Acid-promoted metal-free synthesis of 3-ketoquinolines from amines, enaminones and DMSO

Article abstract of DOI:10.1016/j.tetlet.2019.07.010

A metal-free p-toluenesulfonic acid (TsOH·H₂O) mediated synthesis of 3-ketoquinolines from anilines, enaminones and DMSO has been developed. In this transformation, DMSO was activated by TsOH·H₂O and provided the one-carbon unit of t

Full text of DOI:10.1016/j.tetlet.2019.07.010

Accepted Manuscript
Acid-promoted metal-free synthesis of 3-ketoquinolines from amines, enami-
nones and DMSO
Tao-Shan Jiang, Yuhui Zhou, Long Dai, Xiaojun Liu, Xiuli Zhang
PII:
S0040-4039(19)30656-2
https://doi.org/10.1016/j.tetlet.2019.07.010
TETL 50919
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 May 2019
22 June 2019
5 July 2019
Please cite this article as: Jiang, T-S., Zhou, Y., Dai, L., Liu, X., Zhang, X., Acid-promoted metal-free synthesis of
3-ketoquinolines from amines, enaminones and DMSO, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.07.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Acid-promoted metal-free synthesis of 3-ketoquinolines from
amines, enaminones and DMSO
Tao-Shan Jiang†,a *, Yuhui Zhou†,b, Long Daib, Xiaojun Liub,Xiuli Zhangb,c *
a
School of Life Sciences, Anhui Agricultural University, Hefei, 230036, PR China.
e-mail: jts2015@ahau.edu.cn
b
Department of Applied Chemistry, Anhui Agricultural University, Hefei, Anhui
230036, PR China.
*
Corresponding author. e-mail: zhxiuli@163.com
c
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Shanghai 200032, P.R. China.
†
These authors contributed equally to this work.
Abstract
A metal-free p-toluenesulfonic acid (TsOH·H2O) mediated synthesis of 3-
ketoquinolines from anilines, enaminones and DMSO has been developed. In this
transformation, DMSO was activated by TsOH·H2O and provided the one-carbon unit
of the 3-ketoquinolines. A plausible mechanism involving an electrophilic sulfenium
ion intermediate was proposed.
Keywords: enaminones, DMSO, one carbon synthon, 3-ketoquinolines

1. Introduction
Dimethyl sulfoxide (DMSO) is an important aprotic polar solvent in organic
synthesis and medicinal science due to its low toxicity, high solubility and ready
availability.1 In addition, it also has been widely used as an oxidant2 and ligand.3 In
recent years, DMSO has attracted extensive interest as a versatile synthon donor
which has expanded its applications.4 For example, DMSO has been used as a sulfur
source,5 oxygen source6 and one-carbon source.7 In particular, strategies utilising
DMSO as a one-carbon source to construct quinoline structures have attracted
significant interest.7c-d, 7h-j Generally, DMSO can be activated in two ways under
metal-free conditions to generate a reactive electrophilic intermediate sulfenium ion A
in situ which could be easily captured by nucleophiles (Scheme 1). (i) Oxidation
strategy: activation by a strong oxidant (e.g. K2S2O8);7 (ii) acid strategy: Pummerer
rearrangement under acidic conditions.8-10
Oxidation strategy
K2S2O8
O
S
O
S

S
S
A
Acid strategy
sulfenium ion
H+
reactive electrophile
Scheme 1. Two methods for sulfenium ion A formation from DMSO.
There have been several reports regarding DMSO activation under metal-free
conditions. In this respect, Ma and co-workers reported an efficient AcOH-promoted
method to construct N-heterocycle-fused quinoxalines using DMSO as a one-carbon
unit (Scheme 2a).8 More recently, Wen and co-workers developed a novel acid-
promoted, direct cross-coupling reaction of methyl ketones and DMSO to prepare β-
acyl allylic methylsulfides and sulfones in which DMSO serves as a dual synthon
(Scheme 2b).9 Our group also reported an efficient CH3SO3H-promoted synthesis of
4-arylquinolines from readily available anilines and acetophenones using DMSO as a
one-carbon unit under air (Scheme 2c).10
Quinolines are ubiquitous in pharmacologically and medicinally relevant

