Catalyst and base controlled site-selective sp2 and sp3 direct arylation of azine N-oxides

Article abstract of DOI:10.1016/j.tet.2008.12.004

Site-selective direct arylation of both sp² and sp³ sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner. The sp³ arylation reaction is applied to the synthesis of the natural products, papaverine and crykonisine, and a rationale for low reactivity of electron-deficient aryl halides is provided. Mechanistic investigations point toward the intimate involvement of the base in the mechanism of these reactions.

Full text of DOI:10.1016/j.tet.2008.12.004

Tetrahedron 65 (2009) 3155–3164
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalyst and base controlled site-selective sp2 and sp3 direct arylation
of azine N-oxides
*
Derek J. Schipper, Louis-Charles Campeau, Keith Fagnou
Center for Catalysis Research and Innovation, University of Ottawa, Department of Chemistry, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The
arylation reactions are carried out in either a divergent manner or a sequential manner. The sp3 arylation
reaction is applied to the synthesis of the natural products, papaverine and crykonisine, and a rationale
for low reactivity of electron-deficient aryl halides is provided. Mechanistic investigations point toward
the intimate involvement of the base in the mechanism of these reactions.
Article history:
Received 20 October 2008
Received in revised form 28 November 2008
Accepted 2 December 2008
Available online 7 December 2008
Ó 2008 Published by Elsevier Ltd.
1. Introduction
term goal of chemo- and site-selective direct functionalization
should become increasingly achievable.
While rare even just a decade ago, direct arylation of hetero-
cycles has become a valuable tool in the transformation of other-
wise chemically inert C–H bonds into a number of functional
groups.1 A particularly appealing and frequently discussed aspect of
this chemistry involves the ubiquity of the C–H bond as a ‘func-
tional group’ and the potential to strategically transform these with
high site selectivity.2 In practice, the challenge associated with
achieving a high yielding reaction at even just one position makes
the realization of controlled multi-site selectivity rare. Important
advances have been made with some classes of electron-rich het-
eroaromatics.3 For example, the inherent bias of azoles to undergo
C5 direct arylation can be overridden through the use of copper
additives, which induce reaction at C2.4 3-Carboxy furan and
thiophene can be selectively arylated at either the C2 or C5 posi-
tion.5 Sames et al. have also reported examples of C2/C3 site se-
lectivity in indole arylations.6 Gaunt et al. have demonstrated that
regiocontrol can be achieved in indole and pyrrole alkenylation and
arylation reactions through the choice of the solvent and the azole
N-substituent.7 We have recently demonstrated that the choice of
oxidant as well as the nature of the N-acyl substituent can reverse
the site selectivity of the oxidative coupling of benzene with in-
dole.8 Significantly, these reactions all involve selectivity at aro-
matic sp2 C–H bonds. As a greater appreciation of the possible
mechanisms of C–H bond cleavage/functionalization is gained, and
particularly as transformations and mechanisms, which exhibit
complimentary and orthogonal reactivity are discovered, this long-
We have previously reported the site-selective direct arylation
of 2-methyl azine and diazine N-oxides, where reaction may be
induced to occur at either a benzylic sp3 C–H bond or an aromatic
sp2 C–H bond (Scheme 1).9 In this account, we report (1) opera-
tionally simple catalyst systems for the site-selective direct aryla-
tion of sp2 and sp3 carbons of azine N-oxide substrates and several
new examples, exhibiting broad scope for aryl chlorides, bromides,
and iodides; (2) that the arylation reactions can be carried out in
either a divergent manner or a sequential manner in which either
the sp2 or the sp3 arylation can be carried out first; (3) the appli-
cation of the novel sp3 arylation process to the synthesis of the
natural products, papaverine and crykonisine, in three steps from
simple starting materials; (4) insight into catalyst poisoning with
electron-deficient aryl halides leading to new mechanistic insights;
Ar
Ar
H
sp3 C-H arylation
sp3
catalyst
H
Ar
H
sp3
sp2
sp2 C-H arylation
ArX
H
catalyst
Ar
Ar
sp2
Scheme 1. Catalyst controlled site-selective sp2/sp3 arylation.
* Corresponding author. Tel.: þ1 613 562 5728; fax: þ1 613 562 5170.
E-mail address: keith.fagnou@uottawa.ca (K. Fagnou).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.12.004

3156
D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
(5) mechanistic studies pointing toward the intimate involvement
of the base in the mechanism of the reactions.
(Table 3, entries 5 and 7) are suitable to be employed in the sp2
arylation reaction.
To further demonstrate the utility of these methods for the
functionalization of heterocycles, we have established that the sp2/
sp3 arylations can be carried out in both a divergent and a se-
quential manner (Scheme 2). Reaction of 2-picoline N-oxide (1)
with bromotoluene was chosen as a model reaction. 2-Picoline N-
oxide is arylated with 4-bromotoluene (2) under the sp2 arylation
conditions to give a 56% yield of product 3. N-Oxide 3 is then
subjected to the sp3 arylation conditions with 2-bromotoluene to
2. Results and discussion
As part of a research program targeted at the development of
new direct arylation reactions, we sought to develop catalyst sys-
tems that would enable selective arylation at both sp2 and sp3
centers on the same substrate. We have previously reported that
treatment of 2-picoline N-oxide and 4-bromotoluene with a Pd/X-
Phos catalyst using NaOtBu as the base and toluene as the solvent
resulted in high yield and selectivity of the sp3 arylated product
(Fig. 1).9
Table 1
sp3 Arylation of picoline N-oxidea
Subsequent re-optimization studies revealed that any de-
viations from these reaction conditions resulted in lower yields.
An expanded scope of the sp3 arylation reaction is outlined in
Table 1. Different aryl halides are tolerated including cheap and
readily available chlorides (Table 1, entries 1, 10, and 12) as well as
more commonly used bromides (Table 1, entries 2–5, 7–9, 11, and
13–14 and Table 2 entries 1–7) and iodides (Table 1, entry 6).
Arylation can be carried out using catalyst loadings as low as
1 mol % Pd (Table 1, entry 3). Also near equimolar amounts of the N-
oxide and aryl halide can be employed (Table 1, entry 4). Thermal
heating conditions were also developed utilizing Ru-Phos as the
ligand although this method results in slightly diminished yields
(Table 1, entry 5 and Table 2, entry 3).
A variety of substitution patterns including ortho, meta, and para
are tolerated on the aryl halide (Table 1). Very sterically demanding
substrates require the use of S-Phos as the ligand (Table 1, entries 10
and 11). While electron-rich aryl halides are broadly applicable
(Table 1, entry 13 and Table 2, entry 1), electron-poor aryl halides
are not compatible with this catalyst system (Table 1, entry 15).
Heterocyclic aryl halides can also be employed as illustrated by the
use of an indole halide (Table 1, entry 12).
Pd2dba3 (2.5 mol %)
X-Phos (5 mol %)
H
Ar
ArX
+
N
O
N
O
NaOtBu, PhMe
MW, 45min
Entry N-Oxide
Aryl halide
X=Cl
Product
Yieldb
1
2
3
4
5
6
91
89
Me
Me
X=Br
X=Br
X=Br
X=Br
X=I
84c
77d
78e
85
N
O
Me
1
N
O
X
Me
Me
Br
7
8
1
92
93
N
O
Me
Me
1
N
O
Me
Br
Me
9
1
1
1
72
We have determined that a broad range of N-oxide substrates can
be used in sp3 arylation reactions (Table 2). meta and para Methyl
substituted aryl bromides participate in high yield and complete
selectivity (Table 2, entries 1–3). Quinoline (Table 2, entry 4) and
isoquinoline (Table 2, entry 5) N-oxides are also competent sub-
strates, although 3 equiv of 2-methyl quinoline N-oxide must be used
due to increased amounts of diarylation. Diazine N-oxides can be
employed in the reaction as illustrated by the use of 2,3-dimethyl
diazine N-oxide (Table 2, entry 6). Other alkyl groups can also be
arylated under the reaction conditions with no products arising from
N
O
Br
Me
X
Me
10
11
84f
90f
X=Cl
X=Br
N
O
Me
Me
Me
N
Me
N
12
90
N
O
Cl
a potentially competitive b-hydride elimination (Table 2, entry 7).
