Ligand-dependent site-selective suzuki cross-coupling of 3,5-dichloropyridazines

Article abstract of DOI:10.1021/jo401096u

General methods for the highly site-selective Suzuki monocoupling of 3,5-dichloropyridazines have been discovered. By changing the ligand employed, the preferred coupling site can be switched from the 3-position to the 5-position, typically considered the less reactive C-X bond. These conditions are applicable to the coupling of a wide variety of aryl-, heteroaryl-, and vinylboronic acids with high selectivities, thus enabling the rapid construction of diverse arrays of diarylpyradazines in a modular fashion.

Full text of DOI:10.1021/jo401096u

Note
pubs.acs.org/joc
Ligand-Dependent Site-Selective Suzuki Cross-Coupling of 3,5-
Dichloropyridazines
Xing Dai,*,† Yonggang Chen,*,‡ Stephanie Garrell,† Hong Liu,† Li-Kang Zhang,† Anandan Palani,†
Gregory Hughes,‡ and Ravi Nargund†
†Department of Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033,
United States
‡Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: General methods for the highly site-selective Suzuki monocoupling of 3,5-dichloropyridazines have been
discovered. By changing the ligand employed, the preferred coupling site can be switched from the 3-position to the 5-position,
typically considered the less reactive C−X bond. These conditions are applicable to the coupling of a wide variety of aryl-,
heteroaryl-, and vinylboronic acids with high selectivities, thus enabling the rapid construction of diverse arrays of
diarylpyradazines in a modular fashion.
directing groups in the reactants are all important factors in the
determination of the final site-selectivity.4 Recently, Strotman
and Chobanian reported catalyst-controlled regioselective
Suzuki couplings at both positions of dihaloimidazoles and
dihalooxazoles.5
We have been interested in the synthesis of pyridazine
derivatives that could be utilized in our drug discovery program.
Ideally, we want to identify catalyst systems capable of selective
substitution of C3 and C5 positions, which will give us the
flexibility for SAR studies (Figure 1). Selectivity of the
palladium-catalyzed cross-coupling reactions of heteroarenes
bearing multiple identical halogens is mainly determined by the
relative ease of oxidative addition. Based on the recent work by
Houk and Merlic, the C−Cl bond α to nitrogen of pyridazine
requires less energy to break (bond dissociation enthalpy, BDE,
INTRODUCTION
■
Transition-metal-catalyzed cross-coupling reactions of poly-
halogenated heteroarenes have been investigated extensively
and employed as key steps in the synthesis of important
biological targets or their direct precursors.1 For substrates
bearing different halogens, chemoselective cross-couplings have
been accomplished by taking advantage of reactivity disparities
between the halogens.2 However, with polyhalogenated
heteroarenes bearing identical halogens, selectivity is hard to
achieve. For example, in the synthesis of 11 β-hydroxysteroid
dehydrogenase type 1 (11β-HSD1) inhibitor, a mixture of
compounds 1 and 2 was obtained with no control of
regioselectivity (Scheme 1).3 Thus, in the presence of identical
halogens, steric effects, electronic effects, and the presence of
Scheme 1. Synthesis of 11β-HSD1 Inhibitor 3
Figure 1. Ligand-dependent site-selective Suzuki cross-couplings.
Received: June 15, 2013
© XXXX American Chemical Society
A
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Figure 2),6a suggesting that the order of reactivity for 3,5-
dichloropyridazine is C3 > C5. In other words, it is more
Table 1. Effects of Ligand on Phenylation of 3,5-
Dichloropyridazine
a
Figure 2. C−Cl BDEs (kcal/mol) of monochloropyridazines and 2,4-
dichloropyridine using G3B3 (bold) and B3LYP (in parentheses)
calculations.6a
challenging to develop a catalyst system to effect selective C5
coupling than C3 coupling. In addition, consideration must be
given to avoid bis-coupling products, further complicating the
development of highly selective catalyst system.
