Me3(OMe)tBuXPhos: A surrogate ligand for Me4tBuXPhos in palladium-catalyzed C-N and C-O bond-forming reactions

Article abstract of DOI:10.1021/jo202537e

A new biarylphosphine ligand, Me₃(OMe)tBuXPhos (L3), was designed as a surrogate for Me₄tBuXPhos (L1). The Me ₃(OMe)tBuXPhos could be prepared in a chromatography-free manner from inexpensive and readily available 2,3,6-trimethylphenol. Comparative studies demonstrated that a catalyst based on Me₃(OMe)tBuXPhos displayed the same reactivity as a catalyst based on Me₄tBuXPhos for Pd-catalyzed C-N and C-O bond-forming processes.

Full text of DOI:10.1021/jo202537e

Note
pubs.acs.org/joc
Me3(OMe)tBuXPhos: A Surrogate Ligand for Me4tBuXPhos in
Palladium-Catalyzed C−N and C−O Bond-Forming Reactions
Satoshi Ueda, Siraj Ali, Brett P. Fors, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: A new biarylphosphine ligand, Me3(OMe)
tBuXPhos (L3), was designed as a surrogate for Me4tBuXPhos
(L1). The Me3(OMe)tBuXPhos could be prepared in a
chromatography-free manner from inexpensive and readily
available 2,3,6-trimethylphenol. Comparative studies demon-
strated that a catalyst based on Me3(OMe)tBuXPhos displayed
the same reactivity as a catalyst based on Me4tBuXPhos for
Pd-catalyzed C−N and C−O bond-forming processes.
of nonmethylated ligand tBuXPhos (L2) in several Pd-catalyzed
C−N bond-forming reactions.2,6,7 We felt that ligand L3, which
possesses both 3- and 6-methyl substitutents and is accessible
from inexpensive and readily available 2,3,6-trimethylphenol,9
might be a suitable surrogate for L1. Herein, we report a
synthesis of L3 and its utilization in the Pd-catalyzed arylation
reactions of nitrogen and oxygen nucleophiles.
e4tBuXPhos (L1, Figure 1) is a useful ligand in Au-catalyzed
1
Mcarbocyclization and Pd-catalyzed arylation reactions
The synthesis of L3 is described in Scheme 1. Dibromide 2
was prepared from 2,3,6-trimethylphenol via dibromination and
O-methylation. Notably, both 1 and 2 were crystalline solids
and could be isolated in pure form without chromatography.
Dibromide 2 was treated with Mg and 2,4,6-triisopropylphe-
nylmagnesium bromide in THF at 60 °C for 1.5 h and then
allowed to react with CuCl and ClP(tBu)2 to give L3 in 61%
yield. 1H NMR analysis showed that L3 was an approximately a
1:1 mixture of two regioisomers, suggesting that addition of
the aryl Grignard reagent to the benzyne generated from 2 was
unselective.
In order to compare the activity of the Pd/L1 and Pd/L3
systems, the reaction progress of the N-arylation of nitrogen
heterocycles was investigated (Schemes 2 and 3). Previously,
the N-arylation of 4-methylimidazole and bromobenzene with
Pd/L1 gave N-arylated product 3a in 95% yield with complete
N1 selectivity.7 The same N-arylation reaction using Pd/L3
showed similar progress, and the N-arylated product was ob-
tained in 96% yield with complete N1 selectivity. Similarly, almost
identical yields (90% with L1, 89% with L3) and N2 selectivity
(N2/N1 = 97:3 for both L1 and L3) were observed for the N-
arylation of 1,2,3-triazole.6 These results demonstrate that a
catalyst based on L3 shows identical reactivity to a catalyst based
on L1, indicating that it is excellent surrogate for C−N cross-
coupling reactions.
Figure 1. Structures of biarylphosphine ligands.
of nitrogen/oxygen nucleophiles, including amides,2 benzimi-
dazoles,3 phenols,4 and water.5 We recently demonstrated that
the combination of Pd and L1 was the most effective catalyst
system for the highly N2-selective arylation of 1,2,3-triazoles6
and completely N1-selective arylation of unsymmetric imida-
zoles.7 L1 is synthesized from 1,2,3,4-tetramethylbenzene via
dibromination and then a one-pot biarylphosphine synthesis
protocol, which proceeds through a benzyne intermediate.4,5
However, the high cost and limited availability of the 1,2,3,4-
tetramethylbenzene8 could potentially prevent the utilization of
Pd/L1 systems, as well as the future development of methods
using L1 as a supporting ligand for various metals. To circumvent
this problem, the development of an inexpensive and robust
alternative to L1 is highly desirable.
