Palladium-catalyzed picolinamide-directed halogenation of ortho C-H bonds of benzylamine substrates

Article abstract of DOI:10.1016/j.tet.2014.02.070

We report a new set of methods for the halogenation of the ortho C-H bonds of N-benzyl picolinamides under palladium-catalyzed conditions. These reactions feature the use of a unique combination of K(Na)XO₃ and K ₂S₂O

Full text of DOI:10.1016/j.tet.2014.02.070

Tetrahedron 70 (2014) 4197e4203
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Palladium-catalyzed picolinamide-directed halogenation of ortho
CeH bonds of benzylamine substrates
*
Chengxi Lu, Shu-Yu Zhang, Gang He, William A. Nack, Gong Chen
The Pennsylvania State University, Department of Chemistry, University Park, PA 16802, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a new set of methods for the halogenation of the ortho CeH bonds of N-benzyl picolinamides
under palladium-catalyzed conditions. These reactions feature the use of a unique combination of K(Na)
XO3 and K2S2O8 reagents, which enables the installation of iodo, bromo, and chloro groups onto the ortho
position of N-benzyl picolinamides in a unified fashion. A variety of benzylamine products bearing
complex halogen substitution can be quickly prepared from much simpler precursors in good yield and
selectivity.
Received 22 January 2014
Received in revised form 20 February 2014
Accepted 24 February 2014
Available online 3 March 2014
Keywords:
Palladium
Ó 2014 Elsevier Ltd. All rights reserved.
CeH halogenation
Picolinamide
Benzylamine
1. Introduction
utilized to facilitate Pd-catalyzed ortho CeH chlorination and bro-
mination using N-halosuccinimides/Na2S2O8.6 Notably, most of
Halogenated arenes are versatile building blocks in organic
synthesis.1 Synthetic methods based on metal-catalyzed haloge-
nation of the ortho CeH bonds of arene substrates have been
quickly advanced over the past decade.2e8 These methods provide
unique synthesis solutions that can complement conventional
methods based on electrophilic aromatic substitution (SEAr) and
directed metalation.9 Like directed lithiation chemistry,
heteroatom-based directing groups are typically required to ach-
ieve the desired selectivity and reactivity. Among metal catalysts,
Pd-catalyzed CeH halogenation reactions have been most in-
vestigated.10 In 1970, Fahey pioneered Pd-catalyzed ortho CeH
chlorination and bromination of azobenzenes using chlorine and
bromine.2 In 2004, Sanford reported Pd-catalyzed ortho CeH
chlorination and bromination of benzoquinoline using N-hal-
osuccinimides.3a In 2006, Shi and co-workers reported Pd-
catalyzed ortho CeH chlorination of acetanilides using Cu(OAc)2/
CuCl2.4 In 2008, Yu reported Pd-catalyzed ortho CeH iodination of
triflamide protected 2-arylehtylamines using I2/PhI(OAc)2.5a
Enantioselective, triflamide-directed iodination of symmetric dia-
rylmethylamines with I2 has also been reported.5b More recently,
Rao further expanded the scope of directing groups such that
a range of common ester and amide-based directing groups can be
these reaction systems have been tailored to achieve halogenation
with only one or two of the halogens; there are few unified sets of
conditions capable of introducing Cl, Br, and I.3b
Recently, our laboratory has become interested in investigating
the picolinamide (PA) directing group for use in CeH functionali-
zation reactions.11 The PA group, first introduced by the Daugulis
laboratory,12 has demonstrated excellent capability for a variety of
Pd-catalyzed CeH functionalizations, forming both CeC and
Ceheteroatom bonds.13 Last year, we reported that the PA group
can facilitate mono-selective iodination of ε ortho CeH bonds of g-
arylpropylamines under Pd-free conditions (Eq. 1, Scheme 1).14,15
These reactions proceed through a rarely observed intramolecular
directed electrophilic aromatic substitution (SEAr) pathway with
high efficiency and ortho selectivity. Subsequent Cu-catalyzed
intramolecular CeN coupling of the iodinated intermediates
afforded tetrahydroquinoline products with various substitution
patterns. In contrast, bromination, and chlorination of
pylamine substrates under similar conditions with NBS or NCS was
non-selective. Furthermore, while PA-coupled -phenylethyl-
g-arylpro-
b
amines substrates were ortho-iodinated with excellent mono and
ortho selectivity, iodination of PA-coupled benzylamine substrates
generated a mixture of ortho and para-iodinated products via non-
directed SEAr (Eq. 2). Prompted by the importance and abundance
of benzylamine compounds in organic synthesis, we began to in-
vestigate whether we can achieve the ortho halogenation of ben-
zylamines under metal catalysis. Herein, we report a new set of Pd-
* Corresponding author. Fax: þ1 814 863 5319; e-mail address: guc11@psu.edu
(G. Chen).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.070

4198
C. Lu et al. / Tetrahedron 70 (2014) 4197e4203
catalyzed ortho CeH halogenation reactions of N-benzyl picolina-
mides. A unified set of reaction conditions featuring the use of
K(Na)XO3 and K2S2O8 allows the ortho halogenation of benzyl-
amines with iodo, bromo, and chloro groups.
previously reported NIS/HBF4 conditions gave predominately non-
directed product 3. Iodination of 1 with NIS alone in TFA/DCM also
gave 3 selectively in lower yield (entry 2). Reaction of 1 in the
presence of 10 mol % of Pd(OAc)2 and 2 equiv of NIS in CH3CN at
110 ꢀC gave a mixture of ortho product 2 in 28% yield and 3 in 63%
yield, presumably via non-directed SEAr (entry 3).3c Interestingly,
the yield and selectivity of the reaction were significantly improved
by applying ClePh solvent (entry 4).
