Superacid-catalyzed tandem Meyer–Schuster rearrangement/intramolecular hydroamination of o-anilinopropargyl alcohols for the synthesis of 2,3-dihydro-4(1H)-quinolones

Article abstract of DOI:10.1080/00397911.2016.1196293

A TfOH-catalyzed synthesis of 2,3-dihydro-4(1H)-quinolones from o-anilinopropargyl alcohols was developed. Studies of N-protecting groups and substituents in phenyl rings showed that diverse groups could be applied. By controlling the catalyst loading, o-anilinopropargyl alcohols underwent the expected transformation smoothly to produce N-protected or N-deprotected 2,3-dihydro-4 (1H)-quinolones in good yields. This transformation probably involved a tandem Meyer–Schuster rearrangement/intramolecular hydroamination reaction process.

Full text of DOI:10.1080/00397911.2016.1196293

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Superacid-Catalyzed Tandem Meyer-Schuster
Rearrangement/Intramolecular Hydroamination
of o-Anilinopropargyl Alcohols for the Synthesis of
2,3-dihydro-4(1 h)-quinolones
Guofeng Sun, Fengkai Cheng, Ruiheng Tao, Yuxing Sun, Jinpeng Pan, Yaohua
Zhu, Zhonghua Wang, Fanhong Wu & Yan Yin
To cite this article: Guofeng Sun, Fengkai Cheng, Ruiheng Tao, Yuxing Sun, Jinpeng Pan,
Yaohua Zhu, Zhonghua Wang, Fanhong Wu & Yan Yin (2016): Superacid-Catalyzed Tandem
Meyer-Schuster Rearrangement/Intramolecular Hydroamination of o-Anilinopropargyl
Alcohols for the Synthesis of 2,3-dihydro-4(1 h)-quinolones, Synthetic Communications, DOI:
10.1080/00397911.2016.1196293
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1196293
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Date: 22 June 2016, At: 20:06

Superacid-catalyzed Tandem Meyer-Schuster Rearrangement/Intramolecular
Hydroamination of o-Anilinopropargyl Alcohols for the Synthesis of
2,3-Dihydro-4(1H)-quinolones
Guofeng Sun1, Fengkai Cheng1, Ruiheng Tao1, Yuxing Sun1, Jinpeng Pan1, Yaohua Zhu1,
Zhonghua Wang1, Fanhong Wu1, Yan Yin1,2
1School of Chemical and Environmental Engineering, Shanghai Institute of Technology,
Shanghai, P. R. China 2Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P. R. China
Corresponding author E-mail: yinyan@sit.edu.cn (Y. Yin)
Abstract
A TfOH-catalyzed synthesis of 2,3-dihydro-4(1H)-quinolones from o-anilinopropargyl
alcohols was developed. Studies of N-protecting groups and substituents in phenyl ring
showed that diverse groups could be applied. Controlling the catalyst loading,
o-anilinopropargyl alcohols underwent the expected transformation smoothly to produce
N-protected or N-deprotected 2,3-dihydro-4 (1H)-quinolones in good yields. This
transformation probably involved a tandem Meyer-Schuster
rearrangement/intramolecular hydroamination reaction process.
GRAPHICALABSTRACT
1

KEYWORDS: Meyer-Schuster rearrangement, o-anilinopropargyl alcohols, Superacid,
2,3-Dihydro-4(1H)-quinolones, Hydroamination reaction
INTRODUCTION
2,3-Dihydro-4(1H)-quinolone, an important building block in organic synthesis,[1] is
present in many bioactive agents[2] and electroluminescent materials.[3] As a result various
methods for its synthesis have been developed (Figure 1, previous work). The most
popular method for the preparation of 2,3-dihydro-4(1H)-quinolones was amination
reaction of 2-aminochalcones promoted by acid, base or metal.[4] Sc(OTf)3-mediated
aza-Diels-Alder reaction between N-arylimines and ketene dithioacetals provided a quite
distinctive mean to access 2,3-dihydro-4(1H)-quinolones.[5] Triflic acid-promoted
Fries-rearrangement of N-arylazetidin-2-ones provided a generally effective mean to
generate the 2,3-dihydro-4(1H)-quinolones isomer at or below room temperature.[6]
Pd-catalyzed allylic amination and thiazolium salt-catalyzed Stetter reaction cascade was
also an efficient method to synthesize 3-subsituted 2,3-dihydroquinolin-4-ones.[7] Ennis’
group reported a novel synthesis of 3-methoxycarbonylmethyl derivatives of
dihydroquinolone by application of a palladium-catalyzed carbonylative cyclization as
the key transformation.[8] Intramolecular Pd(0)-catalyzed reaction of
β-(2-iodoanilino)carboxamides was described by Sole’s group to access
2,3-dihydro-4(1H)-quinolones.[9] Yanada’s group reported one-pot dihydroquinolone
synthesis catalyzed by Bi(OTf)3.[10] Although much attention has been paid to construct
2

