Ruthenium(II)-Catalyzed C-H Acylmethylation between (Hetero)arenes and α-Cl Ketones/Sulfoxonium Ylides

Article abstract of DOI:10.1021/acs.joc.9b01013

The first ruthenium(II)-catalyzed (hetero)arene C-H activation coupling with α-Cl ketones/sulfoxonium ylides to efficiently generate acylmethylated (hetero)arenes has been described. Compared with the previous studies, this transformation constitutes the first coupling of α-Cl ketones with arenes under low-cost Ru(II) complex catalysis. Meanwhile, sulfoxonium ylides functioning as the surrogates of α-Cl ketones were also used to facilitate acylmethylation of (hetero)arenes. This strategy features high efficiency, wide substrate tolerance, easily accessible starting materials, and mild reaction conditions.

Full text of DOI:10.1021/acs.joc.9b01013

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Article
Ruthenium(II)-Catalyzed C–H Acylmethylation between
(Hetero)arenes and #-Cl Ketones/Sulfoxonium Ylides
Huihui Li, Chenglin Wu, Hong Liu, and Jiang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01013 • Publication Date (Web): 16 Jul 2019
Downloaded from pubs.acs.org on July 16, 2019
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Page 1 of 14
The Journal of Organic Chemistry
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9
Ruthenium(II)-Catalyzed
(Hetero)arenes and α-Cl Ketones/Sulfoxonium Ylides
C–H
Acylmethylation
between
Huihui Li,a, b Chenglin Wu,b Hong Liu, b, * and Jiang Wang b, *
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aNano Science and Technology Institute, University of Science and Technology of China, 166 Ren Ai Road, Suzhou 215123,
P. R. China.
bState Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China
Supporting Information Placeholder
DG
Het
DG
Het
DG
Het
O
O
S
O
R2
H
R3

Cl
R3
R2

O
O
R1
Ru
R1
Ru
R1
34 examples
up to 92% yield
14 examples
34% to 62% yield
R2/R3 = Aryl, Alkyl, Heterocyclyl
A first Ru(II)-catalyzed (hetero)arenes C H activation coupling with -Cl ketones
-
-Cl ketones function as the surrogates of sulfoxonium ylides in acylmethylation
Inexpensive Ru(II) catalyst & mild conditions
Readily available substrates & gram scale
ABSTRACT: A first ruthenium(II)-catalyzed (hetero)arenes C–H activation coupling with α-Cl ketones/sulfoxonium ylides to
efficiently generate acylmethylated (hetero)arenes has been described. Compared with the previous studies, this transformation
constitutes the first coupling of α-Cl ketones with arenes under a low-cost Ru(II) complex catalysis. Meanwhile, sulfoxonium ylides
function as the surrogates of α-Cl ketones were also used to yield acylmethylation of (hetero)arenes. This strategy features high
efficiency, wide substrate tolerance, easily accessible starting materials, and mild reaction conditions.
INTRODUCTION
structure motifs in many natural products and drugs (Figure
1).18 Acylmethylation is considered as an important reaction in
organic synthesis. In the past, its ubiquitous presence in the
traditional organic reactions synthesis of heterocyclic
compounds,19 such as Bischler-Mohlau indoles synthesis,19a,19b
Hantzsch pyrroles synthesis,19c and Friedlander quinolines
synthesis.19d In recent years, acylmethylation was also
developed in the field of C–H activation, particularly the
acylmethylated compounds as a vital intermediate to synthesis
heterocycles.10c,19e–19j However, a few methods have been
realized the acylmethylation of arenes by employing
sulfoxonium ylides highly stable and safe reagents.20 In 2017,
Aϊssa20a and Li20b groups reported sulfoxonium ylides as
carbene precursors in the application of the C–H activation
catalyzed by Cp*Rh(III) (Scheme 1b). Afterward, a first
sulfoxonium ylide-derived-Cp*Co(III)-carbene complexes has
been exploited successfully for building C–C bonds
developing by Wang and co-workers (Scheme 1b).20c In
contrast with the Cp*Rh(III) and Cp*Co(III) complexes,
[Ru(p-cymene)Cl2]2 with inexpensive advantage, despite
Ru(II)-catalyzed C–H functionalization employing
The development of an efficient and atom-/step-economical
strategy
for
construction
of
C–C
bond
via
transition-metal-catalyzed arenes C–H activation has received
much attention.1 In the past decades, various alkyl reagents as
coupling partners have been developed to construct C–C
bonds, such as imines,2 aziridines,3 alkylboronic acids,4
hydrazones,5 aldehydes,6 alcohols,7 alkenes,8 and others.9
Recently, α-Cl ketones have emerged as a class of practical
carbon synthons and C(sp3)-based electrophiles that has
received attention to form C–C bonds in the field of C–H
activation,10 and it features good security and stability.
Particularly, pioneering work by Glorius10a disclosed a first
Rh(III)-catalyzed
annulation
to
generate
diverse
N-heterocycles by using intrinsically unique coupling partners
α-Cl ketones as oxidized alkyne equivalents. Subsequently,
Li10b and Liu10c groups also employed the similar strategy of
Cp*Rh(III) as
a catalyst to obtain isoquinolines and
3-acylindoles (Scheme 1a), respectively. However, to date,
α-Cl ketones as coupling partner was only employed to
Cp*Rh(III)-catalyzed arenes C–H activation. Compared with
the Cp*Rh(III), Ru(II) complexes have been identified as
lower-cost catalysts.8e,11 Whereas, the coupling partner is
currently limited to alkenes,12 alkynes,13 sulfonyl azides,14
isocyanates,15 amides and diazo compounds.16–17 To the best of
our knowledge, exploiting Ru(II) catalyst to achieve arenes
C–H activation coupling with α-Cl ketones has remained
unexplored, which would be highly desirable.
NH2
OH
OCH3
OCH3
O
O
O
O
O
N
O
O
H3CO
H3CO
O
O
O
N
HCl
Narceine
Protopine
(R)-Methadone
Figure 1. Selected examples of natural products and marketed
drugs containing acylmethylated arenes.
Acylmethylated arenes are frequently reported as important
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Page 2 of 14
Scheme 1. Transition-metal-catalyzed arenes C–H Table 1. Optimization reaction conditions of α-Cl
1
2
3
4
5
6
activation coupling with α-Cl ketones/sulfoxonium ylides.
Previous works:
acetophenone 2a
N
N
(a) Rh-catalyzed annulation cascade of arenes by using -Cl ketones as carbon synthons.
cat. (5 mol%)
Ag salt (30 mol%)
O
H
Ph
O
Cl
R1
DG
+
Rh[III]
Ar
Ph
+
R2
R1
Het
Cl
R2
Ar
additive (1.5 equiv.)
O
H
solvent, temp, 20 h, N2
1a
2a
3aa
(Glorius10a, Li10b, Liu group10c
)
7
8
9
Entry cat.b/Ag salt
additive
solvent
yield (%)c
(b) Rh/Co-catalyzed acylmethylation of aryl CH bonds with sulfoxonium ylides.
DG
DG
1
A/AgSbF6
A/AgSbF6
A/AgSbF6
B/AgSbF6
C/AgSbF6
D/AgSbF6
E/AgSbF6
E/AgOAc
E/AgOTf
E/AgNTf2
E/AgOAc
E/AgOAc
E/AgOAc
E/AgOAc
E/AgOAc
–/AgOAc
E/–
NaOAc
DCE
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
5
O
O
S
R2
H
Rh[III], Co[III]
-DMSO
R1
R1
Ar
+
R2
Ar
2
NaOAc
28
49
0
10
11
12
13
14
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18
19
20
21
22
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27
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51
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53
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57
58
59
60
O
(Aïssa20a, Li20b, Wang20c
)
3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
This work:
4
(c) Ru-catalyzed acylmethylation of (Hetero)arenes by using -Cl ketones/sulfoxonium ylides.
O
5
0
DG
R1 Het
DG
R1 Het
Cl
R2
R2/R3
H
[Ru(p-cymene)Cl2]2
or
O
6
0
+
O
S
O

R3
7
53
61
48
45
N.R.
trace
37
33
13
N.R.
10
38
55

R2/R3 = Aryl, Alkyl, Heterocyclyl
8
NaHCO3 HFIP
sulfoxonium ylides achieved significant progress,21 to the best
of our knowledge, achieving Ru(II)-catalyzed C–H
9
NaHCO3
NaHCO3
HOPiv
HFIP
HFIP
HFIP
HFIP
acylmethylation
between
(hetero)arenes
and
α-Cl
10
11d
12
13
14
15
16
17
18e
19f
ketones/sulfoxonium ylides is still a challenge. In our
continuing efforts on the probe of effective strategies to
construct C–C bonds via Rh/Ru-catalyzed C−H
functionalization,4d,21e,22 we herein report a Ru(II)-catalyzed
C–H activation with α-Cl ketones/sulfoxonium ylides as
coupling partner to directly generate acylmethylated
(hetero)arenes, in which the α-Cl ketones function as the
surrogates of sulfoxonium ylides.
NaOPiv
Zn(OAc)2 HFIP
Na2CO3
–
HFIP
HFIP
NaHCO3 HFIP
NaHCO3 HFIP
NaHCO3 HFIP
NaHCO3 HFIP
RESULTS AND DISCUSSION
According to the investigations and summarized the results of
previous studies,10 α-Cl acetophenone (2a) was only applied to
the Cp*Rh(III)-catalyzed C–H activation to assemble
heterocyclic compounds, therefore, firstly, we initiated our
trial by evaluating [Cp*RhCl2]2 as the catalyst, unfortunately,
the target product 3aa was observed in low conversions
(0%−49%, see SI for more details, Table S1). Then, we
continue investigated various transition-metal catalysts for this
transformation, including [Cp*Co(CO)I2], [Cp*IrCl2]2,
Mn(CO)5Br, and [Ru(p-cymene)Cl2]2 (Table 1, entries 4–7). In
the course of catalyst screening, [Ru(p-cymene)Cl2]2 catalytic
system was found to be the most effective for synthesis of the
desired product 3aa (entry 7, 53%). To improve the reaction
efficiency, then different silver salt as co-catalyst was
examined (entries 7–10), AgOAc exhibited the best efficiency
(entry 8, 61%). A further screening of the additive revealed
that NaHCO3 was the optimized additive (entries 8–15). When
the reaction was in the absence of catalyst, the target product
3aa couldn’t obtain (entry 16). When the reaction was in the
absence of silver salt, the target product 3aa was obtained in a
lower yield (entry 17, 10%). Moreover, we further screened
the effect of the temperature, lower and raising the
temperature the yield led to inferior results (entries 18−19).
Thus, the conditions in entry 8 were adopted for subsequent
studies (conditions A).
E/AgOAc
E/AgOAc
aReaction conditions A: 1a (0.2 mmol), 2a (0.28 mmol), cat. (5
mol%), Ag salt (30 mol%) and additive (1.5 equiv.) in solvent
(3 mL) at 90 °C for 20 h, under N2. bCatalyst A = [RhCp*Cl2]2,
catalyst B = [Cp*Co(CO)I2], catalyst C = [Cp*IrCl2]2, catalyst
c
D = Mn(CO)5Br, catalyst E = [Ru(p-cymene)Cl2]2. Isolated
yields. dN.R. = no reaction. eAt 60 °C. fAt 110 °C.
With the optimized conditions in hand, we next investigated
the reaction between diverse N-heterocycles (1a–1h) and α-Cl
acetophenone 2a (conditions A, Scheme 2). The
para-substituents of the benzene ring with halogens (F and Cl)
and electron-donating group (OCH3) provided in 51%–54%
yields (3ba–3da). Trifluoromethyl- and formyl-substituted
substrates provided the corresponding products in moderate
yields (3ea and 3fa, 46% and 34%). The product 3ga, derived
from 7,8-benzoquinoline 1g, was produced in 44% yield.
Pyrrazole derivative was also obtained in a moderate yield
(3ha, 61%).
Scheme 2. Scope of heterocyclesa, b
DG
Ar
DG
[Ru(p-cymene)Cl2]2 (5 mol%)
O
Ph
H
AgOAc (30 mol%)
R1
Cl
R1
+
Ar
Ph
O
NaHCO3 (1.5 equiv.)
HFIP, 90 oC, 20 h, N2
1a—1h
2a
3aa—3ha
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The Journal of Organic Chemistry
In addition, sulfoxonium ylides acted as the surrogates of
N
N
N
1
2
3
4
5
6
7
8
9
α-Cl ketones, which conducted the Ru(II)-catalyzed conditions
to acquire the similar products. Based on a series of
optimization conditions studies, we confirmed that 5 mol%
[Ru(p-cymene)Cl2]2 and 10 mol% AgSbF6 in HFIP (3 mL) at
90 °C for 20 h under nitrogen atmosphere, offer the best
conditions for this C–H acylmethylation reaction (conditions
B, see SI for more details, Table S2).
