Metal-free oxidative: Para -acylation of unprotected anilines with N-heteroarylmethanes

Article abstract of DOI:10.1039/c7ob02490h

A selective oxidative para-acylation of unprotected anilines with methyl groups in N-heteroarylmethanes was achieved. This transformation proceeds under mild metal-free reaction conditions to produce the corresponding valuable diarylmethanones in good to high yields, featuring high site-selectivity, high functional-group-tolerance, gram-scale synthesis and easy product-derivation. Preliminary mechanistic studies revealed that the present oxidative para-acylation would take place via a Friedel-Crafts-type process of in situ imines and the steric hindrance might be the key issue for the high regio-selectivity.

Full text of DOI:10.1039/c7ob02490h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Metal-Free Oxidative para-Acylation of Unprotected Anilines with
N-Heteroarylmethanes
Received 00th January 20xx,
Accepted 00th January 20xx
,a
,a
Min Liu,
† Xue Chen,†
Tieqiao Chen,*a Qing Xu,b and Shuang-Feng Yin*a
A selective oxidative para-acylation of unprotected anilines with methyl group in N-heteroarylmethanes was achieved.
This transformation proceeds under a mild metal-free reaction conditions to produce the corresponding valuable
diarylmethanones in good to high yields, featuring high site-selectivity, high functional-group-tolerance, gram-scale
synthesis and easy product-derivation. Preliminary mechanistic studies revealed that the present oxidative para-acylation
would take place via a Friedel-Crafts-type process of in-situ imines and the steric hindrance might be the key issue for the
high regio-selectivity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
synthesis of such compounds. Recently, the oxidative site-
selective acylation of sp2C-H bonds with methyl groups is
achieved (Scheme 1a).11 This transformation would be the
Introduction
Selective C-H functionalization is a continuing challenge in
organic synthesis.1 One of the specifically active fields utilizes
the reactions between two hydrocarbons to construct
functional molecules. This strategy is usually achieved by
transition metal catalysis.2 Despite it serves well for
constructing chemical bonds, the concomitant metal
contamination of the products as well as the high price of
metal catalysts makes its application difficult in development
of bioactive reagents and organic electronic devices.3 Recently,
the transition metal-free cross coupling between different C-H
bonds is recognized to be a green alternative and attracts
much attention, however, it remains challengeable.4
most straightforward protocol for preparing diarylmethanones
because of the high step- and atom-economic efficiency;
however, transition metal catalysts, unsafe peroxides and/or
special directing groups are required, leading to issues of low
synthetic efficiency and metal contamination of products. We
envisioned that if the oxidative acylation of sp2C-H bonds with
sp3C-H bond of N-heteroarylmethanes could take place regio-
selectively under metal-free reaction conditions using
dioxygen molecules as an oxidant, it would be highly
appreciated for the green synthesis of diarylmethanones.
Herein, we communicated a selective oxidative para-acylation
of unprotected anilines with methyl groups in N-heteroaryl
methanes to selectively generate the value-added (4-
aminophenyl)arylmethanones under such a mild reaction
condition (Scheme 1b). Mechanistic studies showed that this
reaction proceeded via a Friedel-Crafts-type process of in-situ
imines, in which a strong steric effect ensured the high para-
selectivity of the oxidative acylation.
Diarylmethanones commonly occur as key units in a variety
of natural products, chemical drugs and material molecules. 5
They are also an important kind of building blocks in organic
synthesis.6 Conventional procedures for their synthesis are
highly dependent on the transformation of reactive functional
groups. For example, the cross couplings between acyl halides
and aryl metals can produce diarylmethanones.7 The tandem
a. Oxidative acylation of sp2C-H bonds with methyl groups
strategy
involving
Friedel-Crafts
reaction
of
O
trihalomethylbenzenes with electron-rich aromatics and
subsequent hydrolysis is also extensively used, despite usually
suffering from regio-selective issues.8 The oxidation of
diarylmethanes9 and transition metal-catalyzed carbonylative
Suzuki couplings of aryl borons10 are also developed for the
cat M
Ar
CH3 + H
Ar
Ar
Ar
requirement: transitionmetal catalysts
unsafeperoxides
specialdirecting groups
b. This work: Metal-Free Oxidative para-Acylation
NH2
NH2
I2/DMSO/O2
Het
N
Ar
+
Het
N
Ar
mild condition
CH3
H
Transition metal-free
High para-selectivity
O
up to 95% yield
Gram-scale synthesis
Easy product-derivation
Scheme 1 Preparation of diarylmethanones.
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70% yield of 3a was afforded with 10 mol% loading of I2 under
similar reaction conditions; whereas, no reaction was observed
in the absence of iodine (Table 1, entries 9 and 10), indicating
that the iodine was essential to this reaction. Other iodines
such as NaI and KI could also promote the oxidative para-
acylation, despite with slightly lower yields (Table 1, entries 11
and 12). Debasing the temperature to 40 oC lead to a dramatic
decrease of the yield with the starting material 1a being
retained (Table 1, entry 13). While the reaction was performed
Results and discussion
Discovery of the oxidative para-acylation. In 2016, we
reported a facile I2/DMSO/O2 system which enables the
oxidative
ortho-acylation
of
phenols
with
N-
heteroarylmethanes to regio-selectively produce the
corresponding (2-hydroxyphenyl)arylmethanones in moderate
yields.12 The site-selectivity is deduced to be controlled by the
in-situ hydrogen bonds. Regarding to the similarity of
structures, aniline was used instead of phenols under the
reaction conditions. To our surprise, the para-C-H bond rather
than the ortho-C-H bond was oxidatively acylated selectively
and the product (4-aminophenyl)(quinolin-2-yl)methanone
was produced in ca. 20% yield.
o
at 80 C, 93% yield of 3a was provided (Table 1, entry 14) just
o
o
like that at 60 C. Further elevating the temperature to 100 C
resulted in a reduced production of 3a, probably due to the
decomposition of quinoline fragment under the reaction
conditions (Table 1, entry 15). The reaction could also proceed
under an air atmosphere (Table 1, entry 16); however, in the
absence of dioxygen, only a trace amount of product could be
detected (Table 1, entry 17). Excessive anilines were necessary
aiming to obtain a high yield of 3a (Table 1, entries 18 and
19).14 When 2 equiv. anilines were loaded, 87% yield of 3a was
generated; while only 30% yield was obtained with 1 equiv.
anilines. It should be noted that 90% (0.36 mmol) excess of
anilines in entry 2 of Table 1 were detected after reaction by
GC using tridecane as an internal standard, indicating that the
excessive anilines remained almost intact during the reaction
and would be easily reused.
Table 1 Direct oxidative acylation of aniline with 2-methylquinolinea
Scope of the methodology. With the optimal reaction
conditions in hand, the substrate scope was subsequently
investigated. As shown in Table 2,
a variety of N-
heteroarylmethanes oxidatively coupled with anilines,
producing the corresponding (4-aminophenyl)arylmethanones
in good to excellent yields. Thus, 2-methyl quinolines bearing
6-methyl and 6-methoxy groups reacted with 2a readily, giving
the expected products in high yields (3b and 3c). The halo
groups like F, Cl and Br survived well under the reaction
conditions, facilitating further functionalization of products via
cross coupling (3d-3g). The ester group substituted substrate
also showed good reactivity, furnishing the desired product 3h
in 65% yield. 4-Methyl quinoline, 1-methyl isoquinolines and 2-
methyl quinoxaline underwent oxidative para-acylation with
2a smoothly under similar reaction conditions; the
a A mixture of 1a (0.2 mmol), 2a (0.6 mmol), I2 (0.04 mmol), acid (0.04 mmol) in
DMSO (0.2 mL) was heated at 60 oC for 16 h under O2 atmosphere (1 atm, 25 mL
b
c
glass tube). GC yield using tridecane as an internal standard. 0.02 mmol acid
d
e
f
was loaded. 0.02 mol I2 was used. under air atmosphere. under N2
g
h
corresponding products 3i, 3k and 3l were afforded in 95%,
atmosphere. 0.2 mmol 2a was used. 0.4 mmol 2a was used. N.D. = Not
Detected.
