Palladium catalyzed acetoxylation of benzylic C-H bonds using a bidentate picolinamide directing group

Article abstract of DOI:10.1039/c3ob42196a

A general palladium catalyzed acetoxylation of benzylic C-H bonds has been developed. Picolinamides serve as an excellent directing group for the C-H activation of benzylic methyls. A wide range of 2-amino benzyl alcohol analogues were synthesized in good yields. The products demonstrated broad synthetic utilities toward various benzo-fused heterocycles. Mechanistic studies revealed the key rate-limiting C-H insertion step, which could be affected by the substitution pattern of the parent arene.

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Palladium catalysed oxygenation of inert benzylic C-H bonds offers a straightforward entry to heterocycle
synthesis
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Palladium Catalyzed Acetoxylation of Benzylic C-H
Bonds Using a Bidentate Picolinamide Directing
Group
Tao Cheng,a Weiyu Yin,a Yi Zhang,a Yingnan Zhangb and Yong Huanga,*
A general palladium catalyzed acetoxylation of benzylic C-H bonds has been developed.
Picolinamides serve as an excellent directing group for the C-H activation of benzylic methyls.
A wide scope of 2-amino benzyl alcohol analogues were synthesized in good yields. The
products demonstrated broad synthetic utilities toward various benzo- fused heterocycles.
Mechanistic studies revealed the key rate-limiting C-H insertion step, which could be affected
by the substitution pattern of the parent arene.
Introduction
Transition metal catalyzed selective C-H bond activation
reactions have mushroomed into one of the most actively
studied areas for creating carbon-carbon and carbon-heteroatom
bonds for the past decade.1 While the major effort was devoted
to develop novel directing groups and bond formation reactions
surrounding sp2 C-H bonds, functionalization of sp3 C-H bonds
have also enjoyed impressive progress.2 In particular, various
directing groups have been invented to selectively convert a sp3
C-H to a C-O functionality for a wide spectrum of substrates.3
However, general approach for benzylic oxidation remains
scarce,4 despite the tremendous synthetic capability of
substituted benzyl alcohols, which are indispensable synthons
Scheme 1 Substrate design for benzylic acetoxylation using picolinamides as
the bidenate directing group
toward benzo-heterocycles. Herein, we report
a general
Results and discussion
protocol for benzylic acetoxylation via palladium catalyzed sp3
C-H activation for the synthesis of various 2-amino benzyl
acetates.
The substrates were readily available following literature
procedures from anilines and picolinic acid.10 Most commonly
used transition-metals for C-H activation failed to yield any
product, except palladium. We found that a combination of the
substrate (0.1 mmol, 1 equiv), 10% Pd(OAc)2 and PhI(OAc)2
Picolinamides were first introduced by Daugulis as a
powerful directing group for site selective C-H metallation
using palladium.5 Subsequently, a number of C-H bond
functionalization reactions were developed by various research
groups.6 In 2009, Liang, et al. reported an ortho- C-H
acetoxylation of benzyl amine derived picolinamides.7 A fused
[5,5]-palladacycle was believed to be the key intermediate for
the rate-limiting C-H insertion step. Following a Pd(II)-Pd(IV)-
Pd(II), oxidation-reductive elimination cycle, o-acetoxy benzyl
amine derivatives were synthesized in high yields.8 Inspired by
this result and related [5,5]-palladacycle reports,9 we decided to
move the substrate arene one bond closer to the NH of the
picolinamide, hoping selective benzylic activation would occur
in lieu of the ortho-aryl C-H functionalization (Scheme 1).
o
(0.2 mmol, 2 equiv) in DCE at 110 C for 24 h produced the
desired benzyl acetate in 40% yield. Encouraged by this result,
we surveyed other reaction parameters (Table 1, for the
comprehensive investigation of reaction parameters, see
supporting information). The highest conversion was observed
in toluene among the solvents examined. Various bases were
tested in an attempt to facilitate the chelation of the metal. No
improvement was observed. The reaction was sensitive to
reaction temperature. Decreasing from 110 C to 90 C led to
20% conversion after 24 hours. Further increasing temperature
resulted in substrate decomposition and attenuated yields.
Fortunately, the active catalyst species was quite robust at 110
o
o
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oC and prolonging reaction time to 2 days afforded 72% isomer of 1s reacted in similar rates. When a mixture of trans-
isolated yield.
and cis- isomers was used. The ratio of trans- and cis- products
was very close that of the starting material, indicating similar
reactivity for both isomers.
