Palladium-Catalyzed Heck-type Domino Cyclization and Carboxylation to Synthesize Carboxylic Acids by Utilizing Chloroform as the Carbon Monoxide Source

Article abstract of DOI:10.1021/acs.joc.5b01126

A palladium-catalyzed domino cyclization and carboxylation reaction for synthesis of a variety of carboxylic acids was developed, where chloroform was used as "carbon monoxide" source. The in situ generated neopentylpalladium species by Heck cyclization was efficiently trapped by dichlorocarbene to form a series of carboxylic acids. It was found that in this type of domino reaction CHCl₃ is a convenient and safe alternation for CO gas.

Full text of DOI:10.1021/acs.joc.5b01126

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Article
Palladium-Catalyzed Heck-type Domino Cyclization
and Carboxylation to Synthesize Carboxylic Acids by
Utilizing Chloroform as the Carbon Monoxide Source
Xianglei Liu, Bin Li, and Zhenhua Gu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01126 • Publication Date (Web): 01 Jul 2015
Downloaded from http://pubs.acs.org on July 6, 2015
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Palladium-Catalyzed Heck-type Domino Cyclization and Carboxylation to
Synthesize Carboxylic Acids by Utilizing Chloroform as the Carbon Monoxide
Source
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Xianglei Liu, Bin Li and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei,
Anhui 230026, P. R. China
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ABSTRACT
A palladiumꢀcatalyzed domino cyclization and carboxylation reaction for synthesis of a variety of
carboxylic acids was developed, where chloroform was used as "carbon monoxide" source. The
in-situ generated neopentylpalladium species by Heck cyclization was efficiently trapped by
dichlorocarbene to form a series of carboxylic acids. It was found that in this type of domino
reaction CHCl3 is a convenient and safe alternation for CO gas.
INTRODUCTION
Since developed by Heck and coꢀworkers in early 1970s,1 the transition metalꢀcatalyzed
carbonylation with carbon monoxide became one of the most powerful methods for the synthesis
of carbonyl compounds. In comparison with the traditional magnesiumꢀ or lithiumꢀmediated
reactions, transition metalꢀcatalyzed carbonylation provides a mild and wellꢀfunctional group
tolerated method to prepare carbonyl substances.2 Despite it is cheap and readily available on
large scale, carbon monoxide still has some disadvantages for laboratory use, such as its high
toxicity and explosiveness. Thus, it has advantages and is desirable to seek alternative, easy to
handle and safe CO sources.3 Aromatic aldehydes were found to be able to serve as efficient CO
sources in the rhodiumꢀcatalyzed carbocyclization reactions.4 Phenyl formate was an efficient
alternation for CO gas in nickel and palladiumꢀcatalyzed carbonylations.5 Lindhardt, Skrydstrup
and coꢀworkers found the release of CO could be realized by a palladiumꢀcatalyzed
decarbonylation of tertiary acid chlorides. It was found that only near stoichiometric amount of
carbon monoxide precursor was needed in the aminocarbonylation and carbonylative Heck
reactions.6,7 We also developed an efficient borrowing hydrogen strategy for the synthesis of a
series of linear carboxylic acids by the use of chloroform as CO source, where CHCl3 showed
superior performance over CO gas and phenyl formate in the linear/branched selectivity.8
Besides being used as solvent, chloroform, as well as bromoform have been proven as useful
reagents in organic synthesis. Chloroform was used as a dichlorocarbene precursor to construct
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various dichlorocyclopropanes,9 which was further applied in the synthesis of 3ꢀchloropyridine
derivatives via CiamiciamꢀDennstedt rearrangement.10 The formylation of phenols named as
ReimerꢀTiemann reaction11 and trichloromethylation of aldehyde12 with chloroform are important
oneꢀcarbon elongation methods. In the transition metalꢀinvolved reactions, chloroform was ever
used for the synthesis of metalcarbonyl complexes,13 oxidative reagents14 and trichloromethylation
reagents15 and so on. Herein we report a palladiumꢀcatalyzed Heckꢀtype domino cyclization and
carboxylation reaction by utilizing chloroform as the carbonyl source.16ꢀ18 One of our research
interests is the reaction between alkylpalladium species with carbenes. It was demonstrated by us
and other groups that the in-situ generated alkylpalladium B readily reacted with aryl carbene to
form Eꢀalkene derivatives D via migration and βꢀhydride elimination processes (Scheme 1a).19
We reasoned that alkylpalladium B was possibly able to coordinate with dichlorocarbene to form
complex E.20,21 Under aqueous basic conditions E would hydrolyze and deliver carboxylic acid F
(Scheme 1b).22
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Scheme 1. Domino Heckꢀtype Cyclization and CarbeneꢀTrapping Reactions
RESULTS AND DISCUSSION
Our initial studies commenced with readily available acrylamide 1a. In the presence of
Pd(OAc)2 (5 mol %) and trifurylphosphine (TFP, 5 mol %), the reaction of 1a with chloroform in
aqueous dioxane afforded the acid 2a in 54% of isolated yield after acidic workup (Table 1, entry
1). The yields were significantly improved by increasing the loading of phosphine ligand (entries
2 and 3). Probably due to the solubility problem the reaction became inconstant when water was
used as the single solvent in lieu of the mixed dioxane/H2O, and the isolated yield was varied from
moderate to excellent (entry 4). The amount of chloroform could be reduced to 4.0 equiv without
great decreasing the yields of 2a (entries 5ꢀ7). By the use of bromoform instead of chloroform, the
reaction afforded 2a in a relatively lower yield (entry 8).
Table 1. Reaction Condition Optimization a
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Entry
CHCl3 (equiv)
Dioxane/H2O
TFP
Yield of 2a
(2.0 mL)
1:4
(mol %)
5
/%
54
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8.0
8.0
8.0
8.0
6.0
4.0
3.0
4.0b
1:4
10
73
1:4
15
96
0:1
15
59ꢀ92
96
1:4
15
1:4
15
94
1:4
15
88
1:4
15
78
a The reaction was conducted on 0.20 mmol scale of 1a, palladium (5 mol %), TFP (5ꢀ15 mol %)，
o
b
KOH (8.0 equiv), in solvent (2.0 mL) at 80 C for 1 h. CHBr3 (4.0 equiv) was used instead of
CHCl3.
The generality of this domino cyclization and carboxylation reaction was demonstrated by
subjection of various organic iodides to the optimized reaction conditions. The reactions of
2ꢀmethylacrylamides with either electronꢀrich group (1b) or electronꢀwithdrawing groups (1c-1e)
at the phenyl ring worked as efficiently as the reaction of 1a, which gave the desired carboxylic
acids in excellent yields (Table 2, entries 1ꢀ4). However the nitroꢀsubstituted iodide 1f only
afforded 27% of desired carboxylic acid (entry 5). The reaction of electronꢀrich compound
Nꢀ(2ꢀiodoꢀ5ꢀmethoxyphenyl)ꢀNꢀmethylmethacrylamide gave 96% of acid 2g (entry 6). The
Nꢀbenzylated amide 1h also smoothly reacted with chloroform to give the cyclized compound 2h
in excellent yield (entry 7). The reaction proceeded equally efficiently with acetamides 1i, 1j and
sulfonamide 1k, which furnished the fiveꢀ or sixꢀmembered Nꢀheterocycles in good to excellent
yields (entries 8ꢀ10). Other substituted acrylamides, such as 1l and 1m were competent substrates
and they were smoothly converted to the corresponding acids in 94% and 96%, respectively
(entries 11ꢀ12). However, only a complex mixture was formed when 2ꢀphenylacrylamide 1n was
used (entry 13). The reaction of 1o gave the carboxylic acid 2o in 68% yield, along with reductive
product 3o being isolated in 27% yield (entry 14). Allylic amide 1p underwent the cyclization to
furnish the acid in 58% yield (entry 15). It was found that the reaction of 1q delivered the acid 2q
in 81% yield as a single isomer (entry 16). The relative stereochemistry of 2q was unambiguously
confirmed by single crystal Xꢀray analysis,23 which is consisted with the stereochemistry for the
cisꢀinsertion of C=C double bond to carbonꢀpalladium bond. The reaction of allylic ether 1r only
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resulted a complicated mixture (entry 18), and the malonate derivative 1s decomposed under the
standard aqueous basic conditions (entry 19).
