Efficient synthesis of sterically crowded biaryls by palladium-phosphinous acid-catalyzed cross-coupling of aryl halides and aryl grignards

Article abstract of DOI:10.1021/jo701893m

(Chemical Equation Presented) A series of sterically hindered biaryls have been obtained by palladium- and nickel-phosphinous acid-catalyzed Kumada-Corriu cross-coupling of ortho-substituted aryl halides and Grignard reagents. This method allows formation

Full text of DOI:10.1021/jo701893m

Efficient Synthesis of Sterically Crowded Biaryls by
Palladium-Phosphinous Acid-Catalyzed Cross-Coupling of Aryl
Halides and Aryl Grignards
Christian Wolf* and Hanhui Xu
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057
cw27@georgetown.edu
ReceiVed August 28, 2007
A series of sterically hindered biaryls have been obtained by palladium- and nickel-phosphinous acid-
catalyzed Kumada-Corriu cross-coupling of ortho-substituted aryl halides and Grignard reagents. This
method allows formation of di- and tri-ortho-substituted biaryls in 87-98% yield under mild reaction
conditions even when electron-rich aryl chlorides are used. The reaction also proceeds with aryl iodides
at -20 °C, and under these conditions, functional groups that are generally not compatible with Grignard
reagents are tolerated.
Introduction
Following Kharasch’s seminal work on cobalt(II)-catalyzed
reactions with organomagnesium compounds,10 Kumada and
Corriu independently reported in 1972 the first cross-coupling
of aryl halides and aryl Grignards.11 Despite these early
The biaryl motif is a ubiquitous building block that determines
the properties and applications of many natural products,1
pharmaceuticals,2 catalysts,3 and sensors.4 It has been established
that the dihedral angle between the aryl planes and the barrier
to rotation about the pivotal bond of biaryls mainly depend on
the number and size of ortho substituents, while buttressing
effects and electronic contributions from meta and para sub-
stituents, respectively, play a minor role.5 The synthesis of
sterically crowded biaryls by transition-metal-catalyzed cross-
coupling is quite challenging because strong repulsion between
ortho substituents impedes formation of the incipient aryl-aryl
bond.6 Nevertheless, a wide range of congested biaryls has been
prepared from aryl halides and boronic acids,7 stannanes,8 or
organozinc compounds.9
(5) (a) Rieger, M.; Westheimer, F. H. J. Am. Chem. Soc. 1950, 72, 19-
28. (b) Bott, G.; Field, L. D.; Sternhell, S. J. Am. Chem. Soc. 1980, 102,
5618-5626. (c) Wolf, C.; Ko¨nig, W. A.; Roussel, C. Liebigs Ann. 1995,
781-786. (d) Weseloh, G.; Wolf, C.; Ko¨nig, W. A. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1635-1636. (e) Wolf, C.; Hochmuth, D. H.; Ko¨nig,
W. A.; Roussel, C. Liebigs Ann. 1996, 357-363. (f) Wolf, C.; Pirkle, W.
H.; Welch, C. J.; Hochmuth, D. H.; Ko¨nig, W. A.; Chee, G.-L.; Charlton,
J. L. J. Org. Chem. 1997, 62, 5208-5210. (g) Wolf, C.; Ghebremariam, T.
Tetrahedron: Asymmetry 2002, 13, 1153-1156. (h) Wolf, C.; Tumambac,
G. E. J. Phys. Chem. A 2003, 107, 815-817.
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E.; Lemaire, M. Chem. ReV. 2002, 102, 1359-1469. (b) Littke, A. F.; Fu,
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B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46, 2768-
2813.
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Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162-1163. (b) Jensen, J.
F.; Johannsen, M. Org. Lett. 2003, 5, 3025-3028. (c) Navarro, O.; Kelly,
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Altenhoff, G.; Goddard, R.; Lehmann, C.; Glorius, F. J. Am. Chem. Soc.