Mechanistic investigations by our group on Pd-catalyzed aryl
amidation with L1 indicated that the 3-methyl substituent of
the ligand restricts rotation of the Ar−P bond and fixes the Pd
center over the triisopropylphenyl ring.2a In addition, it was
postulated that 6-methyl group of L1 increases conformational
rigidity in the Pd−ligand complex and possibly accelerates the
rate of reductive elimination.3 On the basis of these two fea-
tures, it was proposed that the utility of L1 was superior to that
We next explored the scope of the Pd/L3 system using
a variety of aryl halides and N/O-nucleophiles (Scheme 4).
Received: December 13, 2011
Published: February 7, 2012
© 2012 American Chemical Society
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Scheme 1. Preparation of L3
Scheme 2. Comparison of Catalysts Based on L1 and L3 for the N-Arylation of 4-Methylimidazole
Scheme 3. Comparison of Catalysts Based on L1 and L3 for the N-Arylation of 1,2,3-Triazole
We found that the use of Pd/L3 gave comparable yields to
those obtained with Pd/L1 in all reactions examined. It should
be noted that N1-aryl-4-methylimidazoles 3c and 3d, which are
key intermediates for the synthesis of GSK213730510 and
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a
Scheme 4. Comparison of Catalysts Based on L1 and L3 for the N- and O-Arylation Reactions
a
Reactions were carried out on a 1.0 mmol scale. Isolated yields, average of two runs. Conditions: (b) Pd2(dba)3 (L/Pd = 1:1), 4-methylimidazole
(2 mmol), K3PO4 (2 mmol), toluene−dioxane (1:1), 130 °C, 6 h; (c) Pd2(dba)3 (L/Pd = 1:1), 4-methylimidazole (2.4 mmol), K3PO4 (2 mmol),
toluene−tBuOH (1:1), 120 °C, 8 h; (d) Pd2(dba)3 (L/Pd = 1:1), imidazole derivative (1.2 mmol), K3PO4 (2 mmol), toluene−dioxane (5:1),
120 °C, 5 h; (e) Pd2(dba)3 (L/Pd = 1:2.5), benzamide (1.2 mmol), K3PO4 (1.2 mmol), tBuOH, 110 °C, 16 h; (f) Pd2(dba)3 (L/Pd = 1:2), KOH
(3 mmol), H2O−dioxane (1:1), 100 °C, 16 h; (g) Pd(OAc)2 (L/Pd = 1:1.5), phenol (1.2 mmol), K3PO4 (2 mmol), toluene, 100 °C, 16 h.
nilotinib (Tasigna),11 were prepared in high yield as single
3 h, and then a saturated aqueous solution of Na2SO3 (150 mL) was
added to quench the residual Br2. The organic phase was separated
regioisomers at 0.3 or 0.5 mol % Pd loadings.
and washed with brine, dried over MgSO4, and concentrated in vacuo
to give a white solid which was triturated with hexanes and collected
In summary, we have designed and synthesized a new biaryl
phosphine ligand, Me3(OMe)tBuXPhos (L3). The ligand L3
could be prepared in a chromatography-free manner from in-
expensive and readily available 2,3,6-trimethylphenol. Compara-
tive studies of L1 and L3 demonstrated that L3 could indeed
serve as a surrogate for the Me4tBuXPhos (L1). We expect wide
use and large-scale application of L3 as an efficient substitute for
L1 in a variety of Pd-catalyzed C−N and C−O bond-forming
reactions.
by filtration. The white solid was dried in vacuo to give 40.1 g (92%
1
yield) of the title compound: mp 142−144 °C; H NMR (400 MHz,
CDCl3) δ 4.73 (s, 1H), 2.43 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 151.23, 136.5, 125.3, 123.3, 122.7, 119.4,
22.3, 18.3, 13.7; IR (film) νmax 3376, 1699, 1652, 1558, 1541, 1456,
1388, 1290, 1199, 1081, 970, 784, 731 cm−1. Anal. Calcd for C9H10Br2O:
C, 36.77; H, 3.43. Found: C, 36.63; H, 3.39.