compounds. Various quinoline syntheses have been developed including classical
named reactions11 and transition metal-catalyzed coupling reactions.12 However, the
development of simple and efficient organic synthetic routes is still desirable
(particularly metal-free procedures using readily available and inexpensive starting
materials). Herein, we report a facile metal-free Brønsted acid-promoted synthesis of
3-ketoquinolines from anilines, enaminones and DMSO (Scheme 2d).
Previous work:
X
X
Y
N
O
S
Y
N
N
HOAc, air
130 oC
O
R
R
X = C, N (a)
Y = C, N
NH2
O
O
O
S
O
TsOH H2O
150 oC
or
Ar
S
(b)
(c)
(d)
Ar
S
2
Ar
O
Ar
O
O
R1
CH3SO3H, air
130 oC
R1
S
Ar
NH2
N
This work:
O
O
Ar
TsOH H2O
DMSO, 110 oC
R1
R1
N
Ar
NH2
N
Scheme 2. Acid promoted DMSO activation and representative reactions.
2. Results and Discussion
We started by examining the model reaction of p-toluidine (1a), enaminone 2a,
CH3SO3H (1.0 equiv.) as the additive and DMSO (1 mL, also used as the solvent) at
120 ºC under air, in accordance with our previous work.10 To our delight, 3-
ketoquinoline 3a was obtained in 30% isolated yield (Table 1, entry 1). Then different
Brønsted acids were examined; TsOH·H2O gave the best result and the desired
product was isolated in 39% yield (Entry 2 vs. entries 1 and 2-7). The acid additive
was determined to be necessary for this reaction (Entry 8). Next we examined the
influence of the amount of the additive. When less than 1.0 equiv. of TsOH·H2O was
added, lower yields were obtained (Entries 9-10). Increasing the amount of
TsOH·H2O to 2.0 equiv. gave an improved 57% yield (Entry 12 vs. entries 11-13).

Gratifyingly, the yield was further improved to 69% (Entry 15) when the temperature
was decreased to 110 ºC. Finally, prolonging the reaction time to 36 h did not increase
the yield (Entry 17). Further attempts (e.g. changing the ratio of 1a and 2a, using
mixed solvents) to improve the yield did not give better results (See ESI, Table 1). It
should be noted that Wan and co-workers reported an unprecedented synthetic
protocol to access 3-ketoquinolines via cleavage of the branched C=C and C=N bond
in enaminones.13 We therefore aimed to establish that DMSO was involved in the
reaction, and other solvents (e.g. DMF, 1,4-dioxane, toluene) were examined (Entries
18-20) and the desired product 3a was only obtained in DMF.14
Table 1. Optimization of the reaction conditions.a
O
O
additive, air
N
NH2
DMSO, temp
N
2a
1a
3a
Entry
1
Additive (equiv.)
CH3SO3H (1.0)
TsOH·H2O(1.0)
D-CSA (1.0)
Temp (oC)
Yield 3a (%)
120
120
120
120
120
120
120
120
120
120
120
120
120
130
30
39
2
3
18
4
HOAc (0.1 mL)
TFA (0.1 mL)
HCl(1.0)
trace
10
5
6
trace
NR
NR
15
7
HCOOH(1.0)
-
8
9
TsOH·H2O (0.2)
TsOH·H2O (0.5)
TsOH·H2O (1.5)
TsOH·H2O (2.0)
TsOH·H2O (2.5)
TsOH·H2O (2.0)
10
11
12
13
14
26
46
57
53
52