2004, 126, 15195-15201. (e) Singh, R.; Viciu, M. S.; Kramareva, N.;
Navarro, O.; Nolan, S. P. Org. Lett. 2005, 7, 1829-1832. (f) Marion, N.;
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125, 10651-10658. (b) Tumambac, G. E.; Wolf, C. J. Org. Chem. 2004,
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J. G. J. Am. Chem. Soc. 2004, 126, 16433-16439. (d) Tumambac, G. E.;
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10.1021/jo701893m CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/06/2007
162
J. Org. Chem. 2008, 73, 162-167

Efficient Synthesis of Sterically Crowded Biaryls
SCHEME 1. Formation of (t-Bu2POH)2ML2
discoveries, Suzuki, Stille, and Negishi reactions have been
studied in much more detail and gained considerably more
popularity due to the inherently superior functional group
tolerance. A remaining drawback of these methods is the limited
reactivity of aryl boronic acids, stannanes, and zinc compounds
which are usually prepared from Grignard or organolithium
precursors. The direct use of Grignard reagents therefore remains
an attractive alternative that eliminates an unnecessary synthetic
step. Since Knochel et al. introduced elegant synthetic entries
to organomagnesium compounds which tolerate the presence
of ester, nitrile, nitro, and other functional groups at 25 °C or
under cryogenic conditions,12 the Kumada-Corriu reaction has
received increasing attention.13 However, many procedures
require high temperatures, and transition-metal-catalyzed coup-
ling of sterically hindered aryl chlorides or bromides with ortho-
substituted aryl Grignard reagents has not been reported.14
sterically unhindered aryl chlorides,17 we decided to explore
the possibility of nickel- and palladium-phosphinous acid-
catalyzed formation of biaryls exhibiting at least two ortho
substituents from readily available aryl Grignard reagents. In
particular, the development of a mild coupling method that
utilizes unactivated, sterically hindered aryl bromides and
chlorides would be very useful.
On the basis of our experience with palladium-phosphinous
acid-catalyzed Suzuki, Stille, and Hiyama reactions and because
of the high nucleophilicity of organomagnesium compounds,
we anticipated that transmetalation might readily occur at room
temperature while oxidative addition would be the rate-limiting
step. We therefore focused our initial efforts on the cross-
coupling of Grignard reagents with aryl bromides which are
more reactive than chlorides. The effects of palladium precata-
lyst, ligand, and solvent on the reaction between 2-bromo-1-
isopropylbenzene, 1, and 2-tolylmagnesium bromide, 2, were
systematically examined. Using 5 mol % of a nickel-phosphi-
nous acid prepared in situ from equimolar amounts of Ni(cod)2
and di-tert-butylphosphine oxide in tetrahydrofuran, we found
that biphenyl 3 can be prepared in 89% yield at room
temperature within 15 h. Further studies revealed that 3 mol %
of Pd2(dba)3 provides slightly better results (Table 1, entries 1,
2, and 7-9). We then used this catalyst to evaluate the scope
of the reaction. As shown in Table 1, a wide range of sterically
hindered biaryls was prepared in up to 96% yield with this
procedure.18
When we employed aryl chlorides in the Kumada-Corriu
reaction, we realized that heating to 50 °C is necessary when
the nickel precatalyst is used while the palladium-phosphinous
acid affords much better results at room temperature (Table 2,
entries 1, 2, 4, and 9). The same yields were obtained by in
situ formation of the palladium-phosphinous acid from Pd2(dba)3
and di-tert-butylphosphine oxide and by direct use of POPd
which can be conveniently stored at room temperature and under
air. This method provides di- and tri-ortho-substituted biaryls
in excellent yields even when electron-rich chlorides, which are
generally reluctant to oxidative addition under mild conditions,
are used. For example, coupling of 1-chloro-2-methoxybenzene,
29, with 2-isopropylphenylmagnesium bromide, 30, or di-ortho-
substituted aryl Grignards 13, 27, and 38 gave biaryls 31, 35,
37, and 40, respectively, in 89-93% yield (entries 1, 5, 7, and
10). To the best of our knowledge, the cross-coupling of ortho-
substituted aryl chlorides with sterically hindered Grignard
reagents is unprecedented.
Results and Discussion
We and others have introduced palladium-phosphinous acids
to Suzuki, Stille, Hiyama, Sonogashira, and other cross-coupling
reactions.15 This class of catalysts enjoys several synthetic
applications, and it is stable to air and water, which facilitates
operation and catalyst handling and storage (Scheme 1).16 Since
Li demonstrated the feasibility of Kumada-Corriu coupling with
(9) Selected examples: (a) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001,
123, 2719-2724. (b) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004,
126, 13028-13032. (c) Genov, M.; Fuentes, B.; Espinet, P.; Pelaz, B.
