One-Pot Synthesis of Arylketones from Aromatic Acids via Palladium-Catalyzed Suzuki Coupling

Article abstract of DOI:10.1021/acs.joc.5b02667

A palladium-catalyzed one-pot procedure for the synthesis of aryl ketones has been developed. Triazine esters when coupled with aryl boronic acids provided aryl ketones in moderate to excellent yields (up to 95%) in the presence of 1 mol % Pd(PPh₃)₂Cl₂ for 30 min. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02667

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Note
One-pot synthesis of arylketones from aromatic
acids via palladium-catalyzed Suzuki coupling
Hongxiang Wu, Baiping Xu, Yue Li, Fengying Hong, Dezhao Zhu, Junsheng Jian, Xiaoer Pu, and Zhuo Zeng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02667 • Publication Date (Web): 05 Mar 2016
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One-pot synthesis of arylketones from aromatic acids via
palladium-catalyzed Suzuki coupling
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Hongxiang Wu,† Baiping Xu, ‡ Yue Li,† Fengying Hong,† Dezhao Zhu,† Junsheng Jian,† Xiaoer
Pu,† Zhuo Zeng*†
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†College of Chemistry and Environment, South China Normal University, Guangzhou 510006,
People’s Republic of China
‡Guangdong Industry Technical College
*E-mail: zhuoz@scnu.edu.cn
OMe
N
OMe
N
Ar'-B(OH)2
O
NMM
1 h
+
O
N
N
Ar COOH
Ar'
Pd(PPh3)2Cl2, K3PO4
toluene, 110 oC, 30 min
Ar
Ar
O
N
OMe
Cl
N
OMe
One-pot
38 examples
up to 95% yield
ABSTRACT: A palladium-catalyzed one-pot procedure for the synthesis of aryl
ketones has been developed. Triazine esters when coupled with aryl boronic acids
provided aryl ketones in moderate to excellent yields (up to 95%) in the presence of 1
mol % Pd(PPh3)2Cl2 for 30 min.
KEYWORDS: Aromatic acid; Triazine ester; Arylketones; One-pot; Suzuki coupling
Arylketones are commonly used compounds in the preparation of pharmaceutical,1
materials2 and act as useful building blocks in organic chemistry.3 Compared with the
traditional Friedel–Crafts acylation, transition-metal catalyzed acylative Suzuki
coupling is a more effective way of obtaining aryl ketones, due to high functional
group tolerance, regioselectivity and the mild reaction conditions employed.
Transition metal-catalyzed cross-coupling reaction between an aryl boronic acid and
an electrophile, including anhydrides,4 acyl chlorides,5 esters,6 nitriles,7 aldehydes8
and amides9 to form a series of symmetrical or asymmetric ketones was developed in
recent years (Scheme 1, a).
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Carbonylative Suzuki coupling utilizing the C1 building block carbon monoxide is
yet another approach for the synthesis of aryl ketones which utilizes a transition
metal-catalyzed coupling reaction (Scheme 1, b).10 However, this approach should be
operated under rigorously controlled conditions, due to the high toxicity and
flammability of carbon monoxide.
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Cleavage of carbon–oxygen bonds is generally regarded as more difficult than
cleavage of carbon-halogen bonds, due to the higher bond dissociation energy of C–O
bond.11 During the past few years, a series of C–O electrophiles such as pivalates,12
acetates,13 carbamates,14 carbonates,15 sulfonates,16 sulfamates17 and sulfuryl
fluoride18 have been investigated as conveniently available coupling partners in
metal-catalyzed cross-coupling reaction.
It is well-known that 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) is an easily
obtained reagent used in the preparation of the corresponding heteroaryl ethers19 or
esters20 which in turn can be employed as powerful coupling partners. The strongly
polar nature of the 1,3,5-triazine makes facilitates the cleavage of the C–O bond in the
ester and the oxygenated 1,3,5-triazine possesses good leaving group potential which
would could accelerate the trans-metalation process in the catalytic cycle of
cross-coupling reactions.21 Carboxylic acids or amino acids 1,3,5-triazine esters are
reacted with a Grignard/CuI reagent to give the corresponding ketones in nearly
quantitative yields.22 In this type of reactions, functional group tolerance for the
Grignard/CuI reagent needed to be improved. However, the reaction times are
typically long and involve two steps procedures.