15
16
TsOH·H2O (2.0)
TsOH·H2O (2.0)
TsOH·H2O (2.0)
TsOH·H2O (2.0)
TsOH·H2O (2.0)
TsOH·H2O (2.0)
110
100
110
110
110
110
69
35
17b
18c
19d
20e
68
25
NR
NR
a Reagents and conditions: 1a (0.2 mmol), 2a (0.3 mmol), additive, DMSO (1.0 mL),
b
c
d
air, 24 h. Reaction time was 36 h. No DMSO, DMF (1.0 mL). No DMSO, 1,4-
dioxane (1.0 mL). e No DMSO, toluene (1.0 mL).
To illustrate the scope of this 3-ketoquinoline synthesis, the reactions of
different anilines 1 and enaminones 2 were conducted under the optimized reaction
conditions (Table 1, entry 15). As summarized in Scheme 3, a variety of anilines and
enaminones with either electron-donating or electron-withdrawing groups afforded
the desired products in good yields (3a-z). For anilines, electron-donating groups on
the aromatic ring were generally preferable to weak electron-withdrawing groups
which required heating at 130 ºC for 36 h (3a-e, 3j-m vs 3f-g). However, acetyl and
hydroxyl substituted anilines, as well as pyridin-2-amine, were not suitable for this
protocol (3h-i, 3n). 3-Methylaniline gave the corresponding products in 77% yield,
but as a mixture of two regioisomers 3j and 3j’ in a ~5:1 ratio.
Then the scope of different enaminone partners with p-toluidine (1a) was
explored. Various substituted enaminones gave the desired products (3o-z) in
moderate to good yields (49-72%). To our delight, enaminones containing an iodine
atom or a free hydroxyl group which could undergo further transformations were
tolerated and afforded the corresponding 3-ketoquinolines 3t (67%) and 3x (55%),
respectively. This protocol was also extended to heteroaryl enaminones including
pyridine and thiophene, and moderate yields of the target products (3y, 3z) were
obtained. It should be noted that alkyl enaminones were not compatible with these
reaction conditions.

Finally, we examined the reactions of different N, N-substituted enaminones.
Other N,N-disubstituted enaminones were suitable for this transformation and
afforded the desired product 3a in moderate yields (30-68%). Enaminones with
primary and secondary amines were not suitable.
O
O
TsOH H2O
R1
Ar
R1
R
Ar
N
R2
DMSO, 110 oC
24 h
NH2
N
3
2
1
different anlines with enaminone 2a:
O
O
O
O
R
N
N
N
3j
3j'
c
3j/3j'
77% (
= 5/1)
3a
3b
3c
3d
3e
3f
(R = CH3), 69%
(R = H), 63%
O
(R = CH3O), 58%
(R = Ph), 59%
N
N
(R = -Pr), 73%
i
3k
, 53%
O
3l,
58%
O
(R = F), 38% b
b
3g
3h
3i
(R = Br), 40%
b
(R = Ac), trace
(R = OH), trace
N
N
N
3m
, 81%
3n
, 0%
p-toluidine (1a) with different enaminones (R1= R2 = CH3):
Cl
O
O
O
N
N
3w
, 72%
O
3v
, 61%
R
N
O
OH
3o
3p
3q
3r
3s
3t
(R = CH3O), 69%
(R = CH3), 65%
(R = F), 62%
(R = Cl), 60%
(R = Br), 65%
(R = I), 67%
N
3y
N
3x
, 55%
, 32%
O
S
3u
(R = NO2), 49%
N
3z
, 57%
3a was obtained from p-toluidine (1a) with different enaminones:
O
O
O
Ph
N
Ph
N
Ph
Ph
N
3a
, 55%
3a
, 68%
3a
, 60%
O
O
O
N
Ph
Ph
NH2
Ph
N
H
3a
, 0%
3a
, 30%
3a
, 0%

