Synthesis of unsymmetrical biaryls from arylsilacyclobutanes

Article abstract of DOI:10.1021/ol991054k

(formula presented) Aryl(fluoro)silacyclobutanes and aryl(chloro)silacyclobutanes have been found to undergo cross-coupling reactions with aryl iodides. The rate of reaction and extent of homocoupling were dramatically affected by the addition of ligands for the palladium catalyst. With (t-Bu)₃P a wide range of electronically and structurally diverse unsymmetrical biaryls have been prepared in good to excellent yields.

Full text of DOI:10.1021/ol991054k

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1495-1498
Synthesis of Unsymmetrical Biaryls
from Arylsilacyclobutanes
Scott E. Denmark* and Zhicai Wu
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 South Mathews AVenue Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received September 15, 1999
ABSTRACT
Aryl(fluoro)silacyclobutanes and aryl(chloro)silacyclobutanes have been found to undergo cross-coupling reactions with aryl iodides. The rate
of reaction and extent of homocoupling were dramatically affected by the addition of ligands for the palladium catalyst. With (t-Bu)3P a wide
range of electronically and structurally diverse unsymmetrical biaryls have been prepared in good to excellent yields.
The biaryl subunit is a commonly found motif in biologically
active molecules.1 Moreover, biaryl-containing compounds
can be used to design novel materials such as organic
semiconductors and liquid crystals.2 Accordingly, the con-
struction of biaryls remains an active area in organic
synthesis.3 Transition metal-catalyzed cross-coupling reac-
tions between arylmetallic nucleophiles and aryl electro-
philes, disclosed by the Kumada-Tamao4 and the Corriu
groups,5 have had a revolutionary impact on the preparation
of biaryls.6 Among the most notable and widely used are
the Stille (Migita-Kosugi) coupling of organostannanes7 and
Suzuki coupling of organoboranes.8 These two methods have
the common advantages of high yields and selectivities and
applying stable, isolable entities. However, they are not
without disadvantages such as attenuated and substrate-
dependent reactivity, oxygen sensitivity, and toxicity.
Organosilicon reagents can, in principle, provide a practical
solution to these problems because they are environmentally
benign and stable to many reaction conditions. Despite their
lower reactivity, acyclic aryl(fluoro)silanes have been shown
through the extensive studies by Hiyama group to participate
in the palladium-catalyzed cross-coupling reactions including
preparing biaryls.9 Alkoxysilanes10 and silanols11 have also
been demonstrated as appropriate coupling partners. Re-
cently, we have introduced the use of alkenylsilacyclobutanes
for highly stereospecific cross-coupling reactions (eq 1).12
(1) (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.
(2) (a) Roncali, J. Chem. ReV. 1992, 92, 711. (b) Yamamura, K.; Ono,
S.; Ogoshi, H.; Masuda, H.; Kuroda, Y. Synlett 1989, 18.
(3) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263. (b) Bringmann, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977. (c)
Sainsbury, M. Tetrahedron 1980, 36, 3327.
(4) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374.
(5) Corriu, R. J. P.; Masse, J. P. Chem. Commun. 1972, 144.
(6) (a) Dielderich, F., Stang, P. J., Eds. Metal-Catalyzed, Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Heck, R. F. Palladium
Reagents in Organic Synthesis; Academic Press: New York, 1985. (c) Tsuji,
I. Palladium Reagents and Catalysis. InnoVations in Organic Synthesis;
Wiley: Chichester, U.K., 1995.
(7) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1.
(8) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(9) (a) Hiyama, T. In Metal-Catalyzed, Cross-Coupling Reactions;
Dielderich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Hiyama,
T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471.
(10) (a) Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997,
1309. (b) Mowery, M. E.; Deshong, P. J. Org. Chem. 1999, 64, 1684.
(11) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama,
T. Org. Lett. 1999, 1, 299.
(12) Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821.
10.1021/ol991054k CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/30/1999