The scope of the sp2 arylation of 2-methyl azine N-oxides is
outlined in Table 3. We have previously described the use of N-
oxides in direct arylation reactions as a means of avoiding the use of
problematic organometallics in the formation of biaryl molecules
and the selective arylation of the sp2 position in the presence of a 2-
methyl substituent.9 The sp2 arylation reaction is compatible with
electron-neutral (Table 3, entries 1–6), electron-rich (Table 3,
entries 7 and 9), and electron-poor (Table 3, entry 8) aryl bromides.
A range of N-oxides, including substituted pyridines (Table 3,
entries 1–4, 8, and 9), isoquinoline (Table 3, entry 6), and diazines
OMe
F
OMe
F
13
14
1
1
72
72
N
O
Br
N
Br
O
R
R
R=CN, CO2Et,
COPh, NO2
15
1
Trace
N
O
Br
a
Conditions: picoline N-oxide (1.5 equiv), aryl halide (1 equiv), Pd2dba3
(0.025 equiv), X-Phos (0.05 equiv), and NaOtBu (3 equiv) in PhMe (0.5–1 M), MW,
110 ꢀC for 45 min.
i
Pr
i
MeO
PrO
b
PCy2
Isolated yield.
Using 1 mol % Pd.
PCy2
OMe
PCy2
i
i
c
Pr
OPr
Ru-Phos
Figure 1.
d
Using 1.1 equiv N-oxide.
Using picoline N-oxide (2 equiv), aryl halide (1 equiv), Pd2dba3 (0.025 equiv),
i
e
Pr
S-Phos
X-Phos
Ru-Phos (0.1 equiv), and NaOtBu (3 equiv) in PhMe (0.3 M), thermal heating, 70 ꢀ
overnight.
C
f
Using S-Phos.

D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
3157
hydrogen peroxide in DCM.12 Compound 7 is then subjected to sp3
arylation conditions with 4-benzyloxybromobenzene, which af-
fords the arylated product 8. Simultaneous removal of the benzyl
group and reduction of the N-oxide take place under hydrogenation
conditions with Pd/C in methanol to yield the natural product
cykonisine in three steps and 34% overall yield from commercially
available starting materials (Scheme 3).
Table 2
sp3 Arylation of azine N-oxidesa
Y
Y
Pd2dba3 (2.5 mol %)
X-Phos (5 mol %)
R
R
H
Ar
+
ArX
N
O
N
O
NaOtBu, PhMe
MW, 45min
Entry
1
N-Oxide
Aryl halide
Product
Yieldb
70
The common intermediate 7 is again subjected to sp3 arylation
conditions with 4-bromoveratrole to yield 10. The N-oxide (10) is
subsequently reduced with zinc in saturated NH4Cl/THF to yield the
natural product papaverine in three steps and 30% overall yield.13
The syntheses of these two natural products from a common in-
termediate demonstrate the potential utility of this method for the
Me
Me
OMe
OMe
N
O
Me
N
O
OMe
Br
OMe
Me
Me
Me
Me
Me
Me
Me
Table 3
2
90
sp2 Arylation azine N-oxidesa
N
O
N
O
Me
Me
Br
Br
Y
Y
Pd(OAc)2 (5 mol %)
R
PtBu3-HBF4 (6 mol %)
R
Me
Me
Me
+
N
O
Me
Me
H
N
O
K2CO3, PhMe
110 °C
3
4
76c
73d
2
R'
N
O
N
O
R'
Br
Entry
N-Oxide
Aryl halide
Br
2
Product
Yieldb
Me
2
2
N
O
Me
N
O
1
2
21c
56
N
O
Me
N
O
Me
Me
Me
Me
Me
Me
NC
NC
5
6
60
3
4
5
2
2
2
74
N
O
Me
N
O
N
O
Me
N
O
Me
N
Me
Me
N
Me
Me
Me
2
2
79
59d
N
O
N
O
N
O
N
O
Me
N
Me
Me
N
Me
Me
7
64d,e
N
O
89
N
Me
N
O
N
O
O
Me
Me
a
Conditions: picoline N-oxide (1.5 equiv), aryl halide (1 equiv), Pd2dba3
(0.025 equiv), X-Phos (0.05 equiv), and NaOtBu (3 equiv) in PhMe (0.5–1 M), MW,
110 ꢀC for 45 min.
b
Isolated yield.
90e
c
6
2
Using picoline N-oxide (2 equiv), aryl halide (1 equiv), Pd2dba3 (0.025 equiv),
Ru-Phos (0.1 equiv), and NaOtBu (3 equiv) in PhMe (0.3 M), thermal heating, 70 ꢀ
overnight.
C
N
O
Me
N
Me
O
d
Using 3 equiv N-oxide.
Using S-Phos.
e
N
Me
Me
N
Me
Me
Br
7
8
86
48
73
N
O
N
O
MeO
F3C
MeO
F3C
give a 77% yield of the differentially diarylated product 5. Alter-
natively, 1 could be first subjected to the sp3 arylation conditions
with 2-bromotoluene to give a 92% yield of product 4, demon-
strating the divergent reactivity of a single substrate under differ-
ent catalytic conditions. Compound 4 can then be arylated under
the sp2 conditions with 4-bromotoluene to give the same differ-
entially diarylated product as the previous route in 59% yield.
The methodology for the sp3 direct arylation of 2-methyl pyri-
dine N-oxides was further validated in an efficient synthesis of
natural products, papaverine (11) and crykonisine (9). Papaverine is
one of the four major components of opium and is used as a non-
narcotic antispasmodic agent.10 Crykonisine is a natural product
isolated from the plant Papaver Triniifolium and the stem bark of
Cryptocarya Chinensis Hemsl.11 Compound 6 is oxidized to the
N-oxide (7) by treatment with methyltrioxorhenium and aqueous
NC
NC
NC
Br
Br
N
O
Me
Me
N
O
Me
NC
9
N
O
N
O
Me
MeO
MeO
a
Conditions: N-oxide (2 equiv), aryl halide (1 equiv), Pd(OAc)2 (0.05 equiv),
PtBu3–HBF4 (0.06 equiv), and K2CO3 (1.5 equiv) in PhMe (0.15 M), 110 ꢀC overnight.
b
Isolated yield.
Previously reported conditions.
Using 3 equiv N-oxide.
Using 1.1 equiv N-oxide.
c
d
e

3158
D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
Me
Br
2
Pd(OAc)2
H
t
H
P Bu3-HBF4
N
O
H
N
O
3
K2CO3, PhMe
110 °C, 56 %
1
Me
(1.5 eq.)
(1.5 eq.)
Pd2dba3
X-Phos
Pd2dba3
Me
Br
Me
Br
X-Phos
NaOtBu, PhMe
MW, 45min
92%
NaOtBu, PhMe
MW, 45min
77%
Me
Br
Me
Me
Pd(OAc)2
t
P Bu3-HBF4
H
N
O
N
O
K2CO3, PhMe
110 °C, 59 %
4
5
Me
(3 eq.)
Scheme 2. Divergent and sequential sp2/sp3 arylation.
generation of a large family of related compounds rapidly from
common intermediates.
were performed, one without additive (Scheme 4, Eq. 1) and one
with 30 mol % 12 (Scheme 4, Eq. 2). The reaction with no additive
resulted in an 89% yield of the desired product, while the reaction
with 30 mol % 12 added resulted in only 13% yield of the desired
product. These results imply product inhibition may account for the
diminished yields associated with electron-deficient aryl halides.