Based on the difficulties outlined in the proceeding sections, and considering the
general utility of aryl ketones we set out to develop of a convenient and practical way
of synthesizing aryl ketones directly from aromatic acids. Hence, we are reporting a
facile, palladium-catalyzed Suzuki coupling which employs a triazine ester as key
intermediate to synthesis aryl ketones in one-pot. Firstly, aromatic carboxylic acids
are reacted with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) under very mild
conditions to provide the corresponding triazine ester. Subsequent treatment of the
triazine ester with an aryl boronic acid in the presence of a palladium catalyst resulted
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in a cross-coupling reaction to give aryl ketones in high yields. This is the first
example of a facile synthesis of a diverse range of aryl ketones from aromatic acids
and aryl boronic acid in a one-pot procedure (Scheme 1, c).
9
Scheme 1. Pd-Catalyzed Carbonylative Suzuki Cross-Couplings
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(a) Acylative Suzuki coupling
Ar'B(OH)2
O
Ar
X
Ar
Ar'
Palladium catalyst
O
Ts
X=-CN, -CHO,
N
Ph
(b) Carbonylative Suzuki coupling with CO
Ar'B(OH)2
O
Ar
I
CO
+
Ar
Ar'
Palladium catalyst
(c) One-pot reaction (this work)
OMe
Ar'B(OH)2
O
NMM
+
N
N
Ar COOH
Ar
Ar'
Pd(PPh3)2Cl2, K3PO4
toluene, 110 oC, 30 min
Cl
N
OMe
One-pot
Benzoic acid 1a and phenylboronic acid 2a were chosen as general substrates for
the one-pot synthesis of benzophenone (Table 1). We first carried out the one-pot
reaction in two sequential steps, firstly reacting the aromatic acid and CDMT in
toluene, using 4-methylmorpholine (NMM) as base at room temperature for 1 h, thus
providing the triazine ester. Secondly further reaction of the triazine ester with equal
molar phenylboronic acid in the presence of 5 mol % Pd(OAc)2 catalyst with Na2CO3
as base resulted in benzophenone at low yield (26%). Through modification of
palladium catalyst, the yield of benzophenone increased significantly, for example,
PdCl2, provided 35% yield; Pd(PPh3)2Cl2, provided 61% yield (Table 1, entries 1-3).
The solvent also plays a crucial role in determining the yield. In nearly every case,
the reactions using toluene as solvent had a higher yield than those of the
corresponding reaction which used the polar solvents DMSO, DMF or 1,4-dioxane
(Table 1, entries 4-6). It was found that benzophenone can not be obtained by reacting
triazine ester with phenylboronic acid under the same conditions without base (Table
1, entry 7). The identity of the base also influenced the yield of benzophenone, for
example, changing the base from Na2CO3 to to either K2CO3, Cs2CO3, KF, or K3PO4
gave rise to an increase yield in this protocol.
Through further optimization of the catalyst loading to 1 mol %, the yield of the
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desire product increased to 85%.
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Table 1. Effects of Catalyst, Solvent and Base
OMe
O
1) NMM, toluene, 25 oC, 1 h
COOH
N
N
+
2) PhB(OH)2, Catalyst, Base, 110 oC, 30 min
Cl
N
OMe
2a
9
1a
3aa
CDMT
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yield c
(%)
26
Entry Catalyst (mol %)
Base
Solvent
1
Pd(OAc)2 (5)
Na2CO3 toluene
Na2CO3 toluene
Na2CO3 toluene
Na2CO3 DMSO
Na2CO3 DMF
2
PdCl2(5)
35
3
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (1)
Pd(PPh3)Cl2 (0.1)
Pd(PPh3)2Cl2 (1)
Pd(OAc)2(1)
61
4
trace
21
5
6
Na2CO3 1,4-dioxane
trace
trace
66
7
ND
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
8
K2CO3
CsCO3
K3PO4
KF
9
70
10
11
12
13
14b
15
83
77
K3PO4
K3PO4
K3PO4
K3PO4
85
65
39
63
aReaction conditions (unless otherwise noted): 1a (0.5 mmol), CDMT
(0.5 mmol), NMM (0.5 mmol), solvent (3 mL) were pre-mixed in a 10
mL flask at rt. for 1h, after charging catalyst, base and 2a (0.5 mmol),
the mixture stirred and heated at 110oC for 30 min. bstirred and heated
at 80 oC for 1h. cIsolated yield.
