Synergistic I2/Amine Promoted Povarov-Type Reaction for the Synthesis of 2-Acyl-3-aryl(alkyl)quinolines Using Aryl(alkyl)acetaldehydes as Alkene Surrogates

Article abstract of DOI:10.1021/acs.orglett.7b01686

A synergistic I₂/amine promoted formal [4 + 2] cycloaddition of methyl ketones, arylamines, and aryl(alkyl)acetaldehydes as alkene surrogates has been established. This protocol allowed the modular synthesis of various 2-acyl-3-aryl(alkyl)quino

Full text of DOI:10.1021/acs.orglett.7b01686

Letter
pubs.acs.org/OrgLett
Synergistic I /Amine Promoted Povarov-Type Reaction for the
2
Synthesis of 2‑Acyl-3-aryl(alkyl)quinolines Using
Aryl(alkyl)acetaldehydes as Alkene Surrogates
Xiao Geng, Xia Wu, Peng Zhao, Jingjing Zhang, 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, P. R. China
*
S Supporting Information
ABSTRACT: A synergistic I /amine promoted formal [4 + 2] cycloaddition of methyl ketones, arylamines, and
2
aryl(alkyl)acetaldehydes as alkene surrogates has been established. This protocol allowed the modular synthesis of various
2
-acyl-3-aryl(alkyl)quinolines, rather than 2,4-substituted quinolines. Notably, the arylamines not only participated as reactants in
this reaction but also acted as indispensable catalysts to promote enamine formation. Moreover, mechanistic investigation
suggested that the reaction occurred via an iodination/Kornblum oxidation/Povarov/aromatization sequence.
1
3
uinoline subunits are widespread in natural products
of sp C−H bonds, followed by cycloaddition with alkenes. For
2
6
Q
and pharmaceutical molecules and are important inter-
mediates for asymmetric synthesis. In past decades, numerous
example, novel strategies have been developed for achieving
sp C−H bond oxidation of N-benzylanilines and glycine deriv-
atives for the synthesis of 2,4-substituted quinoline deriva-
3
3
named reactions, including Skraup, Doebner−Von Miller,
7
Friedlan
̈
der, and Povarov reactions, have been reported for
tives with an alkene (Scheme 1b). In 2014, our group took
4
quinoline synthesis. Among these methods, the Povarov reac-
tion, which is catalyzed by either protic or Lewis acids and
involves the formal [4 + 2] cycloaddition between 2-azadienes
and dienophiles, is an efficient method for synthesizing quino-
lines (Scheme 1a). In recent years, good progress has been
advantage of methyl ketones for building 2-acyl-4-arylquinolines
with p-toluidine and an alkene via Povarov-type reactions
(Scheme 1c). Despite progress in this area, most of the prod-
ucts remain restricted to 2,4-substituted quinolines because of
the inherent regioselectivity of the alkene in the Povarov
reaction. Direct construction of 2-acyl-3-aryl(alkyl)quinolines
via the Povarov-type reaction has not yet been reported, as
tuning the addition of an alkene to aromatic imines to be
α-selective is much more difficult than making it β-selective.
In this context, the investigation and development of suitable
alkene surrogates to construct 2-acyl-3-aryl(alkyl)quinolines
via a Povarov reaction are especially attractive. Inspired by
5
−7
made in Povarov reactions.
The main strategy focused on
the in situ generation of aromatic imines through the oxidation
Scheme 1. Synthesis of Quinolines via Povarov Reaction
8
9
synergistic enamine catalysis theory and our previous work,
we envisaged that aryl(alkyl)acetaldehydes could act as alkene
surrogates. Aryl(alkyl)acetaldehydes would generate enamines
in situ via amine catalysis (Scheme 1d) and exhibit distinctly
different regioselectivity compared with an alkene. Herein, we
present a synergistic I /amine promoted Povarov-type reac-
2
tion for preparing 2-acyl-3-aryl(alkyl)quinolines using methyl
ketones and arylamines as precursors of aromatic imines, and
aryl(alkyl)acetaldehydes as alkene surrogates.
According to the above hypothesis, we commenced the
study by treating model substrates, acetophenone (1.0 mmol),
p-toluidine (1.0 mmol), and phenylacetaldehyde (1.0 mmol),
Received: June 6, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01686
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
,
a b
with I (1.6 mmol) in DMSO at 100 °C. As expected, the reac-
Scheme 2. Scope of Aryl Methyl Ketones
2
tion proceeded smoothly to afford the Povarov-type product
4a in 52% yield (Table 1, entry 1) after 4 h. Based on this
a
Table 1. Optimization of the Reaction Conditions
b
entry
I2 (equiv)
1a:2a:3a
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
1.6
1.6
1.6
1.6
1.6
0.3
0.5
0.8
1.2
2.0
0.8
0.8
0.8
0.8
0.8
0.8
0.8
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:0.5
1:1:1.5
1:0.5:1
1:1.5:1
1:1:1
1:1:1
1:1:1
100
90
52
50
55
56
53
40
48
60
58
52
40
36
53
42
69
72
58
110
120
130
120
120
120
120
120
120
120
120
120
120
120
120
1
1
1
1
1
1
1
1
0
1
2
3
4
5
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol),
and I (0.8 mmol) and NaHCO (0.8 mmol) in DMSO (3 mL) at
2
3
b
1
20 °C for 16 h. Isolated yield.
Subsequently, the scope of the Povarov-type reaction was
further explored using a variety of substituted anilines and
aryl(alkyl)acetaldehyde (Scheme 3). Regarding the arylamine
c
d
6
e
7
a
Reaction conditions: 1a (1.0 mmol), 2a, 3a, I , heated in 3 mL of
2
b
c
Scheme 3. Scope of Anilines and
DMSO within 16 h unless otherwise noted. Isolated yields. With
NaOH. With NaHCO . With Na CO .
a b c
, ,
d
e