RESULTS AND DISCUSSION
■
Our initial study focused on examining the ligand effect for the
coupling of 3,5-dichloropyridazine (3a) and phenylboronic acid
(1 equiv). Reactions were conducted with 10 mol % of
Pd(OAc)2, 10 (bidentate) or 20 (monodentate) mol % of
ligand, and 3 equiv of Cs2CO3. Not surprisingly, a mixture of
monocoupling products (4a and 5a) and bis-coupling product
(6) were observed from these reactions. As summarized in
Table 1, the ligands exert profound effect on the chemo-
selectivity of the coupling, a phenomenon that has not been
reported before. It was observed that, in general, electron-
deficient bidentate ligands prefer coupling at C3 over C5
(Table 1, entries 1, 2, and 4−7) and DPPF gave the highest
selectivity.7 However, the selectivity could be reversed by using
electron-rich monodentate ligands (Table 1, entries 8−14),
with Q-Phos giving the highest selectivity in this position.8 It is
interesting to note that the electron-rich bidentate ligand
DTBPF (Table 1, entry 15) has opposite selectivity as
compared to DPPF (Table1, entry 1). This indicates that
steric effect of the ligand play a role on the selectivity. We
found it particularly surprising that Buchwald’s biaryl-based
monophosphines predominantly give the bis-coupling product
(6), even when only 1 equiv of phenylboronic acid was used
(Table 1, entries 16−20).9 Results of the reaction conditions
using RuPhos in entry 16 of Table 1 were confirmed on a 1
mmol scale, and 6 was isolated in 76% yield.
a
All reactions were set up in a glovebox with 10 μmol scale. Ligand/Pd
ratios of 2:1 for monodentate ligands and 1:1 for bidentate ligands.
b
Structures of all ligands are available in the Supporting Information.
c
d
Second-generation biphenyl precatalyst was used. All of the numbers
e
are normalized ratios of integrated peak areas VS internal standard. 3a
was not consumed completely.
With these two complementary ligands (DPPF for C3-
coupling and Q-Phos for C5-coupling) in hand, further
optimization was perfomed to improve the selectivity and
isolated yields. For C3-coupling, in the presence of DPPF,
more thorough screens of bases, solvents, catalyst loadings and
reaction temperatures were performed. Moreover, for the final
conditions, we targeted more practical and glovebox-free
conditions. After significant investigation, we established that
performing the reaction with 5 mol % of Pd(OAc)2, 5 mol % of
DPPF, 2.5 equiv of Cs2CO3, in dioxane and water (4:1 ratio) at
70 °C for 20 h afforded the C3-coupled product in the highest
yields.
We evaluated the scope of the C3-coupling of 3,5-
dichloropyridazines (3) with various boronic acids under the
optimized conditions, and the results are summarized in Table
2. The scope of the reaction with respect to the aryl boronic
acids is broad. For example, electron-neutral (Table 2, entries 1,
2, 3, and 8), electron-rich (Table 2, entries 5, 11, and 12), and
electron-poor (Table 2, entries 4, 6, and 7) phenylboronic acids
all afford the 3-substituted pyridazines in good yields. Ortho-
substituted phenylboronic acids seem to have better selectivity
and give higher yields (Table 2, entries 3, 5, and 6) than meta-
or para-substituted phenylboronic acids. Besides substituted
phenylboronic acids, 5-indolylboronic acid (entry 13) and
alkenyl pinacol boronate ester (entry 9) are also suitable under
these conditions. We also tested several other electrophiles.
The reactions between 4,6-dichloro-3-methylpyridazine (3b)
and aryl boronic acids formed the desired products in good
yields (Table 2, entries 10−13). Lower yields were obtained
when a more electron-rich substrate, 4,6-dichloro-3-methox-
ypyridazine (3c), was used (Table 2, entries 14 and 15).
Having accomplished mono C3-couplings of 3, we then
turned our attention to optimize the C5-coupling. The
optimization process of C5-coupling was very similar to the
C3-coupling although it was more sensitive to the solvent and
base efffects. We also determined that a 1:1 ratio of Pd:Q-Phos
generated results similar to those with a 1:2 ratio. Additional
experimentation with the combination of Pd(OAc)2 and Q-
B
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a
sterically hindered arylboronic acids (Table 3), identical to
those utilized in the previously mentioned couplings with
DPPF (Table 2). Under these conditions, the selectivity instead
showed preference for substitution at the C5 position
regardless of the boronic acids that was employed.
Table 2. C3-Coupling with DPPF
a
Table 3. C5-Coupling with Q-Phos
a
All reactions were performed on a 1 mmol scale without glovebox.
The final product contains <5% of the other isomer product. The
b
c
final product contains <10% of the borate dimer.
Phos showed that the reaction with 5 mol % of Pd(OAc)2, 5
mol % of Q-Phos, and 2.5 equiv of KF in toluene and water (4
to 1 ratio) at 70 °C for 20 h afforded the desired product with
the best yields. These conditions were then applied to cross-
couple a wide variety of electron-rich, electron-poor, and
a
All reactions were performed on a 1 mmol scale without glovebox.