Table 1
Reaction condition survey for benzylic acetoxylation of
picolinamidesa
Table 2
Palladium-catalyzed acetoxylation of o-tolyl picolinamidesa
entry
1
substrate
product
yield (%)b
72
entry
1
2
3
4
5
6
7
8
cat.
solvent
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
DMF
PivOH
Toluene/HOAc
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
additive
--
--
--
--
--
--
--
conv. (%)b
N.R.
N.R.
N.R.
N.R.
N.R.
40
50
25
30
50
48
29
N.R.
N.R.
27
Fe(acac)3
Ni(acac)2
Cp(Ph3P)2RuCl
[RhCp*Cl2]2
Rh(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
2a
2b
2c
2d
2e
2f
2
3
4
5
6
69
70
82
83
84
--
--
--
9
10
11
12
13
14
15
16
17
Li2CO3
KF
KOH
KHCO3
Na2CO3
AgOAc
--
36
72c
a Reaction condition: 1a (22.6 mg, 0.1 mmol, 1 equiv), PhI(OAc)2 (64 mg,
0.2 mmol, 2 equiv), additive (0.1 mmol, 1 equiv.) and catalyst (0.01 mmol,
0.1 equiv) in a solvent (1 mL) under argon at 110 C for 24 h. b The
conversion was calculated by GC-MS using biphenyl as the internal standard.
c Isolated yield after 48 h.
With the optimized conditions in hand, the substrate scope
for benzylic oxidation was examined using various aniline
derivatives (Table 2). This method was broadly applicable to a
variety of aniline derived picolinamides. Aryl substituents of
various electronic characteristics had little effect on both
reaction rate and yield (entries 1-5, Table 2). When N-(o-
tolyl)picolinamide was used, complete sp3 selectivity was
observed and the 2-(picolinamido)benzyl acetate 2j was
isolated as the sole product. Multi-substituted aryl
picolinamides were well tolerated, except for aniline derivatives
having both ortho- positions substituted.
7
8
82
60
67
85
2g
2h
2i
9
10
2j
11
12
76
67
2k
2l
The standard reaction condition was challenged by using
difficult substrates (secondary benzylic C-H bonds and
aliphatic C-H bonds). The double benzylic substrate 1o was
successfully acetoxylated in 69% yield (entry 1, table 3). The
reaction of the o-ethyl aniline derived picolinamide 1p, on the
other hand, was very sluggish and the product was obtained in
45% yield. When the N-(2-tert-butylphenyl) picolinamide 1q
was used, the dihydroindole product was isolated as a result to
C-N bond formation.11 Similar cyclization was also observed
2
m
13
14
70
70
2n
for isobutyl picolinamide 1s
.
Successful aliphatic sp3
acetoxylation was obtained for N-(2-methylcyclohexyl)
picolinamide 1r (62% yield, entry 4, table 3). Rotational
restriction of the substrate forces the methyl group and the
directing group in close proximity so that the C-H activation
occurs more readily. Interestingly, both the trans- and cis-
a Reaction conditions: picolinamide 1 (0.5 mmol, 1.0 equiv), PhI(OAc)2, (322
mg, 1.0 mmol, 2 equiv) and Pd(OAc)2 (11.4 mg, 0.1 mmol, 0.1 equiv) in
toluene (5 mL) under argon at 110 ˚C for 48 hours. b Isolated yield.
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Scheme 2 Kinetics and isotope effects
The kinetics of the acetoxylation reaction was measured.
Interestingly, this reaction required an initial aging period,
possibly due to trace of amount of oxygen in the system. When
carried out in a glovebox, the acetoxylation for 1a reached 50%
conversion in 4 hours, whereas the same experiment using
traditional degas/refill technique required 12 hours to reach
comparable conversion. The reaction is first order to the
concentration of the substrate and an initial rate of 9x10-4
M/min was determined by GC. The C-H bond cleavage was
evidently the rate-limiting step, supported by a large isotope
effect (kH/kD = 4.5, Scheme 2). The benzylic C-H insertion was
irreversible as deuterated substrate had no isotope scrambling
after the reaction.
We speculated that substitution at 5- and 6- position would
restrict free rotation of the Aryl-N bond so that effective
palladium insertion would be more difficult compared to the
non-substituted substrate. In contrast, steric repulsion from the
3-methyl substrate forces the reacting 2-methyl group closer to
the palladium, facilitating the C-H metallation step. It remains
elusive why the dismal 4-methyl substituent also showed
diminished reactivity. One explanation could be slow
dissociation of the dimer complex. Detailed mechanistic and
theoretical investigations are currently undergoing.