In addition to organic iodonium precursors, we also evaluated
simple alkali metal iodides as iodo donors under oxidative con-
ditions, in order to develop more economical iodination condi-
tions. In recent years, a variety of cheap inorganic iodonium
donating reagents have been applied for the non-catalytic oxi-
dative halogenation of arenes, such as iodineenitrogen dioxide,16
I2/Na2S2O8,17 I2/(NH4)2S2O8,18 KI/oxone,19 NaI/NaOCl,20 KI/KO3,21
and NH4I/H2O2.22 However, these reagents have not been
widely applied for Pd-catalyzed CeH iodination. We first
attempted Pd-catalyzed iodinations of 1 with I2/K2S2O8 or NaI/
A
K2S2O8 at 110 ꢀC, which provided trace amount of the ortho-
23
iodinated product 2 (entries 6 and 7). Interestingly, KIO3
/
24
K2S2O8 afforded 2 in much greater yield; n-BuOH gave notably
better results than other solvents (entry 8). Reaction of 1 with
KIO3 alone did not yield 2 (entry 9). Addition of 1.5 equiv of NaI to
KIO3/K2S2O8 dramatically decreased the yield of 2 (entry 10). No
formation of 2 was observed in the absence of Pd(OAc)2 or K2S2O8
(entries 11, 12).
Scheme 1. PA-directed halogenation of ortho CeH bonds of benzylamines.
2. Results and discussion
The substrate scope of this Pd-catalyzed PA-directed ortho
iodination with KIO3/K2S2O8 (conditions A) was examined next
(Scheme 2). In general, electron-rich arenes were more reactive
and gave higher iodination yields than electron-poor substrates.
It should be noted that electron-poor substrates (see 6 and 9) are
usually unreactive under the typical SEAr halogenation condi-
tions. The Pd-catalyzed iodinations were generally clean and
contained only product and unreacted starting material. Halo-
genation of the PA directing group was not observed presumably
due to the electron-deficiency of the pyridine ring. Reactions of
benzylamines bearing 2 equiv ortho CeH bonds gave a mixture of
mono and di-iodinated products (see 4). Similar to our previously
reported PA-directed ortho CeH functionalization of benzyl-
amines, less hindered ortho CeH positions were selectively io-
dinated (see 5 and 7). Iodination of a naphthalene substrate
selectively occurred at the 2 position to give 8, illustrating the
favorability of five-membered palladacycle intermediate over
larger metallacycle.
Our previous studies have shown that the ortho CeH bonds of
benzyl picolinamides can be readily transformed into various car-
bonecarbon and carboneheteroatom bonds under Pd-catalyzed
conditions.11 Encouraged by these earlier successes, we antici-
pated that Pd-catalyzed CeH functionalization of benzyl picolina-
mides with halides under suitable oxidative conditions would give
ortho halogenated products through the similar catalytic manifold.
However, unlike Pd-catalyzed ortho CeC bond forming reactions,
halogenation via non-directed SEAr pathways often undermines
regio-control due to the involvement of highly reactive halonium
ion intermediates. We commenced our study with the Pd-catalyzed
ortho iodination of electron-rich 2-methoxybenzyl picolinamide 1
(Table 1). As shown in entry 1 of Table 1, iodination of 1 under our
Table 1
Ortho CeH iodination of benzylamine 1
Entry Reagents (equiv)
Solvents/
temp (ꢀC) time/h
Yield (%)a
2
3
1
2
3
4
5
6
7
8
NIS (1.1), HBF4OEt2 (3)
NIS (1.5)
Pd, NIS (1.5)
Pd, NIS (1.5)
Pd, I2 (1.5), PIDA (1.5) NaHCO3 (1) DMF 120/24
Pd, I2 (1.5) K2S2O8 (1.5)
Pd, NaI (1.5) K2S2O8 (2)
Pd KIO3 (2), K2S2O8 (2)
Pd KIO3 (2)
Pd, NaI (1.5) KIO3 (2), K2S2O8 (2)
Pd, NaI (1.5) KIO3 (2)
KIO3 (2), K2S2O8 (2)
TFA/DCM (1/9) 0/4 <4
TFA/DCM (1/9) 0/4 <4
60
27
63
<2
18
<2
<2
CH3CN 110/24
28
ClePh 110/24
91
<2
<2
<2
n-BuOH 120/24
n-BuOH 120/24
n-BuOH 120/24
n-BuOH 120/24
n-BuOH 120/24
n-BuOH 120/24
n-BuOH 120/24
85 (80)b <2
9
<2
<2
<2
<2
<2
<2
<2
<2
10
11
12
TFA: trifluoroacetic acid, DCM: dichloromethane, DMF: dimethylformamide. PIDA:
phenyliodine diacetate.
a
Yields are based on 1H NMR analysis of screening reactions on a 0.2 mmol scale
under Ar.
b
Isolated yield.
Scheme 2. Substrate scope of PA-directed ortho iodination of benzylamines.

C. Lu et al. / Tetrahedron 70 (2014) 4197e4203
4199
Encouraged by the success of the PA-directed ortho iodination
reaction, we next explored Pd-catalyzed ortho CeH bromination of
benzylamines (Table 2). SEAr bromination of 1 under the NBS-
mediated conditions in TFA/DCM predominantly gave the non-
directed bromination product 11 (entries 1, 2). Unlike iodination,
Pd-catalyzed bromination of 1 using 10 mol % of Pd(OAc)2 and
1.5 equiv of NBS in ClePh at 110 ꢀC gave the non-directed 11 in 28%
yield (entry 3). Pd-catalyzed bromination of 1 with Cu(OAc)2/CuBr2
gave little product (entry 4). Finally, we found that Pd-catalyzed
bromination of 1 with KBrO3/K2S2O8 gave the ortho-directed
product 10 in 84% yield (entry 5).25 In contrast with the iodin-
ation reaction, addition of 1.5 equiv of NaBr further improved the
bromination yield (entry 9). No bromination occurred in the ab-
sence of either K2S2O8 or Pd (entries 9, 12).
directed product 13 (entries 3, 4). Pd-catalyzed chlorination with
chloramine-T, Cu(OAc)2/CuCl2, or CaCl2/K2S2O8 gave poor results
(entries 5e7). To our delight, Pd-catalyzed chlorination using
a combination of NaClO3/K2S2O8 in n-BuOH at 110 ꢀC gave the
ortho-directed product 12 in significantly improved yield (entry
8).26 An 80% isolated yield was obtained when 1.5 equiv of NaCl,
1.5 equiv of NaClO3, and 2 equiv of K2S2O8 were used (entry 9). No
ortho CeH chlorination occurred in the absence of Pd (entry 12).
