Direct arylation of azine N-oxides with aryl triflates

Article abstract of DOI:10.1016/j.tet.2009.03.077

Palladium catalyzed direct arylation of azine N-oxides using aryl triflates to afford the corresponding 2-aryl azine N-oxides is described. The reaction is carried out with a range of both N-oxides and aryl triflates. The arylation can be carried out in s

Full text of DOI:10.1016/j.tet.2009.03.077

Tetrahedron 65 (2009) 4977–4983
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Tetrahedron
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Direct arylation of azine N-oxides with aryl triflates
*
Derek J. Schipper, Mohamed El-Salfiti, Christopher J. Whipp, Keith Fagnou
Center for Catalysis Research and Innovation, University of Ottawa, Department of Chemistry, 10 Marie Curie, Ottawa, ON, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium catalyzed direct arylation of azine N-oxides using aryl triflates to afford the corresponding
2-aryl azine N-oxides is described. The reaction is carried out with a range of both N-oxides and aryl
triflates. The arylation can be carried out in sequence to yield differentially diarylated products. The
regioselectivity and scope of 3-substituted azine N-oxides are investigated. The method is applied to the
synthesis of a compound that exhibits antimalarial and antimicrobial activities.
Received 27 February 2009
Received in revised form 23 March 2009
Accepted 26 March 2009
Available online 1 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results
Biaryl compounds represent an important class of molecule.1
Specifically, the 2-aryl azine motif features prominently in ligand,
medicinal, and materials chemistry.2 Transition metal catalyzed
cross coupling reactions of aryl halides with aryl organometallics
such as Suzuki, Stille, and Negishi reactions represent some of the
most important methods for synthesizing biaryl compounds.1
However, the requirement for substrate pre-activation renders
the overall process inefficient and uneconomical. An emerging
alternative to these methods, which has received increased at-
tention in recent years is direct arylation, in which one of the pre-
activated components, usually the organometallic, is replaced by
a simple arene.3 Although direct arylation reactions have been
investigated thoroughly with use of halides, there are few reports
employing the use of aryl triflates.4 Triflates are an important
class of electrophile because they can be easily synthesized from
phenols and consequently can be revealed at a late stage in
a synthetic sequence.
We previously reported the palladium catalyzed direct arylation
of pyridine and diazine N-oxides using a wide range of aryl halides.5
In this account we report (1) an operationally simple catalyst sys-
tem for the direct arylation of azine N-oxide substrates employing
aryl triflates, (2) a sequential arylation to yield deferentially dia-
rylated products that takes advantage of the increased propensity
of aryl triflates to induce diarylation, (3) the scope and regiose-
lectivity of arylation on a range of 3-substituted azine N-oxides, and
(4) the application of this method to the synthesis of an antima-
larial and antimicrobial compounds.
An optimization study commenced with previously reported con-
ditions using pyridine N-oxide and p-tolyl trifluoromethanesulfonate.
These studies revealed that, unlike reactions employing aryl
bromide substrates, diarylation of the N-oxide substrate was a sig-
nificant challenge with aryl triflates leading to diminished yields.
An evaluation of the various reaction variables leads to two opti-
mized reaction conditions (Scheme 1). The first set of conditions
was found to minimize diarylation side products thus maximizing
the yield of the monoarylation product. This method employs the
use of tricyclohexylphosphine as the ligand, Rb2CO3 as the base,
and 40 mol % pivalic acid in toluene (0.15 M) at 100 ꢀC for 15 h
(conditions A). The second set of conditions, which result in in-
creased reactivity, were developed to maximize yields with sub-
strates for which diarylation is not problematic. This method makes
use of di-tert-butylmethylphosphine as the ligand, K2CO3 as the
base, with 30 mol % pivalic acid in toluene (0.5 M) at 110 ꢀC for 15 h
(conditions B). The increased reactivity of this system could be
partially due to the less sterically demanding nature of the
Conditions A - gives highest yields of mono-arylated product:
Pd(OAc)2 (5 mol%)
OTf
HP(Cy3)BF4 (10 mol%)
+
Rb2CO3, PivOH (40 mol%)
PhMe (0.15M)
N
O
H
N
O
H
100 °C
Conditions B - gives highest yield when only one arylation is possible:
Pd(OAc)2 (5 mol%)
OTf
HP(tBu2Me)BF4 (10 mol%)
+
K2CO3, PivOH (30 mol%)
PhMe (0.5M)
N
O
R
H
N
O
R
110 °C
* Corresponding author. Tel.: þ1 613 562 5728; fax: þ1 613 562 5170.
E-mail address: keith.fagnou@uottawa.ca (K. Fagnou).