1,2-Dibromo-4-methoxy-3,5,6-trimethylbenzene (2). A 250 mL
round-bottom flask, which was equipped with a stir bar, was charged
with 3,4-dibromo-2,5,6-trimethylphenol (14.7 g, 50 mmol) and K2CO3
(8.3 g, 60 mmol). Acetone (80 mL) and dimethyl sulfate (5.68 mL,
60 mmol) were added to the mixture, and then the flask was equipped
with a reflux condenser. The reaction mixture was stirred at 75 °C for
6 h. After the mixture was cooled to room temperature, an aqueous
KOH solution (2.0 M, 100 mL) was added, and the mixture was
stirred at room temperature for 20 min. The reaction mixture was
concentrated to remove acetone and then extracted with Et2O, washed
with brine, dried over MgSO4, and concentrated under reduced pre-
ssure to give the title compound as a white solid (15.0 g, 97% yield,
EXPERIMENTAL SECTION
■
General Information. Pd2(dba)3 and Pd(OAc)2 was purchased
from a commercial supplier. Anhydrous tribasic potassium phosphate
was stored in a glovebox. Small portions were removed and stored in a
desiccator for up to 2 weeks (all reactions were set up outside of the
glovebox). L14a was prepared by a literature procedure. Reactions were
monitored by GC and thin-layer chromatography (TLC) using UV
light. Flash chromatography was performed using silica gel (230−400
1
mesh). All H NMR experiments are reported in δ units, parts per
1
million (ppm), and were measured relative to the signals for residual
chloroform (7.26 ppm) or dimethyl sulfoxide-d6 (2.50 ppm) in the
deuterated solvent. All 13C NMR spectra are reported in ppm relative
to deuterochloroform (77.23 ppm) or dimethyl sulfoxide-d6 (39.52 ppm),
unless otherwise stated, and all were obtained with 1H decoupling.
The pure compounds are estimated to be ≥95% pure as determined
GC purity of 99.5% area %): mp 63−65 °C; H NMR (400 MHz,
CDCl3) δ 3.65 (s, 3H), 2.44 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 156.3, 137.1, 131.2, 130.3, 125.6, 123.4,
60.5, 22.2, 18.6, 14.1; IR (film) νmax 2924, 1652, 1540, 1449, 1375,
1213, 1092, 1002, 972, 902, 755, 668 cm−1. Anal. Calcd for C10H12Br2O:
C, 38.99; H, 3.93. Found: C, 38.82; H, 3.86.
1
by H NMR or GC analysis.
Di-tert-butyl(2′,4′,6′-triisopropyl-5-methoxy-3,4,6-
trimethyl[1,1′-biphenyl]-2-yl)phosphine/Di-tert-butyl(2′,4′,6′-
triisopropyl-4-methoxy-3,5,6-trimethyl[1,1′-biphenyl]-2-yl)-
phosphine (L3). An oven-dried 250 mL round-bottom flask, which
was equipped with a stir bar and charged with Mg shavings (1.02 g,
42 mmol), was fitted with a reflux condenser, a glass stopper, and a
3,4-Dibromo-2,5,6-trimethylphenol (1). To a stirred solution of
2,3,6-trimethylphenol (20.4 g, 150 mmol) and I2 (381 mg, 1.5 mmol)
in CH2Cl2 (150 mL) was added Br2 (17.0 mL, 330 mmol) dropwise
(1 drop/1 s) at room temperature. After the addition of Br2 was
complete, the reaction mixture was stirred at room temperature for
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Note
rubber septum. The flask was purged with argon, and then 2-bromo-
1,3,5-triisopropylbenzene (5.07 mL, 20 mmol) and anhydrous THF
(40 mL) were added via syringe. The reaction mixture was heated to