the 2,3-dihydro-4(1H)-quinolone units, development of new synthetic methodology for
this privileged structure is still an important and challenging task for the chemistry
community.
Surprisingly, treatment of N-methoxy-benzenesulfonyl (Mbs) protected
o-anilinopropargyl alcohol 1a with superacid C8F17SO3H gave N-Mbs protected
2,3-dihydro-4(1H)-quinolones 2a in high yield while we studied the superacid-catalyzed
intramolecular hydroamination of N-protected 2-alkynylanilines.[11] The transformation
of 1a to 2a probably involved a Meyer-Schuster rearrangement followed by an
intramolecular hydroamination reaction.[12] In this paper, details concerning optimization,
reaction scope, and limitations were described for the novel method of preparation of
2,3-dihydro-4(1H)-quinolones (Figure 1, this work).
RESULTS AND DISCUSSION
During intramolecular hydroamination reaction, we found that the protecting groups and
substituents in the phenyl ring affects the reaction rate and the ratio of
protected/deprotected cyclization products.[13] So o-anilinopropargyl alcohols 1 with
various N-protecting groups and phenyl ring substituents were prepared through
Pd2+-catalyzed Sonogashina coupling reaction of 2-iodoaniline and propargyl alcohol
followed by nitrogen protection, or nitrogen protection followed by Sonogashina reaction
(Scheme 1).
3

N-Ts protected o-anilinopropargyl alcohol 1b was treated as the substrate of the model
reaction to elaborate the reaction conditions including catalyst, catalyst loading, solvent,
and reaction temperature (Table 1). In the presence of 20 mol% superacid such as
C8F17SO3H and TfOH, 1b was cyclized to N-Ts protected 2,3-dihydro-4(1H)-quinolones
2b in 85% yield after refluxing 6 hours with noncoordinating α,α,α-trifluorotoluene as the
solvent, at the same time trace amount of N-deprotected 2,3-dihydro-4(1H)-quinolones 3
was also separated (entries 1 and 2). Nafion-H, a perfluoroalkanesulfonic acid resin, has
been found to be a recyclable solid acid with/ catalytic activity for many reactions.
Therefore Nafion-H was tested. Unfortunately only 45% yield of 2b was obtained after
refluxing 6 hours (Entry 3). Extending the reaction time or increasing the reaction
temperature, still low yields were obtained (data not shown here). Medium strong acids
such as TFA, H3PO4, HCOOH, and CH3COOH were then investigated. Lower yields
were obtained even with higher catalyst loading and longer reaction time (entries 4-7 vs
2). FeCl3 was reported to be a good agent for the Meyer-Schuster rearrangement of
propargyl alcohols[14] and hydroamination reaction between amine and alkene.[15]
Treatment of 1b with equivalent amount of FeCl3 in refluxing THF gave 80% yield of 2b
after 50 hours (entry 8), however the transformation almost did not take place after
refluxing 6hs catalyzed by 20 mol% FeCl3. So TfOH was chosen as the optimal catalyst
in the following investigation. Next we screened the reaction solvents. Nonprotic and
nonpolar solvents such as benzene and toluene were used, 2b were obtained in only 30%
4