Next, we examined the substrate scope of Pd-catalyzed PA-di-
rected ortho CeH bromination and chlorination under the standard
conditions B and C using NaX/K(Na)XO3/K2S2O8 (Scheme 3). We
observed patterns of reactivity and selectivity similar to the CeH
iodination reactions. The less hindered ortho CeH bonds of asym-
metric substrates are selectively halogenated under the standard
conditions (see 17 and 25). A variety of benzylamine products
carrying complex halogen substitution (e.g., 19 and 22) were ob-
tained from easily accessible starting materials.
Table 2
Ortho CeH bromination of benzylamine 1
Entry Reagents (equiv)
Solvents/temp (ꢀC)/ Yield (%)a
time (h)
10
11
1
2
NBS (1.1), HBF4OEt2 (3)
NBS (1.5)
TFA/DCM (1/9), 0/1 <2
TFA/DCM (1/9), 0/1 <2
53
70
3
4
5
6
7
8
Pd, NBS (1.5)
Pd, Cu(OAc)2 (1.5) CuBr2 (1.5)
Pd KBrO3 (1.5), K2S2O8 (2)
Pd, NaBr (0.5) KBrO3 (1.5), K2S2O8 (2) n-BuOH 100/24
Pd, NaBr (1) KBrO3 (1.5), K2S2O8 (2) n-BuOH 100/24
Pd, NaBr (1.5) KBrO3 (1.5), K2S2O8 (2) n-BuOH 100/24
ClePh 120/24
DCE 110/24
n-BuOH 100/24
<2
<2
84
90
91
28
<2
<2
<2
<2
95 (89)b <2
9
Pd, NaBr (1.5) KBrO3 (1.5)
Pd, NaBr (1.5) K2S2O8 (2)
Pd, KBr (1.5) KBrO3 (1.5), K2S2O8 (2) n-BuOH 100/24
NaBr (1.5) KBrO3 (1.5), K2S2O8 (2) n-BuOH 100/24
n-BuOH 100/24
n-BuOH 100/24
<2
<2
66
<2
<2
<2
<2
10
11
12
<2
a
Yields are based on 1H NMR analysis of reactions on a 0.2 mmol scale.
Isolated yield.
b
Next, we examined the ortho CeH chlorination of 1 (Table 3).
Only small amount of non-directed SEAr chlorination product 13
was formed under the NCS/HBF4-mediated conditions in TFA/DCM
(entry 1). Pd-catalyzed chlorination with NCS gave the non-
Table 3
Ortho CeH chlorination of benzylamine 1
Entry Reagents (equiv)
Solvents/temp (ꢀC)/ Yield (%)a
time (h)
Scheme 3. Substrate scope of PA-directed ortho-bromination and chlorination of
benzylamines.
12
13
1
2
3
4
5
6
7
8
NCS (1.1), HBF4OEt2 (3)
NCS (1.5)
Pd, NCS (1.5)
Pd, NCS (1.5)
Pd, Chloramine-T (1.5)
Pd, Cu(OAc)2 (2), CuCl2 (2)
Pd, CaCl2 (1.5), K2S2O8 (2)
Pd NaClO3 (1.5), K2S2O8 (2)
Pd, NaCl (1.5) NaClO3 (1.5), K2S2O8 (2) n-BuOH 110/24
Pd, NaCl (1.5) NaClO2 (1.5), K2S2O8 (2) n-BuOH 110/24
Pd, KCl (1.5), NaClO3 (1.5), K2S2O8 (2) n-BuOH 110/24
TFA/DCM (1/9) 0/1 <2
TFA/DCM (1/9) 0/1 <2
10
<2
6
71
<2
<2
<2
<2
ClePh 120/24
CH3CN 120/24
AcOH 120/24
DCE 110/24
AcOH 110/24
n-BuOH 110/24
<2
<2
<2
<2
9
These K(Na)XO3/K2S2O8-mediated halogenation reactions likely
share a similar catalytic cycle. First, CeH palladation forms PdII
palladacycle intermediates, then oxidative addition yields higher
valent palladium intermediates, and finally CeX reductive elimi-
nation forms the halogenated products. While a PdII/IV manifold has
been invoked to explain many Pd-catalyzed oxidative halogenation
systems, a catalytic manifold involving PdIII intermediates could
also be operative.18 The identity of the active halogenating and
oxidizing species is elusive due to the involvement of multiple re-
agents. The application of K2S2O8, which is the sole oxidant in
72
9
83 (80)b <2
10
11
12
35
75
<2
<2
<2
<2
NaCl (1.5) NaClO3 (1.5), K2S2O8 (2)
n-BuOH 110/24
a
Yields are based on 1H NMR analysis of reactions on a 0.2 mmol scale.
Isolated yield.
b

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C. Lu et al. / Tetrahedron 70 (2014) 4197e4203
several Pd-catalyzed CeH functionalization systems,24 is critical for
our halogenation reactions. We suspect that X2 is possibly formed
in situ, either from reaction of NaXO3 with NaX25,26 or from dis-
proportionation of K(Na)XO3, and plays a critical role in these re-
action systems. While Cl2, Br2, and I2 are known to oxidize
PdII,2,5b,12b they may also react with K2S2O8 to form new oxidative
halogenating species for these Pd-catalyzed reactions.17,18
(CDCl3, 75 MHz) d 164.5,158.0,150.6,148.5,137.7,130.0,129.2,126.7,
126.4, 122.7, 121.0, 110.8, 55.8, 39.5. HRMS calcd for C15H15N2O2
[MþHþ]: 255.1134, Found: 255.1116.
3.3. Standard procedure for the Pd-catalyzed ortho
CeH iodination reaction
The PA group of the halogenated products obtained above can
be removed under mild conditions (Scheme 4). For instance,
compound 5 was first reacted with Boc2O/DMAP at room temper-
ature to give N-Boc protected intermediate 26, which was depro-
tected with LiOH/H2O2 at room temperature to give Boc protected
benzylamine product 27 in good yield.11f
A mixture of picolinamide 1 (48 mg, 0.2 mmol, 1 equiv),
Pd(OAc)2 (4.4 mg, 0.02 mmol, 0.1 equiv), K2S2O8 (108 mg, 0.4 mmol,
2 equiv), and KIO3 (86 mg, 0.4 mmol, 2.0 equiv) in n-butanol (2 mL)
in a 10 mL glass vial (purged with Ar, sealed with PTFE cap) was
heated at 120 ꢀC for 24 h. The reaction mixture was filtered through
a pad of Celite and concentrated in vacuo. The resulting residue was
purified by silica-gel flash chromatography (hexanes/DCE 1:10) to
give product 2 as a pale solid (78 mg, 82%).