Compared to the other metal reagents, the methyl organo-
silacyclobutanes have the advantages of (1) low molecular
weight, (2) ease of synthesis, (3) stability, (4) mild activation,
and (5) conversion to harmless byproducts. To expand the
scope of this method, we report herein the application of
arylsilacyclobutanes for the synthesis of unsymmetrical
biaryls.
Table 1. The Effect of Additive on the Coupling with 3 at
Room Temperature
Initial studies on the cross-coupling reaction of methyl-
(phenyl)silacyclobutane with either aryl or alkenyl iodides
gave no desired products under various conditions including
those optimized for alkenylsilacyclobutanes. Thus, to enhance
the reactivity of the arylsilacyclobutanes, a heteroatom was
introduced on the silicon. Chlorosilane 2 and fluorosilane 3
were prepared in a straightforward fashion from dichloro-
silacyclobutane (1)13, Scheme 1.
Scheme 1
Orienting experiments with 3 and iodobenzene revealed
that under standard12 coupling conditions (TBAF/Pd(dba)2/
THF/rt), 25% conversion could be obtained in 48 h.
Screening different Pd sources identified [allylPdCl]2 as the
superior catalyst in terms of rate and amount of side reaction.
With this catalyst, fluorosilane 3 was found to be more
reactive than chlorosilane 2 (eq 2) and thus was used to
optimize the other reaction variables.
the desired coupling, the other ligands such as tri(2-furyl)-
phosphine (entry 4) and triphenylarsine (entry 5) and the
bulky ligands such as tri(tert-butyl)phosphine (entry 6)15 and
tricyclohexylphosphine (entry 7) were effective in eliminating
the homocoupling of arylsilanes and significantly suppressing
the homocoupling of aryl iodides. Nevertheless, the desired
cross-coupling was still rather sluggish. It was surprising that
recently introduced ligand 7 did not inhibit the generation
of 5.16
To accelerate the cross-coupling process, the reaction
temperature was increased to 50 °C. Again, a variety of
ligands were surveyed, and the results are collected in Table
2. With the exception of P(C6F5)3 (entry 2) and DMPE (entry
5), all the other ligands allowed the reaction to be com-
plete in 24 h. As is evident from Table 2, the ligands have
a dramatic effect on the generation of homocoupling prod-
uct 5. Tri(tert-butyl)phosphine was the best ligand to sup-
press this side reaction; only 6% of 5 was produced (entry
7).
Careful investigation of the reaction between 3 and
iodobenzene showed that homocoupling of both these
substrates was a serious liability (entry 1, Table 1).9b,14 To
facilitate the transmetalation and eliminate the cross-coupling,
various additives were surveyed with ratio of ligand/
palladium of 2.0. The additives examined cover a wide range
of donor properties and steric bulk. While (o-tol)3P (entry
2), (C6F5)3P (entry 3), and phosphite 8 (entry 9) suppressed
(14) Ikeyashira, K.; Nishihara, Y.; Hirabayashi, K.; Mori, A.; Hiyama,
T. J. Chem. Soc., Chem. Commun. 1997, 1039.
(15) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1998, 37,
3387.
(16) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
(13) Available from Aldrich or Gelest. See also: (a) Denmark, S. E.;
Griedel, B. D.; Coe, D. M.; Schnute, M. E. J. Am. Chem. Soc. 1994, 116,
7026. (b) Laane, J. J. Am. Chem. Soc. 1967, 89, 1144.
1496
Org. Lett., Vol. 1, No. 9, 1999