Tetrahedron: Asymmetry 2006, 17, 2593-2595. (d) Genov, M.; Almorin,
A.; Espinet, P. Tetrahedron: Asymmetry 2007, 18, 625-627.
(10) Kharasch, M. S.; Fuchs, C. F. J. Am. Chem. Soc. 1943, 65, 504-
507.
(11) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972,
94, 4374-4376. (b) Corriu, R. J. P.; Masse, J. P. Chem. Commun. 1972,
144.
(12) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333-3336. (b) Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew.
Chem., Int. Ed. 2004, 43, 4364-4366. (c) Hiriyakkanavar, I.; Baron, O.;
Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 583-593.
(13) (a) Bonnet, V.; Mongin, F.; Trecourt, F.; Queguiner, G.; Knochel,
P. Tetrahedron Lett. 2001, 42, 5717-5719. (b) Korn, T. J.; Cahiez, G.;
Knochel, P. Synlett 2003, 1892-1894. (c) Korn, T. J.; Schade, M. A.;
Cheemala, M. N.; Wirth, S.; Guevara, S. A.; Cahiez, G.; Knochel, P.
Synthesis 2006, 3547-3574.
(14) (a) Minato, A.; Suzuki, K.; Tamao, K.; Kumada, M. J. Chem. Soc.,
Chem. Commun. 1984, 511-513. (b) Huang, J.; Nolan, P. S. J. Am. Chem.
Soc. 1999, 121, 9889-9890. (c) Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.;
Weskamp, T.; Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387-
3389. (d) Mongin, F.; Mojovic, L.; Guillamet, B.; Trecourt, F.; Queguiner,
G. J. Org. Chem. 2002, 67, 8991-8994. (e) Walla, P.; Kappe, C. O. Chem.
Commun. 2004, 564-565. (f) Dankwardt, J. W. J. Organomet. Chem. 2005,
690, 932-938. (g) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org.
Chem. 2005, 70, 9364-9370. (h) Ackermann, L.; Althammer, A. Org. Lett.
2006, 8, 3457-3460. (i) Rueping, M.; Ieawsuwan, W. Synlett 2007, 247-
250. (i) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem.,
Int. Ed. 2005, 44, 7216-7219. (j) Organ, M. G.; Abdel-Hadi, M.; Avola,
S.; Hadei, N.; Nasielski, J.; O’Brien, C. J.; Valente, C. Chem.sEur. J. 2007,
13, 150-157. (k) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3844-3845. (l) Lau, S. Y. W.; Hughes, G.; O’, Shea, P. D.; Davies,
I. W. Org. Lett. 2007, 9, 2239-2242.
(15) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516. (b) Li,
G. Y. J. Org. Chem. 2002, 67, 3643-3650. (c) Wolf, C.; Lerebours, R.;
Tanzini, E. H. Synthesis 2003, 2069-2073. (d) Wolf, C.; Lerebours, R. J.
Org. Chem. 2003, 68, 7077-7084. (e) Wolf, C.; Lerebours, R. J. Org. Chem.
2003, 68, 7551-7554. (f) Wolf, C.; Lerebours, R. Org. Lett. 2004, 6, 1147-
1150. (g) Wolf, C.; Lerebours, R. Org. Biomol. Chem. 2004, 2, 2161-
2164. (h) Lerebours, R.; Wolf, C. Synthesis 2005, 2287-2292. (i) Bigeault,
J.; Giordano, L.; Buono, G. Angew. Chem., Int. Ed. 2005, 44, 4753-4757.
(j) Lerebours, R.; Camacho-Soto, A.; Wolf, C. J. Org. Chem. 2005, 70,
8601-8604. (k) Wolf, C.; Ekoue-Kovi, K. Eur. J. Org. Chem. 2006, 1917-
1925.
As expected, our POPd-catalyzed coupling procedure is also
suitable to aryl iodides. We obtained biaryls 5 and 28 in 90-
96% yield from 1-iodonaphthalene, 42, and Grignards 27 and
30, even when the temperature was lowered to -20 °C (Scheme
2). Under these conditions, the presence of an ester group is
well tolerated. Coupling of 30 and methyl 4-bromo-3-methyl
(17) Li, G. Y. J. Organomet. Chem. 2002, 653, 63-68.