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Table 2. Substrate Scope of Organic Iodidesa
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Pd(OAc)2 (5 mol %)
TFP (15 mol %), KOH
R'
R'
CO2H
R
R
CHCl3
Z
+
Z
dioxane/H2O, 80 o
C
Y
Y
I
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8
1
2
entry
halide 1
structure of 2
yield of 2 (%)b
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Me
R
I
R
CO2H
O
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O
N
N
Me Me
R = Me (1b)
Me
1
98 (
94 (
2b)
2c)
R = Cl (1c)
R = F (1d)
2
3
4
5
93 (2d)
93 (2e)
27 (2f)
R = CF3 (1e)
R = NO2 (1f)
Me
I
CO2H
O
6
(1g)
(1h)
96 (2g)
O
MeO
N
MeO
N
Me
Me
Me Me
I
CO2H
O
7
88 (2h)
O
N
N
Bn Me
Bn
Me
Me
CO2H
( )n
N
R
( )n
N
I
R
8
R = Ac, n = 1 (1i)
R = Ac, n = 2 (1j)
R = Ts, n = 2 (1k)
93 (2i)
93 (2j)
82 (2k)
9
10c
R
I
CO2H
O
O
N
N
Me
R
Me
94 (2l)
96 (2m)
complex
11
12
13
R = Bn (1l)
R = Ph(CH2)2 (1m)
R = Ph (1n)
MeO
MeO
I
O
H
CO2H
14
+
O
O
N
N
N
Me CH2OMe
Me
68 (2o)
Me
27 (3o)
(1o)
Me
CO2H
I
nBu
15
16
(1p)
(1q)
58 (2p)
N
Me
N
O
O
Ph
Me
I
O
CO2H
81 (2q)
single isomer
O
N
Ph
N
Me
Me Me
Me
Me
O
CO2H
(1r)
(1s)
complex
18
19
O
I
Me
CO2H
CO2Me
CO2Me
decomposition
CO2Me
CO2Me
I
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a Reaction conditions: 1 (0.20 mmol), CHCl3 (0.80 mmol), Pd(OAc)2 (5 mol %), TFP (15 mol %),
KOH (1.60 mmol) and dioxane/H2O (1:4, 2.0 mL) at 80 oC for 1 h. b Isolated yields. c CHCl3 (1.60
mmol) at 100 oC for 3 h.
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For the aryl bromides, Pd(PPh3)2Cl2 was found to be the optimum palladium catalyst (Table 3).
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o
For instance, the reaction of 1t-w in dioxane/H2O at 100 C gave the desired products in good to
excellent yields (entries 1ꢀ3). An incomplete conversion was observed with
2ꢀbromoꢀ1ꢀaminonaphthalene derivative 1w as the substrate, and the reaction afforded the 2w in
62% yield along with 28% starting material being recovered (entry 4).
Table 3. Substrate Scope of Organic Bromidesa
a
Reaction conditions: 1 (0.20 mmol), CHCl3 (0.80 mmol), Pd(PPh3)2Cl2 (5 mol %), KOH (1.60
o
b
c
mmol) and dioxane/H2O (1:4, 2.0 mL) at 100 C for 1ꢀ3 h. Isolated yields. With 28% starting
material being recovered.
CONCLUSION
In summary we disclosed a palladiumꢀcatalyzed domino cyclization and carboxylation reaction
for the synthesis of a variety of carboxylic acids. In these reactions chloroform was used as CO
source, which showed advantages in both safety and laboratory operation aspects.
EXPERIMENTAL SECTION
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General Information. All reactions were carried out under a nitrogen atmosphere in flameꢀdried
glassware, unless the reaction procedure states otherwise. Tetrahydrofuran (THF) was distilled
from sodiumꢀbenzophenone in a continuous still under an atmosphere of N2. Dioxane was distilled
from sodiumꢀbenzophenone under an atmosphere of nitrogen. Dichloromethane were distilled
from calcium hydride in a still under an atmosphere of nitrogen. Room temperature reactions were
carried out between 20ꢀ25 °C. Flash column chromatography was performed using 40ꢀ63 ꢁm
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silica gel as the stationary phase. H, 13C and 19F NMR spectra were referenced by using solvent
residue as an internal reference (1H NMR: 7.26 ppm for CDCl3; 2.50 ppm for DMSOꢀd6; 13C
NMR: 77.00 ppm for CDCl3; 39.52 ppm for DMSOꢀd6; 30.92 ppm for acetoneꢀd6). Electron spray
ionization (ESI) mass spectrometry data were acquired by using LTQ analyzer type.
Compounds 1a, 1b, 1c, 1h, 1i, 1k, 1n, 1t were known compounds and prepared by following
the literature. 24
Methacryloyl chloride (0.35 mL, 3.60 mmol, 1.2 equiv) was added to a mixture of
4ꢀfluoroꢀ2ꢀiodoaniline (0.71 g, 3.00 mmol, 1.0 equiv), DMAP (18.3 mg, 0.10 mmol, 5 mol %),
Et3N (0.84 mL, 6.00 mmol, 2.0 equiv) in CH2Cl2 (10 mL) at ꢀ20 °C dropwise. After stirring at
ꢀ20 °C for 30 min and room temperature overnight, the mixture was quenched with saturated
NaHCO3, extracted with CH2Cl2, washed with brine, and dried over Na2SO4. After filtration and
concentration, the obtained crude amide was used in the next step without purification.
Sodium hydride (240 mg, 60% in mineral oil, 4.00 mmol, 2.0 equiv) was added to a solution of
the above amide in THF (15 mL) at 0 °C for portions. After stirring at 0 °C for 20 min MeI (0.56
mL, 9.00 mmol, 3.0 equiv) added dropwise and the reaction mixture was allowed to stir at room
temperature for 3 h. The reaction was quenched with water and THF was removed by evaporation.
The residue was extracted with ethyl acetate. The organic phase was washed with brine, dried over
Na2SO4, filtered, concentrated, and the residue was purified by column chromatography on silica
gel (10% ethyl acetate/hexanes) to afford the desired amide 1d (0.73 g, 77%) as solid: mp
61.2ꢀ62.6 oC (PE/EA). 1H NMR (400 MHz, CDCl3): δ 7.59 (dd, J = 7.6, 2.8 Hz, 1H), 7.19ꢀ7.12 (m,
1H), 7.12ꢀ7.04 (m, 1H), 5.05 (s, 1H), 5.01 (s, 1H), 3.22 (s, 3H), 1.83 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 171.8, 160.8 (d, J = 252.1Hz), 143.3, 140.0, 129.8 (d, J = 8.4Hz), 126.9(d, J = 24.4Hz),
119.0, 116.4 (d, J = 22.7 Hz), 98.9, 36.9, 20.5. 19F NMR (376 MHz, CDCl3): δ ꢀ112.1. HRMS
(ESI) calcd. for C11H11NOFINa+ (M+Na)+ 341.9796, found 341.9769.
