I2-Promoted Povarov-Type Reaction Using 1,4-Dithane-2,5-diol as an Ethylene Surrogate: Formal [4 + 2] Synthesis of Quinolines

Article abstract of DOI:10.1021/acs.orglett.7b00361

A highly efficient I₂-promoted formal [4 + 2] cycloaddition has been developed for the synthesis of 2-acylquinolines from methyl ketones and arylamines using 1,4-dithane-2,5-diol as an ethylene surrogate. Moreover, the investigation of the mechanism suggested that this reaction occurred via an iodination/Kornblum oxidation/Povarov/aromatization sequence. It is noteworthy that the arylamine substrate also played an important role in promoting the reaction.

Full text of DOI:10.1021/acs.orglett.7b00361

Letter
pubs.acs.org/OrgLett
I2‑Promoted Povarov-Type Reaction Using 1,4-Dithane-2,5-diol as an
Ethylene Surrogate: Formal [4 + 2] Synthesis of Quinolines
Xia Wu, Xiao Geng, Peng Zhao, Jingjing Zhang, Xingxing Gong, Yan-dong Wu,* and An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, China
S
* Supporting Information
ABSTRACT: A highly efficient I2-promoted formal [4 + 2] cycloaddition has been developed for the synthesis of 2-
acylquinolines from methyl ketones and arylamines using 1,4-dithane-2,5-diol as an ethylene surrogate. Moreover, the
investigation of the mechanism suggested that this reaction occurred via an iodination/Kornblum oxidation/Povarov/
aromatization sequence. It is noteworthy that the arylamine substrate also played an important role in promoting the reaction.
1,4-Dithane-2,5-diol is a versatile building block for the
construction of various sulfur-containing heterocycles, which
can be found in numerous bioactive natural products,
pharmaceuticals, and drug candidates.1,2 Several synthetic
methods have been reported involving the use of 1,4-dithane-
2,5-diol as a three-atom component for the construction of five-
and six-membered sulfur-containing heterocycles. Among
those, some methods have been developed for the direct
synthesis of five-membered sulfur-containing heterocycles via a
formal [3 + 2] annulation, in which 1,4-dithane-2,5-diol was
used as an S1/C1 or S1/C2 synthon to give thiophenes,3
thiazolidinones,4 and thiazolidine-2-thiones5 (Scheme 1a).
the use of 1,4-dithane-2,5-diol as a C2 unit to generate six-
membered nitrogen heterocycles (e.g., quinolines). These
reactions are particularly challenging because a desulfuration
step is required (Scheme 1c).
The quinoline unit represents a privileged structure that can
be found in a wide range of modern pharmaceuticals and
biologically active natural products.7 For this reason, their
synthesis has attracted considerable attention from synthetic
and medicinal chemists, resulting in the development of several
named reactions8 for the synthesis of the quinoline ring
system.9,10 Notably, the Povarov reaction, which is a formal [4
+ 2] cycloaddition between an aromatic imine and an electron-
rich alkene, has recently emerged as one of the most efficient
protocols for the preparation of quinolines.11 However, recent
progress toward the Povarov reaction has mainly focused on
the use of electron-rich alkenes for the cycloaddition reaction.
Furthermore, there have been no reports pertaining to the
cycloaddition of ethylene to an aromatic imine to give
quinolines. The lack of this progress could be attributed to
the fact that ethylene gas can be difficult to use from a practical
perspective. The development of a simple and practical
ethylene surrogate that can undergo a cycloaddition reaction
with an aromatic imine to give a quinoline is therefore
desperately needed. Herein, we report for the first time the
development of an I2-promoted protocol for the construction
of quinolines via the formal [4 + 2] cycloaddition of an
aromatic methyl ketone to an arylamine using 1,4-dithane-2,5-
diol as an ethylene surrogate.