(18) During the preparation of this paper, a Pd-catalyzed Kumada-Corriu
coupling providing a 2,2′,6-trimethylbiphenyl derivative in 93% yield from
an aryl iodide was reported; see ref 14k.
(16) (a) Ackermann, L. Synthesis 2006, 1557-1571. (b) Lerebours, R.;
Wolf, C. J. Am. Chem. Soc. 2006, 128, 13052-13053.
J. Org. Chem, Vol. 73, No. 1, 2008 163

Wolf and Xu
TABLE 1. Kumada-Corriu Coupling of Aryl Bromides with Palladium- and Nickel-Derived Phosphinous Acidsa
a Reaction conditions: aryl bromide (1.0 mmol), Pd2(dba)3 (3 mol %), di(tert-butyl)phosphine oxide (6 mol %), arylmagnesium bromide (2.0 mmol) in
THF (2.0 M), 25 °C, 15 h. b Isolated yields. c Ni(cod)2 (5 mol %), di(tert-butyl)phosphine oxide (5 mol %).
164 J. Org. Chem., Vol. 73, No. 1, 2008

Efficient Synthesis of Sterically Crowded Biaryls
TABLE 2. Cross-Coupling of Aryl Chlorides with Grignard Reagentsa
a Reaction conditions: aryl chloride (1.0 mmol), POPd (5 mol %), arylmagnesium bromide (2.0 mmol) in THF (2.0 M), 25 °C, 15 h. b Isolated yields.
c 24 h. d Ni(cod)2 (5 mol %), di(tert-butyl)phosphine oxide (5 mol %), 50 °C, 24 h.
J. Org. Chem, Vol. 73, No. 1, 2008 165

Wolf and Xu
SCHEME 2. POPd-Catalyzed Kumada-Corriu Coupling
Using Aryl Iodides
1-(2-Isopropylphenyl)naphthalene, 5. Purification by flash
chromatography (hexanes) gave 0.90 mmol of a colorless oil (90%
from bromide): 1H NMR δ 1.03 (d, J ) 6.8 Hz, 3H), 1.05 (d, J )
6.8 Hz, 3H), 2.64 (sept, J ) 6.8 Hz, 1H), 7.17-7.50 (m, 9H), 7.82-
7.88 (m, 2H); 13C NMR δ 24.1, 25.5, 30.7, 125.9, 126.0, 126.1,
126.4, 126.5, 127.0, 127.5, 128.0, 128.7, 128.8, 131.2, 133.4, 134.1,
139.7, 140.4, 148.3. Anal. Calcd for C19H18: C, 92.64; H, 7.36.
Found: C, 92.60; H, 7.23.
2-Isopropyl-2′-phenylbiphenyl, 7. Purification by flash chro-
matography (hexanes) gave 0.94 mmol of colorless crystals (94%
from bromide): 1H NMR δ 0.64 (d, J ) 6.8 Hz, 3H), 0.95 (d, J )
6.8 Hz, 3H), 2.66 (sept, J ) 6.8 Hz, 1H), 7.06-7.46 (m, 13H); 13
C
NMR δ 22.4, 25.6, 30.0, 125.3, 125.5, 126.7, 127.3, 127.8, 127.9,
128.0, 130.0, 131.1, 140.3, 140.6 141.3, 141.6, 146.7. Anal. Calcd
for C21H20: C, 92.60; H, 7.40. Found: C, 92.24; H, 7.35.
2-Cyclohexyl-2′-isopropylbiphenyl, 9. Purification by flash
chromatography (hexanes) gave 0.95 mmol of a colorless oil (95%
from bromide): 1H NMR δ 0.86-1.34 (m, 8H), 1.46-1.74 (m,
8H), 2.29 (m, 1H), 2.70 (sept, J ) 6.8 Hz, 1H), 7.03-7.38 (m,
8H); 13C NMR δ 23.8, 25.4, 26.8, 27.4, 30.5, 34.1, 36.0, 41.2, 125.7,
125.8, 126.5, 126.6, 128.0, 128.2, 130.3, 130.4, 140.8, 141.1, 146.4,
147.3. Anal. Calcd for C21H26: C, 90.59; H, 9.41. Found: C, 90.51;
H, 9.11.
benzoate, 43, gave ester 44 in 86% yield. Our method thus
extends the scope of this reaction to sterically hindered substrates
bearing functional groups that are usually not compatible with
organomagnesium reagents.