N-(2-Iodo-4-(trifluoromethyl)phenyl)-N-methylmethacrylamide (1e):
1e (10% ethyl acetate/hexanes) (0.53 g, 48%) was prepared following the procedure of 1d in 3.00
mmol scale. Solid: mp 72.1ꢀ74.9 oC (PE/EA). 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.63 (d,
J = 7.6 Hz, 1H), 7.33ꢀ7.26 (m, 1H), 5.04 (s, 2H), 3.25 (s, 3H), 1.86 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 171.5, 150.4 (bs), 139.8, 137.2, 131.1 (q, J = 31.5Hz ), 129.4, 126.5, 122.5 (q, J =
271.1Hz), 119.8 (bs), 98.9, 36.8, 20.4. 19F NMR (376 MHz, CDCl3): δ ꢀ62.6. HRMS (ESI) calcd.
for C12H11NOF3INa+ (M+Na)+ 391.9735, found 391.9733.
N-(2-Iodo-4-nitrophenyl)-N-methylmethacrylamide (1f):
Methacryloyl chloride (0.35 mL, 3.60 mmol, 1.2 equiv) was added to a mixture of
2ꢀiodoꢀ4ꢀnitroaniline (0.79 g, 3.00 mmol, 1.0 equiv), DMAP (18.3 mg, 0.10 mmol, 5 mol %),
Et3N (0.84 mL, 6.00 mmol, 2.0 equiv) in CH2Cl2 (10 mL) at ꢀ20 °C dropwise. After stirring at
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ꢀ20 °C for 30 min and room temperature overnight, the mixture was quenched with saturated
NaHCO3, extracted with CH2Cl2, washed with brine, and dried over Na2SO4. After filtration and
concentration, the obtained crude amide was used in the next step without purification.
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Sodium hydride (240 mg, 60% in mineral oil, 4.00 mmol, 2.0 equiv) was added to a solution of
the above amide in THF/DMF (15/5 mL) at 0 °C for portions. After stirring at 0 °C for 20 min
MeI (0.56 mL, 9.00 mmol, 3.0 equiv) added dropwise and the reaction mixture was allowed to stir
at room temperature for 3 h. The reaction was quenched with water and THF was removed by
evaporation and diluted with 100 mL ethyl acetate. The organic phase was washed with water and
brine, dried over Na2SO4, filtered and concentrated afforded the crude pruduct. After purified by
column chromatography on silica gel (PE: EA = 10: 1 to PE: EA = 5: 1) the desired amide 1f (0.73
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g, 77%) was obtained as solid: mp 97.1ꢀ101.4 oC (PE/EA). H NMR (400 MHz, CDCl3): 8.73 (s,
1H), 8.23 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 5.10 (s, 2H), 3.28 (s, 3H), 1.90 (s, 3H), 13C
NMR (100 MHz, CDCl3): δ 171.2, 152.9 (bs), 146.6, 139.7, 135.3, 129.4, 124.5, 120.1 (bs), 98.6,
36.7 (bs), 20.3 HRMS (ESI) calcd. for C11H11N2O3INa+ (M+Na)+ 368.9712, found 368.9709.
N-(2-Iodo-5-methoxyphenyl)-N-methylmethacrylamide (1g):
1g (10% ethyl acetate/hexanes) (0.80 g, 80%) was prepared following the procedure of 1d in 3.00
o
1
mmol scale. Solid: mp 128.9ꢀ132.8 C (PE/EA). H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.8
Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.62 (dd, J = 8.8, 2.8 Hz, 1H), 5.10 (s, 1H), 5.01 (s, 1H), 3.78 (s,
3H), 3.22 (s, 3H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.7, 160.6, 147.6, 140.2, 140.0,
119.0, 115.4, 115.3, 87.2, 55.5, 36.7, 20.6. HRMS (ESI) calcd. for C12H14NO2INa+ (M+Na)+
353.9967, found 353.9964.
N-(2-Bromo-4-methylphenyl)-N-methylmethacrylamide (1u):
1u (Rf = 0.3, PE: EA = 5: 1) (0.48 g, 85%) as oil was prepared following the procedure of 1d in
2.00 mmol scale. 1H NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.05 (d, J
= 8.0 Hz, 1H), 5.01 (s, 1H), 4.96 (s, 1H), 3.22 (s, 3H), 2.33 (s, 3H), 1.80 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 172.0, 140.8, 140.2, 139.6, 134.1, 129.4, 129.2, 122.5, 118.4, 36.4, 20.7, 20.3.
HRMS (ESI) calcd. for C12H15NO79Br+ (M+H)+ 268.0332, found 268.0331.
N-(2-Bromo-5-methylphenyl)-N-methylmethacrylamide (1v):
1v (Rf = 0.3, PE: EA = 5: 1) (0.50 g, 94%, as oil) was prepared following the procedure of 1d in
2.00 mmol scale. 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.0 Hz, 1H), 7.03ꢀ6.95 (m, 2H), 5.03
(s, 1H), 4.98 (s, 1H), 3.23 (s, 3H), 2.30 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
171.9, 143.2, 140.2, 138.8, 133.3, 130.4, 130.0, 119.3, 118.5, 36.4, 20.8, 20.3. HRMS (ESI) calcd.
for C12H15NO79Br+ (M+H)+ 268.0332, found 268.03334.
N-(1-Bromonaphthalen-2-yl)-N-methylmethacrylamide (1w):
1w (Rf = 0.3, PE: EA = 5: 1) (0.49 g, 89%) was prepared following the procedure of 1d in 1.80
mmol scale. Solid: mp 78.4ꢀ80.8 oC (PE/EA). 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 8.8 Hz,
1H), 7.85 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.68ꢀ7.61 (m, 1H),7.69ꢀ7.54 (m, 1H), 7.30
(d, J = 8.6 Hz, 1H), 5.03 (s, 1H), 4.93 (s, 1H), 3.34 (s, 3H), 1.85 (s, 3H); 13C NMR (100 MHz,
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CDCl3): δ 172.1, 141.4, 140.0, 133.2, 132.7, 128.9, 128.2, 128.1, 127.7, 127.2, 126.8, 123.1, 118.9,
36.4, 20.2. HRMS (ESI) calcd. for C15H15NO79Br+ (M+H)+ 304.0332, found 304.0334.
N-(2-Iodophenyl)-N-(3-methylbut-3-enyl)acetamide (1j):25
7
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n
Potassium hydroxide (0.21 g, 4.00 mmol, 2.0 equiv) and Bu4NHSO4 (33.9 mg, 0.10 mmol,
0.05 equiv) was added successively to a solution of Nꢀ(2ꢀiodophenyl)acetamide (0.52 g, 2.00
mmol, 1.0 equiv) in toluene (5 mL) at 20 °C and the mixture was stirred at this temperature for 1 h
before warmed to 80 °C. 3ꢀMethylbutꢀ3ꢀenyl 4ꢀmethylbenzenesulfonate (0.58 g, 2.40 mmol, 1.2
equiv) was added to the mixture and stirred at 80 °C for 1 h. The resulted solution was cooled to
room temperature, quenched with 10 mL water, extracted with EtOAc, dried over Na2SO4, filtered
and concentrated. The residue was purified by column chromatography on silica gel (PE: EA = 10:
1 to PE: EA: DCM = 10: 1: 1) to afford 1j (0.50 g, 1.50 mmol, 75%) as oil. 1H NMR (400 MHz,
CDCl3): δ 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (td, J = 7.6, 1.6 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz,
1H), 7.08 (td, J = 8.0, 1.6 Hz, 1H), 4.76 (s, 1H), 4.71 (s, 1H), 4.34 (ddd, J = 13.2, 9.6, 6.4 Hz, 1H),
3.13 (ddd, J = 13.2, 9.6, 5.6 Hz, 1H), 2.38ꢀ2.17 (m, 2H), 1.76 (s, 3H), 1.71 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 170.0, 145.0, 142.9, 140.3, 130.4, 129.8, 129.5, 111.7, 100.4, 46.6, 35.5, 23.0,