To investigate the role C–H bond acidity plays in the site selec-
tivity of these reactions, deuterium incorporation experiments
were carried out (Scheme 5). Deuterium exchange of 2-picoline
N-oxide by treatment with KOH in D2O reveals that the methyl sp3
site exchanges at a significantly faster rate than the sp2 site adjacent
to the nitrogen (Eq. 3). Exchange on 2,4-lutidine N-oxide shows
that the 2-methyl position undergoes exchange faster than the
While evaluating the scope of sp3 arylation, it was noticed that
severely reduced yields were obtained for most electron-poor aryl
halides (Table 1, entry 15). Since electron-deficient aryl halides
undergo oxidative addition more readily than electron-rich aryl
halides, we hypothesized that the attenuated reactivity of electron-
poor aryl halides might be explained by product inhibition of the
catalyst. Upon arylation of the sp3 position with an electron-de-
ficient arene the benzylic protons become more acidic, which may
lead to the formation of a stable palladacycle that is unable to
participate in the reaction (Scheme 4). To test this hypothesis,
a poisoning experiment was carried out in which two reactions
MeO
MeO
MeO
H2, Pd/C
N
N
MeOH
MeO
O
87%
8
BnO
HO
Crykonisine 9
Pd2dba3 (2.5 mol %)
Ru-Phos (5 mol %)
NaOtBu, PhMe
MW, 110 °C, 45min
55%
Br
BnO
MeReO3 (5 mol%)
MeO
MeO
MeO
MeO
H2O2, DCM
70%
N
N
O
7
6
H
Pd2dba3 (2.5 mol %)
Ru-Phos (5 mol %)
NaOtBu, PhMe
MW, 110 °C, 45min
45%
MeO
MeO
Br
MeO
MeO
N
Zn, NH4Cl
THF
N
MeO
MeO
O
MeO
MeO
94%
10
MeO
MeO
Papaverine 11
Scheme 3. Synthesis of crykonisine and papaverine.

D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
3159
Br
4-methyl position and that the sp2 position undergoes exchange
at the slowest rate of the three positions (Eq. 4). Exchange on
4-picoline N-oxide shows that in the absence of a 2-methyl sub-
stituent the 4-methyl position undergoes exchange faster than the
sp2 positions (Eq. 5).
A series of experiments were also performed to determine if the
N-oxide moiety influences regioselectivity (Scheme 6). Arylation of
2,4-lutidine N-oxide under the sp3 arylation conditions results in
exclusive reaction at the 2-methyl position (Eq. 6). Arylation of
4-picoline N-oxide under the sp3 arylation protocol results in ex-
clusive arylation of the sp2 center adjacent to the N-oxide (Eq. 7).
No product arising from arylation of the sp3 center is observed
(even though the sp2 and sp3 positions undergo deuterium ex-
change at a similar rate) (Eq. 5). Given that arylation only occurs
adjacent to the N-oxide, it is plausible that N-oxide interactions
with the palladium catalyst could play an important role in gov-
erning the selectivity of these reactions.
Pd2dba3 (2.5 mol %)
X-Phos (5 mol %)
Me
+
Me
(1)
N
O
NaOtBu, PhMe
MW, 110 °C, 45min
N
O
89%
Me
Br
N
O
Me
Pd2dba3 (2.5 mol %)
X-Phos (5 mol %)
Me
+
Me
NaOtBu, PhMe
MW, 110 °C, 45min
(2)
N
O
NO2
13%
N
O
12
30 mol %
Ar
N
O
[Pd]
A series of experiments were also carried out to determine the
role of the base in site selectivity (Table 4). Arylation of 2-picoline
N-oxide with 4-bromotoluene under conditions similar to those
used for sp2 arylation (condition A) using K2CO3 as the base yields
56% of the sp2 arylated product with complete sp2 selectivity (entry
1). Under identical conditions, but with NaOtBu instead of K2CO3,
a complete inversion of the sp2/sp3 selectivity is observed (entry 2).
Similarly, under conditions analogous to those employed for sp3
arylation (condition B) using NaOtBu as the base, a 94% yield of
sp3 arylated product is obtained with complete selectivity for the
sp3 position (entry 3). Again if the base is changed under otherwise
identical conditions from NaOtBu to K2CO3, a complete inversion of
the sp2/sp3 selectivity is observed (entry 4). These results indicate
that it is the nature of the base that is of primary importance in
determining sp2/sp3 site selectivity pointing toward its intimate
involvement in the catalytic cycle.
Scheme 4. Poisoning experiment.
KOH (1eq.)
87% D incorporation
D2O
(3)
(4)
H
H
N
O
CH3
H
N
O
CH3
55 °C,15 hrs
19% D incorporation
16% D incorporation
74% D incorporation
CH3
CH3
KOH (1eq.)
D2O
55 °C,15 hrs
N
O
CH3
H
N
O
CH3
A catalytic cycle for these transformations is proposed in
Scheme 7. The active Pd(0) catalyst oxidatively inserts into the aryl
halide bond to generate intermediate 13. The next step, palladation
of the N-oxide, determines site selectivity and is base dependant.
With the strong base, NaOtBu, the most acidic sp3 2-methyl position
may be deprotonated and proceeds through a pathway similar to
14% D incorporation
40% D incorporation
CH3
CH3
KOH (1eq.)
D2O
(5)
H
N
O
55 °C,15 hrs
H
N
O
a
-arylation of carbonyls to yield 15.14 K2CO3 is not a strong enough
base to deprotonate the 2-methyl position, but it does allow for the
six-membered transition state of a concerted metalation–depro-
tonation (CMD) pathway to activate the sp2 position as depicted in
Scheme 7, which gives rise to 14. We and others have evaluated this
32% D incorporation
Scheme 5.
Me
Me
Me
Me
Me
Me
Me
Pd2dba3 (2.5 mol %)
X-Phos (5 mol %)
+
(6)
N
O
Me
NaOtBu, PhMe
MW, 110 °C, 45min
N
O
Me
Br
N
64%
O
Me
Not Observed
Me
Me
Br
Me
Pd2dba3 (2.5 mol %)
X-Phos (5 mol %)
+
(7)
N
O
NaOtBu, PhMe
MW, 110 °C, 45min
N
O
Me
N
O
Not Observed
Me
21%
Scheme 6.

3160
D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
Table 4
Origin of site selectivity
4. Experimental
4.1. General
Cond. A or B
Ligand
p-Tol
N
O
B
N
O
C
N
O
p-Tol
N
O
A
Me
Me
Picoline N-oxide was purchased from Aldrich and used without
Base
p-Tol
p-Tol
further purification. Reagent grade dichloromethane and degassed
HPLC grade toluene were used without further purification. Palla-
dium sources and ligands were purchased from Strem and stored in
a dessicator and were weighed out to air unless otherwise speci-
fied. All other reagents and solvents were used as is from com-
mercial sources. Unless noted below, all other compounds have
been reported in the literature or are commercially available. All
reactions were performed in air-dried glassware. Coupling re-
actions were performed with regard for exclusion of ambient air.
Microwave heating was performed using a CEM Discover Micro-
wave (specific reaction conditions are described below). Analysis of
crude reaction mixture 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 or Varian
INOVA 500 MHz spectrometer in the specified solvent at ambient
temperature and chemical shifts are reported relative to tetrame-
thylsilane (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 spec-
trometer. Melting points were recorded using a Gallenkamp Melt-
ing Point Apparatus and are reported uncorrected.