Scheme 1. Transformation of 1,4-Dithane-2,5-diol in
Heterocycle Synthesis
As part of our ongoing interest in the development of carbon
synthons for heterocyclic synthesis,12 we envisaged that 1,4-
dithane-2,5-diol could be used as a C2 synthon for the
construction of quinolines. We initially investigated the reaction
of acetophenone (1.0 mmol) with p-toluidine (1.0 mmol) and
Moreover, 1,4-dithane-2,5-diol can be used as a mercaptoace-
taldehyde synthon, which contains a sulfydryl nucleophile and
an aldehyde electrophile, and reacted with azomethine imines
or cyclopropanes to give six-membered sulfur-containing
heterocycles via a formal [3 + 3] annulation (Scheme 1b).6
Despite significant progress toward the use of 1,4-dithane-2,5-
diol as a building block for the synthesis of sulfur-containing
heterocycles, there have not been reports to date pertaining to
Received: February 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00361
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a b
,
1,4-dithane-2,5-diol (1.0 mmol) in the presence of DABCO
(1.0 mmol) and I2 (1.6 mmol) in DMSO at 90 °C, which
afforded (6-methylquinolin-2-yl)(phenyl)methanone (4aa) in
43% yield. The structure of this compound was unambiguously
confirmed by X-raycrystallographic analysis (see Supporting
Information). Encouraged by this result, we proceeded to
optimize the reaction conditions. The reaction was screened at
a variety of different temperatures, and the results indicated that
100 °C was optimum for this formal cycloaddition reaction
(Table 1, entries 2−4). Moreover, when the 1a/2a/3 molar
Scheme 2. Scope of Aryl Methyl Ketones
a
Table 1. Optimization of the Reaction Conditions
b
entry
I2 (equiv)
1a/2a/3
temp (°C)
yield (%)
1
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
0.5
0.8
1.2
2.0
1:1:1
90
100
110
120
100
100
100
100
100
100
100
100
100
100
43
72
40
41
67
40
65
40
52
53
50
41
0
2
1:1:1
3
1:1:1
4
1:1:1
a
5
1:1:0.5
1:1:1.5
1:0.5:1
1:1.5:1
1:1:1
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), 3 (1.0 mmol),
b
6
and I2 (1.6 mmol) in DMSO (3 mL) at 100 °C for 4 h. Isolated yield.
7
8
We subsequently investigated the scope of the Povarov-type
reaction using a variety of substituted anilines, and the desired
products were obtained in satisfactory yields (Scheme 3). The
9
10
11
12
13
1:1:1
1:1:1
a b
,
1:1:1
Scheme 3. Scope of Anilines
1:1:1
c
14
1.6
1:1:1
76
a
Reaction conditions: 1a (1.0 mmol), 2a, 3, I2, and DABCO (1.0
mmol) heated in 3 mL of DMSO within 4 h unless otherwise noted.
Isolated yields. Without of DABCO.
b
c
ratios were 1:1:1, the reaction proceeded smoothly and gave
the best yield (72%) compared to other ratios (Table 1, entries
2 and 5−8). We subsequently investigated the effect of different
amounts of iodine on the outcome of the reaction and found
that the amount of iodine had an important discernible impact
on the yields (Table 1, entries 9−12). The reaction failed to
provide any of the desired product when it was conducted in
the absence of I2 (Table 1, entry 13). The amount of DABCO
added to the reaction was also investigated, and the results
revealed that the reaction gave a good yield in the absence of
DABCO (Table 1, entry 14).
a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol),
b
and I2 (1.6 mmol) in DMSO (3 mL) at 100 °C for 4 h. Isolated yield.
With the optimized conditions in hand, we proceeded to
investigate the substrate scope of this reaction using a variety of
different aryl ketones (Scheme 2). Acetophenone derivatives
bearing a variety of different substituents (e.g., methyl,
methoxyl, ethoxyl, 3,4-methylenedioxyl, chloro, nitro) reacted
smoothly with 2a and 3 to afford the desired products (4aa−ja)
in 62−83% yields. The electronic and steric properties of the
aromatic ketone substrate had very little impact on the
efficiency of this reaction. Moreover, the sterically hindered
substrates 1-acetylnaphthalene (1k) and 2-acetylnaphthalene
(1l) reacted smoothly to furnish the desired products 4ka and
4la in 80 and 82% yields, respectively. It is noteworthy that
various heteroaryl ketones, including furanyl and thienyl methyl
ketones, were found to be compatible with these conditions,
affording the corresponding products in good to excellent
yields (79−83%; 4ma−oa).
electronic and steric effects of the substituents on the anilines
had very little influence on the efficiency of the reaction.
Electron-neutral (4-Me, 3-Me, 2,3-(Me)2), electron-deficient
(4-COOEt), and electron-rich (4-OMe) groups were tolerated
on the phenyl ring of the aniline substrate, affording the
corresponding products in reasonable yields (60−82%; 4ab−
ah). A halogen-substituted aniline (4-Br) also reacted as a
substrate to afford the desired quinoline product in good yield
(61%; 4ai). Notably, α-naphthylamine also reacted smoothly
under the optimized conditions to give the desired product 4aj
in 72% yield.
