Povarov-type reaction using methyl as new input: Direct synthesis of substituted quinolines by I2-mediated formal [3 + 2 + 1] cycloaddition

Article abstract of DOI:10.1021/ol502134u

A highly efficient molecular iodine mediated formal [3 + 2 + 1] cycloaddition reaction for the direct synthesis of substituted quinolines from methyl ketones, arylamines, and styrenes is developed. The methyl group of the methyl ketone represents uniquely reactive input in the Povarov reaction. A self-sequenced iodination/Kornblum oxidation/Povarov/aromatization mechanism has been proposed as a possible reaction sequence to account for the results observed in this study.

Full text of DOI:10.1021/ol502134u

Letter
pubs.acs.org/OrgLett
Povarov-Type Reaction Using Methyl as New Input: Direct Synthesis
of Substituted Quinolines by I2‑Mediated Formal [3 + 2 + 1]
Cycloaddition
Qinghe Gao, Shan Liu, Xia Wu, and Anxin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient molecular iodine mediated formal [3 +
2 + 1] cycloaddition reaction for the direct synthesis of substituted
quinolines from methyl ketones, arylamines, and styrenes is developed.
The methyl group of the methyl ketone represents uniquely reactive
input in the Povarov reaction. A self-sequenced iodination/Kornblum
oxidation/Povarov/aromatization mechanism has been proposed as a
possible reaction sequence to account for the results observed in this study.
he quinoline nucleus is an important scaffold that is found
in a wide range of biologically active compounds, including
Continuing our research toward expanding the scope of
named reactions,7 we recently investigated the Povarov reaction
of methyl ketones. Surprisingly, however, these reactions did not
provide any trace of the classic Povarov products, with large
amounts of acylation products being obtained instead. This
indicated that we had discovered a fascinating new form of
reactivity for the Povarov reaction, where the methyl group of the
methyl ketone reacts instead of the carbonyl carbon.
Mechanistically, the key step in our newly discovered Povarov
reaction involves the cycloaddition reaction between a
dienophile and an in situ generated C-acylimine intermediate
(Scheme 2). Notably, some pioneering oxidative cleavages of
methyl C−H bonds have been reported.8 Liu and co-workers
described CuI-catalyzed oxidation of methyl ketones to
aldehydes in the presence of molecular oxygen, which proceeded
via an arylglyoxal intermediate.9 Furthermore, Kumar et al.
T
natural products and synthetic drugs.1 For this reason,
considerable research has been devoted to developing new
methods for constructing substituted quinoline compounds.2,3
The Povarov reaction,4−6 which is a formal [4 + 2] cycloaddition
reaction between an electron-poor 2-azadiene and an electron-
rich dienophile, has recently emerged as one of the most efficient
protocols for the preparation of quinolines. Notably, this reaction
can be performed in a three-component fashion using a
dienophile and an N-arylamine, generated in situ from a suitable
arylamine and an aldehyde (or a ketone), to allow for the creation
of three bonds in a single operation. The resulting
tetrahydroquinolines can be transformed into the corresponding
quinolines by treatment with an oxidant (Scheme 1a). Although
Scheme 1. Povarov Reactions of Methyl Ketones
Scheme 2. Povarov-Type Reaction via Oxidative Cleavage of
Methyl C−H Bonds
significant progress has been made toward the development of
Povarov reactions involving carbonyl groups, there have been no
reports, to the best of our knowledge, concerning Povarov
reactions with unactivated alkyl groups, such as a simple methyl
group. Herein, we report the development of a reaction
providing novel access to substituted quinolines via the oxidative
cleavage of methyl C−H bonds under metal-free conditions
(Scheme 1b).
Received: July 20, 2014
© XXXX American Chemical Society
A
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Letter
disclosed a copper(I)-catalyzed oxygenase reaction for the
conversion of the allylic methyl group of 3-methylidene oxindole
to the corresponding aldehyde.10 Molecular oxygen can behave
as an efficient oxidant in these types of reaction. However, to the
best of our knowledge, the molecular iodine mediated formal [3
+ 2 + 1] cycloaddition from methyl ketones, arylamines, and
styrenes via the oxidative cleavage of methyl C−H bonds has not
yet been reported, most likely due to the easy overoxidation of C-
acylimines to the α-ketoamides.11
facilitate this reaction. The reaction could also proceed
successfully when it was conducted in the presence of 2.0
equiv of I2 at 80 °C (Table 1, entry 16).