The high yield obtained with the optimized conditions encouraged us to extend this
approach to substituted aromatic acids and aryl boronic acids to synthesize the variety
aryl ketones.
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The scope and limitations of this acylative Suzuki cross-coupling reaction were
explored using aromatic or heterocyclic acids under the optimized reaction conditions
(Table 2). To investigate the influence of electronic factors, a series of aromatic acids
(1b-1g) with electron-withdrawing groups in para-position were coupled to
phenylboronic acid which providing the aryl ketone with yields in the range of
43-90%. The 4-methoxy and 3-methoxy benzoic acids (1h, 1i) were examined as
electron-donating substrates with excellent yield. Further, the methoxy and methyl in
ortho-position on benzene result in decreasing yield, indicating that steric effects are
also a factor. Other aromatic acids 1m, 1n provided 46% and 85% yield respectively.
These results demonstrated that both electron-donating and electron-withdrawing
groups at the aromatic ring are tolerated, except in the case where the aromatic acid
bears a functionality in the ortho-position which provides steric hindrance, for the
examples 1j and 1l. The bulky cyclopentyl and 1-adamantyl acids were coupled to
phenyl boronic acid to give corresponding ketones with 65% and 90% yield
respectively.
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Table 2. Scope of Acylative Suzuki coupling of phenylboronic acid 2a with
Various aromatic acid 1a-1p
O
OMe
OMe
2a
PhB(OH)2
NMM
N
N
O
N
N
Ar
3aa-3pa
Ar COOH
+
toluene, 25 oC, 1 h
Pd(PPh3)2Cl2, K3PO4
toluene, 110 oC, 30 min
Cl
N
OMe
Ar
O
N
OMe
O
1a-1p
O
O
O
Br
F
Cl
43%
3da
74%
3ca
90%
3ba
85%
3aa
O
O
O
O
NC
O2
N
F3C
MeO
81%
3ha
60%
3fa
78%
3ga
68%
3ea
O
O
O
O
OMe
OMe
54%
3la
79%
3ia
19%
3ja
80%
3ka
O
O
O
O
S
46%
3ma
85%
3na
90%
3pa
65%
3oa
In this catalytic system, both electron-deficient and electron-rich aryl boronic acid
demonstrated good reactivity and provided the desire products in moderate to
excellent yields in short reaction times (2b-2p). Coupling of 2-methyl (2d) or 2,
4-dimethyl (2f) phenyl boronic acids with triazine esters gave the corresponding
sterically hindered ketones in 92% and 91% yield, respectively (Table 3).
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Furthermore, heteroaryl ketones 3nt (77%), 3nu (57%), 3vt (55%) and 3wt (61%)
could be synthesized via this approach from 2-thiophenecarboxylic acid and
heteroaryl boronic acids. To our delight, the scope of the aryl boronic acid was wide
in this one-pot reaction, with high functional group compatibility and negligible steric
hindrance effects.
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Table 3. Scope of Acylative Suzuki coupling of thiophene-2-carboxylic acid
acid 1n with Various Arylboronic Acids 2b-2x
OMe
OMe
2b-2x
O
NMM
O
N
N
O
Ar'B(OH)2
N
N
+
toluene, 25 oC, 1 h
OH
O
N
OMe
Pd(PPh3
)2Cl2, K3PO4
Ar'
Cl
N
OMe
S
S
toluene, 110 oC, 30 min
S
1n
3nb-3nx
O
O
O
O
S
S
S
S
S
S
S
92%
3nd
83%
3ne
80%
3nb
82%
3nc
O
O
O
O
S
S
S
OMe
C2H5
95%
3ng
91%
3nf
88%
3nh
85%
3ni
O
O
O
O
F
S
S
S
S
SMe
F
CF3
73%
3nj
79%
3nk
75%
3nl
79%
3nm
O
Cl
O
O
O
Cl
S
S
Cl
80%
3nq
88%
3nn
69%
3no
53%
3np
Cl
O
O
O
O
O
O
S
S
S
S
S
S
45%
3nr
77%
3nt
84%
3ns
57%
3nu
O
O
Boc
O
N
S
S
61%
3nw
55%
3nv
Based on our observations and the known palladium chemistry, a possible
mechanism for the palladium-catalyzed acylative Suzuki coupling reaction is
proposed (Scheme 2): Oxidative addition of the triazine ester to the Pd(0)-species to
generate an acylpalladium(II) complex II; transmetallation between acylpalladium(II)
and the arylboronic acid to create the complex III; finally, reductive elimination to
form the new C-C bond and regeneration of Pd(0)-species.