N
Ph
Ph
Ph
Ph
O
O
O
O
OCH3
3da,
51%
F
Cl
3aa,
3ba,
3ca,
61%
54%
53%
N
N
N
N
Having acquired the optimal conditions, we then
investigated the scope of (hetero)arenes, employing α-benzoyl
sulfur ylide (5a) as the coupling partner, the results are
summaried in Scheme 4. In general, the protocol was
compatible various groups at R1, and the acylmethylation
products were obtained in 54%–92% yields. The structure of
compound 6aa was unambiguously confirmed by X-ray
N
Ph
Ph
Ph
Ph
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
3ea,
CHO
3ha,
3fa,
61%
46%
34%
3ga,
44%
aReaction conditions A:
1
(0.2 mmol), 2a (0.28 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%), AgOAc (30 mol%), NaHCO3 (1.5
crystallography.23
For
example,
indoles
bearing
b
equiv.) in HFIP (3 mL) at 90 °C for 20 h, under N2. Isolated
electron-donating (CH3, OCH3, and Et), electron-withdrawing
(CF3 and CHO), as well as halide (F, Cl, and Br) groups could
yields.
Subsequently, we investigated the scope of α-Cl ketones
(2b–2l) as coupling partner. As shown in Scheme 3, α-Cl
acetophenone with the methoxyl group substituent afforded
the product 3ab in a 51% yield. Halogens monosubstituted
α-Cl acetophenones (F and Br) attached to the para-position,
methyl and halogens monosubstituted α-Cl acetophenones (F
and Cl) attached to the ortho-position, disubstituted α-Cl
acetophenones could also be tolerated and coupled in
moderate yields (3ac–3ah, 28–62%). The reaction also
showed moderate tolerance toward other ketones containing
biphenyl, methyl, tert-butyl and methyl ester groups in
moderate yields (3ai–3al, 26%–46%).
undergo
a smooth reaction in high yields (6ba–6oa,
71%–90%). Moreover, several nitrogen-based arenes were
examined. Introduction of -F, -Cl, -OCH3, -CF3, and -CH3 on
the para-position of phenyl ring to substrates 1b–1e and 4p,
using these materials examined this protocol, which also
obtained the corresponding products in good yields (3ba–3ea
and 6pa 54%–80%). In addition, a pyrazole directed arene
C–H acylmethylation was also compatible with the optimized
conditions in a 61% yield (3ha). Compound 6qa, with a
methyl group at the meta-position of the pyridine ring
exhibited excellent yield (85%).
Scheme 3. Scope of α-Cl ketonesa, b
Scheme 4. Scope of (hetero)arenes substratesa, b
DG
DG
DG
Het
[Ru(p-cymene)Cl2]2 (5 mol%)
DG
R1 Het
4a 4q
O
O
O
S
H
R2
Ph
AgOAc (30 mol%)
[Ru(p-cymene)Cl2]2 (5 mol%)
H
Cl
R1
AgSbF6 (10 mol%)
R2
+
Ar
Ar
+
Ph
O
O
NaHCO3 (1.5 equiv.)
HFIP, 90 oC, 20 h, N2
HFIP, 90 oC, 8 h, N2
5a
6aa6qa
3aa3ea, 3ha

1a
2b-2l
3ab-3al
1a1e,1h
O
R1
O
Ph
N
OCH3
N
F
N
Br
Ph
N
N
N
R1 = Br,
, 85%
N
N
6ba
O
O
O
N
R1 = CH3,
R1 = CHO,
, 90%
6ca
3ab
, 51%
3ac
3ad
, 62%
, 54%
6aa
, 92%
6aa
6da
X-ray structure of
, 71%
O
O
N
R1
Ph
R1 = F,
N
F
N
Cl
Ph
R1 = F,
, 71%
6ea
6ja
, 74%
R1
N
N
R1 = Cl,
, 83%
R1 = Cl,
, 78%
6fa
6ka
6la
N
N
O
R1 = Br,
R1 = OCH3,
, 86%
6ga
O
R1 = Br,
R1 = CH3,
R1 = COOCH3,
, 80%
N
N
O
O
6ha
, 90%
6ma
, 83%
3ae
, 40%
3af
3ag
, 39%
, 28%
R1 = CF3,
, 78%
6ia
6na
, 67%
Ph
R1 = H,
, 74%
, 76%
N
F
F
N
N
Ph
3aa
N
N
N
R1 = F,
N
3ba
N
Ph
R1 = Cl,
, 80%
Ph
Ph
3ca
R1 = OCH3,
N
N
3da
, 69%
O
O
O
O
O
O
R1 = CF3,
R1 = CH3,
3ea
, 65%
6pa
, 35%
R1
3ah
, 56%
3aj
3ai
, 46%
6oa
3ha
6qa
, 85%
, 74%
, 54%
, 61%
aReaction conditions B: 4 or 1 (0.2 mmol), 5a (0.24 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%), AgSbF6 (10 mol%) in HFIP (3
mL) at 90 °C for 8 h, under N2. bIsolated yields.
N
N
O
O
O
O
3al
3ak
, 26%
, 34%
Likewise, the scope of sulfoxonium ylides (5b–5n) were
also examined (Scheme 5). α-substituted benzoyl sulfoxonium
ylides bearing halide substituents (F, Cl, and Br), electron-
donating (CH3) or -withdrawing groups (COOCH3 and CF3) at
the ortho-, meta-, and para-positions of the phenyl ring all
proceeded smoothly and afford the corresponding products in
good yields (6ab–6aj, 60%–91%). The reaction also showed
aReaction conditions A: 1a (0.2 mmol),
2 (0.28 mmol),
[Ru(p-cymene)Cl2]2 (5 mol %), AgOAc (30 mol%), NaHCO3 (1.5
b
equiv.) in HFIP (3 mL) at 90 °C for 20 h, under N2. Isolated
yields.
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high compatibility toward naphthalene and thiophene ring this catalytic process (Scheme 7). Firstly, the
1
2
3
4
5
6
7
8
substituted sulfoxonium ylides (6ak and 6al, 90% and 91%).
In addition, several alkyl substituents, such as cyclohexanyl
and tert-butyl substituted sulfoxonium ylides were also
compatible in good yields (6am and 6an, 75% and 83%).
deuterium-labeling experiment of 1a was conducted with
1,1,1,3,3,3-hexafluoro-2-propanol-d2 (HFIP-d2) in the absence
of 2a, and the recovered substrate 1a showing that 72%
deuteration at the both ortho-positions of the phenyl ring.
Furthermore, the deuterium-labeling experiment of 1a was
conducted with HFIP-d2 in the presence of 2a under standard
Scheme 5. Scope of sulfoxonium ylidesa, b
1
O
conditions A, by H NMR analyses of the product [D]n-3aa,
R3
H
suggesting 58% deuteration at the ortho-position of the phenyl
ring, and the benzene of both the ortho-positions of carbonyl
group observed 25% deuteration. The same exchange scenario
was observed in the coupling of 1a with 5a under standard
conditions B, these results suggested that the C–H activation
was reversible (Scheme 7a). Compared with sulfoxonium
ylides, α-Cl ketone bearing weakly directing group, which can
be used as both coupling partner and aromatic substrates for
further realizing ortho-position of carbonyl C–H deuteration.
To further probe the C–H activation mechanism, the kinetic
isotope effect (KIE) experiment was also conducted. In both
coupling systems, values of KIE = 1.3 or 1.4 were obtained
from parallel experiments using 1a and 1a-d5 in the coupling
with 2a or 5a under standard conditions A or B, respectively.
The small value of KIE suggested that C–H bond cleavage
may not be involved in the turnover-limiting step24 (Scheme
7b). In addition, the intermolecular competition reaction
between equimolar amounts of 1d and 1e with 2a delivered
3da and 3ea in a ratio of 1 : 0.57. while another a competition
experiment was performed likewise. The resultsshowed that
products 6pa and 3ea were afforded at a ratio of 1 : 0.28 (see
1H NMR analysis
N
N
O
O
S
[Ru(p-cymene)Cl2]2 (5 mol%)
N
N
AgSbF6 (10 mol%)
R3
+
9
N
N
HFIP, 90 oC, 8 h, N2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4a
5b5n
6ab 6an
-
Br
F
O
O
O
R3
R3 = p-FPh,
R3 = p-ClPh,
, 77%
6ac
6ab
N
N
N
, 73%
N
N
N
N
6ad
N
N
R3 = p-CH3Ph,
R3 = p-CO2CH3Ph,
6af
, 88%
6ae
, 70%
, 60%
R3 = p-CF3Ph,
, 70%
6ag
O
, 85%
6ah
OCH3
OCH3
OCH3
Br
O
O
N
N
N
N
N
N
N
N
N
6ak
, 90%
6ai
6aj
N
, 81%
, 91%
O
O
O
S
N
N
N
N
N
N
N
N
6an
, 83%
6am
, 75%
6al
, 91%
aReaction conditions B: 4a (0.2 mmol), 5 (0.24 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%), AgSbF6 (10 mol%) in HFIP (3
mL) at 90 °C for 8 h, under N2. bIsolated yields.
Scheme 7. Mechanistic Studies
(a) Deuterium labeling experiments
[Ru(p-cymene)Cl2]2 (5 mol%)
To evaluate the synthetic utility of this transformation, a
gram-scale preparation of product 3aa was carried out with a
moderate yield of 40% (Scheme 6a). Moreover, a gram-scale
synthesis of synthesis of 6aa was also performed, and the
product was isolated in a 79% yield. (Scheme 6b). The
corresponding compound 7aa was obtained easily from 6aa in
26% yield (Scheme 6c).
N
N
AgOAc (30 mol%)
72% D
D/H
72% D
H/D
NaHCO3 (1.5 equiv.)
HFIP-d2, 90 oC, 4 h , N2
[D]n-1a, 65% recovery
N
1a
25% D
D/H
5a
2a
24% D
N
N
standard conditions B
standard conditions A
H/D
58% D
D/H
45% D
D/H
H
HFIP-d2
HFIP-d2
Ph
4 h
2 h
O
H/D
25% D
O
1a
[D]n-3aa
[D]n-3aa
Scheme 6. Gram-scale synthesis of 3aa and 6aa and
synthetic transformation of 6aa
(b) KIE experiments (parallel experiments)
N
(a)
N
2a (0.28 mmol)
standard conditions A
D
D
D
D
or
3aa
3aa-d4
or
4 h
O
N
N
[Ru(p-cymene)Cl2]2 (5 mol%)
Cl
AgOAc (30 mol%)
+
KIE= KH/KD= 1.3
Ph
D
1a-d5
Ph
NaHCO3 (1.5 equiv.)
HFIP, 90 oC, 20 h, N2
1a
O
2a
O
1a
N
3aa
40% yield
N
5a (0.24 mmol)
standard conditions B
1g, 6.5 mol
D
D
D
D
or
3aa
3aa-d4
or
2 h
(b)
O
KIE= KH/KD= 1.4
Ph
D
O
S
1a
1a-d5
[Ru(p-cymene)Cl2]2 (5 mol%)
+
Ph
(c) Competition experiments
N
N
N
AgSbF6 (10 mol%)
HFIP, 90 oC, 8 h, N2
N
N
N
N
N
N
2a (0.28 mmol)
standard conditions A
5a
4a
1g, 5.15 mol
6aa
79% yield
+
Ph
20 h
O
3da R = OMe
3ea R = CF3
(c)
OMe
CF3
R
O
3da/3ea = 1 : 0.57
1d (0.2 mmol)
1e (0.2 mmol)
O
NaOEt (5 equiv.)
N
N
N
N
5a (0.24 mmol)
standard conditions B
DMSO, 120 o
24 h, N2
26%
C
N
+
Ph
N
H
N
8 h
O
6pa R = Me
3ea R = CF3
7aa
6aa
Me
CF3
R
6pa/3ea = 1 : 0.28
4p (0.2 mmol)
1e (0.2 mmol)
A series of experiments were performed to gain insight into
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
MHz and Bruker INVOA 600 MHz instrument (TMS as IS).
1
2
in SI), which indicating that the electron-rich substrate is more
preferable to this reaction systems (Scheme 7c).
Chemical shifts were reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Proton coupling patterns are
described as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), doublet of doublets (dd) and broad (br). The
reagents were purchased from commercial sources (J&K, Alfa
Aesar, TCI, Adamas-beta, Bide, Accela, etc.), and used
without further purification. Melting points were measured
with a micro melting point apparatus. High-resolution mass
spectra (HRMS) were measured on a Micromass Ultra Q-TOF
spectrometer. Unless otherwise noted, substrates (1a–1h, 4p,
and 4q) and α-Cl ketones (2a–2l) were obtained from
commercial suppliers and used without further purification,
substrates (4a–4o) were prepared according to the literature25
and sulfoxonium ylides (5a–5n) were prepared according to
literature.20a,26
On the basis of previous studies, two different and rational
mechanisms were proposed in Scheme 8. On the one hand,
Path I was shown α-Cl ketone reaction mechanism. Initially,
the dimeric precursor [Ru(p-cymene)Cl2]2 was converted into
[Ru(II)LX2] as an active catalyst through the anion exchange.