Scheme 1. Optimized arylation conditions.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.077

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D.J. Schipper et al. / Tetrahedron 65 (2009) 4977–4983
Table 1 (continued)
Table 1
Azine arylation scope
Entry
N-Oxide
Aryl triflate
Product
Cond.a Yieldb
OTf
N
N
O
N
R
R
N
N
O
R'
N
Cond. A or B
+
R'
18
2
A
B
80%
N
O
N
O
Me
Entry
N-Oxide
Aryl triflate
Product
Cond.a Yieldb
Me
Me
N
Me
Me
N
99%g
OTf
19
20
2
1
2
3
4
A
A
A
A
51%c
65%d
89%
N
O
N
O
N
O
N
O
Me
1
91%e
2
N
Me
CN
OTf
N
Me
A
A
60%
43%
N
O
TfO
N
O
5
6
1
1
A
A
49%
75%
N
O
CN
N
N
TfO
TfO
N
O
21
N
O
N
N
O
N
OMe
OMe
OTf
N
O
22
23
A
B
68%
81%
7
8
1
A
A
75%
71%
2
N
O
N
O
Me
Me
Me
2
24
25
2
A
A
B
82%
27%
85%g
N
O
N
O
N
O
N
O
Me
Me
OMe
OMe
OTf
9
2
2
A
39%
N
O
N
O
N
O
N
O
Me
Me
TfO
CN
CN
26
OMe
N
10
11
A
A
38%
59%
N
N
O
N
O
N
O
N
O
MeO
a
ConditionsA: N-oxide(2 equiv),Triflate(1 equiv), Pd(OAc)2 (0.05 equiv),HP(Cy3)BF4
(0.10 equiv), Rb2CO3 (2 equiv),PivOH(0.4 equiv),PhMe(0.15 M),100 ꢀC,15 h.Conditions
B: N-oxide (2 equiv), Triflate (1 equiv), Pd(OAc)2 (0.05 equiv), HP(tBu2)MeBF4
(0.10 equiv), K2CO3 (2 equiv), PivOH (0.3 equiv), PhMe (0.5 M), 110 ꢀC, 15 h.
CO2Me
CO2Me
OTf
b
N
O
Isolated yields.
Using 1.0 equiv of N-oxide.
Using 1.5 equiv of N-oxide.
Using 2.5 equiv of N-oxide.
CuCN (10 mol %) added.
Using 1.1 equiv of N-oxide.
N
O
c
d
e
CN
CN
f
g
12
13
2
B
74%
90%
Me
N
O
Me
N
O
P(tBu2)Me compared to that of the PCy3 ligand. Illustrative exam-
ples for reaction with aryl triflates under the two different reaction
conditions are outlined in Table 1. The arylation proceeds with 89–
91% yield with 2–2.5 equiv of pyridine N-oxide, respectively (Table
1, entries 3 and 4). If less pyridine N-oxide is used diminished yields
of 51–65% are noted (Table 1, entries 1 and 2). Lower yields of 38–
59% are obtained with substitution of electron-donating or elec-
tron-withdrawing groups at the 4-position (Table 1, entries 9–11),
although low solubility of these substrates could explain di-
minished yields. The reaction proceeds well with electron rich aryl
triflates (Table 1, entries 6, 13, and 26).
Me
F
F
TfO
A
N
O
N
O
OMe
OMe
Me
14
15
A
B
51%
99%
N
N
O
2
2
N
N
O
N
Diazine N-oxides are also compatible with the arylation. Pyr-
idazine N-oxide is arylated in 99% when using conditions B (Table 1,
entry 15). Pyrazine N-oxide is also a competent substrate (Table 1,
entries 18–21). Pyrimidine N-oxide is less suitable, resulting in 20%
16
17
A
B
0%
N
N
O
N
O
20%f
Me

D.J. Schipper et al. / Tetrahedron 65 (2009) 4977–4983
4979
Cond. A
Cond.
X
TfO
H
N
N
O
4
N
O
H
O
3
Me
Me
Me
Conditions Equiv. of 3
MeO
Me
X
Yield
89%
Cond. B
Ref 5e
2
4
OTf
Br
84%
50%
Scheme 2. Differential diarylation.
yield when employing conditions B and a 10% CuCN additive (Table
1, entry 17).5 Quinoline (Table 1, entry 23) and isoquinoline (Table 1,
entry 24) substrates are also suitable for the arylation.
Differentially diarylated products can be obtained by carrying
out the arylation reactions in sequence as shown in Scheme 2.
Pyridine N-oxide is arylated with p-tolyl trifluoromethanesulfonate
in 89% yield under conditions A.
The more active nature of conditions B compared to conditions A is
illustrated by two examples. Pyridazine N-oxide, which may undergo
reaction at only one position, is arylated in 51% yield under conditions
A (Table 1, entry 14), but the yield increases to 99% when using con-
ditions B (Table 1, entry 15). Also, quinoline N-oxide is arylated in 68%
yield under conditions A (Table 1, entry 22) but in 81% yield under
conditionsB(Table 1,entry23).Highyieldscanbeobtainedevenwhen
using 1 equiv of N-oxide by utilizing conditions B in conjunction with
an N-oxide substrate where diarylation is not problematic as exem-
plified by the arylation of phthalazine N-oxide (Table 1, entry 26).
The arylation proceeds with a range of aryl triflates. Electron
deficient aryl triflates result in somewhat diminished yields (Table 1,
entries 5 and 21). Sterically demanding aryl triflates undergo re-
action in 59–75% yield (Table 1, entries 7,11, and 20); however, lower
yields are obtained when used in combination with a sterically
demanding N-oxide (Table 1, entry 25). Heterocyclic aryl triflates
can also be employed as illustrated by the use of 3-pyridyl tri-
fluoromethanesulfonate (Table 1, entry 21).
