Cross-coupling reactions of primary alkylboronic acids with aryl triflates and aryl halides

Article abstract of DOI:10.1016/S0040-4020(02)00009-1

The cross-coupling reactions of primary alkylboronic acids with aryl triflates and aryl halides has been successfully achieved using PdCl₂(dppf)·CH₂Cl₂ in the presence of potassium carbonate to provide the corresponding Su

Full text of DOI:10.1016/S0040-4020(02)00009-1

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 1465±1470
Cross-coupling reactions of primary alkylboronic acids
with aryl tri¯ates and aryl halides
Gary A. Molanderp and Chang-Soo Yun
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, 231 South 34th Street, Philadelphia,
PA 19104-6323, USA
Received 8 November 2001; accepted 17 December 2001
AbstractÐThe cross-coupling reactions of primary alkylboronic acids with aryl tri¯ates and aryl halides has been successfully achieved
using PdCl2,dppf)´CH2Cl2 in the presence of potassium carbonate to provide the corresponding Suzuki coupled products in high yields.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
using 9-BBN derivatives are not atom economic, as the
cyclooctyl unit must be disposed of after the cross coupling.
Finally, in some instances stereocomplementary hydro-
borations can be achieved under rhodium-catalyzed con-
ditions as compared to those carried out with 9-BBN.9±11
For all of these these reasons, it is imperative to consider
alternative organoboron reagents for Suzuki coupling
reactions.
The palladium-catalyzed cross-coupling reaction of aryl
tri¯ates and aryl halides with organoboron compounds has
emerged as a powerful method for carbon±carbon bond
formation.1,2 Among all possible organometallics, tin ,Stille
coupling)3,4 and boron derivatives ,Suzuki coupling)5±7 are
most frequently used for cross-coupling reactions because
of their tolerance of a broad range of functional groups. The
use of organoboron derivatives is especially valued for
several reasons: they are more easily accessed by a variety
of routes, nontransferable groups can be readily incorpo-
rated into the organometallic, and the inorganic byproducts
of the reaction are nontoxic and can be readily removed by
simple workup procedures.
In one such procedure, methylation reactions have been
carried out using Suzuki coupling of methylborinate
esters.12,13 These reagents couple with a variety of electro-
philic substrates, but their synthesis is a bit involved.
Additionally, extrapolation to other alkylborinates has not
been demonstrated and this approach does not deal with the
issue of atom economy.
Trialkylboranes have been employed extensively in the
Suzuki cross coupling reactions.1,2,5,6 The most widely
utilized trialkylboranes are the 9-BBN derivatives. These
are enormously successful in general, but there are some
drawbacks. For example, the alkyl-9-BBN compounds are
extremely air-sensitive, and therefore dif®cult to isolate and
purify. Typically the cross coupling is carried out in situ
immediately after ole®n hydroboration. Thus there is no
opportunity to purify the organoboron intermediate in the
event the hydroboration reaction has not proceeded well.
The dif®culty involved in isolating the organoboron would
appear to limit their application in combinatorial library
synthesis as well. Some functional groups ,ketones, for
example) must be protected during the 9-BBN hydro-
boration. This is not the case for rhodium-catalyzed
catecholborane hydroborations.8 Further, coupling reactions
Except for the recent example of cyclopropylboronic acids
or -esters that possess signi®cant sp2-carbon character,14,15
more highly oxygenated derivatives such as alkylboronic
acids or -esters have presented dif®culties in Suzuki
coupling reactions. An early study utilizing alkylboronic
acids provided the coupled products in only 20±30%
yield,16 while coupling of methylboronic acid required the
addition of 40 mol% of triphenylarsine.17 More recent
studies show promise of improving this situation, although
the scope of this particular protocol has not been fully
investigated.18 A similar situation exists for various alkyl-
boronic esters, where very low yields in the cross-coupling
reaction have been obtained19 unless highly toxic20 thallium
compounds such as TlOH or TI2CO3 were utilized as bases
for the reaction.21 It has been assumed that this is because of
the dif®culty in transmetalation between the boronic ester
and the intermediate Pd species. Thus, although Suzuki
coupling reactions incorporating aryl- and alkenylboron
reagents are reasonably well in hand, new and effective
methods for the successful coupling of simple primary
Keywords: Suzuki coupling; cross-coupling reaction; alkylboronic acid;
palladium catalyst.