Entry
Conditiona,b
Base
Ratio A/B/C
Yieldc (%)
1
2
3
4
A
A
B
B
K2CO3
1:0:0
56
45
94
2
NaOtBu
NaOtBu
K2CO3
0:1:1.5
0:20:1
1:0:0
a
Condition A: 2-picoline N-oxide (2 equiv), 4-bromotoluene (1 equiv), Pd(OAc)2
(0.05 equiv), PtBuHBF4 (0.06 equiv), base (1.5 equiv) in PhMe (0.15 M), 110 ꢀ
C
overnight.
b
Condition B: 2-picoline N-oxide (1.5 equiv), 4-bromotoluene (1 equiv), Pd2dba3
(0.025 equiv), X-Phos (0.05 equiv), base (3 equiv) in PhMe (1 M), MW, 110 ꢀC for
45 min.
c
NMR yield using 1,3,5-trimethoxybenzene as standard.
pathway for the C–H activation of arenes.15 Both intermediates 14
and 15 then undergo reductive elimination to form products 16 and
17, respectively.
Ar
N
O
Ar
N
O
Me
4.2. sp3 Direct arylation (Tables 1 and 2)
LnPd(0)
17
16
4.2.1. Procedure A: using microwave irradiation
ArX
All reactions were performed on 0.6 mmol scale: Pd2dba3
(0.025 equiv), X-Phos (0.05 equiv), NaOtBu (3 equiv), and azine
N-oxide (1.5 equiv) are weighed to air and placed in a microwave
tube with a magnetic stir bar (if the aryl halide is a solid, it is also
added). The flask is capped with a rubber septum and purged with
argon. The aryl halide (1 equiv) is then added via syringe followed
by degassed (with argon) ACS grade toluene (0.5–1.0 M). The rub-
ber septum is then replace by a microwave tube cap and the mix-
ture is then placed in a CEM Discover microwave reactor at 110 ꢀC
for 30–45 min (conditions: max power: 200 W; To: 110 ꢀC; max
pressure: 250 psi). The reaction mixture is then diluted with 50 mL
of DCM and filtered through Celite and then evaporated under re-
duced pressure. The residue is then loaded onto a silica gel column
for chromatography typically using DCM/acetone/MeOH mixtures.
Ar
N
Me
N
PdLn
O
O
PdLn(Ar)X
13
15
Ar
Pd
Ln
14
NaOtBu
K2CO3
CH3
H
N
O
H
N
O
H
4.2.2. Procedure B: using conventional heating
O
All reactions were performed on 0.6 mmol scale: Pd2dba3
(0.025 equiv), Ru-Phos (0.1 equiv), NaOtBu (3 equiv), and azine
N-oxide (2 equiv) are weighed to air and placed in a test tube with
a magnetic stir bar (if the aryl halide is a solid, it is also added). The
flask is capped with a rubber septum and purged with argon. The
aryl halide (1 equiv) is then added via syringe followed by degassed
(with argon) ACS grade toluene (0.3 M). The mixture is then placed
in an oil bath and the heat source is set to 70 ꢀC. Reaction mixture
was left stirring at this temperature for 12–15 h (overnight, reaction
times were not optimized). The reaction mixture is then diluted
with 50 mL of DCM and filtered through Celite and then evaporated
under reduced pressure. The residue is then loaded onto a silica gel
column for chromatography typically using DCM/acetone/MeOH
mixtures.
RO
Pd
CMD Transition State
O
PR3
Scheme 7. Catalytic cycle for sp2/sp3 arylation.
3. Conclusion
In conclusion, we have developed completely site-selective
arylation reactions on both sp2 and sp3 positions compatible with
a broad range of azine N-oxides and aryl halides. The reactions are
carried out in both a divergent and a sequential manner. The effi-
cacy of sp3 arylation is demonstrated by the rapid synthesis of the
natural products papaverine and crykonisine in three steps.
Mechanistic studies reveal the importance of the nature of the base
for catalyst controlled site selectivity. These reactions should find
use for the rapid functionalization of azine derivatives and the
mechanistic insights should lead to investigations of similar re-
activity to other substrate classes.
4.2.3. 2-(4-Methylbenzyl)pyridine 1-oxide (Table 1, entries 1–6)
Obtained in 89% yield as a yellow oil by following sp3 direct
arylation procedure A or B. 1H NMR (400 MHz, CDCl3, 293 K, TMS):
2.35 (3H, s), 4.22 (2H, s), 6.92–6.95 (1H, m), 7.10–7.17 (6H, m), 8.28–
8.30 (1H, m); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 21.1, 36.1,

D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
3161
123.4, 125.5, 125.7, 129.6, 129.6, 133.1, 136.7, 139.4, 152.3; IR (nmax
/
152.4, 158.7; IR (nmax/cmꢁ1): 2931, 1512, 1436, 1247, 1031; HRMS
calculated for C13H13NO2 (Mþ) 215.0946, found: 215.0948; mp: 94–
96 ꢀC (chloroform) Rf: 0.16 (1% MeOH, 20% Me2CO, DCM).
cmꢁ1): 2922, 1436, 1245, 766; HRMS calculated for C13H13NO (Mþ)
199.0997, found: 199.1010; mp: 47–49 ꢀC (Chloroform) Rf: 0.18
(1%MeOH, 15% Me2CO, DCM).
4.2.10. 2-(4-Fluorobenzyl)pyridine 1-oxide (Table 1, entry 14)
Obtained in 72% yield as a yellow solid by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 4.24
(2H, s), 6.95–7.00 (1H, m), 7.01–7.06 (2H, m), 7.14–7.19 (2H, m),
7.23–7.28 (2H, m), 8.27–8.31 (1H, m); 13C NMR (100 MHz, CDCl3,
293 K, TMS): 35.8, 115.7 (d, J¼21.3 Hz), 123.8, 125.5, 125.7, 131.2 (d,
J¼8.1 Hz), 132.0 (d, J¼3.3 Hz), 139.5, 151.7, 162.0 (d, J¼245.4 Hz); IR
4.2.4. 2-(2-Methylbenzyl)pyridine 1-oxide (Table 1, entry 7)
Obtained in 92% yield as a yellow oil by following sp3 direct
arylation procedure A. 1H NMR (300 MHz, CDCl3, 293 K, TMS): 2.20
(3H, s), 4.25 (2H, s), 6.71 (1H,d, J¼7.5 Hz), 7.10–7.25 (6H, m), 8.33
(1H, d, J¼6.0 Hz); 13C NMR (75 MHz, CDCl3, 293 K, TMS): 19.3, 34.4,
123.4, 125.0, 125.6, 126.5, 127.5, 130.6, 134.4, 137.2, 139.4, 151.3.
There is a missing peak even with prolonged scans. IR (nmax/cmꢁ1):
3019, 1489, 1435, 1244, 745; HRMS calculated for C13H13NO (Mþ)
199.0997, Found: 199.0987; Rf: 0.22 (1% MeOH, 20% Me2CO, DCM).
(
nmax/cmꢁ1): 3075, 2928, 1508, 1222, 770; HRMS calculated for
C12H10FNO (Mþ) 203.0746, found: 203.0753; mp: 79–81 ꢀC (chlo-
roform) Rf: 0.17 (1% MeOH, 20% Me2CO, DCM).
4.2.5. 2-(3,5-Dimethylbenzyl)pyridine 1-oxide (Table 1, entry 8)
Obtained in 93% yield as a yellow oil by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 2.30
(6H, s), 4.20 (2H, s), 6.88–7.14 (6H, m), 8.28 (1H, s); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 21.3, 36.3, 123.4, 125.8, 127.5, 128.7,
136.1, 138.4, 139.5, 152.4. There is a missing peak even with pro-
longed scans. IR (nmax/cmꢁ1): 2923, 1604, 1487, 1435, 1239, 848;
HRMS calculated for C14H15NO (Mþ) 213.1154, found: 213.1175; Rf:
0.17 (1% MeOH, 20% Me2CO, DCM).