Scheme 3. Substrate scope. a Reagents and conditions: 1a (0.2 mmol), 2a (0.3 mmol),
TsOH·H2O (0.4 mmol), DMSO (1.0 mL), air, 110 ºC, 24 h. b 130 ºC for 36 h. c Ratio
was determined by the 1H NMR analysis.
To demonstrate additional applications of this protocol, we examined the
two-fold cyclization of 1,4-diaminobenzene (1aa) with enaminone 2a. To our
delight, the novel hetero-anthracene derivative 3aa was obtained in 20%
isolated yield. Although lower yielding, this method represents a simple
synthesis of hetero-anthracene derivatives. Similarly, 4,4'-diaminobiphenyl
(1bb) reacted with 2a to give the corresponding product 3bb in 24% isolated
yield (Scheme 4).
O
TsOH H2O
(4.0 equiv.)
DMSO, 110 oC, 48 h
O
N
H2N
H2N
Ph
O
Ph
N
Ph
N
NH2
O
1aa
, 0.2 mmol
2a,
0.6 mmol
3aa
, 20%
N
TsOH H2O
(4.0 equiv.)
Ph
2a
Ph
DMSO, 110 oC, 48 h
NH2
O
N
1bb,
0.2 mmol
2a,
0.6 mmol
3bb
, 24%
Scheme 4. Reactions of diamino compounds with enaminone 2a.
To understand the reaction mechanism and the position of the one-carbon unit,
several control experiments were conducted (Scheme 5). Considering the in situ
formed electrophilic intermediate sulfenium ion A,9 the reaction was performed by
adding chloromethyl methyl sulfide (10 equiv.) in the absence of DMSO, to give
product 3a in 29% yield (Scheme 5a). A deuterium-labeling experiment in DMSO-d6
was carried out, and only 30% deuteration at the C-2 position was observed (Scheme
5b). Interestingly, when product 3a was subjected to a deuterium-labeling experiment,
product 3a″ was obtained with approximately 20% incorporation of deuterium at the
C-2 position (Scheme 5c). These results indicated that DMSO provided the one-

carbon unit at the C-2 position of the desired product and H-D exchange of quinoline
occurred under the acidic conditions.15 However, enaminone intermediate 4a was
observed during the reaction and disappeared at the end.16 The reaction of 4a was
performed under the standard reaction conditions, and surprisingly product 3a was
isolated in 52% yield which inferred that the one-carbon unit at the C-4 position of
quinoline was derived from DMSO (Scheme 5d).
O
O
TsOH H2O,
DMA, air
N
(a)
CH3SCH2Cl (10 equiv.)
N
3a,
NH2
110 oC, 24 h
29%
2a
1a
1a
O
D
TsOH H2O, air
(b)
(c)
(d)
2a
NH2
DMSO-d6, 110 oC
N
24 h
30% D
3a',
62%
O
O
TsOH H2O, air
DMSO-d6, 110 oC
N
3a
N
D
24 h
~20% D
O
3a''
TsOH H2O, air
N
H
DMSO, 110 oC
O
N
24 h
4a
3a
, 52%
Scheme 5. Control experiments.
Plausible mechanisms (path a and path b) are shown below (Scheme 6). In path
a, the in situ formed reactive intermediate A is attacked by 1a to give intermediate B
which undergoes demethylthioation to form iminium ion C. Then intermediate D is
obtained via nucleophilic addition of enaminone 2a to C and subsequent cyclization
occurs to produce intermediate E. The elimination of HNMe2 and subsequent
oxidation leads to the formation of 3-ketoquinoline 3a.17 In path b, intermediate G
which is formed from A and 4a undergoes demethylthioation to form intermediate H,
then subsequent cyclization and oxidation furnishes the desired product 3a. Based on
the above experiments, path a and path b both occur in this system.

N
O
N
O
S
NH2
Ph
O
Ph
-CH3SH
1a
2a
N
N
H
N
H
H
a
path
C
D
B
O
S
N
O
O
H+
Ph
Ph
-NH(CH3)2
[O]
Ph
Ph
N
H
N
N
3a
S
H
E
F
A
O
Ph
S
O
O
O
N
Ph
Ph
H
-CH3SH
4a
N
N
N
b
path
G
H
3a
Scheme 6. Proposed mechanism.
3. Conclusion
We have developed an efficient acid promoted synthesis of 3-ketoquinolines
from anilines, enaminones and DMSO under metal-free conditions. In this protocol,
DMSO was used as a one-carbon synthon. Mechanistically, DMSO may undergo a
Pummerer rearrangement to generate a reactive electrophilic intermediate sulfenium
ion A in situ under acidic conditions.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (21702002)
and Natural Science Foundation of Anhui Province (1608085MB26) for financial
support.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
References
[1]
(a) D. Martin, A. Weise, H. J. Niclas. Angew. Chem. Int. Ed. 6 (1967) 318; (b) Dimethyl
Sulfoxide Producers Association, US Environmental Protection Agency. IUCLID Data Set;
Leesburg, VA, Sept. 8, 2003, report number 201–14721A;
[2]
(a) W. W. Epstein, F. W. Sweat. Chem. Rev. 67 (1967) 247; (b) T. T. Tidwell. Synthesis
(1990) 857.
[3] M. Calligaris. Coordin. Chem. Rev. 248 (2004) 351.

