Carbon annulation of ortho-vinylanilines with dimethyl sulfoxide to access 4-aryl quinolines

Article abstract of DOI:10.1039/c6ob02714h

A palladium-catalyzed annulation of ortho-vinylanilines with dimethyl sulfoxide was developed to access 4-aryl quinolines in moderate to good yields. Activated by 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), DMSO served as a “=CH-” fragment in this transformation. It represents a facile pathway leading to 4-aryl quinolines.

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Carbonannulation of ortho-Vinylanilines with Dimethyl Sulfoxide to
Access 4-Aryl Quinolines
Jin Yuan, Jin-Tao Yu, Yan Jiang and Jiang Cheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A palladium-catalyzed annulation of ortho-vinylanilines
with dimethyl sulfoxide was developed to access 4-aryl
Scheme 1. DMSO as “=CH-” fragment in the constuction of heterocycle
quinolines in moderate to good yields. Activated by 1,4-
diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct
10 (DABSO), DMSO served as a “=CH-” fragment in this
transformation. It represents a facile pathway leading to 4-
aryl quinolines.
Dimethyl sulfoxide (DMSO) was well known as aprotic polar
15 solvent1 and oxidant in organic reactions, such as Swern
oxidation,2 Kornblum oxidation,3 Pfitzner-Moffatt oxidation2a,4
and Corey-Chaykovsky reaction.5 The typical employment of
DMSO as building block in organic synthesis6 was Pummerer
reaction, where the fragment of “-CH2SMe” was incorporated
20 into the final product.7 With the development of organometallic
chemistry, DMSO was widely employed in many synthetic routes
after proper activations, including DMSO-based methylation,8
methylenation,9 formylation,10 cyanation,11 thiomethylation,12 and
methylsulfonylation.13 Besides, DMSO could also provide “=CH-
Table 1. Screening the optimized reaction conditionsa
50
Additive (equiv)
DABCO·HCl (0.5)
DABCO·HOAc (0.5)
DABCO·H2SO4 (0.5)
DABCO·CH3I (0.5)
DABCO·C3H5Br (0.5)
DABCO (0.5)
Yield(%)
Entry
1
Catalyst
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
PdCl2
25
” fragment in sequential annulation/aromatization reaction,
8
< 5
53
allowing rapid access to hetero- aromatic compounds. For
example, recently, Yuan reported the preparation of pyridine via
the four component cyclization of two methyl ketones, DMSO
and ammonium (Scheme 1, eq. 1). 14 Zhang described the copper-
30 catalyzed annulation of amidine and DMSO toward quinazolines
(Scheme 1, eq. 2).15 Very recently, Ma developed the annulation
of 2-aminobenzophenone, aqueous ammonium and DMSO
leading to quinazoline.16 Undoubtedly, the application of DMSO
as a synthon in organic synthesis greatly depends on the
35 development of new way to activate DMSO.
Quinoline skeleton is among the most prevalent heterocycles
found in biologically active molecules.17 In the light of its
importance, its preparation has attracted much attention over the
past few years. Classic synthetic methods include the base-
40 catalyzed Friedlaender reaction and acid-catalyzed Knorr
reaction.18 Recently, approaches catalyzed by transition metals
have been proved to be effective for quinolinone synthesis.19
Herein, we wish to report a palladium-catalyzed annulation of
ortho-vinylanilines with DMSO which serves as a “=CH-”
45 fragment leading to 4-aryl quinolones (Scheme 1, eq. 3).
2
3
< 5
< 5
< 5
80, 14b, 57c
61
4
5
6
DABSO (0.5)
7
DABSO (0.5)
8
DABSO (0.5)
67
9
DABSO (0.5)
70
10
11
12
13
14
15
16
17
DABSO (0.5)
58
Pd(CF3COO)2
Pd(acac)2
Pd(PPh3)2Cl2
Pd(dba)2
Pd(dba)2
--
DABSO (0.5)
65
DABSO (0.5)
72
DABSO (0.5)
62
DABSO (0.2)
60
DABSO (1.0)
69
DABSO (0.5)
24
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a
Reaction conditions: substituted 2-(1-arylvinyl)aniline 1 (0.1 mmol),
Pd(dba)2 (10 mol%), DABSO (0.5 equiv), in DMSO (2 mL), under N2,
140 oC, 18 h, sealed tube.