4.2.11. 2-(3,5-Dimethoxybenzyl)-4-methylpyridine 1-oxide
(Table 2, entry 1)
Obtained in 70% yield as a yellow solid by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 2.24
(3H, s), 3.75 (6H, s), 4.10 (2H, s), 6.38 (1H, t, J¼2.3 Hz), 6.55 (2H, d,
J¼2.3 Hz), 7.02–7.09 (2H, m), 8.09 (1H, d, J¼6.7 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 20.1, 36.7, 55.5, 99.2, 108.3, 125.6,
127.4, 136.3, 139.2, 140.7, 150.9, 162.0; IR (nmax/cmꢁ1): 2938, 1595.
1495, 1205, 1064; HRMS calculated for C15H17NO3 (Mþ) 259.1208,
found: 259.1195; mp: 109–111 ꢀC (CHCl3); Rf: 0.21 (3% MeOH, 15%
Me2CO, DCM).
4.2.6. 2-(Naphthalen-2-ylmethyl)pyridine 1-oxide (Table 1, entry 9)
Obtained in 72% yield as a yellow oil by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 4.44
(2H, s), 6.95 (1H, d, J¼7.1 Hz), 7.05–7.17 (2H, m), 7.38 (1H, d,
J¼8.4 Hz), 7.44–7.50 (2H, m), 7.74 (1H, s), 7.79–7.84 (3H, m), 8.30
(1H, s); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 123.5, 125.6, 125.9,
126.3, 127.6, 127.7, 127.8, 128.4, 128.6, 128.8, 132.5, 133.6, 133.8,
4.2.12. 2-(3,5-Dimethylbenzyl)-3-methylpyridine 1-oxide
(Table 2, entry 2)
Obtained in 90% yield as a orange solid by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 2.24
(6H, s), 2.32 (3H, s), 4.36 (2H, s), 6.82 (1H, br s), 6.86 (2H, br s), 7.05
(2H, d, J¼4.1 Hz), 8.19 (1H, d, J¼3.9 Hz); 13C NMR (100 MHz, CDCl3,
293 K, TMS): 19.3, 21.3, 32.5, 122.8, 126.1, 127.4, 128.2, 135.9, 136.6,
137.5, 138.0, 150.4; IR (nmax/cmꢁ1): 2915, 1603, 1422, 1248, 822;
HRMS calculated for C15H17NO (Mþ) 227.1310, found: 227.1297; mp:
108–110 ꢀC (CHCl3); Rf: 0.16 (1.5% MeOH, 15% Me2CO, DCM).
139.5. There is a missing peak even with prolonged scans. IR (nmax
/
cmꢁ1): 3054, 2927, 1487, 1434, 1241; HRMS calculated for C16H13NO
(Mþ) 235.0997, found: 235.0987; Rf: 0.18 (1% MeOH, 20% Me2CO,
DCM).
4.2.7. 2-(2,6-Dimethylbenzyl)pyridine 1-oxide (Table 1, entries
10 and 11)
4.2.13. 3-Methyl-2-(4-methylbenzyl)pyridine 1-oxide
Obtained in 90% yield as a yellow oil by following sp3 direct
arylation procedure A except S-Phos was used instead of X-Phos. 1H
NMR (400 MHz, CDCl3, 293 K, TMS): 2.18 (6H, s), 4.26 (2H, s), 6.56
(1H, d, J¼7.7 Hz), 7.07–7.18 (5H, m), 8.36 (1H, d, J¼6.3 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS):20.0, 30.6, 123.3, 123.9, 125.7, 127.2,
128.4, 133.0, 137.5, 139.4, 150.5; IR (nmax/cmꢁ1): 3072, 2921, 1488,
1433, 1242; HRMS calculated for C14H15NO (Mþ) 213.1154, found:
213.1155; Rf: 0.21 (1% MeOH, 20% Me2CO, DCM).
(Table 2, entry 3)
Obtained in 90% yield as a yellow solid by following sp3 direct
arylation procedure B. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 2.28
(3H, s), 2.32 (3H, s), 4.38 (2H, s), 7.04–7.07 (4H, m), 7.17 (2H, d,
J¼7.84 Hz), 8.18 (1H, s); 13C NMR (100 MHz, CDCl3, 293 K, TMS):
19.3, 21.0, 32.3, 122.8, 127.7, 128.3, 129.2, 133.7, 135.7, 136.0, 137.5,
150.6; IR (nmax/cmꢁ1): 3049, 1429, 1250, 809; HRMS calculated for
C14H15NO (Mþ) 213.1154, found: 213.1143; mp: 100–102 ꢀC (CHCl3);
Rf: 0.18 (1.5% MeOH, 15% Me2CO, DCM).
4.2.8. 2-((1-Methyl-1H-indol-5-yl)methyl)pyridine 1-oxide
(Table 1, entry 12)
4.2.14. 2-(4-Methylbenzyl)quinoline 1-oxide (Table 2, entry 4)
Obtained in 73% yield as a yellow oil by following sp3 direct
arylation procedure A except 3 equiv of the N-oxide was used. 1H
NMR (400 MHz, CDCl3, 293 K, TMS): 2.35 (3H, s), 4.44 (2H, s), 7.06
(1H, d, J¼8.7 Hz), 7.16 (2H, d, J¼7.9 Hz), 7.22 (2H, d, J¼8.0 Hz), 7.57–
7.61 (2H, m), 7.75 (1H, ddd, J¼7.2, 7.0, and 1.18 Hz), 7.80 (1H, d,
J¼8.1 Hz), 8.81 (1H, d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3, 293 K,
TMS): 21.1, 37.0, 119.8, 121.9, 125.1, 127.9, 128.0, 129.1, 129.6, 129.6,
130.4, 133.4, 136.6, 141.6. There is a missing peak even with pro-
longed scans. IR (nmax/cmꢁ1): 2922, 1513, 1349, 1240, 807; HRMS
calculated for C17H15NO (Mþ) 249.1154, found: 249.1151; Rf: 0.19
(1% MeOH, 1% Me2CO, DCM).
Obtained in 90% yield as a yellow oil by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 3.79
(3H, s), 4.36 (2H, s), 6.45 (1H, d, J¼2.9 Hz), 6.88 (1H, d, J¼7.4 Hz),
7.04–7.12 (4H, m), 7.31 (1H, d, J¼8.3 Hz), 7.52 (1H, s), 8.28 (1H, s);
13C NMR (100 MHz, CDCl3, 293 K, TMS): 32.9, 36.5, 100.7, 109.6,
121.9, 123.1, 123.4, 125.6, 125.8, 126.8, 128.9, 129.4, 135.9, 139.2,
153.4; IR (nmax/cmꢁ1): 3091, 1488, 1435,1245, 763; HRMS calculated
for C15H14N2O (Mþ) 238.1106, found: 238.1116; Rf: 0.17 (1% MeOH,
20% Me2CO, DCM).
