh, J.-C.; Rayabarapu, D. K.; Cheng, C.-H. Chem.
Commun. 2004, 532.
(9) Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2004, 6, 2821
(10) Biaryl ring system is regarded as a “previledged structure” compris-
ing about 4.3% of marketed drug compounds. See: Hadjuk, P. J.; Bures,
M.; Praestgard, J.; Fesik, S. W. J. Med. Chem. 2000, 43, 3443.
(11) (a) Torssell, K. G. B. Natural Product Chemistry; Wiley: Chichester,
1983. (b) Thomson, R. H. The Chemistry of Natural Products; Blackie and
Son: Glasgow, 1985. (c) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001,
34, 615.
(12) For biaryls in material science, see: (a) Yamamoto, T. Synlett 2003,
425. (b) Elsenbauer, R. L.; Schacklett, L. W. In Handbook of Conducting
Polymers; Skotheim, T. A., Ed.; Marcel-Dekker: New York, 1986; Vol. 1,
Chapter 7. (c) Shih, H.-T.; Shih, H.-H.; Cheng, C.-H. Org. Lett. 2001, 3,
811.
(13) (a) Takoka, S.; Nakade, K.; Fukuyama, Y. Tetrahedron Lett. 2002,
43, 6919. (b) Seo, E.-K.; Huang, L.; Wall, M. E.; Wani, M. C.; Navarro,
H.; Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D. J. Nat. Prod. 1999,
62, 1484.
The scope and generality of the present catalytic reaction
can be further extended to various arylboronic acids. Under
the standard conditions, the reaction of 1a and 2a with
3-methoxybenzeneboronic acid (3b), 4-fluorobenzeneboronic
acid (3c), 4-bromobenzeneboronic acid (3d), and 3-nitroben-
zeneboronic acid (3e) gave the corresponding o-allylbiphenyl
derivatives 4k-n in 81-87% yields (entries 10-13). The
presence of a formyl group (3f) and a vinyl group (3g) at
the 4-position of benzeneboronic acid was compatible with
the present catalytic reaction, yielding products 4o and 4p
in 78 and 81% yields, respectively (entries 14 and 15).
1-Naphthaleneboronic acid also successfully underwent the
three-component reaction with 1b and 2a to give 4q in 71%
yield (entry 16). The present protocol can also be applied to
heterocyclic reagents; 2-thiopheneboronic acid (3i) and
2-benzo[b]furanboronic acid (3j) gave the desired product
4r and 4s in 85% and 68% yields, respectively, (entries 17
and 18).
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Org. Lett., Vol. 7, No. 14, 2005

Table 1. Results of Palladium-Catalyzed Three-Component Reaction of Benzyne Precursors 1, Allylic Chlorides 2, and Arylboronic
Acids 3a
a Reaction conditions: 0.50 mmol of benzyne precursor 1, 0.60 mmol of allyl chloride 2, 0.50 mmol of arylboronic acid 3, 0.025 mmol of Pd(dba)2 and
dppb, and 2.0 mmol of CsF under nitrogen in 3.0 mL of CH3CN at room temperature for 6 h. b Isolated yields; yields in parentheses were determined by
1
the H NMR integration method with mesitylene as an internal standard.
Org. Lett., Vol. 7, No. 14, 2005
2923

Allyl acetates and allyl carbonates, commonly used as
allylic electrophiles in industrial and organic synthesis, also
reacted with 1a and 3a under the present conditions to yield
4a in 72% and 61% yields, respectively. While allyl bromide
gave the corresponding product 4a in good yield (81%), allyl
iodide underwent the reaction only in 44% yield. It should
be noted that in these reactions, the conditions were not
optimized and the same reaction conditions as shown in
Table 1 were employed.
We further found that the three-component assembly
reaction could also be extended to other common aryl
organometallic reagents. Thus, when phenyltributyltin was
treated with 1a and 2a under the present conditions, 4a was
obtained in 67% yield. Similarly, when phenyltrimethoxysi-
lane was treated with 1a and 2a in the presence of Pd(dba)2/
dppb (5 mol %) and CsF in acetonitrile at 80 °C for 8 h, 4a
was obtained in 41% yield.
8 gives intermediate 9 and B(OH)2F. Subsequent reductive
elimination of 9 affords the final product and regenerates
the Pd(0) catalyst.
Strong support for the involvement of benzyne in the
reaction is the formation of two regioisomers, 4i and 4j, in
a ca. 50:50 ratio (entry 9, Table 1). The lack of regioselec-
tivity of the reaction is consistent with insertion of unsym-
metrical benzyne into a palladium-carbon bond. The
insertion of benzyne into Pd(II)-allyl intermediate 8 is
proposed in the literature.6c,d
One other possible pathway is the oxidative addition of
allyl chloride to Pd(0) to give π-allylpalladium complex 6,
followed by transmetalation of arylboronic acid 3 with 6 to
give an aryl π-allyl palladium intermediate. Subsequent
transfer of the aryl and allyl groups to the benzyne moiety
affords the final product 4 and regenerates the Pd(0)
catalyst.14 This pathway cannot be completely ruled out.
A third possible pathway involves the addition of aryl-
boronic acid to benzyne forming 2-biphenylboronic acid
followed by coupling with allyl electrophile. However, the
stoichiometric reaction of benzyne, generated from precursor
1a in the presence of CsF, with benzeneboronic acid 3a in
acetonitrile and Pd(dba)2/dppb at ambient temperature for 6
h did not afford the corresponding 2-biphenylboronic acid.
The observation rules out the possibility of this pathway.
In conclusion, we have described a carbopalladation of
highly reactive benzynes in a catalytic manner employing a
variety of allyl electrophiles and aryl nucleophiles, thereby
preparing various o-allylbiaryls in good yields. Further
studies on the use of other carbopalladation partners,
mechanistic details as well as potential synthetic applications
of the present methodology are underway.
On the basis of the known palladium-catalyzed domino
reactions,2-8 a mechanism is proposed to account for the
present catalytic reaction (Scheme 1). The first step involves
Scheme 1
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China (NSC 93-2113-M-007-033) for
support of this research.
Supporting Information Available: General experimen-
tal procedures, spectral data for all compounds, and 1H and
13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
oxidative addition of allyl chloride to Pd(0) to give the π-allyl
palladium complex 6. Benzyne 7 generated from 1 in the
presence of CsF then inserts into 6 to afford aryl palladium
intermediate 8. Transmetalation of the arylboronic acid 3 with
OL050859R
(14) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 729-731.
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