[4]
[5]
For select reviews about DMSO in organic transformations, see: (a) E. Jones-Mensah, M.
Karki, J. Magolan. Synthesis 48 (2016) 1421; (b) X.-F. Wu, K. Natte. Adv. Synth. Catal.
358 (2016) 336.
For recent articles, see: (a) J. Zhang, S. Cheng, Z. Cai, P. Liu, P. Sun. J. Org. Chem. 83
(2018) 9344; (b) M. Huang, J. Zhu, C. He, Y. Zhu, W. Hao, D. Wang, S. Tu, B. Jiang. Org.
Chem. Front. 5 (2018) 1643; (c) T.-S. Jiang, Q. Zhang, G. Li, X. Cheng, Y. Cai, Synthesis
50 (2018) 4611‒4616. (d) N. Xu, Y. Zhang, W. Chen, P. Li, L. Wang, Adv. Synth. Catal.
360 (2018) 1199; (e) Y. Yang, R.-J. Song, X.-H. Ouyang, C.-Y. Wang, J.-H. Li, S Luo.
Angew. Chem. Int. Ed. 56 (2017) 7916; (f) A. Shao, M. Gao, S. Chen, T. Wang, A. Lei.
Chem. Sci. 8 (2017) 2175; (g) M. M. D. Pramanik, N. Rastogi. Chem. Commun. 52 (2016)
8557; (h) X. Gao, X. Pan, J. Gao, H. Jiang, G. Yuan, Y. Li. Org. Lett. 17 (2015) 1038; (i) T.
Shen, X. Huang, Y. -F. Liang, N. Jiao. Org. Lett. 17 (2015) 6186; (j) P. Sharma, S. Rohilla,
N. Jain, J. Org. Chem. 80 (2015) 4116. (k) G. Yin, B. Zhou, X. Meng, A. Wu, Y. Pan. Org.
Lett. 8 (2006) 2245.
[6]
[7]
For recent articles, see: (a) Y. -F. Liang, X. Li, X. Wang, M. Zou, C. Tang, Y. Liang, S.
Song, N. Jiao. J. Am. Chem. Soc. 138 (2016) 12271; (b) S. Song, X. Huang, Y. -F. Liang, C.
Tang, X. Li, N. Jiao, Green Chem. 17 (2015) 2727; (c) Y. -F. Liang, K. Wu, S. Song, X. Li,
X. Huang, N. Jiao, Org. Lett. 17 (2015) 876; (d) R. Chebolu, A. Bahuguna, R. Sharma, V. K.
Mishra, P. C. Ravikumar, Chem. Commun. 51 (2015) 15438.
For recent articles, see: (a) X. Zhu, W. Li, X. Luo, G. Deng, Y. Liang, J. Liu. Green Chem.
20 (2018) 1970; (b) K.-S. Du, J.-M. Huang, Green Chem. 20 (2018) 1405; (c) C. Xu, S.-F.
Jiang, X.-H. Wen, Q. Zhang, Z.-W. Zhou, Y. Wu, F.-C. Jia, A. Wu. Adv. Synth. Catal. 360
(2018) 2267; (d) Y. Liu, Y. Hu, Z. Cao, Z. Xi, W.-P. Luo, L. Qiang, C.-C. Guo. Adv. Synth.
Catal. 360 (2018) 2691; (e) Y.-Y. Liu, X.-H. Yang, R.-J. Song, S. Luo, J.-H. Li. Nature
Commun. 8 (2017) 14720; (f) R. Pothikumar, C. Sujatha, K. Namitharan. ACS Catal. 7
(2017) 7783; (g) Y. -F. Liu, P. -Y. Ji, J. -W. Xu, Y. -Q. Hu, Q. Liu, W. -P. Luo, C. -C. Guo,
J. Org. Chem. 82 (2017) 7159; (h) S. D. Jadhav, A. Singh, Org. Lett. 19 (2017) 5673; (i) S.
B. Wakade, D. K. Tiwari, P. S. K. P Ganesh, M. Phanindrudu, P. R. Likhar, D. K. Tiwari.
Org Lett. 19 (2017) 4948; (j) J. Yuan, J. -T. Yu, Y. Jiang, J. Cheng, Org. Biomol. Chem. 15
(2017) 1334; (k) H. Wang, S. Sun, J. Cheng, Tetrahedron Lett. 58 (2017) 3875. (l) X. Wu, J.
Zhang, S. Liu, Q. Gao, A. Wu. Adv. Synth. Catal. 358 (2016) 216.
[8] C. Xie, Z. Zhang, D. Li, J. Gong, X. Han, X. Liu, C. Ma, J. Org. Chem. 82 (2017) 3491.
[9] Z.-K. Wen, X.-H. Liu, Y.-F. Liu, J.-B. Chao, Org. Lett. 19 (2017) 5798.
[10] T.-S. Jiang, X. Wang, X. Zhang. Tetrahedron Lett. 59 (2018) 2979.
[11] For selected reviews, see: (a) M. Fallah-Mehrjardi, Mini-Rev. Org. Chem. 14 (2017) 187;
(b) G. A. Ramann, B. J. Cowen, Molecules 21 (2016) 986; (c) A. Majumder, R. Gupta, A.
Jain, Green Chem. Lett. Rev. 6 (2013) 151; (d) J. Marco-Contelles, E. Pérez-Mayoral, A.
Samadi, M. d. C. Carreiras, E. Soriano, Chem. Rev. 109 (2009) 2652.