p
Corresponding author. Tel.: 11-215-573-8604; fax: 11-215-573-7165;
e-mail: gmolandr@sas.upenn.edu
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00009-1

1466
G. A. Molander, C.-S. Yun / Tetrahedron 58 02002) 1465±1470
Table 1. Cross-coupling reactions of alkylboronic acids with aryl tri¯ates
Entry
Boronic acid
Tri¯ate
TfOPhp-Ac
TfOPhp-NO2
TfOPhp-Ac
TfOPhp-NO2
TfOPhp-Cl
Product
% Yield
91a,97b)
93a
1
2
3
4
5
6
7
PhCH2CH2B,OH)2 ,1a)
,1a)
PhCH2CH2B,OH)2 ,1b)
93a ,94b)
94a
,1b)
,1a)
,1a)
,1a)
94b
TfOPhm-CN
TfOPhm-CF3
93b
92b
8
9
CH3B,OH)2 ,1c)
,1c)
TfOPhp-Ac
TfOPhp-NO2
CH3Php-Ac ,2h)
CH3Php-NO2 ,2i)
85b
80b
10
,1a)
TfOPhp-OCH3
15b
a
Condition A: PdCl2,dppf´CH2Cl2 ,9 mol%), Cs2CO3 ,3 equiv.), THF/H2O ,10/1), re¯ux.
Condition B: PdCl2,dppf´CH2Cl2 ,9 mol%), K2CO3 ,3 equiv.), THF/H2O ,10/1), re¯ux.
b
alkylboron species are still subject to signi®cant improve-
ment.
were maintained when potassium carbonate was used as a
base instead of cesium carbonate ,entries 1 and 3). Also, the
yields of the reaction with various aryl tri¯ates were high
regardless of the position of the functional group on the ring.
However, the use of the electron rich 4-methoxyphenyl-
tri¯ate provided the desired coupled product in only 15%
yield ,entry 10). As in the case of the alkyltri¯uoroborate
chemistry, nitro groups can be tolerated in the aryl tri¯ate
substrate ,entries 2, 4, and 9). It has been reported
that B-alkyl-9-BBN cross-couplings provide mixtures of
reduced anilines in these cases.29
We recently published the cross-coupling reaction of potas-
sium alkyltri¯uoroborates with aryl- or alkenyl tri¯ates.22
The cross-coupling reaction worked smoothly, providing
satisfactory yields of the coupled products in most cases.
The reaction was tolerant of a variety of functional groups
including ketones, esters, nitriles, and nitro groups despite
the aqueous basic conditions. These alkyltri¯uoroborates
are usually considered more reactive than boronic
acids.23±26
Catalyst loadings were typically quite high in these reac-
tions ,9 mol%). To explore the possibility of a lower
catalyst loading, we examined the cross-coupling reaction
of 2-phenylethylboronic acid ,1a) with 4-acetylphenyl-
tri¯ate using only 5 and 2 mol% of the palladium catalyst.
Unfortunately, the yield of coupled product decreased to 48
and 25%, respectively.
In the present study we have investigated the reactivity of
alkylboronic acids in Suzuki coupling reactions. Herein, we
outline the scope of the cross-coupling reaction of these
substrates with aryl tri¯ates and aryl halides as the coupling
partner ,Eq. ,1)).
Signi®cantly, using the conditions developed we were able
to obtain higher yields for methylation than in many of those
procedures reported previously.17,30±32 Thus, the coupling
reaction of methylboronic acid with 4-acetyl- and 4-nitro-
phenyltri¯ate provided the desired coupled products in 85
and 80% yield, respectively ,entries 8 and 9).
ꢀ1†
2. Results and discussion
We have conducted several coupling reactions with various
aryl bromides to compare their reactivity with that of aryl
tri¯ates ,Table 2). As outlined in Table 2, the cross-coupling
reaction with aryl bromides provided the coupled products
with satisfactory yields in most cases, except for the electron
rich 4-bromoanisole ,entry 1). A similar result was observed
when 4-methoxyphenyltri¯ate was used ,entry 10, Table 1).