Table 3
Reactions of other substratesa
entry
substrate
product
yield (%)b
69
1
2
1o
1p
2o
2p
45c
53
3
1q
2q
Scheme 3 Substitution effect on initial rate
4
5
62
80
1r
1s
2r
2s
The acetoxylated products could be readily hydrolyzed
under basic conditions to generate the 2-amino benzyl alcohols
which were transformed to several heterocycles of medicinal
chemistry interests. Condensation of 3a with acetophenone in
the present of t-BuOK resulted the corresponding quinoline in
75% yield.12 Acid promoted cycloaddition with 3-methyl indole
rendered 5,6-fused indoline aminals, which are widely found in
the Communesin family natural products.13 Reductive
amination using o-nitrobenzaldehyde, followed by base
a 0.5 mmol scale. b Isolated yield. c Another potion of PhI(OAc)2 (64
mg, 0.2 mmol, 2 equiv.) was added after 24 h.
Substrates bearing an additional methyl groups exhibited
some degree of rate discrepancy, depending on the substitution
pattern. The initial rates of those substrates were determined
individually and results are summarized in Scheme 3. When a
methyl group was introduced next to the reacting methyl, the
initial rate of the reaction increased to k2 = 0.0012 M/min; when
the methyl group was moved to the 4- and 5- position, the
reaction rates decreased to 0.0006 M/min. A 6-methyl group
resulted in complete reaction inhibition. In order to better
understand the substitution effect, substrate 1j was heated with
mediated
cyclization
afforded
the
5H-
benzo[4,5][1,3]oxazino[3,2-b]indazole scaffold.14
o
Pd(OAc)2 (1:1) in toluene at 110 C. A large amount of yellow
solid formed after 5 min. The structure of this solid was
determined as a dimeric palladium amide by X-ray. Attempt to
intercept the benzyl palladium intermediate was unsuccessful.
Scheme 4 Synthesis of various heterocycles using the 2-amino benzyl acetate
product
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reaction mixture was stirred at 110 ˚C for 48 hours, cooled to
room temperature and concentrated in vacuum. The residue was
purified by silica gel column flash chromatograph (eluent:
Conclusions
In summary, we developed a general protocol for Pd catalyzed
acetoxylation of benzylic C-H bonds by employing a bidenate
picolinamide as the directing group. This transformation has
broad functional group tolerance and interesting mechanistic
aspects. The benzyl acetate products demonstrated far-reaching
utilization for heterocycle synthesis.
Hexane/EtOAc) to give compound 2.
4-Methyl-2-(picolinamido)benzyl acetate (2a): 102 mg, 72%;
1H NMR (300 MHz, CDCl3) δ 10.58 (s, 1H), 8.67–8.56 (m, 1H),
8.31 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.93 (m, 1H), 7.50 (m,
1H), 7.26 (d, J = 6.7 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 5.17 (s,
2H), 2.41 (s, 3H), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.90, 162.33, 149.99, 148.12, 140.03, 137.68, 136.70, 130.32,
126.52, 125.42, 123.07, 123.01, 122.53, 64.42, 21.54, 20.95;
HRMS (ESI-TOF) calcd. for C16H16N2NaO3 ([M+Na+]) =
307.1059, Found 307.1053.
4-Bromo-2-(picolinamido)benzyl acetate (2b): 120 mg, 69%;
1H NMR (500 MHz, CDCl3) δ 10.64 (s, 1H), 8.62 (d, J = 4.4
Hz, 1H), 8.59 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.94 (t, J = 7.6
Hz, 1H), 7.59-7.47 (m, 1H), 7.26 (m, 2H), 5.16 (s, 2H), 2.20 (s,
3H) 13C NMR (125 MHz, CDCl3) δ 170.51, 162.31, 149.65,
148.13, 138.10, 137.73, 131.46, 127.47, 126.70, 125.13, 124.59,
123.48, 122.63, 63.79, 20.74; HRMS (ESI-TOF) calcd. for
C15H13BrN2NaO3 ([M+Na+]) = 371.0007, Found 371.0001.
Acknowledgements
This work was financially supported by grants of the National
Basic Research Program of China (2010CB833201), National
Natural Science Foundation of China (21372013), the Shenzhen
Peacock Program (KQTD201103) and Shenzhen innovation
funds (GJHZ20120614144733420). Y. H. thanks the MOE for
the Program for New Century Excellent Talents in University.
The Shenzhen municipal development and reform commission
is thanked for a public service platform program.