Scheme 2. Proposed Mechanism for palladium-catalyzed Acylative Suzuki
coupling
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OMe
N
N
ArCOOH
+
Ph3
Ph3
P
P
Cl
Cl
Cl
N
OMe
Pd
+ K3PO4
5
6
7
Ar'B(OH)2
NMM
OMe
N
Ar'-Ar'
(PPh3)nPd(0)
O
N
Ar
O
N
OMe
O
Ar'
8
Ar
9
OMe
N
Ar
O
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O
m(Ph3P)(II)Pd
N
N
OMe
O
Ar
Ar'B(OH)2
Pd(II)(PPh3
Ar'
)
m
B(OH)2
O
N
N
N
MeO
OMe
CONCLUSIONS
In conclusion, a one-pot reaction was developed for the synthesis of asymmetric
aryl ketones using aromatic triazine esters as electrophiles. The procedure employs
low catalyst loadings, and has demonstrated tolerance to a variety of functional
groups. Compared with the previous transition metal-catalyzed protocols, this facile
palladium-catalyzed Suzuki cross-coupling reaction has greater efficiency due to the
two reactions sequence being carried out in a one-pot procedure. This is particularly
important in large-scale synthesis of asymmetric aryl ketones.
EXPERIMENT SECTION
General Procedure: For the synthesis of benzophenone 3. A mixture of the
2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (1.00 mmol, 175.6 mg), benzoic acid
(1.00 mmol, 122.1 mg) and 4-methylmorpholine (1.00 mmol, 101.2 mg) in toluene (5
ml) was stirred at room temperature for 1h. After reaction completion monitoring by
TLC, the flask was charged with Pd(PPh3)2Cl2 (0.01mmol, 7.0mg), K3PO4 (2.00
mmol, 424.5 mg), phenylboronic acid (1.00mmol, 121.9mg) before standard cycles of
evacuation and backfilling with dry nitrogen. The mixture was stirred and heated at
110oC for 30 min. After cooling to room temperature, the mixture was filtrated
through a short pad of silica gel, then the silica gel was washed with CH2Cl2 (3 × 15
mL) and the organic phases were combined. After the solvent was removed, the crude
product was purified by silica gel column chromatography (petroleum
ether/dichloromethane =5:1) to give benzophenone, 3aa. This approach also could be
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run in 10mmol scale to give 83% benzophenone.
Benzophenone (3aa).5b Following general procedure, 3aa was isolated as a white
solid (155 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 7.85 – 7.78 (m, 4H), 7.61 – 7.56
(m, 2H), 7.50 – 7.45 (m, 4H).
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(4-Fluorophenyl)(phenyl)methanone (3ba).10e Following general procedure, 3ba
was isolated as a white solid (181 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.82 (dd,
J = 8.6, 5.5 Hz, 2H), 7.78 – 7.70 (m, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.7 Hz,
2H), 7.14 (t, J = 8.6 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -106.00.
(4-Chlorophenyl)(phenyl)methanone (3ca).5b Following general procedure, 3ca
1
was isolated as a white solid (160 mg, 74%). H NMR (500 MHz, CDCl3) δ 7.76 (dt,
J = 4.2, 3.7 Hz, 4H), 7.62 – 7.58 (m, 1H), 7.52 – 7.45 (m, 4H).
(4-Bromophenyl)(phenyl)methanone (3da).23a Following general procedure, 3da
was isolated as a white solid (113 mg, 43%). 1H NMR (500 MHz, CDCl3) δ 7.77 (dd,
J = 8.2, 1.2 Hz, 2H), 7.69 – 7.57 (m, 5H), 7.49 (t, J = 7.7 Hz, 2H).
4-Benzoylbenzonitrile (3ea).5b Following general procedure, 3ea was isolated as a
1
white solid (141 mg, 68%). H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H),
7.84 – 7.72 (m, 4H), 7.65 (s, 1H), 7.52 (t, J = 7.7 Hz, 2H).