The final product contains <5% of the other isomer product.
b
C
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Note
were premixed in reaction solvent at 25 °C for 15 min before addition
of subsequent reagents and starting materials. The metal 96-well block
was sealed with a prefluoroelastomeric backed metal top plate, heated
to the indicated temperature, and holded for 16 h. Analysis was
acomplished by reversed-phase HPLC using an internal standard such
as naphthalene to facilitate quantitative HPLC solution assay yield
determination.
Like dichloropyridazines, dichloropyridines are very impor-
tant and commonly used synthetic building blocks. While many
efforts have been done to achieve site selectivity, most have
been in the presence of directing groups.1,4 Moreover, it is
almost impossible to reverse the selectivity based on the recent
work by Houk and Merlic, which indicated about 1000 fold of
C2/C4 selectivity (Figure 2).6b By simply applying Table 2
conditions to 2,4-dichloropyridine (7), we were able to achieve
predominant C2-coupling and obtain the 2-substituted product
(8) in 90% yields (eq 1). When the ligand was switched from
Representative Procedure A for Table 2 (Table 2, Entry 1, as
an Example) and Compound 8. A mixture of 3,5-dichloropyr-
idazine (149 mg, 1.00 mmol), phenylboronic acid (122 mg, 1.00
mmol), palladium(II) acetate (11.23 mg, 0.05 mmol), 1,1′-bis-
(diphenylphosphino)ferrocene (27.7 mg, 0.05 mmol), and cesium
carbonate(815 mg, 2.50 mmol) in 1,4-dioxane (4.0 mL) and water
(1.0 mL) was degassed for 10 min with N2 and sealed in a microwave
vial. The reaction was heated at 70 °C for 20 h. The reaction was
cooled to room temperature, diluted with ethyl acetate (20 mL),
filtered through Celite, and concentrated. The residue was purified by
flash column chromatography (0−100% EtOAc/hexanes) and afforded
the product 5-chloro-3-phenylpyridazine (4a, 139.9 mg, 0.734 mmol,
73.4% yield) as a white solid. The ratio of the crude products is
1
82:4:14 (C3 coupling/C5 coupling/bis coupling): H NMR (CDCl3,
500 MHz) δ 9.16 (s, 1 H), 8.08 (d, J = 6.06 Hz; 2 H), 7.89 (s, 1 H),
7.55 (m, 3 H); 13C NMR (CDCl3, 125 MHz) δ 159.9, 149.8, 138.8,
135.2, 130.8, 129.3, 127.4, 123.6; HRMS (ESI-Orbitrap) m/z [M +
H]+ calcd for C10H8N2Cl 191.0371, found 191.0370.
DPPF to Q-Phos, the regioselectivity was reversed and the 4-
substituted product (9) was isolated in 36% yields (eq 2). To
the best of our knowledge, this is the first example of a C4-
coupling of 2,4-dichloropyridine in the absence of a directing
group. Further optimization of the conditions for the site-
selective cross-coupling of dichloropyridines is under inves-
tigation.
Compound 4b. Representative procedure A in 79% yield (161 mg)
as an amorphous solid. The ratio of the crude products is 85:3:12 (C3
1
coupling/C5 coupling/bis coupling): H NMR (CDCl3, 500 MHz) δ
= 9.07 (s, 1 H), 7.93 (d, J = 7.98 Hz, 2 H), 7.79 (s, 1 H), 7.31−7.27
(m, 2 H), 2.40 (s, 3 H); 13C NMR (CDCl3, 125 MHz): δ = 160.0,
149.6, 141.3, 138.7, 132.4, 130.1, 127.4, 123.3, 21.6; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C11H10N2Cl 205.0527, found
205.0525.
Compound 4c. Representative procedure A in 92% yield (188 mg)
CONCLUSIONS
■
as an amorphous solid. The ratio of the crude products is 96:2:2 (C3
1
In summary, we have reported the first ligand-dependent site-
selective Suzuki coupling of 3,5-dichloropyridazines. In the
presence of Pd(OAc)2 and the bidentate ligand DPPF, the 3-
substituted product can be obtained, while switching to the
monodentate ligand Q-Phos affords the 5-substituted analogs.