81% and 85% yields, respectively. However, when 3-methyl
quinoline was employed as a substrate, no reaction was
observed even at a high temperature (3j). By elevating the
temperature to 110 oC, 4-methylpyridine also oxidatively
coupled with 2a to give 3m in 90% yield; whereas 2-
methylpyridine exhibited low reaction efficiency under similar
reaction conditions (3n). Benzothiazole derivatives were also
found as reactive as quinolines to produce the corresponding
Inspired by the interesting feedback, we further optimized
the reaction conditions and the results obtained were
compiled in Table 1. After
a comprehensive condition
screening, it was found that this transformation could proceed
efficiently under a milder reaction condition (close to neutral
condition). Heating the mixture of 2-methylquinoline, aniline
and 20 mol% I2 in DMSO at 60 oC for 16 h under an
atmospheric pressure of dioxygen molecules, 3a was
generated in 74% yield (Table 1, entry 1). By addition of 20
mol% salicylic acid, the yield was increased to 93% (Table 1,
entry 2). Further raising the loading of salicylic acid to 40 mol%
gave a similar yield (Table 1, entry 3). Other acids like phenol,
AcOH, PhC(O)OH, CF3C(O)OH and TsOH also showed a positive
effect on the oxidative acylation (Table 1, entries 4-8).13 Only
products in excellent yields (3o-3q). The results obtained here
are consistent with those of deuteration at the methyl groups
of N-heteroarylmethanes,13 in which 1) both 2-methyl and 4-
methyl groups were deuterated, 2) 3-methyl group remained
intact, and 3) 4-methylpyridine showed higher reactivity than
2-methylpyridine. Thus, a similar activation of methyl groups
would be involved in the present oxidative para-acylation
reactions.
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Table
heteroarylmethanesa
2
Metal-free direct oxidative para-acylation of anilines with N-
methylated, the reactions also hardly occurred in the current
catalytic system (3ae and 3af).14
Demonstration of Synthetic Value of the Reaction. Practically,
this reaction could be conducted in a gram-scale, affording the
desired product in 85% yield (Scheme 2a, for detailed
procedure, see experimental section). Worth noting is that the
present oxidative para-acylation strategy was applicable to the
derivation of bioactive molecules, i.e. chloroxine derivative
5,7-dichloro-8-methoxy-2-methylquinoline coupled readily
with 2a under similar reaction conditions, producing the
corresponding diarylmethanone 3ag in 78% yield (Scheme 2b).
The synthetic value of this new reaction was further
demonstrated by complexity of the resulting products through
transformation of the free amino group (Scheme 2c).15 For
instance, 3a reacted with nitrobenzene, generating an azo
compound 3ah 15a
converted to an internal alkyne 3ai 15b
.
3m coupled with phenylacetylene and was
.
a
A mixture of 1 (0.2 mmol), 2 (0.6 mmol), I2 (0.04 mmol), salicylic acid (0.04
mmol) in DMSO (0.2 mL) was heated at the indicated temperature for 16 h under
O2 atmosphere (1 atm, 25 mL glass tube), isolated yield. b GC yield using tridecane
as an internal standard.
As for the anilines, both electron-rich and electron-deficient
2-substituted derivatives served well in the current catalytic
system. Thus, the substrates with 2-methyl, 2-ethyl, 2-
isopropyl and 2-tert-butyl groups were converted to the
corresponding products in good to high yields. It should be
noted that the yields seemed to decrease with increase of the
Scheme 2 Demonstration of synthetic value of this new reaction. Condition
a: 3a (3 equiv.), PhNO2 (0.5 mmol), KOH (5 equiv.), DMF (3 mL), 150 oC, 24 h.
Condition b: 3m (1.3 equiv.), phenylacetylene (0.4 mmol), Pd(OAc)2 (5 mol%),
tri(furan-2-yl)phosphane (15 mol%), t-BuONO (1.3 equiv.), AcOH (1.3 equiv.),
DMSO (1 mL), 35 oC, N2, 16 h.
steric hindrance of substituent groups (3a, 3r-3u). Methoxy
and the easily hydrolytic CF3O groups were compatible to this
reaction (3v and 3w). Halo groups like F, Cl and Br also
Mechanistic Studies. To gain some mechanistic information on
the oxidative para-acylation, several control experiments were
performed. In the presence of excess radical scavenger TEMPO
survived (3x-3z). Anilines having electron-withdrawing groups
(CF3 and ester groups) were also oxidatively para-acylated,
though a high temperature was required (3aa and 3ab). When
m-toluidine was employed as a substrate, only a trace amount
of product 3ac was detected, indicating that a strong steric
effect existed in this reaction. As described below, this
reaction would be a Friedel-Crafts-type process; the oxidative
acylation might take place at the ortho-position of aniline
when its para-site is occupied. Therefore, p-toluidine was
tested; however the reaction proceeded sluggishly (3ad). The
result perhaps was ascribed to the steric hindrance of amino
group. Those results compiled above also implied that the
steric effect might contribute to the high regio-selectiviy in the
present oxidative para-acylation of anilines with methyl
groups. After the free amino group was methylated or double
(2,2,6,6-tetramethylpiperidinyloxy)
or
BHT
(butylated
hydroxytoluene), the oxidative para-acylation of 2a with 1a
still took place, indicating that this reaction would be a Friedel-
Crafts-type process rather than a radical process (eqn 1).
Under
the
standard
reaction
conditions,
2-
(iodomethyl)quinoline 5a coupled with anilines to produce 3a
in 75% yield (eqn 2). According to the Kornblum oxidation,
aldehyde 6a could be easily formed from the reaction of 5a
with DMSO in the presence of a base (In this case, excess
aniline present in the reaction mixture may play such a role).
Thus, 6a was tested. It was found that 6a showed high
reactivity in the reaction with anilines to produced 3a in
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excellent yields even at 40 oC (eqn 3); however, the reaction of Crafts-type process is proposed in Scheme 3.16 At first, N-
6a with N-Me-anilines 2o proceeded sluggishly under the heteroarylmethane underwent enamine isomerization,13
reaction conditions (eqn 4).14 It was known that the aldehyde followed by iodination with I2 to produce a benzylic iodide. The
would react with anilines to generate imines. Thus, it was benzylic iodide was then converted to aldehyde in the
deduced that an in-situ imines would be formed and acted as presence of base via Kornblum oxidation, which was captured
an active intermediate in this reaction. Indeed, when 7a was by an aniline at once, furnishing an active imine
allowed to react with 2 equiv. anilines under the standard intermediate.14 Subsequently, the imine coupled with another
reaction conditions, a quantitative 3a was afforded (eqn 5). aniline through Friedel-Crafts-type process,17 giving
The hypothesis was further supported by the experiment: the secondary amine. After dehydrogenation by I2 and hydrolysis,
reaction of 4-benzylpyridine 1t with anilines took place readily the product
was produced.18 During the reaction, I2 was
a
3
to produce N-(phenyl(pyridin-4-yl)methylene)aniline chemo- regenerated from iodo ions by DMSO and O2 to complete the
selectively in ca. 40% yield in the current catalytic system (eqn catalytic cycle.19
.