3.3.1. N-(2-Methoxy-6-iodo)-benzyl picolinamide (2). 1H NMR
(300 MHz, CDC13)
d
8.51 (d, J¼4.0 Hz, 1H), 8.23 (br, 2H), 7.85
(t, J¼7.8 Hz, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.40e7.38 (m, 1H), 6.97
(t, J¼8.0 Hz, 1H), 6.88 (d, J¼7.7 Hz, 1H), 4.88 (d, J¼5.6 Hz, 2H), 3.87
(s, 3H); 13C NMR (75 MHz, CDCl3)
d 164.1, 158.7, 150.4, 148.4, 137.6,
Scheme 4. Removal of the PA group.
132.1, 130.8, 129.5, 126.4, 122.6, 111.2, 102.1, 56.4, 43.9. HRMS calcd
for: C14H14IN2O2 [MþHþ]: 369.0100, Found: 369.0101.
In summary, we have developed a new set of methods to ha-
logenate the ortho CeH bonds of N-benzyl picolinamides under
palladium-catalyzed conditions. These reactions feature the use of
a unique combination of K(Na)XO3 and K2S2O8 reagents, which can
enable the installation of iodo, bromo, and chloro groups on the
ortho position of benzylamines in a unified fashion. A variety of
benzylamine products bearing complex halogen substitution can
be quickly prepared from much simpler precursors in good yield
and selectivity.
3.3.2. N-(2-Methoxy-5-iodo)-benzyl picolinamide (3). 1H NMR
(300 MHz, CDC13)
d
8.55 (d, J¼4.2 Hz, 1H), 8.42 (br, 1H), 8.21
(d, J¼7.8 Hz, 1H), 7.87e7.82 (m, 1H), 7.60 (d, J¼2.1 Hz, 1H), 7.54
(dd, J¼2.4, 8.7 Hz,1H), 7.44e7.40 (m,1H), 6.65 (d, J¼8.7 Hz,1H), 4.61
(d, J¼6.3 Hz, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 162.7,
157.9, 138.1, 137.8, 137.7, 129.1, 126.5, 122.8, 113.0, 83.1, 55.9, 38.7
HRMS calcd for: C14H14IN2O2 [MþHþ]: 369.0100, Found: 369.0110.
3.3.3. N-(2-Iodo)-benzyl picolinamide (4). 1H NMR (300 MHz,
3. Experimental sections
3.1. General conditions
CDC13)
d
8.56 (br, 2H), 8.22 (d, J¼7.8 Hz, 2H), 7.86e7.83 (m, 2H),
7.45e7.43 (m, 2H), 7.32 (t, J¼7.5 Hz, 1H), 6.98 (t, J¼3.5 Hz, 1H), 4.70
(d, J¼6.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 162.7, 150.1, 148.6,
140.8, 139.9, 137.8, 129.9, 129.7, 129.0, 126.70, 122.8, 99.5, 48.6.
HRMS calcd for: C13H12IN2O [MþHþ]: 338.9994, Found: 339.0001.
All commercial materials were used as received unless other-
wise noted. All solvents were obtained from a JC Meyer solvent
dispensing system and used without further purification. Flash
chromatography was performed using 230e400 mesh SiliaFlash
60Ò silica gel (Silicycle Inc.). PhI(OAc)2 (98%, Aldrich), Pd(OAc)2
(98%, Aldrich) were used in the Pd-catalyzed reactions. NMR
spectra were recorded on Bruker CDPX-300, DPX-300, DPX-400
instruments, and calibrated by using residual solvent peaks as the
internal reference. Multiplicities are recorded as: s¼singlet,
d¼doublet, t¼triplet, dd¼doublet of doublets, m¼multiplet. High-
resolution ESI mass experiments were operated on a Waters LCT
Premier instrument.
3.3.4. N-(2,6-Diiodo)-benzyl picolinamide (4d). 1H NMR (300 MHz,
CDC13)
d
8.54 (d, J¼4.2 Hz, 1H), 8.25 (d, J¼7.8 Hz, 1H), 8.19 (br, 1H),
7.90e7.82 (m, 3H), 7.44e7.40 (m, 1H), 6.34 (t, J¼7.8 Hz, 1H), 5.06
(d, J¼5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 148.5, 143.6, 141.9,
141.7, 139.2, 131.6, 126.6, 122.8, 100.5, 54.8. HRMS calcd for:
C
13H11I2N2O [MþHþ]: 464.8961, Found: 464.8995.
3.3.5. N-(2-Iodo-5-bromo)-benzyl picolinamide (5). 1H NMR
(300 MHz, CDC13)
d
8.56e8.55 (br, 2H), 8.20 (d, J¼7.8 Hz, 1H),
7.88e7.82 (m, 1H), 7.66 (d, J¼8.1 Hz, 1H), 7.51 (s, 1H), 7.46e7.41
(m, 1H), 7.10 (dd, J¼2.1, 8.4 Hz, 1H), 4.64 (d, J¼6.3 Hz, 2H); 13C NMR
3.2. Standard procedure for the preparation of N-benzyl
(75 MHz, CDCl3) d 164.7,149.8,148.6,142.8,141.0,137.8,132.7,132.4,
picolinamide11f
126.8, 123.3, 122.8, 97.1, 48.2. HRMS calcd for: C13H11BrIN2O
[MþHþ]: 416.9099, Found: 418.9100.