These reactions exhibit a broad substrate scope with numerous
aryl, heteroaryl, and alkenyl boronic acids having been
selectively coupled. The ability to cross-couple at either C−
Cl bond has allowed us to install a specific aryl or alkenyl group
at either of the two positions, leaving open the opportunity to
add a wide variety of coupling partners at the other C−Cl bond.
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
8.88 (s, 1H), 7.38 (s, 1H), 7.15−7.03 (m, 4H), 2.15 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 162.5, 149.3, 137.9, 136.4, 136.0, 131.2, 130.0,
129.7, 126.8, 126.3, 20.4; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd
for C11H10N2Cl 205.0527, found 205.0526.
Compound 4d. Representative procedure A in 82% yield (190 mg)
as an amorphous solid. The ratio of the crude products is 87:2:11 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.12 (s, 1H), 8.58 (s, 1H), 8.25 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 8.0
Hz, 1H), 7.93 (s, 1H), 7.60−7.57 (m, 1H), 2.63 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 197.6, 159.1, 150.2, 139.1, 138.0, 135.8, 131.9,
130.6, 129.8, 127.2, 123.8, 27.0; HRMS (ESI-Orbitrap) m/z [M + H]+
calcd for C12H10ON2Cl 233.0476, found 233.0474.
Compound 4e. Representative procedure A in 89% yield (209 mg)
EXPERIMENTAL SECTION
■
as an amorphous solid. The ratio of the crude products is 91:2:7 (C3
General Information. 1H NMR and 13C NMR spectra were
recorded on a 400 or 500 NMR spectrometer and calibrated using
residual undeuterated solvent as an internal reference. The high-
resolution LC/ESI-MS analysis was performed on a LTQ Orbitrap
mass spectrometer operated at a resolution of 30000. An aliquot of
each compound was injected into an HPLC system consisting of an
YMC C18 column, 150 × 4.6 mm, 3.0 μm particle size. The ratio of
the crude products is based on crude HNMR or LCMS.
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.11 (s, 1H), 8.19 (s, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 7.5
Hz, 1H), 7.15 (m, 2H), 2.62 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
162.4, 152.0, 149.8, 137.6, 132.2, 131.2, 128.8, 127.3, 122.9, 118.5,
44.4; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C12H13N3Cl
234.0793, found 234.0791.
Compound 4f. Representative procedure A in 90% yield (233 mg)
as an amorphous solid. The ratio of the crude products is 92:1:5 (C3
General Procedure for Table 1: Screening Palladium-
Catalyzed Suzuki Coupling Conditions with Respect to Ligand,
Solvent, Base and Order of Addition. All operations were carried
out in a nitrogen-filled glovebox. Commercially available materials
were used as received. Reactions for high-throughput screening were
performed in 8 × 30 mm borosilicate glass shell vials arranged in 96
well metal blocks with magnetic stirring. Ligands were dispensed to
the vials as solutions followed by evaporation of the solvent in vacuo in
the nitrogen-filled glovebox. Materials were dispensed to the vials as
solution/slurry in the reaction solvent via micropipets. Bases such as
Cs2CO3 and KF were dispensed either from arrays of 96 vials into
which the bases were preweighted robotically in the glovebox or as
aqueous solution via micropipets. The palladium source and ligand
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.22 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.69−7.61 (m, 3H), 7.54 (d, J =
7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 161.0, 150.5, 138.0,
135.5, 132.3, 132.0, 131.9, 130.1, 127.0, 126.9, 124.0 (q, J = 272 Hz);
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C11H7N2ClF3
259.0244, found 259.0242.
Compound 4g. Representative procedure A in 74% yield (167 mg)
as an amorphous solid. The ratio of the crude products is 83:3:14 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.19 (s, 1H), 7.88 (s, 1H), 7.64−7.62 (m, 2H), 6.99−6.95 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 163.8 (d, J = 248 Hz); 163.7 (d, J =
248 Hz); 157.5, 150.7, 139.3, 138.5, 123.7, 110.6 (d, J = 21.0 Hz);
D
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110.5 (d, J = 21.0 Hz); 106.3 (t, d = 25.0); HRMS (ESI-Orbitrap) m/z
[M + H]+ calcd for C10H6N2ClF2 227.0182, Found 227.0181.
Compound 4h. Representative procedure A in 75% yield (181 mg)
as an amorphous solid. The ratio of the crude products is 84:3:13 (C3
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C11H9NCl 190.0418,
found 190.0417.