This product can then be resubmitted to arylation conditions
with 4-methoxyphenyl trifluoromethanesulfonate under the more
active conditions B to generate the differentially diarylated com-
pound 4 in 84% yield. Previously reported conditions for the ary-
lation of pyridine N-oxide with aryl bromides resulted in 50% yield
of the desired product.5e These conditions also require 4 equiv of
the N-oxide to obtain satisfactory yields. Conditions B, which em-
ploys aryl triflates, results in not only higher yield than the pre-
viously reported conditions but also requires less equivalents of
intermediate 3. Therefore, it can be advantageous to employ aryl
triflates when low yields are obtained with aryl bromides or when
N-oxide substrates are precious.
To further investigate the reactivity and selectivity for reaction
with aryl triflates, the arylation was carried out on a series of 3-
substituted azine N-oxides (Table 2), affording a mixture of 2-, 6-
and disubstituted products. Alkyl substitution favors arylation at
the 2-position, but diarylation is a significant by-product (Table 2,
Table 2
3-Substituted azine N-oxides
R
R
R
R
Cond. A or B
OTf
N+
O-
N+ Ar Ar
N+
Ar
N+ Ar
O-
A
O-
B
O-
C
Me
N-Oxide
Me
Me
Entry
Cond.a
Yield (A:B:C)b
1
2
Conditions Ac
Conditions B
94 (28:55:11)
92 (16:32:44)
N+
O-
MeO
3
4
Conditions A
Conditions B
85 (11:67:7)
81 (9:64:8)
N+
O-
Et2NOC
5
6
Conditions Ac
Conditions B
Conditions A
97 (73:14:10)
N+
O-
NC
F
68 (trace:61:7)
90 (trace:90:trace)
N+
O-
7
N+
O-
a
Conditions A: N-oxide (2 equiv), Triflate (1 equiv), Pd(OAc)2 (0.05 equiv), HP(Cy3)BF4 (0.10 equiv), Rb2CO3 (2 equiv), PivOH (0.4 equiv), PhMe (0.15 M), 100 ꢀC, 15 h. Con-
ditions B: N-oxide (2 equiv), Triflate (1 equiv), Pd(OAc)2 (0.05 equiv), HP(tBu2)MeBF4 (0.10 equiv), K2CO3 (2 equiv), PivOH (0.3 equiv), PhMe (0.5 M), 110 ꢀC, 15 h.
b
Isolated yields.
Using 4 equiv of N-oxide.
c

4980
D.J. Schipper et al. / Tetrahedron 65 (2009) 4977–4983
8
Previous synthesis:
O
O
CO2H
O
160 °C
O
O
F3C
OH
F3C
neat
40 min
quant.
F3C
80 °C
62%
COOH
CO2H
CO2H
NH4OAc
MeOH
Reflux, 6 hr
80%
N
Py/EtOH
Br2
O
O
F3C
F3C
8
F3C
CHCl3, rt
83%
reflux
95%
F3C
CF3
Py
Br
Br-
Synthesis employing aryl triflates:
1) zinc dust
CO2Me
CO2Me
NH4Cl:THF (1:1)
r.t. 15 hr
Cond. B
8
TfO
2) LiOH, MeOH
73% (2 steps)
N
O
7
N
O
CF3
F3C
CF3
2 equiv
76 %
6
HO
N
H
ref 6d
8
N
5
F3C
CF3
antimalarial and antimicrobial activity
Scheme 3. Formal synthesis of 5.
entries 1 and 2). Electron-donating groups give more favorable
selectivities for the 2-position and diarylation is not as problematic
(Table 2, entries 3 and 4). Electron-withdrawing substituents are
the most selective substituents for the 2-position as only trace
amounts of the 6-arylated product are observed (Table 2, entries 6
and 7). The only substitution that results in preferential arylation at
the 6-postion is a diethylamide substituent, which gives the 6-
arylated product as the major regioisomer, which is possibly due to
the increased steric requirements of this group (Table 2, entry 5).
The methodology for the direct arylation of azine N-oxides using
aryl triflates was also evaluated in the context of the synthesis of
key intermediate 8 in the synthesis of diarylpyridine 5,6d which
exhibits both antimalarial6 and antimicrobial7 activities. A previous
synthesis of 8, shown in Scheme 3, involves the assembly of the
pyridine core with aryl groups already attached.8 We envisioned
that, given that 8 is symmetrically bis-arylated, the greater pro-
pensity of aryl triflates to undergo bis-arylation compared to aryl
halides may be capitalized upon. Consequently, methyl iso-
nicotinate N-oxide was subjected to conditions B with two equiv-
alents of 4-(trifluoromethyl)phenyl trifluoromethanesulfonate to
yield 76% of the bis-arylated product 7. Compound 7 was then
subsequently reduced and saponified to give 8 in 73% yield over
two steps. Compared to the previous synthesis of 7, the direct
arylation approach saves several chemical steps and is more ame-
nable to the synthesis of derivatives.