60 °C, and 1,2-dibromoethane (50 μL) was added via syringe. The
reaction was stirred at 60 °C for 1.5 h. 1,2-Dibromo-4-methoxy-3,5,6-
trimethylbenzene (6.16 g, 20 mmol) was added portionwise to the
reaction mixture over a 30 min period under a stream of argon. After
the addition of 1,2-dibromo-4-methoxy-3,5,6-trimethylbenzene was
complete, the reaction mixture was stirred at 60 °C for 1.5 h. The
reaction mixture was cooled to room temperature, and CuCl (1.98 g,
20 mmol) and ClPtBu2 (4.6 mL, 24 mmol) were quickly added under
a stream of argon. The reaction mixture was heated to reflux at 75 °C
for 30 h. The reaction mixture was cooled to room temperature,
diluted with Et2O, washed three times with 30% NH4OH, dried over
MgSO4, and concentrated under reduced pressure to give a pale yellow
crude oil. The crude oil was diluted with EtOAc (5 mL), and then
MeOH (50 mL) was added. The mixture was cooled to 0 °C, and the
white precipitate that had formed was collected by filtration, washed
two times with cold MeOH, and dried in vacuo to yield a white
powder (6.03 g, 61% yield, mp 130−132 °C) as an approximately
1:0.98 mixture of two isomers as determined by methoxy proton
signals (methoxy proton signal of major isomer: 3.75 ppm, minor
isomer: 3.68 ppm): 1H NMR (400 MHz, CDCl3) δ 6.95/6.94 (s, 2H),
3.76/3.68 (s, 3H), 2.97−2.86 (m, 1H), 2.57/2.53 (s, 3H), 2.48−2.33
(m, 2H), 2.26/2.20 (s, 3H), 1.76/1.73 (s, 3H), 1.31−1.25 (m, 6H),
1.23−1.19 (m, 6H), 1.16−1.09 (m, 18H), 0.93/0.89 (d, J = 6.6 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 157.7, 155.8, 150.0, 149.6,
147.5, 147.5, 146.5, 146.5, 146.2, 141.6, 141.6, 138.1, 137.8, 137.7,
136.1, 136.0, 134.0, 133.9, 130.5, 130.4, 129.0, 128.9, 127.6, 120.7,
120.6, 59.7, 59.6, 34.7, 34.6, 34.3, 34.3, 34.2, 32.8, 32.6, 31.0, 31.0,
31.0, 26.2, 26.2, 25.5, 25.5, 24.8, 24.7, 24.7, 24.7, 24.4, 24.4, 21.9, 21.9,
21.1, 21.0. (Observed complexity is due to C−P splitting); 31P NMR
(121 MHz, CDCl3) δ 39.17, 38.16; IR (film) νmax 2956, 2362, 1542,
1461, 1381, 1311, 1208, 1166, 1090, 1011, 911 cm−1. Anal. Calcd for
C33H53OP: C, 79.79; H, 10.75. Found: C, 79.71; H, 10.69.
a screw-cap septum and then evacuated and backfilled with argon (this
process was repeated a total of three times) and then bromobenzene
(106 μL, 1.0 mmol); 1,2,3-triazole (70 μL, 1.2 mmol) and the pre-
heated catalyst solution were added via syringe to the second vial. The
reaction mixture was heated at 120 °C for 5 h. The reaction mixture
was cooled to room temperature, diluted with EtOAc, washed with
brine, dried over MgSO4, and concentrated in vacuo. The crude product
was purified via flash chromatography (hexanes/EtOAc, 9:1) to provide
the title compound as colorless oil (129 mg, 89% (with L3)): 1H NMR
(400 MHz, CDCl3) δ 8.12−8.06 (m, 2H), 7.80 (s, 2H), 7.51−7.44 (m,
2H), 7.38−7.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 140.0, 135.6,
129.4, 127.6, 119.1; IR (film) νmax 3128, 3059, 2362, 1745, 1598, 1500,
1410, 1376, 1259, 1152, 1069, 953, 820, 757, 692, 668, 510, 455 cm−1.
Anal. Calcd for C8H7N3: C, 66.19; H, 4.86. Found: C, 66.23; H, 4.91.