(4-Nitrophenyl)(phenyl)methanone (3fa).5b Following general procedure, 3fa was
1
isolated as a pale yellow solid (137 mg, 60%). H NMR (500 MHz, CDCl3) δ 8.41 –
8.29 (m, 2H), 7.97 – 7.90 (m, 2H), 7.81 (dd, J = 8.2, 1.1 Hz, 2H), 7.66 (dd, J = 10.6,
4.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H).
Phenyl(4-(trifluoromethyl)phenyl)methanone (3ga).5b Following general
1
procedure, 3ga was isolated as a white solid (195 mg, 78%). H NMR (400 MHz,
CDCl3) δ 7.89 (d, J = 8.1 Hz, 2H), 7.84 – 7.78 (m, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.63
(t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -63.05 (s,
1H).
(4-Methoxyphenyl)(phenyl)methanone (3ha).5b Following general procedure,
3ha was isolated as a white solid (172 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 8.7 Hz, 2H), 7.78 – 7.70 (m, 2H), 7.55 (d, J = 7.1 Hz, 1H), 7.47 (t, J = 7.7 Hz,
2H), 6.96 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H).
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(3-Methoxyphenyl)(phenyl)methanone (3ia).4c Following general procedure, 3ia
was isolated as a colourless oil (167 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.80 (d,
J = 7.8 Hz, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.40 – 7.30 (m, 3H),
7.13 (s, 1H), 3.84 (s, 3H).
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(2-Methoxyphenyl)(phenyl)methanone (3ja).5b Following general procedure, 3ja
was isolated as a colourless oil (41 mg, 19%). 1H NMR (500 MHz, CDCl3) δ 7.81 (dd,
J = 5.1, 3.3 Hz, 2H), 7.59 – 7.51 (m, 1H), 7.47 (ddd, J = 8.4, 7.6, 1.7 Hz, 1H), 7.42
(dd, J = 10.6, 4.8 Hz, 2H), 7.36 (dd, J = 7.5, 1.7 Hz, 1H), 7.04 (td, J = 7.5, 0.8 Hz,
1H), 6.99 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H).
Phenyl(p-tolyl)methanone (3ka).5b Following general procedure, 3ka was isolated
1
as a white solid (157 mg, 80%). H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz,
2H), 7.71 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.1 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.26
(d, J = 8.0 Hz, 2H), 2.41 (s, 3H).
Phenyl(o-tolyl)methanone (3la). 10e Following general procedure, 3la was isolated
as a colourless oil (106 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz,
2H), 7.57 (s, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.39 (s, 1H), 7.30 (s, 2H), 7.24 (s, 1H),
2.33 (s, 3H).
Naphthalen-1-yl(phenyl)methanone (3ma).5b Following general procedure, 3ma
was isolated as a white solid (107 mg, 46%). 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J
= 8.3 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.87 (dd, J = 8.3, 1.2 Hz,
2H), 7.61 – 7.55 (m, 2H), 7.55 – 7.48 (m, 3H), 7.45 (dd, J = 10.8, 4.7 Hz, 2H).
Phenyl(thiophen-2-yl)methanone (3na).5b Following general procedure, 3na was
isolated as a pale yellow oil (160 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 7.86 (dt, J
= 8.4, 1.6 Hz, 2H), 7.72 (dd, J = 5.0, 1.1 Hz, 1H), 7.64 (dd, J = 3.8, 1.1 Hz, 1H), 7.61
– 7.57 (m, 1H), 7.51 – 7.47 (m, 2H), 7.16 (dd, J = 4.9, 3.8 Hz, 1H).
Cyclopentyl(phenyl)methanone (3oa).23b Following general procedure, 3pa was
isolated as a colourless oil (113 mg, 65%). 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J =
8.0 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 3.76 – 3.67 (m, 1H),
1.92 (dd, J = 12.7, 6.0 Hz, 4H), 1.80 – 1.46 (m, 4H).
Adamantane-1-yl(phenyl)methanone (3pa). Following general procedure, 3qa
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was isolated as a white solid (216 mg, 90%). 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J
= 7.3 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.3 Hz, 2H), 2.07 (s, 3H), 2.01 (s,
6H), 1.74 (q, J = 12.4 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 210.3, 139.6, 130.2,
128.0, 127.1, 47.0, 39.1, 36.5, 28.1. HRMS (EI) m/z: [M]+ Calcd. for C17H20O
240.1514; Found 240.1517. mp 58–59oC.