6). These results were well associated with experimental
phenomenon: 1) Imines were an efficient intermediate,
therefore N-methyl-aniline and N,N-dimethyl-aniline were
ineffective;14 2) because of the high steric hindrance of imines,
this reaction showed high steric effect, thus ensuring high
para-selectivity. Kinetic isotope effect (KIE) experiments were
also performed and two kinetic isotope effects were obtained.
For 1a-CD3, kH/kD = 3.3 (eqn 7); when 2a-C6D5 was tested, kH/kD
= 2.0 (eqn 8), implying that both the C-H bonds in methyl
group of N-heteroarylmethanes and the para-C-H bond in
anilines would play an important role in this reaction.
Scheme 3 Proposed mechanism for the metal-free oxidative acylation.
Conclusions
In summary, we have disclosed an oxidative para-acylation of
unprotected anilines with N-heteroarylmethanes under a mild
metal-free reaction condition via sp3C-H and sp2C-H dual
activation. The reaction proceeded in a facile I2/DMSO/O2
catalytic system, highly regio-selectively producing the
corresponding (4-aminophenyl)arylmethanones in good to
excellent yields. The high site-selectivity, broad functional-
group-compatibility, scale-up experiment, and easy derivation
of products
3 through transformation of free amino group
clearly demonstrated the potential synthetic value of this new
reaction.
Acknowledgements
Partial financial supports from NFSC (21373080, 21403062,
21273067), HNNSF 2015JJ3039 and the Fundamental Research
Funds for the Central Universities (Hunan University) are
gratefully acknowledged.
Experimental Section
Thus, on the basis of these results described above and
previous literatures, a plausible mechanism involving a Friedel-
A typical procedure: An oven-dried Schlenk tube containing a
stir bar was charged with I2 (0.04 mmol) and salicylic acid (0.04
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mmol), then degassed and refilled with O2 for 3 times. After
(4-aminophenyl)(6-fluoroquinolin-2-yl)methanone (3d). Following
addition of 0.2 mL DMSO, 1a (0.2 mmol) and 2a (0.6 mmol) the typical procedure (80 oC), after reaction, the mixture was
o
under O2 atmosphere, the mixture was stirred at 60 C for 16 diluted with 3-5 mL DCE, then the volatiles was removed and the
h. After dilution with 3-5 mL DCE and subsequent removal of residues were passed through
a short silica chromatography
the volatiles, the residues were passed through a short silica column to afford analytically pure product 3d (93% yield, 24.7 mg,
chromatography column (particle size 37–54 μm, petroleum Yellow solid, m.p. 165.8-167.1 oC). 1H NMR (400 MHz, d6-DMSO) δ
ether/ethyl acetate/NEt3 as eluent) to afford analytically pure 8.53 (d, J = 8.4 Hz, 1H), 8.16-8.19 (m, 1H), 7.85-7.92 (m, 4H), 7.76
3a in 90% isolated yield.
(dd, J = 7.2 Hz, J = 7.2 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 6.32 (s, 2H);
Gram-scale para-acylation.: An oven-dried 100 mL Schlenk 13C NMR (100 MHz, d6-DMSO) δ 190.85, 160.93 (d, JF-C = 245.9 Hz),
tube containing a stir bar was charged with I2 (2 mmol, 508 156.70 (d, JF-C = 2.7 Hz), 154.80, 143.60, 137.29 (d, JF-C = 5.4 Hz),
mg), salicylic acid (2 mmol, 280 mg), and degassed and refilled 134.04, 132.93 (d, JF-C = 9.5 Hz), 129.39 (JF-C = 10.7 Hz), 123.23,
with O2 for 3 times. After addition of 10 mL DMSO, 1a 2- 121.78, 120.88 (d, JF-C = 25.9 Hz), 112.99, 111.57 (d, JF-C = 21.9 Hz).
methylquinoline (10 mmol, 1.35 mL) and 2a aniline (30 mmol, HRMS (EI) m/z: [M] Calcd for C16H11FN2O 266.0855, Found
2.7 mL) under O2 atmosphere, the mixture was stirred at 60 oC 266.0861.
for 16 h. During the reaction, O2 was refilled at 5 h, 10 h. After
(4-aminophenyl)(6-chloroquinolin-2-yl)methanone (3e). Following
reaction, the mixture was washed with saturated NaHCO3 the typical procedure (80 oC), after reaction, the mixture was
aqueous and extracted with DCM. Then the organic layer was diluted with 3-5 mL DCE, then the volatiles was removed and the
evaporated and the residues were passed through a short residues were passed through
a short silica chromatography
silica chromatography column (particle size 37–54 μm, column to afford analytically pure product 3e (88% yield, 24.8 mg,
petroleum ether/ethyl acetate/NEt3 as eluent) to afford Yellow solid, m.p. 190.5-191.2 oC). 1H NMR (400 MHz, d6-DMSO) δ
analytically pure product 3a (2.11 g, 85% yield).
8.53 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.92 (d, J
= 8.4 Hz, 1H), 7.83-7.87 (m, 3H), 6.63 (d, J = 8.0 Hz, 2H), 6.33 (s, 2H);
Characterized Data of the Products
(4-aminophenyl)(quinolin-2-yl)methanone (3a). Following the 13C NMR (100 MHz, d6-DMSO) δ 190.77, 157.59, 154.87, 144.87,
typical procedure (60 oC), after reaction, the mixture was diluted 137.10, 134.02, 132.71, 132.07, 131.29, 129.27, 127.18, 123.11,
with 3-5 mL DCE, then the volatiles was removed and the residues 121.98, 112.99. HRMS (EI) m/z: [M] Calcd for C16H11ClN2O 282.0560,
were passed through a short silica chromatography column to Found 282.0563.
afford analytically pure product 3a (90% yield, 22.3 mg, Yellow
(4-aminophenyl)(7-chloroquinolin-2-yl)methanone (3f). Following
solid, m.p. 163.5-164.2 oC). 1H NMR (400 MHz, d6-DMSO) δ 8.55 (d, J the typical procedure (90 oC), after reaction, the mixture was
= 8.4 Hz, 1H), 8.10 (t, J = 9.0 Hz, 2H), 7.86-7.88 (m, 4H), 7.73 (t, J = diluted with 3-5 mL DCE, then the volatiles was removed and the
7.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 2H), 6.31 (s, 2H); 13C NMR (100 MHz, residues were passed through
a short silica chromatography
d6-DMSO) δ 191.16, 157.19, 154.77, 146.43, 137.70, 134.02, 130.77, column to afford analytically pure product 3f (86% yield, 24.3 mg,
129.97, 128.51, 128.46, 128.36, 123.31, 120.98, 112.97. HRMS (EI) Yellow solid, m.p. 165.4-166.7 oC). 1H NMR (400 MHz, d6-DMSO) δ
m/z: [M] Calcd for C16H12N2O 248.0950, Found 249.1022 (M+H).