Representative Procedure B for Table 3 (Table 3, Entry 1, as
an Example) and Compound 9. A mixture of 3,5-dichloropyr-
idazine (149 mg, 1.00 mmol), phenylboronic acid (122 mg, 1.00
mmol), and potassium fluoride (145 mg, 2.50 mmol) in toluene (4.0
mL) and water (1.0 mL) was degassed for 10 min with N2.
Palladium(II) acetate (11.23 mg, 0.05 mmol) and 1,2,3,4,5-
pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (35.5 mg, 0.05
mmol) were then added, and the solution was further degassed for
an additional 5 min. The vial was sealed, and the reaction was heated
at 70 °C for 20 h. The reaction was cooled to room temperature and
diluted with EtOAc (20 mL), filtered through Celite, and
concentrated. The residue was purified by flash column chromatog-
raphy (0 to 100% EtOAc/hexanes) and afforded the product 3-chloro-
5-phenylpyridazine (5a, 145.3 mg, 0.762 mmol, 76.2% yield). The
ratio of the crude products is 84:7:9 (C5 coupling/C3 coupling/bis
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.23 (s, 1H), 8.02−7.90 (m, 3H), 7.72 (s, 1H), 7.62−7.49 (m, 4H);
13C NMR (125 MHz, CDCl3) δ 161.8, 149.7, 138.1, 134.0, 133.9,
130.8, 130.5, 128.7, 128.6, 127.6, 127.3, 126.4, 125.4, 125.0; HRMS
(ESI-Orbitrap) m/z [M + H]+ calcd for C14H10N2Cl 241.0527, found
241.0526.
Compound 4i. Representative procedure A in 66% yield (185 mg)
as an amorphous solid. The ratio of the crude products is 78:3:19 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.02 (s, 1 H); 7.70 (s, 1 H); 6.64 (m, 1 H); 4.68−4.62 (m, 2 H);
4.39−4.34 (m, 2 H); 1.19 (s, 9 H); 13C NMR (125 MHz, CDCl3) δ
155.0, 154.5, 150.2, 138.5, 136.1, 128.7, 123.1, 80.2, 54.3, 53.2, 28.7;
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C13H17O2N3Cl
282.1004, found 282.0999.
1
coupling): H NMR (CDCl3, 500 MHz) δ 9.40 (s, 1 H), 7.71 (m, 3
H), 7.59 (m, 3 H); 13C NMR (CDCl3, 125 MHz) δ 157.5, 149.2,
141.4, 133.3, 131.1, 130.0, 127.5, 124.9; HRMS (ESI-Orbitrap) m/z
[M + H]+ calcd for C10H8N2Cl 191.0371, found 191.0370.
Compound 4j. Representative procedure A in 77% yield (158 mg)
as an amorphous solid. The ratio of the crude products is 86:2:12 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.81 (t, J = 5.88 Hz, 2 H); 7.53−7.55 (m, 1 H); 7.24−7.29 (m, 3 H);
2.58 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 158.3, 157.2, 138.8,
135.2, 130.3, 129.1, 127.0, 123.5, 20.3; HRMS (ESI-Orbitrap) m/z [M
+ H]+ calcd for C11H10N2Cl 205.0527, found 205.0526.
Compound 5b. Representative procedure B in 61% yield (124 mg)
as an amorphous solid. The ratio of the crude products is 74:8:18 (C5
coupling/C3 coupling/bis coupling): H NMR (CDCl3, 500 MHz) δ
1
9.07 (s, 1 H), 7.93 (d, J = 7.98 Hz, 2 H), 7.79 (s, 1 H), 7.31−7.27 (m,
2 H), 2.40 (s, 3 H); 13C NMR (CDCl3, 125 MHz) δ 160.0, 149.6,
141.3, 138.7, 132.4, 130.1, 127.4, 123.3, 21.6; HRMS (ESI-Orbitrap)
m/z [M + H]+ calcd for C11H10N2Cl 205.0527, found 205.0526.
Compound 5c. Representative procedure B in 78% yield (160 mg)
as an amorphous solid. The ratio of the crude products is 84:6:10 (C5
Compound 4k. Representative procedure A in 70% yield (174 mg)
as an amorphous solid. The ratio of the crude products is 81:3:16 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.96 (d, J = 9.0 Hz, 2H), 7.69 (s, 1H), 6.77 (d, J = 9.0 Hz, 2H), 3.03
(s, 6H), 2.77 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.7, 155.8,
152.0, 138.7, 130.0, 128.1, 126.7, 122.6, 40.4, 20.4; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C13H15N3Cl 248.0949, found
248.0947.