With the optimized conditions in hand, the generality and
scope of the I2-mediated formal [3 + 2 + 1] cycloaddition was
next explored. To our delight, the reaction demonstrated wide
substrate scope in terms of the aromatic ketone unit (Scheme 3).
a b
,
Scheme 3. Scope of Methyl Ketones
This cycloaddition process prompted us to investigate the
reaction parameters in greater detail to evaluate their impact on
the outcome of the reaction. The reaction of acetophenone (1a)
with p-toluidine (2a) and styrene (3a) was selected as a model
reaction for the current study and evaluated under various
conditions. Pleasingly, the reaction proceeded smoothly over 4 h
using 1.6 equiv of I2 at 100 °C in DMSO to afford the Povarov
cycloaddition product (4a) in 63% yield as a single regioisomer
(Table 1, entry 1). The structure of this compound was
a
Table 1. Optimization of the Reaction Conditions
b
entry
I2 (equiv)
Lewis acid
temp (°C)
yield (%)
1
1.6
1.6
1.6
1.6
1.6
1.6
1.6
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
63
62
58
40
60
44
53
0
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
b
2
FeCl3
and I2 (1.0 mmol) in DMSO (2 mL) at 80 °C. Isolated yield.
3
ZnCl2
4
AlCl3
Aryl methyl ketones bearing electron-neutral (4-H), electron-
rich (e.g., 4-Me, 4-OMe, 2,4-OMe), and electron-deficient (e.g.,
4-NO2) phenyl rings were successfully converted to the
corresponding products in moderate to good yields (62−84%;
4a−e). The electronic and steric properties of the aromatic
ketones had a little influence on the efficiency of this reaction.
Furthermore, the optimized conditions were mild enough to be
compatible with a broad range of halogenated (e.g., 4-Cl, 3,4-Cl2,
4-Br) substrates (57−71%; 4f−h), which provided the possibility
for further functionalization. 2-Naphthyl methyl ketone also
provided the expected product (4i) in 45% yield. Furthermore,
the optimized conditions could be applied to various heteroaryl
ketones, including furanyl, thienyl, and benzofuryl methyl
ketones, which gave the corresponding products in moderate
to good yields (62−81%; 4j−l).
This strategy for oxidation of methyl C−H bonds was
subsequently applicable to a variety of substituted anilines and
styrenes, and the desired products were obtained in satisfactory
yields (Scheme 4). Regarding the arylamine substrate, both
electron-rich and electron-deficient anilines could be smoothly
converted to the desired products (53−90%; 4m−o). Interest-
ingly, substrates bearing halogen substituents were well tolerated
with the corresponding halo-substituted products being isolated
in reasonable yields (68−78%; 4p−r). β-Naphthylamine also
reacted smoothly under the optimized conditions to give 4s in
42% yield. The use of aniline unexpectedly resulted in the
formation of a complex mixture of products. Regarding the
styrenes, experimentation revealed that electron-rich styrenes
(62−71%; 4t−v) gave higher yields of the desired quinolines
compared with weakly electron-deficient styrenes (43−57%;
4w−y). Nevertheless, 4-cyanostyrene, which is a strong electron-
deficient styrene, prevented the reaction from proceeding
because of the decreased electron density on the aryl ring. Steric
hindrance had a little influence on the efficiency of the reaction,
5
InCl3
6
Cu(OTf)2
Sc(OTf)2
7
8
9
2.0
3.0
5.0
1.0
0.5
2.0
2.0
2.0
2.0
2.0
74
63
32
47
18
74
10
74
74
74
10
11
12
13
c
14
15
16
17
18
80
110
130
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
Lewis acid (0.25 mmol), solvent (2 mL). Isolated yields. 3a (1.0
mmol).
b
c
unambiguously confirmed by X-ray crystallography analysis. On
the basis of this encouraging result, several Lewis acid catalysts
were also evaluated, including FeCl3, ZnCl2, AlCl3, InCl3,
Cu(OTf)2, and Sc(OTf)2, but none of these catalysts had a
positive impact on the outcome of the reaction (Table 1, entries
2−7). These results indicated that I2 could also act as a Lewis acid
to promote the direct cycloaddition step. A control experiment
was conducted without I2 to test this hypothesis and failed to
provide any of the desired product (Table 1, entry 8). On the
basis of this result, the reaction was further optimized using I2 as
the promoter. Interestingly, an increase in the loading of I2 to 2.0
equiv gave 4a in a higher yield (Table 1, entry 9), whereas a
reduction in the charge of I2 to 0.5 equiv resulted in a significant
decrease in the yield (Table 1, entry 13). These results therefore
demonstrated that catalytic amounts of I2 could not be used to
B
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Letter
a
Taken together, these experimental results indicated that C-
Scheme 4. Scope of Anilines and Styrenes
acylimines were the key intermediates in the current reaction.
Scheme 6. 13C Labeling Experiment
The reaction of 1a (0.2 mmol) with 2c (0.2 mmol) and 3a (0.2
mmol) in the presence of I2 (0.4 mmol) in DMSO-d6 was
monitored by 13C NMR spectroscopy to develop a deeper
understanding of the reaction mechanism (Figure 1). The results
of this study also revealed that phenacyl iodine (1aa),
phenylglyoxal (1ab), and C-acyl imine (5n) were important
intermediates in the overall transformation.
a
Isolated yield.
as exemplified by β-vinylnaphthalene, which reacted under the
optimized conditions to give the desired product (4z) in 60%
yield.