8.59 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.83-
(4-aminophenyl)(6-methylquinolin-2-yl)methanone
(3b). 7.89 (m, 3H), 7.74 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.34 (s,
Following the typical procedure (70 C), after reaction, the mixture 2H); 13C NMR (100 MHz, d6-DMSO) δ 190.79, 158.27, 154.78,
was diluted with 3-5 mL DCE, then the volatiles was removed and 146.78, 137.88, 135.29, 134.05, 130.45, 128.88, 128.55, 127.10,
the residues were passed through a short silica chromatography 123.07, 121.38, 113.01. HRMS (EI) m/z: [M] Calcd for C16H11ClN2O
column to afford analytically pure product 3b (94% yield, 24.6 mg, 282.0560, Found 283.0633 (M+H).
o
Yellow solid, m.p. 201.3-202.1 oC). 1H NMR (400 MHz, d6-DMSO) δ (4-aminophenyl)(6-bromoquinolin-2-yl)methanone (3g). Following
8.42 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.82-7.88 (m, 4H), the typical procedure (80 oC), after reaction, the mixture was
7.68 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.28 (s, 2H), 2.54 (s, diluted with 3-5 mL DCE, then the volatiles was removed and the
3H); 13C NMR (100 MHz, d6-DMSO) δ 191.10, 156.27, 154.67, residues were passed through
a short silica chromatography
145.01, 138.15, 136.87, 134.02, 132.91, 129.74, 128.55, 127.08, column to afford analytically pure product 3g (90% yield, 29.3 mg,
123.45, 121.04, 112.94, 21.70. HRMS (EI) m/z: [M] Calcd for Yellow solid, m.p. 189.4-191.6 oC). 1H NMR (400 MHz, d6-DMSO) δ
C17H14N2O 262.1106, Found 263.1179 (M+H).
8.52 (d, J = 8.4 Hz, 1H), 8.39 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.90-
(4-aminophenyl)(6-methoxyquinolin-2-yl)methanone
(3c). 7.97 (m, 2H), 7.84 (d, J = 8.0 Hz, 2H), 6.63 (d, J = 8.0 Hz, 2H), 6.33 (s,
Following the typical procedure (80 C), after reaction, the mixture 2H); 13C NMR (100 MHz, d6-DMSO) δ 190.78, 157.65, 154.87,
was diluted with 3-5 mL DCE, then the volatiles was removed and 145.04, 137.00, 134.03, 133.82, 132.11, 130.48, 129.75, 123.10,
the residues were passed through a short silica chromatography 121.94, 121.39, 113.00. HRMS (EI) m/z: [M] Calcd for C16H11BrN2O
column to afford analytically pure product 3c 84% yield, 23.3 mg, 326.0055, Found 326.0064.
o
Yellow solid, m.p. 189.5-190.7 oC). 1H NMR (400 MHz, d6-DMSO) δ
methyl 2-(4-aminobenzoyl)quinoline-6-carboxylate (3h). Following
8.48 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.91-7.96 (m, 3H), the typical procedure (60 oC), after reaction, the mixture was
7.55 (d, J = 9.6 Hz, 1H), 7.54 (s, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.31 (s, diluted with 3-5 mL DCE, then the volatiles was removed and the
2H), 4.01 (s, 3H); 13C NMR (100 MHz, d6-DMSO) δ 190.92, 158.87, residues were passed through
a short silica chromatography
154.60, 154.54, 142.34, 136.25, 134.03, 131.56, 129.99, 123.60, column to afford analytically pure product 3h (65% yield, 19.9 mg,
123.34, 121.42, 112.06, 106.13, 56.16. HRMS (EI) m/z: [M] Calcd for Yellow solid, m.p. 186.4-188.4 oC). 1H NMR (400 MHz, d6-DMSO) δ
C17H14N2O2 278.1055, Found 278.1059.
8.18 (s, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.22 (d, J
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o
1
= 8.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 6.66 (d, Yellow solid, m.p. 169.5-171.3 C.). H NMR (400 MHz, d6-DMSO) δ
J = 8.0 Hz, 2H), 6.38 (s, 2H), 3.99 (s, 3H); 13C NMR (100 MHz, d6- 8.41 (d, J = 8.4 Hz, 2H), 8.24 (dd, J = 9.2 Hz, J = 9.6 Hz, 2H), 7.58-7.66
DMSO) δ 190.83, 166.26, 159.36, 154.98, 148.25, 139.31, 134.03, (m, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.56 (s, 2H); 13C NMR (100 MHz, d6-
131.25, 130.54, 129.56, 128.84, 127.79, 122.98, 121.80, 113.03, DMSO) δ 180.87, 169.50, 155.73, 153.87, 136.28, 134.38, 127.79,
53.01. HRMS (EI) m/z: [M] Calcd for C18H14N2O3 306.1004, Found 127.53, 125.40, 123.09, 121.69, 113.11. HRMS (EI) m/z: [M] Calcd
306.1013.
for C14H10N2OS 254.0514, Found 255.0558 (M+H).
(4-aminophenyl)(quinolin-4-yl)methanone (3i). Following the
(4-aminophenyl)(6-methoxybenzo[d]thiazol-2-yl)methanone (3p).
typical procedure (90 oC), after reaction, the mixture was diluted Following the typical procedure (100 oC), after reaction, the mixture
with 3-5 mL DCE, then the volatiles was removed and the residues was diluted with 3-5 mL DCE, then the volatiles was removed and
were passed through a short silica chromatography column to the residues were passed through a short silica chromatography
afford analytically pure product 3i (95% yield, 23.3 mg, Yellow solid, column to afford analytically pure product 3p (90% yield, 25.5 mg,
m.p. 234.0-234.7 oC). 1H NMR (400 MHz, d6-DMSO) δ 9.05 (s, 1H), yellow solid, m.p. 182.7-184.6 oC). 1H NMR (400 MHz, d6-DMSO) δ
8.17 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 6.8 Hz, J = 8.0 Hz, 1H), 7.75 (d, J 8.38 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.24 (d, J
= 8.4 Hz, 1H), 7.63 (dd, J = 6.8 Hz, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, = 8.8 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.49 (s, 2H), 3.89 (s, 3H); 13C
2H), 7.53 (s, 1H), 6.63 (d, J = 8.0 Hz, 2H), 6.50 (s, 2H); 13C NMR (100 NMR (100 MHz, d6-DMSO) δ 180.71, 166.90, 159.46, 155.51,
MHz, d6-DMSO) δ 192.63, 155.55, 150.52, 148.30, 146.19, 133.15, 148.38, 138.36, 134.19, 126.20, 121.83, 117.76, 113.26, 104.81,
130.34, 129.98, 127.80, 125.80, 125.06, 123.98, 119.41, 113.24. 56.34. HRMS (EI) m/z: [M] Calcd for C15H12N2O2S 284.0619, Found
HRMS (EI) m/z: [M] Calcd for C16H12N2O 248.0950, Found 249.1022 284.0623.
(M+H).
(4-aminophenyl)(5-bromobenzo[d]thiazol-2-yl)methanone (3q).
(4-aminophenyl)(isoquinolin-1-yl)methanone (3k). Following the Following the typical procedure (100 oC), after reaction, the mixture
typical procedure (80 oC), after reaction, the mixture was diluted was diluted with 3-5 mL DCE, then the volatiles was removed and
with 3-5 mL DCE, then the volatiles was removed and the residues the residues were passed through a short silica chromatography
were passed through a short silica chromatography column to column to afford analytically pure product 3q (80% yield, 26.5
afford analytically pure product 3k (81% yield, 20.1 mg, Yellow oil). mg,yellow solid, m.p. 186.0-191.3 oC). 1H NMR (400 MHz, d6-DMSO)
1H NMR (400 MHz, d6-DMSO) δ 8.56 (d, J = 5.2 Hz, 1H), 8.07 (d, J = δ 8.49 (s, 1H), 8.37 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.8 Hz, 1H), 7.77
8.0 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.81 (dd, (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.60 (s, 2H); 13C NMR (100
J = 7.2 Hz, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.6 Hz, J = 7.6 Hz, 1H), 7.53 MHz, d6-DMSO) δ 180.47, 171.40, 155.90, 155.00, 135.44, 134.46,
(d, J = 8.0 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 6.38 (s, 2H); 13C NMR (100 130.50, 127.67, 124.99, 121.41, 120.21, 113.34. HRMS (EI) m/z: [M]
MHz, d6-DMSO) δ 192.21, 158.82, 155.24, 141.74, 136.37, 133.32, Calcd for C14H9BrN2OS 331.9619, Found 331.9439.