Then, cyclometalation of 2-phenylpyridine (1a) affords a
five-membered cyclo-ruthenium intermediate A. Coordination
of oxygen atom of α-Cl acetophenone (2a) gives a Ru(II) alkyl
species B, in which the nucleophilic C(aryl)–Ru species
further attacks the methylenes of α-Cl acetophenone to
produce α-aryl ketones species C. Eventually, the final product
3aa is released from C accompanying regenerates the Ru(II)
catalyst. On the other hand, the mechanism of sulfoxonium
ylide was shown in Path II. Firstly, the five-membered cyclic
ruthenacycle species A′ could be generated via a similar
mechanism to Path I. Then, the α-benzoyl sulfur ylide (5a)
coordinates with species A′ to produce an intermediate B′, and
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL
PROCEDURES
FOR
ACYLMETHYLATION
General procedure-1 for the synthesis of products 3aa–3ha
and 3ab–3ag (compound 3aa as the example). To a 25 mL
of Schlenk tube, 2-phenylpyridine (1a, 0.2 mmol) and α-Cl
acetophenone (2a, 0.28 mmol), [Ru(p-cymene)Cl2]2 (5 mol%),
AgOAc (30 mol%) and NaHCO3 (1.5 equiv.) were added
under air. The mixture was then evacuated and backfilled with
nitrogen (three times). HFIP (3.0 mL) was added subsequently.
subsequent
elimination
of
DMSO
generates
the
ruthenium-carbene C′, migratory insertion of the Ru–aryl
bond into the activated carbene generates a six-membered
ruthenacycle intermediate D′. Eventually, the Ru–alkyl bond
cleavage leads to the final product 3aa by HSbF6, together
with regeneration of the Ru(II) catalyst.
o
The reaction mixture was stirred at 90 C for 20 h. After that,
Scheme 8. Proposed Catalytic Cycles
the solvent was removed under reduced pressure and the
residue was purified by silica gel chromatography using
PE/EA (8:1) to afford the desired product 3aa as a yellow
solid (33.3 mg, 61%).
RuLCl2
2 AgSbF6
2 AgCl
1/2 [RuLCl2]
RuLCl2
2 AgOAc
2 AgCl
1/2 [RuLCl2
]
2
2
L = p-cymene
L = p-cymene
1a
+
3aa
1a
3aa + Cl
base (NaHCO3
)
RuL(SbF6
)
2
RuL(OAc)2
HSbF6
N
AcO
N
General procedure-2 for the synthesis of products 6aa–6pa,
3aa–3ea, and 3ha (compound 6aa as the example). To a 25
mL of Schlenk tube, (pyrimidin-2-yl)-1H-indole (4a, 0.2
mmol) and α-benzoyl sulfur ylide (5a, 0.24 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%) and AgSbF6 (10 mol%) were
added under air. The mixture was then evacuated and
backfilled with nitrogen (three times). HFIP (3.0 mL) was
added subsequently. The reaction mixture was stirred at 90 oC
for 8 h. After that, the solvent was removed under reduced
pressure and the residue was purified by silica gel
chromatography using PE/EA (8:1) to afford the desired
product 6aa as a white solid (57.7 mg, 92%).
HSbF6
+
AcO
+
SbF6
+
AcO
SbF6
N
Ru
L
N
Ru
L
Ph
Ru
A
L
Path I
Ph
Path II
O
D'
A'
O
RuLOAcCl
N
5a
-
C
O
O
S
2a
O
+
+
+
Ph
SbF6
O
AcO
Cl
N
L
SbF6
O
L
Ph
N
L
Ru
Ru
Ru
O
Ph
Ph
+
O
S
Ph
C'
B'
Cl
B
DMSO
CONCLUSION
In summary,
we
have
developed
the
first
1-phenyl-2-(2-(pyridin-2-yl)phenyl)ethan-1-one
(3aa).
ruthenium(II)-catalyzed acylmethylation of (hetero)arenes
coupling with α-Cl ketones/sulfoxonium ylides via C–H
activation. This method provides access to acylmethylated
derivatives in moderate to good yields. In addition, this
reaction features mild reaction conditions, broad substrate
scope, good functional group compatibility, and easily
accessible starting materials. Meanwhile, the discovery of α-Cl
ketones as a coupling partner may promote the development of
C–C bonds construction and the utility of this efficient
coupling strategy may find applications in the synthesis of
important heterocycles after subsequent investigations.
Yellow solid, (according to the general procedure-1: 27.3 mg,
yield 61%; according to the general procedure-2: 40.5 mg,
yield 74%). M.p. 85–87 oC. (purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 8.41 (d, J = 4.0 Hz, 1H), 7.92 – 7.90 (m, 2H),
7.71 (td, J = 7.7, 1.9 Hz, 1H), 7.56 – 7.50 (m, 2H), 7.49 – 7.47
(m, 1H), 7.45 – 7.39 (m, 4H), 7.36 – 7.34 (m, 1H), 7.17 – 7.14
(m, 1H), 4.54 (s, 2H). 13C{1H} NMR (125 MHz, Chloroform-d)
δ 198.0, 159.6, 148.7, 140.0, 137.2, 136.8, 133.4, 132.82,
132.0, 130.0, 128.7, 128.6, 128.4, 127.4, 123.9, 121.9, 43.7.
ESI-LRMS (m/z): 274 [M+H]+; HRMS (ESI) calculated for
C19H16NO [M+H]+: 274.1226, found: 274.1231
EXPERIMENTAL SECTION
2-(5-fluoro-2-(pyridin-2-yl)phenyl)-1-phenylethan-1-one
(3ba). Yellow oil, (according to the general procedure-1:
31.5 mg, yield 54%; according to the general procedure-2:
44.3 mg, yield 76%). (Purified by silica gel chromatography
using PE/EA 15:1–5:1). 1H NMR (500 MHz, Chloroform-d) δ
8.38 (d, J = 4.2 Hz, 1H), 7.88 (d, J = 7.1 Hz, 2H), 7.69 (td, J =
7.7, 1.8 Hz, 1H), 7.55 – 7.52 (m, 1H), 7.48 – 7.41 (m, 4H),
7.15 – 7.13 (m, 1H), 7.10 – 7.04 (m, 2H), 4.51 (s, 2H). 13C{1H}
General Information
Analytical thin layer chromatography (TLC) was HSGF 254
(0.15–0.2 mm thickness), visualized by irradiation with UV
light (254 nm). Column chromatography was performed on
silica gel (300–400 mesh) using ethyl acetate (EA)/petroleum
ether (PE). Nuclear magnetic resonance spectra were recorded
on a Brucker AMX-400 MHz and Bruker Avance III-500
ACS Paragon Plus Environment

The Journal of Organic Chemistry
2-(benzo[h]quinolin-10-yl)-1-phenylethan-1-one
Page 6 of 14
(3ga).
NMR (125 MHz, Chloroform-d) δ 197.3, 162.7 (d, JC-F
=
247.8 Hz), 158.6, 148.7, 137.0, 136.1, 136.0 (d, JC-F = 7.9 Hz),
133.0, 131.6 (d, JC-F = 8.5 Hz), 128.6, 128.3, 123.9, 122.0,
118.9 (d, JC-F = 21.7 Hz), 114.3 (d, JC-F = 21.1 Hz), 43.6. 19F
NMR (471 MHz, Chloroform-d) δ -113.50. ESI-LRMS (m/z):
292 [M+H]+; HRMS (ESI) calculated for C19H15FNO [M+H]+:
292.1132, found: 292.1136.
1
2
3
4
5
6
7
8
Yellow solid, (according to the general procedure-1: 26.2 mg,
yield 44%). M.p. 180–182 oC. (purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 8.21 (d, J = 7.4 Hz, 2H), 8.10 – 8.07 (m, 2H),
7.92 (d, J = 7.9Hz, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.70 (t, J =
7.6 Hz, 1H), 7.67 – 7.56 (m, 5H), 7.28 – 7.26 (m, 1H), 5.22 (s,
2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 197.9, 146.8,
146.3, 138.8, 135.7, 135.4, 134.6, 132.9, 132.1, 129.2, 128.9,
128.6, 128.4, 128.3, 127.7, 127.4, 125.6, 120.9, 48.7.
ESI-LRMS (m/z): 298 [M+H]+; HRMS (ESI) calculated for
C21H16NO [M+H]+: 298.1226, found: 298.1230.
2-(5-chloro-2-(pyridin-2-yl)phenyl)-1-phenylethan-1-one
(3ca). Light yellow solid, (according to the general
procedure-1: 32.6 mg, yield 53%; according to the general
9
o
procedure-2: 49.2 mg, yield 80%). M.p. 61–63 C. (purified
by silica gel chromatography using PE/EA 15:1–5:1). 1H
NMR (500 MHz, Chloroform-d) δ 8.36 (d, J = 4.2 Hz, 1H),
7.88 (d, J = 7.2 Hz, 2H), 7.69 (td, J = 7.7, 1.9 Hz, 1H), 7.54 (t,
J = 7.4 Hz, 1H), 7.44 – 7.41 (m, 4H), 7.37 – 7.33 (m, 2H),
7.15 – 7.13 (m, 1H), 4.51 (s, 2H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 197.2, 158.4, 148.8, 138.5, 137.0, 137.0,
135.4, 134.5, 133.0, 132.0, 131.1, 128.6, 128.3, 127.6, 123.8,
122.1, 43.4. ESI-LRMS (m/z): 308 [M+H]+; HRMS (ESI)
calculated for C19H15ClNO [M+H]+: 308.0837, found:
308.083.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(2-(1H-pyrazol-1-yl)phenyl)-1-phenylethan-1-one (3ha).
Light yellow solid, (according to the general procedure-1/2:
o
32.0 mg, yield 61%). M.p. 97–99 C. (Purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 7.88 – 7.86 (m, 2H), 7.61 – 7.60 (m, 2H),
7.56 – 7.52 (m, 1H), 7.44 – 7.34 (m, 6H), 6.34 (t, J = 2.1 Hz,
1H), 4.39 (s, 2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ
197.2, 140.7, 140.1, 136.8, 133.2, 132.2, 131.1, 131.0, 128.6,
128.6, 128.4, 128.1, 126.1, 106.6, 41.8. ESI-LRMS (m/z): 263
[M+H]+; HRMS (ESI) calculated for C17H15N2O [M+H]+:
263.1179, found: 263.1184.
2-(5-methoxy-2-(pyridin-2-yl)phenyl)-1-phenylethan-1-one
(3da). Yellow solid, (according to the general procedure-1:
30.9 mg, yield 51%; according to the general procedure-2:
1-(4-methoxyphenyl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-one
(3ab). Yellow solid, (according to the general procedure-1:
o
41.9 mg, yield 69%). M.p. 121–123 C. (purified by silica gel
1
o
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
30.9 mg, yield 51%). M.p. 91–93 C. (Purified by silica gel
1
Chloroform-d) δ 8.35 (d, J = 4.8 Hz, 1H), 7.89 (d, J = 7.6 Hz,
2H), 7.66 (td, J = 7.7, 1.9 Hz, 1H), 7.54 – 7.50 (m, 1H), 7.45 –
7.39 (m, 4H), 7.11 – 7.08 (m, 1H), 6.91 (dd, J = 8.5, 2.7 Hz,
1H), 6.87 (d, J = 2.6 Hz, 1H), 4.52 (s, 2H), 3.84 (s, 3H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 197.9, 159.8,
159.3, 148.6, 137.3, 136.7, 135.0, 132.8, 132.6, 131.2, 128.6,
128.4, 123.7, 121.4, 117.5, 112.8, 55.4, 44.0. ESI-LRMS (m/z):
304 [M+H]+; HRMS (ESI) calculated for C20H18NO2 [M+H]+:
304.1332, found: 304.1332.
chromatography using PE/EA 10:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 8.47 (d, J = 4.0 Hz, 1H), 7.87 (d, J = 8.9 Hz,
2H), 7.70 (td, J = 7.7, 1.8 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.39 –
7.35 (m, 2H), 7.33 – 7.31 (m, 1H), 7.16 (dd, J = 7.0, 4.3 Hz,
1H), 6.89 – 6.86 (m, 2H), 4.46 (s, 2H), 3.84 (s, 3H). 13C{1H}
NMR (125 MHz, Chloroform-d) δ 196.7, 163.3, 159.7, 148.8,
140.1, 136.8, 133.7, 131.7, 130.7, 130.2, 130.0, 128.7, 127.2,
124.1, 121.9, 113.7, 55.6, 43.2. ESI-LRMS (m/z): 304 [M+H]+;
HRMS (ESI) calculated for C20H18NO2 [M+H]+: 304.1332,
found: 304.1332.
