An efficient system for the Pd-catalyzed cross-coupling of amides and aryl chlorides

Article abstract of DOI:10.1016/j.tet.2009.04.096

A catalyst based on a new biarylphosphine ligand (3) for the Pd-catalyzed cross-coupling reactions of amides and aryl chlorides is described. This system shows the highest turnover frequencies reported to date for these reactions, especially for aryl chloride substrates bearing an ortho substituent. An array of amides and aryl chlorides were successfully reacted in good to excellent yields.

Full text of DOI:10.1016/j.tet.2009.04.096

Tetrahedron 65 (2009) 6576–6583
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient system for the Pd-catalyzed cross-coupling of amides
and aryl chlorides
*
Brett P. Fors, Karin Dooleweerdt, Qingle Zeng, Stephen L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalyst based on a new biarylphosphine ligand (3) for the Pd-catalyzed cross-coupling reactions of
amides and aryl chlorides is described. This system shows the highest turnover frequencies reported to
date for these reactions, especially for aryl chloride substrates bearing an ortho substituent. An array of
amides and aryl chlorides were successfully reacted in good to excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 19 March 2009
Received in revised form 28 April 2009
Accepted 29 April 2009
Available online 8 May 2009
This paper is dedicated to Larry Overman
on the occasion of his receipt of the 2008
Tetrahedron Prize in Organic Chemistry
Keywords:
Palladium
Phosphine
Cross-Coupling
Amidation
1. Introduction
that the methyl substituent ortho to the di-tert-butylphosphino
group in ligand 1 prohibited rotation around the P–CAr bond,
Metal-catalyzed amidation reactions of aryl halides or pseudo
halides are an attractive method for synthesizing N-arylamides.
These reactions were traditionally performed with aryl iodides
under Goldberg-modified Ullman cross-coupling conditions using
stoichiometric Cu and high reaction temperatures.1 Recent ad-
vances in this area have allowed for the reactions of amides and aryl
iodides or aryl bromides to be performed using catalytic amounts of
Cu under milder conditions.2 Pd-based catalyst systems using
phosphine ligands have also been developed, which allow for the
coupling of amides with aryl sulfonates,3 aryl bromides,4 and most
recently, aryl chlorides.5 These methods have proven to be useful to
synthetic chemists and have been widely used in both industrial
and academic laboratories.6
Of the aryl halides, aryl chlorides are generally the most at-
tractive substrates for cross-coupling reactions because they are
less expensive and more readily available. Our group previously
reported a catalyst system, based on ligand 1 (Fig.1), that effectively
promoted the cross-coupling of amides and unhindered aryl
chlorides,5a but was less effective with ortho-substituted aryl
chlorides. Mechanistic studies and DFT calculations indicated to us
forcing the Pd(II) center of the resulting oxidative addition complex
to position itself over the non-phosphine-containing ring (Fig. 2). It
was postulated that this confirmation inhibited the formation of
the k
2-amidate complex, accelerating reductive elimination. On the
other hand, DFT calculations have also indicated that the amine
binding step of the catalytic cycle using biarylphosphine ligands is
slower when the Pd(II) is positioned over the non-phosphine
containing ring.7 Having an ortho substituent on the arene in these
complexes compounds this effect by increasing the crowding
around the Pd(II) center, hence, further slowing ‘transmetallation’
(amide binding/deprotonation). Herein, we report
a catalyst
system, which displays high activity for the amidation of aryl
chlorides, including those with ortho substitution, by facilitating
transmetallation while still inhibiting the formation of a
intermediate.
k
2-amidate
2. Results and discussion
2.1. Optimization of the Pd-catalyzed amidation reactions
of aryl chlorides
Our group recently disclosed a catalyst system, based on 2, that
was highly active and selective for the monoarylation of primary
* Corresponding author. Tel.: þ1 617 253 1885; fax: þ1 617 253 3297.
E-mail address: sbuchwal@mit.edu (S.L. Buchwald).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.096

B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
6577
Figure 1. Biarylphosphine ligands.
dba ligands to the Pd, which is a well known effect of dba in cross-
coupling reactions.10 The use of Pd(II) salts (e.g., [(allyl)PdCl]2,
(H3CCN)2PdCl2, or Pd(OAc)2) without preactivation, all of which
need to be reduced quickly and efficiently in order to generate an
active catalyst, leads to yields below 60%.11 These results demon-
strated the importance of forming the active monoligated Pd(0)
complex in these reactions. The use of carbonate bases showed
similar results for this coupling reaction,12 but a substantial decline
in yield was observed with all bases examined when other common
solvents were used (Table 1, entries 9 and 10).
Figure 2. Pd(II) oxidative addition complex based on ligand 1.
amines.8 In this study we observed that, in solution, the oxidative
addition complexes of 2 existed as two rotamers; for one of which
the environment around the Pd center was less sterically
demanding. We hypothesized that the substitution of a methoxy
substituent ortho to the di-tert-butylphosphino group in 1 (see
ligand 3) would allow for more freedom of rotation around the P–
CAr bond and help promote transmetallation with relatively hin-
dered substrates. This new ligand (3) was easily synthesized in two
steps from commercially available starting materials (see Experi-
mental section).