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Thiophen-2-yl(p-tolyl)methanone (3nb).10e Following general procedure, 3nb was
isolated as a pale yellow oil (162 mg, 80%). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J
= 8.1 Hz, 2H), 7.70 (dd, J = 5.0, 1.1 Hz, 1H), 7.65 (dd, J = 3.8, 1.1 Hz, 1H), 7.30 (d, J
= 7.9 Hz, 2H), 7.16 (dd, J = 4.9, 3.8 Hz, 1H), 2.44 (s, 3H).
Thiophen-2-yl(m-tolyl)methanone (3nc).23c Following general procedure, 3nc
was isolated as a pale yellow oil (165 mg, 82%). 1H NMR (400 MHz, cdcl3) δ 7.70 (d,
J = 5.0 Hz, 1H), 7.64 (dd, J = 7.4, 4.7 Hz, 3H), 7.41 – 7.34 (m, 2H), 7.15 (dd, J = 6.4,
2.3 Hz, 1H), 2.42 (s, 3H).
Thiophen-2-yl(o-tolyl)methanone (3nd).23d Following general procedure, 3nd was
isolated as a pale yellow oil (186 mg, 92%). 1H NMR (500 MHz, CDCl3) δ 7.72 (dd, J
= 4.9, 1.1 Hz, 1H), 7.44 (dd, J = 7.6, 1.1 Hz, 1H), 7.42 (dd, J = 3.8, 1.1 Hz, 1H), 7.38
(dd, J = 7.5, 1.3 Hz, 1H), 7.30 – 7.25 (m, 2H), 7.11 (dd, J = 4.9, 3.8 Hz, 1H), 2.39 (s,
3H).
(3,5-Dimethylphenyl)(thiophen-2-yl)methanone (3ne). Following general
procedure, 3ne was isolated as a pale yellow oil (179 mg, 83%). 1H NMR (400 MHz,
CDCl3) δ 7.67 (d, J = 4.9 Hz, 1H), 7.62 – 7.60 (m, 1H), 7.44 (s, 2H), 7.19 (s, 1H),
13
7.13 (dd, J = 4.8, 3.9 Hz, 1H), 2.36 (s, 6H). C NMR (100 MHz, CDCl3) δ 188.6,
143.9, 138.3, 138.1, 134.8, 134.0, 133.9, 127.9, 126.9, 21.3. HRMS (EI) m/z: [M]+
Calcd. for C13H12OS 216.0609; Found 216.0606.
(2,4-Dimethylphenyl)(thiophen-2-yl)methanone (3nf). Following general
procedure, 3nf was isolated as a pale yellow oil (197 mg, 91%). 1H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 3.8 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H),
7.10 (d, J = 4.5 Hz, 2H), 7.06 (d, J = 7.8 Hz, 1H), 2.37 (d, J = 1.6 Hz, 6H). 13C NMR
(100 MHz, CDCl3) δ 190.3, 145.2, 140.7, 136.9, 135.6, 135.2, 134.5, 132.0, 128.6,
128.0, 125.8, 21.4, 19.8. HRMS (EI) m/z: [M]+ Calcd. for C13H12OS 216.0609; Found
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216.0608.
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(4-Ethylphenyl)(thiophen-2-yl)methanone (3ng). Following general procedure,
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3ng was isolated as a pale yellow oil (205 mg, 95%). H NMR (400 MHz, CDCl3) δ
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7.80 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 4.9 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.30 (d, J
= 8.0 Hz, 2H), 7.15 – 7.12 (m, 1H), 2.71 (t, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 188.0, 149.2, 143.8, 135.7, 134.5, 133.8, 129.5, 127.9,
127.9, 29.0, 15.3. HRMS (EI) m/z: [M]+ Calcd. for C13H12OS 216.0609; Found
216.0602.
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(4-tert-Butylphenyl)(thiophen-2-yl)methanone
(3nh).
Following general
procedure, 3nh was isolated as a pale yellow oil (215 mg, 88%). 1H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 4.9 Hz, 1H), 7.67 (d, J = 3.7 Hz, 1H),
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7.51 (d, J = 8.3 Hz, 2H), 7.15 (t, J = 4.3 Hz, 1H), 1.37 (s, 9H). C NMR (100 MHz,
CDCl3) δ 187.9, 156.0, 143.8, 135.4, 134.6, 133.8, 129.2, 127.9, 125.4, 35.1, 31.2.