1-(4-fluorophenyl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-one
(3ac). Yellow oil, (according to the general procedure-1:
31.5 mg, yield 54%). (Purified by silica gel chromatography
using PE/EA 10:1–5:1). 1H NMR (500 MHz, Chloroform-d) δ
8.39 (d, J = 4.1 Hz, 1H), 7.94 – 7.91 (m, 2H), 7.71 (td, J = 7.7,
1.9 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.41 – 7.37 (m, 2H), 7.33 –
7.31 (m, 1H), 7.17 – 7.14 (m, 1H), 7.10 – 7.05 (m, 2H), 4.49 (s,
2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 196.5, 165.6
(d, JC-F = 254.0 Hz), 159.5, 148.6, 139.8, 136.9, 133.6 (d, JC-F
= 3.2 Hz), 133.3, 132.0, 131.0 (d, JC-F = 9.1 Hz), 130.0, 128.8,
127.5, 124.0, 121.9, 115.6 (d, JC-F = 21.9 Hz), 43.6. 19F NMR
(471 MHz, Chloroform-d) δ -105.89. ESI-LRMS (m/z): 292
[M+H]+; HRMS (ESI) calculated for C19H15FNO [M+H]+:
292.1132, found: 292.1134.
1-(4-bromophenyl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-one
(3ad). Yellow oil, (according to the general procedure-1:
43.7 mg, yield 62%). (Purified by silica gel chromatography
using PE/EA 15:1–5:1). 1H NMR (500 MHz, Chloroform-d) δ
8.36 (d, J = 4.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.71 (td, J =
7.7, 1.8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.51 – 7.46 (m, 2H),
7.40 – 7.38 (m, 2H), 7.33 – 7.31 (m, 1H), 7.17 – 7.16 (dd, J =
7.5, 4.9 Hz, 1H), 4.48 (s, 2H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 197.0, 159.4, 148.6, 139.7, 137.0, 136.0,
133.2, 132.0, 131.9, 130.0, 128.8, 127.9, 127.6, 123.9, 122.0,
43.7. ESI-LRMS (m/z): 352 [M+H]+; HRMS (ESI) calculated
for C19H15BrNO [M+H]+: 352.0332, found: 352.0329.
1-phenyl-2-(2-(pyridin-2-yl)-5-(trifluoromethyl)phenyl)etha
n-1-one (3ea). Yellow solid, (according to the general
procedure-1: 31.4 mg, yield 46%; according to the general
o
procedure-2: 44.4 mg, yield 65%). M.p. 65–67 C. (purified
by silica gel chromatography using PE/EA 15:1–5:1). 1H
NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 4.1 Hz, 1H),
7.89 (d, J = 7.0 Hz, 2H), 7.72 (td, J = 7.7, 1.9 Hz, 1H), 7.66 –
7.59 (m, 3H), 7.57 – 7.53 (m, 1H), 7.49 – 7.42 (m, 3H), 7.17
(dd, J = 7.1, 5.4 Hz, 1H), 4.60 (s, 2H). 13C{1H} NMR (125
MHz, Chloroform-d) δ 197.0, 158.3, 148.9, 143.5, 137.0,
137.0, 134.6, 133.1, 130.5 (d, JC-F = 62.5 Hz), 130.3, 129.1 (q,
JC-F = 3.8 Hz), 128.7, 128.3, 124.3 (q, JC-F = 3.6 Hz), 124.2 (q,
JC-F = 272.3 Hz), 124.0, 122.5, 43.6. 19F NMR (471 MHz,
Chloroform-d) δ -62.51. ESI-LRMS (m/z): 342 [M+H]+;
HRMS (ESI) calculated for C20H15F3NO [M+H]+: 342.11,
found: 342.1105.
3-(2-oxo-2-phenylethyl)-4-(pyridin-2-yl)benzaldehyde (3fa).
Yellow oil, (according to the general procedure-1: 20.5 mg,
yield 34%). (purified by silica gel chromatography using
PE/EA 10:1–5:1). 1H NMR (500 MHz, Chloroform-d) δ 10.07
(s, 1H), 8.40 (d, J = 4.1 Hz, 1H), 7.93 – 7.90 (m, 3H), 7.85 (d,
J = 1.6 Hz, 1H), 7.74 (td, J = 7.7, 1.8 Hz, 1H), 7.67 (d, J = 7.9
Hz, 1H), 7.59 – 7.49 (m, 2H), 7.46 – 7.43 (m, 2H), 7.19 (dd, J
= 7.0, 5.5 Hz, 1H), 4.63 (s, 2H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 197.2, 192.0, 158.2, 148.8, 145.7, 137.1,
137.0, 136.2, 134.8, 133.8, 133.1, 130.6, 128.7, 128.4, 128.2,
124.0, 122.6, 43.5. ESI-LRMS (m/z): 302 [M+H]+; HRMS
(ESI) calculated for C20H16NO2 [M+H]+: 302.1176, found:
302.1181.
2-(2-(pyridin-2-yl)phenyl)-1-(o-tolyl)ethan-1-one
(3ae).
Yellow oil, (according to the general procedure-1: 23.0 mg,
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The Journal of Organic Chemistry
yield 40%). (Purified by silica gel chromatography using
PE/EA 15:1–5:1). H NMR (500 MHz, Chloroform-d) δ 8.42
1-(2-(pyridin-2-yl)phenyl)propan-2-one (3aj). Yellow oil,
(according to the general procedure-1: 14.8 mg, yield 35%).
(Purified by silica gel chromatography using PE/EA 10:1–5:1).
1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 4.7 Hz, 1H),
7.75 (td, J = 7.7, 1.9 Hz, 1H), 7.48 – 7.43 (m, 2H), 7.40 – 7.35
(m, 2H), 7.29 – 7.27 (m, 1H), 7.25 – 7.22 (m, 1H), 3.87 (s,
2H), 2.08 (s, 3H). 13C{1H} NMR (125 MHz, Chloroform-d) δ
206.6, 159.5, 148.7, 140.2, 136.8, 133.3, 131.8, 129.9, 128.8,
127.4, 123.8, 122.0, 48.8, 29.6. ESI-LRMS (m/z): 212 [M+H]+;
HRMS (ESI) calculated for C14H14NO [M+H]+: 212.1070,
found: 212.1069.
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3
4
5
6
7
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(d, J = 5.8 Hz, 1H), 7.68 (td, J = 7.7, 1.9 Hz, 1H), 7.53 (d, J =
7.8 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.42 – 7.37 (m, 2H), 7.36 –
7.31 (m, 2H), 7.23 – 7.13 (m, 2H), 4.46 (s, 2H), 2.38 (s, 3H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 201.4, 159.6,
148.6, 140.1, 138.3, 138.2, 136.7, 133.5, 132.2, 131.8, 130.9,
129.9, 128.7, 128.3, 127.4, 125.5, 123.9, 121.8, 46.7, 21.1.
ESI-LRMS (m/z): 288 [M+H]+; HRMS (ESI) calculated for
C20H18NO [M+H]+: 288.1383, found: 288.1373.
9
1-(2-fluorophenyl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-one
(3af). Yellow solid, (according to the general procedure-1:
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14
15
16
17
18
19
20
21
22
23
24
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3,3-dimethyl-1-(2-(pyridin-2-yl)phenyl)butan-2-one (3ak).
Yellow oil, (according to the general procedure-1: 17.2 mg,
yield 34%). (Purified by silica gel chromatography using
o
16.3 mg, yield 28%). M.p. 112–114 C. (Purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
1
Chloroform-d) δ 8.42 (d, J = 4.4 Hz, 1H), 7.69 (td, J = 7.7, 1.9
Hz, 1H), 7.48 – 7.46 (m, 1H), 7.43 (d, J = 7.9Hz, H), 7.41 –
7.37 (m, 3H), 7.36 – 7.30 (m, 3H), 7.26 – 7.23 (m, 1H), 7.17 –
7.15 (m, 1H), 4.50 (s, 2H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 200.5, 159.4, 148.6, 140.1, 139.6, 136.8,
132.7, 132.3, 131.4, 130.8, 130.4, 129.9, 129.4, 128.7, 127.6,
126.7, 123.9, 121.9, 47.9. 19F NMR (471 MHz, Chloroform-d)
δ -109.73. ESI-LRMS (m/z): 292 [M+H]+; HRMS (ESI)
calculated for C19H15FNO [M+H]+: 292.1124, found:
292.1124.
1-(2-chlorophenyl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-one
(3ag). Yellow oil, (according to the general procedure-1:
24.0 mg, yield 39%). (purified by silica gel chromatography
using PE/EA 15:1–5:1). 1H NMR (600 MHz, Chloroform-d) δ
8.42 (d, J = 4.0 Hz, 1H), 7.70 (td, J = 7.7, 1.9 Hz, 1H), 7.47 –
7.42 (m, 2H), 7.41 – 7.37 (m, 3H), 7.36 – 7.31 (m, 3H), 7.26 –
7.23 (m, 1H), 7.17 (m, 1H), 4.50 (s, 2H).13C{1H} NMR (150
MHz, Chloroform-d) δ 200.6, 159.4, 148.5, 140.0, 139.6,
136.9, 132.7, 132.3, 131.4, 130.8, 130.4, 129.9, 129.4, 128.8,
127.6, 126.7, 124.0, 121.9, 47.9. ESI-LRMS (m/z): 308
[M+H]+; HRMS (ESI) calculated for C19H15ClNO [M+H]+:
308.0837, found: 308.0838.
PE/EA 10:1–3:1). H NMR (600 MHz, Chloroform-d) δ 8.61
(d, J = 4.4 Hz, 1H), 7.72 (td, J = 7.7, 1.9 Hz, 1H), 7.41 – 7.38
(m, 2H), 7.37 – 7.32 (m, 2H), 7.22 – 7.18 (m, 2H), 4.12 (s,
2H), 1.03 (s, 9H). 13C{1H} NMR(150 MHz, Chloroform-d) δ 213.1,
160.2, 148.7, 140.6, 136.7, 133.4, 131.8, 129.8, 128.4, 127.1,
124.3, 121.8, 44.3, 41.6, 26.7. ESI-LRMS (m/z): 255 [M+H]+;
HRMS (ESI) calculated for C17H20NO [M+H]+: 254.1539,
found: 254.1538.
methyl 3-oxo-4-(2-(pyridin-2-yl)phenyl)butanoate (3al).
Yellow oil, (according to the general procedure-1: 14.0 mg,
yield 26%). (Purified by silica gel chromatography using
1
PE/EA 10:1–3:1). H NMR (500 MHz, Chloroform-d) δ 8.61
(d, J = 4.0 Hz, 1H), 7.75 (td, J = 7.7, 1.9 Hz, 1H), 7.50 – 7.44
(m, 2H), 7.39 – 7.36 (m, 2H), 7.31 – 7.27 (m, 1H), 7.23 (m,
1H), 3.92 (s, 2H), 3.67 (s, 3H), 3.51 (s, 2H). 13C{1H} NMR
(125 MHz, Chloroform-d) δ 200.2, 168.1, 158.9, 148.4, 139.8,
136.9, 132.5, 132.2, 129.8 (d, J = 4.2 Hz), 128.8 (d, J = 4.3
Hz), 127.8, 123.6, 122.1, 52.2, 48.4, 48.2. ESI-LRMS (m/z):
270 [M+H]+; HRMS (ESI) calculated for C16H16NO3 [M+H]+:
270.1125, found: 270.1124.
1-phenyl-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)ethan-1-one
(6aa). White solid, (according to the general procedure-2:
o
1-(3,4-difluorophenyl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-on
e (3ah). Yellow solid, (according to the general procedure-1:
57.7 mg, yield 92%). M.p. 138–140 C. (Purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (400 MHz,
o
34.6 mg, yield 56%). M.p. 100–102 C. (purified by silica gel
Chloroform-d) δ 8.63 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 4.8 Hz,
2H), 8.04 – 8.01 (m, 2H), 7.62 – 7.56 (m, 2H), 7.53 – 7.48 (m,
2H), 7.31 – 7.27 (m, 1H), 7.25 – 7.21 (m, 1H), 6.92 (t, J = 4.8
Hz, 1H), 6.64 (s, J = 0.8 Hz, 1H), 4.82 (s, J = 0.8 Hz, 2H).
13C{1H} NMR (100 MHz, Chloroform-d) δ 196.1, 158.1,
157.7, 137.5, 137.1, 134.4, 132.8, 129.5, 128.7, 128.3, 123.4,
122.3, 120.2, 116.5, 115.9, 110.6, 40.9. ESI-LRMS (m/z): 314
[M+H]+; HRMS (ESI) calculated for C20H16N3O [M+H]+:
314.1288, found: 314.1293.
2-(4-bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ba). White solid, (according to the general
procedure-2: 66.7 mg, yield 85%). M.p. 177–179 oC.
(Purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 8.4 Hz, 1H),
8.39 (d, J = 4.8 Hz, 2H), 8.03 – 8.00 (m, 2H), 7.63 – 7.58 (m,
1H), 7.53 – 7.49 (m, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.14 (t, J =
8.1 Hz, 1H), 6.95 (t, J = 4.8 Hz, 1H), 6.71 (s, 1H), 4.82 (s, 2H).
13C{1H} NMR (100 MHz, Chloroform-d) δ 196.2, 158.0,
157.8, 137.4, 137.3, 135.3, 133.0, 129.9, 128.8, 128.2, 125.1,
124.2, 117.0, 115.1, 113.9, 110.3, 40.9. ESI-LRMS (m/z): 392
[M+H]+; HRMS (ESI) calculated for C20H15BrN3O [M+H]+:
392.0393, found: 392.0391.
