A new protocol for the one-pot synthesis of symmetrical biaryls

Article abstract of DOI:10.1021/jo0490393

Biaryls play an important role in modern organic chemistry. Although a large number of protocols for the synthesis of symmetrical and unsymmetrical biaryls already exist, most of them are not generally applicable. In our studies toward the total synthesis of the secalonic acids, we were interested in bis(pinacolato)diboron as a reagent for transforming haloarenes into arylboronic esters. By optimizing the reaction conditions, we were able to obtain biaryls containing various functional groups in good to excellent yields.

Full text of DOI:10.1021/jo0490393

A New P r otocol for th e On e-P ot Syn th esis of Sym m etr ica l Bia r yls
Carl F. Nising,† Ulrike K. Schmid,† Martin Nieger,‡ and Stefan Bra¨se*,†
Institut fu¨r Organische Chemie, Universita¨t Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe,
Germany, and Institut fu¨r Anorganische Chemie, Universita¨t Bonn, Gerhard-Domagk-Strasse 1, 53121
Bonn, Germany
braese@ioc.uka.de
Received J une 8, 2004
Biaryls play an important role in modern organic chemistry. Although a large number of protocols
for the synthesis of symmetrical and unsymmetrical biaryls already exist, most of them are not
generally applicable. In our studies toward the total synthesis of the secalonic acids, we were
interested in bis(pinacolato)diboron as a reagent for transforming haloarenes into arylboronic esters.
By optimizing the reaction conditions, we were able to obtain biaryls containing various functional
groups in good to excellent yields.
Biaryls play an important role in modern organic
chemistry. Many natural products, often possessing
biological activity, contain symmetrical or unsymmetrical
biaryl units.1 Prominent examples for such molecules are
Michellamine A (1) or the secalonic acids 2 (Figure 1).2
Since the first coupling reaction performed by Ullmann
over a century ago,3 considerable efforts have led to a
variety of procedures to form biaryls, which have recently
been reviewed.4 Whereas the first coupling reactions were
performed with stoichometric amounts of metal, the
catalytic use of metals, especially palladium, is nowadays
established. Palladium-catalyzed cross-coupling reactions
with organometallic compounds based on tin,5 boron,6 or
zinc,7 for example, are among the most popular reactions.
F IGURE 1. Structures of Michellamine A (1) and the seca-
Recently, several papers for the synthesis of symmetrical
biaryls have been published which reflect the current
efforts in this field of research.8 Because of their high
compatibility with functional groups and the low toxicity
of organoboronic compounds,9 Suzuki cross-coupling re-
actions are frequently used in natural product synthe-
ses.10 Nevertheless, the formation of the boronic acid
lonic acids 2.
derivatives remains challenging as it often requires the
use of strong bases, such as organolithium compounds.
In 1995, Miyaura et al. introduced bis(pinacolato)diboron
as a reagent for the transformation of arylhalides to
arylboronic esters under mild conditions (Scheme 1).11
This procedure allows the synthesis of arylboronic
esters in good yields while tolerating various functional
groups. In another publication, the Miyaura group de-
scribed the cross-coupling of aryl triflates to arylboronic
esters as well as the synthesis of unsymmetrical biaryls
using a modified protocol.12,13 In both cases, the authors
used KOAc as base since stronger bases such as K2CO3
afforded symmetrical biaryls as byproducts. The proposed
mechanism of this reaction is depicted in Scheme 2.
Oxidative addition of the catalyst to haloarene 3 followed
by displacement of the halide leads to the corresponding
† Universita¨t Karlsruhe (TH). Fax: +49-721-608-8581.
‡ Universita¨t Bonn. Fax: +49-228-73-532.7
(1) Bringmann, G.; Ochse, M.; Schupp, O.; Tasler, S. In Progress in
the Chemistry of Organic Natural Products; Springer: Wien, Germany,
2001; Vol. 82.
(2) Bringmann, G.; Tasler, S. Tetrahedron 2001, 57, 331-343.
Franck, B.; Gottschalk, E. M.; Ohnsorge, U.; Hu¨per, F. Chem. Ber.
1966, 99, 3842-3862.
(3) Ullmann, F.; Bielecki, J . Chem. Ber. 1901, 34, 2174.
(4) For reviews see: Hassan, J .; Se´vignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359-1469. Bringmann, G.;
Walter, R.; Weirich, R. Angew. Chem., Int. Ed. 1990, 29, 977-991;
Angew. Chem. 1990, 102, 1006-1019. Diederich, F.; Stang, P. J . Metal-
catalysed Cross-coupling reactions; Wiley-VCH: Weinheim, Germany,
1998.
(5) Stille, J . K. Angew. Chem., Int. Ed. 1986, 25, 508-524; Angew.
Chem. 1986, 98, 504-519.
(10) Chemler, S. R.; Trauner, D.; Danishefsky, S. J . Angew. Chem.,
Int. Ed. 2001, 40, 4544-4568; Angew. Chem. 2001, 113, 4676-4701.
(11) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995, 60,
7508-7510.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(7) Erdik, E. Tetrahedron 1992, 48, 9577.
(8) Demir, A. S.; Reis, O¨ .; Emrullahoglu, M. J . Org. Chem. 2003,
68, 10130-10134. Abiraj, K.; Srinivasa, G. R.; Channe Gowda, D.
Tetrahedron Lett. 2004, 45, 2081-2084. Li, J .-H.; Xie, Y.-X.; Yin, D.-
L. J . Org. Chem. 2003, 68, 9867-9869.
(12) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447-3450.
(13) Amatore, C.; J utand, A. Acc. Chem. Res. 2000, 33, 314-321.
Amatore, C.; J utand, A. J . Organomet. Chem. 1999, 576, 254-278.
(9) Martin, A. R.; Yang, Y. Acta Chem. Scand. 1993, 47, 221.
10.1021/jo0490393 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/03/2004
6830
J . Org. Chem. 2004, 69, 6830-6833