yield and the reactions mainly underwent the unexpected Friedel-Crafts processes (entries
9 and 10). Nonprotic solvents such as chloroform and dichloromethane were used, a little
bit lower yields were observed compared with α,α,α-trifluorotoluene as solvent (entries
11 and 12 vs. 2). So the optimized reaction conditions for this reaction were 20 mol%
TfOH as the catalyst, and α,α,α-trifluorotoluene as the solvent.
The effects of protected groups were then investigated, and the results were summarized
in Table 2. All substrates with protecting groups, such as sulfonyl, benzoyl, and alkyl,
underwent the cyclizaiton smoothly to give N-protected products 2a-2e in 35% - 85%
yields and N-deprotected product 3 in only 25% yield after refluxing 6hs (Entries 1-9).
The transformation rates were almost the same for substrates with sulfonyl, benzoyl, or
alkyl protecting groups. The benzoyl protected substrates were easier to undergo the
N-deprotection reaction to give 3 than sulfonyl protected substrates due to the higher
leaving ability of acyl groups under acid conditions (entries 6-8 vs. entries 1-5), and the
yields of 3 decreased with the increasing electron-withdrawing ability of the protecting
groups (entries 3 and 4 vs. entries 1 and 2, and entries 7 and 8 vs. entry 6). Surprisingly,
aniline 1j without protecting groups can also underwent the cylization to give 3, but only
moderated yields were achieved after 6hs for the free NH2 that trapped the proton and
decreased the acidity of the catalyst, then the reactivity became very low (entry 10).
5

To gain insight of the electron density effect of the phenyl ring on the intramolecular
cyclization, o-anilinopropargyl alcohols bearing substituted groups in the phenyl ring (R
is 4-CH3 for 1k, 4-H for 1b, 4-F for 1l, 4-Cl for 1m, 4-Br for 1n, and 3, 4-dimethyl for 1o)
were then subjected to the optimized conditions (Table 3). The substituents of phenyl ring
had no obvious effects on the reaction and 2 were the major products after refluxing 6
hours, at the same time trace amount of 3 were also isolated. Increasing the charge
density on the nitrogen cause faster reaction rate compared 1o with 1b and 1k-1n (entry 6
vs. 1-5).
A number of cleavage methods of the N-S bond were available, especially for
N-detosylation.[16] Thus, we turned our attention to the one-pot transformation of
tosylated o-anilinopropargyl alcohols to N-free quinolones (Table 4). Treated with 70
mol% TfOH, 1b and 1k-1n underwent the rearrangement/cyclization/deprotection
smoothly to give N-deproteced quinolones in high yields (80% for 3k, 82% for 3, 79%
for 3l, 77% for 3m, and 80% for 3n). In fact, we observed the transformation of
N-protected quinolones to N-deprotected quinolones in all these cyclizations listed in
Table 4, also reflected by TLC.
CONCLUSIONS
We developed a superacid-catalyzed tandem Meyer-Schuster
rearrangement/intramolecular hydroamination of o-anilinopropargyl alcohol to build up
6

2,3-unsubstituted 2,3-dihydro-4(1H)-quinolones. Our studies indicated a low catalyst
loading, short reaction time and high yield cyclization, making it a potentially attractive
method in organic synthesis.
EXPERIMENTAL
Commercially available reagents and anhydrous solvents were used without further
purification unless other wised specified. Thin layer chromatography analyses were
performed with Huanghai TLC plate. All the products were purified by column
chromatography on silica gel with ethyl acetate-hexane in an appropriate ratio as the
eluent. 1H and 13C NMR spetra were recorded at Bruker 500 MHz or 400 MHz with
TMS as an internal standard. IR spectra (KBr) were recorded on a FT-IR spectrometer in
the range of 400-4000 cm−1. The melting points were measured on a Melting point SGW
X-4. HRMS experiments were performed with Thermo Finnigan orbitrap mass analyzer
or Advion expression CMS.
General Procedure For The Synthesis Of 2a-2i, 2k-2o, 3, And 3k-3n
To a mixture of o-anilinopropargyl alcohol 1a-1o (0.1 mmol) with α,α,α-trifluorotoluene
(1 mL), TfOH (0.02 mmol) was added slowly. The mixture was stirred and refluxed until
the starting material disappeared completely (TLC). Then the reaction was quenched by
adding saturated NaHCO3 and extracted with ethyl acetate. The combined organic phases
were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced
7