[12] For selected reviews, see: (a) S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal, H.
D. Patel, RSC Adv. 4 (2014) 24463; (b) Y. Yamamoto, Chem. Soc. Rev. 43 (2014) 1575; (c)
J. Barluenga, F. Rodriguez, F. J. Fananas, Chem. Asian J. 4 (2009) 1036; (d) D. M. D'Souza,
T. J. Mueller, Chem. Soc. Rev. 36 (2007) 1095.
[13] (a) J.-P. Wan , Y. Zhou, S. Cao. J. Org. Chem. 79 (2014) 9872; (b) J.-P. Wan , Y. Zhou, Y.
Liu, S. Sheng. Green Chem. 18 (2016) 402; (c) J.-P. Wan , Y. Jing, L. Wei. Asian J. Org.
Chem. 6 (2017) 666.
[14] DMF could be used as one-carbon unit, see: (a) Y. Lv, Y. Li, T. Xiong, W. Pu, H. Zhang, K.
Sun, Q. Liu, Q. Zhang, Chem. Commun. 49 (2013) 6439; (b) X. Xu, M. Zhang, H. Jiang, J.
Zheng, Y. Li, Org. Lett. 16 (2014) 3540.
[15] R. K. Saunthwal, M. Patel, A. K. Verma, J. Org. Chem. 81 (2016) 6563.
[16] Y. Liu, R. Zhou, J.-P. Wan. Synth. Commun. 43 (2013) 2475.
[17] Y. Li, X. Cao, Y. Liu, J.-P. Wan. Org. Biomol. Chem. 15 (2017) 9585.
Acid-promoted metal-free synthesis of 3-ketoquinolines from
amines, enaminones and DMSO
Tao-Shan Jiang†,a *, Yuhui Zhou†,b , Long Daib, Xiaojun Liub and Xiuli Zhangb,c *
O
O
O
S
Ar
metal-free
R
R
N
Ar
N
NH2
up to 81% yield
Readily available starting materials
DMSO serves a one-carbon unit
Electrophilic sulfenium ion via Pummerer rearrangement

Highlights:
A metal-free synthesis of 3-ketoquinolines directly from anilines, enaminones and
DMSO
DMSO was activated by the acid and provided the one-carbon unit
An easy synthetic route to hetero-anthracene derivatives.