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 8.36 (d, J = 4.9 Hz, 1H), 7.77 – 7.69 (m, 3H),
7.51 – 7.47 (m, 2H), 7.42 – 7.31 (m, 3H), 7.21 – 7.15 (m, 2H),
4.47 (s, 2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 195.5,
159.3, 153.4 (dd, JC-F = 256.2, 12.8 Hz), 150.4 (dd, JC-F
=
250.4, 12.8 Hz), 148.6, 139.61, 136.9, 134.3 (t, JC-F = 3.9 Hz),
132.9, 132.0, 130.0, 128.8, 127.6, 125.3 (dd, JC-F = 7.4, 3.5
Hz), 123.9, 122.0, 117.7 (d, JC-F = 18.1 Hz), 117.4 (d, JC-F
=
17.7 Hz), 43.6. 19F NMR (471 MHz, Chloroform-d) δ -130.54,
-136.35. ESI-LRMS (m/z): 310 [M+H]+; HRMS (ESI)
calculated for C19H14F2NO [M+H]+: 310.1038, found:
310.1043.
1-([1,1'-biphenyl]-4-yl)-2-(2-(pyridin-2-yl)phenyl)ethan-1-o
ne (3ai). Yellow solid, (according to the general procedure-1:
o
32.1 mg, yield 46%). M.p. 107–109 C. (purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 8.45 (d, J = 4.0 Hz, 1H), 7.97 (d, J = 8.3 Hz,
2H), 7.71 (td, J = 7.7, 1.9 Hz, 1H), 7.65 – 7.61 (m, 4H), 7.52 –
7.45 (m, 4H), 7.43 – 7.37 (m, 3H), 7.36 – 7.35 (m, 1H), 7.17 –
7.15 (m, 1H), 4.55 (s, 2H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 197.6, 159.6, 148.8, 145.5, 140.1, 136.8,
135.9, 133.5, 131.9, 130.0, 129.1, 129.0, 128.8, 128.3, 127.4,
127.4, 127.2, 124.0, 121.9, 43.7. ESI-LRMS (m/z): 350
[M+H]+; HRMS (ESI) calculated for C25H20NO [M+H]+:
350.1539, found: 350.1539.
2-(4-methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ca). White solid, (according to the general
procedure-2: 58.9 mg, yield 90%). M.p. 165–167 oC.
(Purified by silica gel chromatography using PE/EA 15:1–5:1).
ACS Paragon Plus Environment

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1H NMR (400 MHz, Chloroform-d) δ 8.46 (d, J = 8.4 Hz, 1H),
2-(5-methoxy-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyleth
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8.38 (d, J = 4.8 Hz, 2H), 8.05 – 8.02 (m, 2H), 7.62 – 7.58 (m,
1H), 7.53 – 7.49 (m, 2H), 7.22 – 7.18 (m, 1H), 7.03 (d, J = 7.4
Hz, 1H), 6.91 (t, J = 4.8 Hz, 1H), 6.68 (s, 1H), 4.82 (s, 2H),
2.56 (s, 3H). 13C{1H} NMR (100 MHz, Chloroform-d) δ 196.7,
158.2, 157.6, 137.5, 136.9, 133.7, 132.8, 129.4, 129.1, 128.7,
128.3, 123.5, 122.7, 116.4, 113.4, 109.1, 41.0, 18.8.
ESI-LRMS (m/z): 328 [M+H]+; HRMS (ESI) calculated for
C21H18N3O [M+H]+: 328.1444, found: 328.1443.
2-(2-oxo-2-phenylethyl)-1-(pyrimidin-2-yl)-1H-indole-4-car
baldehyde (6da). Yellow solid, (according to the general
procedure-2: 48.5 mg, yield 71%). M.p. 174–176 oC.
(Purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 10.27 (s, 1H), 8.91 (d, J
= 8.3 Hz, 1H), 8.44 (d, J = 4.7 Hz, 2H), 8.04 – 8.01 (m, 2H),
7.72 (d, J = 6.5 Hz, 1H), 7.63 – 7.59 (m, 1H), 7.53 – 7.49 (m,
3H), 7.45 – 7.41 (m, 1H), 7.00 (t, J = 4.7 Hz, 1H), 4.92 (s, 2H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 196.1, 192.9,
158.0, 157.9, 138.2, 137.9, 137.3, 133.1, 128.8, 128.7, 128.2,
127.9, 127.7, 122.9, 121.9, 117.2, 110.0, 41.0. ESI-LRMS
(m/z): 342 [M+H]+; HRMS (ESI) calculated for C21H16N3O2
[M+H]+: 342.1237, found: 342.1239.
2-(5-fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ea). Yellow solid, (according to the general
procedure-2: 58.9 mg, yield 71%). M.p. 189–192 oC.
(Purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.61 (dd, J = 9.2, 4.8 Hz,
1H), 8.38 (d, J = 4.8 Hz, 2H), 8.05 – 8.02 (m, 2H), 7.63 – 7.58
(m, 1H), 7.54 – 7.49 (m, 2H), 7.21 (dd, J = 8.9, 2.6 Hz, 1H),
7.01 (td, J = 9.2, 2.7 Hz, 1H), 6.93 (t, J = 4.8 Hz, 1H), 6.60 (s,
1H), 4.82 (s, 2H). 13C{1H} NMR (100 MHz, Chloroform-d) δ
196.3, 159.2 (d, JC-F = 238.2 Hz), 157.7, 137.4, 136.1, 133.5,
an-1-one (6ha). White solid, (according to the general
procedure-2: 61.8 mg, yield 90%). M.p. 151–153 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J = 9.1 Hz, 1H),
8.37 (d, J = 4.8 Hz, 2H), 8.03 – 8.01 (m, 2H), 7.61 – 7.57 (m,
1H), 7.52 – 7.48 (m, 2H), 7.04 (d, J = 2.6 Hz, 1H), 6.92 (d, J =
2.6 Hz, 1H), 6.91 – 6.89 (m, 1H), 6.57 (s, 1H), 4.80 (s, 2H),
3.87 (s, 3H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 196.4,
158.0, 157.6, 155.6, 137.6, 135.0, 132.8, 132.0, 130.3, 128.7,
128.3, 117.0, 116.2, 112.2, 110.6, 102.6, 55.8, 41.1.
ESI-LRMS (m/z): 344 [M+H]+; HRMS (ESI) calculated for
C18H19FN3O3 [M+H]+: 344.1405, found: 344.1409.
1-phenyl-2-(1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-indol
-2-yl)ethan-1-one (6ia). White solid, (according to the general
procedure-2: 59.5 mg, yield 78%). M.p. 185–187 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 9.6 Hz, 1H),
8.44 (d, J = 4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.85 (s, 1H),
7.63 – 7.59 (m, 1H), 7.54 – 7.50 (m, 3H), 7.00 (t, J = 4.8 Hz,
1H), 6.71 (s, 1H), 4.87 (s, 2H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 196.1, 157.9, 157.8, 138.5, 137.3, 136.4,
133.1, 129.0, 128.8, 128.3, 126.3, 124.4 (q, JC-F = 31.8 Hz),
120.0 (q, JC-F = 3.8 Hz), 117.5 (q, JC-F = 4.3 Hz), 117.2, 116.2,
110.5, 40.8. 19F NMR (471 MHz, Chloroform-d) δ -60.85.
ESI-LRMS (m/z): 382 [M+H]+; HRMS (ESI) calculated for
C21H15F3N3O [M+H]+: 382.1162, found: 382.1161.
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19
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27
28
29
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31
32
33
34
35
36
37
38
39
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41
42
43
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48
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2-(6-fluoro-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ja). White solid, (according to the general
procedure-2: 49.0 mg, yield 74%). M.p. 162–164 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (500 MHz, Chloroform-d) δ 8.44 (dd, J = 11.4, 2.4
Hz, 1H), 8.38 (d, J = 4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.62 –
7.58 (m, 1H), 7.52 – 7.45 (m, 3H), 7.01 – 6.97 (m, 1H), 6.93 (t,
J = 4.8 Hz, 1H), 6.60 (s, 1H), 4.81 (s, 2H). 13C{1H} NMR (125
MHz, Chloroform-d) δ 196.3, 160.5 (d, JC-F = 237.1 Hz),
133.0, 130.2 (d, JC-F = 10.1 Hz), 128.8, 128.23, 117.1 (d, JC-F
=
8.8 Hz), 116.6, 111.0 (d, JC-F = 24.7 Hz), 110.4 (d, JC-F = 4.0
Hz), 105.3 (d, JC-F = 23.5 Hz), 41.0. 19F NMR (471 MHz,
Chloroform-d) δ -122.02. ESI-LRMS (m/z): 332 [M+H]+;
HRMS (ESI) calculated for C20H15FN3O [M+H]+: 332.1194,
found: 332.1196.
158.0, 157.7, 137.4, 137.1 (d, JC-F = 13.2 Hz), 134.8 (d, JC-F
=
3.8 Hz), 132.9, 128.8, 128.2, 125.8, 120.5 (d, JC-F = 10.0 Hz),
116.7, 110.5 (d, JC-F = 24.3 Hz), 110.3, 103.5 (d, JC-F = 29.4
Hz), 41.0. 19F NMR (471 MHz, Chloroform-d) δ -119.10.
ESI-LRMS (m/z): 332 [M+H]+; HRMS (ESI) calculated for
C20H15FN3O [M+H]+: 332.1194, found: 332.1202.
2-(5-chloro-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6fa). White solid, (according to the general
procedure-2: 57.7 mg, yield 83%). M.p. 167–169 oC.
(Purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 8.9 Hz, 1H),
8.38 (d, J = 4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.63 – 7.58 (m,
1H), 7.53 – 7.49 (m, 3H), 7.23 (dd, J = 8.9, 2.2 Hz, 1H), 6.94
(t, J = 4.8 Hz, 1H), 6.58 (s, 1H), 4.81 (d, J = 0.9 Hz, 2H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 196.1, 157.9,
157.7, 137.4, 135.9, 135.4, 133.0, 130.6, 128.8, 128.2, 127.7,
123.4, 119.5, 117.2, 116.8, 109.9, 40.9. ESI-LRMS (m/z): 348
[M+H]+; HRMS (ESI) calculated for C20H15ClN3O [M+H]+:
348.0898, found: 348.0899.
2-(5-bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ga). White solid, (according to the general
procedure-2: 67.5 mg, yield 86%). M.p. 167–169 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.53 (d, J = 8.9 Hz, 1H),
8.39 (d, J = 4.8 Hz, 2H), 8.03 – 8.01 (m, 2H), 7.69 (d, J = 2.0
Hz, 1H), 7.63 – 7.58 (m, 1H), 7.53 – 7.49 (m, 2H), 7.36 (dd, J
= 8.9, 2.0 Hz, 1H), 6.95 (t, J = 4.8 Hz, 1H), 6.58 (s, 1H), 4.82
(s, 2H). 13C{1H} NMR (100 MHz, Chloroform-d) δ 196.2,
157.9, 157.7, 137.4, 135.8, 135.8, 133.0, 131.2, 128.8, 128.3,
126.1, 122.6, 117.6, 116.8, 115.5, 109.8, 40.9. ESI-LRMS
(m/z): 392 [M+H]+; HRMS (ESI) calculated for C20H15BrN3O
[M+H]+: 392.0393, found: 392.0397.
2-(6-chloro-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ka). Yellow solid, (according to the general
procedure-2: 54.3 mg, yield 78%). M.p. 163–165 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 2.0 Hz, 1H),
8.40 (d, J = 4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.62 – 7.58 (m,
1H), 7.53 – 7.46 (m, 3H), 7.20 (dd, J = 8.3, 1.9 Hz, 1H), 6.96
(t, J = 4.8 Hz, 1H), 6.61 (s 1H), 4.82 (s, 2H). 13C{1H} NMR
(100 MHz, Chloroform-d) δ 196.3, 157.9, 157.8, 137.4, 137.4,
135.2, 133.0, 129.2, 129.0, 128.3, 128.0, 122.80, 120.8, 116.8,
116.2, 110.3, 40.9. ESI-LRMS (m/z): 348 [M+H]+; HRMS
(ESI) calculated for C20H15ClN3O [M+H]+: 348.0898, found:
348.0898.
2-(6-bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6la). White solid, (according to the general
procedure-2: 62.8 mg, yield 80%). M.p. 165–167 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 1.7 Hz, 1H),
8.40 (d, J = 4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.62 – 7.58 (m,
1H), 7.53 – 7.49 (m, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.34 (dd, J
= 8.3, 1.8 Hz, 1H), 6.96 (t, J = 4.8 Hz, 1H), 6.60 (s, 1H), 4.81
(s, 2H). 13C{1H} NMR (100 MHz, Chloroform-d) δ 196.3,
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157.9, 157.8, 137.7, 137.3, 135.2, 133.0, 129.0, 128.3, 128.3, 146.5, 140.2, 138.4, 136.9, 133.4, 132.9, 132.6, 131.2, 129.3,
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125.4, 121.2, 119.0, 117.0, 116.8, 110.4, 40.9. ESI-LRMS
(m/z): 393 [M+H]+; HRMS (ESI) calculated for C20H15BrN3O
[M+H]+: 392.0393, found: 392.0402.