Experimental
4-Fluoro-2-(picolinamido)benzyl acetate (2c)
: 101 mg,
General methods
70%;1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 8.61 (d, J =
4.1 Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.22 (d, J = 10.9 Hz, 1H),
7.93 (t, J = 7.6 Hz, 1H), 7.55-7.45 (m, 1H), 7.36-7.29 (m, 1H),
6.84 (t, J = 8.0 Hz, 1H), 5.18 (s, 2H), 2.20 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 170.75, 164.52, 162.21, 149.59, 148.17,
138.56, 137.79, 131.70, 126.78, 122.63, 121.03, 111.02, 109.34,
63.92, 20.87; HRMS (ESI-TOF) calcd. for C15H13FN2NaO3
([M+Na+]) = 311.0808, Found 311.0801.
All reactions were carried out under an argon atmosphere with
dry solvents under anhydrous conditions. All other reagents
were purchased and used without further purification unless
specified otherwise. Toluene was distilled from CaH2 prior to
use. Solvents for chromatography were technical grade and
distilled prior to use. Flash chromatography was performed
using 200-300 mesh silica gel with the indicated solvent system
according to standard techniques. Analytical thin-layer
chromatography (TLC) was performed using Huanghai silica
gel plates with HSGF 254. Qingdao Haiyang Chemical
HG/T2354-92 silica gel was used for silica gel flash chro-
matography. Visualization of the developed chromatogram was
performed by UV absorbance (254 nm) or appropriate stains.
1H NMR and 13C NMR data were recorded on Bruker 400
Mnuclear resonance spectrometers unless otherwise specified,
respectively. Chemical shifts (δ) in ppm are reported as quoted
relative to the residual signals of chloroform (1H 7.26 ppm or
13C 77.16 ppm). Multiplicities are described as: s (singlet), bs
(broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet);
and coupling constants (J) are reported in Hertz (Hz). 13C NMR
spectra were recorded with total proton decoupling. HRMS
(ESI) analysis was performed by The Analytical
Instrumentation Center at Peking University, Shenzhen
Graduate School and (HRMS) data were reported with ion
mass/charge (m/z) ratios as values in atomic mass units.
(3-(Picolinamido)-[1,1'-biphenyl]-4-yl)methyl acetate (2d)
:
1
142 mg, 82%; H NMR (400 MHz, CDCl3) δ 10.69 (s, 1H),
8.63 (d, J = 1.5 Hz, 2H), 8.33 (d, J = 7.7 Hz, 1H), 7.93 (td, J =
7.7, 1.4 Hz, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.50-7.35 (m, 6H),
5.26 (s, 2H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.87, 162.48, 149.93, 148.17, 142.82, 140.31, 137.76, 137.27,
130.80, 128.79, 127.70, 127.31, 126.63, 124.77, 123.23, 122.57,
121.19, 64.32, 20.95; HRMS (ESI-TOF) calcd. for
C21H18N2NaO3 ([M+Na+]) = 369.1215, Found 369.1212.
Methyl 3-(acetoxymethyl)-4-(picolinamido)benzoate (2e)
:
1
136 mg, 83%; H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H),
8.92 (s, 1H), 8.63 (d, J = 4.6 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H),
7.98-7.90 (m, 1H), 7.89-7.84 (m, 1H), 7.52 (dd, J = 6.9, 5.0 Hz,
1H), 7.46 (d, J = 7.9 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H), 2.22 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.54, 166.44, 162.45,
149.64, 148.15, 137.74, 136.82, 131.50, 130.75, 130.08, 126.70,
125.84, 123.58, 122.64, 63.90, 52.24, 20.78; HRMS (ESI-TOF)
calcd. for C17H16N2NaO5 ([M+Na+]) = 351.0957, Found
351.0961.
General procedure for palladium catalysed acetoxylation of
benzylic C-H bonds
5-Methoxy-2-(picolinamido)benzyl acetate (2f): 126 mg, 84%;
1H NMR (300 MHz, CDCl3) δ 10.40 (s, 1H), 8.62 (d, J = 4.4
Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.92
(t, J = 7.2 Hz, 1H), 7.50 (dd, J = 6.8, 5.2 Hz, 1H), 6.97 (dd, J =
12.1, 3.2 Hz, 2H), 5.16 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H);
13CNMR (75 MHz, CDCl3) δ 170.87, 162.45, 156.68, 149.96,
148.13, 137.64, 129.52, 128.36, 126.45, 124.73, 122.50, 115.73,
The picolinamide
1 (0.5 mmol, 1.0 equiv.), PhI(OAc)2, (322 mg,
1.0 mmol, 2 equiv) and Pd(OAc)2 (11.4 mg, 0.1 mmol, 0.1
equiv) were placed in Schlenk tube and capped with a rubber
septum. The reaction vessel was degased and backfilled with
argon three times. Toluene (5 mL) was added via a syringe. The
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114.40, 64.29, 55.56, 20.91; HRMS (ESI-TOF) calcd. for (td, J = 7.7, 1.6 Hz, 1H), 7.50–7.48 (m, 1H), 7.33 (t, J = 7.9 Hz,
C16H16N2NaO4 ([M+Na+]) = 323.1008, Found 323.1013.