Initial studies employing the supporting ligand 3 focused on the
coupling of acetamide and 2-chlorotoluene in the presence of
various Pd sources, bases, and solvents. We found that when the
catalyst was formed using our recently reported water-mediated
catalyst preactivation method9 with 3, Pd(OAc)2, and K3PO4 as the
base in t-BuOH, the reaction gave a 99% GC yield after 40 min at
110 ꢀC (Table 1, entry 1). This initial result was very promising as it
represented the highest turnover frequency observed to date for
the Pd-catalyzed amidation reactions of aryl chlorides bearing an
ortho substituent.5a Switching the Pd source to Pd2(dba)3 or
Pd(dba)2 resulted in a dramatic reduction in yield (Table 1, entries 2
and 3). This loss of activity is likely caused by coordination of the
2.2. Comparison of ligands for the Pd-catalyzed amidation
reactions of aryl chlorides
Encouraged by our initial results, we set out to compare re-
actions with ligand 3 directly with those employing other biaryl-
phosphine ligands that had previously been used for Pd-catalyzed
amidation reactions. Using a catalyst based on 1 for the cross-
coupling of acetamide and 2-chlorotoluene resulted in a 12% yield
(GC), whereas using a catalyst supported by 3 afforded the product
in a 99% yield (Fig. 3). This result demonstrates that changing the
substituent ortho to the di-tert-butylphosphino group in 1 from
a methyl to a methoxy group, as in 3, has a dramatic effect on the
activity of these systems. We believe this increase in activity is due
to the increased freedom of rotation around the P–CAr bond in 3,
which may accelerate transmetallation. With 2, the dicyclohexyl-
phosphino analogue of 3, a 65% yield of product was realized. With
Table 1
Screen of reaction parameters for the cross-coupling of acetamide and 2-
chlorotoluene
Entry
Pd Source
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2/H2O Act.
Pd2(dba)3
Pd(dba)2
[(allyl)PdCl]2
(H3CCN2)PdCl2
Pd(OAc)2
Pd(OAc)2/H2O Act.
Pd(OAc)2/H2O Act.
Pd(OAc)2/H2O Act.
Pd(OAc)2/H2O Act.
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
K3PO4
K3PO4
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
Toluene
1,4-Dioxane
99
27
25
48
46
57
99
96
10
0
Figure 3. Results observed for the coupling of acetamide and 2-chlorotoluene with
various ligands.

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B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
Table 2
Pd-catalyzed cross-coupling of amides and aryl chloridesa
Entry
1
ArCl
Amide
Product
Time
Yieldb (%)
83
40 min
2
3
1.5 h
3 h
78
91
4
3 h
93
5
6
1.5 h
92
80
2 h
7
8
9
5 h
2 h
3 h
83
98
85
10
11
12
1.5 h
3 h
90
84
96
1.5 h
13
14
5 h
4 h
90
70

B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
6579
Table 2 (continued )
Entry
ArCl
Amide
Product
Time
12 h
Yieldb (%)
61
15
16
1.5 h
93
a
Reaction conditions: ArCl (1.0 equiv), amide (1.2 equiv), K3PO4 (1.4 equiv), Pd(OAc)2 (1 mol %), 3 (2.2 mol %), H2O (4 mol %), t-BuOH (2 mL/mmol), 110 ꢀC.
Isolated yields, average of two runs.
b
the ligand lacking the two methoxy substituents, t-BuXPhos (4), only
of amides with aryl chlorides bearing an ortho substituent. An array
of amides were successfully combined with aryl chlorides in good to
excellent yields using 1 mol % Pd and with reaction times <5 h.
a 15% yield of the desired product was formed.5a,13 These results re-
veal that both the methoxy group ortho to the di-tert-butylphosphino
group and the di-tert-butyl groups on the phosphorus center in 3 are
important to the high activity observed when this ligand is employed.
Finally, with ligand 5 (XPhos), which had previously been reported to
be suitable ligand for Pd-catalyzed amidation reactions of aryl tosy-
lates, only a trace of product was observed.3e
4. Experimental
4.1. General reagent information
All reactions were set up in the air and carried out under an
atmosphere of argon. Flash chromatography was performed using
(a) silica gel from American International Chemical or (b) a Biotage
SP4 instrument with prepacked silica cartridges. The tert-butanol
was purchased from Aldrich Chemical Co. in Sure-Seal bottles and
was used as received. Pd(OAc)2 was a gift from BASF. Aryl halides
and amides were purchased from Aldrich Chemical Co., Alfa Aesar,
Acros Organics, or Oakwood Products and were used as purchased
without further purification. Deionized water was degassed by
brief (30 s) sonication under vacuum and then evacuated and
backfilled with argon (this procedure was repeated three times).
Anhydrous tribasic potassium phosphate was purchased from Fluka
Chemical Co., stored in a nitrogen filled glovebox and removed in
small quantities and stored on the bench for up to two weeks.
Ligands 1,5a 2,7 and 43e were synthesized using literature pro-
cedures and ligand 5 was purchased from Strem Chemicals Inc.
2.3. Substrate scope for the Pd-catalyzed amidation reactions
of aryl chlorides using a catalyst system based on ligand 3
We next explored the scope of the Pd-catalyzed cross-coupling
reactions of aryl chlorides and amides with our new catalyst sys-
tem. We began by examining the effect of the ortho substituent on
the aryl chloride. As we had already observed, 2-chlorotoluene was
successfully coupled with acetamide in high yield (Table 2, entry 1).
When the methyl substituent was replaced with the larger ethyl
group the coupling still proceeded in good yield (Table 2, entry 2).
When the ortho substituent was changed to an electron-donating
methoxy group the rate of the coupling decreased slightly, the re-
action took 3 h to proceed to completion, but still gave 91% of the
desired product (Table 2, entry 3). Aryl chlorides with ortho sub-
stitution were also coupled with benzamide in excellent yields
(Table 2, entries 4 and 5). These examples show the superior re-
activity of this system over previously reported catalysts. Un-
fortunately, the reactions of aryl chlorides with two ortho
substituents failed to provide product under these conditions.
We next examined the reactions of aryl chlorides that lacked an
ortho substituent. Utilizing 3 as the ligand, the reaction of 4-
chlorotoluene with 4-trifluoromethylbenzamide gave the desired
product in good yield with 1 mol % Pd in only 2 h (Table 2, entry 6).