128.5, 128.4, 128.4, 126.9, 122.5, 42.8, 19.4. ESI-LRMS (m/z):
288 [M+H]+; HRMS (ESI) calculated for C20H18NO [M+H]+:
288.1383, found: 288.1377.
2-(6-methyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenyletha
n-1-one (6ma). Yellow solid, (according to the general
procedure-2: 54.3 mg, yield 83%). M.p. 178–180 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 8.39 (d, J =
4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.61 – 7.57 (m, 1H), 7.51 –
7.44 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 4.8 Hz, 1H),
6.58 (s, 1H), 4.78 (s, 2H), 2.52 (s, 3H). 13C{1H} NMR (100
MHz, Chloroform-d) δ 196.6, 158.2, 157.6, 137.5, 137.4,
133.7, 133.2, 132.8, 128.7, 128.3, 127.2, 123.7, 119.7, 116.3,
115.8, 110.4, 40.9, 22.3. ESI-LRMS (m/z): 328 [M+H]+;
HRMS (ESI) calculated for C21H18N3O [M+H]+: 328.1444,
found: 328.1452.
Methyl 2-(2-oxo-2-phenylethyl)-1-(pyrimidin-2-yl)-1H-indo
le-6-carboxylate (6na). White solid, (according to the general
procedure-2: 49.8 mg, yield 67%). M.p. 177–179 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 9.31 – 9.30 (m, 1H),
8.45 (d, J = 4.8 Hz, 2H), 8.04 – 8.01 (m, 2H), 7.93 (dd, J = 8.2,
1.5 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.53 – 7.49 (m, 2H), 6.99 (t,
J = 4.8 Hz, 1H), 6.68 (s, 1H), 4.86 (s, 2H), 3.95 (s, 3H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 196.0, 168.3,
157.9, 157.8, 137.8, 137.3, 136.5, 133.2, 133.0, 128.8, 128.2,
125.0, 123.5, 119.7, 118.0, 117.0, 110.4, 52.1, 40.9.
ESI-LRMS (m/z): 372 [M+H]+; HRMS (ESI) calculated for
C22H18N3O3 [M+H]+: 372.1343, found: 372.1345.
2-(7-ethyl-1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-phenylethan-
1-one (6oa). White solid, (according to the general
procedure-2: 49.8 mg, yield 74%). M.p. 175–177 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.65 (d, J = 4.9 Hz, 2H),
7.92 (d, J = 7.3 Hz, 2H), 7.57–7.53 (m, 3H), 7.45 –7.42 (m,
3H), 7.18 – 7.09 (m, 1H), 6.57 (s, 2H), 4.57 (s, 1H), 2.45 (q, J
= 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125
MHz, Chloroform-d) δ 196.1, 158.9, 158.3, 136.7, 136.1,
135.0, 133.1, 130.1, 129.0, 128.7, 128.4, 123.7, 122.0, 118.7,
118.4, 107.8, 38.9, 26.5, 13.8. ESI-LRMS (m/z): 342 [M+H]+;
HRMS (ESI) calculated for C22H20N3O [M+H]+: 342.1601,
found: 342.1605.
1-(4-fluorophenyl)-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)etha
n-1-one (6ab). White solid, (according to the general
procedure-2: 51.0 mg, yield 77%). M.p. 168–170 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 8.3 Hz, 1H),
8.40 (d, J = 4.7 Hz, 2H), 8.07 – 8.03 (m, 2H), 7.57 (d, J = 8.4
Hz, 1H), 7.31 – 7.28 (m, 1H), 7.24 – 7.21 (m, 1H), 7.19 – 7.14
(m, 2H), 6.93 (t, J = 4.8 Hz, 1H), 6.63 (s, 1H), 4.78 (s, 2H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 195.0, 165.6 (d,
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5
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7
8
9
10
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12
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16
17
18
19
20
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34
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36
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40
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48
49
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53
54
55
56
57
58
59
60
JC-F = 254.2 Hz), 158.2, 157.7, 137.1, 134.1, 133.8 (d, JC-F
=
2.8 Hz), 130.9 (d, JC-F = 9.1 Hz), 129.4, 123.5, 122.3, 120.2,
116.5, 115.8 (d, JC-F = 21.9 Hz), 110.7, 40.8. 19F NMR (471
MHz, Chloroform-d) δ -105.82. ESI-LRMS (m/z): 332
[M+H]+; HRMS (ESI) calculated for C20H15FN3O [M+H]+:
332.1194, found: 332.1191.
1-(4-chlorophenyl)-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)eth
an-1-one (6ac). White solid, (according to the general
procedure-2: 50.8 mg, yield 73%). M.p. 179–181 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 8.4 Hz, 1H),
8.39 (d, J = 4.7 Hz, 2H), 7.98 – 7.95 (m, 2H), 7.57 (d, J = 8.0
Hz, 1H), 7.49 – 7.46 (m, 2H), 7.31 – 7.28 (m, 1H), 7.23 (td, J
= 7.5, 1.1 Hz, 1H), 6.93 (t, J = 4.8 Hz, 1H), 6.63 (s, 1H), 4.77
(s, 2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 195.0,
158.1, 157.7, 139.2, 137.1, 135.8, 134.0, 129.7, 129.4, 129.1,
123.5, 122.4, 120.2, 116.5, 116.0, 110.8, 40.9. ESI-LRMS
(m/z): 348 [M+H]+; HRMS (ESI) calculated for C20H15ClN3O
[M+H]+: 348.0898, found: 348.0907.
2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-(p-tolyl)ethan-1-one
(6ad). Yellow solid, (according to the general procedure-2:
o
57.6 mg, yield 88%). M.p. 163–165 C. (purified by silica gel
chromatography using PE/EA 15:1–5:1). 1H NMR (400 MHz,
Chloroform-d) δ 8.61 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 4.8 Hz,
2H), 7.92 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.31 –
7.20 (m, 4H), 6.93 (t, J = 4.8 Hz, 1H), 6.63 (s, 1H), 4.80 (s,
2H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, Chloroform-d) δ
196.2, 158.2, 157.7, 143.6, 137.1, 134.9, 134.6, 129.5, 129.4,
128.4, 123.3, 122.2, 120.1, 116.5, 115.8, 110.5, 40.8, 21.8.
ESI-LRMS (m/z): 328 [M+H]+; HRMS (ESI) calculated for
C21H18N3O [M+H]+: 328.1444, found: 328.1446.
2-(5-methyl-2-(pyridin-2-yl)phenyl)-1-phenylethan-1-one
(6pa). Light yellow solid, (according to the general
Methyl 4-(2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)acetyl)benzo
ate (6ae). Yellow solid, (according to the general
procedure-2: 52.0 mg, yield 70%). M.p. 164–166 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J = 8.3 Hz, 1H),
8.33 (d, J = 4.8 Hz, 2H), 8.18 – 8.15 (m, 2H), 8.08 – 8.05 (m,
2H), 7.57 (d, J = 7.0 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.25 – 7.21
(m, 1H), 6.90 (t, J = 4.8 Hz, 1H), 6.65 (s, 1H), 4.79 (s, 2H),
3.97 (s, 3H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 195.8,
166.4, 158.0, 157.6, 140.9, 137.1, 133.8, 133.6, 130.0, 129.4,
128.2, 123.5, 122.4, 120.2, 116.5, 116.0, 111.0, 52.6, 41.1.
ESI-LRMS (m/z): 372 [M+H]+; HRMS (ESI) calculated for
C22H18N3O3 [M+H]+: 372.1343, found: 372.1351.
2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-(4-(trifluoromethyl)p
henyl)ethan-1-one (6af). White solid, (according to the
general procedure-2: 45.8 mg, yield 60%). M.p. 168–170 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 7.4 Hz, 1H),
8.35 (d, J = 4.8 Hz, 2H), 8.11 (d, J = 7.7 Hz, 2H), 7.77 (d, J =
8.1 Hz, 2H), 7.58 (d, J = 7.7 Hz, 1H), 7.33 – 7.29 (m, 1H),
o
procedure-2: 31.0 mg, yield 54%). M.p. 66–68 C. (purified
by silica gel chromatography using PE/EA 15:1–5:1). 1H
NMR (500 MHz, Chloroform-d) δ 8.36 (d, J = 4.7 Hz, 1H),
7.90 (d, J = 7.7 Hz, 2H), 7.67 (t, J = 8.7 Hz, 1H), 7.53 – 7.50
(m, 1H), 7.45 – 7.39 (m, 4H), 7.19 (d, J = 7.9 Hz, 1H), 7.15 (s,
1H), 7.12 – 7.10 (m, 1H), 4.50 (s, 2H), 2.39 (s, 3H). 13C{1H}
NMR (125 MHz, Chloroform-d) δ 198.2, 159.6, 148.6, 138.5,
137.3, 137.2, 136.7, 133.3, 132.7, 129.9, 128.5, 128.4, 128.2
123.8, 121.6, 43.7, 21.3. ESI-LRMS (m/z): 288 [M+H]+;
HRMS (ESI) calculated for C20H18NO [M+H]+: 288.1383,
found: 288.1378.
2-(2-(3-methylpyridin-2-yl)phenyl)-1-phenylethan-1-one
(6qa). Yellow solid, (according to the general procedure-2:
o
48.9 mg, yield 85%). M.p. 86–88 C. (purified by silica gel
1
chromatography using PE/EA 15:1–5:1). H NMR (500 MHz,
Chloroform-d) δ 8.42 (d, J = 6.6 Hz, 1H), 7.76– 7.73 (m, 2H),
7.51 – 7.46 (m, 2H), 7.37 – 7.32 (m, 5H), 7.25 – 7.23 (m, 1H),
7.10 (dd, J = 7.7, 4.7 Hz, 1H), 4.22 (s, 2H), 2.13 (s, 3H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 197.9, 158.9,
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7.24 – 7.22 (m, 1H), 6.92 (t, J = 4.8 Hz, 1H), 6.64 (s, 1H), 1-(naphthalen-2-yl)-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)eth
4.78 (s, 2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 195.2,
158.0, 157.6, 140.3, 137.1, 134.2 (q, JC-F = 32.9 Hz), 133.6,
129.4, 128.6, 125.8 (q, JC-F = 3.7 Hz), 123.8 (q, JC-F = 272.7
Hz), 123.6, 122.4, 120.2, 116.5, 116.1, 110.9, 41.1. 19F NMR
(471 MHz, Chloroform-d) δ -62.97. ESI-LRMS (m/z): 382
[M+H]+; HRMS (ESI) calculated for C21H15F3N3O [M+H]+:
382.1162, found: 382.1169.
1-(3-bromophenyl)-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)eth
an-1-one (6ag). Yellow solid, (according to the general
procedure-2: 66.7 mg, yield 85%). M.p. 180–182 oC.
(purified by silica gel chromatography using PE/EA 15:1–5:1).
1H NMR (500 MHz, Chloroform-d) δ 8.64 (d, J = 8.3 Hz, 1H),
8.40 (d, J = 4.8 Hz, 2H), 8.17 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H),
7.72 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.38 (t, J =
7.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H),
6.94 (t, J = 4.8 Hz, 1H), 6.64 (s, 1H), 4.77 (s, 2H). 13C{1H}
NMR (125 MHz, Chloroform-d) δ 195.1, 158.1, 157.7, 139.3,
137.1, 135.7, 133.8, 131.3, 130.4, 129.4, 126.8, 123.6, 123.1,
122.4, 120.2, 116.5, 116.0, 110.8, 41.0. ESI-LRMS (m/z): 392
[M+H]+; HRMS (ESI) calculated for C20H15BrN3O [M+H]+:
392.0393, found: 392.0400.
1-(2-fluorophenyl)-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)etha
n-1-one (6ah). Yellow solid, (according to the general
procedure-2: 46.4 mg, yield 70%). M.p. 132–134 oC.
(purified by silica gel chromatography using PE/EA 8:1–2:1).
1H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 8.4 Hz, 1H),
8.41 (d, J = 4.8 Hz, 2H), 7.84 (td, J = 7.6, 1.9 Hz, 1H), 7.58 (d,
J = 7.7 Hz, 1H), 7.56 – 7.51 (m, 1H), 7.31 – 7.17 (m, 4H),
6.93 (t, J = 4.8 Hz, 1H), 6.67 (s, 1H), 4.79 (d, J = 2.4 Hz, 2H).
13C{1H} NMR (125 MHz, Chloroform-d) δ 194.8, 161.6 (d, J
= 253.5 Hz), 158.0, 157.6, 137.0, 134.2 (d, J = 11.7 Hz), 134.1,
131.0 (d, J = 3.0 Hz), 129.4, 126.5 (d, J = 13.6 Hz), 124.6 (d, J
= 3.5 Hz), 123.4, 122.3, 120.2, 116.7 (d, J = 23.6 Hz), 116.4,
115.9, 110.6, 45.2 (d, J = 8.5 Hz). 19F NMR (471 MHz,
Chloroform-d) δ -109.70. ESI-LRMS (m/z): 332 [M+H]+;
HRMS (ESI) calculated for C20H14FN3O [M+H]+: 332.1194,
found: 332.1186.