2-Methoxybenzylamine (0.68 g, 5 mmol), 2-picolinic acid
(0.74 g, 6 mmol), EDCI (1.16 g, 6 mmol), HOBt (0.92 g, 6 mmol), and
DIPEA (2.2 mL, 13 mmol) were dissolved in 20 mL of anhydrous
DMF. The mixture was stirred at room temperature for 24 h. 200 mL
water was then added to quench the reaction and the mixture was
extracted with EtOAc. The combined organic layers was washed
with H2O and brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The residue was purified by silica-gel flash chro-
matography (EtOAc/Hex: 1/15) to give the desired product 1 (1.10 g,
3.3.6. N-(2-Trifluoromethyl-6-iodo)-benzyl picolinamide (6). 1H
NMR (300 MHz, CDC13)
d
8.50 (d, J¼4.8 Hz, 1H), 8.24 (d, J¼7.8 Hz,
1H), 8.12 (d, J¼7.8 Hz, 1H), 8.01 (br, 1H), 7.88e7.82 (m, 1H), 7.72
(d, J¼8.1 Hz), 7.43e7.39 (m, 1H), 7.14 (t, J¼7.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3)
d 164.0, 149.9, 148.5, 144.5, 138.3, 137.8, 130.0,
126.9, 126.8, 126.7, 122.8, 104.48, 45.7. HRMS calcd for:
C
14H11F3IN2O [MþHþ]: 406.9868, Found: 406.9886.
90%). 1H NMR (CDCl3, 400 MHz)
d
8.57e8.54 (m, 1H), 8.47 (br, 1H),
3.3.7. N-(3-Methoxy-6-iodo)-benzyl picolinamide (7). 1H NMR
(300 MHz, CDC13)
8.23 (dd, J¼0.8, 7.8 Hz,1H), 7.85 (td, J¼7.7, 2.0 Hz, 1H), 7.43e7.39 (m,
1H), 7.37 (dd, J¼1.2, 7.4 Hz, 1H), 7.28 (td, J¼9.5, 1.5 Hz, 1H),
6.96e6.91 (m, 2H), 4.69 (d, J¼6.2 Hz, 2H), 3.9 (s, 3H); 13C NMR
d
8.56e8.54 (br, 2H), 8.22 (d, J¼7.8 Hz, 1H),
7.87e7.82 (m, 1H), 7.69 (d, J¼8.4 Hz, 1H), 7.45e7.43 (m, 1H), 7.01
(d, J¼2.8 Hz, 1H), 6.58 (dd, J¼3.0, 8.7 Hz, 1H), 4.65 (d, J¼6.3 Hz, 2H),

C. Lu et al. / Tetrahedron 70 (2014) 4197e4203
4201
3.76 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
164.6, 160.6, 150.1, 148.6,
(d, J¼5.7 Hz, 2H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
164.1,
141.8, 140.3, 138.8, 126.73, 122.8, 116.0, 115.5, 87.6, 55.8, 48.5; HRMS
158.7, 150.4, 148.4, 137.6, 132.1, 130.8, 129.5, 126.4, 122.7, 111.2, 102.1,
56.4, 43.9, 30.1. HRMS calcd for: C14H14ClN2O2 [MþHþ]: 277.0744,
Found: 277.0745.
calcd for: C14H14IN2O2 [MþHþ]: 369.0100, Found: 369.0110.
3.3.8. N-(1-(2-Iodo)-naphthyl)-methyl picolinamide (8). 1H NMR
(300 MHz, CDC13)
d
8.45 (d, J¼3.9 Hz, 1H), 8.33e8.24 (m, 3H),
3.5.2. N-(2-Methoxy-5-chloro)-benzyl picolinamide (13). 1H NMR
7.92e7.80 (m, 3H), 7.58e7.48 (m, 3H), 7.39e7.36 (m, 1H), 5.34
(300 MHz, CDC13)
d
8.52 (d, J¼4.2 Hz, 1H), 8.45 (br, 1H), 7.82e7.79
(d, J¼5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d
164.2, 150.0, 148.5,
(m, 1H), 7.41e4.39 (m, 1H), 7.29 (s, 1H), 7.17 (dd, J¼2.4, 8.7 Hz, 1H),
137.7, 136.9, 136.4, 133.8, 133.0, 130.6, 129.0, 128.2, 127.0, 126.6,
125.1, 122.8, 101.3, 46.1. HRMS calcd for: C17H14IN2O [MþHþ]:
389.0151, Found: 389.0164.
6.77 (d, J¼8.7 Hz, 1H), 4.61 (d, J¼6.3 Hz, 2H), 3.84 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d 164.6, 156.5, 150.2, 148.5, 137.7, 129.4, 128.5,
128.5, 126.5, 125.8, 122.7, 111.8, 56.1, 38.8. HRMS calcd for:
C
14H14ClN2O2 [MþHþ]: 277.0744, Found: 276.7182.
3.3.9. N-(2-Nitro-6-iodo)-benzyl
(300 MHz CDC13) 8.52e8.51 (br, 2H), 7.18e7.10 (m, 2H), 7.84e7.79
(m, 2H), 7.42e7.38 (m, 1H), 7.15 (t, J¼7.8 Hz, 1H), 3.93 (d, J¼6 Hz,
2H); 13C NMR (75 MHz, CDCl3)
164.46, 151.5, 149.7, 148.6, 144.7,
picolinamide
(9). 1H
NMR
d
3.5.3. N-(2-Bromo)-benzyl picolinamide (14). 1H NMR (300 MHz,
CDC13)
d
8.56e8.54 (br, 2H), 8.21 (d, J¼7.8 Hz, 1H), 7.88e7.82
d
(m, 1H), 7.56 (d, J¼7.8 Hz, 1H), 7.48e7.41 (m, 2H), 7.30e7.26 (m, 1H),
137.7, 134.6, 130.4, 126.8, 124.9, 122.8, 103.3, 45.5. HRMS calcd for
7.14 (td, J¼1.5, 7.8 Hz, 1H), 4.75 (d, J¼6.3 Hz, 2H); 13C NMR (75 MHz,
C
13H11IN3O3 [MþHþ]: 383.9845, Found: 383.9859.