The reactions of similar substrates with the best previously reported
catalyst system required times between 12 and 24 h.5a
4.2. General analytical information
Yields refer to isolated yields of compounds greater than 95%
purity as determined by gas chromatography (GC) and 1H NMR. All
yields reported in Table 2 are for an average of two experiments. All
compounds were characterized by 1H NMR, 13C NMR, IR spectros-
copy, melting point, and in most cases, elemental analysis. Nuclear
Magnetic Resonance spectra were recorded on a Varian 300 MHz
instrument or a Bruker 400 MHz instrument. All 1H NMR experi-
Due to the ubiquity of heterocycles in many biologically active
molecules, we next wanted to extend the scope of this system to
heteroaryl substrates. Amides containing furans, pyridines, and
thiophenes were all well tolerated in these reactions. These could
be successfully coupled with a variety of aryl chlorides in good to
excellent yields, all with reaction times that were <5 h using
1 mol % Pd (Table 2, entries 8–14). For example, the coupling of
furan-2-carboxamide with 2-chloroanisole gave a 98% yield of the
desired product in 2 h (Table 2, entry 8). Additonally, a heteroaryl
chloride, 3-chloropyridine, was also an excellent coupling partner
for this reaction (Table 2, entries 15 and 16).
ments are reported in
d units, parts per million (ppm), and were
measured relative to the solvent residual peak. All 13C NMR spectra
are reported in parts per million relative to solvent residual peak
and were obtained with 1H decoupling. All IR spectra were made on
a Perkin–Elmer 2000 FTIR. All GC analyses were performed on an
Agilent 6890 gas chromatograph with an FID detector using a J & W
DB-1 column (10 m, 0.1 mm I.D.). Elemental analyses were per-
formed by Atlantic Microlabs Inc., Norcross, GA. HRMS spectra were
performed on a Bruker APEXIV 4.7t FT-ICR mass spectrometer.
4.3. Synthesis of 3
3. Conclusion
An oven-dried 300 mL round bottom Schlenk flask, which was
equipped with a magnetic stir bar, fitted with a rubber septum, and
charged with 2-iodo-20,40,60-triisopropyl-3,6-dimethoxybiphenyl7
(3.78 g, 8.11 mmol), was evacuated and backfilled with argon (this
process was repeated a total of three times). THF (40 mL) was added
via syringe, the reaction mixture was cooled to ꢁ78 ꢀC, and t-BuLi
In summary, a catalyst based on the new ligand 3 was developed
for the Pd-catalyzed cross-coupling of amides and aryl chlorides.
This system was much more active than previous catalyst systems
that have been used for these reactions, particularly for the coupling

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B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
(1.7 M in hexane, 9.54 mL, 16.22 mmol) was added in a dropwise
fashion over a 20 min period. The solution was stirred for 30 min
and then under a positive pressure of argon the septum was re-
moved from the Schlenk flask and anhydrous CuCl (804 mg,
8.11 mmol), which was weighed out in nitrogen filled glovebox,
was added rapidly. The flask was refitted with the rubber septum
and ClP(t-Bu)2 (1.70 mL, 8.92 mmol) was added in a dropwise
fashion over a 10 min period. The reaction mixture was warmed
from ꢁ78 ꢀC to room temperature at which point the flask was
sealed with a Teflon screw cap and heated to 70 ꢀC for 60 h. The
solution was cooled to room temperature, diluted with ethyl ace-
tate, washed with aqueous NH4OH (this process was repeated
a total of three times), washed with brine, dried over MgSO4, and
concentrated in vacuo. The crude material was recrystallized from
hot methanol to yield the desired product as white crystals
4.6. N-(2-Ethylphenyl)acetamide14 (Table 2, entry 2)
Following the general procedure, a mixture of 1-chloro-2-eth-
ylbenzene (132
(297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg,
0.022 mmol), H2O (0.7 L, 0.04 mmol), and t-BuOH (2.0 mL) was
mL, 1.0 mmol), acetamide (71 mg, 1.2 mmol), K3PO4
m
heated to 110 ꢀC for 1.5 h. The crude product was purified by flash
chromatography on silica gel (50% EtOAc in hexanes) to provide the
title compound as a white solid (129 mg, 79%). Mp¼115–116 ꢀC (lit.
111–111.8 ꢀC). 1H NMR (300 MHz, CDCl3)
d
: 7.63 (d, J¼7.2 Hz, 1H),
7.33 (br s, 1H), 7.21–7.10 (m, 3H), 2.57 (q, J¼7.5 Hz, 2H), 2.15 (s, 3H),
1.20 (t, J¼7.8 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3)
d: 168.9, 136.0,
135.0, 128.6, 126.6, 125.9, 124.6, 24.27, 24.19, 14.0 ppm. IR (neat,
cmꢁ1): 3271, 3037, 2964, 2929, 2869, 1653, 1588, 1540, 1448, 1373,
1296, 1053, 1018, 971, 749, 717, 610, 487. HRMS (ESI) calcd for
C10H14NO [MþHþ]: 164.1070; found: 164.1077.