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
8.93 (d, J = 3.0 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.20−7.10 (m, 4H),
2.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 156.8, 151.2, 142.8,
135.6, 133.8, 131.4, 130.1, 129.7, 127.7, 126.9, 20.3; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C11H10N2Cl 205.0527, found
205.0526.
Compound 4l. Representative procedure A in 73% yield (171 mg)
as an amorphous solid. The ratio of the crude products is 83:2:15 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.63 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.27−7.23 (m,
1H), 6.88 (d, J = 7.5 Hz, 1H), 3.75 (s, 3H), 2.68 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ 160.3, 158.2, 157.5, 138.9, 136.6, 130.1, 123.7,
119.3, 116.6, 112.0, 55.5, 20.3; HRMS (ESI-Orbitrap) m/z [M + H]+
calcd for C12H12ON2Cl 235.0633, found 235.0630.
Compound 5d. Representative procedure B in 57% yield (134 mg)
as an amorphous solid. The ratio of the crude products is 74:8:18 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.43 (s, 1H), 8.29 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.5
Hz, 1H), 7.78−7.70 (m, 2H), 2.71 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 197.2, 157.7, 149.0, 140.5, 138.6, 134.1, 131.7, 130.8, 130.4,
127.2, 125.2, 27.0; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C12H10ON2Cl 233.0476, found 233.0474.
Compound 4m. Representative procedure A in 89% yield (230 mg)
as an amorphous solid. The ratio of the crude products is 94:1:5 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
8.28 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J = 8.5
Hz, 1H), 7.11 (s, 1H), 6.58 (s, 1H), 3.80 (s, 3H), 2.81 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 160.0, 156.4, 130.4, 129.1, 126.7, 123.8,
120.9, 120.4, 110.1, 102.4, 33.2, 25.1; HRMS (ESI-Orbitrap) m/z [M
+ H]+ calcd for C14H13N3Cl 258.0793, found 258.0791.
Compound 5e. Representative procedure B in 57% yield (133 mg)
as an amorphous solid. The ratio of the crude products is 75:9:16 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.48 (s, 1H), 7.77 (s, 1H), 7.44 (d, J = 6.5, 1H), 7.29 (d, J = 7.5, 1H),
7.20−7.15 (m, 2H), 2.63 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
157.4, 152.2, 151.0, 143.2, 131.5, 126.4, 126.3, 123.0, 119.2, 44.2;
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C12H13N3Cl 234.0793,
found 234.0790.
Compound 4n. Representative procedure A in 57% yield (135 mg)
as an amorphous solid. The ratio of the crude products is 72:4:24 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.59 (s, 1H), 7.41−7.30 (m, 4H), 4.29 (s, 3H), 2.43 (s, 3H); 13C NMR
(500 MHz, CDCl3) δ 160.3, 158.5, 136.5, 136.2, 131.3, 129.9, 129.5,
127.4, 126.4, 56.1, 20.7; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd
for C12H12ON2Cl 235.0633, found 235.0631.
Compound 5f. Representative procedure B in 61% yield (158 mg)
as an amorphous solid. The ratio of the crude products is 78:9:13 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.07 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.70−7.62 (m, 2H), 7.53 (s,
1H), 7.35 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 156.8,
150.4, 140.1, 132.9, 132.6, 131.5, 130.2, 127.8, 127.1, 127.0, 123.8 (q, J
= 272 Hz); HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for
C11H7N2ClF3 259.0244, found 259.0243.
Compound 4o. Representative procedure A in 58% yield (152 mg)
as an amorphous solid. The ratio of the crude products is 74:7:19 (C3
1
coupling/C5 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.77 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 4.18
(s, 3H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.4, 155.9,
140.1, 132.5, 129.9, 127.8, 126.6, 126.3, 55.9, 21.5; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C12H12ON2Cl 235.0633, found
235.0630.
Compound 5g. Representative procedure B in 74% yield (168 mg)
as an amorphous solid. The ratio of the crude products is 84:6:10 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, acetone-
d6) δ 9.64 (s, 1 H), 8.19 (s, 1 H), 7.71 (d; J = 7.39 Hz; 2 H), 7.28 (t; J
= 8.91 Hz; 1 H); 13C NMR (125 MHz, acetone-d6) δ 163.9 (d, J = 246
Hz), 163.7 (d, J = 246 Hz), 157.4, 149.1, 138.8, 138.8, 137.1, 125.4,
111.3 (d, J = 21.0 Hz), 111.2 (d, J = 21 Hz), 105.9 (t, d = 25.4);
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C10H6N2ClF2
227.0182, found 227.0180.