Pd(dba)2
Pd(dba)2
--
0
18
19
DABSO (0.5)
21d, 74e, 60f
a
Reaction conditions: 2-(1-phenylvinyl)aniline 1a (0.1 mmol), Pd (10
After the establishment of the optimized conditions, this
35 procedure was applied to access a variety of 4-aryl quinoline
derivatives. The procedure tolerated methyl, chloro, bromo and
fluoro groups, which provided handles for potentially further
functionalizations. As expected, 6-substituted-4-aryl quinolines
(3b-3k) were prepared in moderate to good yields (63-81%).
40 Importantly, besides 6-substituted-4-aryl quinolines, this
procedure allowed to access n-substituted analogues quickly (n =
3, 5, 7, 8). For example, 5,7-dimethyl-4-phenyl quinoline 3l
(36%), 3-methyl-4-phenyl quinoline 3m (30%), 8-methoxyl-4-
phenyl quinoline 3o (94%) and 7-methyl-4-phenyl quinoline 3p
45 (53%) were accessed facilely, respectively. Notably, 4-phenyl-
benzo[h]quinoline 3n was isolated in 92% yield. Importantly, this
procedure was applicable to access the analogues with 4-hetero-
aromatic ring and alkyl, since 3q and 3r were isolated in 59% and
28% yields, respectively. Moreover, other 5-, 7-, 8-substituted-4-
50 aryl quinolones (3s-3v) were obtained in moderate to good yields
(61-87%). However, any attempt to access 2-substituted-4-aryl
quinoline failed since replacing DMSO with diethyl sulfoxide,
and methyl phenyl sulfoxide resulted in no reaction under the
standard procedure. The practicability of this transformation was
55 further increased as 3a was isolated in an acceptable 67% yield in
a 2 mmol scale reaction.
mol%), additive (0.5 equiv), in DMSO (2 mL), under N2, 140 oC, 18 h, in
sealed tube. b Under O2. c Under air. d 130 oC. e 150 oC. f 12 h.
Initially, we tested the reaction of 2-(1-phenylvinyl)aniline 1a
o
5
in DMSO under N2 at 140 C in the presence of Pd(dba)2 (10
mol%) and DABCO·HCl (0.5 equiv, DABCO
diazabicyclo[2.2.2]octane, Table 1, entry 1). After 18 h, the
desired product 4-phenyl quinoline 3a was isolated in 8% yield
(Table 1, entry 1). Replacing DABCO·HCl with DABCO·HOAc
=
1,4-
10 resulted in no reaction (Table 1, entry 2). To our delight, the yield
dramatically increased to 53% by using DABCO·H2SO4 (Table 1,
entry 3). Encouraged by this inspiring result, DABCO and its
adducts, such as DABCO·CH3I, and DABCO·C3H5Br were
tested, but all failed to work (Table 1, entries 4-6). However, 1,4-
15 diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO)
showed high efficiency with 80% yield (Table 1, entry 7). The
reaction efficiency decreased under either O2 (14%) or air (57%).
Other palladium catalysts, such as Pd2(dba)3 (61%), Pd(PPh3)4
(67%) , Pd(OAc)2 (70%) ,PdCl2 (58%) and Pd(acac)2 (72%) were
20 all inferior to Pd(dba)2 (Table 1, entries 8-14). Changing the
loading of DABSO slightly decreased the reaction efficiency
(Table 1, entries 15 and 16). Without palladium, the yield
dropped to 24% (Table 1, entry 17); while it did not work in the
absence of DABSO (Table 1, entry 18). An inferior result was
25 obtained when the temperature was changed to 130 oC or 150 oC.
The yield dropped to 60% when the time was shortened to 12 h
(Table 1, entry 19).
Scheme 3. Preliminary mechanism studies.