(2.081 g, 53%). 1H NMR (300 MHz, CDCl3)
d: 6.96 (s, 2H), 6.87 (d,
J¼8.7 Hz, 1H), 6.83 (d, J¼9.0 Hz, 1H), 3.78 (s, 3H), 3.56 (s, 3H), 2.95
(septet, J¼6.9 Hz, 1H), 2.49 (septet, J¼6.6 Hz, 2H), 1.32 (d, J¼6.9 Hz,
6H), 1.21 (d, J¼6.6 Hz, 6H), 1.14 (s, 9H), 1.10 (s, 9H), 0.93 (d, J¼6.6 Hz,
4.7. N-(2-Methoxyphenyl)acetamide5a (Table 2, entry 3)
6H) ppm. 13C NMR (75 MHz, CDCl3)
d: 155.9, 152.6, 152.5, 147.2,
Following the general procedure, a mixture of 2-chloroanisole
146.7, 140.5, 140.0, 133.0, 127.6, 127.0, 120.1, 110.9, 108.2, 54.4, 54.0,
34.2, 34.1, 33.8, 32.1, 31.8, 31.3, 25.7, 24.3, 23.6 ppm (observed
(127
1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg, 0.022 mmol),
H2O (0.7
L, 0.04 mmol), and t-BuOH (2.0 mL) was heated to 110 ꢀC
mL, 1.0 mmol), acetamide (71 mg, 1.2 mmol), K3PO4 (297 mg,
complexity is due to P–C splitting). 31P NMR (121 MHz, CDCl3)
d:
m
34.78 ppm. IR (neat, cmꢁ1): 2958, 2864, 1581, 1486, 1421, 1250,
1086, 1020, 799, 715. HRMS (ESI) calcd for C31H50O2P [MþHþ]:
485.3543; found: 485.3537.
for 3 h. The crude product was purified by flash chromatography on
silica gel (40% EtOAc in hexanes) to provide the title compound as
a white solid (150 mg, 91%). Mp¼87–88 ꢀC (lit. 87–88). 1H NMR
(300 MHz, CDCl3)
d
: 8.35 (dd, J¼8.1, 1.7 Hz, 1H), 7.78 (br s, 1H), 7.03
4.4. General procedure for Table 2
(td, J¼7.5, 1.8 Hz, 1H), 6.95 (td, J¼7.8, 1.5 Hz, 1H), 6.86 (dd, J¼8.1,
1.5 Hz, 1H), 3.87 (s, 3H), 2.19 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3)
An oven-dried test tube, which was equipped with a magnetic
stir bar and fitted with a Teflon screwcap septum, was charged with
Pd(OAc)2 (1 mol %) and 3 (2.2 mol %). The vessel was evacuated and
backfilled with argon (this process was repeated a total of three
times) and t-BuOH (2.0 mL) and degassed H2O (4 mol %) were
added via syringe. After addition of the water, the solution was
heated to 110 ꢀC for 1.5 min. A second oven-dried test tube,
equipped with a magnetic stir bar and fitted with a Teflon screwcap
septum, was charged with amide (1.2 mmol) and K3PO4 (1.4 mmol)
(aryl chlorides that were solids at room temperature were added
with the base). The vessel was evacuated and backfilled with argon
(this process was repeated a total of three times) and then the aryl
chloride (1.0 mmol) was added via syringe and the activated cata-
lyst solution was transferred from the first reaction vessel into the
second via cannula. The solution was heated to 110 ꢀC until the aryl
chloride had been completely consumed as judged by GC analysis.
The reaction mixture was then cooled to room temperature, diluted
with ethyl acetate, and washed with water. The layers were sepa-
rated and the organic layer was dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The crude product was purified
via flash chromatography on silica gel.
d: 168.3, 147.7, 127.8, 123.7, 121.1, 119.8, 109.9, 55.7, 25.0 ppm. IR
(neat, cmꢁ1): 3249, 3195, 3137, 3063, 3021, 2964, 1659, 1596, 1544,
1496, 1468, 1459, 1436, 1368, 1323, 1291, 1272, 1252, 1025, 751. Anal.
Calcd for C9H11NO2: C, 65.44; H, 6.71. Found: C, 65.89; H, 6.90.
4.8. N-(2,5-Dimethylphenyl)benzamide (Table 2, entry 4)
Following the general procedure, a mixture of 2-chloro-p-xylene
(133
1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg, 0.022 mmol),
H2O (0.7
L, 0.04 mmol), and t-BuOH (2.0 mL) was heated to 110 ꢀC
mL, 1.0 mmol), benzamide (145 mg, 1.2 mmol), K3PO4 (297 mg,
m
for 3 h. The crude product was purified by flash chromatography on
silica gel (20% EtOAc in hexanes) to provide the title compound as
a white solid (215 mg, 95%). Mp¼151–152 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
: 7.88 (dt, J¼6.6, 1.5 Hz, 2H), 7.78 (s, 1H), 7.71 (br s, 1H), 7.56
(tt, J¼6.9, 1.8 Hz, 1H), 7.49 (tt, J¼6.6, 1.5 Hz, 2H), 7.11 (d, J¼7.8 Hz,
1H), 6.94 (dd, J¼7.5, 0.9 Hz, 1H), 2.34 (s, 3H), 2.28 (s, 3H) ppm. 13C
NMR (75 MHz, CDCl3) d: 136.7, 135.6, 135.1, 131.9, 130.43, 130.41,
128.9, 127.1, 126.2, 123.8, 21.3, 17.5 ppm. IR (neat, cmꢁ1): 3253,
2922, 1644, 1618, 1580, 1530, 1489, 1501, 1308, 1290, 1029, 875, 808,
708, 602, 450. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71. Found: C,
79.81; H, 6.78.
4.5. N-o-Tolylacetamide5a (Table 2, entry 1)
4.9. N-(2,5-Dimethoxyphenyl)benzamide15 (Table 2, entry 5)
Following the general procedure, a mixture of 2-chlorotoluene
(117
1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg, 0.022 mmol),
H2O (0.7
L, 0.04 mmol), and t-BuOH (2.0 mL) was heated to 110 ꢀC
m
L, 1.0 mmol), acetamide (71 mg, 1.2 mmol), K3PO4 (297 mg,
Following the general procedure, a mixture of 2,5-dimethoxy-
chlorobenzene (143
mL, 1.0 mmol), benzamide (145 mg, 1.2 mmol),
m
K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol),
3
for 40 min. The crude product was purified by flash chromatography
on silica gel (40% hexanes in EtOAc) to provide the title compound as
a white solid (119 mg, 80%). Mp¼108–109 ꢀC (lit. 108–109). 1H NMR
(11 mg, 0.022 mmol), H2O (0.7 mL, 0.04 mmol), and t-BuOH (2.0 mL)
was heated to 110 ꢀC for 1.5 h. The crude product was purified by
flash chromatography on silica gel (10% EtOAc in hexanes) to pro-
vide the title compound as a white-tan solid (242 mg, 94%).