HRMS (EI) m/z: [M]+ Calcd. for C15H16OS 244.0922; Found 244.0918.
(4-Methoxyphenyl)(thiophen-2-yl)methanone (3ni).23e Following general
procedure, 3ni was isolated as a pale yellow oil (185 mg, 88%). 1H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 4.9 Hz, 1H), 7.62 (d, J = 3.8 Hz, 1H),
7.13 (s, 1H), 6.97 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H).
(4-(Methylthio)phenyl)(thiophen-2-yl)methanone (3nj).23f Following general
procedure, 3nj was isolated as a pale yellow oil (171 mg, 73%). 1H NMR (400 MHz,
CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 5.0 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H),
7.31 (d, J = 8.3 Hz, 2H), 7.16 (s, 1H), 2.54 (s, 3H).
Thiophen-2-yl(4-(trifluoromethyl)phenyl)methanone
(3nk).23g
Following
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general procedure, 3nk was isolated as a pale yellow solid (202 mg, 79%). H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H), 7.78 (t, J = 5.4 Hz, 3H), 7.63 (d, J = 3.8
Hz, 1H), 7.19 (t, J = 4.4 Hz, 1H). 19F NMR (376 MHz, cdcl3) δ -63.04.
(4-Fluorophenyl)(thiophen-2-yl)methanone
(3nl).10e
Following
general
procedure, 3nl was isolated as a pale yellow oil (156 mg, 75%). 1H NMR (500 MHz,
CDCl3) δ 7.91 (dd, J = 8.8, 5.4 Hz, 2H), 7.73 (dd, J = 5.0, 1.1 Hz, 1H), 7.63 (dd, J =
3.8, 1.1 Hz, 1H), 7.20 – 7.16 (m, 3H). 19F NMR (471 MHz, CDCl3) δ -106.21 –
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-106.29.
(3-Fluorophenyl)(thiophen-2-yl)methanone (3nm).23h Following general
procedure, 3nm was isolated as a pale yellow oil (163 mg, 79%). 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 4.9 Hz, 1H), 7.65 (d, J = 4.2 Hz, 2H), 7.55 (d, J = 9.1 Hz, 1H),
7.48 (dd, J = 13.5, 7.9 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.18 (t, J = 4.3 Hz, 1H). 19F
NMR (376 MHz, CDCl3) δ -111.80.
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(4-Chlorophenyl)(thiophen-2-yl)methanone
(3nn).10f
Following
general
1
procedure, 3nn was isolated as a pale yellow solid (196 mg, 88%). H NMR (400
MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 4.9 Hz, 1H), 7.63 (d, J = 3.7 Hz,
1H), 7.48 (d, J = 8.3 Hz, 2H), 7.17 (s, 1H).
(2-Chlorophenyl)(thiophen-2-yl)methanone
(3no).10e
Following
general
procedure, 3no was isolated as a pale yellow oil (153 mg, 69%). 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 4.9 Hz, 1H), 7.48 – 7.40 (m, 4H), 7.35 (t, J = 7.3 Hz, 1H), 7.12
(t, J = 4.2 Hz, 1H).
(3,5-Dichlorophenyl)(thiophen-2-yl)methanone (3np).23i Following general
1
procedure, 3np was isolated as a pale yellow solid (147 mg, 53%). H NMR (400
MHz, CDCl3) δ 7.79 (d, J = 4.9 Hz, 1H), 7.72 – 7.69 (m, 2H), 7.64 (d, J = 3.8 Hz, 1H),
7.57 (t, J = 1.4 Hz, 1H), 7.20 (dd, J = 6.5, 2.2 Hz, 1H).
(1,1'-Biphenyl)-4-yl-2-thienyl-methanone (3nq). Following general procedure,
3nq was isolated as a pale yellow solid (211 mg, 80%). 1H NMR (400 MHz, CDCl3) δ
7.96 (d, J = 8.1 Hz, 2H), 7.72 (dt, J = 3.6, 2.3 Hz, 4H), 7.65 (d, J = 7.8 Hz, 2H), 7.49
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(t, J = 7.6 Hz, 2H), 7.42 (d, J = 7.4 Hz, 1H), 7.19 (t, J = 4.4 Hz, 1H). C NMR (100
MHz, CDCl3) δ 187.8, 145.1, 143.7, 140.0, 136.8, 134.7, 134.2, 129.9, 129.0, 128.2,
128.0, 127.3, 127.1. HRMS (EI) m/z: [M]+ Calcd. for C17H12OS 264.0609; Found
264.0611. mp 102.–103 oC.