131.26, 128.58, 127.67, 126.17, 125.62, 123.96, 121.88, 113.11.
HRMS (EI) m/z: [M] Calcd for C16H12N2O 248.0950, Found 249.1022 Following the typical procedure (80 C), after reaction, the mixture
(M+H). was diluted with 3-5 mL DCE, then the volatiles was removed and
(4-amino-3-methylphenyl)(quinolin-2-yl)methanone
(3r).
o
(4-aminophenyl)(quinoxalin-2-yl)methanone (3l). Following the the residues were passed through a short silica chromatography
typical procedure (80 oC), after reaction, the mixture was diluted column to afford analytically pure product 3r (84% yield, 22.0 mg,
with 3-5 mL DCE, then the volatiles was removed and the residues Yellow solid, m.p. 153.5-154.9 oC). 1H NMR (400 MHz, d6-DMSO) δ
were passed through a short silica chromatography column to 8.51 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.0 Hz,
afford analytically pure product 3l (85% yield, 21.1 mg, red solid, 1H), 7.82-7.87 (m, 2H), 7.78 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (dd,
m.p. 208.8-210.0 oC). 1H NMR (400 MHz, d6-DMSO) δ 9.25 (s, 1H), J = 7.2 Hz, J = 7.6 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.09 (s, 2H), 2.12
8.20 (d, J = 8.0 Hz, 2H), 7.95-8.01 (m, 2H), 7.89 (d, J = 8.4 Hz, 2H), (s, 3H); 13C NMR (100 MHz, d6-DMSO) δ 191.49, 157.34, 153.05,
6.65 (d, J = 8.0 Hz, 2H), 6.44 (s, 2H); 13C NMR (100 MHz, d6-DMSO) δ 146.48, 137.61, 134.03, 132.04, 130.74, 129.97, 128.48, 128.44,
189.40, 155.25, 151.42, 145.62, 142.49, 140.16, 134.13, 132.09, 128.28, 123.63, 120.97, 120.31, 112.96, 17.92. HRMS (EI) m/z: [M]
131.51, 130.28, 129.43, 122.86, 113.08. HRMS (EI) m/z: [M] Calcd Calcd for C17H14N2O 262.1106, Found 262.1109.
for C15H11N3O 249.0902, Found 249.0912.
(4-amino-3-ethylphenyl)(quinolin-2-yl)methanone (3s). Following
(4-aminophenyl)(pyridin-4-yl)methanone (3m). Following the the typical procedure (80 oC), after reaction, the mixture was
typical procedure (110 oC), after reaction, the mixture was diluted diluted with 3-5 mL DCE, then the volatiles was removed and the
with 3-5 mL DCE, then the volatiles was removed and the residues residues were passed through
a short silica chromatography
were passed through a short silica chromatography column to column to afford analytically pure product 3s (82% yield, 21.5 mg,
afford analytically pure product 3m (90% yield, 17.8 mg, Yellow Yellow solid, m.p. 142.1-144.5 oC). 1H NMR (400 MHz, d6-DMSO) δ
1
solid). H NMR (400 MHz, d6-DMSO) δ 8.73 (d, J = 4.0 Hz, 2H), 7.49- 8.55 (d, J = 8.4 Hz, 1H), 8.10 (dd, J = 9.2 Hz, J = 9.2 Hz, 2H), 7.84-7.89
7.55 (m, 4H), 6.62 (d, J = 8.4 Hz, 2H), 6.38 (s, 2H); 13C NMR (100 (m, 3H), 7.73 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 8.4 Hz, 1H), 6.10 (s, 2H),
MHz, d6-DMSO) δ 192.26, 155.08, 150.38, 146.74, 133.27, 122.85, 2.47-2.52 (m, 2H), 1.15 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz, d6-
122.73, 113.20. Compound 3m is known.20
DMSO) δ 191.34, 157.26, 152.43, 146.45, 137.65, 132.08, 131.94,
(4-aminophenyl)(benzo[d]thiazol-2-yl)methanone (3o). Following 130.80, 129.93, 128.50, 128.46, 128.35, 125.80, 123.65, 121.02,
the typical procedure (100 oC), after reaction, the mixture was 113.29, 23.62, 13.35. HRMS (EI) m/z: [M] Calcd for C18H16N2O
diluted with 3-5 mL DCE, then the volatiles was removed and the 276.1263, Found 262.1261.
residues were passed through
a
short silica chromatography
(4-amino-3-isopropylphenyl)(quinolin-2-yl)methanone
(3t).
o
column to afford analytically pure product 3o (86% yield, 21.8 mg, Following the typical procedure (80 C), after reaction, the mixture
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was diluted with 3-5 mL DCE, then the volatiles was removed and 149.54 (JF-C = 236.2 Hz), 146.37, 143.10 (JF-C = 3.0 Hz), 137.91,
the residues were passed through a short silica chromatography 130.89, 130.17, 130.08, 128.69, 128.64, 128.48, 123.30 (JF-C = 5.1
column to afford analytically pure product 3t (78% yield, 22.6 mg, Hz), 121.00, 117.83 (JF-C = 18.7 Hz), 114.83 (JF-C = 4.7 Hz). HRMS (EI)
red oily liquid). 1H NMR (400 MHz, d6-DMSO) δ 8.54 (d, J = 8.4 Hz, m/z: [M] Calcd for C16H11FN2O 266.0855, Found 266.0861.
1H), 8.09 (dd, J = 8.8 Hz, J = 8.8 Hz, 2H), 8.01 (s, 1H), 7.84-7.92 (m,
(4-amino-3-chlorophenyl)(quinolin-2-yl)methanone
(3y).
2H), 7.70-7.72 (m, 2H), 6.69 (d, J = 8.4 Hz, 1H), 6.16 (s, 2H), 2.99- Following the typical procedure (100 oC), after reaction, the mixture
3.05 (m, 1H), 1.17 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, d6-DMSO) was diluted with 3-5 mL DCE, then the volatiles was removed and
δ 191.17, 157.16, 151.84, 146.42, 137.65, 131.76, 130.81, 130.17, the residues were passed through a short silica chromatography
129.91, 129.43, 128.51, 128.47, 128.38, 123.66, 121.08, 113.69, column to afford analytically pure product 3y (80% yield, 22.6 mg,
26.65, 22.63. HRMS (EI) m/z: [M] Calcd for C19H18N2O 290.1419, Yellow solid, m.p. 167.8-169.2 oC). 1H NMR (400 MHz, d6-DMSO) δ
Found 290.1423.