(300 MHz, CDCl3)
d
: 7.68 (d, J¼7.8 Hz, 1H), 7.23–7.15 (m, 3H) 7.07 (t,
J¼7.5 Hz,1H), 2.23 (s, 3H), 2.17 (s, 3H) ppm.13C NMR (75 MHz, CDCl3)
Mp¼87–88 ꢀC (lit. 82–84 ꢀC). 1H NMR (300 MHz, CDCl3)
d: 8.60 (br
d
: 168.8,135.7,130.5,130.1,126.6,125.5,124.0, 24.1,17.9 ppm. IR (neat,
s, 1H), 8.30 (d, J¼3.0 Hz, 1H), 7.89 (dt, J¼6.6, 1.8 Hz, 2H), 7.58–7.46
(m, 3H), 6.83 (d, J¼9.0 Hz, 1H), 6.61 (dd, J¼9.0, 3.0 Hz, 1H), 3.87 (s,
cmꢁ1): 3290, 3028, 2981, 1654, 1588, 1531, 1486, 1460, 1369, 1288,
1272, 1118, 1039, 1018, 756, 714, 700, 653, 608, 562, 534, 446. Anal.
Calcd for C9H11NO: C, 72.46; H, 7.43. Found: C, 72.25; H, 7.59.
3H), 3.82 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3)
d: 165.3, 154.0,
142.4, 135.2, 131.9, 128.9, 128.5, 127.1, 110.7, 108.9, 105.9, 56.3,

B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
6581
55.9 ppm. IR (neat, cmꢁ1): 3427, 3335, 3057, 3000, 2937, 2955,
4.13. N-(2-Ethylphenyl)nicotinamide (Table 2, entry 9)
2833, 1668, 1601, 1532, 1498, 1478, 1464, 1423, 1268, 1220, 1202,
1179, 1164, 1047, 1024, 862, 797, 704, 679. Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88. Found: C, 69.89; H, 6.03.
Following the general procedure, a mixture of 1-chloro-2-ethyl-
benzene (132 L, 1.0 mmol), nicotinamide (147 mg, 1.2 mmol),
K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol),
(11 mg, 0.022 mmol), H2O (0.7 L, 0.04 mmol), and t-BuOH (2.0 mL)
m
3
4.10. N-p-Tolyl-4-(trifluoromethyl)benzamide16 (Table 2,
entry 6)
m
was heated to 110 ꢀC for 3 h. The crude product was purified by
flash chromatography on silica gel (80% EtOAc in hexanes) to pro-
vide the title compound as a white solid (189 mg, 83%). Mp¼101–
Following the general procedure, a mixture of 4-chlorotoluene
102.5 ꢀC. 1H NMR (300 MHz, (CD3)2SO)
d: 10.1 (s, 1H), 9.13 (d,
(118
K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol),
(11 mg, 0.022 mmol), H2O (0.7 L, 0.04 mmol), and t-BuOH (2.0 mL)
mL, 1.0 mmol), 4-trifluoromethylbenzamide (227 mg, 1.2 mmol),
J¼2.1 Hz, 1H), 8.77 (dd, J¼4.8, 1.2 Hz, 1H), 8.31 (d, J¼7.8 Hz, 1H), 7.58
3
(dd, J¼8.1, 4.8 Hz, 1H), 7.33–7.23 (m, 4H), 2.63 (q, J¼7.8 Hz, 2H), 1.13
m
(t, J¼7.8 Hz, 3H) ppm. 13C NMR (75 MHz, (CD3)2SO)
d: 164.3, 152.2,
was heated to 110 ꢀC for 2 h. The crude product was dissolved in
acetone, evaporated on to a small amount of silica gel, and purified
by flash chromatography on silica gel (gradient eluent: 10–30%
EtOAc in hexanes) to provide the title compound as a white solid
(222 mg, 80%). Mp¼235–236 ꢀC (lit. 236–238 ꢀC). 1H NMR
148.7, 139.9, 135.4, 130.1, 128.6, 127.6, 126.8, 126.2, 123.6, 24.0,
14.2 ppm. IR (neat, cmꢁ1): 3262, 3035, 2968, 2934, 2875, 1651, 1591,
1525, 1491, 1473, 1452, 1418, 1306, 1275, 1026, 759, 749, 706. HRMS
(ESI) calcd for C14H15N2O [MþHþ]: 227.1179; found: 227.1176.
(300 MHz, (CD3)2SO)
d
: 10.4 (s, 1H), 8.14 (d, J¼7.8 Hz, 2H), 7.90 (d,
4.14. N-(4-Methoxyphenyl)-2-(thiophen-2-yl)acetamide
(Table 2, entry 10)
J¼8.4 Hz, 2H), 7.66 (dd, J¼8.4 Hz, 2H), 7.17 (d, J¼8.1 Hz, 2H), 2.28 (s,
3H) ppm. 13C NMR (75 MHz, (CD3)2SO)
d
: 164.2, 138.9, 136.4, 133.1,
131.5, 131.1, 129.5, 129.1, 128.6, 125.8, 125.4, 125.4, 120.5, 20.5 ppm
(complexity is due to CF3-group). IR (neat, cmꢁ1): 3333, 2919, 1649,
1599, 1580, 1530, 1407, 1160, 1125, 861, 815, 770. Anal. Calcd for
C15H12F3NO: C, 64.51; H, 4.33. Found: C, 65.00; H, 4.68.
