Cleavage of C-C Bonds for the Synthesis of C2-Substituted Quinolines and Indoles by Catalyst-Controlled Tandem Annulation of 2-Vinylanilines and Alkynoates

Article abstract of DOI:10.1021/acs.orglett.8b00260

The strategy for the synthesis of C2-substituted indoles and quinolines from 2-vinylanilines and alkynoates through C-C bond cleavage is developed. With these general methods, 2-substituted indoles and quinolines can be accessed via tandem Michael addition and cyclization with no requirement of oxidant. This strategy not only provides a method for the synthesis C2-substituted indoles in good yields through the simultaneous cleavage of C=C and C=C bonds under metal-free conditions but also provides a simple method for the generation of the C2-substituted quinolines in moderate yields via Pd-catalyzed C=C bond cleavage.

Full text of DOI:10.1021/acs.orglett.8b00260

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cleavage of C−C Bonds for the Synthesis of C2-Substituted
Quinolines and Indoles by Catalyst-Controlled Tandem Annulation of
2‑Vinylanilines and Alkynoates
Jixiang Ni,† Yong Jiang,‡ Zhenyu An,† and Rulong Yan*,†
†State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Gansu, China
‡School of Chemistry and Chemical Engineering, Yangtze Normal University, Chongqing, China
S
* Supporting Information
ABSTRACT: The strategy for the synthesis of C2-substituted
indoles and quinolines from 2-vinylanilines and alkynoates through
C−C bond cleavage is developed. With these general methods, 2-
substituted indoles and quinolines can be accessed via tandem
Michael addition and cyclization with no requirement of oxidant.
This strategy not only provides a method for the synthesis C2-
substituted indoles in good yields through the simultaneous
cleavage of CC and CC bonds under metal-free conditions
but also provides a simple method for the generation of the C2-
substituted quinolines in moderate yields via Pd-catalyzed CC
bond cleavage.
Scheme 1. CC Bond Cleavage of Alkynoates
elective C−C bond cleavage is an invaluable and atom-
Seconomic tool for new heterocyclic compounds construc-
tion.1As compared to the highly developed C−C bond
formations, the process of the selective cleavage of C−C bond
remains a great challenge.2 In the past decade, the direct cleavage
of CC and CC bonds have been significantly developed.3
Alkynoates, as attractive substrates, have drawn much attention
for their growing applications in the synthesis of N-heterocyclic
compounds. To date, the CC bond cleavage of disubstituted
acetylenes has been heavily studied.4 The group of Jiang
demonstrated a palladium-catalyzed cleavage reaction of CC
triple bonds of alkynes to give carboxylic esters using molecular
oxygen as the sole oxidant (Scheme 1).5 Recently, the group of
Jiao has developed an unexpected and efficient approach to
synthesize highly valuable tryptophol derivatives through CC
triple bond cleavage and dioxygen activation under metal-free
conditions.6 To our best knowledge, the formation of C2-
substituted quinolines and indoles through the C−C bond
cleavage of alkene and alkyne is very rare.
The substituted indole is a privileged heterocyclic scaffold
prevalent in a wide range of interesting compounds, including
natural products, medicinal agents, and agrochemicals.7 Indole
moieties have been disclosed to possess a diverse range of
biological activities, such as anticancer, antiviral, and anti-
bacterial.8 The demand for efficient syntheses of indoles has
burgeoned since the development of the classical Fischer indole
synthesis.9 Various methods have focused on the transition-
metal-catalyzed cyclization to build new C−N/C−C bonds for
rapid access to indole derivatives.10 Although these significant
developments have been achieved in the field of transition metal
catalysis, the synthesis of C2 functional indoles remains a
challenge due to the inherently poor nucleophilic reactivity of the
C2 position.