Then, we proceeded to investigate the mechanism associated
with this transformation using a series of control experiments.
Acetophenone 1a (1.0 mmol) was heated with I2 (1.6 mmol) in
B
DOI: 10.1021/acs.orglett.7b00361
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DMSO at 100 °C to give phenylglyoxal 1ab and the
corresponding hydrated species 1ac in quantitative yield
(Scheme 4a). The reaction of α-iodo ketone 1aa with 2a in
Scheme 5. Proposed Mechanism
Scheme 4. Control Experiments
intermediate B, which would be trapped by intermediate 5a
immediately to yield expected product 4aa. Intermediate D
would then undergo an oxidative aromatization to yield the
desired product 4aa via desulfurization and deamination
steps.14 Enamine intermediate A would continue to participate
in the reaction.
In summary, we have developed a highly efficient molecular
iodine−amine synergistic promoted formal [4 + 2] cyclo-
addition for the direct synthesis of 2-acylquinolines using
methyl ketones, arylamines, and 1,4-dithiane-2,5-diol. This
preliminary work demonstrates the first example of an
arylamine substrate that plays an important role in promoting
1,4-dithiane-2,5-diol to participate in Povarov reaction, in which
1,4-dithiane-2,5-diol was used as an ethylene surrogate.
Moreover, this method represents a new strategy for the use
of 1,4-dithiane-2,5-diol as a C2 synthon for the construction of
nitrogen-containing heterocycles rather than sulfur-containing
heterocycles via desulfurization. Further studies toward the
application of this iodine-mediated formal cycloaddition are
currently underway in our laboratory and will be reported in
due course.
the presence of 3 under standard conditions afforded the
desired product 4aa in 80% yield (Scheme 4b). The hydrated
species 1ac was also subjected to the optimized reaction
conditions and gave 4aa in 89% yield, whereas no product was
obtained in the absence of molecular iodine (Scheme 4c). This
result clearly confirmed the intermediacy of phenacyl iodine
1aa and phenylglyoxal 1ab in this transformation. Moreover,
the intermediate of phenacyl iodine 1aa, phenylglyoxal 1ab, and
hydrated species 1ac were monitored by 1H NMR spectroscopy
(see Supporting Information). Furthermore, these results
demonstrated that iodine played an important role in the
Povarov/oxidation process (Scheme 4c). Substrate 2a reacted
with 3 could give 6a in 94% yield (Scheme 4d). Moreover, the
reaction of substrate 6a with 1ac and 2a under the standard
reaction conditions gave quinoline 4aa in 90% yield (Scheme
4e). The reaction of C-acylimine 5b with 6a gave the desired
product 4ab in good yield (Scheme 4f). This result implied the
intermediacy of C-acylimine in the transformation.
Based on the experimental results described above, as well as
the results of previous reports,13 we proposed a plausible
mechanism for this reaction (Scheme 5). Acetophenone (1a)
would be converted to phenylglyoxal 1ab with released HI and
DMS via an iodination/Kornblum oxidation sequence (see
Supporting Information). Intermediate 1ab would then under-
go a dehydration reaction with p-toluidine (2a) to give the
iminium ion 5a. The mercaptoacetaldehyde generated from
1,4-dithiane-2,5-diol under equilibrium conditions would be
activated by p-toluidine (2a) to form enamine intermediate B,
which would react with 5a to generate intermediate D. It is
noteworthy that intermediate B could undergo a continuous
intramolecular nucleophilic attack to give 6a in the absence of
intermediate 5a. Moreover, intermediate B and compound 6a
are reversible when compound 6a is transformed into
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00361.
Experimental procedures, product characterizations,
crystallographic data, and copies of the 1H and 13C
NMR spectra (PDF)
Crystallographic data for 4aa (CIF)
Crystallographic data for 6a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chwuyd@mail.ccnu.edu.cn.
*E-mail: chwuax@mail.ccnu.edu.cn.
ORCID
An-xin Wu: 0000-0001-7673-210X
C
DOI: 10.1021/acs.orglett.7b00361
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(10) (a) Zheng, J.; Li, Z.; Huang, L. B.; Wu, W. Q.; Li, J. X.; Jiang, H.