1H), 7.06 (d, J = 7.6 Hz, 1H), 5.27 (s, 2H), 2.47 (s, 3H), 2.17 (s,
5-Chloro-2-(picolinamido)benzyl acetate (2g): 125 mg, 82%; 3H); 13C NMR (75 MHz, CDCl3) δ 171.31, 162.76, 150.12,
1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.61 (d, J = 4.4 148.25, 138.50, 137.58, 137.18, 129.34, 127.18, 126.46, 125.33,
Hz, 1H), 8.27 (dd, J = 12.5, 8.2 Hz, 2H), 7.92 (td, J = 7.7, 1.5 122.59, 121.47, 60.48, 20.88, 19.74; HRMS (ESI-TOF) calcd.
Hz, 1H), 7.54–7.44 (m, 1H), 7.42–7.33 (m, 2H), 5.16 (s, 2H), for C16H16N2NaO3 ([M+Na+]) = 307.1059, Found 307.1065.
2.20 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.65, 162.41, 5-Methyl-2-(picolinamido)benzyl acetate (2n): 100 mg, 70%;
149.63, 148.17, 137.76, 135.33, 130.04, 129.63, 129.59, 127.72, 1H NMR (500 MHz, CDCl3) δ 10.50 (s, 1H), 8.61 (d, J = 4.3
126.72, 123.78, 122.62, 63.66, 20.83; HRMS (ESI-TOF) calcd. Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.91
for C15H13ClN2NaO3 ([M+Na+]) = 327.0512, Found: 327.0509.
(td, J = 7.7, 1.5 Hz, 1H), 7.49 (dd, J = 6.7, 4.9 Hz, 1H), 7.26–
2-Fluoro-6-(picolinamido)benzyl acetate (2h): 60 mg, 60%; 7.22 (m, 1H), 7.18 (s, 1H), 5.17 (s, 2H), 2.36 (s, 3H), 2.20 (s,
1H NMR (400 MHz, CDCl3) δ 10.81 (s, 1H), 8.63 (d, J = 4.3 3H); 13C NMR (125 MHz, CDCl3) δ 170.81, 162.32, 150.09,
Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.92 148.10, 137.62, 134.46, 134.23, 130.89, 130.29, 126.43, 126.06,
(t, J = 7.6 Hz, 1H), 7.54–7.44 (m, 1H), 7.40 (dd, J = 15.0, 7.8 122.71, 122.52, 64.53, 20.90, 20.84; HRMS (ESI-TOF) calcd.
Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H), 5.29 (s, 2H), 2.20 (s, 3H); 13C for C16H16N2NaO3 ([M+Na+]) = 307.1059, Found 307.1065.
NMR (100 MHz, CDCl3) δ 171.08, 162.63, 160.10, 149.76, Phenyl(2-(picolinamido)phenyl)methyl acetate (2o): 120 mg,
1
148.23, 138.59, 137.70, 130.66, 126.69, 122.66, 118.28, 113.98, 69%; H NMR (400 MHz, CDCl3) δ 10.59 (s, 1H),8.61–8.60
111.43, 56.72, 20.80; HRMS (ESI-TOF) calcd. for (m, 1H), 8.28 (dd, J = 13.2, 8.0 Hz, 2H), 7.87 (td, J = 7.7, 1.7
C15H13FN2NaO3 ([M+Na+]) = 311.0808, Found 311.0810.
Hz, 1H), 7.50–7.43 (m, 1H), 7.43–7.35 (m, 4H), 7.33–7.23 (m,
2-Chloro-6-(picolinamido)benzyl acetate (2i): 102 mg, 67%; 3H), 7.23–7.15 (m, 1H), 7.08 (s, 1H), 2.26 (s, 3H); 13C NMR
1H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H), 8.65 (s, 1H), 8.31 (100 MHz, CDCl3) δ 169.97, 162.35, 149.90, 147.96, 138.44,
(d, J = 7.1 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.93 (s, 1H), 7.52 137.58, 135.71, 130.40, 129.21, 128.94, 128.47, 128.04, 126.87,
(s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 5.40 126.46, 124.85, 123.38, 122.48, 74.93, 21.19; HRMS (ESI-TOF)
(s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.17, calcd. for C21H18N2NaO3 ([M+Na+]) = 369.1215, Found
162.69, 149.75, 148.26, 138.74, 137.70, 135.46, 130.35, 126.70, 369.1220.