4.2.9. 2-(4-Methoxybenzyl)pyridine 1-oxide (Table 1, entry 13)
Obtained in 72% yield as a white solid by following sp3 direct
arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K, TMS): 3.81
(3H, s), 4.20 (2H, s), 6.88–6.91 (2H, m), 6.93–6.96 (1H, m), 7.10–7.16
(2H, m), 7.18–7.22 (2H, m), 8.28 (1H, s); 13C NMR (100 MHz, CDCl3,
293 K, TMS): 35.7, 55.3, 114.3, 123.4, 125.5, 125.7, 128.2, 130.8, 139.4,
4.2.15. 1-(4-Methylbenzyl)isoquinoline 2-oxide (Table 2, entry 5)
Obtained in 60% yield as a light yellow solid by following sp3
direct arylation procedure A. 1H NMR (400 MHz, CDCl3, 293 K,
TMS): 2.26 (3H, s), 4.77 (2H, s), 7.05 (2H, d, J¼7.8 Hz), 7.24 (2H, d,

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D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
J¼8.0 Hz), 7.51–7.56 (2H, m), 7.59 (1H, ddd, J¼7.0, 7.0, and 1.3 Hz),
7.75 (1H, d, J¼7.9 Hz), 8.00 (1H, d, J¼8.0 Hz), 8.22 (1H, d, J¼7.0 Hz);
13C NMR (100 MHz, CDCl3, 293 K, TMS): 21.0, 31.3, 122.5, 124.0,
127.4,128.1,128.5,128.9,128.9,129.3,133.9,136.1,136.9 (br),147.1; 1
overlapping signal as one peak is missing even with prolonged
scans. IR (nmax/cmꢁ1): 3051, 1513, 1336, 1219, 749; HRMS calculated
for C17H15NO (Mþ) 249.1154, found: 249.1133; mp: 170–172 ꢀC
(CHCl3); Rf: 0.20 (1% MeOH, 15% Me2CO, DCM).
J¼8.1 Hz), 7.53 (2H, d, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3, 293 K,
TMS): 19.0, 21.6, 110.9, 115.4, 125.1, 126.7, 127.4, 129.3, 129.6, 141.0,
152.5, 154.6; IR (nmax/cmꢁ1): 2919, 2231, 1348, 1269, 815; HRMS
calculated for C14H12N2O (Mþ) 224.0950, found: 224.0943; mp:
137–139 ꢀC (CH2Cl2); Rf: 0.20 (1% MeOH, 5% Me2CO, DCM).
4.3.3. 2-(2-Methylbenzyl)-6-p-tolylpyridine 1-oxide (Table 3,
entry 4 and Scheme 2)
Obtained in 77% yield as a yellow solid by following the general
sp2 direct arylation procedure except using 3 equiv of the N-oxide.
1H NMR (400 MHz, CDCl3, 293 K, TMS): 2.23 (3H, s), 2.41 (3H, s),
4.29 (2H, s), 6.63 (1H, dd, J¼7.1 and 2.1 Hz), 7.10 (1H, t, J¼7.8 Hz),
7.19–7.26 (4H, m), 7.27–7.31 (3H, m), 7.73 (2H, d, J¼8.2 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 19.4, 21.4, 35.0, 123.4, 124.6, 124.7,
126.5, 127.4, 128.8, 129.4, 130.4, 130.6, 130.7, 135.1, 137.3, 139.4,
149.4, 151.9; IR (nmax/cmꢁ1): 3019, 2921, 1479, 1378, 1254, 770;
HRMS calculated for C20H19NO (Mþ) 289.1467, found: 289.1445;
mp: 99–100 ꢀC (CHCl3) Rf: 0.2 (20% EtOAc, petroleum ether).
4.2.16. 3-Methyl-2-(4-methylbenzyl)pyrazine 1-oxide (Table 2,
entry 6)
Obtained in 79% yield as a yellow oil by following sp3 direct
arylation procedure A. 1H NMR (300 MHz, CDCl3, 293 K, TMS): 2.30
(3H, s), 2.60 (3H, s), 4.31 (2H, s), 7.08 (2H, d, J¼8.1 Hz), 7.14 (2H, d,
J¼8.1 Hz), 8.04 (1H, d, J¼4.3 Hz), 8.21 (1H, d, J¼4.3 Hz); 13C NMR
(75 MHz, CDCl3, 293 K, TMS): 21.0, 22.4, 31.4, 128.2, 129.4, 132.0,
132.6, 136.6, 143.6, 145.2, 157.0; IR (nmax/cmꢁ1): 2923, 1513, 1423,
1251, 791; HRMS calculated for C15H17NO (Mþ) 214.1166, found:
214.1166; mp: 95–97 ꢀC (CHCl3); Rf: 0.20 (2% MeOH, 10% Me2CO,
DCM).
4.3.4. 2,3-Dimethyl-6-p-tolylpyrazine 1-oxide (Table 3, entry 5)
Obtained in 89% yield as a light yellow solid by following the
general sp2 direct arylation procedure. Spectral data correspond to
that previously described in the literature.16
4.2.17. 7-p-Tolyl-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide
(Table 2, entry 7)
This compound was obtained in 64% yield as a light yellow oil by
following sp3 direct arylation procedure A except S-Phos and
3 equiv of the N-oxide was used. 1H NMR (400 MHz, CDCl3, 293 K,
TMS): 2.14–2.22 (1H, m), 2.28 (3H, s), 2.59–2.69 (1H, m), 2.99 (1H,
ddd, J¼16.4, 9.2, and 2.1 Hz), 3.15–3.24 (1H, m), 4.71 (1H, dd, J¼9.2
and 1.3 Hz), 6.69–7.19 (6H, m), 8.01 (1H, d, J¼6.2 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 21.0, 30.3, 32.9, 47.0, 122.2, 124.5,
127.0, 129.3, 136.2, 138.0, 138.4, 142.5, 154.1; IR (nmax/cmꢁ1): 3083,
2843, 1603, 1444, 1257, 1013; HRMS calculated for C15H15NO (Mþ)
225.1159, found: 225.1140; Rf: 0.10 (1% MeOH, 10% Me2CO, DCM).
4.3.5. 3-Methyl-1-p-tolylisoquinoline 2-oxide (Table 3, entry 6)
Obtained in 98% yield as a white solid by following the general
sp2 direct arylation procedure except using 1.1 equiv of the N-oxide.
1H NMR (500 MHz, CDCl3, 293 K, TMS): 2.47 (3H, s), 2.68 (3H, s),
7.37–7.41 (5H, m), 7.44 (1H, d, J¼8.3 Hz), 7.50 (1H, td, J¼7.3 and
1.2 Hz), 7.67 (1H, s), 7.72 (1H, d, J¼7.8 Hz); 13C NMR (100 MHz,
CDCl3, 293 K, TMS): 18.3, 21.5, 122.2, 125.6, 126.0, 127.7, 127.9, 128.5,
128.7, 128.9, 129.4, 130.0, 139.0, 146.2, 146.4; IR (nmax/cmꢁ1): 3050,
1329, 1292, 1212, 1109, 811; HRMS calculated for C17H15NO (Mþ)
249.1154, found: 249.1146; mp: 168–170 ꢀC (CHCl3); Rf: 0.20 (1.5%
MeOH, 8.5% Me2CO, DCM).
4.3. sp2 Direct arylation (Table 3)
Pd(OAc)2 (5 mol %), PtBu3$HBF4 (6 mol %), potassium carbonate
powder (K2CO3, 1.5 equiv), aryl halide (1 equiv), and azine N-oxide
(1.1-4 equiv) are weighed to air and placed inside the flask. The
flask is then fitted with a reflux condenser, which is capped with
a rubber septum. The whole setup is then evacuated under vacuum
and refilled with argon four times. Toluene (0.15 M) is then added
under a steady flow of argon. After addition, the reaction mixture is
immersed in the oil bath. Stirring is commenced and the heating
source is turned on (set to 125 ꢀC). The reaction mixture is left
stirring for 12–18 h (overnight), then allowed to cool, diluted with
DCM, and filtered over Celite. The residues are then purified using
silica gel chromatography.
4.3.6. 6-(4-Methoxyphenyl)-2,3-dimethylpyrazine 1-oxide
(Table 3, entry 7)
This compound was obtained in 86% yield as a light yellow solid
by following the general sp2 direct arylation procedure. 1H NMR
(400 MHz, CDCl3, 293 K, TMS): 2.53 (3H, s), 2.61 (3H, s), 3.86 (3H, s),
7.01 (2H, d, J¼8.6 Hz), 7.75 (2H, d, J¼8.7 Hz), 8.36 (1H, s); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 13.5, 22.5, 55.4, 113.9, 122.2, 130.8,
141.7, 142.8, 143.1, 153.2, 160.8; IR (nmax/cmꢁ1): 3004, 2873, 1610,
1467, 1302, 1251, 832; HRMS calculated for C13H14N2O2 (Mþ)
230.1055, found: 230.1042; mp: 104–106 ꢀC (CH2Cl2); Rf: 0.51 (2%
MeOH, 8% Me2CO, DCM).