Following the general procedure, a mixture of 4-chloroanisole
(122
mL, 1.0 mmol), 2-thiopheneacetamide (169 mg, 1.2 mmol),
K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol),
3
(11 mg, 0.022 mmol), H2O (0.7 mL, 0.04 mmol), and t-BuOH (2.0 mL)
was heated to 110 ꢀC for 1.5 h. The crude product was purified via
the Biotage SP4 (silica-packed 25þM; 0–100% EtOAc/hexanes) to
provide the title compound as a pale yellow solid (223 mg, 90%).
4.11. Methyl 3-(cyclopropanecarboxamido)benzoate (Table 2,
entry 7)
Mp¼122–123 ꢀC. 1H NMR (400 MHz, CD3CN)
d: 8.35 (br s, 1H), 7.43
(dt, J¼9.0, 3.4 Hz, 2H), 7.29 (dd, J¼4.4, 2.0 Hz, 1H), 6.99–6.97 (m,
Following the general procedure, a mixture of methyl 3-chloro-
2H), 6.86 (dt, J¼9.0, 3.3 Hz, 2H), 3.82 (s, 2H), 3.75 (s, 3H) ppm. 13C
benzoate (139
mL, 1.0 mmol), cyclopropanecarboxamide (102 mg,
1.2 mmol), K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg,
NMR (100 MHz, CD3CN) d: 168.9, 157.1, 138.1, 132.7, 127.7, 127.6,
125.9, 122.3, 114.8, 55.9, 38.4. IR (neat, cmꢁ1): 3329, 3106, 2960,
2834, 1659, 1609, 1544, 1511, 1454, 1407, 1310, 1242, 1173, 1025, 831,
702. HRMS (ESI) calcd for C13H14NO2S [MþHþ]: 248.0740; found:
248,0740.
0.010 mmol), 3 (11 mg, 0.022 mmol), H2O (0.7 mL, 0.04 mmol), and
t-BuOH (2.0 mL) was heated to 110 ꢀC for 5 h. The crude product
was purified by flash chromatography on silica gel (gradient eluent:
20–30% EtOAc in hexanes) to provide the title compound as a white
solid (169 mg, 77%). Mp¼129–130 ꢀC. 1H NMR (300 MHz, CDCl3)
d:
8.10–8.07 (m, 2H), 7.86 (d, J¼7.8 Hz, 1H), 7.74 (d, J¼7.8 Hz, 1H), 7.35
4.15. N-(2-Ethylphenyl)-2-(thiophen-2-yl)acetamide (Table 2,
entry 11)
(t, J¼8.1 Hz, 1H), 3.87 (s, 3H), 1.55 (sep, J¼3.9 Hz, 1H), 1.08 (dt, J¼6.9,
3.9 Hz, 2H), 0.85–0.79 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3)
d:
172.6, 167.0, 138.5, 130.8, 129.2, 125.1, 124.4, 120.7, 52.4, 15.7,
8.3 ppm. IR (neat, cmꢁ1): 3294, 3013, 2952, 1724, 1663, 1596, 1548,
1488, 1431, 1395, 1302, 1273, 1241, 1197, 1178, 1107, 1082, 956, 755,
688. Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98. Found: C, 65.47;
H, 6.10.
Following the general procedure, a mixture of 1-chloro-2-ethyl-
benzene (132
mL, 1.0 mmol), 2-thiopheneacetamide (169 mg,
1.2 mmol), K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg,
0.010 mmol), 3 (11 mg, 0.022 mmol), H2O (0.7 mL, 0.04 mmol), and
t-BuOH (2.0 mL) was heated to 110 ꢀC for 3 h. The crude product
was purified by flash chromatography on silica gel (20% EtOAc in
hexanes) to provide the title compound as a white solid (207 mg,
4.12. N-(2-Methoxyphenyl)furan-2-carboxamide (Table 2,
entry 8)
84%). Mp¼120.5–121.5 ꢀC. 1H NMR (300 MHz, CDCl3)
d: 7.92 (d,
J¼7.8 Hz, 1H), 7.35–7.33 (m, 1H), 7.20 (td, J¼8.1, 2.1 Hz, 1H), 7.14–
Following general procedure A, a mixture of 2-chloroanisole
7.05 (m, 4H), 3.99 (s, 3H), 2.31 (q, J¼7.5 Hz, 2H), 0.99 (t, J¼7.5 Hz,
(127
1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg, 0.022 mmol),
H2O (0.7
L, 0.04 mmol), and t-BuOH (2.0 mL) was heated to 110 ꢀC
mL, 1.0 mmol), 2-furamide (133 mg, 1.2 mmol), K3PO4 (297 mg,
3H) ppm. 13C NMR (75 MHz, CDCl3)
d: 168.0, 136.0, 134.8, 134.3,
128.8, 128.2, 127.8, 126.9, 126.4, 125.4, 122.6, 38.5, 24.5, 14.1 ppm. IR
(neat, cmꢁ1): 3257, 3034, 2963, 2930, 2871, 1655, 1585, 1532, 1447,
1405, 1342, 1256, 967, 752, 689. HRMS (ESI) calcd for C14H16NOS
[MþHþ]: 246.0947; found: 246.0949.