8.57 (d, J = 8.4 Hz, 1H), 8.08-8.14 (m, 3H), 7.86-7.95 (m, 3H), 7.74
(4-amino-3-(tert-butyl)phenyl)(quinolin-2-yl)methanone
(3u). (dd, J = 7.2 Hz, J = 6.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.53 (s, 2H);
Following the typical procedure (80 C), after reaction, the mixture 13C NMR (100 MHz, d6-DMSO) δ 190.15, 156.12, 150.29, 146.34,
was diluted with 3-5 mL DCE, then the volatiles was removed and 137.96, 133.36, 132.20, 130.95, 130.04, 128.72, 128.70, 128.49,
the residues were passed through a short silica chromatography 124.40, 121.01, 116.45, 114.44. HRMS (EI) m/z: [M] Calcd for
column to afford analytically pure product 3u (68% yield, 20.7 mg, C16H11ClN2O 282.0560, Found 282.0563.
o
red oily liquid). 1H NMR (400 MHz, d6-DMSO) δ 8.55 (d, J = 8.4 Hz,
(4-amino-3-bromophenyl)(quinolin-2-yl)methanone
(3z).
1H), 8.15 (s, 1H), 8.09 (dd, J = 8.8 Hz, J = 8.4 Hz, 2H), 7.84-7.91 (m, Following the typical procedure (100 oC), after reaction, the mixture
2H), 7.71-7.73 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 6.04 (s, 2H), 1.35 (s, was diluted with 3-5 mL DCE, then the volatiles was removed and
9H); 13C NMR (100 MHz, d6-DMSO) δ 191.10, 157.12, 152.24, the residues were passed through a short silica chromatography
146.40, 137.67, 131.55, 131.14, 130.83, 130.58, 129.90, 128.49, column to afford analytically pure product 3z (86% yield, 28.1 mg,
128.46, 128.39, 123.36, 121.08, 115.82, 34.34, 29.36. HRMS (EI) Yellow solid, m.p. 180.6-182.3 oC). 1H NMR (400 MHz, d6-DMSO) δ
m/z: [M] Calcd for C20H20N2O 304.1576, Found 304.1573.
8.57 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.08-8.13 (m, 2H), 7.94 (d, J =
(4-amino-3-methoxyphenyl)(quinolin-2-yl)methanone
(3v). 8.8 Hz, 2H), 7.87 (dd, J = 7.2 Hz, J = 8.0 Hz, 1H), 7.74 (dd, J = 7.2 Hz, J
Following the typical procedure (80 C), after reaction, the mixture = 7.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.49 (s, 2H); 13C NMR (100
was diluted with 3-5 mL DCE, then the volatiles was removed and MHz, d6-DMSO) δ 189.96, 156.07, 151.34, 146.34, 137.95, 136.77,
the residues were passed through a short silica chromatography 132.70, 130.95, 130.05, 128.72, 128.71, 128.50, 124.90, 121.04,
column to afford analytically pure product 3v (81% yield, 22.5 mg, 114.35, 106.39. HRMS (EI) m/z: [M] Calcd for C16H11BrN2O
Yellow solid, m.p. 177.4-179.1 oC). 1H NMR (400 MHz, d6-DMSO) δ 326.0055, Found 326.0064.
o
8.54 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.0 Hz,
(4-amino-3-(trifluoromethyl)phenyl)(quinolin-2-yl)methanone
1H), 7.83-7.91 (m, 2H), 7.68-7.73 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), (3aa). Following the typical procedure (110 oC), after reaction, the
6.70 (d, J = 8.0 Hz, 1H), 6.02 (s, 2H), 3.85 (s, 3H); 13C NMR (100 MHz, mixture was diluted with 3-5 mL DCE, then the volatiles was
d6-DMSO) δ 191.04, 157.14, 146.45, 145.73, 144.88, 137.66, 130.79, removed and the residues were passed through a short silica
129.98, 128.61, 128.51, 128.44, 128.37, 123.55, 121.06, 111.98, chromatography column to afford analytically pure product 3aa
111.88, 55.75. HRMS (EI) m/z: [M] Calcd for C17H14N2O2 278.1055, (70% yield, 22.1 mg, Yellow solid, m.p. 166.6-168.2 oC). 1H NMR
Found 278.1059.
(400 MHz, d6-DMSO) δ 8.59 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 8.10-
8.14 (m, 3H), 7.99 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 7.6 Hz, J = 7.6 Hz,
(4-amino-3-(trifluoromethoxy)phenyl)(quinolin-2-yl)methanone
(3w). Following the typical procedure (90 oC), after reaction, the 1H), 7.76 (dd, J = 7.6 Hz, J = 7.6 Hz, 1H), 6.94 (d, J = 8.8Hz, 1H), 6.74
mixture was diluted with 3-5 mL DCE, then the volatiles was (s, 2H); 13C NMR (100 MHz, d6-DMSO) δ 190.01, 155.77, 151.02,
removed and the residues were passed through a short silica 146.31, 138.05, 136.23, 131.73 (JF-C = 5.3 Hz ), 131.03, 130.01,
chromatography column to afford analytically pure product 3w 128.84 (b), 128.79, 128.50, 125.06 (JF-C = 270.4 Hz), 122.73, 121.05
(80% yield, 26.6 mg, Yellow solid, m.p. 188.4-190.1 oC). 1H NMR (b), 116.50, 109.84 (JF-C = 30.1 Hz). HRMS (EI) m/z: [M] Calcd for
(400 MHz, d6-DMSO) δ 8.60 (d, J = 8.4 Hz, 1H), 8.11-8.15 (m, 3H),
7.95-8.01 (m, 2H), 7.90 (dd, J = 7.2 Hz, J = 7.6 Hz, 1H), 7.77 (dd, J =
C
17H11F3N2O 316.0823, Found 316.0830.
methyl 2-amino-5-(quinoline-2-carbonyl)benzoate
(3ab).
7.6 Hz, J = 6.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.66 (s, 2H); 13C NMR Following the typical procedure (110 oC), after reaction, the mixture
(100 MHz, d6-DMSO) δ 189.81, 155.86, 147.16, 146.30, 138.00, was diluted with 3-5 mL DCE, then the volatiles was removed and
133.61, 132.46, 130.99, 129.98, 128.79, 128.76, 128.50, 125.91, the residues were passed through a short silica chromatography
123.08, 121.10 (q, JF-C = 255.0 Hz), 121.05, 115.35. HRMS (EI) m/z: column to afford analytically pure product 3ab (70% yield, 21.3 mg,
[M] Calcd for C17H11F3N2O2 332.0773, Found 332.0781.
Yellow solid, m.p. 130.2-132.2 oC). 1H NMR (400 MHz, d6-DMSO) δ
(4-amino-3-fluorophenyl)(quinolin-2-yl)methanone
(3x). 8.77 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.08-8.14 (m, 3H), 7.97 (d, J =
Following the typical procedure (100 oC), after reaction, the mixture 8.4 Hz, 1H), 7.87 (dd, J = 7.6 Hz, J = 7.6 Hz, 1H), 7.74 (dd, J = 7.2 Hz, J
was diluted with 3-5 mL DCE, then the volatiles was removed and = 7.6 Hz, 1H), 7.59 (s, 2H), 6.92 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H); 13C
the residues were passed through a short silica chromatography NMR (100 MHz, d6-DMSO) δ 190.46, 167.79, 156.08, 155.41,
column to afford analytically pure product 3x (76% yield, 20.3 mg, 146.38, 137.94, 137.08, 136.48, 130.95, 130.04, 128.73, 128.71,
o
1
Yellow solid, m.p. 146.1-148.2 C.). H NMR (400 MHz, d6-DMSO) δ 128.48, 122.93, 121.04, 116.67, 108.37, 52.22. HRMS (EI) m/z: [M]
8.58 (d, J = 7.6 Hz, 1H), 8.09-8.15 (m, 2H), 7.75-7.95 (m, 5H), 6.85 (b, Calcd for C18H14N2O3 306.1004, Found 306.1013.