One-Pot Synthesis of Symmetrical Biaryls
SCHEME 1. Tr a n sfor m a tion of Ha loa r en es 3 in to
Ar ylbor on ic Ester s 5
SCHEME 4. Syn th esis of Sym m etr ica l Bia r yls
of bis(pinacolato)diboron, the described procedures pos-
sess a high value for organic synthesis due to the mild
coupling conditions. This reagent has consequently been
used in several total syntheses for introducing boronic
acid esters or biaryl units. In their studies toward the
total synthesis of diazonamide A, Nicolaou and associates
employed this reagent to synthesize one of the key
intermediates.16 Although there have been several stud-
ies on the synthesis of unsymmetrical biaryls by employ-
ing bis(pinacolato)diboron, the potential of this reagent
for the synthesis of symmetrical biaryls has not been
examined to date.17 In the course of our investigations
toward the total synthesis of the secalonic acids 2, which
contain a symmetrical biaryl core, we became interested
in the possibility of a direct coupling reaction according
to Scheme 4.
SCHEME 2. P r op osed Rea ction Mech a n ism for
th e Gen er a tion of Ar ylbor on ic Ester s13
In our first attempts we applied the original protocol
published by Miyaura and associates using K2CO3 as the
base on several haloarenes and were pleased to obtain
the corresponding biaryls in good to excellent yields
(Table 1).
SCHEME 3. P r op osed Rea ction Mech a n ism for
th e F or m a tion of th e Bia r yls
As shown in Table 1, the reaction tolerates a variety
of functional groups such as cyano, acetoxy, or ester
groups. However, limitations are clearly visible. The
reaction is slow for substrates containing electron-donat-
ing or bulky substituents such as methoxy or tert-butyl
groups and chloroarenes are not suitable substrates. One
of the major disadvantages of the reaction is the fast
degradation of the catalyst leading to a black palladium
precipitate. As the reaction proceeds slowly for electron-
rich or sterically-hindered substrates such as entry 3 or
13, we decided to add diphenylphosphinoferrocene (dppf)
to slow the catalyst decomposition. According to Table
1, the additional ligand leads to good results even for
difficult substrates such as entry 3 or 13. Recrystalliza-
tion of bis-3,3′([1,3]-dioxolano)-4,4′-dimethoxybiphenyl
(14) yielded colorless crystals which were suitable for
single-crystal X-ray diffraction. The structure is included
in the Supporting Information. To expand the range of
substrates, we also used aryltriflates for this homocou-
pling reaction. As depicted in Table 2, aryltriflates are
also excellent substrates for the synthesis of symmetrical
biaryls. Interestingly, the reaction also worked with
DMSO as the solvent whereas the reported transforma-
tion of aryltriflates into arylboronates is only successful
when using dioxane.12 In our case, DMSO as well as
dioxane led to good results.
pentacoordinate palladium(II) species. Transmetalation
with bis(pinacolato)diboron (4) followed by reductive
elimination yields the arylboronic ester 5.
The effect of stronger bases such as K2CO3 probably
lies in their stronger nucleophilicity. After exchange of
the halide against carbonate the neutral arylboronic ester
5 is coordinated leading to the formation of the corre-
sponding biaryl 6 as shown in Scheme 3. This mechanism
seems to be plausible regarding studies by Soderquist et
al., who could show that halide exchange followed by
reaction with the neutral borane species dominates the
formation of rather unstable boronic ate complexes in the
case of oxygenated organoboron compounds.14 However,
these studies did not make use of carbonate salts as base.
As a result, the reaction does not stop with the for-
mation of the arylboronic ester 5 but continues with a
Suzuki coupling step to yield the corresponding biaryls
6. In following studies, Miyaura and co-workers also
introduced an efficient protocol for the conversion of
alkenyl halides and triflates into the corresponding
alkenylboronic esters.15 Despite the relatively high cost
Relating to the total synthesis of the secalonic acids
(2), we were also interested in applying the present
protocol to functionalized xanthones which represent the
core of the secalonic acids. Due to the acidic protons next
to the xanthone carbonyl function, we chose racemic
xanthenol methyl ether 22 as the substrate for homo-
(16) Nicolaou, K. C.; Snyder, S. A.; Simonsen, K. B.; Koumbis, A.
E. Angew. Chem., Int. Ed. 2000, 39, 3473-3478; Angew. Chem. 2000,
112, 3615-3620.
(17) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841-
3844.
(14) Matos, K.; Soderquist, J . A. J . Org. Chem. 1998, 63, 461-470.
(15) Takagi, J .; Takahashi, K.; Ishiyama, T.; Miyaura, N. J . Am.
Chem. Soc. 2002, 124, 8001-8006.
J . Org. Chem, Vol. 69, No. 20, 2004 6831