m
for 2 h. The crude product was purified by flash chromatography on
silica gel (10% EtOAc in hexanes) to provide the title compound as
a white solid (208 mg, 96%). Mp¼123–124 ꢀC. 1H NMR (300 MHz,
CDCl3)
d
: 8.78 (br s, 1H), 8.50 (dd, J¼7.8, 1.8 Hz, 1H), 7.52 (dd, J¼1.5,
4.16. Methyl 3-(furan-2-carboxamido)benzoate (Table 2,
entry 12)
0.6 Hz, 1H), 7.22 (dd, J¼3.6, 0.9 Hz, 1H), 7.08 (td, J¼7.8, 1.8 Hz, 1H),
7.00 (tdd, J¼7.7, 1.5, 0.3 Hz, 1H), 6.91 (dd, J¼8.1, 1.5 Hz, 1H), 6.54 (dd,
J¼3.6, 1.8 Hz, 1H) 3.93 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3)
d:
Following the general procedure, a mixture of methyl 3-chloro-
156.0, 148.3, 148.1, 144.28, 144.26, 127.3, 124.0, 121.2, 119.8, 115.03,
114.98, 112.57, 112.53, 110.0, 55.9 ppm (complexity of 13C NMR data
is due to detection of rotamers). IR (neat, cmꢁ1): 3410, 3141, 3118,
3019, 2979, 2943, 2843, 1672, 1606, 1584, 1534, 1524, 1462, 1437,
1251, 1226, 1216, 1105, 1020, 1012, 765, 750, 653, 604, 593. Anal.
Calcd for C12H11NO3: C, 66.35; H, 5.10. Found: C, 66.16; H, 5.19.
benzoate (139
mL, 1.0 mmol), 2-furamide (133 mg, 1.2 mmol), K3PO4
(297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg,
0.022 mmol), H2O (0.7 mL, 0.04 mmol), and t-BuOH (2.0 mL) was
heated to 110 ꢀC for 1.5 h. The crude product was purified by flash
chromatography on silica gel (30% EtOAc in hexanes) to provide the
title compound as a white solid (237 mg, 97%). Mp¼83–85 ꢀC. 1H

6582
B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
NMR (300 MHz, CDCl3)
d
: 8.39 (br s, 1H), 8.19 (t, J¼1.8 Hz, 1H), 8.02
1335,1278, 1196,1173,1131, 949, 896, 804, 761, 707, 635. HRMS (ESI)
(ddd, J¼8.1, 2.4,1.2 Hz,1H), 7.78 (ddd, J¼7.8, 1.5, 0.9 Hz,1H), 7.45 (dd,
J¼1.8, 0.8 Hz, 1H), 7.39 (t, J¼8.1 Hz, 1H), 7.21 (dd, J¼4.2, 0.8 Hz, 1H),
6.51 (dd, J¼3.6, 1.8 Hz, 1H), 3.87 (s, 3H) ppm. 13C NMR (75 MHz,
calcd for C12H17N2O [MþHþ]: 205.1335; found: 205.1326.
4.20. N-(Pyridin-3-yl)furan-2-carboxamide (Table 2, entry 16)
CDCl3) d: 166.7, 156.3, 147.5, 144.54, 144.51, 137.7, 130.9, 129.3, 125.5,
124.5, 120.9, 115.7, 115.6, 112.71, 112.67, 52.3 ppm (complexity of 13C
NMR data is due to detection of rotamers). IR (neat, cmꢁ1): 3325,
3130, 2952, 2845,1722,1668,1598,1583,1542,1489,1473,1441,1323,
1294, 1265, 1230, 1165, 1118, 1083, 1012, 884, 755, 684, 594. HRMS
(ESI) calcd for C13H12NO4 [MþHþ]: 246.0761; found: 246.0771.
Following general procedure A, a mixture of 3-chloropyridine
(95
1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg, 0.022 mmol),
H2O (0.7
L, 0.04 mmol), and t-BuOH (2.0 mL) was heated to 110 ꢀC
mL, 1.0 mmol), 2-furamide (133 mg, 1.2 mmol), K3PO4 (297 mg,
m
for 1.5 h. The crude product was purified by flash chromatography
on silica gel (gradient eluent: 50–100% EtOAc in CH2Cl2) to provide
the title compound as a white-tan solid (181 mg, 96%). Mp¼142–
4.17. N-(4-Methoxyphenyl)nicotinamide (Table 2, entry 13)
143 ꢀC. 1H NMR (300 MHz, CD3OD)
d
: 8.88 (dd, J¼2.4, 0.8 Hz, 1H),
8.27 (dd, J¼4.5, 1.4 Hz, 1H), 8.22 (ddd, J¼8.4, 2.4, 1.5 Hz, 1H), 7.74
(dd, J¼1.8, 0.9 Hz, 1H), 7.41 (ddd, J¼8.4, 4.8, 0.6 Hz, 1H), 7.29 (dd,
J¼3.6, 0.8 Hz, 1H), 6.63 (dd, J¼3.5, 1.7 Hz, 1H) ppm. 13C NMR
Following the general procedure, a mixture of 4-chloroanisole
(122
(297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), 3 (11 mg,
0.022 mmol), H2O (0.7 L, 0.04 mmol), and t-BuOH (2.0 mL) was
mL, 1.0 mmol), nicotinamide (147 mg, 1.2 mmol), K3PO4
(75 MHz, CD3OD) d: 159.0, 148.5, 147.0, 145.5, 142.6, 137.0, 129.8,
m
125.2, 116.8, 113.4 ppm. IR (neat, cmꢁ1): 3248, 3118, 3044, 1670,
1601, 1578, 1538, 1483, 1470, 1423, 1332, 1298, 1229, 1167, 1012, 884,
802, 756, 706, 595. HRMS (ESI) calcd for C10H9N2O2 [MþHþ]:
189.0659; found: 189.0661.