1H), 6.39 (s, 2H); 13C NMR (100 MHz, d6-DMSO) δ 190.35, 156.30,
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(4-aminophenyl)(5,7-dichloro-8-methoxyquinolin-2-yl)methanone
Notes and references
(3ag). An oven-dried Schlenk tube containing a stir bar was charged
with I2 (0.2 mmol, 50.8 mg), salicylic acid (0.2 mmol, 28 mg), 1ag
5,7-dichloro-8-methoxy-2-methylquinoline (1 mmol, 244 mg), the
tube was degassed and refilled with O2 for 3 times. Then 1 mL
DMSO and 2a aniline (3 mmol, 270 uL) were charged under O2
1
(a) J.-Q. Yu and Z. Shi, C-H Activation, Springer, MIAMI, FL,
USA, 2010; (b) C. Cheng and J. F. Hartwig, Chem. Rev., 2015,
115, 8946; (c) M. Moselage, J. Li and L. Ackermann, ACS
Catal., 2016,
Glorius and J. Wencel-Delord, Chem. Soc. Rev., 2016, 45
6, 498; (d) T. Gensch, M. N. Hopkinson, F.
,
2900; (e) F. Wang, S. J. Yu and X. W. Li, Chem. Soc. Rev.,
2016, 45, 6462; (f) N. Kuhl, M. N. Hopkinson, J. Wencel-
o
successively. Then the mixture was stirred at 100 C for 16 h. After
reaction, the mixture was diluted with 6 mL DCE, then the volatiles
was removed and the residues were passed through a short silica
chromatography column to afford analytically pure product 3ag
(78% yield, Yellow solid, m.p. 206.1-207.5 oC). 1H NMR (400 MHz,
d6-DMSO) δ 8.72 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.06 (s,
1H), 7.90 (d, J = 8.4 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.37 (s, 2H), 4.09
(s, 3H); 13C NMR (100 MHz, d6-DMSO) δ 190.11, 157.24, 155.02,
152.00, 141.64, 134.99, 134.16, 129.10, 126.55, 126.47, 125.72,
122.84, 122.64, 112.97, 62.85. HRMS (EI) m/z: [M] Calcd for
C17H12Cl2N2O2 346.0276, Found 347.03667 (M+H).
Delord and F. Glorius, Angew. Chem. Int. Ed., 2012, 51
10236; (g) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu,
Angew. Chem. Int. Ed., 2009, 48, 5094.
(a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (b) C. S. Yeung and
V. M. Dong, Chem. Rev., 2011, 111, 1215; (c) C. Liu, J. Yuan,
M. Gao, S. Tang, W. Li, R. Shi and A. Lei, Chem. Rev., 2015,
,
2
115, 12138; (d) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39
,
540; (e) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc.
Rev., 2011, 40, 5068; (f) D. Zhao, J. You and C. Hu, Chem. Eur.
J. 2011, 17, 5466. (g) F.-F. Wang, C.-P. Luo, G. Deng and L.
Yang, Green Chem., 2014, 16, 2428.
(a) Guideline on the specification limits for residues of metal
catalysts of metal reagents, EMEA: London, UK, February,
2008; (b) F. C. Krebs, R. B. Nyberg and M. Jørgensen, Chem.
Mater., 2004, 16, 1313. (c) N. Camaioni, F. Tinti, L. Franco, M.
Fabris, A. Toffoletti, M. Ruzzi, L. Montanari, L. Bonoldi, A.
3
4
5
(E)-(4-(phenyldiazenyl)phenyl)(quinolin-2-yl)methanone (3ah). An
oven-dried Schlenk tube containing a stirbar was charged with (4-
aminophenyl)(quinolin-2-yl)methanone (3 equiv), and KOH (10
equiv), the tube was degassed and refilled with N2 for 3 times. Then
nitrobenzene (0.5 mmol) and 3 mL DMF were charged under N2
successively. The reaction mixture was heated at 150 °C for 24 h
then cooled to room temperature. The mixture was washed with
water and extracted with EtOAc, followed by evaporating the
volatiles to obtain the crude product. Purification was done by
column chromatography using petroleum ether/ethyl acetate (10:1)
to give the pure product 3ah (71% yield, red solid, m.p. 149.5-151.3
oC). 1H NMR (400 MHz, CD3Cl) δ 8.35 (d, J = 8.0 Hz, 2H), 8.19-8.25
(m, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.93-7.98 (m, 3H), 7.84 (d, J = 8.0
Hz, 1H), 7.75 (dd, J = 7.2 Hz, J = 8.0 Hz, 1H), 7.48-7.56 (m, 4H); 13C
NMR (100 MHz, CD3Cl) δ 156.25, 153.05, 152.79, 148.37, 141.86,
136.94, 132.59, 131.21, 129.88, 129.16, 128.36, 127.53, 127.37,
126.64, 123.41, 123.22, 123.02, 118.98. HRMS (EI) m/z: [M] Calcd
for C22H15N3O 337.1215, Found 337.1225.
Pellegrino, A. Calabrese and R. Po, Org. Electron., 2012, 13
550.
,
For selected examples, see (a) T. Y. Yanagi, S. Otsuka, Y.
Kasuga, K. Fujimoto, K. Murakami, K. Nogi, H. Yorimitsu and
A. Psuka, J. Am. Chem. Soc., 2016, 138, 14582; (b) J. A.
Fernández-Salas, A. J. Eberhart and D. J. Procter, J. Am.
Chem. Soc., 2016, 138, 790; (c) K. Morimoto, K. Sakamoto, T.
Ohshika, T. Dohi and Y. Kita, Angew. Chem. Int. Ed., 2016, 55
3652.
,
(a) M. L. Barreca, S. Ferro, A. Rao, L. D. Luca, M. Zappala,
A.M. Monforte, Z. Debyser, M. Witvrouw and A. Chimirri, J.
Med. Chem., 2005, 48, 7084; (b) S. Tao, L. Li, J. Yu, Y. Jiang, Y.
Zhou, C.-S. Lee, S.-T. Lee, X. Zhang and O. Kwon, Chem.
Mater., 2009, 21, 1284; (c) W. Zhang, Z. Liu, S. Li, Y. Lu, Y.
Chen, H. Zhang, G. Zhang, Y. Zhu, G. Zhang, W. Zhang, J. Liu
and C. Zhang, J. Nat. Prod., 2012, 75, 1937; (d) R. Nishikawa-
Shimono, Y. Sekiguchi, T. Koami, M. Kawamura, D. Wakasugi,
K. Watanabe, S. Wakahara, K. Matsumoto and T. Takayama,
Bioorg. Med. Chem. Lett., 2012, 22, 3305; (e) J. Zhang, L.-l.
Fu, M. Tian, H.-Q. Liu, J.-J. Li, Y Li, J. He, J. Huang, L. Ouyang,
H.-Y. Gao and J.-H. Wang, Bioorg. Med. Chem., 2015, 23, 976.
(a) D. Chen, R. Chen, R. Wang, J. Li, K. Xie, C. Bian, L. Sun, X.
Zhang, J. Liu, L. Yang, F. Ye, X. Yu and J. Dai, Angew. Chem.