Scheme 2. Substrate scope of 2-(1-arylvinyl)anilines.a
To gain some insights into the reaction mechanism, some
60 control experiments were conducted. First, the reaction could not
be shut down even though 10 equivalents of 2,6-di-tert-butyl-p-
cresol (BHT) was added, indicating no radical pathway was
involved (Scheme 3, eq 1). Second, replacing DMSO with
DMSO-D6, 2-D-4-phenyl quinoline was isolated in 77% yield,
30
2
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which not only confirmed the participation of DMSO in the
annulation reaction, but also provided a facile pathway to access
2-deuterized quinoline derivatives (Scheme 3, eq 2).20 Third, the
transformation. DABSO played dual roles in this procedure: one
is to activate DMSO; the other is to regenerate the palladium
catalyst by the oxidation of DABCO oxide. It represents a facile
intra molecular kinetic isotope effect (KIE, KH/KD) of the methyl 45 pathway leading to n-substituted-4-aryl quinolines (n = 3, 5-8).
5
in DMSO was found to be 1.1, indicating the cleavage of C-H
bond in DMSO was not the rate determining step (Scheme 3, eq
3). Fourth, both Z (24%) and E (35%) configuration of 1b served
as reaction partners, which was consistent with the electrocyclic
pathway (Scheme 3, eq 4).21 Finally, the presumed intermediate
We thank the National Natural Science Foundation of
China (nos. 21572025 and 21672028), the Key University
Science
Research
Project
of
Jiangsu
Province
(15KJA150001), Jiangsu Key Laboratory of Advanced
50 Catalytic Materials
financial supports.
& Technology (BM2012110) for
10 C was not stable enough to be detected by GC-MS and to be
isolated for further characterizations. However, after the reaction
of 2-(1-phenylvinyl)aniline and chloromethyl methyl sulfide (10
equiv) in DMSO, we found: (1) 4-phenyl quinolone was isolated
in 46% yield with the combination of Pd(dba)2 (0.1 equiv) and
15 DABSO (0.5 equiv), indicating the possibility of compound C
serving as the intermediate; (2) cyclization took place with 38%
yield in the presence of stoichiometric of Pd(OAc)2; (3) it did not
work in the presence of either Pd(dba)2 (1 equiv) or the
combination of Pd(dba)2 (1 equiv) and DABSO (0.5 equiv)
20 (Scheme 3, eq 5). This results revealed Pd(II) may serve as
oxidant in the transformation of tertiary amine to other
intermediate, which was probably iminium. And it was other
species rather than DABSO oxidized Pd(0) to Pd(II).
Notes and references
School of Petrochemical Engineering, Jiangsu Key Laboratory of
Advanced Catalytic Materials and Technology, Jiangsu Province Key
55 Laboratory of Fine Petrochemical Engineering, Changzhou University,
Changzhou 213164, P. R. China; E-mail: jiangcheng@cczu.edu.cn
† Electronic Supplementary Information (ESI) available: See DOI:
10.1039/b000000x/
1
Review: D. Martin, A. Weise and H. J. Niclas, Angew. Chem., Int.
Ed.,1967, 6, 318.
Review: (a) T. T. Tidwell, Org. React., 1990, 39, 297-572; (b) N. M.
Ahmad, In Name Reactions for Functional Group Transformations; J.
J. Li , E. J. Corey and Eds, John Wiley & Sons: Hoboken, NJ, 2007;
pp 291-308.
60
2
65 3 (a) N. Kornblum, W. J. Jones and G. J. Anderson, J. Am. Chem. Soc.,
1959, 81, 4113. (b) N. Kornblum, J. W. Powers, G. J. Anderson, W. J.
Jones, H. O. Larson, O. Levand and W. M. Weaver, J. Am. Chem.
Soc., 1957, 79, 6562.
K. E. Pfitzner and J. G. Moffatt, J. Am. Chem. Soc., 1963, 85, 3027.
70 5 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1353.
Based on these experimental results, a proposed mechanism
25 was outlined in Scheme 4. Firstly, the activation of DMSO by
DABSO produces intermediate A.22 Then, the deprotonation of
intermediate A provides a thionium ion intermediate B, which
encounters the nucleophillic attack by substrate 1a leading to
intermediate C. Meanwhile, Pd(0) is oxidized to Pd(II) by
30 DABCO oxide G. Then, intermediate C is transformed into
iminium ion D by the oxidation of Pd(II).23 After that, Pd(II) is
regenerated by the oxidation of DABCO oxide G. Subsequently,
the 6π-electrocyclic takes place to produce intermediate E, which
reacts with B to access intermediate F.24 Finally, as confirmed by
35 GC-MS, the elimination of CH3SCH2SCH3 delivers the final
product 3a.25
4
6
For reviews on the application of DMSO as synthon in organic
synthesis, see: (a) E. Jones-Mensah, M. Karki and J. Magolan,
Synthesis, 2016, 48, 1421. (b) X.-F. Wu and K. Natte, Adv. Synth.