22.5. HRMS (ESI) calcd. for C13H17NOI+ (M+H)+ 330.0349, found 330.0349.
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2-Benzyl-N-(2-iodophenyl)-N-methylacrylamide (1l):
Sodium hydride (0.40 g, 60% in mineral oil, 10.0 mmol, 1.0 equiv) was added to a solution of
dimethyl malonate (1.14 mL, 10.0 mmol, 1.0 equiv) in THF (20 mL) at 0 °C for portions under
nitrogen，after stirring for 20 min BnBr (1.20 mL, 10.0 mmol, 1.0 equiv) was added to the mixture
dropwise and the reaction mixture was allowed to warm to room temperature，and heated to reflux
for 24 h. After cooling to room temperature, NaOH aq. (2 M, 10 mL) and MeOH (10 mL) was
added to the reaction mixture and stirred at 90 °C for 1 h. After cooling down, MeOH and THF
was removed by evaporation. The residue was acidized with 2 M HCl, extracted with ethyl acetate,
dried over Na2SO4, concentrated, and the resulted mixture was added to a solution of diethylamine
(1.2 mL, 11.5 mmol, 1.15 equiv) in EtOAc (20 mL) at 0 °C. Then paraformaldehyde (0.42 g, 14.0
mmol, 1.4 equiv) was added in portions. The mixture was warmed to reflux and maintained for 2 h.
After cooled to room temperature, the reaction was acidized with 2 M HCl, extracted with EtOAc,
washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by
column chromatography on silica gel (PE: EA = 20: 1 to PE: EA = 7: 1) to afford 2ꢀbenzylacrylic
acid (1.08 g, 6.70 mmol, 67%).26
Oxalyl dichloride (0.34 mL, 4.00 mmol, 2.0 equiv) was added to a solution of 2ꢀbenzylacrylic
acid (0.32 g, 2.00 mmol, 1.0 equiv) with a drop of DMF in DCM (10 mL) at room temperature
dropwise. The reaction was maintain at room temperature for 30 min and the excess oxalyl
dichloride and DCM was removed by evaporation.
The above acid chloride in DCM (10 mL) was added to a mixture of 2ꢀiodoaniline (0.44 g, 2.00
mmol, 1.0 equiv), DMAP (12.2 mg, 0.10 mmol, 0.05 equiv), Et3N (0.56 mL, 4.00 mmol, 2.0 equiv)
in CH2Cl2 (10 mL) at ꢀ20 °C dropwise. After stirring at ꢀ20 °C for 30 min and room temperature
overnight, the mixture was quenched with saturated NaHCO3, extracted with CH2Cl2, washed with
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brine, and dried over Na2SO4. After filtration and concentration, the crude amide was used in next
step without further purification.
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Sodium hydride (0.24 g, 60% in mineral oil, 6.00 mmol, 3.0 equiv) was added to a solution of
the above amide in THF (10 mL) at 0 °C for portions. After stirring for 20 min at 0 °C MeI (0.37
mL, 6.00 mmol, 3.0 equiv) added dropwise and the reaction mixture was stirred at room
temperature for 2 h and 50 °C overnight. The reaction was quenched by the addition of water,
extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated. The
crude product was purified by column chromatography on silica (PE: EA = 10: 1) to afford 1l
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(0.31 g, 0.84 mmol, 42%) as oil. Rotamers (10: 1) were observed. The major isomer H NMR
(400 MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz, 1H), 7.35ꢀ7.19 (m, 3H), 7.14 (t, J = 7.2 Hz, 1H), 7.07 (d,
J = 6.8 Hz, 2H), 6.95 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 5.08 (s, 1H), 4.84 (s, 1H), 3.71
(d, J = 15.2 Hz, 1H), 3.42 (d, J = 15.2 Hz, 1H), 3.20 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
170.9, 146.7, 143.7, 140.0, 137.8, 129.6, 129.5, 129.3, 129.1, 128.4, 126.4, 118.7, 98.9, 40.3, 36.9.
HRMS (ESI) calcd. for C17H17NOI+ (M+H)+ 378.0349, found 378.0346.
N-(2-Iodophenyl)-N-methyl-2-methylene-4-phenylbutanamide (1m):
Sodium hydride (0.37 g, 60% in mineral oil, 9.20 mmol, 1.2 equiv) was added to MeOH (10
mL) at 0 °C for portions under nitrogen. Then dimethyl malonate (0.89 mL, 7.70 mmol, 1.0 equiv)
was added to the solution and the mixture was warmed to 65 °C. Followed by this BnCH2I (1.80 g,
7.70 mmol, 1.0 equiv) in MeOH (10 mL) was added to the above mixture in dropwise. After
stirring at 65 °C for 4 h, NaOH (1 M, 40 mL) was added to the reaction mixture and stirred for 1 h.
After cooling down, MeOH and was removed by evaporation. The residue was acidized with 2 M
HCl, extracted with ethyl acetate, dried over Na2SO4, concentrated, and the resulted mixture was
added to a solution of diethylamine (0.90 mL, 8.90 mmol, 1.15 equiv) in EtOAc (20 mL) at 0 °C.
After stirring at 0 °C for 5 min, paraformaldehyde (0.32 g, 10.0 mmol, 1.4 equiv) was added in
portions. The mixture was heated to reflux for 2 h. After cooled to room temperature, the reaction
was acidized by 2 M HCl, extracted with EtOAc, washed with brine, dried over Na2SO4,
concentrated. The residue was purified by column chromatography on silica (PE: EA = 5: 1) to
afford 2ꢀmethyleneꢀ4ꢀphenylbutanoic acid (0.24 g, 1.35 mmol, 18%).
Oxalyl dichloride (0.23 mL, 2.70 mmol, 2.0 equiv) was added to a solution of
2ꢀmethyleneꢀ4ꢀphenylbutanoic acid (0.24 g, 1.35 mmol, 1.0 equiv) with a drop of DMF in DCM
(6 mL) at room temperature dropwise. The reaction was maintain at room temperature for 30 min
and the excess oxalyl dichloride and DCM was removed by evaporation.
The above acid chloride in DCM (6 mL) was added to a mixture of 2ꢀiodoaniline (0.30 g, 1.35
mmol, 1.0 equiv), DMAP (8.2 mg, 0.067 mmol, 0.05 equiv), Et3N (0.38 mL, 2.70 mmol, 2.0 equiv)
in CH2Cl2 (6 mL) at ꢀ20 °C dropwise. After stirring at ꢀ20 °C for 30 min and room temperature
overnight, the mixture was quenched with saturated NaHCO3, extracted with CH2Cl2, washed with
brine, and dried over Na2SO4. After filtration and concentration, the crude amide was used in next
step without further purification.
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Sodium hydride (0.11 g, 60% in mineral oil, 2.7 mmol, 2.0 equiv) was added to a solution of the
above amide in THF (10 mL) at 0 °C for portions. After stirring at 0 °C for 20 min MeI (0.25 mL,
4.05 mmol, 3.0 equiv) added dropwise and the reaction mixture was allowed to stir at room
temperature for 3 h. The reaction was quenched by the addition of water, extracted with ethyl
acetate, washed with brine, dried over Na2SO4, concentrated. The crude product was purified by
column chromatography on silica (PE: EA = 10: 1 to PE: EA = 5: 1) to afford 1m (0.32 g, 0.82
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mmol, 61%) as oil. Rotamers (8: 1) were observed. The major isomer’s H NMR (400 MHz,
CDCl3): δ 7.88 (d, J = 8.0 Hz, 1H), 7.37ꢀ7.09 (m, 7H), 7.01 (t, J = 7.6 Hz, 1H), 5.16 (s, 1H), 5.02
(s, 1H), 3.26 (s, 3H), 2.87ꢀ2.65 (m, 2H), 2.57ꢀ2.36 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 171.4,
146.7, 143.8, 141.3, 140.2, 129.6, 129.3, 129.2, 128.3, 128.2, 125.9, 118.2, 99.1, 36.9, 35.2, 34.1.