We initiated the investigation based on our experience in the
construction of heterocyclic scaffolds,11 examining the reaction
of 2-(1-phenylvinyl)aniline 1a with dimethyl but-2-ynedioate 2a
Received: January 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00260
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Letter
a
as the model reaction (Table 1). The use of AcOH as the catalyst
in DMSO promoted the sequential cleavage and cyclization of 1a
Scheme 2. Scope of 2-Vinylanilines and Alkynoates
a
Table 1. Optimization of Reaction Conditions
b
entry
acid
solvent
temp (°C)
yield (%)
1
AcOH
TfOH
TfOH
TFA
DMSO
DMF
THF
130
120
120
120
120
120
120
120
80
63
61
93
73
55
78
70
−
2
3
4
THF
5
PivOH
TfOH
TfOH
−
THF
6
MeCN
toluene
THF
7
8
9
TfOH
THF
32
10
TfOH
THF
rt
−
a
All reactions were carried out in a nitrogen atmosphere using 1a
(0.30 mmol), 2a (0.60 mmol), and acid (10 mol %) in 2 mL of
b
solvent. Isolated yield.
and 2a to afford the C-2 functionalized indole 3aa in 63% yield
(Table 1, entry 1). Switching the solvent to THF significantly
increased the yield of this process, and the yield of 3aa was
improved to 93%. Then the evaluation of various other acids,
such as TfOH, TFA, PivOH, showed that TfOH was the best
acid for this reaction (Table 1, entries 3−5). The temperature
was also examined, and the yield was sharply decreased to 32%
when the reaction temperature was reduced to 80 °C (Table 1,
entry 9). Finally, the desired substituted indole cannot be
detected in the absence of acid (Table 1, entry 10).
With suitable access to indole in hand, we proceeded to
investigate the scope of the reaction using a variety of different 2-
vinylaniline derivatives (Scheme 2). As shown in Scheme 2, the
cleavage and cyclization proceeded efficiently with substrates
bearing electron-deficient or electron-rich groups, providing the
corresponding products in excellent yields. This access, which
allowed substituting at random positions of the 2-vinylanines
framework, illustrated the great generality and flexibility of this
approach. The nature of the groups R1 did not significantly affect
the reaction. When R1 was an electron-deficient group at the C7
position of the aryl ring, the yields of 3pa and 3ra were lowered to
70% and 62%, respectively. The substrate 2-(prop-1-en-2-
yl)aniline 1t can generate the desired product in satisfactory
yield. The methodology also can be extended to diethyl but-2-
ynedioate; the desired product 3ab was afforded in 96% yield.
The substrates, such as methyl 3-phenylpropiolate 2c and 1,2-
diphenylethyne 2d, were also employed for this transformation,
and no desired products were detected. Moreover, the substrate
1aa also could not work under the optimized conditions.
Similarly, quinolines not only have been widely found in
natural products with biological activities but also have also been
broadly used in medical chemistry, drug synthesis, and functional
compound materials as building blocks.12 In the course of
optimizing the experimental conditions, substituted quinoline
was detected when the catalyst Pd(OAc)2 was used. The product
methyl 4-phenylquinoline-2-carboxylate 4aa was isolated when
compounds 1a and 2a were used as substrate (Scheme 3).
Subsequently, we extensively screened acids, solvents, and other
factors under argon. The results were summarized in Table S1
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), and TfOH (10
mol %) in 2 mL of THF at 120 °C under N2 for 8 h.
(Supporting Information). The highest yield of 4aa was achieved
when the reaction was operated with 1a and 2a (2 equiv),
Pd(OAc)2(10 mol %), and TfOH (10 mol %) in toluene at 120
°C under nitrogen (Table S1, entry 13).
The next step was to explore the generality of this approach to
assemble a range of substituted quinolines under established
optimal reaction conditions. As a result, the optimized conditions
were consistent with various substituted 2-vinylanilines with Me,
Et, iPr, tBu, Ph, F, and Br groups on the aryl ring and the desired
quinolines were isolated in moderate yields. In general, the
electron-withdrawing substituents R1 at the aromatic ring (4ka
and 4la) led to a higher yield in this reaction than the electron-
donating groups except tBu. Moreover, these reaction conditions
were also compatible with different substituents on aromatic
rings, such as 1n and 1o, generating the desired products in 61%
and 48% yields. Using 2-(prop-1-en-2-yl)aniline 1p as substrate
bearing a methyl group at the R2 position afforded desired
quinoline 4pa in ideal yield.