The requisite alkylboronic acids were easily synthesized
using established literature protocols involving the addition
of Grignard reagents to trimethylborate,27 or the hydro-
boration of alkenes with dibromoborane±dimethylsul®de
complex followed by hydrolysis.28 As a starting point, the
conditions for carrying out the coupling reactions were the
same as those previously optimized for the Suzuki coupling
of alkyltri¯uoroborates. Under these conditions the cross-
coupling reactions of alkylboronic acids with various aryl
tri¯ates proceeded readily with high yields in most cases as
outlined in Table 1.
We have examined several different reaction conditions in
an attempt to increase the reactivity of this coupling reac-
tion. The use of THF without water produced an increase in
the yield of the desired products ,entries 9 and 10, Table 1).
Surprisingly, the cross-coupling reaction of 4-bromobenzo-
phenone and 4-bromobenzonitrile worked in good yield
Surprisingly, the high yields of the cross-coupling reaction

G. A. Molander, C.-S. Yun / Tetrahedron 58 02002) 1465±1470
Table 2. Cross-coupling reactions of phenylethylboronic acid with aryl bromides
1467
Entry
1
Boronic acid
Bromide
Product
% Yield
42a
PhCH2CH2B,OH)2 ,1a)
BrPhp-OCH3
2
3
,1a)
,1a)
BrPh
73a
73a
4
5
6
7
8
9
,1a)
,1a)
,1a)
,1a)
,1a)
,1a)
BrPho-CH3
BrPhp-Ac
80a
87a ,71b)
67a
BrPhp-CF3
BrPhp-NO2
BrPhp-COPh
BrPhp-CN
53a ,67c, 60d)
64a ,80c)
60a ,79e, 72f)
10
,1a)
61a ,64e, 63f)
a
Condition B: PdCl2 ,dppf)´CH2Cl2 ,9 mol%), K2CO3 ,3 equiv.), THF/H2O ,10/1), re¯ux.
1,4-Dioxane/H2O was used as a solvent.
Condition D: Pd,PPh3)4 ,10 mol%), K2CO3 ,3 equiv.), 1,4-dioxane, re¯ux.
Condition E: PdCl2 ,dppf)´CH2Cl2 ,9 mol%), K2CO3 ,3 equiv.), 1,4-dioxane, re¯ux.
Condition C: PdCl2 ,dppf)´CH2Cl2 ,9 mol%), K2CO3 ,3 equiv.), THF, re¯ux.
Condition F: Pd2,dba)3 ,10 mol%), dppf ,15 mol%), Cs2CO3 ,3 equiv.), 1,4-dioxane, re¯ux.
b
c
d
e
f
even though Pd,PPh3)4 was used as the catalyst ,entries 7
Finally, we have investigated the cross-coupling reaction of
a few heteroaryl chlorides and 1a. The results of these reac-
tions are displayed in Table 3. The cross-coupling reaction
of heteroaryl chlorides did not work under our standard
conditions or when Pd2,dba)3/dppf was used as a catalyst
instead of PdCl2,dppf)´CH2Cl2 ,entries 1 and 2). However,
and 8). Of importance in this case was that we did not
observe b-hydride elimination processes in any of the
examples we have studied. Additionally, we obtained
high yields when Pd2,dba)3 was used to generate the
homogeneous catalyst ,entries 9 and 10).
Table 3. Cross-coupling reactions of phenylethylboronic acid with heteroaryl chlorides
Entry
Boronic acid
Aryl chloride
Product
% Yield
NRa,b
1
PhCH2CH2B,OH)2 ,1a)
2
3
,1a)
,1a)
NRa,b
52c
4
,1a)
53c ,53d)
a
Condition B: PdCl2 ,dppf)´CH2Cl2 ,9 mol%), K2CO3 ,3 equiv.), THF/H2O ,10/1), re¯ux.
b
c
d
Condition F: Pd2,dba)3 ,10 mol%), dppf ,15 mol%), Cs2CO3 ,3 equiv.), 1,4-dioxane, re¯ux.
Condition D: Pd,PPh3)4 ,10 mol%), K2CO3 ,3 equiv.), 1,4-dioxane, re¯ux.
Condition C: PdCl2,dppf)´CH2Cl2 ,9 mol%) K2CO3 ,3 equiv.), THF, re¯ux.

1468
G. A. Molander, C.-S. Yun / Tetrahedron 58 02002) 1465±1470
in non-aqueous solvent systems and using either Pd,PPh3)4
or PdCl2,dppf)´CH2Cl2 as the catalyst, the reaction pro-
ceeded to give moderate yields of the desired coupled
products ,entries 3 and 4).