Int. Ed., 2015, 54, 12678; (b) W.-T. Wei, Y.-J. Cheng, Y. Hu, Y.-
Y. Chen, X.-J. Zhang, Y. Zou and M. Yan, Adv. Synth. Catal.,
(4-(phenylethynyl)phenyl)(pyridin-4-yl)methanone (3ai). A 10
mL Schlenk flask, charged with Pd(OAc)2 (5 mol%), TFP (15
mol%), a stirring bar and septum, was evacuated and backfilled
with N2 (the cycle was performed three times) and then
charged under a positive pressure of N2 with DMSO (1 mL), (4-
aminophenyl)(pyridin-4-yl)methanone (1.3 equiv), AcOH (1.3
equiv), tert-BuONO (1.3 equiv) and phenyl acetylene (0.4
mmol) at room temperature. Then, the Schlenk was
transferred to an oil bath and heated at 35 oC for 16 hours. The
cooled mixture was partitioned between ethyl acetate and
saturated NH4Cl, the organic layer was washed with brine,
dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to provide the
desired product 3ai (58% yield, Yellow solid, m.p. 158.7-160.2
6
2015, 357, 3474; (c) P. Nimnual, J. Tummatorn, C.
Thongsornkleeb and S. Ruchirawat, J. Org. Chem., 2015, 80
,
8657; (d) H. Sterckx, J. D. Houwer, C. Mensch, W. Herrebout,
K. A. Tehrani and B. U. W. Maes, Beilstein J. Org. Chem.,
2016, 12, 144.
(a) F. Diederich and P.J. Stang, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, 1998; (b) K. C.
Nicolau and E. J. Corenses, Classics in Total Synthesis, Wiley-
VCH, Weinheim, 1996, 565.
(a) G. L. Rebeiro and B. M. Khadilkar, Synth. Commun., 2000,
30, 1605; (b) G. Semple, H. Ryder, M. Ohta and M. Satoh,
Synth. Commun., 1996, 26, 721.
(a) J. D. Houwer, K. A. Tehrani and B. U. W. Maes, Angew.
Chem. Int. Ed., 2012, 51, 2745; (b) J.-M. Liu, X. Zhang, H. Yi, C.
Liu, H. Zhang, K.-L. Zhuo and A. Lei, Angew. Chem. Int. Ed.,
2015, 54, 1261; (c) H. Yi, C. Bian, X. Hu, L. Niu and A. Lei,
Chem. Commun., 2015, 51, 14046; (d) L. Ren, L. Wang, Y. Lv,
G. Li and S. Gao, Org. Lett., 2015, 17, 2078; (e) H. Sterckx, J.
7
oC) 1H NMR (400 MHz, d6-DMSO) δ 8.84 (b, 2H), 7.84 (d, J = 7.6
.
8
9
Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.62-7.65 (m, 4H), 7.48 (b, 3H);
13C NMR (100 MHz, d6-DMSO) δ 194.56, 150.83, 144.21,
135.38, 132.18, 132.10, 130.73, 129.92, 129.36, 127.92,
123.05, 122.08, 93.36, 88.95. HRMS (EI) m/z: [M] Calcd for
C20H13NO 283.0997, Found 283.0993.
8 | J. Name., 2012, 00, 1-3
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ARTICLE
D. Houwer, C. Mensch, I. Caretti, K. A. Tehrani, W. A.
Herrebout, S. V. Doorslaerb and B. U. W. Maes, Chem. Sci.,
2016, 7, 346.
10 (a) J. Tjutrins and B. A. Arndtsen, J. Am. Chem. Soc., 2015,
137, 12050; (b) M.-N. Zhao, L. Ran, M. Chen, Z.-H. Ren, Y.-Y.
Wang and Z.-H. Guan, ACS Catal., 2015,
Weires, E. L. Baker and N. K. Garg, Nat. Chem., 2016,
5
, 1210; (c) N. A.
, 75; (d)
8
X. Qi, L.-B. Jiang, H.-P. Li and X.-F. Wu, Chem. Eur. J., 2015,
21, 17650.
11 (a) R. Vanjari and K. N. Singh, Chem. Soc. Rev., 2015, 44, 8062;
(b) Y.-F. Liang, X. Li, X. Wang, Y. Yan, P. Feng and N. Jiao, ACS
Catal., 2015, 5, 1956; (c) S. Kim, S. Han, J. Park, S. Sharma, N.
K. Mishra, H. Oh, J. H. Kwaka and I. S. Kim, Chem. Commun.,
2017, 53, 3006.
12 M. Liu, T. Chen, Y. Zhou and S.-F. Yin, Catal. Sci. Technol.,
2016, 6, 5792.
13 M. Liu, X. Chen, T. Chen and S.-F. Yin, Org. Biomol. Chem.,
2017, 15, 2507.
14 Excessive anilines may also guarantee the formation of
imines in this reaction. Secondary and tertiary amines cannot
capture the in-situ generated aldehydes forming the active
intermediate imines. This hypothesis was further supported
by the experiment: by addition of 1 equiv. aniline 2a, ca. 20%
yield of para-acylated product was detected from the
reaction of 1a and 2 equiv. N,N-dimethyl aniline at 60 oC by
GC and GC-MS.
15 Transformation of amino groups was well known even in the
text book. For selected recent elegant works, see: (a) R. Zhao,
C. Tan, Y. Xie, C. Gao, H. Liu and Y. Jiang, Tetrahedron Lett.,
2011, 52, 3805; (b) X.-F. Wu, H. Neumann and M. Beller,
Chem. Commun., 2011, 47, 7959; (c) X. Fang, R. Jackstell and
M. Beller, Angew. Chem. Int. Ed., 2013, 52, 14089; (d) L. Wen,
L. Tang, Y. Yang, Z. Zha and Z. Wang, Org. Lett., 2016, 18
1278.
,
16 The reaction path involving Friedel-Crafts-type reaction of
benzylic iodide with anilines and subsequent oxidation of the
resulting diarylmethanes was ever considered. However, this
mechanism cannot explain the experimental results that N-
methyl aniline, N,N-dimethyl aniline and p-toluidine hardly
work under the current reaction conditions. Thus, the
probability was excluded out.
17 For selected examples on Friedel-Crafts-type reaction of
imines, see: (a) Y. Chen and Z. Xie, Chin. J. Org. Chem., 2012,
32, 462; (b) Y.-Q. Wang, J. Song, R. Hong, H. Li and L. Deng, J.
Am. Chem. Soc., 2006, 128, 8156; (c) Q. Kang, Z.-A. Zhao and
S.-L. You, J. Am. Chem. Soc., 2007, 129, 1484.
18 A referee pointed out that the free amino group of aniline
might also attack the imine forming an aminal species. After
Friedel-Crafts-type reaction of the resulting aminal with
another imine motif, dehydrogenation by I2, hydrolysis and
subsequent liberation of free amino group, the
corresponding diarylmethanones could also be produced.
The possibility could not be excluded out at the present
stage.
19 The oxidation of iodide ions by DMSO is a reversible process;
the dioxygen may promote the regeneration of I2 in the
reaction. (a) T. Eiki and W. Tagaki, Chem. Lett. 1980, 1063.
(b) P. R. Young and M. Till, J. Org. Chem., 1982, 47, 1416. (c)
P. R. Young and L.-S. Hsieh, J. Org. Chem., 1982, 47, 1419. (d)
J. T. Doi and W. K. Musker, J. Am. Chem. Soc., 1981, 103
,
1159.
20 H. Sterckx, J. De Houwer, C. Mensch, W. Herrebout, K. A.
Tehrani, and Maes, B. U. W.; Beilstein J. Org. Chem. 2016, 12
144.
,
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