1-(2-bromophenyl)-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)eth
an-1-one (6ai). Yellow solid, (according to the general
procedure-2: 71.4 mg, yield 91%). M.p. 172–174 oC.
(purified by silica gel chromatography using PE/EA 8:1–2:1).
1H NMR (500 MHz, Chloroform-d) δ 8.58 (d, J = 8.4 Hz, 1H),
8.54 (d, J = 4.8 Hz, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.59 – 7.57
(m, 2H), 7.37 (td, J = 7.5, 1.2 Hz, 1H), 7.30 – 7.27 (m, 2H),
7.22 (td, J = 7.4, 1.1 Hz, 1H), 7.01 (t, J = 4.8 Hz, 1H), 6.69 (s,
1H), 4.82 (s, 2H). 13C{1H} NMR (125 MHz, Chloroform-d) δ
198.7, 158.1, 157.9, 140.9, 137.0, 134.2, 133.4, 131.8, 129.8,
129.4, 127.4, 123.5, 122.3, 120.3, 119.4, 116.6, 115.7, 110.9,
44.4. ESI-LRMS (m/z): 392 [M+H]+; HRMS (ESI) calculated
for C20H15BrN3O [M+H]+: 392.0393, found: 392.0398.
an-1-one (6ak). White solid, (according to the general
procedure-2: 65.4 mg, yield 90%). M.p. 147–149 oC.
(purified by silica gel chromatography using PE/EA 8:1–2:1).
1H NMR (600 MHz, Chloroform-d) δ 8.66 (d, J = 8.3 Hz, 1H),
8.59 (s, 1H), 8.34 (d, J = 4.7 Hz, 2H), 8.09 (dd, J = 8.5, 1.8 Hz,
1H), 8.00 (d, J = 8.3 Hz, 1H), 7.95 – 7.91 (m, 2H), 7.65 – 7.62
(m, 1H), 7.60 – 7.57 (m, 2H), 7.33 – 7.30 (m, 1H), 7.26 – 7.23
(m, 1H), 6.85 (t, J = 4.8 Hz, 1H), 6.68 (s, 1H), 4.95 (s, 2H).
13C{1H} NMR (150 MHz, Chloroform-d) δ 196.4, 158.1,
157.6, 137.1, 135.5, 134.8, 134.4, 132.7, 129.6, 129.6, 129.5,
128.5, 128.4, 127.9, 126.9, 124.3, 123.4, 122.2, 120.1, 116.4,
115.9, 110.6, 41.0. ESI-LRMS (m/z): 364 [M+H]+; HRMS
(ESI) calculated for C24H18N3O [M+H]+: 364.1444, found:
364.1447.
2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-(thiophen-2-yl)ethan
-1-one (6al). Yellow solid, (according to the general
procedure-2: 58.1 mg, yield 91%). M.p. 133–135 oC.
(purified by silica gel chromatography using PE/EA 15:1–8:1).
1H NMR (600 MHz, Chloroform-d) δ 8.62 (d, J = 8.4 Hz, 1H),
8.44 (d, J = 4.8 Hz, 2H), 7.78 (dd, J = 3.8, 1.2 Hz, 1H), 7.62
(dd, J = 5.0, 1.2 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.31 – 7.29
(m, 1H), 7.25 – 7.22 (m, 1H), 7.15 (dd, J = 5.0, 3.7 Hz, 1H),
6.94 (t, J = 4.8 Hz, 1H), 6.66 (s, 1H), 4.74 (s, 2H). 13C{1H}
NMR (125 MHz, Chloroform-d) δ 189.2, 158.1, 157.7, 144.2,
137.1, 133.8, 133.0, 131.7, 129.4, 128.1, 123.5, 122.3, 120.2,
116.6, 115.8, 110.8, 42.0. ESI-LRMS (m/z): 320 [M+H]+;
HRMS (ESI) calculated for C18H14N3OS [M+H]+: 320.0852,
found: 320.0852.
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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42
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58
59
60
1-cyclohexyl-2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)ethan-1-o
ne (6am). White solid, (according to the general procedure-2:
o
47.9 mg, yield 75%). M.p. 124–126 C. (purified by silica gel
chromatography using PE/EA 15:1–8:1). 1H NMR (400 MHz,
Chloroform-d) δ 8.66 (d, J = 4.8 Hz, 2H), 8.55 (d, J = 9.3 Hz,
1H), 7.56 (d, J = 8.3 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.24 – 7.20
(m, 1H), 7.07 (t, J = 4.8 Hz, 1H), 6.56 (s, 1H), 4.22 (s, 2H),
2.56 (tt, J = 11.5, 3.4 Hz, 1H), 1.91 – 1.62 (m, 5H), 1.45 –
1.34 (m, 2H), 1.29 – 1.19 (m, 3H). 13C{1H} NMR (125 MHz,
Chloroform-d) δ 209.7, 158.1, 157.8, 137.0, 134.5, 129.3,
123.3, 122.2, 120.1, 116.7, 115.4, 110.0, 49.8, 43.1, 28.7, 26.0,
25.8. ESI-LRMS (m/z): 320 [M+H]+; HRMS (ESI) calculated
for C20H22N3O [M+H]+: 320.1757, found: 320.1766.
3,3-dimethyl-1-(1-(pyrimidin-2-yl)-1H-indol-2-yl)butan-2-o
ne (6an). White solid, (according to the general procedure-2:
o
48.7 mg, yield 83%). M.p. 139–141 C. (purified by silica gel
1
chromatography using PE/EA 15:1–8:1). H NMR (400 MHz,
Chloroform-d) δ 8.67 (d, J = 4.8 Hz, 2H), 8.53 (d, J = 9.2 Hz,
1H), 7.54 (d, J = 8.3 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.22 – 7.18
(m, 1H), 7.04 (t, J = 4.8 Hz, 1H), 6.50 (s, 1H), 4.53 (s, 2H),
1.24 (s, 9H). 13C{1H} NMR (125 MHz, Chloroform-d) δ 211.0,
158.5, 157.8, 137.3, 134.5, 129.3, 123.1, 122.1, 120.0, 116.6,
115.5, 109.6, 44.3, 39.2, 27.1. ESI-LRMS (m/z): 294 [M+H]+;
HRMS (ESI) calculated for C18H20N3O [M+H]+: 294.1601,
found: 294.1607.
Gram-Scale Synthesis of 3aa. To a 25 mL of Schlenk tube,
2-phenylpyridine (1a, 6.5 mmol) and α-Cl acetophenone (2a,
9.1 mmol), [Ru(p-cymene)Cl2]2 (199 mg, 5 mol%), AgOAc
(326 mg, 30 mol%) and NaHCO3 (819 mg, 9.75 mmol) was
added under air. The mixture was then evacuated and
backfilled with nitrogen (three times). HFIP (10.0 mL) was
added subsequently. The reaction mixture was stirred at 90 oC
for 20 h. After that, the solvent was removed under reduced
pressure and the residue was purified by silica gel
chromatography using PE/EA (8:1) to afford the desired
2-(1-(pyrimidin-2-yl)-1H-indol-2-yl)-1-(3,4,5-trimethoxyphe
nyl)ethan-1-one (6aj). White solid, (according to the general
procedure-2: 65.4 mg, yield 81%). M.p. 177–179 oC.
(purified by silica gel chromatography using PE/EA 8:1–2:1).
1H NMR (400 MHz, Chloroform-d) δ 8.60 (d, J = 8.4 Hz, 1H),
8.47 (d, J = 4.8 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.32 – 7.27
(m, 3H), 7.22 (td, J = 7.4, 1.1 Hz, 1H), 6.97 (t, J = 4.8 Hz, 1H),
6.63 (s, 1H), 4.81 (s, 2H), 3.92 (d, J = 18.3 Hz, 9H). 13C{1H}
NMR (100 MHz, Chloroform-d) δ 195.3, 158.2, 157.8, 153.2,
142.3, 137.1, 134.34, 132.6, 129.4, 123.4, 122.3, 120.2, 116.6,
115.8, 110.4, 105.7, 61.1, 56.4, 40.8. ESI-LRMS (m/z): 404
[M+H]+; HRMS (ESI) calculated for C23H22N3O4 [M+H]+:
404.1605, found: 404.1613.
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7.50 – 7.47 (m, 2H), 7.43 – 7.41 (m, 1H), 7.23 (ddd, J = 6.7,
product 3aa as a yellow solid (710.7 mg, 40%).
1
2
3
4
5
6
7
Gram-Scale Synthesis of 6aa. To a 25 mL of Schlenk tube,
(pyrimidin-2-yl)-1H-indole (1a, 5.15 mmol) and α-benzoyl
sulfur ylide (5a, 6.18 mmol), [Ru(p-cymene)Cl2]2 (158 mg, 5
mol%) and AgSbF6 (177 mg, 10 mol%) was added under air.
The mixture was then evacuated and backfilled with nitrogen
(three times). HFIP (10.0 mL) was added subsequently. The
4.8, 1.7 Hz, 1H).
Deuterium incorporation experiment of products [D]n-3aa.
To a 25 mL of Schlenk tube, 2-phenylpyridine (1a, 0.2 mmol)
and α-Cl acetophenone (2a, 0.28 mmol), [Ru(p-cymene)Cl2]2
(5 mol%), AgOAc (30 mol%) and NaHCO3 (1.5 equiv.) was
added under air. The mixture was then evacuated and
backfilled with nitrogen (three times). HFIP-d2 (3.0 mL) was
added subsequently. The reaction mixture was stirred at 90 oC
for 4 h. After that, the solvent was removed under reduced
pressure and the residue was purified by silica gel
chromatography using PE/EA (8:1) to afford the product
o
reaction mixture was stirred at 90 C for 8 h. After that, the
solvent was removed under reduced pressure and the residue
was purified by silica gel chromatography using PE/EA (8:1)
to afford the desired product 6aa as a white solid (1.3 g, 79%).
Removal of the Pyrimidyl Group Following the modified
procedure from Aϊssa et al.,20a a dried schlenk tube was
charged with 6aa (94 mg, 0.3 mmol, 1.0 equiv), freshly
prepared NaOEt (82 mg, 2.0 mmol, 4 equiv.) and then
evacuated and backfilled with nitrogen (three times). DMSO
(2.0 mL) was added subsequently. The reaction mixture was
8
9
10
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12
13
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15
16
17
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19
20
21
22
23
24
25
26
27
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46
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48
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54
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56
57
58
59
60
1
[D]n-3aa as a yellow solid, which was characterized by H
NMR spectroscopy. 1H NMR analysis of the product [D]n-3aa,
suggesting 58% deuterated ratio at the ortho position of the
pyridine ring, and the benzene of both ortho positions of
carbonyl group observed 25% deuteration (see SI, 1H NMR).
[D]n-3aa (coupling with 2a): 1H NMR (500 MHz,
Chloroform-d) δ 8.40 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 7.3 Hz,
1.5H), 7.69 (td, J = 7.7, 1.9 Hz, 1H), 7.54 – 7.49 (q, J = 9.2,
8.3 Hz, 1.42H), 7.46 (d, J = 7.9 Hz, 1H), 7.43 – 7.37 (m, 4H),
7.35 – 7.32 (m, 1H), 7.13 (dd, J = 7.5, 4.9 Hz, 1H), 4.52 (s,
2H).
o
stirred at 120 C for 24 h. Once completed, the reaction was
cooled down to room temperature, diluted with EtOAc and
washed with brine. The aqueous phase was extracted three
time with EtOAc and the combined organic phase was dried
over MgSO4. After filtration and evaporation of the solvent in
vacuo, the crude product was purified by flash
chromatography on silica gel (PE/EA = 15:1 to 5:1) to give
7aa as a solid (18.4 mg, 26%)
To a 25 mL of Schlenk tube, 2-phenylpyridine (1a, 0.2 mmol)
and
α-benzoyl
sulfur
ylide
(5a,
0.24
mmol),
2-(1H-indol-2-yl)-1-phenylethan-1-one (7aa). solid, (18.4
[Ru(p-cymene)Cl2]2 (5 mol%) and AgSbF6 (10 mol%) was
added under air. The mixture was then evacuated and
backfilled with nitrogen (three times). HFIP-d2 (3.0 mL) was
added subsequently. The reaction mixture was stirred at 90 oC
for 2 h. After that, the solvent was removed under reduced
pressure and the residue was purified by silica gel
chromatography using PE/EA (8:1) to afford the product
o
mg, yield 26%). M.p. 167–169 C. (purified by silica gel
1
chromatography using PE/EA 15:1–8:1). H NMR (500 MHz,
Chloroform-d) δ 8.75 (s, 1H), 8.07 – 8.05 (m, 2H), 7.62 – 7.58
(m, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.51 – 7.47 (m, 2H), 7.35
(dd, J = 8.0 Hz, 1H), 7.16 – 7.13 (m, 1H), 7.09 – 7.05 (m, 1H),
6.40 (d, J = 1.1 Hz, 1H), 4.48 (s, 2H). 13C{1H} NMR (125
MHz, Chloroform-d) δ 197.2, 136.6, 136.4, 133.9, 131.5,
129.0, 128.7, 128.4, 121.8, 120.2, 119.9, 111.0, 102.1, 37.8.