CDCl3) d 164.7, 150.1, 148.6, 137.8, 137.7, 133.2, 130.5, 129.5, 128.1,
126.7, 124.2, 122.7, 44.1. HRMS calcd for C13H12BrN2O [MþHþ]:
3.4. Standard procedure for the Pd-catalyzed ortho CeH
291.0133, Found: 291.0129.
bromination reaction
3.5.4. N-(2,6-Dibromo)-benzyl
(300 MHz, CDC13)
picolinamide
8.52 (d, J¼3.9 Hz, 1H), 8.31 (br, 1H), 8.23
(14d). 1H
NMR
A mixture of picolinamide 1 (48 mg, 0.2 mmol, 1 equiv),
Pd(OAc)2 (4.4 mg, 0.01 mmol, 0.05 equiv), K2S2O8 (108 mg,
0.4 mmol, 2 equiv), KBrO3 (50 mg, 0.3 mmol, 1.5 equiv), and NaBr
(31 mg, 0.3 mmol, 1.5 equiv) in n-butanol (2 mL) in a 10 mL glass
vial (purged with Ar, sealed with PTFE cap) was heated at 100 ꢀC for
24 h. The reaction mixture was filtered through a short pad of Celite
and concentrated in vacuo. The resulting residue was purified by
silica-gel flash chromatography (hexanes/DCE 1:10) to give the
product 10 as a pale white solid (57 mg, 89%).
d
(d, J¼7.8 Hz,1H), 7.87e7.81 (m, 1H), 7.56 (d, J¼8.1 Hz, 2H), 7.43e7.41
(m, 1H), 7.03 (t, J¼8.1 Hz, 1H), 5.03 (d, J¼5.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 164.2, 150.1, 148.6, 137.7, 136.7, 133.0, 130.8, 128.1,
126.7, 126.6, 122.8, 45.03. HRMS calcd for C13H11Br2N2O [MþHþ]:
368.9238, Found: 368.9247.
3.5.5. N-(2-Methyl-6-bromo)-benzyl picolinamide (15). 1H NMR
(300 MHz, CDC13)
d
8.52 (d, J¼3.6 Hz, 1H), 8.23e8.20 (br, 2H),
7.86e7.81 (m, 1H), 7.72 (d, J¼7.8 Hz, 1H), 7.42e4.38 (m, 1H), 7.16
(d, J¼7.2 Hz, 1H), 6.89 (t, J¼7.2 Hz, 1H), 4.84 (d, J¼7.2 Hz, 2H), 2.52
3.4.1. N-(2-Methoxy-6-bromo)-benzyl picolinamide (10). 1H NMR
(300 MHz CDC13)
d
8.50 (d, J¼4.2 Hz, 1H), 8.27 (br, 1H), 8.22
(s, 3H); 13C NMR (75 MHz, CDCl3)
d 164.3, 150.1, 148.5, 140.3, 137.7,
(d, J¼7.8 Hz, 1H), 7.84e7.79 (m, 1H), 7.40e7.36 (m, 1H), 7.20e7.10
135.7, 131.1, 130.3, 129.6, 126.5, 126.4, 122.6, 41.3, 21.0. HRMS calcd
(m, 2H), 6.85 (d, J¼7.8 Hz, 1H), 4.88 (d, J¼5.7 Hz, 2H); 13C NMR
for: C14H14BrN2O [MþHþ]: 305.0290, Found: 305.0291.
(75 MHz, CDCl3) d 164.1,159.5,150.4,148.4,137.6,130.2,126.4,126.2,
125.4, 122.7, 110.27, 56.5, 38.8, 30.1. HRMS calcd for: C14H14BrN2O2
3.5.6. N-(2-Bromo-6-fluoro)-benzyl picolinamide (16). 1H NMR
[MþHþ]: 321.0239, Found: 321.0236.
(300 MHz, CDC13)
d
8.52 (d, J¼4.5 Hz, 1H), 8.36 (br, 1H), 8.21
(d, J¼8.1 Hz, 1H), 7.86e7.80 (m, 1H), 7.43e7.38 (m, 2H), 7.16
3.4.2. N-(2-Methoxy-5-bromo)-benzyl picolinamide (11). 1H NMR
(q, J¼7.2 Hz, 1H), 7.06 (t, J¼8.4 Hz, 1H), 4.86 (d, J¼5.7 Hz, 2H); 13C
(300 MHz, CDC13)
(m, 1H), 7.42e7.30 (m, 3H), 7.30 (d, J¼8.4 Hz, 1H), 4.61 (d, J¼6.3 Hz,
2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3)
164.6, 157.0, 150.3,
d
8.52 (d, J¼3.9 Hz, 1H), 8.44 (br, 1H), 7.84e7.79
NMR (75 MHz, CDCl3) d 164.3, 150.1, 148.5, 137.7, 130.7, 130.5, 129.1,
129.1, 126.6, 122.82, 115.6, 115.3. HRMS calcd for: C13H11BrFN2O
d
[MþHþ]: 309.0039, Found: 309.0045.
148.5, 137.7, 132.3, 131.7, 129.0, 126.6, 122.7, 113.1, 112.4, 56.1, 38.8.
HRMS calcd for:
321.0240.
C
14H14BrN2O2 [MþHþ]: 321.0239, Found:
3.5.7. N-(2-Bromo-5-methoxy)-benzyl picolinamide (17). 1H NMR
(300 MHz, CDC13)
d
8.55e8.51 (br, 2H), 8.21 (d, J¼7.8 Hz, 1H),
7.87e7.81 (m, 1H), 7.45e7.40 (m, 2H), 7.00 (d, J¼3.0 Hz, 1H), 6.69
3.5. Standard procedure for the Pd-catalyzed ortho CeH
chlorination reaction
(dd, J¼3.0, 8.7 Hz, 1H), 4.70 (d, J¼7.2 Hz, 2H), 3.75 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 164.7, 259.5,150.1,148.6,138.6,137.8,133.8,126.7,
122.8, 116.2, 115.09, 114.4, 55.9, 44.2. HRMS calcd for: C14H14BrN2O2
A mixture of picolinamide 1 (48 mg, 0.2 mmol, 1 equiv),
Pd(OAc)2 (4.4 mg, 0.01 mmol, 0.05 equiv), K2S2O8 (108 mg,
0.4 mmol, 2 equiv), NaClO3 (32 mg, 0.3 mmol, 1.5 equiv), and
NaCl (18 mg, 0.3 mmol, 1.5 equiv) in n-butanol (2 mL) in a 10 mL
glass vial (purged with Ar, sealed with PTFE cap) was heated at
100 ꢀC for 24 h. The reaction mixture was filtered through
a short pad of Celite and concentrated in vacuo. The resulting
residue was purified by silica-gel flash chromatography (hex-
anes/DCE 1:10) to give the product 12 as a pale white solid
(57 mg, 80%).