3.1.3. 1-%4-Nitrophenyl)-3-phenylpropane %2d). Yieldˆ
1
94%; Rfˆ0.72 ,EtOAc/hexaneˆ1/8); H NMR ,500 MHz,
CDCl3) d 8.12 ,d, Jˆ8.6 Hz, 2H), 7.31±7.27 ,m, 4H), 7.19±
7.16 ,m, 3H), 2.75±2.72 ,m, 2H), 2.67±2.64 ,m, 2H), 1.99±
1.97 ,m, 2H); 13C NMR ,125 MHz, CDCl3) d 150.2, 146.3,
141.5, 129.2, 128.4, 128.3, 125.9, 123.6, 35.2, 35.1, 32.4;
IR ,CH2Cl2) 1517, 1452 cm21; HRMS ,CI) calcd for
C15H16NO2 ,M1H)1 242.1181, found 242.1181.
In summary, the palladium-catalyzed cross-coupling reac-
tion of primary alkylboronic acids with various aryl tri¯ates
and aryl halides has been achieved without resorting to toxic
ligands or bases. Additionally, we have determined that
alkylboronic acids can be coupled under diverse catalytic
conditions without the interference of b-hydride elimination
products.
3.1.4. Representative procedure B for the cross-coupling
reaction of alkylboronic acids with aryl tri¯ates and aryl
halides. 1-%4-Acetylphenyl)-3-phenylpropane %2c). To a
suspension of 3-phenylpropylboronic acid ,1b) ,82 mg,
0.50 mmol), K2CO3 ,207 mg, 1.50 mmol), PdCl2,dppf)´
CH2Cl2 ,36 mg, 0.045 mmol), and 4-acetylphenyltri¯ate
,148 mg, 0.55 mmol) in THF ,5 mL) was added water
,0.5 mL) under an argon atmosphere. The reaction mixture
was stirred at re¯ux temperature for 18 h, then cooled to rt,
diluted with water ,10 mL), then extracted with ether
,20 mL£3). The combined organic layers were washed
with 1N HCl ,20 mL) and brine ,20 mL) and then dried
over magnesium sulfate. The solvent was removed in
vacuo and the crude product was puri®ed by silica gel
column chromatography ,eluting with hexane/EtOAcˆ
8/1) to yield 2c ,112 mg, 94%). Rfˆ0.51 ,EtOAc/
3. Experimental
3.1. General
All experiments were carried out under an inert atmosphere.
1H and 13C NMR spectra were measured on spectrometers
at 500.13 and 125.77 MHz, respectively. Palladium cata-
lysts, Cs2CO3, 4-acetylphenyltri¯ate, 4-nitrophenyltri¯ate,
4-methoxyphenyltri¯ate, 4-bromoanisole, 4-bromobenzene,
4-bromoacetophenone, 1-bromonaphthalene, 4-bromoben-
zotri¯uoride, 4-bromonitrobenzene, 4-bromobenzophenone,
4-bromobenzonitrile, 2-bromo-5-nitrobenzotri¯uoride, 3-nitro-
2-chloropyridine, 5-nitro-2-chloropyridine, and methyl-
boronic acid were obtained from Aldrich. The tri¯ates,
2-phenylethylboronic acid ,1a), and 3-phenylpropylboronic
acid ,1b) were prepared by reported procedures.33±35 All of
the coupling reactions were performed on a 0.5 mmol scale.
1
hexaneˆ1/8); H NMR ,500 MHz, CDCl3) d 7.94 ,d, Jˆ
7.6 Hz, 2H), 7.34±7.23 ,m, 7H), 2.75±2.69 ,m, 4H), 2.61 ,s,
3H), 2.03±2.01 ,m, 2H); 13C NMR ,125 MHz, CDCl3) d
197.5, 147.9, 141.7, 134.9, 128.5, 128.4, 128.3, 128.2,
125.7, 35.2, 35.1, 32.4, 26.3; IR ,CH2Cl2) 1681,
1605 cm21; HRMS ,CI) calcd for C17H19O ,M1H)1
239.1436, found 239.1425.