4. Experimental
4.1. General
Pyridine N-oxide was purchased from Aldrich and used without
further purification. Reagent grade dichloromethane and degassed
HPLC grade toluene were used without further purification. Palla-
dium sources and ligands were purchased from Strem, stored in
a desiccator and weighed out to air unless otherwise specified. All
other reagents and solvents were used as is from commercial
sources. Unless noted below, all other compounds have been
reported in the literature or are commercially available. Unless
otherwise notes, all reactions were performed in oven-dried
glassware under an argon atmosphere. Coupling reactions were
performed with regard for exclusion of ambient air. Analysis of
crude reaction mixtures was done using TLC or NMR. Reactions
were purified by flash chromatography on silica gel. 1H and 13C
NMR spectra were recorded on a Bruker AVANCE 400 MHz spec-
trometer in the specified solvent at ambient temperature and
chemical shifts are reported relative to tetramethylsilane (TMS).
Fourier-transform infra-red (FTIR) spectra were obtained as thin
films on sodium chloride plates. High resolution mass spectra were
obtained with a Kratos Concept IIH mass spectrometer. Melting
points and are reported uncorrected.
4.2. Direct arylation
3. Conclusion
4.2.1. Procedure A
In conclusion, we have developed a method for the arylation of
azine N-oxides with aryl triflates. The reaction is broadly applicable
to a wide range of both azine N-oxides and aryl triflates. The ary-
lation can be carried out in sequence to afford diarylated products.
The method was applied to the formal synthesis of a medicinally
relevant compound.
All reactions were performed on 0.5 mmol scale. A test tube is
charged with Pd(OAc)2 (5 mol %), PCy3$HBF4 (10 mol %), Rb2CO3
(2 equiv), PivOH (0.4 equiv), and azine N-oxide (1.1–2 equiv.). The
tube is then sealed and purged with Argon. In a solution of toluene
(0.15 M), the aryl triflate (1 equiv) is then added. The reaction is
stirred at 100 ꢀC for 15–18 h, and then allowed to cool, diluted with

D.J. Schipper et al. / Tetrahedron 65 (2009) 4977–4983
4981
CH2Cl2, and filtered over Celite. The residues are then purified using
silica gel chromatography.
136.7 (d, J¼3.6 Hz), 140.4 (d, J¼24.5 Hz), 158.3 (d, J¼250.5 Hz),
160.7; IR (nmax/cmꢁþ1): 2966,1432,1227,1024, 842; HRMS calculated
for C12H10FNO2 (M ) 219.0696, found: 219.0700; mp: 132–134 ꢀC
(CH2Cl2); Rf: 0.32 (2:6:92 MeOH/acetone/CH2Cl2).
4.2.2. Procedure B
All reactions were performed on 0.5 mmol scale. A test tube is
charged with Pd(OAc)2 (5 mol %), PtBu2Me$HBF4 (10 mol %), K2CO3
(2 equiv), PivOH (0.3 equiv), and azine N-oxide (1.1–2 equiv). The
tube is then sealed and purged with Argon. In a solution of toluene
(0.5 M), the aryl triflate (1 equiv) is then added. The reaction is
stirred at 110 ꢀC for 15–18 h, and then allowed to cool, diluted with
CH2Cl2, and filtered over Celite. The residues are then purified using
silica gel chromatography.
4.2.8. 2-(Pyridin-3-yl)pyrazine 1-oxide (Table 1, entry 21)
This compound was obtained in 43% yield as a white solid by
following direct arylation procedure A. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 7.47 (1H, ddd, J¼8.0, 4.9, and 0.8 Hz), 8.24 (1H, dd,
J¼4.1 and 0.6 Hz), 8.30 (1H, dt, J¼8.0 and 2.0 Hz), 8.46 (1H, d,
J¼4.1 Hz), 8.68 (1H, s), 8.74 (1H, dd, J¼4.8 and 1.6 Hz), 9.0 (1H, dd,
J¼2.3 and 0.6 Hz); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 123.2,
125.4, 134.5, 136.8, 142.0, 146.6, 148.0, 149.4, 151.3; IR (nmax/cmꢁ1):
3175, 1287, 1005, 813, 703; HRMS calculated for C9H7N3O (Mþ)
173.0589, found: 173.0574; mp: 188–189 ꢀC (CH2Cl2); Rf: 0.23
(3:15:82 MeOH/acetone/CH2Cl2).
4.2.3. 2-(4-Cyanophenyl)pyridine 1-oxide (Table 1, entry 5)
Obtained in 49% yield as a white solid by following direct ary-
lation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 7.30–
7.34 (1H, m), 7.36 (1H, td, J¼7.6 and 1.4 Hz), 7.45 (1H, dd, J¼7.7 and
2.2 Hz), 7.78 (2H, d, J¼8.4 Hz), 7.96 (2H, d, J¼8.4 Hz), 8.35 (1H, dd,
J¼6.4 and 1.1 Hz); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 113.2,
118.4, 125.7, 125.8, 127.3, 130.0, 132.1, 136.9, 140.7; IR (nmax/cmꢁ1):
2950, 2217, 1481, 1246, 835; HRMS calculated for C12H8N2O (Mþ)
196.0637, found: 196.0659; mp: 162–168 ꢀC (CH2Cl2); Rf: 0.32
(3:10:87 MeOH/acetone/CH2Cl2).