125.91, 124.36, 122.69, 121.78, 60.70, 20.81; HRMS (ESI-TOF) 1-(2-(Picolinamido)phenyl)ethyl acetate (2p): 64 mg, 45%;
calcd. for C15H13ClN2NaO3 ([M+Na+]) =327.0512, Found 1H NMR (400 MHz, CDCl3) δ 10.86 (s, 1H), 8.65 (d, J = 4.1
327.0518.
Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.92
1
2-(Picolinamido)benzyl acetate (2j): 115 mg, 85%; H NMR (td, J = 7.7, 1.7 Hz, 1H), 7.49 (m, 1H), 7.39 (dd, J = 12.1, 4.5
(500 MHz, CDCl3) δ 10.62 (s, 1H), 8.64 (d, J = 4.1 Hz, 1H), Hz, 2H), 7.24–7.12 (m, 1H), 6.03 (q, J = 6.7 Hz, 1H), 2.17 (s,
8.33 (d, J = 7.9 Hz, 2H), 7.94 (m, 1H), 7.51 (m, 1H), 7.46 (m, 3H), 1.62 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
1H), 7.40 (d, J = 6.9 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 5.23 (s, 170.42, 162.57, 150.17, 148.21, 137.61, 135.41, 131.54, 128.97,
2H), 2.23 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.66, 127.52, 126.44, 125.02, 123.51, 122.59, 70.97, 21.25, 20.50;
162.34, 150.08, 148.09, 137.62, 136.91, 130.28, 129.74, 126.46, HRMS (ESI-TOF) calcd. for C16H16N2NaO3 ([M+Na+]) =
126.02, 124.62, 122.55(2C), 64.49, 20.82; HRMS (ESI-TOF) 307.1059, Found 307.1065.
calcd. for C15H14N2NaO3 ([M+Na+]) = 293.0902, Found (3,3-Dimethylindolin-1-yl)(pyridin-2-yl)methanone (2q): 67
1
293.0910.
mg, 53%; H NMR (300 MHz, CDCl3) δ 8.64 (d, J = 4.4 Hz,
5-Bromo-4-fluoro-2-(picolinamido)benzyl acetate (2k): 140 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.53–7.33 (m, 1H),
mg, 76%; 1H NMR (500MHz, CDCl3) δ 10.71 (s, 1H), 8.62 (d, 7.33–7.23 (m, 1H), 7.22–7.06 (m, 2H), 4.09 (s, 2H), 1.33 (s,
J = 3.8 Hz, 1H), 8.34 (d, J = 10.7, 1H), 8.30 (d, J = 7.6 Hz, 1H), 6H); 13C NMR (75 MHz, CDCl3) δ 166.08, 154.57, 148.15,
7.94 (t, J = 7.4 Hz, 1H), 7.53 (m, 2H), 5.15 (s, 2H), 2.20 (s, 3H); 142.05, 141.54, 137.21, 127.71, 125.17, 124.80, 124.42, 121.99,
13C NMR (100 MHz, CDCl3) δ 170.60, 162.36, 160.63, 158.17, 118.04, 65.15, 40.73, 30.42, 28.30; HRMS (ESI-TOF) calcd.
149.35, 148.20, 137.86, 137.67, 134.61, 126.92, 122.70, 110.23, for C16H16N2NaO ([M+Na+]) = 275.1160, Found 275.1165.
103.19, 63.11, 20.82; HRMS (ESI-TOF) calcd. for (2-(Picolinamido)cyclohexyl)methyl acetate (2r): 86 mg, 62%;
C15H12BrFN2NaO3 ([M+Na+]) = 388.9913, Found 388.9920.