3.1.1. Representative procedure A for the cross-coupling
reaction of alkylboronic acids with aryl tri¯ates. 1-%4-
Acetylphenyl)-2-phenylethane %2a). To a suspension of
2-phenylethylboronic acid ,1a) ,75 mg, 0.50 mmol),
Cs2CO3 ,489 mg, 1.50 mmol), PdCl2,dppf)´CH2Cl2 ,36
mg, 0.045 mmol), and 4-acetylphenyltri¯ate ,148 mg,
0.55 mmol) in THF ,5 mL) was added water ,0.5 mL)
under an argon atmosphere. The reaction mixture was
stirred at re¯ux temperature for 18 h, then cooled to rt,
diluted with water ,10 mL), then extracted with ether
,20 mL£3). The combined organic layers were washed
with 1N HCl ,20 mL) and brine ,20 mL) and then dried
over magnesium sulfate. The solvent was removed in
vacuo and the crude product was puri®ed by silica gel
column chromatography ,eluting with hexane/EtOAcˆ
8/1) to yield 2a ,92 mg, 91%). Rfˆ0.47 ,EtOAc/hexaneˆ
1/8); 1H NMR ,500 MHz, CDCl3) d 7.87 ,d, Jˆ8.8 Hz, 2H),
7.29±7.14 ,m, 7H), 2.99±2.94 ,m, 4H), 2.57 ,s, 3H); 13C
NMR ,125 MHz, CDCl3) d 197.7, 147.3, 140.9, 135.0,
128.6, 128.4, 128.3, 126.0, 37.7, 37.3, 26.4; IR ,CH2Cl2)
1677, 1604 cm21; HRMS ,CI) calcd for C16H17O ,M1H)1
225.1279, found 225.1286.
3.1.5. 1-%4-Chlorophenyl)-2-phenylethane %2e). Yieldˆ
94%; Rfˆ0.56 ,EtOAc/hexaneˆ1/20); 1H NMR ,500
MHz, CDCl3) d 7.27±7.05 ,m, 9H), 2.87 ,s, 4H); 13C
NMR ,125 MHz, CDCl3) d 141.2, 140.0, 131.6, 129.8,
28.9, 128.4, 128.3, 127.5, 126.2, 126.0, 37.7, 37.2;
HRMS ,EI) calcd for C14H13Cl ,M1) 216.0706, found
216.0697.
3.1.6. 1-%3-Cyanophenyl)-2-phenylethane %2f). Yieldˆ
93%; Rfˆ0.43 ,EtOAc/hexaneˆ1/10); 1H NMR ,500
MHz, CDCl3) d 7.45±7.11 ,m, 9H), 2.93±2.89 ,m, 4H);
13C NMR ,125 MHz, CDCl3) d 143.0, 140.6, 133.2,
132.3, 132.1, 131.2, 129.2, 128.7, 128.5, 128.4, 127.6,
126.7, 119.1, 37.4, 37.3; HRMS ,EI) calcd for C15H13N
,M1) 207.1048, found 207.1049.
3.1.7. 1-%3-Tri¯uoromethylphenyl)-2-phenylethane %2g).
Yieldˆ92%; Rfˆ0.51 ,EtOAc/hexaneˆ1/20); 1H NMR
,500 MHz, CDCl3) d 7.45±7.14 ,m, 9H), 2.98±2.91 ,m,
4H); 13C NMR ,125 MHz, CDCl3) d 142.6, 141.1, 131.9,
131.2, 128.8, 128.5, 126.4, 125.2, 124.4, 122.8, 37.7, 37.6;
HRMS ,EI) calcd for C15H13F3 ,M1) 250.0969, found
250.0969.
3.1.2. 1-%4-Nitrophenyl)-2-phenylethane %2b). Yieldˆ
1
93%; Rfˆ0.63 ,EtOAc/hexaneˆ1/8); H NMR ,500 MHz,
3.1.8. 4-Methylacetophenone36 %2h). Yieldˆ85%; Rfˆ0.42
CDCl3) d 8.11 ,d, Jˆ8.4 Hz, 2H), 7.30±7.26 ,m, 4H), 7.22±
7.21 ,m, 1H), 7.15±7.13 ,m, 2H), 3.05±3.02 ,m, 2H), 2.97±
2.94 ,m, 2H); 13C NMR ,125 MHz, CDCl3) d 149.4, 146.4,
140.4, 129.3, 128.4, 128.3, 126.2, 123.5, 37.6, 37.1; IR
,CH2Cl2) 1517 cm21; HRMS ,CI) calcd for C14H14NO2
,M1H)1 228.1024, found 228.1021.