4.3.7. 3-Cyano-6-methyl-2-(4-(trifluoromethyl)phenyl)pyridine
1-oxide (Table 3, entry 8)
4.3.1. 2-Methyl-6-p-tolylpyridine 1-oxide (Table 3, entries 1 and 2)
Obtained in 54% yield as a tan solid by following the general sp2
direct arylation procedure. 1H NMR (500 MHz, CDCl3, 293 K, TMS):
2.41 (3H, s), 2.57 (3H, s), 7.18 (1H, t, J¼7.8 Hz), 7.22 (1H, dd, J¼7.8
and 1.9 Hz), 7.26–7.31 (3H, m), 7.70 (2H, d, J¼8.3 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 18.7, 21.4, 124.6, 124.8 (br), 128.8,
129.3, 130.5, 139.3, 149.5, 149.8; 1 overlapping signal as one peak is
missing even with prolonged scans. IR (nmax/cmꢁ1): 3040, 1729,
1374, 1225, 757; HRMS calculated for C13H13NO (Mþ) 199.0997,
found: 199.0982; mp: 102–104 ꢀC (CHCl3) Rf: 0.21 (2% MeOH, 10%
Me2CO, DCM).
This compound was obtained in 48% yield as a clear oil by fol-
lowing the general sp2 direct arylation procedure. 1H NMR
(400 MHz, CDCl3, 293 K, TMS): 2.61 (3H, s), 7.43 (1H, d, J¼8.1 Hz),
7.53 (1H, d, J¼8.1 Hz), 7.77 (2H, d, J¼8.4 Hz), 7.82 (2H, d, J¼8.4 Hz);
13C NMR (100 MHz, CDCl3, 293 K, TMS): 18.9, 111.0, 114.8, 125.7 (q,
J¼3.7 Hz), 126.0, 127.5, 130.4, 132.4, 132.7, 133.2, 150.8, 155.0; IR
(
nmax/cmꢁ1): 3038, 2921, 1353, 1325, 1169, 1135, 1065, 839; HRMS
calculated for C14H9N2O1F3 (Mþ) 278.0667, found: 278.0672; Rf:
0.61 (30% Me2CO, DCM).
4.3.8. 3-Cyano-2-(4-methoxyphenyl)-6-methylpyridine 1-oxide
(Table 3, entry 9)
This compound was obtained in 73% yield as a light yellow solid
by following the general sp2 direct arylation procedure. 1H NMR
(400 MHz, CDCl3, 293 K, TMS): 2.59 (3H, s), 3.88 (3H, s), 7.04 (2H, d,
J¼8.9 Hz), 7.33 (1H, d, J¼8.1 Hz), 7.47 (1H, d, J¼8.1 Hz), 7.63 (2H, d,
4.3.2. 3-Cyano-6-methyl-2-p-tolylpyridine 1-oxide (Table 3,
entry 3)
Obtained in 74% yield as a white solid by following the general
sp2 direct arylation procedure. 1H NMR (500 MHz, CDCl3, 293 K,
TMS): 2.42 (3H, s), 2.59 (3H, s), 7.33–7.36 (3H, m), 7.47 (1H, d,

D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
3163
J¼8.9 Hz); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 19.2, 55.5, 110.8,
806; HRMS calculated for
355.1415; Rf: 0.33 (5% MeOH, 10% Me2CO, DCM).
C
20H21NO5 (Mþ) 355.1420, found:
114.1, 115.7, 121.7, 124.9, 127.7, 131.6, 152.3, 154.7, 161.5; IR (nmax
/
cmꢁ1): 2912, 2235, 1614, 1272, 1260, 1017; HRMS calculated for
C14H12N2O2 (Mþ) 240.0899, found: 240.08825; mp: 193–195 ꢀC
(CH2Cl2); Rf: 0.14 (1% MeOH, 3% Me2CO, DCM).
4.4.5. 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxyisoquinoline (11)
N-Oxide reduction was carried out using a procedure described
by Ohta et al.17 The N-oxide (30 mg, 0.084 mmol) is dissolved in
THF (1.3 mL). To this mixture is then added saturated NH4Cl
solution (1.3 mL) and zinc dust (55.2 mg, 0.844 mmol). This
mixture is then stirred for 1 h. The deposit is then collected by
filtration on Celite and washed with Et2O. The organic layer is
then separated and the aqueous layer is extracted with Et2O. The
organics are combined, dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification via silica gel column
chromatography using 3% MeOH/7% Me2CO/DCM gave papaverine
in 94% yield. Spectral data corresponds to that previously de-
scribed in the literature.13a
4.4. Natural product synthesis (Scheme 3)
4.4.1. 6,7-Dimethoxy-1-methylisoquinoline 2-oxide (7)
Prepared by a method adopted from Sharpless et al.12 A mixture
of 6,7-dimethoxy-1-methylisoquinoline (1 g, 4.9 mmol) and
MeReO3 (60 mg, 0.24 mmol) in CH2Cl2 (5 mL) was treated with
4 mL of 50% aqueous H2O2 and stirred for 15 h at 24 ꢀC. The biphasic
reaction mixture was then treated with a catalytic amount of MnO2
and stirred until oxygen evolution ceased. Following phase sepa-
ration, the water layer was extracted with CH2Cl2 and the combined
organic layers were dried over MgSO4, filtered, concentrated, and
flashed over silica gel using 5% MeOH/10% Me2CO/CH2Cl2 to give
753 mg (70%) of a light yellow solid: 1H NMR (400 MHz, CDCl3,
293 K, TMS): 2.87 (3H, s), 4.02 (3H, s), 4.05 (3H, s), 7.04 (1H, s), 7.13
(1H, s), 7.39 (1H, d, J¼7.0 Hz), 8.13 (1H, d, J¼7.0 Hz); 13C NMR
(100 MHz, CDCl3, 293 K, TMS): 13.2, 56.1, 56.2, 102.8, 106.0, 120.3
124.7, 125.2, 135.0, 143.8, 151.2, 151.5; IR (nmax/cmꢁ1): 2842, 1619,
1517, 1433, 1270, 1201, 1058, 805; HRMS calculated for C12H13NO3
(Mþ) 219.0895, found: 219.0876; mp: 84–86 ꢀC (CH2Cl2) Rf: 0.18 (5%
MeOH, 10% Me2CO, DCM).
Acknowledgements
The authors thank NSERC, the University of Ottawa, the Re-
search Corporation, Boehringer Ingelheim (Laval), Merck Frosst
Canada, Merck Inc., and Astra Zeneca Montreal for support of this
work.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.12.004.
4.4.2. 1-(4-(Benzyloxy)benzyl)-6,7-dimethoxyisoquinoline
2-oxide (8)
This compound was obtained in 55% yield as a brown solid using
the general sp3 arylation procedure except Ru-Phos was used in
place of X-Phos as the ligand. 1H NMR (400 MHz, CDCl3, 293 K,
TMS): 3.93 (3H, s), 3.98 (3H, s), 4.73 (2H, s), 4.99 (2H, s), 6.87 (2H, d,
J¼8.6 Hz), 7.02 (1H, s), 7.18 (1H, s), 7.26–7.41 (8H, m), 8.15 (1H, d,
J¼7.0 Hz); 13C NMR (100 MHz, CDCl3, 293 K, TMS): 31.3, 56.0, 56.1,
70.0, 103.0, 106.0, 115.1, 120.9, 124.7, 125.5, 127.4, 127.9, 128.5, 129.6,
129.7, 135.2, 137.0, 145.8, 151.1, 151.6, 157.5; IR (nmax/cmꢁ1): 3036,
2932, 1612, 1267, 1235, 803; HRMS calculated for C25H23NO4 (Mþ)
401.1627, found: 401.1643; mp: 74–77 ꢀC; Rf: 0.31 (5% MeOH, 10%
Me2CO, DCM).