1H NMR (500 MHz, CDCl3) δ 8.60–8.49 (m, 1H), 8.19 (d, J =
4-Bromo-5-chloro-2-(picolinamido)benzyl acetate (2l): 129 7.8 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz,
mg, 67%; 1H NMR (400 MHz, CDCl3) δ10.66 (s, 1H), 8.63 (d, 1H), 7.42 (m, 1H), 4.11 (m, 1H), 4.00 (dd, J = 11.2, 6.2 Hz,
J = 4.4 Hz, 1H), 8.59 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H), 7.95 (m, 1H), 3.90 (m, 1H), 2.17–2.06 (m, 1H), 1.98 (s, 3H), 1.95–1.85
1H), 7.62 (s, 1H), 7.54 (m, 1H), 5.16 (s, 2H), 2.22 (s, 3H);13C (m, 1H), 1.77 (m, 3H), 1.41 (m, 1H), 1.35–1.24 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.54, 162.34, 149.32, 148.21, NMR (75 MHz, CDCl3) δ 171.18, 163.64, 149.86, 147.93,
137.85, 136.87, 135.54, 134.68, 126.91, 125.72, 123.55, 122.68, 137.40, 126.14, 122.34, 66.89, 50.21, 42.54, 33.44, 29.00,
116.94, 63.02, 20.80; HRMS (ESI-TOF) calcd. for 25.15, 25.09, 20.89; HRMS (ESI-TOF) calcd for
C15H12BrClN2NaO3 ([M+Na+]) = 404.9618, Found 404.9623.
C15H20N2NaO3 ([M+Na+]) = 299.1372, Found 299.1380.
2-Methyl-6-(picolinamido)benzyl acetate (2m): 100 mg, 70%; (3-Methylazetidin-1-yl)(pyridin-2-yl)methanone (2s): 70 mg,
1
1H NMR (500 MHz, CDCl3) δ 10.72 (s, 1H), 8.65 (d, J = 4.6 80%; H NMR (500 MHz, CDCl3) δ 8.56 (d, J = 4.2 Hz, 1H),
Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.92 8.08 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 10.9, 4.5 Hz, 1H), 7.34
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(m, 1H), 4.79 (t, J = 9.2 Hz, 1H), 4.34 (t, J = 9.3 Hz, 1H), 4.25 (ESI-TOF) calcd for C16H12BrNNa ([M+Na+]) = 320.0051,
(dd, J = 10.2, 5.6 Hz, 1H), 3.79 (dd, J = 10.2, 5.5 Hz, 1H), 2.77 Found 320.0060
(m, 1H), 1.27 (t, J = 10.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 165.34, 152.13, 148.03, 136.75, 125.16, 123.75, 61.65, 55.71, 2-methyl-5H-benzo[4,5][1,3]oxazino[3,2-b]indazole (6a): 2-
24.89, 19.67; HRMS (ESI-TOF) calcd for C10H12N2NaO Nitrobenzaldehyde (50 mg, 0.33 mmol, 1 equiv), Compound 3a
([M+Na+]) = 199.0847, Found 199.0853.
(44 mg, 0.36mmol, 1.1 equiv) were dissolved in methanol (1.6
mL). The resulting solution was stirred at room temperature for
5 minutes before HOAc (1.6 mmol, 4.8 equiv) was added. The
Product derivatization
(2-Amino-4-methylphenyl)methanol (3a): Compound 2a (570 mixture was stirred under argon for 3 hours. NaCH3CN (1.32
mg, 2.0 mmol, 1 equiv) and NaOH (320 mg, 8.0 mmol, 4 equiv) mmol, 4 equiv) was added. The reaction was stirred for 3 hours.
were heated in ethanol (10 mL) for 8 hours at 70 C. EtOH was Solvent was removed under vacuum. The residue was dissolved
removed under vacuum. The residue was dissolved in EtOAc, in iPrOH (3.5 mL). KOH (10% w/w) was added and the basic
neutralized with sat. NH4Cl, washed with water and extracted solution was stirred for 3 hours. The reaction was concentrated
with EtOAc for 3 times. The combined organic layer was and the residue was dissolved in EtOAc and washed with water.
washed with brine, dried over anhydrous Na2SO4, filtered and The aqueous phase was extracted with EtOAc three times. The
concentrated under vacuum to give compound 3a as a yellow combined the organic layer was washed with brine, dried over
solid (260 mg 95%) and used direct in next step without Na2SO4, filtered and concentrated. The residue was purified by
purification.