4.2.9. 1-(Naphthalen-1-yl)isoquinoline 2-oxide (Table 1, entry 25)
This compound was obtained in 27% yield as a beige solid by
following direct arylation procedure A. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 7.20 (1H, d, J¼8.5 Hz), 7.27 (1H, d, J¼8.4 Hz), 7.38 (2H,
t, J¼7.5 Hz), 7.48–7.55 (3H, m), 7.66 (1H, t, J¼7.6 Hz), 7.77 (1H, d,
J¼7.2 Hz), 7.84 (1H, d, J¼8.2 Hz), 7.96 (1H, d, J¼8.2 Hz), 8.04 (1H, d,
J¼8.3 Hz), 8.36 (1H, d, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3, 293 K,
TMS): 123.7, 125.1, 125.5, 125.6, 126.4, 126.8, 127.0, 128.3, 128.4,
128.7, 128.8, 128.9, 129.2, 130.0, 130.3, 131.3, 133.8, 137.5, 145.5; IR
4.2.4. 4-Methyl-2-p-tolylpyridine 1-oxide (Table 1, entry 8)
This compound was obtained in 71% yield as a light green oil by
following direct arylation procedure A. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 2.35 (3H, s), 2.39 (3H, s), 7.00 (1H, dd, J¼6.6 and
2.1 Hz), 7.20 (1H, d, J¼2.5 Hz), 7.26 (2H, d, J¼7.9 Hz), 7.70 (2H, d,
J¼8.2 Hz), 8.20 (1H, d, J¼6.6 Hz); 13C NMR (100 MHz, CDCl3, 293 K,
TMS): 20.3, 21.4, 125.1, 127.8, 128.9, 129.2, 129.8, 137.6, 139.6, 139.7,
148.5; IR (nmax/cmꢁ1): 2922, 1623, 1480, 1224, 784; HRMS calcu-
lated for C13H13NO (Mþ) 199.0997, found: 199.1012; Rf: 0.35 (4:6:90,
MeOH/acetone/CH2Cl2).
(
nmax/cmꢁ1): 3058, 1320, 1224, 945, 777; HRMS calculated for
C19H13NO (Mþ) 271.0997, found: 271.0992; mp: 160–162 ꢀC
(CH2Cl2); Rf: 0.30 (2:6:92 MeOH/acetone/CH2Cl2).
4.2.10. 1-(4-Methoxyphenyl)phthalazine 2-oxide (Table 1, entry 26)
This compound was obtained in 85% yield as a tan solid by fol-
lowing direct arylation procedure B. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 3.91 (3H, s), 7.11 (2H, dd, J¼6.7 and 2.1 Hz), 7.53–7.57
(3H, m), 7.63–7.67 (1H, m), 7.69–7.74 (1H, m), 7.93 (1H, d, J¼7.7 Hz),
9.07 (1H, s); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 55.4, 114.4,
121.3, 121.6, 124.6, 127.2, 128.7, 131.7, 132.9, 133.5, 151.5, 160.6, one
overlapping signal as one peak is missing even with prolonged
scans; IR (nmax/cmꢁ1): 3428, 1609, 1352, 1249, 829; HRMS calcu-
lated for C15H12N2O2 (Mþ) 252.0899, found: 252.0905; mp: 216 ꢀC
(decomp.) (CH2Cl2); Rf: 0.37 (2:10:88 MeOH/acetone/CH2Cl2).
4.2.5. 4-Cyano-2-p-tolylpyridine 1-oxide (Table 1, entry 10)
This compound was obtained in 38% yield as a light green solid
by following direct arylation procedure A. 1H NMR (400 MHz,
CDCl3, 293 K, TMS): 2.42 (3H, s), 7.30 (2H, d, J¼8.0 Hz), 7.41 (1H, dd,
J¼6.8 and 2.5 Hz), 7.66 (3H, dd, J¼5.5 and 2.7 Hz), 8.31 (1H, d,
J¼6.8 Hz); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 21.5, 107.6, 116.1,
126.3, 127.7, 129.0, 129.3, 129.8, 141.0, 141.4, 150.6; IR (nmax/cmꢁ1):
3050, 2217, 1272, 896, 828; HRMS calculated for C13H10N2O (Mþ)
210.0793, found: 210.0790; mp: 192–194 ꢀC (CH2Cl2); Rf: 0.42 (5:95
acetone/CH2Cl2).
4.2.11. 2-(4-Methoxyphenyl)-6-p-tolylpyridine 1-oxide (Scheme 2)
This compound was obtained in 84% yield as a tan solid by fol-
lowing direct arylation procedure B. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 2.40 (3H, s), 3.85 (3H, s), 6.98 (2H, dd, J¼6.8 and 2.1 Hz),
7.26–7.30 (3H, m), 7.33–7.38 (2H, m), 7.74 (2H, dd, J¼6.5 and 1.7 Hz),
7.84 (2H, dd, J¼6.8 and 2.1 Hz); 13C NMR (100 MHz, CDCl3, 293 K,
TMS): 21.4, 55.3, 113.4, 124.9, 125.4, 125.5, 125.6, 128.7, 129.4, 130.6,
131.1, 139.3, 149.5, 149.9, 160.3; IR (nmax/cmꢁ1): 2933, 1609, 1476,
1180, 782; HRMS calculated for C19H17NO2 (Mþ) 291.1259, found:
291.1286; mp: 170–173 ꢀC (CH2Cl2); Rf: 0.45 (10:90 EtOAc/CH2Cl2).