Conclusion
1-(2-Isopropylphenyl)-2-methylnaphthalene, 11. Purification
by flash chromatography (hexanes) gave 0.92 mmol of a colorless
oil (92% from bromide): 1H NMR δ 0.95 (d, J ) 6.8 Hz, 3H),
1.06 (d, J ) 6.8 Hz, 3H), 2.15 (s, 3H), 2.47 (sept, J ) 6.8 Hz,
1H), 7.04 (dd, J ) 7.6, 1.5 Hz, 1H), 7.20-7.41 (m, 6H), 7.45 (dd,
J ) 7.8, 1.5 Hz, 1H), 7.72 (d, J ) 8.3 Hz, 1H), 7.77 (d, J ) 7.8
Hz, 1H); 13C NMR δ 21.4, 24.6, 25.0, 30.8, 125.4, 126.3, 126.4,
126.9, 127.8, 128.4, 128.6, 128.7, 129.2, 130.8, 132.6, 133.9, 134.0,
138.2, 138.5, 148.2. Anal. Calcd for C20H20: C, 92.26; H, 7.74.
Found: C, 91.84; H, 7.41.
2,2′,6-Trimethylbiphenyl, 14.19 Purification by flash chroma-
tography (hexanes) gave 0.89 mmol of a colorless oil (89% from
bromide): 1H NMR δ 1.94 (s, 6H), 1.96 (s, 3H), 7.00-7.27 (m,
7H); 13C NMR δ 20.1, 21.0, 126.7, 127.6, 127.7, 127.9, 129.5,
130.6, 136.2, 136.5, 141.2, 141.7.
In summary, we have developed a broadly applicable pal-
ladium-catalyzed Kumada-Corriu cross-coupling method that
utilizes sterically hindered substrates under mild reaction
conditions. Our procedure furnishes di- and tri-ortho-substituted
biaryls in 87-98% yield and is suited for a range of aryl halides,
including electron-rich aryl chlorides. The reaction proceeds with
aryl iodides at -20 °C, and under these conditions, functional
groups that are generally not compatible with Grignard reagents
are tolerated. The POPd-catalyzed Kumada-Corriu reaction
provides efficient access to sterically congested multifunctional
biaryls and eliminates the need for conversion of intermediate
aryl Grignard reagents to the corresponding boronic acids or
stannanes prior to the cross-coupling step.
1-(2-Tolyl)naphthalene, 15.20 Purification by flash chromato-
graphy (hexanes) gave 0.96 mmol of colorless crystals (96% from
bromide): 1H NMR δ 2.00 (s, 3H), 7.21-7.36 (m, 6H), 7.41-
7.51 (m, 3H), 7.83 (d, J ) 8.3 Hz, 1H), 7.87 (d, J ) 8.5 Hz, 1H);
13C NMR δ 20.7, 126.0, 126.2, 126.4, 126.6, 126.8, 127.3, 128.1,
128.2, 128.9, 130.5, 131.0, 132.7, 134.2, 137.4, 140.4, 140.9.
2-Methoxy-2′-methylbiphenyl, 17.21 Purification by flash chro-
matography (hexanes/CH2Cl2 10:1) gave 0.89 mmol of a colorless
oil (89% from bromide): 1H NMR δ 2.13 (s, 3H), 3.70 (s, 3H),
6.90-7.33 (m, 8H); 13C NMR δ 20.3, 55.7, 111.1, 120.9, 125.9,
127.7, 129.0, 130.0, 130.4, 131.3, 131.4, 137.2, 139.1, 157.0.
2-Dimethylamino-2′-methylbiphenyl, 19.22 Purification by flash
chromatography (hexanes/CH2Cl2 9:1) gave 0.83 mmol of a
colorless oil (83% from bromide): 1H NMR δ 2.15 (s, 3H), 2.50
(s, 6H), 6.95-7.30 (m, 8H); 13C NMR δ 20.6, 43.8, 118.1, 121.7,
126.3, 127.4, 128.6, 130.6, 130.7, 132.4, 135.2, 136.8, 142.4, 152.2.