1
,EtOAc/hexaneˆ1/8); H NMR ,200 MHz, CDCl3) d 8.05
,d, Jˆ8 Hz, 2H), 7.45 ,d, Jˆ8 Hz, 2H), 2.77 ,s, 3H), 2.60 ,s,
3H).
3.1.9. 4-Nitrotoluene36 %2i). Yieldˆ80%; Rfˆ0.52 ,EtOAc/

G. A. Molander, C.-S. Yun / Tetrahedron 58 02002) 1465±1470
1469
1
hexaneˆ1/8); H NMR ,200 MHz, CDCl3) d 8.30 ,d, Jˆ
The solvent was removed in vacuo and the crude product
was puri®ed by silica gel column chromatography ,eluting
with hexane/EtOAcˆ15/1) to yield 2q ,94 mg, 64%). Rfˆ
0.47 ,EtOAc/hexaneˆ1/10); 1H NMR ,500 MHz, CDCl3) d
8.56 ,s, 1H), 8.31 ,d, Jˆ8.4 Hz, 1H), 7.46 ,d, Jˆ8.4 Hz,
1H), 7.36±7.35 ,m, 2H), 7.29±7.27 ,m, 1H), 7.23±7.21
,m, 2H), 3.25±3.22 ,m, 2H), 3.00±2.97 ,m, 2H); 13C
NMR ,125 MHz, CDCl3) d 147.9, 146.0, 140.1, 132.6,
128.5, 128.4, 126.5, 126.3, 121.7, 37.4, 34.9; IR ,CH2Cl2)
1595, 1530 cm21; HRMS ,CI) calcd for C15H13NO2F3
,M1H)1 296.0898, found 296.0899.
8.6 Hz, 2H), 7.50 ,d, Jˆ8.6 Hz, 2H), 2.65 ,s, 3H).
3.1.10. 1-%4-Methoxyphenyl)-2-phenylethane %2j). Yieldˆ
1
15%; Rfˆ0.36 ,ether/hexaneˆ1/20); H NMR ,500 MHz,
CDCl3) d 7.30±7.28 ,m, 2H), 7.20±7.19 ,m, 3H), 7.11 ,d,
Jˆ8.4 Hz, 2H), 6.84 ,d, Jˆ8.5 Hz, 2H), 3.81 ,s, 3H), 2.90±
2.89 ,m, 4H); 13C NMR ,125 MHz, CDCl3) d 157.8, 141.8,
133.9, 129.3, 128.4, 128.3, 128.2, 125.8, 113.7, 55.2, 38.2,
36.9; IR ,CH2Cl2) 1583, 1495, 1301 cm21; HRMS ,CI)
calcd for C15H17O ,M1H)1 213.1279, found 213.1279.
3.1.11. 1,2-Diphenylethane36 %2k). Yieldˆ73%; Rfˆ0.47
,EtOAc/hexaneˆ1/20); 1H NMR ,500 MHz, CDCl3) d
7.28±7.25 ,m, 4H), 7.19±7.16 ,m, 6H), 2.91 ,s, 4H); 13C
NMR ,125 MHz, CDCl3) d 141.8, 128.4, 128.3, 125.9, 37.9.
3.1.17. Representative procedure D for the cross-
coupling reaction of alkylboronic acids with aryl halides.
1-%4-Nitro-2-pyridyl)-2-phenylethane %2s). A suspension
of 2-phenylethylboronic acid ,1a) ,75 mg, 0.50 mmol),
K2CO3 ,207 mg, 1.50 mmol), Pd,PPh3)4 ,58 mg, 0.050
mmol), and 5-nitro-2-chloropyridine ,87 mg, 0.55 mmol)
in 1,4-dioxane ,5 mL) was stirred at re¯ux temperature for
18 h, then cooled to rt, diluted with water ,10 mL), then
extracted with ether ,20 mL£3). The combined organic
layers were washed with 1N HCl ,20 mL) and brine
,20 mL) and then dried over magnesium sulfate. The solvent
was removed in vacuo and the crude product was puri®ed by
silica gel column chromatography ,eluting with hexane/
EtOAcˆ6/1) to yield 2s ,60 mg, 53%). Rfˆ0.37 ,EtOAc/
3.1.12. 1-%1-Naphthyl)-2-phenylethane %2l). Yieldˆ73%;
Rfˆ0.58 ,EtOAc/hexaneˆ1/15); 1H NMR ,500 MHz,
CDCl3) d 8.07±7.20 ,m, 12H), 3.35±3.32 ,m, 2H), 3.03±
3.01 ,m, 2H); 13C NMR ,125 MHz, CDCl3) d 141.9, 137.7,
133.8, 131.7, 129.9, 128.4, 128.3, 128.1, 127.8, 126.7,
126.5, 126.1, 125.9, 125.8, 125.4, 123.6, 37.0, 35.0;
HRMS ,EI) calcd for C18H16 ,M1) 232.1252, found
232.1243.