HRMS (ESI) calcd. for C18H19NOI+ (M+H)+ 392.0506, found 392.0502.
N-(2-Iodophenyl)-2-(methoxymethyl)-N-methylacrylamide (1o):
Thionyl chloride (0.87 mL, 12.0 mmol, 1.2 equiv) was added to acrylic acid (0.90 mL, 13.0
mmol, 1.3 equiv) at 80 °C dropwise. The reaction was stirred at 80 °C for 30 min. After cooling
down, the excess thionyl chloride was carefully removed by evaporation at about 40 mmHg.
The above acid chloride in DCM (20 mL) was added to a mixture of 2ꢀiodoaniline (2.2 g, 10.0
mmol, 1.0 equiv), DMAP (60.0 mg, 0.50 mmol, 0.05 equiv), Et3N (2.8 mL, 20.0 mmol, 2.0 equiv)
in CH2Cl2 (20 mL) at ꢀ20 °C dropwise. After stirring at ꢀ20 °C for 30 min and room temperature
overnight, the mixture was quenched with saturated NaHCO3, extracted with CH2Cl2, washed with
brine, and dried over Na2SO4. After filtration and concentration, the crude amide was used in next
step without further purification.
Sodium hydride (0.80 g, 60% in mineral oil, 20.0 mmol, 2.0 equiv) was added to a solution of
the above amide in THF (10 mL) at 0 °C for portions. After stirring at 0 °C for 20 min MeI (1.90
mL, 30.0 mmol, 3.0 equiv) added dropwise and the reaction mixture was allowed to stir at room
temperature for 3 h. The reaction was quenched by the addition of water, extracted with ethyl
acetate, washed with brine, dried over Na2SO4, concentrated. The crude product was purified by
column
chromatography on
silica
gel (PE:
EA
=
10:
1)
to
afford
Nꢀ(2ꢀiodophenyl)ꢀNꢀmethylacrylamide (1.47 g, 5.00 mmol, 50%).27 1H NMR (400 MHz, CDCl3):
δ 7.93 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (td, J = 7.6, 1.6 Hz, 1H), 7.29ꢀ7.22 (m, 1H), 7.08 (td, J = 7.6,
1.6 Hz, 1H), 6.38 (dd, J = 16.4, 1.6 Hz, 1H), 5.83 (dd, J = 16.8, 10.4 Hz, 1H), 5.51 (dd, J = 10.4,
2.0 Hz, 1H), 3.24 (s, 3H).
Nꢀ(2ꢀIodophenyl)ꢀNꢀmethylacrylamide (1.44 g, 5.00 mmol, 1.0 equiv) was added to a mixture
of paraformaldehyde (0.75 g, 25.0 mmol, 5.0 equiv), DABCO (0.56 g, 5.00 mmol, 1.0 equiv),
BnOH (130 ꢁl, 1.25 mmol, 0.25 equiv) in tꢀBuOH/H2O (1:4, 2.0 mL) at 55 °C dropwise. The
t
reaction mixture was stirred at 55 °C for 5 h. After cooling down, BuOH was removed by
evaporation. The residue was extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated.
the crude product was purified by column chromatography on silica gel (PE: EA = 1: 1) to afford
2ꢀ(hydroxymethyl)ꢀNꢀ(2ꢀiodophenyl)ꢀNꢀmethylacrylamide 4 (1.23 g, 3.90 mmol, 77%).28
Rotamers (13: 1) were observed. The major isomer’s 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J =
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7.6 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.27 (s,
1H), 5.06 (s, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.10 (d, J = 13.6 Hz, 1H), 3.25 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 170.2, 146.6, 142.5, 140.2, 129.6, 129.4, 119.9, 98.8, 64.6, 37.0. HRMS
(ESI) calcd. for C11H13NO2I+ (M+H)+ 317.9986, found 317.9984.
Sodium hydride (0.12 g, 60% in mineral oil, 3.0 mmol, 1.5 equiv) was added to a solution of the
2ꢀ(hydroxymethyl)ꢀNꢀ(2ꢀiodophenyl)ꢀNꢀmethylacrylamide 4 (0.63 g, 2.00 mmol, 1.0 equiv) in
THF (5 mL) at 0 °C for portions. After stirring at 0 °C for 20 min MeI (0.25 mL, 4.00 mmol, 2.0
equiv) added dropwise and the reaction mixture was allowed to stir at room temperature for 2 h.
The reaction was quenched by the addition of water, extracted with ethyl acetate, washed with
brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column
chromatography on silica gel (PE: EA = 7: 1 to PE: EA = 5: 1) to afford 1o (0.39 g, 1.17 mmol,
60%) as viscous oil. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz,
1H), 7.25ꢀ7.19 (m, 1H), 7.05ꢀ6.95 (m, 1H), 5.22 (s, 1H), 5.17 (s, 1H), 4.16 (d, J = 13.2 Hz, 1H),
3.87 (d, J = 13.2 Hz, 1H), 3.27 (s, 3H), 3.23 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.5, 146.6,
140.7, 140.0, 129.8, 129.4, 129.2, 119.0, 98.9, 72.8, 58.4, 36.9. HRMS (ESI) calcd. for
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C12H15NO2I+ (M+H)+ 332.0142, found 332.0139.
N-Butyl-2-iodo-N-(2-methylallyl)benzamide (1p):
Sodium hydride (0.26 g, 60% in mineral oil, 6.70 mmol, 1.3 equiv) was added to a solution of
Nꢀbutylꢀ2ꢀiodobenzamide (1.56 g, 5.15 mmol, 1.0 equiv) in DMF (10 mL) at 0 °C for portions.
The reaction mixture was warmed to 50 °C and stirred for 20 min. Then the mixture was cooled to
35 °C and 3ꢀchloroꢀ2ꢀmethylpropꢀ1ꢀene (0.71 mL, 7.73 mmol, 1.5 equiv) added dropwise. After
stirring at 35 °C for 1 h the reaction quenched by the addition of water and extracted with ethyl
acetate, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was
purified by column chromatography on silica gel to afford 1p (Rf = 0.7, PE: EA = 3: 1) (1.42 g,
1
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3.98 mmol, 77%) as oil. Rotamers (~1.6: 1) were observed. The H NMR as follows : major H
NMR (400 MHz, CDCl3): δ 7.79 (dd, J = 8.0, 0.8 Hz, 1H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.21 (d,
J = 1.6 Hz, 1H), 7.09ꢀ6.98 (m, 1H), 4.92ꢀ4.87 (m, 1H), 4.85 (t, J = 1.6 Hz, 1H), 3.66 (d, J = 16.0
Hz, 1H), 3.60 (d, J = 16.0 Hz, 1H), 3.10ꢀ2.88 (m, 2H), 1.80ꢀ1.59 (m, 2H), 1.56 (s, 3H), 1.47ꢀ1.31
(m, 2H), 0.96 (t, J = 7.2 Hz, 3H); minor 1H NMR (400 MHz, CDCl3): δ 7.83 (dd, J = 8.0, 1.2 Hz,
1H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 7.19 (d, J = 1.6 Hz, 1H), 7.09ꢀ6.98 (m, 1H), 5.00 (d, J = 1.6 Hz,
1H), 4.96 (t, J = 1.6 Hz, 1H), 4.39 (d, J = 15.2 Hz, 1H), 4.04ꢀ3.82 (m, 3H), 1.85 (s, 3H), 1.80ꢀ1.59
(m, 1H), 1.47ꢀ1.31 (m, 1H), 1.14ꢀ1.02 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3), (selected peaks): δ 170.7, 170.6, 142.8, 142.3, 140.6, 140.2, 139.3, 139.0, 129.93, 129.90,
128.03, 128.00, 127.3, 127.2, 113.6, 112.9, 92.7, 92.5, 54.3, 44.3, 49.2, 47.2, 28.7, 29.9, 20.8, 20.5,
20.1, 19.8, 13.9, 13.5. HRMS (ESI) calcd. for C15H21NOI+ (M+H)+ 358.0662, found 358.0663.