(5aR*,10bS*)-6,10
silica gel flash column chromatograph (EtOAc:Hexane = 1:10)
to give compound 6a (55 mg, 70%). 1H NMR (500 MHz,
b
-dimethyl-5
a
,6,10
b
,11-tetrahydro-5
H
-
indolo[2,3-b]quinolone (4a): Compound 3a (27.4 mg, 0.2 MeOD) δ 7.72 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.9
mmol, 1 equiv) and 3-methyl indole (58.08 mg, 0.4 mmol, 2 Hz, 1H), 7.29 (dd, J = 13.2, 7.6 Hz, 2H), 7.20 (d, J = 7.6 Hz,
equiv) were dissolved in DCE (1 mL), TFA (6.8 mg, 0.06 1H), 7.00–6.89 (m, 1H), 5.50 (s, 2H), 2.46 (s, 3H); 13C NMR
mmol, 0.3 equiv) was added. The reaction was stirred at 50

C
(75 MHz, MeOD) δ 148.87, 140.07, 132.77, 129.43, 128.50,
for 3 hours, cooled to room temperature, and washed with sat. 127.61, 124.90, 120.16, 118.97, 118.88, 115.93, 115.46, 106.42,
aqueous NaHCO3 solution. The aqueous layer was extracted 68.17, 20.08; HRMS (ESI-TOF) calcd. for C15H13N2O ([M+H+])
with DCM three times. The combined organic layer was = 237.1028, Found: 237.1030.
washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated. The residue was purified by silica gel column
flash chromatograph (EtOAc:Hexane = 1:20) to give compound
4a (40 mg, 80%) as white solid. 1H NMR (500 MHz, CDCl3) δ
7.14 (dd, J = 13.8, 7.1 Hz, 2H), 6.89 (d, J = 7.4 Hz, 1H), 6.79 (t,
J = 7.4 Hz, 1H), 6.53 (t, J = 8.3 Hz, 2H), 6.48 (s, 1H), 4.60 (s,
1H), 4.13 (d, J = 14.2 Hz, 1H), 2.78 (s, 3H), 2.76 (s, 1H) 2.48
(d, J = 15.1 Hz, 1H), 2.28 (s, 3H), 1.24 (s, 3H); 13C NMR (100
Notes and references
a
Key Laboratory of Chemical Genomics, School of Chemical Biology
and Biotechnology, Peking University, Shenzhen Graduate School,
Shenzhen, 518055, China
b
Division of Food-borne Diseases Surveillance, China National Center
for Food Safety Risk Assessment, Building 2, Guangqu Road 37, Beijing,
100022, China
MHz, CDCl3) δ 149.19, 140.86, 137.21, 136.67, 128.95, 127.71,
Electronic Supplementary Information (ESI) available: Comprehensive
121.31, 118.77, 118.57, 114.07, 107.95, 83.78, 38.95, 37.13,
reaction condition survey; kinetic experiments and images of 1H and
32.13, 30.95, 21.39, 21.28; HRMS (ESI-TOF) calcd. for
13CNMR of all products. See DOI: 10.1039/b000000x/
C18H20N2Na ([M+Na+]) = 287.1524, Found 287.1534
3-(4-Bromophenyl)-7-methylquinoline (5a): To a solution of
compound 3a (27 mg, 0.2 mmol, 1 equiv) in 1,4-dioxane (1 mL)
were added 4-bromo benzophenone (40 mg, 0.2 mmol, 1 equiv)
and tBuOK (22 mg, 0.2 mmol, 1 equiv) under argon. The
1 For recent reviews on C-H activation, see: (a) C. Wang and Y. Huang,
Synlett, 2013, 24, 145; (b) H. Ohno, Asian J. Org. Chem., 2013,
S. I. Kozhushkov, H. K. Potukuchi and L. Ackermann, Catal. Sci.
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2, 18; (c)
3
resulting solution was heated at 90 C for 30 minutes. The
4
reaction mixture was poured into sat. aqueous solution of
NH4Cl (10 mL) and extracted with EtOAc three times. The
combined organic layer was back extracted using dilute HCl (2
M, 3x10 mL). The combined aqueous phase was treated with
NaOH solution until pH = 13, and extracted with EtOAc 3
times. The combined organic layer was washed with brine,
dried over Na2SO4, filtered and concentrated to give compound
Chem., 2013, 723, 224; (f) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord
and F. Glorius, Angew. Chem. Int. Ed., 2012, 51, 10236; (g) C. Zhu, R.
Wang and J. R. Falck, Asian Chem. J., 2012, 7, 1502; (h) D. Y.-K. Chen
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1
5a (45 mg, 75%). H NMR (500 MHz, CDCl3) δ 8.20 (d, J =
8.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.97 (s, 1H), 7.80 (d, J =
8.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H),
7.43 – 7.36 (m, 1H), 2.61 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 156.00, 148.51, 140.15, 138.69, 136.60, 131.91, 129.06,
128.79, 128.72, 127.10, 125.34, 123.78, 117.68, 21.85; HRMS
6 | J. Name., 2012, 00, 1-3
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ARTICLE
3 For recent examples on sp3 C-H oxygenation reactions, see: (a) M. A.
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