Compound 8. Representative procedure A in 92% yield (174 mg)
as an amorphous solid. The ratio of the crude products is >98:<1:<1
(C2 coupling/C4 coupling/bis coupling): 1H NMR (500 MHz,
CDCl3) δ 8.62 (d, J = 5.5 Hz, 1H), 8.01 (d, J = 7.0 Hz, 2H), 7.77 (s,
1H), 7.54−7.47 (m, 3H), 7.28−7.27 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 159.2, 150.8 144.9, 138.4, 129.9, 129.1, 127.3, 122.5, 121.0;
E
dx.doi.org/10.1021/jo401096u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Compound 5h. Representative procedure B in 53% yield (128 mg)
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
■
as an amorphous solid. The ratio of the crude products is 75:9:16 (C5
S
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.20 (s, 1H), 7.95−7.90 (m, 2H), 7.69 (m, J = 8.0, 1H), 7.60 (s, 1H),
7.56−7.48 (m, 4H), 7.39 (d, J = 6.5, 1H); 13C NMR (125 MHz,
CDCl3) δ 157.2, 151.8, 142.0, 134.0, 132.0, 130.8, 130.5, 129.2, 128.5,
128.2, 127.9, 127.0, 125.7, 124.2; HRMS (ESI-Orbitrap) m/z [M +
H]+ calcd for C14H10N2Cl 241.0527, Found 241.0526.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xing.dai@merck.com, yonggang.chen@merck.com.
Notes
■
Compound 5i. Representative procedure B in 56% yield (157 mg)
as an amorphous solid. The ratio of the crude products is 80:7:13 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
9.12 (s, 1H), 7.31 (s, 1H), 6.67 (d, J = 23 Hz, 1H), 4.23 (m, 4H), 1.19
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 157.6, 154.0, 147.5, 133.8,
132.2, 130.0, 123.2, 80.5, 54.5, 52.4, 28.7; HRMS (ESI-Orbitrap) m/z
[M + H]+ calcd for C13H17O2N3Cl 282.1004, found 282.1001.
Compound 5j. Representative procedure B in 65% yield (133 mg)
as an amorphous solid. The ratio of the crude products is 82:6:12 (C5
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Mary Senior for NMR studies, Drs. Shane Krska
and Brendan Crowley for helpful discussion, and Dr. Matthew
Tudge for providing 2nd generation biphenyl precatalysts. We
also thank Drs. Sha Lou and Michael Lo for proofreading.
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.41−7.36 (m, 3H), 7.27−7.22 (m, 3H), 2.52 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 158.0, 155.1, 143.0, 135.3, 129.6, 129.2, 128.6, 127.5,
21.0; HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C11H10N2Cl
205.0527, found 205.0528.
DEDICATION
■
This paper is dedicated to Professor Gregory Fu on the
occasion of his 50th birthday.
Compound 5k. Representative procedure B in 62% yield (152 mg)
as an amorphous solid. The ratio of the crude products is 78:8:14 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
REFERENCES
7.25 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 3.00
(s, 6H), 2.67 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.1, 155.1,
151.2, 143.3, 129.9, 126.6, 122.2, 112.2, 40.4, 21.5; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C13H15N3Cl 248.0949, found
248.0950.
■
(1) For recent reviews and references therein: (a) Rossi, R.; Bellina,
F.; Lessi, M. Adv. Synth. Catal. 2012, 354, 1181. (b) Rossi, R.; Bellina,
F.; Lessi, M. Tetrahedron 2011, 67, 6969. (c) Fairlamb, I. J. S. Chem.
Soc. Rev. 2007, 36, 1036. (d) Schroter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245.
̈
Compound 5l. Representative procedure B in 57% yield (134 mg)
as an amorphous solid. The ratio of the crude products is 75:8:17 (C5
(2) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(3) Claremon, D. A.; Zhuang, L.; Leftheris, K.; Tice, C. M.; Xu, Z.;
Ye, Y.; Singh, S. B.; Cacatian, S.; Zhao, W.; Himmelsbach, F.;
Eckhardt, M. Patent WO 2009134392, 2009.