References and notes
1. For general reviews on direct arylation, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174; (b) Campeau, L.-C.; Stuart, D. R.; Fagnou,
K. Aldrichimica Acta 2007, 40, 35; (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev.
2007, 36, 1173; (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200; (e) Lewis, J. C.;
Bergman, R. C.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013.
2. For reviews on C–H activation, see: (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.;
Sanford, M. S. Tetrahedron 2006, 62, 11483; (b) Labinger, J. A.; Bercaw, J. E.
Nature 2002, 417, 507; (c) Ritleng, V.; Silin, C.; Pfeffer, M. Chem. Rev. 2002, 102,
1731; (d) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633; (e)
Godula, K.; Sames, D. Science 2006, 312, 67; (f) Li, J.-J.; Giri, R.; Yu, J.-Q. Tetra-
hedron 2008, 64, 6979; (g) Ferreira, E. M.; Zhang, H.; Stoltz, B. M. Tetrahedron
2008, 64, 5987.
3. For reviews, see Refs. 1c and 1d. For recent examples, see: (a) Lane, B. S.;
Sames, D. Org. Lett. 2004, 6, 2897; (b) Li, W. J.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835; (c)
Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada, K.;
Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700; (d) Wang, X.; Lane,
B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996; (e) Chiong, H. A.; Daugulis, O.
Org. Lett. 2007, 9, 1449; (f) Turner, G. L.; Morris, J. A.; Greany, M. F. Angew.
Chem., Int. Ed. 2007, 46, 7996; (g) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org.
4.4.3. 4-((6,7-Dimethoxyisoquinolin-1-yl)methyl)phenol (9)
A mixture of 8 (60 mg, 0.15 mmol) and Pd/C (10%, 2 mg) was
stirred in MeOH (1 mL) under a hydrogen atmosphere (1 atm) for
72 h at 24 ꢀC. The reaction mixture was then filtered, concentrated,
and flashed over silica gel using 20–30% Me2CO/CH2Cl2 to give
38 mg (87%) of a light yellow oil: 1H NMR (400 MHz, DMSO-d6,
293 K, TMS): 3.86 (3H, s), 3.89 (3H, s), 4.42 (2H, s), 6.63 (2H, d,
J¼8.5 Hz), 7.11 (2H, d, J¼8.5 Hz), 7.31 (1H, s), 7.47 (1H, s), 7.52 (1H, d,
J¼5.6 Hz), 8.24 (1H, d, J¼5.6 Hz), 9.16 (1H, s); 13C NMR (100 MHz,
DMSO-d6, 293 K, TMS): 40.3, 55.5, 55.6, 104.2, 105.5, 115.0, 118.2,
ꢀ
Chem. 2007, 72, 8543; (h) Pozgan, F.; Rogerm, J.; Doucet, H. ChemSusChem
2008, 1, 404.
4. (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1998, 71, 467; (b) Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111.
5. Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003,
5, 301.
6. Lane, B. S.; Brown, M. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
7. (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2005, 44, 3125; (b) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am.
Chem. Soc. 2006, 128, 2528; (c) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 8172.
121.9, 129.4, 129.8, 132.7, 140.4, 149.4, 152.0, 155.4, 158.1; IR (nmax
/
cmꢁ1): 2923, 1595, 1233, 1157, 835; HRMS calculated for C18H17NO3
(Mþ) 295.1208, found: 295.1181; Rf: 0.38 (30% Me2CO, DCM).
4.4.4. 1-(3,4-Dimethoxybenzyl)-6,7-dimethoxyisoquinoline
2-oxide (10)
8. (a) Stuart, D. R.; Fagnou, K. Science 2007, 317, 1172; (b) Stuart, D. R.; Villemure,
E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
9. Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266.
10. (a) Bentley, K. W. In The Isoquinoline Alkaloids; Ravindranath, B., Ed.; Harwood
Academic: Amsterdam, 1998; pp 107–122; (b) Bentley, K. W. Nat. Prod. Rep.
2005, 22, 249; (c) Isolation of papaverine: Merck, G. Ann. 1848, 66, 125.
11. (a) Sar, A.; Saryar, G. Pharmazie 2000, 55, 471; (b) Lin, F. W.; Wang, J. J.; Wu, T. S.
Chem. Pharm. Bull. 2002, 50, 157.
12. Coperet, C.; Adolfsson, H.; Khovong, T. V.; Yudin, A. K.; Sharpless, K. B. J. Org.
Chem. 1998, 63, 1740.
13. For previous syntheses of papaverine, see: (a) Gilmore, C. D.; Allan, K. M.; Stoltz,
B. M. J. Am. Chem. Soc. 2008, 130, 1558; (b) Pictet, A.; Finkelstein, M. Ber. Dtsch.
Chem. Ges. 1909, 42, 1979; (c) Rosenmund, K. W.; Nothnagel, M.; Riesenfeldt, H.
Ber. Dtsch. Chem. Ges. 1927, 60, 392; (d) Mannich, C.; Walther, O. Arch. Pharm.
This compound was obtained in 45% yield as a brown solid using
the general sp3 arylation procedure except Ru-Phos was used in
place of X-Phos as the ligand. 1H NMR (400 MHz, DMSO-d6, 293 K):
3.66 (3H, s), 3.68 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 4.66 (2H, s), 6.79
(1H, d, J¼8.2 Hz), 6.84 (1H, dd, J¼8.2, 1.5 Hz), 7.15 (1H, d, J¼1.5 Hz),
7.37 (1H, s), 7.39 (1H, s), 7.66 (1H, d, J¼7.0 Hz), 8.12 (1H, d, J¼7.0 Hz);
13C NMR (100 MHz, DMSO-d6, 293 K): 30.2, 55.3, 55.4, 55.7, 55.8,
102.9, 106.5, 111.9, 112.7, 115.1, 120.3, 121.2, 124.0, 124.5, 130.6, 134.7,
147.3, 148.5, 150.4, 151.2; IR (nmax/cmꢁ1): 2933, 1517, 1265, 1026,

3164
D.J. Schipper et al. / Tetrahedron 65 (2009) 3155–3164
1927, 265, 1; (e) Galat, A. J. Am. Chem. Soc. 1951, 73, 3654; (f) Wahl, H. Bull. Soc.
Chim. Fr. 1950, 17, 680; (g) Popp, F. D.; McEwen, W. E. J. Am. Chem. Soc. 1957, 79,
3773; (h) Hirsenkorn, R. Tetrahedron Lett. 1991, 32, 1775.
Garcı´a-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A.
M. J. Am. Chem. Soc. 2007, 129, 6880; (e) Lafrance, M.; Rowley, C. N.; Woo, T. K.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754; (f) Garcia-Cuadrado, D.; Braga, A.
A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066; (g)
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848; (h)
Pascual, S.; Mendoza, P.; dBraga, A. A. C.; Maseras, F.; Echavarren, A. M. Tetra-
hedron 2008, 64, 6021.
14. (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
1360; (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
15. (a) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlauoen, C.; Maseras, F.; Bruneau, C.;
Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156; (b) Ackermann, L.; Vicente, R.;
Althammer, A. Org. Lett. 2008, 10, 2299; (c) Davies, D. L.; Donald, S. M. A.;
Al-Duaij, O.; Macgregor, S. A.; Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210; (d)
16. Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781.
17. Aoyagi, Y.; Tomomitsu, A.; Ohta, A. Synthesis 1997, 8, 891.