1-(2-Cyclohexylphenyl)naphthalene, 21. Purification by flash
chromatography (hexanes) gave 0.94 mmol of a colorless oil (94%
from bromide): 1H NMR δ 0.78-1.75 (m, 10H), 2.25 (m, 1H),
7.06-7.41 (m, 7H), 7.45 (t, J ) 8.8 Hz, 2H), 7.82 (t, J ) 8.8 Hz,
2H); 13C NMR δ 26.7, 27.3, 34.3, 36.0, 41.3, 125.8, 125.9, 126.3,
126.4, 126.8, 127.0, 127.4, 128.0, 128.5, 128.7, 131.2, 133.4, 134.1,
139.8, 140.3, 147.3. Anal. Calcd for C22H22: C, 92.26; H, 7.74.
Found: C, 91.80; H, 7.83.
Experimental Section
All chemicals used were of reagent grade, and reactions were
carried out under nitrogen. Flash chromatography was performed
on Kieselgel 60, particle size 0.032-0.063 mm. NMR spectra were
obtained at 300 MHz (1H NMR) and 75 MHz (13C NMR) using
CDCl3 as solvent. Chemical shifts are reported in parts per million
relative to TMS.
General Procedure for the Palladium-Phosphinous Acid-
Catalyzed Cross-Coupling of Aryl Halides and Aryl Grignard
Reagents. A solution of Pd2(dba)3 (0.03 mmol) and di(tert-butyl)-
phosphine oxide (0.06 mmol) in anhydrous tetrahydrofuran (1.0
mL) was stirred under nitrogen for 4 h. Then, a solution of the
aryl halide (1.00 mmol) in anhydrous tetrahydrofuran (1.0 mL) was
added, and the mixture was stirred for another 15 min. This was
followed by dropwise addition of the aryl Grignard reagent (2.00
mmol, ∼2 M, prepared prior to use from another aryl halide (2.0
mmol) and magnesium (3.0 mmol) in anhydrous tetrahydrofuran)
at room temperature. The mixture was stirred at 25 °C for 15 h,
quenched with water, extracted with diethyl ether, and dried over
anhydrous MgSO4. The solvents were removed under vacuum, and
the crude product was purified by flash chromatography on silica
gel.
2-Isopropyl-2′-methylbiphenyl, 3. Purification by flash chro-
matography (hexanes) gave 0.90 mmol of a colorless oil (90% from
bromide): 1H NMR δ 1.07 (d, J ) 6.8 Hz, 3H), 1.14 (d, J ) 6.8
Hz, 3H), 2.05 (s, 3H), 2.69 (sept, J ) 6.8 Hz, 1H), 7.04-7.40 (m,
8H); 13C NMR δ 20.2, 23.2, 24.7, 29.8, 125.3, 125.5, 127.1, 127.6,
129.3, 129.4, 129.6, 129.7, 136.0, 140.3, 141.5, 146.5. Anal. Calcd
for C16H18: C, 91.37; H, 8.63. Found: C, 90.95; H, 8.41.
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T.; Tsuji, Y. Org. Lett. 2007, 9, 89-92.
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166 J. Org. Chem., Vol. 73, No. 1, 2008

Efficient Synthesis of Sterically Crowded Biaryls
2-Cyclohexyl-2′-dimethylaminobiphenyl, 22. Purification by
flash chromatography (hexanes/CH2Cl2 9:1) gave 0.94 mmol of a
colorless oil (94% from bromide): 1H NMR δ 0.83-1.65 (m, 10H),
1.79 (m, 1H), 2.47 (s, 6H), 6.94-7.34 (m, 8H); 13C NMR δ 27.0,
27.7, 34.0, 36.2, 41.4, 43.8, 118.1, 121.8, 126.1, 127.0, 127.7, 128.5,
130.8, 132.6, 135.6, 141.2, 146.4, 152.2. Anal. Calcd for C20H25N:
C, 85.97; H, 9.02; N, 5.01. Found: C, 85.71; H, 8.52; N, 4.94.
2-Cyclohexyl-2′-methoxybiphenyl, 23. Purification by flash
chromatography (hexanes/CH2Cl2 10:1) gave 0.93 mmol of a
colorless oil (93% from bromide): 1H NMR δ 1.04-1.87 (m, 10H),
2.36 (m, 1H), 3.68 (s, 3H), 6.90-7.35 (m, 8H); 13C NMR δ 26.9,
27.6, 34.3, 35.6, 41.5, 55.8, 111.0, 121.0, 125.9, 126.4, 128.2, 129.0,
130.8, 131.5, 131.9, 138.2, 147.0, 157.3. Anal. Calcd for C19H22O:
C, 85.67; H, 8.32. Found: C, 85.75; H, 8.06.