heated to 110 ꢀC for 5 h. The crude product was purified by flash
chromatography on silica gel with EtOAc as eluent to provide the
title compound as a white solid (192 mg, 84%). Mp¼152–154 ꢀC. 1H
NMR (300 MHz, (CD3)2SO)
d
: 10.3 (s, 1H), 9.11 (dd, J¼2.1, 0.8 Hz,1H),
8.75 (dd, J¼4.8, 1.5 Hz, 1H), 8.28 (ddd, J¼7.8, 2.1, 1.5 Hz, 1H), 7.69 (d,
J¼9.0 Hz, 2H), 7.55 (ddd, J¼7.8, 4.8, 0.9 Hz, 1H), 6.95 (d, J¼9.0 Hz,
Acknowledgements
2H), 3.75 (s, 3H) ppm. 13C NMR (75 MHz, (CD3)2SO)
d: 163.6, 155.8,
We thank the National Institutes of Health (NIH) for financial
support of this project (Grant GM-58160). We thank Merck, BASF
(Pd compounds), Chemetall (Cs2CO3), and Nippon Chemical for
additional support. B.P.F. thanks the William Asbornsen Albert
Memorial Fund for a fellowship. K.D. thanks the Department of
Chemistry and the Interdisciplinary Nanoscience Center, University
of Aarhus for funding. Q.Z. thanks the China Scholarship Council
and the National Science Foundation of China (Grant No. 20672088)
for financial support. The Varian NMR instrument used was sup-
ported by the NSF (Grants CHE 9808061 and DBI 9729592).
152.0, 148.7, 135.4, 131.9, 130.7, 123.5, 122.0, 113.8, 55.2 ppm. IR
(neat, cmꢁ1): 3321, 3010, 2952, 2838, 1672, 1643, 1614, 1546, 1510,
1485, 1423, 1409, 1276, 1248, 1177, 1124, 1030, 824, 706. Anal. Calcd
for C13H12N2O2: C, 68.41; H, 5.30. Found: C, 67.86; H, 5.26.
4.18. N-Phenyl-2-(pyridin-2-yl)acetamide (Table 2, entry 14)
Following the general procedure, a mixture of chlorobenzene
(102
K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol),
(11 mg, 0.022 mmol), H2O (0.7 L, 0.04 mmol), and t-BuOH (2.0 mL)
mL, 1.0 mmol), pyridine-2-acetamide (163 mg, 1.2 mmol),
3
m
Supplementary data
was heated to 110 ꢀC for 4 h. The crude product was purified via the
Biotage SP4 (silica-packed 25þM; 0–100% EtOAc/hexanes) to pro-
vide the title compound as a white solid (178 mg, 84%). Mp¼135–
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.04.096.
136 ꢀC. 1H NMR (400 MHz, (CD3)2SO)
d: 10.3 (s, 1H), 8.45 (d,
J¼4.4 Hz, 1H), 7.75 (td, J¼7.6, 1.8 Hz, 1H), 7.62 (d, J¼7.7 Hz, 2H), 7.40
References and notes
(d, J¼7.8 Hz, 1H), 7.32–7.25 (m, 3H), 7.04 (t, J¼7.4 Hz, 1H), 3.85 (s,
2H) ppm. 13C NMR (100 MHz, (CD3)2SO)
d: 168.2, 156.1, 149.0, 139.2,
1. (a) Lindley, J. Tetrahedron 1984, 40,1433; (b) Goldberg, I. Chem. Ber.1906, 39,1691.
2. (a) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78; (b)
Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450; (c) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400; (d) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428; (e) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421; (f) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727.
136.6, 128.7, 124.0, 123.2, 121.9, 119.1, 45.9. IR (neat, cmꢁ1): 3228,
3185, 3011, 2973, 1676, 1593, 1545, 1496, 1476, 1444, 1343, 1326,
1274, 1209, 1150, 1002, 780, 747, 685. HRMS (ESI) calcd for
C13H13N2O [MþHþ]: 213.1022; found: 213.1025.
3. (a) Imbriglio, J. E.; DiRocco, D.; Raghavan, S.; Ball, R. G.; Tsou, N.; Mosley, R. T.;
Tata, T. R.; Colletti, S. L. Tetrahedron Lett. 2008, 49, 4897; (b) Klapars, A.; Campos,
K. R.; Chen, C.; Volante, R. P. Org. Lett. 2005, 7, 1185; (c) Willis, M. C.; Brace, G. N.;
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4.19. N-(Pyridin-3-yl)cyclohexanecarboxamide17 (Table 2,
entry 15)
Following the general procedure, a mixture of 3-chloropyridine
(95
K3PO4 (297 mg, 1.4 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol),
(11 mg, 0.022 mmol), H2O (0.7 L, 0.04 mmol), and t-BuOH (2.0 mL)
mL, 1.0 mmol), cyclohexanecarboxamide (153 mg, 1.2 mmol),
3
m
was heated to 110 ꢀC for 12 h. The crude product was purified by
flash chromatography on silica gel with EtOAc as eluent followed by
a second purification via the Biotage SP4 (silica-packed 25þM; 70–
100% EtOAc in hexanes) to provide the title compound as a white
solid (133 mg, 65%). Mp¼128.5–130.5 ꢀC (lit. 134–135 ꢀC). 1H NMR
(300 MHz, (CD3)2SO)
d
: 10.0 (s, 1H), 8.75 (d, J¼2.4 Hz, 1H), 8.22 (dd,
J¼4.8, 1.5 Hz, 1H), 8.05 (dt, J¼8.4, 1.8 Hz, 1H), 7.30 (dd, J¼8.1, 1.5 Hz,
1H), 2.34 (tt, J¼11.4, 3.3 Hz, 1H), 1.82–1.62 (m, 5H), 1.46–1.14 (m,
5H) ppm. 13C NMR (75 MHz, CDCl3)
d: 174.9, 143.9, 140.7, 136.1,
7. Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003.
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125.9, 123.5, 44.8, 29.1, 25.4, 25.2 ppm. IR (neat, cmꢁ1): 3299, 3180,
3121, 3047, 2931, 2855, 1667, 1600, 1587, 1543, 1483, 1450, 1422,
9. Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10, 3505.

B.P. Fors et al. / Tetrahedron 65 (2009) 6576–6583
6583
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