4.2.6. 4-(Methoxycarbonyl)-2-(naphthalen-1-yl)pyridine 1-oxide
(Table 1, entry 11)
This compound was obtained in 59% yield as a yellow solid by
following direct arylation procedure A. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 3.91 (3H, s), 7.42–7.58 (5H, m), 7.90–7.98 (3H, m), 8.06
(1H, d, J¼2.5 Hz), 8.40 (1H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3,
293 K, TMS): 52.7, 125.0, 125.3, 125.3, 125.8, 126.4, 127.0, 127.9,
128.6, 129.0, 130.2, 130.5, 130.7, 133.4, 140.4, 149.9, 164.1; IR (nmax
/
4.2.12. 2-(3,5-Dimethylphenyl)-3-methylpyridine 1-oxide
(Table 2, entry 1, B)
cmþꢁ1): 2950, 1722, 1271, 1241, 770; HRMS calculated for C17H13NO3
(M ) 279.0895, found: 279.0895; mp: 138–140 ꢀC (CH2Cl2); Rf: 0.32
(5:95 acetone/CH2Cl2).
This compound was obtained in 55% yield as an off-white solid
by following conditions A with the exception of using 4 equiv of
the N-oxide and in 32% yield following conditions B. 1H NMR
(400 MHz, CDCl3, 297 K, TMS): 2.09 (3H, s), 2.36 (6H, d, J¼0.5 Hz),
6.96–6.92 (2H, m), 7.09–7.05 (1H, m), 7.15–7.10 (1H, m), 7.18–7.14
(1H, m), 8.22 (1H, ddd, J¼6.1, 1.5, and 0.5 Hz); 13C NMR (100 MHz,
CDCl3, 298 K, TMS): 19.9, 21.4, 123.6, 126.4, 127.3, 130.7, 132.2,
136.0, 137.7, 138.4, 150.2; IR (nmax/cmꢁ1): 2911, 1601, 1413, 1268.
1237, 1196, 1076, 784; HRMS calculated for C14H15NO (Mþ)
213.1154, found: 213.1151; mp: 149–151 ꢀC (CHCl3); Rf: 0.39 (2%
MeOH, 10% Me2CO, CHCl3).
4.2.7. 3-Fluoro-2-(4-methoxyphenyl)pyridine 1-oxide
(Table 1, entry 13)
This compound was obtained in 90% yield as a tan solid by fol-
lowing direct arylation procedure A. 1H NMR (400 MHz, CDCl3,
293 K, TMS): 3.84 (3H, s), 7.02 (2H, dd, J¼6.9 and 2.0 Hz), 7.08–7.17
(2H, m), 7.61 (2H, dt, J¼7.4 and 2.1 Hz), 8.19 (1H, d, J¼6.2 Hz); 13C
NMR (100 MHz, CDCl3, 293 K, TMS): 55.3, 113.4 (d, J¼23.0 Hz),
113.8, 118.4 (d, J¼1.8 Hz), 123.1 (d, J¼10.5 Hz), 131.7 (d, J¼2.4 Hz),

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D.J. Schipper et al. / Tetrahedron 65 (2009) 4977–4983
4.2.13. 2,6-Bis(3,5-dimethylphenyl)-3-methylpyridine 1-oxide
(Table 2, entries 1 and 2, C)
4.2.18. 3-Cyano-2,6-bis(3,5-dimethylphenyl)pyridine 1-oxide
(Table 2, entry 6, C)
This compound was obtained in 11% yield as a yellow oil by
following conditions A with the exception of using 4 equiv of the N-
oxide and in 44% yield following conditions B. 1H NMR (400 MHz,
CDCl3, 297 K, TMS): 2.14 (3H, s), 2.33 (6H, d, J¼0.5 Hz), 2.34 (6H, d,
J¼0.5 Hz), 6.99–6.96 (2H, m), 7.03–7.01 (1H, m), 7.05–7.03 (1H, m),
7.18 (1H, dd, J¼8.1 and 0.5 Hz), 7.33 (1H, d, J¼8.1 Hz), 7.48–7.45 (2H,
m); 13C NMR (100 MHz, CDCl3, 298 K, TMS): 19.9, 21.3, 21.4, 124.9,
126.7, 126.8, 127.3, 130.3, 132.9, 133.1, 134.0, 137.4, 138.2, 147.3,
150.5; IR (nmax/cmꢁ1): 2920, 2863, 1603, 1346, 1275, 1219, 850, 729;
HRMS calculated for C22H23NO (Mþ) 317.1780, found: 317.1786; Rf:
0.92 (2% MeOH, 10% Me2CO, CHCl3).
This compound was obtained in 7% yield as a yellow oil by fol-
lowing conditions B. 1H NMR (400 MHz, CDCl3, 297 K, TMS): 2.35
(6H, d, J¼0.5 Hz), 2.38 (6H, d, J¼0.5 Hz), 7.13–7.10 (1H, m), 7.15–7.13
(1H, m), 7.25–7.23 (2H, m), 7.47–7.45 (2H, m), 7.49 (1H, d, J¼8.3 Hz),
7.56 (1H, d, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3, 298 K, TMS):
21.31, 21.34, 111.5, 115.3, 125.9, 127.1, 127.2, 127.6, 129.6, 131.5, 132.2,
132.4, 138.0, 138.3, 153.8, 153.9; IR (nmax/cmꢁ1): 2924, 2866, 2363,
2223, 1592, 1541, 1342, 848; HRMS calculated for C22H20N2O (Mþ)
328.1576, found: 328.1565; Rf: 0.89 (2% MeOH, 10% Me2CO, CHCl3).