3-(4-(4-Methyl-1H-imidazol-1-yl)phenyl)-1,4-diazaspiro[4.4]-
non-3-en-2-one (3c). An oven-dried vial was equipped with a
magnetic stir bar and charged with Pd2(dba)3 (4.6 mg, 0.005 mmol)
and L1 or L3 (0.01 mmol). The vial was sealed with a screw-cap
septum and then evacuated and backfilled with argon (this process was
repeated a total of three times). Anhydrous toluene (0.6 mL) was
added via syringe, and the resulting dark purple mixture was stirred at
130 °C for 3 min. A second oven-dried vial which was equipped with a
stir bar was charged with 3-(4-chlorophenyl)-1,4-diazaspiro[4.4]non-3-
en-2-one7 (249 mg, 1.0 mmol), 4-methylimidazole (164 mg, 2.0 mmol),
and K3PO4 (424 mg, 2.0 mmol). The vial was sealed with a screw-
cap septum and then evacuated and backfilled with argon (this process
was repeated a total of three times). The preheated catalyst solution
(0.18 mL, 0.3 mol % Pd) was transferred to the second vial via syringe,
and then toluene (0.5 mL) and dioxane (0.5 mL) were added (a total
1.18 mL of solvent). The reaction mixture was heated at 130 °C for
6 h. The reaction mixture was cooled to room temperature, diluted
with EtOAc, washed with brine, dried over MgSO4, and concen-
trated in vacuo. The crude product was purified via flash chroma-
tography (EtOAc−MeOH, 15:1) to provide the title compound as a
1
white solid (268 mg, 91% (with L3)): mp 194−195 °C; H NMR
4-Methyl-1-phenyl-1H-imidazole (3a). An oven-dried vial was
equipped with a magnetic stir bar and charged with Pd2(dba)3 (6.9 mg,
0.0075 mmol) and L1 or L3 (0.018 mmol). The vial was sealed with a
screw-cap septum and then evacuated and backfilled with argon (this
process was repeated a total of three times). Anhydrous toluene
(0.83 mL) and anhydrous 1,4-dioxane (0.17 mL) were added via
syringe The resulting dark purple mixture was stirred at 120 °C for
3 min; at this point, the color of the mixture turned to red-brown.
A second oven-dried vial, which was equipped with a stir bar, was
charged with 4-methylimidazole (98 mg, 1.2 mmol) and K3PO4
(424 mg, 2.0 mmol). The vial was sealed with a screw-cap septum
and then evacuated and backfilled with argon (this process was
repeated a total of three times) and then bromobenzene (106 μL,
1.0 mmol), and the preheated catalyst solution was added via syringe
to the second vial. The reaction mixture was heated at 120 °C for 5 h.
The reaction mixture was cooled to room temperature, diluted with
EtOAc, washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude product was purified via flash chromatography
(EtOAc/MeOH, 50:1) to provide the title compound as a pale-yellow
(400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.26
(d, J = 1.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 2.17 (s,
3H), 2.00−1.77 (m, 8H); 13C NMR (100 MHz, DMSO-d6) δ 164.1,
158.8, 138.9, 138.8, 134.7, 129.4, 128.5, 119.3, 113.8, 89.6, 37.1, 23.9,
13.6; IR (film) νmax 3854, 3745, 3158, 3050, 2962, 2360, 1704, 1606,
1518, 1442, 1254, 1191, 1063, 963, 848, 752, 540 cm−1. Anal. Calcd
for C17H18N4O: C, 69.37; H, 6.16. Found: C, 69.21; H, 6.12.