(E)-N-(2-Iodophenyl)-N,2-dimethyl-3-phenylacrylamide (1q):
Oxalyl dichloride (0.51 mL, 6.0 mmol, 2.0 equiv) was added to a solution of 2ꢀphenylacrylic
acid (0.49 g, 3.0 mmol, 1.0 equiv) with a drop of DMF in DCM (10 mL) at room temperature
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dropwise. The reaction was maintain at room temperature for 30 min and the excess oxalyl
dichloride and DCM was removed by evaporation.
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mmol, 1.0 equiv), DMAP (18.3 mg, 0.15 mmol, 0.05 equiv), Et3N (0.84 mL, 6.0 mmol, 2.0 equiv)
in CH2Cl2 (10 mL) at ꢀ20 °C dropwise. After stirring at ꢀ20 °C for 30 min and room temperature
overnight, the mixture was quenched with saturated NaHCO3, extracted with CH2Cl2, washed with
brine, and dried over Na2SO4. After filtration and concentration, the crude amide was used in next
step without further purification.
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Sodium hydride (0.36 g, 60% in mineral oil, 9.0 mmol, 3.0 equiv) was added to a solution of the
above amide in THF (10 mL) at 0 °C for portions. After stirring at 0 °C for 20 min MeI (0.56 mL,
9.00 mmol, 3.0 equiv) added dropwise and the reaction mixture was allowed to stir at room
temperature for 2 h. After quenched with water and evaporated THF, the residue was extracted
with ethyl acetate, washed with brine, dried over Na2SO4, filtered, concentrated, and the crude
product was purified by column chromatography on silica gel (PE: EA = 10: 1) to afford 1q (0.59
g, 1.56 mmol, 52%) as solid: mp114.0ꢀ118.0 oC (PE/EA). 1H NMR (400 MHz, CDCl3): δ 7.90 (dd,
J = 7.6, 1.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.29ꢀ7.15 (m, 4H), 7.08ꢀ6.95 (m, 3H), 6.69 (s, 1H),
3.31 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 173.2, 147.1, 140.3, 136.0, 133.1,
132.9, 129.40, 129.39, 129.1, 128.9, 128.1, 127.3, 99.0, 37.1, 16.2. These data are identical with
the reproted results.29
2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetic acid (2a):
Typical Procedure A (Table 1, entry 6): Chloroform (65 ꢁl, 0.80 mmol, 4.0 equiv) was added to a
mixture of 1a (60.2 mg, 0.20 mmol, 1.0 equiv), Pd(OAc)2 (2.2 mg, 0.01 mmol, 5 mol %), KOH
(89.8 mg, 1.60 mmol, 8.0 equiv) and TFP (7.0 mg, 0.03 mmol, 15 mol %) under nitrogen,
followed by H2O (1.6 ml) was added. After stirring at room temperature for 0.5 min, dioxane (0.4
mL) was added and the reaction mixture was stirred at room temperature for additional 0.5 min
before heated to 80 °C for 1 h. The reaction was quenched with 1 M HCl (6 mL) and extracted
with EtOAc (3×20 mL) and dichloromethane (2×10 mL). The organic layer was dried over
Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica
gel (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50: 50: 1) to afford
2a (41.2 mg, 94%). Solid: mp 172.0ꢀ176.0 oC (PE/EA). 1H NMR (400 MHz, CDCl3): δ 7.29 (td, J
= 7.6, 1.2 Hz,1H), 7.19 (dd, J = 7.2, 1.2 Hz, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 6.86 (d, J = 7.6 Hz,
1H), 3.22 (s, 3H), 2.98 (d, J = 16.4 Hz, 1H), 2.80 (d, J = 16.4 Hz, 1H), 1.40 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 180.5, 173.4, 143.0, 132.7, 128.3, 122.9, 122.3, 108.5, 45.3, 41.3, 26.5, 23.8.
ꢀ
HRMS (ESI) calcd. for C12H12NO3 (MꢀH)ꢀ 218.0812, found 218.0819. These data are identical
with the reproted results.30
2-(1,3,5-Trimethyl-2-oxoindolin-3-yl)acetic acid (2b):
Table 1, entry 1: 2b (45.8 mg, 98%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate:
hexanes: AcOH = 50: 50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of
o
1b (63.0 mg, 0.20 mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 162.6 C (PE/EA). 1H NMR (400
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MHz, CDCl3): δ 7.08 (d, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.74 (d, J = 7.6 Hz, 1H), 3.20 (s, 3H), 2.97
(d, J = 16.8 Hz, 1H), 2.77 (d, J = 16.8 Hz, 1H), 2.33 (s, 3H), 1.38 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 180.5, 173.4, 140.6, 132.8, 132.5, 128.6, 123.2, 108.2, 45.3, 41.4, 26.5, 23.9, 21.1.
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2-(5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)acetic acid (2c):
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2c (47.7 mg, 94%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1c (67.1 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 167.3ꢀ171.3 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 7.25 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 3.19 (s, 3H), 3.00 (d, J =
16.8 Hz, 1H), 2.80 (d, J = 17.2 Hz, 1H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 179.6, 173.8,
141.9, 134.4, 128.2, 128.0, 122.9, 109.3, 45.5, 41.0, 26.6, 24.0. HRMS (ESI) calcd. for
C12H13NO335Cl+ (M+H)+ 254.0579, found 254.0578.
2-(5-Fluoro-1,3-dimethyl-2-oxoindolin-3-yl)acetic acid (2d):
2d (46.1 mg, 97%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1d (63.8 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 202.4ꢀ205.6 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 7.03ꢀ6.95 (m, 2H), 6.78 (dd, J = 8.4, 4.0 Hz, 1H), 3.22 (s, 3H), 3.00 (d, J = 16.7 Hz,
1H), 2.81 (d, J = 16.7 Hz, 1H), 1.40 (s, 3H); 13C NMR (100 MHz, Acetoneꢀd6): δ 181.2, 172.5,
160.9 (d, J = 235.8 Hz), 142.2 (d, J = 1.5 Hz), 137.5 (d, J = 8.2 Hz), 115.6 (d, J = 23.4 Hz), 112.4 (d, J
= 25.0 Hz), 110.5 (d, J = 8.1 Hz), 47.5, 42.5, 27.7, 25.6. 19F NMR (376 MHz, CDCl3): δ ꢀ120.0.
HRMS (ESI) calcd. for C12H12NO3FNa+ (M+Na)+ 260.0699, found 260.0699.