4.2.19. 4-(Methoxycarbonyl)-2,6-bis(4-(trifluoromethyl)-
phenyl)pyridine 1-oxide (Scheme 3)
4.2.14. 2-(3,5-Dimethylphenyl)-5-methoxypyridine 1-oxide
(Table 2, entries 3 and 4, A)
This compound was obtained in 76% yield as a yellow solid by
following conditions B with the exception of using 2 equiv of the
triflate and 1 equiv of the N-oxide. 1H NMR (400 MHz, CDCl3, 296 K,
TMS): 3.98 (3H, s), 7.76 (4H, d, J¼8.2 Hz), 7.95 (4H, d, J¼8.1 Hz), 8.08
(2H, s); 13C NMR (100 MHz, CDCl3, 298 K, TMS): 53.0, 123.8 (q,
J¼272.4 Hz), 125.4 (q, J¼3.7 Hz), 125.9, 130.0, 131.8 (q, J¼32.7 Hz),
135.7, 149.1, 164.0; IR (nmax/cmꢁ1): 2957, 1726, 1620, 1562, 1325,
1251, 1169, 1125, 1067, 846, 818, 764; HRMS calculated for
C21H13F6NO3 (Mþ) 441.0800, found: 441.0776; mp: 152–153 ꢀC
(CHCl3); Rf: 0.66 (CH2Cl2).
This compound was obtained in 11% yield as a pale yellow oil by
following conditions A and in 9% yield following conditions B. 1H
NMR (400 MHz, CDCl3, 297 K, TMS): 2.36 (6H, s), 3.87 (3H, s), 6.91
(1H, dd, J¼8.9 and 2.4 Hz), 7.08–7.02 (1H, m), 7.27 (1H, d, J¼8.7 Hz),
7.36–7.31 (2H, m), 8.08 (1H, d, J¼2.4 Hz); 13C NMR (100 MHz, CDCl3,
298 K, TMS): 21.6, 56.2, 113.7, 126.87, 126.93, 127.8, 130.8, 132.5,
137.8, 143.1, 156.6; IR (nmax/cmꢁ1): 2918, 2849, 1598, 1512, 1375,
1308, 1198, 1172, 1024; HRMS calculated for C14H15NO2 (Mþ)
229.1103, found: 229.1098; Rf: 0.20 (1% MeOH, 10% Me2CO, CHCl3).
4.2.20. Methyl 2,6-bis(4-(trifluoromethyl)phenyl)isonicotinate
(Scheme 3)
4.2.15. 2,6-Bis(3,5-dimethylphenyl)-3-methoxypyridine 1-oxide
(Table 2, entries 3 and 4, C)
A solution of 4-(methoxycarbonyl)-2,6-bis(4-(trifluoromethyl)-
phenyl)pyridine 1-oxide (148 mg, 0.335 mmol, 1 equiv) and zinc
dust (99 mg, 1.509 mmol, 4.5 equiv) in THF:NH4Cl satd 1:1 (3.5 ml)
is stirred at room temperature overnight. The reaction is diluted
with ether, dried over MgSO4, and filtered over Celite. The crude
product is purified by column chromatography (10–15% ether/pet.
ether) to give a white solid in 87% yield. 1H NMR (400 MHz, CDCl3,
296 K, TMS): 4.05 (3H, s), 7.79 (4H, d, J¼8.2 Hz), 8.31 (4H, d,
J¼8.1 Hz), 8.34 (2H, s); 13C NMR (100 MHz, CDCl3, 297 K, TMS):
53.0, 119.0, 124.10 (q, J¼272.2 Hz), 125.83 (q, J¼3.7 Hz), 131.51 (q,
J¼32.6 Hz), 139.7, 141.5, 156.6, 165.4; IR (nmax/cmꢁ1): 2957, 1730,
1563, 1325, 1254, 1123, 1067, 847; HRMS calculated for C21H13F6NO2
(Mþ) 425.0850, found: 425.0835; mp: 143–145 ꢀC (CHCl3); Rf: 0.33
(10% ether/pet. ether).
This compound was obtained in 7% yield as a yellow oil by fol-
lowing conditions A and in 8% yield following conditions B. 1H NMR
(400 MHz, CDCl3, 297 K, TMS): 2.33 (6H, d, J¼0.5 Hz), 2.34 (6H, d,
J¼0.5 Hz), 3.82 (3H, s), 6.98 (1H, d, J¼9.0 Hz), 7.03–7.00 (1H, m),
7.05–7.03 (1H, m), 7.13–7.10 (2H, m), 7.35 (1H, d, J¼8.9 Hz), 7.42–7.39
(2H, m); 13C NMR (100 MHz, CDCl3, 298 K, TMS): 21.3, 21.4, 56.4,
108.7, 124.7, 127.4, 127.8, 129.8, 130.4, 130.7, 133.0, 137.4, 137.6, 141.4,
143.4, 154.6; IR (nmax/cmꢁ1): 3008, 2924, 1605, 1563, 1498, 1459,
1345, 1293, 1235, 1086, 852; HRMS calculated for C22H23NO2 (Mþ)
333.1729, found: 333.1734; Rf: 0.86 (1% MeOH, 10% Me2CO, CHCl3).