[MþHþ]: 321.0239, Found: 321.0238.
3.5.8. N-(1-(2-Bromo)-naphthyl)-methyl picolinamide (18). 1H NMR
(300 MHz, CDC13)
d
8.44 (d, J¼5.2 Hz, 1H), 8.34 (d, J¼8.1 Hz, 1H),
8.25 (d, J¼7.8 Hz, 1H), 7.85e7.80 (m, 2H), 7.70e7.63 (m, 2H), 7.60
(t, J¼7.2 Hz, 1H), 7.50 (t, J¼7.2 Hz, 1H), 7.38e7.34 (m, 1H), 5.32
(d, J¼5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 164.3, 150.0, 148.5,
137.7, 133.4, 133.2, 133.0, 130.4, 129.0, 128.2, 126.7, 124.9, 124.5,
122.8, 40.7. HRMS calcd for: C17H14BrN2O [MþHþ]: 341.0290,
Found: 341.0296.
3.5.1. N-(2-Methoxy-6-chloro)-benzyl picolinamide (12). 1H NMR
3.5.9. N-(3,6-Dibromo)-benzyl
picolinamide
(19). 1H
NMR
(300 MHz, CDC13)
(d, J¼7.8 Hz, 1H), 7.81 (t, J¼7.2 Hz, 1H), 7.39e7.36 (m, 1H), 7.19
(t, J¼8.1 Hz, 1H), 7.00 (d, J¼7.8 Hz, 1H), 6.81 (d, J¼8.4 Hz, 1H), 4.87
d
8.50 (d, J¼3.9 Hz, 1H), 8.23 (br, 1H), 8.21
(300 MHz, CDC13)
d
8.61e8.56 (br, 2H), 8.25 (d, J¼7.8 Hz, 1H),
7.93e7.88 (m, 1H), 7.59 (d, J¼2.1 Hz, 1H), 7.51e7.45 (m, 2H), 7.32 (m,
1H), 4.74 (d, J¼6.3 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 149.9, 148.7,

4202
C. Lu et al. / Tetrahedron 70 (2014) 4197e4203
139.8,137.9,134.6,133.0,132.5,126.9,122.9,122.6,122.0,110.0, 43.8.
126.1, 123.5, 123.5, 95.5, 84.1, 53.9, 27.7. HRMS calcd for:
C
HRMS calcd for C13H11Br2N2O [MþHþ]: 368.9238, Found: 368.9250.
18H19BrIN2O3 [MþHþ]: 516.9624, Found: 516.9664.
Step b: Boc protected picolinamide 26 (41 mg, 0.08 mmol,
3.5.10. N-(2-Chloro)-benzyl picolinamide (20). 1H NMR (300 MHz,
1 equiv) was dissolved in 1 mL of THF/H2O (4:1) at 0 ꢀC. LiOH$H2O
CDC13)
d
8.55 (d, J¼6.4 Hz, 1H), 8.50 (br, 1H), 8.21 (d, J¼7.8 Hz, 1H),
(13 mg, 0.25 mmol), 30% H2O2 (55 mL, 0.4 mmol) were added. Re-
7.88e7.82 (m, 1H), 7.48e7.37 (m, 3H), 7.26e7.21 (m, 2H), 7.70
action was stirred at room temperature for 6 h. The reaction mix-
ture was filtered through a short pad of Celite and concentrated in
vacuo. The resulting residue was purified by silica-gel flash chro-
matography (hexanes/EtOAc: 20:1) to give the product 27 as
a white solid (18.8 mg, 57%).
(d, J¼5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 164.7, 150.1, 148.5,
137.8, 136.0, 134.1, 130.4, 129.9, 129.3, 127.5, 126.7, 122.7, 41.7. HRMS
calcd for C13H12ClN2O [MþHþ]: 247.0638, Found: 247.0627.
3.5.11. N-(2-Methyl-6-chloro)-benzyl picolinamide (21). 1H NMR
(300 MHz, CDC13)
d
8.52 (d, J¼4.5 Hz, 1H), 8.33 (br, 1H), 8.23
3.6.2. Boc-N-(2-iodo-5-bromo)-benzylamine
(300 MHz, CDC13)
7.54 (d, J¼8.4 Hz,1H), 7.45 (d, J¼2.1 Hz,1H), 7.10
(dd, J¼2.1, 8.4 Hz, 1H), 5.03 (br, 2H), 4.28 (d, J¼8.0 Hz, 2H), 1.46
(27). 1H
NMR
(d, J¼7.8 Hz, 1H), 7.87e7.82 (m, 1H), 7.43e7.39 (m, 1H), 7.27
(d, J¼6.9 Hz, 1H), 7.18e7.10 (m, 2H), 4.85 (d, J¼5.7 Hz, 2H), 2.54
d
(s, 3H); 13C NMR (75 MHz, CDCl3)
d
164.4, 150.2, 148.5, 140.2, 137.8,
(s, 9H); 13C NMR (75 MHz, CDCl3)
d 143.5, 141.0, 132.5, 131.9, 96.6,
135.9, 134.2, 129.7, 129.2, 127.8, 126.6, 122.7, 38.8, 20.7. HRMS calcd
49.3, 28.8. HRMS calcd for: C12H16BrINO2 [MþHþ]: 411.9409,
for: C14H14ClN2O [MþHþ]: 261.0795, Found: 261.0790.
Found: 411.9415.
3.5.12. N-(2-Fluoro-6-chloro)-benzyl picolinamide (22). 1H NMR
Acknowledgements
(300 MHz, CDC13)
d
8.15 (d, J¼4.2 Hz, 1H), 8.35 (br, 1H), 8.20
(d, J¼7.5 Hz, 1H), 7.84e7.79 (m, 1H), 7.41e7.37 (m, 1H), 7.23e7.20
We gratefully thank The Pennsylvania State University and the
NSF (CAREER CHE-1055795) for financial support of this work. G.C.
is an Amgen Young Investigator.
(m, 2H), 7.04e6.98 (m, 1H), 4.84 (d, J¼5.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 164.3, 163.7, 160.4, 150.0, 148.4, 137.7, 136.1, 136.1,
130.1, 126.6, 125.8, 125.8, 122.7, 114.9, 114.6, 35.1, 35.1. HRMS calcd
for C13H11ClFN2O [MþHþ]: 265.0544, Found: 265.0538.