2-(1,3-Dimethyl-2-oxo-5-(trifluoromethyl)indolin-3-yl)acetic acid (2e):
2e (53.1 mg, 93%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1e (73.8 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 167.8ꢀ170.0 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 8.2, 0.9 Hz, 1H), 7.41 (s, 1H), 6.91 (d, J =
8.2 Hz, 1H), 3.24 (s, 3H), 3.04 (d, J = 17.0 Hz, 1H), 2.87 (d, J = 17.0 Hz, 1H), 1.38 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 180.0, 173.7, 146.4, 133.3, 126.1 (q, J = 3.9 Hz), 124.8 (q, J = 32.5
Hz), 124.3(q, J = 270.0 Hz), 119.3 (q, J = 3.6 Hz), 108.0, 45.2, 40.9, 26.6, 24.0. 19F NMR (376
MHz, CDCl3): δ ꢀ61.4. HRMS (ESI) calcd. for C13H12NO3F3Na+ (M+Na)+ 310.0667, found
310.0661.
2-(1,3-Dimethyl-5-nitro-2-oxoindolin-3-yl)acetic acid (2f):
2f (14.5 mg, 27%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1f (69.2 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 168.8ꢀ172.5 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 8.26 (dd, J = 8.6, 1.8 Hz, 1H), 8.07 (d, J = 1.7 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 3.27 (s,
3H), 3.10 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.3 Hz, 1H), 1.39 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 180.0, 173.5, 149.3, 133.7, 125.7, 118.1, 107.8, 45.2, 40.8, 26.8, 24.1. HRMS (ESI)
ꢀ
calcd. for C12H11N2O5 (MꢀH)ꢀ 263.0668, found 263.0673.
2-(6-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)acetic acid (2g):
2g (48.0 mg, 96%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1g (66.2 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 165.0ꢀ167.2 C (PE/EA). H NMR (400 MHz,
CDCl3): δ7.09 (d, J = 7.6 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 6.44 (s, 1H), 3.82 (s, 3H), 3.20 (s,
3H), 2.94 (d, J = 15.7 Hz, 1H), 2.77 (d, J = 15.9 Hz, 1H), 1.37 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 181.0, 173.4, 160.3, 144.3, 124.7, 123.0, 106.5, 96.6, 55.5, 44.8, 41.5, 26.5, 24.0.
HRMS (ESI) calcd. for C13H15NO4Na+ (M+Na)+ 272.0899, found 272.0897.
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2-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)acetic acid (2h):
2h (52.0 mg, 88%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1h (75.4 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 159.6ꢀ164.5 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 7.32ꢀ7.23 (m, 5H), 7.19 (d, J = 7.6 Hz, 1H), 7.15 (td, J = 8.0, 1.2 Hz, 1H), 7.02 (td, J =
7.6, 0.8 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.98 (d, J = 16.0 Hz, 1H), 4.88 (d, J = 15.6 Hz, 1H),
3.09 (d, J = 16.8 Hz, 1H), 2.89 (d, J = 16.8 Hz, 1H), 1.44 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
180.4, 173.5, 142.2, 135.6, 132.7, 128.8, 128.2, 127.6, 127.2, 122.9, 122.2, 109.6, 45.3, 44.0, 41.1,
24.6. The compound was identical with the reported data.31
2-(N-Acetyl-3-methylindolin-3-yl)acetic acid (2i):
2i (43.5 mg, 93%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1i (63.0 mg, 0.20
o
mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 168.5ꢀ170.4 C (PE/EA). Rotamers (10:1) were
abserved. 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.14
(d, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 4.28 (d, J = 10.8 Hz, 1H), 3.86 (d, J = 10.8 Hz, 1H),
2.73 (d, J = 15.6 Hz, 1H), 2.67 (d, J = 15.6 Hz, 1H), 2.25 (s, 3H), 1.47 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 175.4, 169.2, 141.5, 138.0, 128.4, 124.1, 122.1, 117.3, 60.9, 44.5, 42.0, 26.3, 24.1.
ꢀ
HRMS (ESI) calcd. for C13H14NO3 (MꢀH)ꢀ 232.0968, found 232.0976.
2-( N-Acetyl-4-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetic acid (2j):
2j (46.1 mg, 93%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1j (65.8 mg, 0.20
mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 132.2 oC (PE/EA). Rotamers were observed, and as a
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result broad peaks were observed in both H and 13C NMR spectroscopies. H NMR (400 MHz,
CDCl3): δ 8.46 (bs, 1H), 7.34ꢀ7.24 (m, 1H), 7.22ꢀ6.81 (m, 3H), 4.44ꢀ4.05 (brs, 1H), 3.44 (brs, 1H),
2.63 (d, J = 14.8 Hz, 1H), 2.58 (d, J = 14.8 Hz, 1H), 2.31ꢀ2.10 (m, 4H), 1.80ꢀ1.62 (m, 1H), 1.41 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 175.5, 170.8, 138.1(brs), 126.4, 125.9, 125.6, 124.8,
44.3(brs), 40.9(brs), 35.8, 35.5, 28.2, 22.8. HRMS (ESI) calcd. for C14H18NO3+ (M+H) + 248.1281,
found 248.1281.
2-(4-Methyl- N-tosyl-1,2,3,4-tetrahydroquinolin-4-yl)acetic acid (2k):
2k (58.9 mg, 82%, as oil) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH
= 50: 50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1k (88.3 mg,
0.20 mmol, 1.0 equiv) with CHCl3 (8.0 equiv) at 100 °C for 3 h. 1H NMR (400 MHz, CDCl3): δ
7.85ꢀ7.79 (m, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.24ꢀ7.16 (m, 4H), 7.16ꢀ7.09 (m, 1H), 3.89 (ddd, J =
14.0, 8.4, 3.6 Hz, 1H), 3.78 (ddd, J = 14.0, 7.6, 3.6 Hz, 1H), 2.42 (d, J = 14.4 Hz, 1H), 2.36 (s,
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3H), 2.16 (d, J = 14.4 Hz, 1H), 1.87 (ddd, J = 14.0, 7.6, 3.6 Hz, 1H), 1.49 (ddd, J = 14.0, 8.4, 3.6
Hz, 1H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 176.5, 143.8, 136.7, 136.3, 135.7, 129.6,
127.2, 126.9, 126.7, 125.2, 124.8, 45.9, 43.3, 34.6, 32.7, 28.5, 21.5. HRMS (ESI) calcd. for
C19H20NO4Sꢀ (MꢀH)ꢀ 358.1108, found 358.1114.
2-(3-Benzyl- N-methyl-2-oxoindolin-3-yl)acetic acid (2l):
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2l (56.2 mg, 94%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1l (75.4 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 136.6ꢀ142.6 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 7.19 (td, J = 7.6, 1.2 Hz, 1H), 713ꢀ7.00 (m, 5H), 6.75 (d, J = 7.2 Hz, 2H), 6.58 (d, J =
7.6 Hz, 1H), 3.14 (d, J = 16.4 Hz, 1H), 3.07 (d, J = 12.8 Hz, 1H), 3.03 (d, J = 13.2 Hz, 1H), 2.94
(s, 3H), 2.91 (d, J = 16.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 179.0, 173.5, 143.6, 134.4,
129.9, 128.4, 127.5, 126.8, 123.2, 122.4, 108.1, 51.0, 43.6, 40.1, 26.1. HRMS (ESI) calcd. for
C18H18NO3+ (M+H)+ 296.1281, found 296.1278.
2-(N-Methyl-2-oxo-3-phenethylindolin-3-yl)acetic acid (2m):
2i (59.7 mg, 96%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1m (78.2 mg, 0.20
mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 95.4ꢀ99.6 oC (PE/EA). 1H NMR (400 MHz, CDCl3):
δ 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.24ꢀ7.17 (m, 3H), 7.16ꢀ7.08 (m, 2H), 7.02ꢀ6.96 (m, 2H), 6.86 (d,
J = 7.8 Hz, 1H), 3.20 (s, 3H), 3.01 (d, J = 16.4 Hz, 1H), 2.82 (d, J = 16.0 Hz, 1H), 2.35ꢀ2.16 (m,
2H), 2.06 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 179.3, 173.6, 144.0, 140.6, 130.5, 128.6, 128.3,
ꢀ
128.2, 126.0, 123.0, 122.6, 108.4, 49.5, 41.1, 39.3, 30.0, 26.4. HRMS (ESI) calcd. for C19H18NO3
(MꢀH)ꢀ 308.1281, found 308.1288.