With the scope of the method established, the reaction
mechanism was subsequently considered. Acetophenone (1a)
was reacted with I2 in DMSO at 90 °C to give phenylglyoxal
(1ab) and the corresponding hydrated species (1ac) in
quantitative yield (Scheme 5a). The hydrated species (1ac)
Scheme 5. Control Experiments
Figure 1. Progress of the reaction of 1a (0.2 mmol), 2c (0.2 mmol), and
3a (0.2 mmol) with I2 (0.4 mmol) at 90 °C by 13C NMR (150 MHz,
DMSO-d6, 298 0.5 K).
On the basis of the results of the current study as well as
previous reports,13 a possible mechanism was proposed using
acetophenone (1a), p-toluidine (2a), and styrene (3a) as the
substrates (Scheme 7). The initial reaction of molecular iodine
Scheme 7. Possible Mechanism
was subjected to the optimized reaction conditions and gave 4a
in 86% yield (Scheme 5b). This result demonstrated that 1ac was
an intermediate in the current reaction. When the acetophenone
substrate was replaced with α-iodo acetophenone (1aa), which
was identified as a probable precursor of α-ketoaldehyde (1ab),
the desired quinoline product was obtained in 79% yield
(Scheme 5c). When C-acylimine (5n)12 was used as a substrate
in the reaction, the desired product 4n was formed in 78% yield.
However, the use of 5n as a substrate did not result in the
formation of 4n when the reaction was conducted in the absence
of I2 (Scheme 5d). This suggested that iodine played an
important role in the Povarov/oxidation process.
with 1a would result in the formation of the α-iodo ketone (1aa),
which would be converted to phenylglyoxal by a subsequent
Kornblum oxidation. The reaction of p-toluidine (2a) with the
aldehyde group of 1ab would then give the C-acyl imine 5a,
which would react with HI to give the activated C-acyl imine ion
5a′. This activated species would be involved in the key step of
A
13C-labeling experiment was also conducted under the
optimized conditions using acetophenone-β-13C as a substrate,
which gave the desired product (4a′) in 70% yield (Scheme 6).
C
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Letter
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the Povarov-type reaction, and would react smoothly with
styrene (3a) to give intermediate B in the presence of an excess
or regenerated iodine.14 Intermediate B would then undergo
sequential oxidation and aromatization reactions to give the
desired product 4a.
In summary, a highly efficient I2-mediated formal [3 + 2 + 1]
cycloaddition for the direct synthesis of substituted quinolines
using methyl ketones, arylamines, and styrenes has been
developed. This synthetic pathway represents a fascinating new
form of reactivity for the Povarov reaction, where the methyl
group of the methyl ketone reacts instead of the carbonyl carbon.
Initial studies of the mechanism suggested that this reaction
proceeded through a self-sequenced iodination/Kornblum
oxidation/Povarov/aromatization cascade reaction. Further-
more, this autotandem catalytic process was easy to operate
and could sequentially promote three mechanistically distinct
reactions in a single reactor using molecular iodine. Further
studies of the application of this I2-mediated formal cycloaddition
are currently underway in our laboratory and will be reported in
due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
(9) Zhang, L.; Bi, X. H.; Guan, X. X.; Li, X. Q.; Liu, Q.; Barry, B. D.;
General experimental procedure and characterization data of the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
Liao, P. Q. Angew. Chem., Int. Ed. 2013, 52, 11303.
(10) Wang, Y.; Bauer, J. O.; Strohmann, C.; Kumar, K. Angew. Chem.,
Int. Ed. 2014, 53, 7514.
(11) (a) Zhang, C.; Zong, X. L.; Zhang, L. R.; Jiao, N. Org. Lett. 2012,
14, 3280. (b) Wei, W.; Shao, Y.; Hu, H. Y.; Zhang, F.; Zhang, C.; Xu, Y.;
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Battula, S.; Kushwaha, M.; Gupta, A. P.; Ahmed, Q. N.; Vishwakarma, R.
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chwuax@mail.ccnu.edu.cn.
Mancheno, O. G. J. Org. Chem. 2013, 78, 6050.
̃
Notes
(12) (a) Kunzi, S. A.; Morandi, B.; Carreira, E. M. Org. Lett. 2012, 14,
̈
The authors declare no competing financial interest.
1900.
(13) (a) Bunescu, A.; Wang, Q.; Zhu, J. P. Org. Lett. 2014, 16, 1756.
ACKNOWLEDGMENTS
(b) Richter, H.; Mancheno, O. G. Org. Lett. 2011, 13, 6066. (c) Jia, X. D.;
̃
■
Peng, F. F.; Qing, C.; Huo, C. D.; Wang, X. C. Org. Lett. 2012, 14, 4030.
(d) Liu, J.; Wang, Y. X.; Yu, L. L.; Huo, C. D.; Wang, X. C.; Jia, X. D. Adv.
Synth. Catal. 2014, DOI: 10.1002/adsc.201400005. (e) Yang, J. M.; Wu,
L.; Fang, D.; Cao, J.; Zhou, Y. J.; Wang, X. S. Res. Chem. Intermed. 2014,
40, 1103.
This work was supported by the National Natural Science
Foundation of China (Grant 21032001, 21272085).
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