ESI-LRMS (m/z): 236 [M+H]+; HRMS (ESI) calculated for
C14H15NNaO [M+Na]+: 236.1046, found: 236.1049.
1
[D]n-3aa as a yellow solid , which was characterized by H
NMR spectroscopy. 1H NMR analysis of the product [D]n-3aa
revealed 45% deuteration at the ortho position of the
2-phenylpyridine and 24% deuteration at the methine proton
(see SI, 1H NMR).
Mechanistic Investigations
Deuterium Incorporation Experiments
[D]n-3aa (coupling with 5a): 1H NMR (600 MHz,
Chloroform-d) δ 8.39 (d, J = 3.9 Hz, 1H), 7.89 (d, J = 7.4 Hz,
2H), 7.70 (td, J = 7.7, 1.9 Hz, 1H), 7.54 – 7.49 (m, 1.55H),
7.47 (d, J = 7.9 Hz, 1H), 7.43 – 7.38 (m, 4H), 7.34 – 7.32 (m,
1H), 7.15 – 7.13 (m, 1H), 4.53 (s, 1.76H).
Preparation of substrates 1a-d5 and 1a. The structure of
2-(phenyl-d5)pyridine (1a-d5) and 2-phenylpyridine (1a) were
characterized by 1H NMR analysis (see SI, 1H NMR);
2-(phenyl-d5)pyridine (1a-d5) was synthesized according to the
known procedure.27
KIE Experiments
KIE experiment of products 3aa and 3aa-d4 (with 2a). To a
25 mL of Schlenk tube, α-Cl acetophenone (2a, 0.28 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%), AgOAc (30 mol%) and
NaHCO3 (1.5 equiv.) was added under air. The mixture was
then evacuated and backfilled with nitrogen (three times).
HFIP (3.0 mL) was added subsequently. To the parallel tubes
was then separately introduced 1a or 1a-d5 (0.2 mmol). The
1
1a-d5: H NMR (600 MHz, Chloroform-d) δ 8.70 (d, J = 5.0
Hz, 1H), 7.77 – 7.72 (m, 2H), 7.25 – 7.22 (m, 1H);
1a: 1H NMR (600 MHz, Chloroform-d) δ 8.70 (d, J = 4.6 Hz,
1H), 8.01 – 7.99 (m, 2H), 7.76 – 7.72 (m, 2H), 7.50 – 7.47 (m,
2H), 7.43 – 7.41 (m, 1H), 7.24 – 7.22 (m, 1H).
Deuterium incorporation experiment of substrate 1a. To a
25 mL of Schlenk tube, 2-phenylpyridine (1a, 0.2 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%), AgOAc (30 mol%) and
NaHCO3 (1.5 equiv.) was added under air. The mixture was
then evacuated and backfilled with nitrogen (three times).
HFIP-d2 (3.0 mL) was added subsequently. The reaction
mixture was stirred at 90 oC for 4 h. After that, the solvent was
removed under reduced pressure and the residue was purified
by silica gel chromatography using PE/EA (8:1) to afford the
recovery product [D]n-1a as a white oil (20.2 mg, 65%), which
was characterized by 1H NMR spectroscopy. 1H NMR analysis
of the product [D]n-1a revealed 72% deuteration at both ortho
positions of the phenyl ring (see SI, 1H NMR).
o
reaction mixtures were stirred side-by-side at 90 C for 4 h.
After that, the mixtures were then combined and removed
under reduced pressure and the residue was purified by silica
gel chromatography using PE/EA (8:1) to afford a mixture of
3aa and 3aa-d4. The KIE value was determined to be kH/kD =
1
1
0.56/0.44 = 1.3 on the basis of H NMR analysis (see SI, H
NMR).
KIE experiment of products 3aa and 3aa-d4 (with 5a). To a
25 mL of Schlenk tube, α-benzoyl sulfur ylide (5a, 0.24
mmol), [Ru(p-cymene)Cl2]2 (5 mol%) and AgSbF6 (10 mol%)
was added under air. The mixture was then evacuated and
backfilled with nitrogen (three times). HFIP (3.0 mL) was
added subsequently. To the parallel tubes was then separately
introduced 1a or 1a-d5 (0.2 mmol). The reaction mixtures were
[D]n-1a: 1H NMR (600 MHz, Chloroform-d) δ 8.71 – 8.70 (m,
1H), 8.00 (dd, J = 8.3, 1.3 Hz, 0.56H), 7.77 – 7.72 (m, 2H),
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o
(b) Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N.
stirred side-by-side at 90 C for 4 h. After that, the mixtures
were then combined and removed under reduced pressure and
the residue was purified by silica gel chromatography using
PE/EA (8:1) to afford a mixture of 3aa and 3aa-d4. The KIE
value was determined to be kH/kD = 0.58/0.42 = 1.4 on the
basis of 1H NMR analysis (see SI, 1H NMR).
Ruthenium-catalyzed regioselective direct alkylation of arenes
with unactivated alkyl halides through C-H bond cleavage.
Angew. Chem. Int. Ed. 2009, 48, 9792–9826. (c) Lyons, T. W.;
Sanford, M. S. Palladium-Catalyzed Ligand-Directed C−H
Functionalization Reactions. Chem. Rev. 2010, 110,
1147–1169. (d) Yeung, C. S.; Dong, V. M. Catalytic
Dehydrogenative Cross-Coupling: Forming Carbon–Carbon
Bonds by Oxidizing Two Carbon−Hydrogen Bonds. Chem.
Rev. 2011, 111, 1215–1292. (e) Ackermann, L.
Carboxylate-Assisted Transition-Metal-Catalyzed C−H Bond
Functionalizations: Mechanism and Scope. Chem. Rev. 2011,
111, 1315–1345. (f) Arockiam, P. B.; Bruneau, C.; Dixneuf, P.
H. Ruthenium(II)-Catalyzed C–H Bond Activation and
Functionalization. Chem. Rev. 2012, 112, 5879−5918. (g)
Zhang, Y. F.; Jie, X. M.; Zhao, H. Q.; Li, G.; Su, W. P. Recent
advances in directed C-H functionalizations using monodentate
nitrogen-based directing groups. Org. Chem. Front. 2014, 1,
843–895.
1
2
3
4
5
6
7
8
Competition Experiments
Competition experiment of 1d and 1e coupling with 2a. To
a 25 mL of Schlenk tube, 2-(4-methoxyphenyl)pyridine (1d,
0.2 mmol), 2-[4-(trifluoromethyl)phenyl]pyridine (1e, 0.2
mmol) and α-Cl acetophenone (2a, 0.28 mmol),
[Ru(p-cymene)Cl2]2 (5 mol%), AgOAc (30 mol%) and
NaHCO3 (1.5 equiv.) was added under air. The mixture was
then evacuated and backfilled with nitrogen (three times).
HFIP (3.0 mL) was added subsequently. The reaction mixture
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24
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26
27
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
was stirred at 90 C for 20 h. After that, the solvent was
removed under reduced pressure and the residue was purified
by silica gel chromatography using PE/EA (8:1) to afford a
mixture of 3da and 3ea. The ratio of 3da : 3ea = 1 : 0.57 was
determined on the basis of H NMR analysis (see SI, H
NMR).
Competition experiment of 4p and 1e coulping with 5a. To
a 25 mL of Schlenk tube, 2-(4-methylphenyl)pyridine (4p, 0.2
mmol), 2-[4-(trifluoromethyl)phenyl]pyridine (1e, 0.2 mmol)
(2) (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A.
Rhodium(III)-Catalyzed Arylation of Boc-Imines via C−H
Bond Functionalization. J. Am. Chem. Soc. 2011, 133,
1248–1250. (b) Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang,
X.-S.; Chen, K.; Shi, Z.-J. Rhodium-Catalyzed Direct Addition
of Aryl C-H Bonds to N-Sulfonyl Aldimines. Angew. Chem.
Int. Ed. 2011, 50, 2115–2119. (c) Li, Y.; Zhang, X.-S.; Li, H.;
Wang, W.-H. Chen, K.; Li, B.-J.; Shi, Z.-J. Mechanistic
understanding of Rh-catalyzed N-sulfonylaldimine insertion
into aryl C–H bonds. Chem. Sci. 2012, 3, 1634–1639. (d) Gao,
K.; Yoshikai, N. Cobalt-catalyzed arylation of aldimines via
directed C–H bond functionalization: addition of
2-arylpyridines and self-coupling of aromatic aldimines. Chem.
Commun. 2012, 48, 4305–4307. (e) Li, Y.; Zhang, X.-S.; Li, H.;
Wang, W.-H.; Chen, K.; Li, B.-J.; Shi, Z.-J. Mechanistic
understanding of Rh-catalyzed N-sulfonylaldimine insertion
into aryl C–H bonds. Chem. Sci. 2012, 3, 1634–1639. (f) Li, Y.;
Zhang, X.-S.; Chen, K.; He, K.-H.; Pan, F.; Li, B.-J.; Shi, Z.-J.
N-Directing Group Assisted Rhodium-Catalyzed Aryl C–H
Addition to Aryl Aldehydes. Org Lett. 2012, 14, 636–639. (g)
K. Parthasarathy, A. R. Azcargorta, Y. Cheng and C. Bolm,
Directed Additions of 2-Arylpyridines and Related Substrates
to Cyclic Imines through Rhodium-Catalyzed C–H
Functionalization. Org Lett. 2014, 16, 2538–2541.
1
1
and
α-benzoyl
sulfur
ylide
(5a,
0.24
mmol),
[Ru(p-cymene)Cl2]2 (5 mol%) and AgSbF6 (10 mol%) was
added under air. The mixture was then evacuated and
backfilled with nitrogen (three times). HFIP (3.0 mL) was
added subsequently. The reaction mixture was stirred at 90 oC
for 24 h. After that, the solvent was removed under reduced
pressure and the residue was purified by silica gel
chromatography using PE/EA (8:1) to afford a mixture of 6pa
and 3ea. The ratio of 6pa : 3ea = 1 : 0.28 was determined on
the basis of 1H NMR analysis (see SI, 1H NMR).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
Optimization studies, mechanistic experiments, single crystal
(3) (a) Li, X.; Yu, S.; Wang, F.; Wan, B.; Yu, X.
Rhodium(III)-Catalyzed C–C Coupling between Arenes and
Aziridines by C–H Activation. Angew. Chem. Int. Ed. 2013, 52,
2577–2580. (b) Gao, K.; Paira, R.; Yoshikai, N.
Cobalt-Catalyzed ortho-C–H Alkylation of 2-Arylpyridines via
Ring−Opening of Aziridines. Adv. Synth. Catal. 2014, 356,
1486–1490. (c) Kong, L.; Biletskyi, B.; Nuel, D.; Clavier, H.
Cobalt(III)-catalysed C–H allylation with vinylaziridines. Org.
Chem. Front. 2018, 5, 1600–1603.
1
structure and crystallographic data for 6aa, and copies of H
NMR, 13C{1H} NMR and 19F NMR spectra for the products.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jwang@simm.ac.cn (J. W.).
*E-mail: hliu@simm.ac.cn (H. L.).
(4) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. Palladium-Catalyzed
Alkylation of sp2 and sp3 C−H Bonds with Methylboroxine and
Alkylboronic Acids:ꢀ Two Distinct C−H Activation Pathways.
J. Am. Chem. Soc. 2006, 128, 12634-12635. (b) Neufeldt, S. R.;
Seigerman, C. K.; Sanford, M. S. Mild Palladium-Catalyzed
C–H Alkylation Using Potassium Alkyltrifluoroborates in
Combination with MnF3. Org. Lett. 2013, 15, 2302–2305. (c)
Wang, H.; Yu, S.; Qi, Z.; Li, X. Rh(III)-Catalyzed C–H
Alkylation of Arenes Using Alkylboron Reagents. Org. Lett.
2015, 17, 2812–2815. (d) Peng, P.; Wang, J.; Jiang, H.; Liu, H.
Rhodium(III)-Catalyzed Site-Selective C–H Alkylation and
Arylation of Pyridones Using Organoboron Reagents. Org.
Lett. 2016, 18, 5376–5379.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (No.21672232, 21632008, 21877118, and 81620108027),
National S&T Major Projects (2015ZX09103003) and the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDA12040201) for financial support.
(5) (a) Xiao, Q.; Zhang, Y.; Wang, J. Diazo Compounds and
N-Tosylhydrazones: Novel Cross-Coupling Partners in
Transition-Metal-Catalyzed Reactions. Acc. Chem. Res. 2013,
46, 236–247. (b) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.;
Zhang, Y.; Wang, J. Rhodium(III)-Catalyzed ortho
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