4.2.16. 3-(Diethylcarbamoyl)-2-(3,5-dimethylphenyl)pyridine
1-oxide (Table 2, entry 5, B)
This compound was obtained in 14% yield as a pale yellow oil by
following conditions A with the exception of using 4 equivalents of
the N-oxide. 1H NMR (400 MHz, CDCl3, 297 K, TMS): 0.73 (3H, t,
J¼7.1 Hz), 0.90 (3H, t, J¼7.1 Hz), 2.88–2.68 (2H, m), 3.13–3.00 (1H,
m), 3.82–3.69 (1H, m), 7.05 (1H, br s), 7.15 (2H, br s), 7.21 (1H, dd,
J¼7.8 and 1.3 Hz), 7.29–7.24 (1H, m), 8.35 (1H, dd, J¼6.3 and 1.3 Hz);
13C NMR (100 MHz, CDCl3, 298 K, TMS): 11.5, 13.7, 21.3, 38.5, 42.6,
123.2, 124.6, 127.2, 129.8, 131.5, 136.8, 137.8, 140.1, 146.7, 165.8; IR
4.2.21. 2,6-Bis(4-(trifluoromethyl)phenyl)isonicotinic
acid (Scheme 3)
A solution of methyl 2,6-bis(4-(trifluoromethyl)phenyl)isonicotinate
(75 mg, 0.176 mmol, 1 equiv) and lithium hydroxide (37 mg,
0.882 mmol, 5 equiv) in MeOH (1 ml) is stirred at room tempera-
ture overnight. The reaction is diluted with water and the methanol
is removed under reduced pressure. The solution is acidified with
10% HCl and extracted with EtOAc (3ꢂ20 ml). The combined or-
ganic extracts were dried over MgSO4. The crude product is purified
by flash chromatography (5% MeOH, 7% acetone, CHCl3) to afford
a white solid in 84% yield. 1H NMR (400 MHz, (CD3)2CO, 296 K):
7.84 (4H, d, J¼7.3 Hz), 8.45 (4H, d, J¼7.3 Hz), 8.46 (2H, s); 13C NMR
(100 MHz, (CD3)2CO, 297 K): 119.4, 124.5 (q, J¼271.4 Hz), 125.7 (q,
(
nmax/cmꢁ1): 2977, 2929, 1633, 1433, 1406, 1289, 1258, 1196, 859;
HRMS calculated for C18H22N2O2 (Mþ) 298.1681, found: 298.1688;
Rf: 0.15 (2% MeOH, 10% Me2CO, CHCl3).
4.2.17. 3-(Diethylcarbamoyl)-2,6-bis(3,5-dimethylphenyl)pyridine
1-oxide (Table 2, entry 5, C)
This compound was obtained in 10% yield as a pale yellow oil by
following conditions A with the exception of using 4 equiv of the
N-oxide. 1H NMR (400 MHz, CDCl3, 297 K, TMS): 0.75 (3H, t,
J¼7.1 Hz), 0.94 (3H, t, J¼7.1 Hz), 2.30 (6H, s), 2.35 (6H, s), 2.92–2.72
(2H, m), 3.25–3.10 (1H, m), 3.85–3.72 (1H, m), 7.02 (1H, s), 7.06 (1H,
s), 7.20 (2H, br s), 7.24 (1H, d, J¼8.1 Hz), 7.44 (1H, d, J¼8.2 Hz), 7.46
(2H, br s); 13C NMR (100 MHz, CDCl3, 298 K, TMS): 11.5, 13.7, 21.3,
38.5, 42.6, 122.6, 126.0, 127.2, 127.4, 130.4, 131.1, 131.2, 132.6, 134.9,
137.5, 137.6, 147.0, 149.9, 166.1; IR (nmax/cmꢁ1): 2973, 2919, 1636,
1451, 1427, 1286, 846; HRMS calculated for C26H30N2O2 (Mþ)
402.2307, found: 402.2301; Rf: 0.80 (2% MeOH, 10% Me2CO, CHCl3).
J¼7.3 Hz), 127.7, 130.7 (q, J¼32.1 Hz), 142.0, 156.0, 165.9; IR (nmax
/
cmꢁ1): 3088, 2940, 1709, 1327, 1167, 1123, 1068, 1017, 847; HRMS
calculated for C20H11F6NO2 (Mþ) 411.0694, found: 411.0683; mp:
274–277 ꢀC (CHCl3); Rf: 0.53 (5% MeOH, 7% Me2CO, CHCl3).
Acknowledgements
The authors thank NSERC, the University of Ottawa, the Research
Corporation, Boehringer Ingelheim (Laval), Merck Frosst Canada,
Merck Inc., and Astra Zeneca Montreal for support of this work.

D.J. Schipper et al. / Tetrahedron 65 (2009) 4977–4983
4983
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.03.077.
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