F. Org. Lett. 2016, 18, 3514. (b) Yi, X. L.; Xi, C. J. Org. Lett. 2015, 17,
5836. (c) Neuhaus, J. D.; Morrow, S. M.; Brunavs, M.; Willis, M. C.
Org. Lett. 2016, 18, 1562. (d) Liu, G. Y.; Yi, M. C.; Liu, L.; Wang, J. J.;
Wang, J. H. Chem. Commun. 2015, 51, 2911.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) (a) Richter, H.; Garcia Mancheno, O. Org. Lett. 2011, 13, 6066.
̃
This work was supported by the National Natural Science
Foundation of China (Grants 21472056 and 21602070). We
also thank Dr. Chuanqi Zhou, Hebei University, for analytical
support. This work was supported by “The Fundamental
Research Funds for the Central Universities” (CCNU15ZX002
and CCNU16A05002). This work was also supported by the
111 Project B17019.
(b) Dai, W.; Jiang, X. L.; Tao, J. Y.; Shi, F. J. Org. Chem. 2016, 81, 185.
(c) Jia, X. D.; Peng, F. F.; Qing, C.; Huo, C. D.; Wang, X. C. Org. Lett.
2012, 14, 4030. (d) Jia, X. D.; Wang, Y. X.; Peng, F. F.; Huo, C. D.;
Yu, L. L.; Liu, J.; Wang, X. C. J. Org. Chem. 2013, 78, 9450. (e) Liu, J.;
Wang, Y. X.; Yu, L. L.; Huo, C. D.; Wang, X. C.; Jia, X. D. Adv. Synth.
Catal. 2014, 356, 3214. (f) Huo, C. D.; Yuan, Y.; Wu, M. X.; Jia, X. D.;
Wang, X. C.; Chen, F. J.; Tang, J. Angew. Chem., Int. Ed. 2014, 53,
13544. (g) Liu, J.; Liu, F.; Zhu, Y. Z.; Ma, X. G.; Jia, X. D. Org. Lett.
2015, 17, 1409. (h) Gao, Q. H.; Liu, S.; Wu, X.; Wu, A. X. Org. Lett.
2014, 16, 4582. (i) Sashidhara, K. V.; Palnati, G. R.; Singh, L. R.;
Upadhyay, A.; Avula, S. R.; Kumar, A.; Kant, R. Green Chem. 2015, 17,
3766.
REFERENCES
■
(1) (a) Tian, Y.; Wei, X.; Xu, H. J. Nat. Prod. 2006, 69, 1241.
(b) Aurelio, L.; Valant, C.; Flynn, B. L.; Sexton, P. M.; Christopoulos,
A.; Scammells, P. J. J. Med. Chem. 2009, 52, 4543. (c) Lethu, S.;
Ginisty, M.; Bosc, D.; Dubois, J. J. Med. Chem. 2009, 52, 6205.
(d) Briel, D.; Rybak, A.; Kronbach, C.; Unverferth, K. Eur. J. Med.
Chem. 2010, 45, 69. (e) Valant, C.; Aurelio, L.; Devine, S. M.; Ashton,
T. D.; White, J. M.; Sexton, P. M.; Christopoulos, A.; Scammells, P. J.
J. Med. Chem. 2012, 55, 2367. (f) Wang, W.; Lv, D.; Qiu, N.; Zhang,
L.; Hu, C.; Hu, Y. Bioorg. Med. Chem. 2013, 21, 2886.
(12) (a) Wu, X.; Zhang, J. J.; Liu, S.; Gao, Q. H.; Wu, A. X. Adv.
Synth. Catal. 2016, 358, 218. (b) Wang, M.; Xiang, J. C.; Cheng, Y.;
Wu, Y. D.; Wu, A. X. Org. Lett. 2016, 18, 524. (c) Gao, Q. H.; Liu, S.;
Wu, X.; Zhang, J. J.; Wu, A. X. Org. Lett. 2015, 17, 2960.
(13) (a) Wu, X.; Gao, Q. H.; Liu, S.; Wu, A. X. Org. Lett. 2014, 16,
2888. (b) Wu, X.; Gao, Q. H.; Geng, X.; Zhang, J. J.; Wu, Y. D.; Wu, A.
X. Org. Lett. 2016, 18, 2507.
(2) (a) Lamb, E. Top 200 Drugs of 2008. Pharmacy Times, 2009.