3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline
(3d). An oven-dried vial was equipped with a magnetic stir bar and
charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol) and L1 or L3 (0.0025
mmol). The vial was sealed with a screw-cap septum and then
evacuated and backfilled with argon (this process was repeated a total
of three times). Then anhydrous toluene (0.5 mL) was added via
syringe. This dark purple mixture was stirred at 120 °C for 3 min. The
color of the mixture turned to dark brown after 3 min. A second oven-
dried vial which was equipped with a stir bar was charged with 3-
amino-5-bromobenzotrifluoride (240 mg, 1.0 mmol), 4-methylimida-
zole (197 mg, 2.4 mmol), and K3PO4 (424 mg, 2.0 mmol). The vial
was sealed with a screw-cap septum and then evacuated and backfilled
with argon (this process was repeated a total of three times). The
preheated catalyst solution followed by anhydrous toluene (0.5 mL)
and tBuOH (1.0 mL) were added via syringe to the second vial (a total
2 mL of toluene−tBuOH 1:1 solution). The reaction was heated at
120 °C for 8 h. The reaction mixture was cooled to room temperature,
diluted with EtOAc, washed with brine, dried over MgSO4, con-
centrated in vacuo, and purified via flash chromatography (Et2O/
EtOAc/MeOH, 125:125:1) to provide the title compound as a white
1
solid (152 mg, 96% (with L3)): mp 60 °C; H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 1.6 Hz, 1H), 7.36−7.29 (m, 2H), 7.25−7.17 (m,
3H), 6.89 (s, 1H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
139.4, 137.3, 134.4, 129.7, 126.9, 120.8, 114.4, 13.6; IR (film) νmax
3385, 3108, 2921, 1599, 1507, 1448, 1392, 1366, 1291, 1241, 1070,
1003, 969, 817, 759, 692 cm−1. Anal. Calcd for C10H10N2: C, 75.92; H,
6.37. Found: C, 76.04; H, 6.33.
2-Phenyl-1,2,3-triazole (3b). An oven-dried vial was equipped
with a magnetic stir bar and charged with Pd2(dba)3 (6.9 mg, 0.0075
mmol) and L1 or L3 (0.018 mmol). The vial was sealed with a screw-
cap septum and then evacuated and backfilled with argon (this process
was repeated a total of three times). Anhydrous toluene (1.0 mL) was
added via syringe, and the resulting dark purple mixture was stirred at
120 °C for 3 min; at this point, the color of the mixture turned to red-
brown. A second oven-dried vial, which was equipped with a stir bar,
was charged with K3PO4 (424 mg, 2.0 mmol). The vial was sealed with
1
solid (219 mg, 91% (with L3)): mp 125 °C; H NMR (400 MHz,
DMSO-d6) δ 8.09 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 6.99 (s, 1H), 6.96
(s, 1H), 6.85 (s, 1H), 5.91 (s, 2H), 2.16 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 150.9, 138.5, 134.8, 131.3 (q, J = 38 Hz), 124.1 (q, J =
272 Hz), 114.2, 107.9, 103.3 (q, J = 4 Hz), 13.5; IR (film) νmax 3854,
3745, 3414, 3215, 2362, 1620, 1509, 1412, 1328, 1293, 1254, 1199,
1158, 1115, 843, 807, 735, 691, 621 cm−1. Anal. Calcd for C11H10F3N3:
C, 54.77; H, 4.18. Found: C, 54.61; H, 4.11.
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2-(1-(6-Methoxypyridin-2-yl)-1H-imidazol-4-yl)acetonitrile
(3e). An oven-dried vial was equipped with a magnetic stir bar and
charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol) and L1 or L3 (0.005
mmol). The vial was sealed with a screw-cap septum and then
evacuated and backfilled with argon (this process was repeated a total
of three times). Anhydrous toluene (0.41 mL) and anhydrous 1,4-
dioxane (0.19 mL) were added via syringe. The resulting dark purple
mixture was stirred at 120 °C for 3 min; at this point the color of the
mixture turned to red-brown. A second oven-dried vial, which was
equipped with stir bar, was charged with 4-cyanomethylimidazole
(64 mg, 0.6 mmol) and K3PO4 (212 mg, 1.0 mmol). The vial was
sealed with a screw-cap septum and then evacuated and backfilled with
argon (this process was repeated a total of three times); 6-bromo-2-
methoxypyridine (61 μL, 0.5 mmol) and the preheated catalyst
solution were added via syringe to the second vial. The reaction
mixture was heated at 120 °C for 5 h. The reaction mixture was cooled
to room temperature, diluted with EtOAc, washed with brine, dried
over MgSO4, and concentrated in vacuo. The crude product was
purified via flash chromatography (EtOAc) to provide the title
compound as a white solid (94 mg, 87% (with L3)): mp 77−78 °C;