pressure. Finally, the residue was purified by column chromatography on silica gel
(200-300 mesh) with hexane/EtOAc as eluent to afford the products 2a-2i, 2k-2o, 3, and
3k-3n.
1-(Toluene-4-sulfonyl)-2,3-dihydro-1H-quinolin-4-one (2b) [17]: white solid; m.p.
138-139OC; 1H NMR (400 MHz, CDCl3) δ = 7.90-7.87 (m, 1H), 7.82-7.80 (m, 1H),
7.54-7.51 (m, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.21-7.20 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H),
4.17 (t, J = 7.2 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.33 (s, 3H); IR (KBr，cm-1) 3067, 2954,
2924, 2885, 1687, 1598, 1475, 1353, 1296, 1167, 1090, 946, 772, 684, 577.
SUPPLEMENTARY MATERIAL
Full experimental details, 1H and13C NMR spectra for this article can be found via the
“Supplementary Content” section of this article’s webpage.
ACKNOWLEDGEMENTS
The work was supported by National Natural Science Foundation of China (No.
21502117), and Shanghai Municipal Education Commission (PlateauDiscipline
Construction Program). Support from Prof. Gang Zhao and Prof. Guanjun Wang was also
gratefully acknowledged.
REFERENCES
8

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10

Table 1 Survey the reaction conditions. a
Entry Catalyst
Solvent Catalyst loading
Time (h) Yield of 2b
Yield of 3
(%)b
(mol%)
20
(%)b
CF
CF
CF
CF
3
3
3
3
1
C8F17SO3H
6
85
85
45
60
70
70
20
80
30
30
70
70
Trace
Trace
trace
trace
trace
trace
trace
trace
NR
2
TfOH
20
6
3c
4c
5c
6c
7c
8
Nafion-NR50
TFA
20
6
40
24
24
48
48
50
6
CF3
H3PO4
40
CF
CF
3
3
HCOOH
CH3COOH
FeCl3
200
200
100
20
THF
9d
10d
11c
12c
TfOH
CH
3
TfOH
20
6
NR
TfOH
CHCl3 20
CH2Cl2 20
6
trace
trace
TFOH
6
a Reaction conditions: 1b (0.1 mmol), solvent (1 mL), reflux.
b Isolated yield after flash chromatography.
c The unconsumed starting material 1b was recovered.
11

d By-product was separated.
12

Table 2 Effect of the protecting groups a
Entry Substrate PG
Yield of 2 (%)b Yield of 3 (%)b
O
S
H CO
3
1
85
83
85
85
80
50
35
40
70
NR
Trace
trace
trace
trace
trace
25
1a
1b
1c
1d
1e
1f
O
O
H C
3
S
2
O
O
S
F
3
O
O
Br
S
4
O
O
S
H C
3
5
O
6
O
F
7
25
1g
1h
1i
O
Cl
8
25
O
9
trace
50
10c
H
1j
a Reaction conditions: 1 (0.1 mmol), TfOH (0.02 mmol), trifluoromethyl-benzene (1
mL)，reflux, 6h.
b Isolated yield after flash chromatography.
c The unconsumed starting material was recovered.
13

Table 3 Electronic effects of phenyl ring.a
Entry Substrate R
Time (h) Yield of 2 (%)b Yield of 3 (%)b
1
2
3
4
5
6
4-CH3
4-H
6
6
6
6
6
5
82
83
80
80
80
85
trace
trace
trace
trace
trace
NR
1k
1b
1l
4-F
4-Cl
1m
1n
1o
4-Br
3, 4-CH3
a Reaction conditions: 1 (0.1 mmol), TfOH (0.02 mmol), trifluoromethyl-benzene (1 mL),
reflux.
b Isolated yield after flash chromatography.
14

Table 4 Superacid catalyzed one-pot cyclizationa
Entry Substrate R
Product Time (h) Yield (%)b
1
2
3
4
5
4-CH3
4-H
8
8
8
8
8
80
82
79
77
80
1k
1b
1l
3k
3
4-F
3l
4-Cl
4-Br
1m
1n
3m
3n
a Reaction conditions: 1 (0.1 mmol), TfOH (0.07 mmol), trifluoromethyl-benzene (1 mL),
reflux.
b Isolated yield after flash chromatography.
15

Scheme 1. Synthesis route of 1 Reagents and conditions: (a) Propargyl alcohol,
PdCl2(PPh3)2, CuI, Et3N; (b) PG-X.
16

Figure 1. Synthesis of 2,3-dihydro-4-quinolones
17