(b) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles; Wiley: New York, 2003; Chapter 5, Section 5.6.
(c) Gronowitz, S.; Hornfeldt, A. B. Thiophenes; Elsevier: Oxford,
U.K., 2004. (d) Handbook of Thiophene-Based Materials: Applications in
Organic Electronics and Photonics; Perepichka, I. F., Perepichka, D. F.,
Eds.; John Wiley & Sons: West Sussex, U.K., 2009.
(14) Yan, R. L.; Liu, X. X.; Pan, C. M.; Zhou, X. Q.; Li, X. N.; Kang,
X.; Huang, G. S. Org. Lett. 2013, 15, 4876.
(3) (a) Bharathiraja, G.; Sathishkannan, G.; Punniyamurthy, T. J. Org.
Chem. 2016, 81, 2670−2674. (b) Ni, C. J.; Wang, M. L.; Tong, X. F.
Org. Lett. 2016, 18, 2240. (c) Kowalczyk, D.; Wojciechowski, J.;
Albrecht, Ł. Tetrahedron Lett. 2016, 57, 2533. (d) Selvi, T.; Vanmathi,
G.; Srinivasan, K. RSC Adv. 2015, 5, 49326. (e) Chen, B. H.; Ni, H. C.;
Guo, X.; Zhang, G. L.; Yu, Y. P. RSC Adv. 2014, 4, 44462. (f) Zaghi,
A.; Bernardi, T.; Bertolasi, V.; Bortolini, O.; Massi, A.; De Risi, C. J.
Org. Chem. 2015, 80, 9176. (g) Ling, J.-B.; Su, Y.; Zhu, H. L.; Wang,
G.-Y.; Xu, P.-F. Org. Lett. 2012, 14, 1090. (h) Zhong, Y.; Ma, S. X.; Li,
B.; Jiang, X. X.; Wang, R. J. Org. Chem. 2015, 80, 6870.
(4) Cheng, P.; Guo, W. G.; Chen, P.; Liu, Y.; Du, X.; Li, C. Chem.
Commun. 2016, 52, 3418.
(5) Kumar, S. V.; Muthusubramanian, S.; Perumal, S. RSC Adv. 2015,
5, 90451.
(6) (a) Fang, X.; Li, J.; Tao, H. Y.; Wang, C.-J. Org. Lett. 2013, 15,
5554. (b) Fu, X.; Lin, L. L.; Xia, Y.; Zhou, P. F.; Liu, X. H.; Feng, X. M.
Org. Biomol. Chem. 2016, 14, 5914.
(7) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd
ed.; Wiley-VCH: Weinheim, 2003; p 316. (b) Musiol, R.; Jampilek, J.;
Kralova, K.; Richardson, D. R.; Kalinowski, D.; Podeszwa, B.; Finster,
J.; Niedbala, H.; Palka, A.; Polanski, J. Bioorg. Med. Chem. 2007, 15,
1280. (c) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223. (d) Solomon, V.
R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488 and references cited
therein. (e) Singh, B.; Chetia, D.; Puri, S. K.; Srivastava, K.; Prakash, A.
Med. Chem. Res. 2011, 20, 1523. (f) Singh, M.; Singh, M. P.;
Ablordeppey, S. Drug Dev. Ind. Pharm. 1996, 22, 377.
(8) For representative references, see: (a) Skraup, Z. H. Ber. Dtsch.
Chem. Ges. 1880, 13, 2086. (b) Friedlander, F. Ber. Dtsch. Chem. Ges.
1882, 15, 2572. (c) Pfitzinger, W. J. Prakt. Chem. 1886, 33, 100.
(d) Conrad, M.; Limpach, L. Ber. Dtsch. Chem. Ges. 1887, 20, 944.
(e) Bergstrom, F. W. Chem. Rev. 1944, 35, 77.
(9) For representative reviews, see: (a) Jones, G. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: New York, 1996; Vol. 5, p 167. (b) Kouznetsov, V. V.; Mendez,
L. Y. V.; Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141. (c) Madapa,
S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12, 1116. (d) Marco-
Contelles, J.; Per
E. Chem. Rev. 2009, 109, 2652.
́
ez-Mayoral, E.; Samadi, A.; Carreiras, M. D.; Soriano,
D
DOI: 10.1021/acs.orglett.7b00361
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