Supplementary data
3.5.13. N-(2,6-Dichloro)-benzyl
picolinamide
(23). 1H
NMR
1H and 13C NMR spectra for all new compounds are available.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.070.
(300 MHz, CDC13) 8.52 (d, J¼4.5 Hz, 1H), 8.32 (br, 1H), 8.22
(d, J¼7.8 Hz, 1H), 7.86e7.81 (m, 1H), 7.42e7.39 (m, 1H), 7.33
(d, J¼8.1 Hz, 2H), 7.18 (t, J¼7.8 Hz, 1H), 4.99 (d, J¼6.0 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 164.2, 150.0, 148.4, 137.7, 136.7, 133.9, 130.0,
128.9, 126.6, 122.8, 39.52. HRMS calcd for C13H11Cl2N2O [MþHþ]:
References and notes
281.0248, Found: 281.0244.
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2523; (c) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006,
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4. Wan, X. B.; Ma, Z. X.; Li, B. J.; Zhang, K. Y.; Cao, S. K.; Zhang, S. W.; Shi, Z. J. J. Am.
Chem. Soc. 2006, 128, 7416.
3.5.14. N-(1-(2-Chloro)-naphthyl)-methyl picolinamide (24). 1H
NMR (300 MHz, CDC13)
d
8.43 (d, J¼3.9 Hz, 1H), 8.32 (d, J¼8.1 Hz,
2H), 8.24 (d, J¼7.5 Hz, 1H), 7.83e7.74 (m, 3H), 7.59 (t, J¼7.8 Hz, 1H),
7.51e7.47 (m, 2H), 7.38e7.34 (m, 1H), 5.30 (d, J¼5.7 Hz); 13C NMR
(75 MHz, CDCl3) d 164.3, 150.0,148.4,137.7, 133.5, 133.2, 132.8,131.0,
130.2, 128.9, 128.18, 127.5, 126.5, 126.5, 124.6, 122.7, 37.7. HRMS
calcd for: C17H14ClN2O [MþHþ]: 297.0795, Found: 297.0789.
3.5.15. N-(2-Chloro-4-bromo)-benzyl picolinamide (25). 1H NMR
5. (a) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452; (b) Chu, L.;
Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135,
16344.
(300 MHz, CDC13)
d
8.56e8.52 (br, 2H), 8.21 (d, J¼7.8 Hz, 1H),
7.88e7.83 (m, 1H), 7.55 (s, 1H), 7.46e7.42 (m, 1H), 7.33 (d, J¼8.1 Hz,
6. Sun, X. Y.; Shan, G.; Sun, Y. H.; Rao, Y. Angew. Chem., Int. Ed. 2013, 52, 4440.
7. For other representative Pd-catalyzed CeH halogenations: (a) Mei, T. S.; Giri, R.;
Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215; (b) Zhao, X.;
1H), 7.23 (d, J¼8.4 Hz, 1H), 4.72 (d, J¼6.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3)
d 164.8, 149.8, 148.6, 138.1, 137.8, 132.9, 132.8, 132.2, 131.3,
ꢀ
126.8, 122.8, 121.16. HRMS calcd for: C13H11BrClN2O [MþHþ]:
Dimitrijevic, E.; Dong, V. J. Am. Chem. Soc. 2009, 131, 3466; (c) Kakiuchi, F.;
Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato, M.; Nishiyama, S.; Ta-
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Huang, C.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 8729; (e) Song, B.;
Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal. 2010, 352, 329; (f) Mei, T.-S.; Wang, D.-
H.; Yu, J.-Q. Org. Lett. 2010, 12, 3140; (g) Bedford, R. B.; Haddow, M. F.; Mitchell,
C. J.; Webster, R. L. Angew. Chem., Int. Ed. 2011, 50, 5524; (h) Wang, X.-C.; Hu, Y.;
Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 10326.
8. For representative CeH halogenations catalyzed by other metals: (a) Mo, F. Y.;
Yan, J. M.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J. B. Angew. Chem., Int. Ed. 2010, 49,
2028; (b) For an elegant work on Ru-catalyzed ortho bromination and iodin-
324.9743, Found: 324.9747.
3.6. Revomal of the picolinamide group
Step a: A mixture of picolinamide 3 (41.7 mg, 0.1 mmol, 1 equiv),
(Boc)2O (43.6 mg, 0.2 mmol, 2 equiv), and DMAP (2.5 mg,
0.02 mmol, 0.2 equiv) in anhydrous MeCN (0.3 mL) in a 10 mL glass
vial was stirred at room temperature for 12 h. The reaction mixture
was diluted with dichloromethane, filtered through a short pad of
Celite, and concentrated in vacuo. The resulting residue was puri-
fied by silica-gel flash chromatography (hexanes/EtOAc 10:1) to
give the Boc protected product 26 as a white solid (45.5 mg, 88%).
€
ation of arenes under mild conditions: Schroder, N.; Wencel-Delord, J.; Glorius,
F. J. Am. Chem. Soc. 2012, 134, 8298.
9. (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306; (b) Snieckus, V. Chem. Rev.
1990, 90, 879.
10. For selected reviews on Pd-catalyzed directed CeH functionalizations: (a) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (b)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
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Org. Lett. 2011, 13, 4850; (c) He, G.; Zhao, Y.; Zhang, S.-Y.; Lu, C.; Chen, G. J. Am.
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3.6.1. N-Boc-N-(2-iodo-5-bromo)-benzyl picolinamide (26). 1H NMR
(300 MHz, CDC13)
d
8.64 (d, J¼4.5 Hz, 1H), 7.86e7.81 (m, 1H), 7.77
(d, J¼7.8 Hz, 1H), 7.68e7.62 (m, 2H), 7.45e7.41 (m, 1H), 7.08
(dd, J¼2.1, 8.1 Hz, 1H), 4.96 (s, 2H), 1.16 (s, 9H); 13C NMR (75 MHz,
CDCl3)
d 172.0, 154.3, 153.3, 148.7, 141.9, 140.9, 137.4, 132.2, 129.9,

C. Lu et al. / Tetrahedron 70 (2014) 4197e4203
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