2-Cyclohexyl-2′-phenylbiphenyl, 25. Purification by flash chro-
matography (hexanes) gave 0.96 mmol of colorless crystals (96%
from bromide): 1H NMR δ 0.56 (m, 1H), 0.92-1.23 (m, 5H),
1.43-1.57 (m, 4H), 2.22 (m, 1H), 7.06-7.45 (m, 13H); 13C NMR
δ 26.8, 27.6, 32.8, 36.2, 41.1, 125.7, 126.6, 127.1, 127.7, 128.0,
128.1, 128.3, 130.3, 130.4, 131.5, 131.7, 140.9, 150.0, 141.6, 142.0,
146.0. Anal. Calcd for C24H24: C, 92.26; H, 7.74. Found: C, 91.98;
H, 7.52.
of a colorless oil (91% from chloride): 1H NMR δ 2.17 (s, 3H),
3.50 (s, 3H), 6.92 (d, J ) 8.3 Hz, 1H), 7.00 (ddd, J ) 7.3, 7.3, 1.2
Hz, 1H), 7.10 (dd, J ) 7.4, 1.8 Hz, 1H), 7.20-7.38 (m, 5H), 7.69
(d, J ) 8.3 Hz, 1H), 7.74 (d, J ) 8.3 Hz, 1H); 13C NMR δ 21.1,
56.0, 111.7, 121.3, 125.2, 126.3, 126.5, 127.8, 128.4, 128.8, 129.1,
129.4, 132.4, 132.6, 133.6, 134.4, 135.3, 157.9.
9-(2-Tolyl)anthracene, 39.28 Purification by flash chromato-
graphy (hexanes/CH2Cl2 10:1) gave 0.90 mmol of white crystals
(90% from chloride): 1H NMR δ 1.84 (s, 3H), 7.21-7.41 (m, 8H),
7.50 (d, J ) 8.8 Hz, 2H), 7.97 (d, J ) 8.6 Hz, 2H), 8.42 (s, 1H);
13C NMR δ 20.41, 125.8, 126.1, 126.5, 127.1, 127.2, 128.5, 129.1,
130.6, 130.7, 131.9, 132.1, 137.1, 138.4, 138.8.
9-(2-Methoxyphenyl)anthracene, 40.29 Purification by flash
chromatography (hexanes/CH2Cl2 9:1) gave 0.89 mmol of white
crystals (89% from chloride): 1H NMR δ 3.53 (s, 3H), 7.08 (d, J
) 8.3 Hz, 1H), 7.12 (ddd, J ) 7.3, 7.3, 1.0 Hz, 1H), 7.24 (dd, J )
7.5, 1.8 Hz, 1H), 7.26-7.32 (m, 2H), 7.36-7.42 (m, 2H), 7.47
(ddd, J ) 7.8, 7.8, 2.0 Hz, 1H), 7.59 (dd, J ) 9.8, 1.0 Hz, 2H),
7.97 (d, J ) 8.3 Hz, 2H), 8.42 (s, 1H); 13C NMR δ 56.3, 111.9,
121.3, 125.6, 125.8, 126.5, 127.4, 128.0, 129.1, 130.0, 131.0, 132.1,
133.5, 134.4, 158.7.
9-(1-Naphthyl)anthracene, 41.30 Purification by flash chroma-
tography (hexanes/CH2Cl2 9:1) gave 0.85 mmol of white crystals
(85% from chloride): 1H NMR δ 7.06-7.09 (m, 2H), 7.11-7.17
(m, 2H), 7.32-7.40 (m, 5H), 7.46 (dd, J ) 7.1, 1.2 Hz, 1H), 7.58
(dd, J ) 7.6, 7.6 Hz, 1H), 7.91 (d, J ) 8.3 Hz, 1H), 7.97 (dd, J )
8.3, 8.3 Hz, 3H), 8.49 (s, 1H); 13C NMR δ 125.8, 126.2, 126.6,
126.9, 127.2, 127.6, 128.7, 128.9, 129.0, 129.7, 131.6, 132.1, 134.2,
134.3, 135.6, 137.2.