The presumption of a radical mechanism guided the
conceptual development of the indole formation reaction. To
gain more insight into the reaction mechanism, some control
experiments were conducted. Control experiments with added
TEMPO gave the expected results. Only a trace amount of
B
DOI: 10.1021/acs.orglett.8b00260
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a
Scheme 3. Scope of Quinolines
Scheme 4. Control Experiments
On the basis of the results described above, the proposed
mechanism is illustrated in Scheme 5. The proposed mechanism
for the synthesis of the indole is described as follows: generally,
enamine A is quickly formed by Michael addition of 1 and 2.13
Later, intramolecular thermal [2 + 2] cyclization14 occurs to form
the key intermediate 5aa, which is highly reactive and easily
undergoes C−C bond homolytic cleavage to generate biradical
intermediate B.6 Then the desired indole 3aa is afforded through
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), Pd(OAc)2 (10
mol %), and TfOH (10 mol %) in 2 mL of toluene at 120 °C under
N2.
desired product 3aa was detected when TEMPO was employed
under the standard conditions to synthesize the indoles. When
BHT was added, the desired product 3aa was generated in 20%
yield (Scheme 4). Therefore, these results suggested that this
reaction proceeded via a free radical process. The result of entry 2
in Scheme 4 suggested that the transformation to form the
quinoline was not a radical pathway under the standard
conditions because no suppression occurred with the addition
of TEMPO. It is worth noting that the compound 5aa was
isolated in 35% yield when the reaction was conducted under
room temperature with TfOH (10 mol %) in THF, while the 5aa
was not detected with the standard conditions of generating
quinoline at room temperature. In a follow-up study, the
compound 5aa was also employed as substrate for this reaction,
giving the desired indole 3aa in 95% yield and 4aa in 0% yield.
Obviously, a dramatic decrease in the yield (trace) of the
reaction to form indole with 5aa was observed in the presence of
TEMPO as a potent radical inhibitor. Given these data, a
proposed mechanism for the formation of indoles proceeding
through the Michael addition and cyclization of 2-vinylanilines
and alkynoates could be envisioned, and an important
intermediate 5aa was indeed synthesized under the optimized
reaction conditions. In order to certify the CC cleavage of the
substrate 1a for the synthesis of indole, the compound 1ab was
employed for this reaction under optimized conditions.
According to our expectation, the desired indole 3aa was isolated
in 91% yield.
Scheme 5. Proposed Mechanism
C
DOI: 10.1021/acs.orglett.8b00260
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Wang, F.; Hu, H.; Wang, X.; Wu, H.; Liu, Y. J. Org. Chem. 2014, 79, 3992.
(g) Dutta, U.; Lupton, D. W.; Maiti, D. Org. Lett. 2016, 18, 860.
(h) Chinchilla, R.; Najera, C. Chem. Rev. 2014, 114, 1783. (i) Long, Z.;
Yang, Y.; You, J. Org. Lett. 2017, 19, 2781.
(5) Wang, A.; Jiang, H. J. Am. Chem. Soc. 2008, 130, 5030.
(6) Shen, T.; Zhang, Y.; Liang, Y.-F.; Jiao, N. J. Am. Chem. Soc. 2016,
cleavage of C−C bonds. The proposed mechanism for the
synthesis of the quinolines is also shown as follows: the enamine
A is coordinated with Pd catalysis to generate the intermediate C.
Then, the intermediate D is formed through the intramolecular
nucleophilic addition. Finally, the quinoline is produced through
cleavage of the CC bond.
138, 13147.
In summary, we have demonstrated a novel and convenient
method to synthesize the C2-substituted indoles and quinoline
from 2-vinylanilines and alkynoates through cleavage of C−C
bonds. Furthermore, this protocol shows good functional group
compatibility and various substituted 2-vinylanilines proceed
smoothly with alkynoates, generating the desired products in
moderate to good yields.