Catal., 2016, 358, 336.
75 7 For reviews, see: (a) K. S. Feldman, Tetrahedron, 2006, 62, 5003. (b)
S. K. Bur and A. Padwa, Chem. Rev., 2004, 104, 2401. (c) S. Akai
and Y. Kita, Top. Curr. Chem., 2007, 274, 35.
8
X. Jiang, C. Wang, Y. Wei, D. Xue, Z. Liu and J. Xiao, Chem. Eur. J.,
2014, 20, 58.
80 9 (a) J. Wang, F. D. Rochon, Y. Yang, L. Hua and M. M. Kayser,
Tetrahedron: Asymmetry, 2007, 18, 1115. (b) P. S. Mahajan, S. D.
Tanpure, N. A. More, J. M. Gajbhiye and S. B. Mhaske, RSC Adv.,
2015, 5, 101641. (c) Q. Wang, L. Sun, Y. Jiang and C. Li, Beilstein J.
Org. Chem., 2008, 4, 51.
Scheme 4. A tentative mechanism
85 10 (a) H. Fei, J. Yu, Y. Jiang, H. Guo and Cheng, J, Org. Biomol. Chem.,
2013, 11, 7092. (b) J. Qian, Z. Zhang, Q. Liu, T. Liu and G. Zhang,
Adv. Synth. Catal., 2014, 356, 3119. (c) Z. Zhang, Q. Tian, J. Qian, Q.
Liu, T. Liu, L. Shi and G. Zhang, J. Org. Chem., 2014, 79, 8182. (d)
H. Cao, S. Lei, N. Li, L. Chen, J. Liu, H. Cai, S Qiu and J. Tan, Chem.
90
Commun., 2015, 51, 1823. (e) G. Chu, Z. Yu, F. Gao and C. Li, Synth.
Commun., 2013, 43, 44.
11 X. Ren, J. Chen, F. Chen and J. Cheng, Chem. Commun., 2011, 47,
6725.
12 (a) F. Luo, C. Pan, L. Li, F. Chen and J. Cheng, Chem. Commun.,
2011, 47, 5304. (b) K. Ghosh, S. Ranjit and D. Mal, Tetrahedron
Lett., 2015, 56, 5199. (c) L. Chu, X. Yue and F.-L. Qing, Org. Lett.,
2010, 12, 1644. (d) P. Sharma, S. Rohilla and N. Jain, J. Org. Chem.,
2015, 80, 4116. (e) F.-L. Liu, J.-R. Chen, Y.-Q. Zou, Q. Wei and W.-
J. Xiao, Org. Lett., 2014, 16, 3768. (f) H.-Y. Li, L.-J. Xing, M.-M.
Lou, H. Wang, R.-H. Liu and B. Wang, Org. Lett., 2015, 17, 1098.
13 (a) G. Yuan, J. Zheng, X. Gao, X. Li, L. Huang, H. Chen and H.
Jiang, Chem. Commun., 2012, 48, 7513. (b) Y. Jiang and T.-P. Loh,
Chem. Sci., 2014, 5, 4939. (c) X. Gao, X. Pan, J. Gao, H. Huang, G.
Yuan and Y. Li, Chem. Commun., 2015, 51, 210.
95
100
In conclusion, we have developed a palladium-catalyzed
40 DMSO-based annulation/aromatization leading to 4-aryl
quinolines. DMSO served as a “=CH-” fragment in this
105 14 X. Pan, Q. Liu, L. Chang and G. Yuan, RSC Adv., 2015, 5, 51183.
15 Y. Lv, Y. Li, T. Xiong, W. Pu, H. Zhang, K. Sun, Q. Liu and Q.
Zhang, Chem. Commun., 2013, 49, 6439.