2-Methyl-1,1′-binaphthyl, 28.23 Purification by flash chroma-
tography (hexanes) gave 0.92 mmol of colorless crystals (92% from
bromide): 1H NMR δ 2.07 (s, 3H), 7.06-7.56 (m, 9H), 7.80-
7.89 (m, 4H); 13C NMR δ 21.2, 125.5, 126.0, 126.3, 126.5, 126.6,
126.7, 126.8, 126.9, 128.2, 128.3, 128.4, 128.9, 129.3, 132.6, 133.2,
134.1, 134.4, 135.0, 136.7, 138.2.
2-Isopropyl-2′-methoxybiphenyl, 31.24 Purification by flash
chromatography (hexanes/CH2Cl2 10:1) gave 0.91 mmol of a
colorless oil (91% from chloride): 1H NMR δ 1.04 (d, J ) 6.8
Hz, 3H), 1.19 (d, J ) 6.8 Hz, 3H), 2.77 (sept, J ) 6.8 Hz, 1H),
3.69 (s, 3H), 6.93 (d, J ) 8.3 Hz, 1H), 6.98 (ddd, J ) 7.3, 7.3, 1.0
Hz, 1H), 7.10-7.15 (m, 2H), 7.19 (ddd, J ) 7.6, 7.6, 2.2 Hz, 1H),
7.29-7.38 (m, 3H); 13C NMR δ 23.6, 25.0, 30.5, 55.6, 110.8, 120.7,
125.4, 125.6, 128.1, 128.8, 130.4, 131.2, 131.6, 137.7, 147.8, 157.1.
2-Methoxy-2′,6′-dimethylbiphenyl, 35.25 Purification by flash
chromatography (hexanes/CH2Cl2 10:1) gave 0.93 mmol of a
colorless oil (93% from chloride): 1H NMR δ 2.00 (s, 6H), 3.65
(s, 3H), 6.93 (d, J ) 8.3 Hz, 1H), 6.97-7.02 (m, 2H), 7.06-7.16
(m, 3H), 7.29 (m, 1H); 13C NMR δ 21.1, 55.9, 111.4, 121.3, 127.6,
129.0, 130.1, 131.2, 137.1, 138.8, 157.1.
Methyl 2-methyl-2′-isopropylbiphenyl-4-carboxylate, 44. Pu-
rification by flash chromatography (hexanes/ethyl acetate 50:1) gave
0.86 mmol of a colorless oil (86%): 1H NMR δ 1.06 (d, J ) 6.8
Hz, 3H), 1.14 (d, J ) 6.8 Hz, 3H), 2.10 (s, 3H), 2.62 (sept, J )
6.8 Hz, 1H), 3.92 (s, 3H), 7.01 (dd, J ) 1.1, 7.2 Hz, 1H), 7.17-
7.23 (m, 2H), 7.32-7.41 (m, 2H), 7.90 (dd, J ) 1.2, 7.8 Hz, 1H),
7.97 (s, 1H); 13C NMR δ 20.7, 23.7, 25.2, 30.5, 52.6, 126.0, 126.1,
127.2, 128.6, 129.4, 129.6, 130.4, 131.5, 137.0, 139.9, 146.7, 147.1,
167.7. Anal. Calcd for C18H20O2: C, 80.56; H, 7.51. Found: C,
80.25; H, 7.31.
Acknowledgment. We thank Combiphos Catalysts, Inc.
(www.combiphos.com) for a generous supply of palladium-
phosphinous acids.
2-Methyl-1-(2-tolyl)naphthalene, 36.26 Purification by flash
chromatography (hexanes) gave 0.89 mmol of a colorless oil (89%
from chloride): 1H NMR δ 1.88 (s, 3H), 2.12 (s, 3H), 7.07 (d, J )
6.6 Hz, 1H), 7.20-7.36 (m, 7H), 7.71 (d, J ) 8.3 Hz, 1H), 7.77
(d, J ) 8.1 Hz, 1H); 13C NMR δ 20.2, 21.0, 125.4, 126.4, 126.6,
126.7, 127.8, 128.1, 128.5, 129.2, 130.7, 132.7, 133.2, 133.7, 137.4,
138.1, 139.8.
Supporting Information Available: NMR spectra of all
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
1-(2-Methoxyphenyl)-2-methylnaphthalene, 37.27 Purification
by flash chromatography (hexanes/CH2Cl2 10:1) gave 0.91 mmol
JO701893M
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J. Org. Chem, Vol. 73, No. 1, 2008 167