Nising et al.
TABLE 1. Syn th esis of Sym m etr ica l Bia r yls fr om
Ha loa r en es (Sch em e 4)a
TABLE 2. Syn th esis of Sym m etr ica l Bia r yls fr om
Ar yltr ifla tesa
a
All reactions were performed at 80 °C in DMSO or dioxane,
using haloarene (1 equiv), 4 (0.5 equiv), PdCl2dppf (4 mol %), and
b
d
K2CO3 (3 equiv). Isolated yields. c Solvent DMSO. Solvent di-
oxane. e 4 mol % of dppf was added.
SCHEME 5. Syn th esis of Bisxa n th en e 23
coupling. The bromide 22 is readily available from 5-bro-
mosalicylic aldehyde and 2-cyclohexenone in a 3-step
synthesis.18,19 As shown in Scheme 5, when subjected to
the cross-coupling conditions, the xanthone gave the
bisxanthene 23 in reasonable yield. However, we could
only isolate one apparent diastereomer of 23 and there
were no traces of other diastereomers detectable by NMR
or GC.
In summary, we have developed an easy and widely
applicable procedure for the synthesis of symmetrical
biaryls. Bromo- and iodoarenes as well as arenetriflates
are suitable substrates for the reaction and due to its
mild conditions, a large variety of functional groups can
be tolerated. As shown before, the reaction is also
applicable to complex and sterically hindered substrates
such as tetrahydroxanthones. Further studies on the
scope of this reaction, as well as its application in the
total synthesis of the secalonic acids, are currently in
progress.
Exp er im en ta l Section
All reactions were carried out according to the following
procedure: A dry flask with an argon atmosphere was charged
with haloarene or arenetriflate (1.0 equiv), 4 (0.5 equiv),
PdCl2dppf (4.0 mol %), and K2CO3 (3.0 equiv). In some cases,
4.0 mol % of dppf was added. After addition of 6 mL of DMSO
or dioxane, the reaction was stirred at 80 °C for 14 h. The
reaction mixture was cooled to room temperature and ex-
(18) 7-Bromo-2,3,4,4a-tetrahydroxanthene-1-one (24), which was
synthesized following a literature procedure,17 was reduced to 7-bromo-
2,3,4,4a-tetrahydroxanthene-1-ol (25) yielding only one diastereomer.
The last step included the protection of the alcohol function as methyl
ether. Further details are included in the Supporting Information.
(19) Lesch, B.; Bra¨se, S. Angew. Chem., Int. Ed. 2004, 43, 115-118;
Angew. Chem. 2004, 116, 118-120.
a
All reactions were performed at 80 °C in DMSO, using
haloarene (1 equiv), 4 (0.5 equiv), PdCl2dppf (4 mol %), and K2CO3
(3 equiv). Isolated yields. c 4 mol % of dppf was added.
b
6832 J . Org. Chem., Vol. 69, No. 20, 2004