(7) (a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489. (b) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24,
843. (c) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ.
2010, 87, 1348. (d) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132,
13226. (e) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257. (f) Stempel, E.; Gaich, T. Acc. Chem. Res. 2016, 49, 2390.
(8) (a) Kumar, D.; Kumar, N. M.; Akamatsu, K.; Kusaka, E.; Harada,
H.; Ito, T. Bioorg. Med. Chem. Lett. 2010, 20, 3916. (b) Dolusic, E.;
Larrieu, P.; Moineaux, L.; Stroobant, V.; Pilotte, L.; Colau, D.; Pochet,
L.; Eynde, B. V. d.; Masereel, B.; Wouters, J.; Frederick, R. J. Med. Chem.
2011, 54, 5320. (c) Robinson, M. W.; Overmeyer, J. H.; Young, A. M.;
Erhardt, P. W.; Maltese, W. A. J. Med. Chem. 2012, 55, 1940.
(d) Venkatesan, A. M.; Santos, O. D.; Ellingboe, J.; Evrard, D. A.;
Harrison, B. L.; Smith, D. L.; Scerni, R.; Hornby, G. A.; Schechter, L. E.;
Andree, T. H. Bioorg. Med. Chem. Lett. 2010, 20, 824. (e) Steuer, C.;
Gege, C.; Fischl, W.; Heinonen, K. H.; Bartenschlager, R.; Klein, C. D.
Bioorg. Med. Chem. 2011, 19, 4067. (f) Venkatesan, P.; Sumathi, S. J.
Heterocycl. Chem. 2010, 47, 81.
(9) (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172. (b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
(c) Kruger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153.
(d) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev.
2012, 41, 3929. (e) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(f) Shiri, M. Chem. Rev. 2012, 112, 3508. (g) Inman, M.; Moody, C. J.
Chem. Sci. 2013, 4, 29. (h) Kim, H.; Chang, S. ACS Catal. 2016, 6, 2341.
(i) Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564.
(j) Liu, X. D.; Tong, K.; Zhang, A. H.; Tan, R. X.; Yu, S. Y. Org. Chem.
Front. 2017, 4, 1354.
(10) (a) Tsvelikhovsky, D.; Buchwald, L. J. Am. Chem. Soc. 2010, 132,
14048. (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173−1193.
(d) Shiri, M. Chem. Rev. 2012, 112, 3508. (e) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2005, 105, 2873. (f) Sandtorv, A. H. Adv. Synth. Catal. 2015,
357, 2403. (g) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod.
Rep. 2015, 32, 1389. (h) Tanner, M. E. Nat. Prod. Rep. 2015, 32, 88.
(11) (a) Xiang, L.; Niu, Y.; Pang, X.; Yang, X.; Yan, R. Chem. Commun.
2015, 51, 6598. (b) Yan, R.; Li, X.; Yang, X.; Kang, X.; Xiang, L.; Huang,
G. Chem. Commun. 2015, 51, 2573. (c) Yuan, B.; Zhang, F.; Li, Z.; Yang,
S.; Yan, R. Org. Lett. 2016, 18, 5928. (d) Kang, X.; Yan, R.; Yu, G.; Pang,
X.; Liu, X.; Li, X.; Xiang, L.; Huang, G. J. Org. Chem. 2014, 79, 10605.
(e) Pang, X.; Xiang, L.; Yang, X.; Yan, R. Adv. Synth. Catal. 2016, 358,
321. (f) Yang, X.; Yan, R. Org. Biomol. Chem. 2017, 15, 3571. (g) An, Z.;
She, Y.; Yang, X.; Pang, X.; Yan, R. Org. Chem. Front. 2016, 3, 1746.