1
3.1.13. 1-%2-Methylphenyl)-2-phenylethane %2m). Yieldˆ
80%; Rfˆ0.56 ,EtOAc/hexaneˆ1/15); 1H NMR ,500 MHz,
CDCl3) d 7.28±7.13 ,m, 9H), 2.88±2.87 ,m, 4H), 2.29 ,s,
3H); 13C NMR ,125 MHz, CDCl3) d 141.9, 139.9, 135.9,
130.1, 128.8, 128.4, 128.3, 126.1, 125.9, 36.7, 35.4; HRMS
,EI) calcd for C15H16 ,M1) 196.1252, found 196.1254.
hexaneˆ1/3); H NMR ,500 MHz, CDCl3) d 8.77 ,s, 1H),
8.20 ,d, Jˆ8.2 Hz, 1H), 7.35±7.20 ,m, 6H), 3.44±3.40 ,m,
2H), 3.12±3.09 ,m, 2H); 13C NMR ,125 MHz, CDCl3) d
155.9, 152.7, 146.0, 140.9, 134.1, 132.5, 128.4, 126.2,
122.9, 121.9, 37.7, 34.9; IR ,CH2Cl2) 2930, 1522,
1351 cm21; HRMS ,CI) calcd for C13H13N2O2 ,M1H)1
229.0977, found 229.0973.
3.1.14. 1-%4-Tri¯uoromethylphenyl)-2-phenylethane %2n).
1
Yieldˆ67%; Rfˆ0.52 ,ether/hexaneˆ1/8); H NMR ,500
3.1.18. 1-%3-Nitro-2-pyridyl)-2-phenylethane %2r). Yieldˆ
1
MHz, CDCl3) d 7.55 ,d, Jˆ7.8 Hz, 2H), 7.33±7.18 ,m,
7H), 3.03±2.95 ,m, 4H); 13C NMR ,125 MHz, CDCl3) d
145.7, 141.0, 128.8, 128.5, 128.4, 127.9, 127.6, 127.5,
52%; Rfˆ0.44 ,EtOAc/hexaneˆ1/8); H NMR ,500 MHz,
CDCl3) d 9.37 ,s, 1H), 8.31 ,d, Jˆ8.4 Hz, 1H), 7.28±7.15
,m, 6H), 3.25±3.22 ,m, 2H), 3.12±3.09 ,m, 2H); 13C NMR
,125 MHz, CDCl3) d 167.9, 144.8, 142.6, 140.4, 128.5,
128.3, 126.3, 123.1, 40.0, 35.3; IR ,CH2Cl2) 3064, 1527,
1348 cm21; HRMS ,EI) calcd for C13H12N2O2 ,M1)
228.0899, found 228.0898.
126.1, 125.2, 37.6, 37.5; IR ,CH2Cl2) 1495, 1417 cm21
;
HRMS ,EI) calcd for C15H13F3 ,M1) 250.0969, found
250.0958.
3.1.15. 1-%4-Benzoylphenyl)-2-phenylethane %2o). Yieldˆ
1
64%; Rfˆ0.42 ,ether/hexaneˆ1/10); H NMR ,500 MHz,
3.1.19. Representative procedure E for the cross-
coupling reaction of alkylboronic acids with aryl halide.