2-(3-(Methoxymethyl)-N-methyl-2-oxoindolin-3-yl)aceticacid(2o),
3-(Methoxymethyl)-1,3-dimethylindolin-2-one (3o):
and
The reaction of chloroform (65 ꢁl, 0.80 mmol, 4.0 equiv) and 1o (66.2 mg, 0.20 mmol, 1.0
equiv) following Typical Procedure A at 80 °C for 1 h afforded 2o (31.1 mg, 68% as oil) and 3o
(11.2 mg, 27%, as viscous oil), (ethyl acetate: hexanes = 1: 5 to dichloromethane: ethyl acetate =
20: 3 to ethyl acetate: hexanes: AcOH = 50: 50: 1). 1H NMR (400 MHz, CDCl3): δ 7.34ꢀ7.24 (m,
2H), 7.05 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.64 (d, J = 8.8 Hz, 1H), 3.45 (d, J = 8.8 Hz,
1H), 3.23 (s, 3H), 3.21 (s, 3H), 2.96 (s, 2H); 13C NMR (100 MHz, CDCl3): 177.7, 173.6, 144.0,
+
129.8, 128.6, 123.4, 122.6, 108.2, 76.1, 59.6, 50.5, 37.5, 26.5. HRMS (ESI) calcd. for C13H16NO4
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(M+H)+ 250.1074, found 250.1069. 3o: H NMR (400 MHz, CDCl3): δ 7.33ꢀ7.22 (m, 2H), 7.07
(td, J = 7.6, 0.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.63 (d, J = 9.0 Hz, 1H), 3.62 (d, J = 9.0 Hz,
1H), 3.23 (s, 3H), 3.22 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 179.1, 143.5, 132.8,
+
128.0, 122.8, 122.4, 108.0, 77.1, 59.5, 49.3, 26.2, 19.7. HRMS (ESI) calcd. for C12H16NO2
(M+H)+ 206.1176, found 206.1173.
2-( N-Butyl-4-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid (2p):
2p (32.0 mg, 58%, as viscous oil) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes:
AcOH = 50: 50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1p (71.4
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mg, 0.20 mmol, 1.0 equiv) at 80 °C for 1 h. H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz,
1H), 7.47 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.78ꢀ3.61 (m, 2H),
3.55ꢀ3.37 (m, 2H), 2.71 (d, J = 14.4 Hz, 1H), 2.51 (d, J = 14.4 Hz, 1H), 1.70ꢀ1.54 (m, 2H), 1.50 (s,
3H), 1.43ꢀ1.30 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 175.0, 164.2,
144.4, 132.2, 128.7, 128.2, 127.4, 123.6, 55.0, 47.4, 42.6, 36.2, 29.5, 22.5, 20.2, 13.8. HRMS (ESI)
calcd. for C16H20NO3 (MꢀH)ꢀ 274.1438, found 274.1444.
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2-(1,3-Dimethyl-2-oxoindolin-3-yl)-2-phenylacetic acid (2q):
2q (47.7 mg, 81%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure A at 0.20 mmol scale of 1q (75.4 mg, 0.20
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mmol, 1.0 equiv) at 80 °C for 1 h. Solid: mp 163.8ꢀ168.6 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 7.26ꢀ7.21 (m, 2H), 7.19ꢀ7.05 (m, 4H), 7.01ꢀ6.95 (m, 2H), 6.71ꢀ6.66 (m, 1H), 4.27 (s,
1H), 3.06 (s, 3H), 1.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 181.3, 172.1, 142.2, 133.2, 131.7,
128.7, 128.5, 128.1, 128.0, 123.6, 123.2, 108.8, 59.9, 50.7, 26.4, 22.8. HRMS (ESI) calcd. for
C18H18NO3+ (M+H)+ 296.1279, found 296.1281.
Typical Procedure B: The reaction of chloroform (65 ꢁl, 0.80 mmol, 4.0 equiv), 1t (50.8 mg,
0.20 mmol, 1.0 equiv), Pd(PPh3)2Cl2 (7.0 mg, 0.01 mmol, 5 mol %), KOH (89.8 mg, 1.60 mmol,
8.0 equiv) in H2O (1.6 mL)/dioxane (0.4 mL) at 100 °C for 1 h afforded 2a (38.3 mg, 87%)
(dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50: 50: 1).
2-(1,3,6-Trimethyl-2-oxoindolin-3-yl)acetic acid (2v):
2v (37.8 mg, 81%) (dichloromethane: ethyl acetate = 20: 3 to ethyl acetate: hexanes: AcOH = 50:
50: 1) was obtained following Typical Procedure B at 0.20 mmol scale of 1v (53.6 mg, 0.20
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mmol, 1.0 equiv) at 100 °C for 1 h. Solid: mp 168.6ꢀ170.5 C (PE/EA). H NMR (400 MHz,
CDCl3): δ 7.07 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 3.21 (s, 3H), 2.96 (d, J =
16.4 Hz, 1H), 2.77 (d, J = 16.4 Hz, 1H), 2.38 (s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 180.8, 173.5, 143.1, 138.5, 129.8, 123.4, 122.1, 109.5, 45.0, 41.4, 26.4, 23.9, 21.8. HRMS (ESI)
ꢀ
calcd. for C13H14NO3 (MꢀH)ꢀ 232.0968, found 232.0977.
2-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[g]indol-3-yl)acetic acid (2w):
The reaction of chloroform (65 ꢁl, 0.80 mmol, 4.0 equiv) and 1w (60.8 mg 0.20 mmol, 1.0
equiv) following Typical Procedure B at 100 °C for 3 h afforded 1w (16.9 mg, 28%)
(dichloromethane: ethyl acetate = 200: 5 to dichloromethane: ethyl acetate = 20: 3 to ethyl acetate:
AcOH = 100: 1) and 2w (33.2 mg, 62%). Solid: mp 259.3ꢀ261.9 oC (PE/EA). 1H NMR (400 MHz,
DMSOꢀd6): δ 11.87 (bs, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 8.4, 3.2 Hz, 2H), 7.50 (t, J =
7.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 3.24 (s, 3H), 3.03 (d, J = 16.6 Hz,
1H), 1.43 (s, 3H); 13C NMR (100 MHz, DMSOꢀd6): 180.5, 170.9, 141.4, 129.9, 129.5, 129.0,
128.6, 127.0, 124.0, 123.1, 121.8, 110.3, 46.5, 41.4, 26.4, 23.9. HRMS (ESI) calcd. for
C16H16NO3+ (M+H)+ 270.1125, found 270.1122.
ASSOCIATED CONTENT
Supporting Information
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CIF file for compound 2q, copies of H, 13C and 19F NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
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Corresponding Author
*Eꢀmail: zhgu@ustc.edu.cn.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the '973' project from the MOST of China (2015CB856600), NSFC
(21272221, 21472179), the Recruitment Program of Global Experts, and the Fundamental
Research Funds for the Central Universities (WK 2060190028, 2060190026 and 3430000001), the
Fundamental Research Funds for Central Universities and Crossꢀdisciplinary Collaborative Teams
Program for Science, Technology and Innovation (2014ꢀ2016) from Chinese Academy of
Sciences.
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