This journal is © The Royal Society of Chemistry [year]
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Page 4 of 4
16 T. Duan, T. Zhai, H. Liu, Z. Yan, Y. Zhao, L. Feng and C. Ma, Org.
Biomol. Chem., 2016, 14, 6561.
17 (a) J. P. Michael, Nat. Prod. Rep., 2001, 18, 543. (b) S. Andrews, S. J.
Burgess, D. Skaalrud, J. X. Kelly and D. H. Peyton, J. Med. Chem.,
2010, 53, 916. (c) S. Funayama, K. Murata and T. Noshita,
Heterocycles, 2001, 54, 1139.
18 (a) F. Dominguez-Fernandez, J. Lpez-Sanz, E. Perez-Mayoral, D.
Bek, R. M. Martin-Aranda, A. J. Lopez-Peinado and J. Cejka,
ChemCatChem, 2009, 1, 241. (b) R. M. Forbis and K. L. Rinehart, J.
Am. Chem. Soc., 1973, 95, 5003. (c) M. Marull, O. Lefebvre and M.
Schlosser, Eur. J. Org. Chem., 2004, 54.
5
10
15
19 Selected reports: (a) J.-B. Feng and X.-F. Wu, Adv. Synth. Catal.,
2016, 358, 2179. (b) J. Chen, K. Natte, A. Spannenberg, H. Neumann,
M. Beller and X.-F. Wu, Chem. Eur. J., 2014, 20, 14189. (c) Y. Wang,
C. Chen, J. Peng and M. Li, Angew. Chem. Int. Ed., 2013, 52, 5323. (d)
T. Takahashi, Y. Li, P. Stepnicka, M. Kitamura, Y. Liu, K. Nakajima
and M. Kotora, J. Am. Chem. Soc., 2002, 124, 576. (e) R. Yan, X. Liu,
C. Pan, X. Zhou and X. Li, Org. Lett., 2013, 15, 4876. (f) M. Zhong, S.
Sun, J. Cheng, and Y. Shao, J. Org. Chem., 2016, 81, 10825. (g) L.
Wang, J. Ferguson and F. Zeng, Org. Biomol. Chem., 2015, 13, 11486.
20 For reviews on the application of deuterized compounds, see (a) T.
Junk and W. J. Catallo, Chem. Soc. Rev., 1997, 26, 401. (b) J. Atzrodt,
V. Derdau, T. Fey and J. Zimmermann, Angew. Chem. Int. Ed., 2007,
46, 7744. (c) J. R. Hanson, In The Organic Chemistry of Isotopic
Labelling; The Royal Society of Chemistry: Cambridge, 2011.
21 (a) V. L. K. Valli and H. Alper, J. Org. Chem., 1995, 60, 257. (b) L.
Luo, M. D. Bartberger and W. R. Dolbier, Jr, J. Am. Chem. Soc., 1997,
119, 12366.
22 The activation of DMSO by trimethyl(ethyl)amine/SO2 complex was
reported by Olah, where SO2 was oxidized to SO3. See: G. A. Olah, Y.
D. VanKar and M. Arvanaghi, Synthesis, 1979, 984. In the case of
DABSO, this pathway can’t thoroughly be ruled out. However, this
pathway was not consistent with the results shown in entries 1 and 3,
where DABCO·HCl and DABCO·H2SO4 could promote the annulation
reaction.
20
25
30
35
40
45
23 For the Pd(II)-promoted transformation of tertiary amine into
iminium ion, please see: (a) R. S. Mane and B. M. Bhanage, J. Org.
Chem., 2016, 81, 1223. (b) Y.-S. Bao, B. Zhaorigetu, M. Baiyin and M.
Jia, J. Org. Chem., 2014, 79, 803. (c) Y. Liu, B. Yao, C.-L. Deng, R.-Y.
Tang, X.-G. Zhang, and J.-H. Li, Org. Lett., 2011, 13, 2184. (d) J.
Sheng, Y. Guo and J. Wu, Tetrahedron Lett., 2013, 69, 6495.
24 R. Tanikaga, Y. Hiraki, N. Ono and A. Kaji, J. Chem. Soc., Chem.
Commun., 1980, 41.
25 In entries 4-6 and 14 of Table 1, where yields of 4-phenyl quinolone
were less than 5%, no CH3SCH2SCH3 was detected by GC-MS.
4
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