(4) (a) Houpis, I. N.; Liu, R.; Wu, Y.; Yuan, Y.; Wang, Y.;
Nettekoven, U. J. Org. Chem. 2010, 75, 6965. (b) Yang, W.; Wang, Y.;
Corte, J. R. Org. Lett. 2003, 5, 3131. (c) Houpis, I. N.; Huang, C.;
Nettekoven, U.; Chen, J. G.; Liu, R.; Canters, M. Org. Lett. 2008, 10,
5601.
(5) Strotman, N. A.; Chobanian, H. R.; He, J.; Guo, Y.; Dormer, P.
G.; Jones, C. M.; Steves, J. E. J. Org. Chem. 2010, 75, 1733.
(6) (a) Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.;
Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632. (b) Legault, C. Y.;
Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2007, 129,
12664. For another DFT study of site-selectivity in oxidative addition
reactions with Pd0 complexes, see: (c) Herrebout, W. A.; Nagels, N.;
Verbeeck, S.; van der Veken, B. J.; Maes, B. U. W. Eur. J. Org. Chem.
2010, 3152. (d) Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.
(7) C3-coupling product was the major product obtained although
PPh3 is not bi-dentate. For reference of the second-generation
biphenyl pre-catalyst please see: Kinzel, T.; Zhang, Y.; Buchwald, S. L.
J. Am. Chem. Soc. 2010, 132, 14073.
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.39 (t, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.90 (d,
J = 7.5 Hz, 1H), 6.85 (s, 1H), 3.84 (s, 3H), 2.64 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 160.1, 158.1, 155.2, 143.0, 136.8, 130.4, 127.5,
120.8, 114.9, 114.5, 55.7, 21.0; HRMS (ESI-Orbitrap) m/z [M + H]+
calcd for C12H12ON2Cl 235.0633, found 235.0632.
Compound 5m. Representative procedure B in 60% yield (171 mg)
as an amorphous solid. The ratio of the crude products is 79:7:14 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.51 (s, 1 H), 7.39 (d, J = 8.53 Hz, 1 H), 7.27 (s, 1 H), 7.13 (m, 2 H),
6.51 (d, J = 3.12 Hz, 1 H), 3.80 (s, 3 H), 2.64 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 158.6, 155.1, 144.6, 137.0, 130.8, 128.8, 127.7, 126.4,
121.9, 121.6, 110.0, 101.8, 33.3, 21.4; HRMS (ESI-Orbitrap) m/z [M
+ H]+ calcd for C14H13N3Cl 258.0793, found 258.0792.
Compound 5n. Representative procedure B in 67% yield (157 mg)
as an amorphous solid. The ratio of the crude products is 83:6:11 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.39 (d, J = 7.5 Hz, 1H), 7.33−7.30 (m, 3H), 7.17 (d, J = 7.5 Hz, 1H),
4.13 (s, 3H), 2.20 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.6,
151.3, 136.5, 134.2, 132.6, 130.6, 130.5, 129.7, 129.5, 126.3, 55.6, 20.0;
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C12H12ON2Cl
235.0633, found 235.0631.
(8) (a) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem.
Soc. 2000, 122, 10718. (b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.;
Hartwig, J. J. Org. Chem. 2002, 67, 5553.
(9) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 2008, 47,
6338.
Compound 5o. Representative procedure B in 68% yield (161 mg)
as an amorphous solid. The ratio of the crude products is 81:7:12 (C5
1
coupling/C3 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
7.48 (d, J = 8.0 Hz, 2 H), 7.30 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 4.11
(s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.0, 151.6,
140.5, 132.9, 129.6, 129.4, 129.2, 128.4, 55.6, 21.6; HRMS (ESI-
Orbitrap) m/z [M + H]+ calcd for C12H12ON2Cl 235.0633, found
235.0631.
Compound 9. Representative procedure B in 36% yield (68 mg) as
an amorphous solid. The ratio of the crude products is 60:25:15 (C4
1
coupling/C2 coupling/bis coupling): H NMR (500 MHz, CDCl3) δ
8.47−8.45 (m, 1H), 7.68−7.40 (m, 7H); 13C NMR (125 MHz,
CDCl3) δ 152.4, 151.8, 150.3, 137.0, 130.0, 129.5, 127.3, 122.3, 120.7;
HRMS (ESI-Orbitrap) m/z [M + H]+ calcd for C11H9NCl 190.0418,
found 190.0413.
F
dx.doi.org/10.1021/jo401096u | J. Org. Chem. XXXX, XXX, XXX−XXX