One-Pot Synthesis of Symmetrical Biaryls
tracted with CH2Cl2, and the combined organic layers were
washed with water and aqueous sodium hydroxide solution
(20%). Drying over anhydrous sodium sulfate followed by
column chromatography yielded the corresponding biaryls.
8,8′-Dim eth oxy-5,7,8,10a ,5′,7′,8′,10′a -octa h yd r o-6H,6′H-
[2,2′]bixa n th en yl (23). Yellow solid (71 mg, 165 µmol, 42%
yield). Analytical TLC (silica gel 60, cyclohexane/EtOAc 5/1
v/v) Rf 0.28; 1H NMR (500 MHz, CDCl3) δ 1.28-1.46 (m, 4H),
1.75-1.92 (m, 4H), 2.11-2.21 (m, 4H), 3.50 (s, 6H), 3.58 (dd,
J ) 11.0, 4.7 Hz, 2H), 4.90 (dd, J ) 11.3, 5.0 Hz, 2H), 6.33 (s,
2H), 6.70 (d, J ) 8.2 Hz, 2H), 7.08 (d, J ) 2.2 Hz, 2H), 7.19
(dd, J ) 8.5, 2.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 20.4,
33.5, 35.2, 57.9, 77.0, 79.9, 113.8, 115.3, 121.0, 124.9, 126.9,
134.0, 138.2, 151.9; IR (cm-1, KBr) 2938 (m, ν Ar-H); EI-MS
m/z (rel intensity) 430 (18%) [M+]; HR-MS (EI) for C28H30O4
(M+) calcd 430.2144, found 430.2147.
HR-MS (EI) for C20H22O6 (M+) calcd 358.1416, found 358.1419.
Anal. Calcd for C20H22O6: C 67.03, H 6.19. Found: C 66.94, H
6.20.
4-(4,4′-B is b e n zy lo x y -3′-m e t h y lb ip h e n y l-3-y l)[1,3]-
d ioxola n e (4). Colorless solid (166 mg, 325 µmol, 65% yield).
Analytical TLC (silica gel 60, cyclohexane/EtOAc 5/1 +2% NEt3
v/v) Rf 0.12; mp 178-179 °C; 1H NMR (500 MHz, CDCl3) δ
4.03-4.17 (m, 8H), 5.18 (s, 4H), 6.28 (s, 2H), 6.97 (d, J ) 8.8
Hz, 2H), 7.32-7.48 (m, 12H), 7.73 (d, J ) 2.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 65.7, 70.8, 99.9, 113.1, 125.9, 126.9,
127.5, 128.2, 128.9, 129.1, 133.9, 137.4, 156.4; IR (cm-1, KBr)
3029 (w, ν Ar-H); EI-MS m/z (rel intensity) 510 (55%) [M+],
419 (28%) [(M - Bn)+], 91 (100%) [Bn+]; HR-MS (EI) for
C
C
32H30O6 (M+) calcd 510.2042, found 510.2043. Anal. Calcd for
32H30O6: C 75.28, H 5.92. Found: C 75.11, H 5.95.
2-(4,4′-Dim et h oxy-3′-m et h ylb ip h en yl-3-yl)-[1,3]d iox-
ola n e (14). Colorless solid (106 mg, 296 µmol, 60% yield).
Analytical TLC (silica gel 60, cyclohexane/EtOAc 2/1 +2% NEt3
v/v) Rf 0.08; mp 112-114 °C;1H NMR (500 MHz, CDCl3) δ 3.90
(s, 6H), 4.04-4.18 (m, 8H), 6.20 (s, 2H), 6.95 (d, J ) 8.5 Hz,
2H), 7.51 (dd, J ) 8.5, 2.5 Hz, 2H), 7.73 (d, J ) 2.5 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 56.2, 65.7, 99.8, 111.4, 125.6,
126.3, 128.9, 133.7, 157.2; IR (cm-1, KBr): 3046 (w, ν Ar-H);
EI-MS m/z (rel intensity) 358 (3%) [M+], 43 (100%) [C2H3O+];
Ack n ow led gm en t. We thank the Fonds der Che-
mischen Industrie for a fellowship (C.F.N.).
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for all products not described in the text as
well as X-ray structure data for compound 14. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0490393
J . Org. Chem, Vol. 69, No. 20, 2004 6833