Table 2. The Effect of Additive for the Coupling with 3 at 50
°C
Table 4. The Effect of Ligand/Pd Ratio on the Coupling with
2
From the foregoing studies it is apparent that both
chlorosilane 2 and fluorosilane 3 are appropriate partners
for the cross-coupling with aryl iodides. The fluorosilane is
more reactive and can perform the coupling at slightly lower
temperature and with less additive. On the other hand, the
chlorosilane can be easily prepared in one step. With an eye
toward practicality, we selected the more readily available
aryl(chloro)silacyclobutanes to demonstrate this scope of this
new method.
Optimized conditions were established as follows: pre-
treatment of 2 with TBAF (3.0 equiv), [allylPdCl]2 (2.5 mol
%) as catalyst, and tri(tert-butyl)phosphine (20 mol %) as
ligand in refluxing THF. The reactions with a variety of aryl
iodides bearing electron-withdrawing or -donating groups in
the para, meta, or ortho positions were investigated to show
the generality of the electrophilic component (Table 5). The
desired unsymmetrical biaryls were obtained in good to
excellent yields within several hours for all the aryl iodides
tested. The mild reaction conditions are compatible with a
wide range of functional groups including carbethoxy (entry
2), acetyl (entry 3), nitro (entry 4), and cyano (entry 5). It is
noteworthy that even though the coupling is slightly slowed
by ortho substituents, the reaction still goes to completion
within 3 h for both 2-nitrophenyl iodide (entry 11) and
2-methylphenyl iodide (entry 10). Also, heteroaromatic
iodides such as 3-iodopyridine (entry 12) are well-suited for
the cross-coupling reaction.
To further reduce the amount of 5, the ligand/Pd ratio was
examined with most effective additive tri(tert-butyl)phos-
phine. As is apparent from Table 3, the more ligand added,
the less 5 generated. However, the desired cross-coupling
reaction was also retarded by the ligand. When the ligand/
Pd ratio was over 4.2, the reaction was not complete in 22
h. Thus, the preferred ratio of (tert-Bu)3P/Pd is 2.0 for the
coupling of fluorosilane 3 with aryl iodides at 50 °C.
Table 3. The Effect of Ligand/Pd Ratio on the Coupling with
3a
entry
(t-Bu)3Pb
(t-Bu)3P/Pd
conversion (%)
4:5
1
2
3
4
6
10
21
36
1.2
2.0
4.2
7.2
100
100
57
7:1
12:1
56:1
1:0
35
a See Table 2 for reaction conditions. b Mole % (t-Bu)3P with respect to
3.
To investigate the effect of ortho substitution at the
arylsilane, aryl(chloro)silacyclobutane 9 was synthesized and
its reactivity was examined with several aryl iodides (Table
6). Even though the reactions were slower than those with
silane 2, all the couplings with 9 give good yields of the
corresponding biaryl compounds. Remarkably, sterically
crowded 2-methyl-2′-nitrobiphenyl (entry 3) and 2,2′-di-
methylbiphenyl (entry 4) can be prepared cleanly in 77%
and 85% yields, respectively.
In summary, we have demonstrated the utility of hetero-
substituted arylsilacyclobutanes for efficient and high-
yielding cross-coupling reactions with aryl iodides. The
precursors are readily prepared, stable, and storable reagents.
Although our preliminary studies found fluorosilane 3 to
be superior to chlorosilacyclobutane 2, we felt that our better
understanding of reaction variables now warranted a re-
investigation of this reagent. Under the identical conditions
noted above in Table 3, the reaction was not complete within
22 h. By carrying out the reaction in refluxing THF, complete
conversion could be observed within 16 h (Table 4).
However, at the elevated temperature, the amount of side
product 5 increased to 11% with a (t-Bu)3P/Pd ratio of 2.2.
We were pleased to find that amount of 5 can be reduced to
less than 5% when the ratio of P(t-Bu)3/Pd was increased to
4.0.
Org. Lett., Vol. 1, No. 9, 1999
1497

Table 5. Cross-Coupling of Selected Aryl Iodides with 2
Table 6. Cross-Coupling of Selected Aryl Iodides with Aryl
Silane 9
When fluorosilanes are employed, the reaction is run at 50
°C with a ligand/Pd ratio equal to 2.0. If chlorosilanes are
used, the reaction is performed in refluxing THF with a
ligand/Pd ratio of 4.0. For the biaryl synthesis, these
conditions are milder than the other palladium-catalyzed
processes including the acyclic arylsilanes and the typical
Stille and Suzuki reactions.
Extension of the scope of the silacyclobutane cross-
coupling reactions and a study of the mechanistic details will
be reported in due course.
Acknowledgment. Financial support was provided by the
National Science Foundation (NSF CHE 9803124). Z.W.
gratefully acknowledges the University of Illinois for a
Graduate Fellowship.
Extensive reaction optimization revealed five critical vari-
ables: (1) palladium source, (2) arylsilane, (3) additive, (4)
ligand/Pd ratio, and (5) reaction temperature. The optimal
conditions involve [allylPdCl]2 as catalyst and (t-Bu)3P as
the additive. A heteroatom substituent on the silicon of
arylsilacyclobutanes is needed to enhance the reactivity.
Supporting Information Available: Preparation and full
characterization of 2, 3, and 9 and a representative procedure
for the coupling. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL991054K
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Org. Lett., Vol. 1, No. 9, 1999