1-%4-Nitrophenyl)-2-phenylethane %2b). A suspension of
2-phenylethylboronic acid ,1a) ,75 mg, 0.50 mmol),
K2CO3 ,207 mg, 1.50 mmol), PdCl2,dppf)´CH2Cl2 ,36 mg,
0.045 mmol), and 4-bromonitrobenzene ,111 mg, 0.55
mmol) in 1,4-dioxane ,5 mL) was stirred at re¯ux tempera-
ture for 18 h, then cooled to rt, diluted with water ,10 mL),
then extracted with ether ,20 mL£3). The combined organic
layers were washed with 1N HCl ,20 mL) and brine ,20 mL)
and then dried over magnesium sulfate. The solvent was
removed in vacuo and the crude product was puri®ed by
silica gel column chromatography ,eluting with hexane/
EtOAcˆ10/1) to yield 2b ,68 mg, 60%). All spectral data
were identical to material prepared by procedure A.
CDCl3) d 7.80 ,d, Jˆ7.6 Hz, 2H), 7.75 ,d, Jˆ7.9 Hz, 2H),
7.60±7.57 ,m, 1H), 7.50±7.47 ,m, 2H), 7.31±7.23 ,m, 4H),
7.22±7.19 ,m, 3H), 3.05±2.96 ,m, 4H); 13C NMR
,125 MHz, CDCl3) d 196.4, 146.8, 141.1, 137.8, 135.3,
132.2, 130.3, 129.9, 128.4, 128.3, 128.2, 126.1, 37.8, 37.4;
IR ,CH2Cl2) 1654, 1604 cm21; HRMS ,CI) calcd for
C21H19O ,M1H)1 287.1436, found 287.1444.
3.1.16. Representative procedure C for the cross-
coupling reaction of alkylboronic acids with aryl halides.
1-%2-Tri¯uoromethyl-4-nitrophenyl)-2-phenylethane %2q).
A suspension of 2-phenylethylboronic acid ,1a) ,75 mg,
0.50 mmol), K2CO3 ,207 mg, 1.50 mmol), PdCl2,dppf)´
CH2Cl2 ,36 mg, 0.045 mmol), and 2-bromo-5-nitrobenzotri-
¯uoride ,149 mg, 0.55 mmol) in THF ,5 mL) was stirred at
re¯ux temperature for 18 h, then cooled to rt, diluted with
water ,10 mL), then extracted with ether ,20 mL£3). The
combined organic layers were washed with 1N HCl ,20 mL)
and brine ,20 mL) and then dried over magnesium sulfate.
3.1.20. Representative procedure F for the cross-
coupling reaction of alkylboronic acids with aryl halide.
1-%4-Cyanophenyl)-2-phenylethane %2p). A suspension
of 2-phenylethylboronic acid ,1a) ,75 mg, 0.50 mmol),

1470
G. A. Molander, C.-S. Yun / Tetrahedron 58 02002) 1465±1470
11. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc.
1992, 114, 6671±6679.
Cs2CO3 ,489 mg, 1.50 mmol), Pd2,dba)3 ,46 mg, 0.05
mmol), dppf ,0.075 mmol, 42 mg), and 4-bromobenzo-
nitrile ,100 mg, 0.55 mmol) in 1,4-dioxane ,5 mL) was
stirred at re¯ux temperature for 18 h, then cooled to rt,
diluted with water ,10 mL), then extracted with ether
,10 mL£3). The combined organic layers were washed
with 1N HCl ,20 mL) and brine ,20 mL) and then dried
over magnesium sulfate. The solvent was removed in
vacuo and the crude product was puri®ed by silica gel
column chromatography ,eluting with hexane/EtOAcˆ
6/1) to yield 2p ,75 mg, 72%). Rfˆ0.65 ,EtOAc/hexaneˆ
1/3); 1H NMR ,500 MHz, CDCl3) d 7.53 ,d, Jˆ7.6 Hz, 2H),
7.27±7.22 ,m, 5H), 7.12 ,d, Jˆ6.8 Hz, 2H), 2.97 ,d, Jˆ
7 Hz, 2H), 2.93 ,d, Jˆ7 Hz, 2H); 13C NMR ,125 MHz,
CDCl3) d 147.1, 140.5, 132.0, 129.2, 128.4, 128.3, 126.2,
119.0, 109.7, 37.8, 37.1; IR ,CH2Cl2) 2226 cm21; HRMS
,CI) calcd for C15H14N ,M1H)1 208.1126, found 208.1125.
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Acknowledgements
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We acknowledge the Merck Research Laboratories, Aldrich
Chemical Co., Inc., and Johnson Matthey for their generous
support. This work was also supported by a postdoctoral
fellowshipto C. -S. Yun from the Korean Science and
Engineering Foundation ,KOSEF).
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