(12) (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543. (b) Rouffet, M.; de
Oliveira, C. A. F.; Udi, Y.; Agrawal, A.; Sagi, I.; McCammon, J. A.;
Cohen, S. M. J. Am. Chem. Soc. 2010, 132, 8232. (c) Bhalla, V.; Vij, V.;
Kumar, M.; Sharma, P. R.; Kaur, T. Org. Lett. 2012, 14, 1012.
(13) (a) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407.
(b) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00260.
Experimental methods and 1H and 13C NMR spectra of all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yanrl@lzu.edu.cn.
ORCID
Rulong Yan: 0000-0002-0450-3065
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Natural Science
Foundation of China (21672086), Gansu Province Science
Foundation for Youths (1606RJYA260), and the Fundamental
Research Funds for the Central Universities (lzujbky-2018-39).
REFERENCES
■
(1) (a) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222.
(b) Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2009, 48, 2452.
(c) Masarwa, A.; Marek, I. Chem. - Eur. J. 2010, 16, 9712. (d) Murakami,
M.; Matsuda, T. Chem. Commun. 2011, 47, 1100. (e) Souillart, L.;
Cramer, N. Chem. Rev. 2015, 115, 9410. (f) Lei, Z.-Q.; Li, H.; Li, Y.;
Zhang, X.-S.; Chen, K.; Wang, X.; Sun, J.; Shi, Z.-J. Angew. Chem., Int. Ed.
2012, 51, 2690. (g) Tang, C.; Jiao, N. Angew. Chem., Int. Ed. 2014, 53,
6528. (h) Gao, Q.; Liu, S.; Wu, X.; Zhang, J.; Wu, A. Org. Lett. 2015, 17,
2960. (i) Zhou, W.; Fan, W.; Jiang, Q.; Liang, Y.-F.; Jiao, N. Org. Lett.
2015, 17, 2542. (j) Saidalimu, I.; Suzuki, S.; Tokunaga, E.; Shibata, N.
Chem. Sci. 2016, 7, 2106.
(2) (a) Zhang, C.; Feng, P.; Jiao, N. J. Am. Chem. Soc. 2013, 135, 15257.
(b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613.
(3) For reviews and selected examples: (a) Miyamoto, K.; Tada, N.;
Ochiai, M. J. Am. Chem. Soc. 2007, 129, 2772. (b) Travis, B. R.; Narayan,
R. S.; Borhan, B. J. J. Am. Chem. Soc. 2002, 124, 3824. (c) Martinez, C.;
Muniz, K. Angew. Chem., Int. Ed. 2012, 51, 7031. (d) Wang, T.; Jiao, N.
Acc. Chem. Res. 2014, 47, 1137. (e) Wang, T.; Jiao, N. J. Am. Chem. Soc.
2013, 135, 11692. (f) Shen, T.; Wang, T.; Qin, C.; Jiao, N. Angew. Chem.,
Int. Ed. 2013, 52, 6677. (g) Qin, C.; Feng, P.; Ou, Y.; Shen, T.; Wang, T.;
Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 7850. (h) Jun, C.-H. Chem. Soc.
Rev. 2004, 33, 610.
(14) (a) Brannock, K. C.; Bell, A.; Burpitt, R. D.; Kelly, C. A. J. Org.
Chem. 1964, 29, 801. (b) Ichihara, A.; Kimura, R.; Yamada, S.; Sakamura,
S. J. Am. Chem. Soc. 1980, 102, 6353. (c) Sheldrake, H. M.; Wallace, T.
W.; Wilson, C. P. Org. Lett. 2005, 7, 4233.
(4) (a) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736. (b) Liu, Q.;
Chen, P.; Liu, G. ACS Catal. 2013, 3, 178. (c) Sheng, W.-B.; Jiang, Q.;
Luo, W.-P.; Guo, C.-C. J. Org. Chem. 2013, 78, 5691. (d) Okamoto, N.;
Ishikura, M.; Yanada, R. Org. Lett. 2013, 15, 2571. (e) Jiang, Q.; Zhao, A.;
Xu, B.; Jia, J.; Liu, X.; Guo, C. J. Org. Chem. 2014, 79, 2709. (f) Sun, J.;
D
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