Benzo[d][1,3]dioxol-5-yl(thiophen-2-yl)methanone (3nr).23j Following general
1
procedure, 3nr was isolated as a white solid (105 mg, 80%). H NMR (400 MHz,
CDCl3) δ 7.69 (d, J = 5.0 Hz, 1H), 7.64 (d, J = 3.8 Hz, 1H), 7.49 (s, 1H), 7.38 (s, 1H),
7.15 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.07 (s, 2H).
Naphthalen-1-yl(thiophen-2-yl)methanone (3ns). Following general procedure,
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3ns was isolated as a pale yellow solid (199 mg, 84%). 1H NMR (400 MHz, CDCl3) δ
8.19 – 8.11 (m, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.92 – 7.87 (m, 1H), 7.72 (t, J = 6.2 Hz,
2H), 7.51 (dd, J = 9.8, 5.7 Hz, 3H), 7.46 (d, J = 3.7 Hz, 1H), 7.08 (t, J = 4.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 189.7, 145.4, 136.2, 135.7, 135.1, 133.8, 131.3, 130.6,
128.4, 128.2, 127.3, 127.1, 126.6, 125.5, 124.3. HRMS (EI) m/z: [M]+ Calcd. for
C15H10OS 238.0452; Found 238.0456. mp 71–72 oC.
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Thiophen-2-yl(thiophen-3-yl)methanone (3nt).10f Following general procedure,
3nt was isolated as a pale yellow solid (150 mg, 77%). 1H NMR (400 MHz, CDCl3) δ
8.12 – 8.04 (m, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 4.9 Hz, 1H), 7.62 (d, J =
5.1 Hz, 1H), 7.39 (dd, J = 5.0, 2.9 Hz, 1H), 7.17 (t, J = 4.4 Hz, 1H).
Dithiophen-2-ylmethanone (3nu).23k Following general procedure, 3nu was
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isolated as a white solid (111 mg, 57%). H NMR (500 MHz, CDCl3) δ 7.91 (d, J =
3.7 Hz, 2H), 7.71 (d, J = 4.9 Hz, 2H), 7.19 (t, J = 4.3 Hz, 2H).
Furan-2-yl(thiophen-2-yl)methanone (3nv).23l Following general procedure, 3nv
was isolated as a pale yellow solid (98 mg, 55%). 1H NMR (500 MHz, CDCl3) δ 8.18
(d, J = 3.7 Hz, 1H), 7.75 – 7.65 (m, 2H), 7.41 (d, J = 3.5 Hz, 1H), 7.20 (t, J = 4.3 Hz,
1H), 6.67 – 6.52 (m, 1H).
tert-Butyl 2-(thiophene-2-carbonyl)-1H-pyrrole-1-carboxylate (3nw). Following
1
general procedure, 3nw was isolated as a white solid (169 mg, 61%). H NMR (400
MHz, CDCl3) δ 7.66 (ddd, J = 4.9, 4.3, 1.1 Hz, 2H), 7.42 (dd, J = 3.1, 1.6 Hz, 1H),
7.12 (dd, J = 4.9, 3.8 Hz, 1H), 6.75 (dd, J = 3.5, 1.6 Hz, 1H), 6.22 (t, J = 3.3 Hz, 1H),
1.44 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 178.3, 148.4, 144.6, 133.8, 133.7, 132.1,
127.9, 126.4, 120.6, 110.3, 85.1, 27.5. HRMS (EI) m/z: [M]+ Calcd. for C14H15N1O3S
277.0773; Found 277.0777. mp 86–87 oC.
ASSOCIATED CONTENT
Supporting Information
1
Copies of H NMR, 19F NMR and 13C NMR of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Authors
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*E-mail: zhuoz@scnu.edu.cn
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the support of National Natural Science
Foundation of China (21272080). The Scientific Research Foundation for the
Returned Overseas Chinese Scholars, State Education Ministry. Guangdong Province
Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme (2012).
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