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 1.2 Hz, 1H), 7.63 (t, J =
1046, 854, 775, 690 cm−1. Anal. Calcd for C14H13NO2: C, 73.99; H,
5.77. Found: C, 73.73; H, 5.75.
2-Methyl-5-phenoxybenzo[d]thiazole (3i). An oven-dried vial
was equipped with a magnetic stir bar and charged with 5-chloro-2-
methylbenzothiazole (184 mg, 1.0 mmol), phenol (113 mg, 1.2 mmol),
K3PO4 (424 mg, 2.0 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), and L1 or
L3 (0.03 mmol). The vial was sealed with a screw-cap septum and then
evacuated and backfilled with argon (this process was repeated a total of
three times). Toluene (1.5 mL) was added via syringe, and the reaction
mixture was heated at 100 °C for 16 h. The reaction mixture was cooled
to room temperature, diluted with EtOAc, washed with brine, dried over
MgSO4, and concentrated in vacuo. The crude product was purified
via flash chromatography (hexanes/EtOAc, 7:1) to provide the title
1
compound as colorless oil (224 mg, 93% (with L3)): H NMR (400
MHz, CDCl3) δ 7.72 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H),
7.37−7.30 (m, 2H), 7.14−7.02 (m, 4H), 2.81 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 168.8, 157.4, 156.3, 154.6, 130.3, 129.9, 123.6, 122.1,
119.0, 117.3, 112.1, 20.3; IR (film) νmax 3064, 2922, 1590, 1558, 1522,
1489, 1453, 1311, 1266, 1216, 1169, 1133, 1069, 1002, 950, 872, 810,
752, 693, 643 cm−1. Anal. Calcd for C14H11NOS: C, 69.68; H, 4.59.
Found: C, 69.63; H, 4.64.
8.0 Hz, 1H), 7.58 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.24 (d, J = 8.4 Hz,
1H), 3.91 (s, 3H), 3.73 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
163.8, 146.5, 141.2, 135.2, 133.0, 117.4, 114.0, 109.2, 103.6, 53.8, 17.9;
IR (film) νmax 3397, 2954, 1614, 1580, 1481, 1452, 1421, 1321, 1253,
1091, 1035, 1000, 860, 793 cm−1. Anal. Calcd for C11H10N4O: C,
61.67; H, 4.71. Found: C, 61.65; H, 4.77.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
1-(Pyrimidin-5-yl)-1H-benzimidazole (3f). An oven-dried vial
was equipped with a magnetic stir bar and charged with Pd2(dba)3
(2.3 mg, 0.0025 mmol) and L1 or L3 (0.005 mmol). The vial was
sealed with a screw-cap septum and then evacuated and backfilled with
argon (this process was repeated a total of three times). Anhydrous
toluene (0.3 mL) was added via syringe. The resulting dark purple
mixture was stirred at 120 °C for 3 min; at this point, the color of the
mixture turned to red-brown. A second oven-dried vial, which was
equipped with a stir bar, was charged with benzimidazole (142 mg,
1.2 mmol), 5-bromopyrimidine (159 mg, 1.0 mmol), and K3PO4 (424
mg, 2.0 mmol). The vial was sealed with a screw-cap septum and then
evacuated and backfilled with argon (this process was repeated a total
of three times); the preheated catalyst solution, toluene (0.53 mL),
and dioxane (0.17 mL) were added to the second vial. The reaction
mixture was heated at 120 °C for 5 h. The reaction mixture was cooled
to room temperature, diluted with EtOAc, washed with brine, dried
over MgSO4, and concentrated in vacuo. The crude product was puri-
fied via flash chromatography (EtOAc/MeOH, 15:1) to provide the
title compound as a white solid (190 mg, 97% (with L3)): mp 137−
AUTHOR INFORMATION
Corresponding Author
*E-mail: sbuchwal@mit.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Institutes of Health
(GM58160). We gratefully acknowledge Dr. Xiaohua Huang
who first prepared L3. S.U. thanks the Japan Society for the
Promotion of Sciences (JSPS) for a Postdoctoral Fellowship for
Research Abroad. S.A. thanks the MIT UROP program for support.
B.P.F. thanks Bristol-Myers Squibb for a graduate fellowship.
REFERENCES
■
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139 °C; H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.95 (s, 2H),
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2H), 7.33−7.26 (m, 2H), 7.19−7.11 (m, 2H), 6.67−6.61 (m, 1H), 3.67
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131.7, 129.6, 128.6, 127.2, 112.9, 110.5, 106.3, 55.2; IR (film) νmax
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