Aryl(alkyl)acetaldehydes
3
2
3
encouraging result, we then examined various reaction condi-
tions to improve the yield. First, different temperatures were
applied to this Povarov-type reaction, with 120 °C giving the
best yield (Table 1, entries 1−5). We subsequently investigated
the effect of different amounts of iodine on the reaction
outcome, finding that 0.8 equiv of iodine gave the optimum
yield (Table 1, entries 6−10). We also investigated the effect of
different molar ratios of 1a/2a/3a, with no improvement
obtained compared with 1/1/1 (Table 1, entries 11−14).
Finally, the yield was further improved to 72% using NaHCO3
(0.8 mmol) as an additive.
With the optimized reaction conditions in hand, we next
investigated the substrate scope of this reaction. As summarized
in Scheme 2, a variety of acetophenone derivatives bearing
different substituents were transformed into the desired 2-acyl-
a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol),
and I (0.8 mmol) and NaHCO (0.8 mmol) in DMSO (3 mL) at
120 °C for 16 h. Isolated yield. Gram reaction (5 mmol.)
2
3
b
c
3
-arylquinolines in moderate to high yields. For example, aryl
methyl ketones bearing electron-neutral (4-H), electron-rich
e.g., 4-Me, 4-OMe, 4-OEt, and 3,4-OCH O), and electron-
(
2
substrates, both electron-rich (4-OMe and 4-CH(CH ) ) and
electron-deficient (4-CO Et and 4-CN) substituents were
tolerated on the phenyl ring of the aniline substrates, affording
the corresponding products in satisfactory yields (60−71%;
4
3
2
deficient (e.g., 4-NO and 3-NO ) groups were tolerated,
2
2
2
affording the corresponding products in moderate to good
yields (63−72%, 4a−g). The optimized conditions were mild
enough to be compatible with a broad range of halogenated
o−r). Furthermore, arylacetaldehydes containing electron-rich
(
e.g., 4-Cl, 3,4-Cl , and 4-Br) substrates (63−73%, 4h−j),
2
groups (4-Me and 3-OMe) were transformed into the desired
which provided the possibility for further functionalization.
Notably, 1-naphthyl methyl ketone also readily reacted in the
reaction, giving the expected product (4k) in 61% yield.
Furthermore, various heteroaryl ketones, including furanyl,
benzofuryl, and thienyl methyl ketones, were tolerated under
these conditions, giving the corresponding products in mod-
erate yields (58−65%, 4l−n).
2
4
2
-acyl-3-arylquinoline products in moderate yields (60−62%,
s−t). Notably, alkylaldehydes were also employed, affording
-acyl-3-alkylquinolines in high yields (77−85%, 4u−x). More-
over, the structure of 4v was unambiguously confirmed by
X-ray crystallographic analysis (see Supporting Information).
To verify a possible mechanism, a series of control experi-
ments associated with this transformation were performed.
B
DOI: 10.1021/acs.orglett.7b01686
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
2
Aryl methyl ketone (1a, 1.0 mmol) was heated with I (0.8 mmol)
enamine A via base promoted tautomerization. Enamine A
was then used as a dienophile in the Povarov-type reaction via a
formal [4 + 2] cycloaddition with the in situ generated iminium
ion 5a, forming intermediate B. Finally, the desired product 4a
2
in DMSO at 120 °C to afford phenylglyoxal 1ab and the corre-
sponding hydrated species 1ac in quantitative yield (Scheme 4a).
When acetophenone 1a was replaced by α-iodoacetophenone
13
was obtained via deamination of B. p-Toluidine 2a then con-
tinued to participate in the reaction.
Scheme 4. Control Experiments
In summary, we have developed a synergistic iodine-amine
promoted process for the synthesis of 2-acyl-3-aryl(alkyl)-
quinolines via a Povarov-type reaction, in which aryl(alkyl)-
acetaldehydes are used as useful alkene surrogates. Moreover,
this protocol is an efficient method for enriching the scope of
Povarov-type reactions. Notably, arylamines play dual pivotal
roles in this reaction, promoting enamine formation and serving
as a reactant. Further studies toward applications of this process
are currently underway in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01686.
Experimental procedures, product characterizations, crys-
1
13
tallographic data, and copies of the H and CNMR
spectra (PDF)
Crystallographic data for 4v (CIF)
1aa under the optimized conditions with 2a and 3a, the desired
product 4a was afforded in 78% yield (Scheme 4b). Hydrated
species 1ac was also subjected to the optimized reaction con-
ditions, affording 4a in 80% yield (Scheme 4c). These results
confirmed the intermediacy of phenacyl iodine 1aa and
phenylglyoxal 1ac in this transformation. When C-acylimine
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
ORCID
5
4
b was used as a substrate in the reaction, the desired product
o was formed in 83% yield under the standard conditions
10
An-Xin Wu: 0000-0001-7673-210X
Notes
(see Supporting Information), but no desired product was
obtained in the absence of I (Scheme 4d). These results
The authors declare no competing financial interest.
2
implied the intermediacy of C-acylimine in the transformation
and clearly suggested that iodine played an vital role in the
Povarov/oxidation process.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grants 21472056 and 21602070). We
thank Dr. Chuanqi Zhou, Hebei University, for analytical
support. This work was supported by “The Fundamental
Research Funds for the Central Universities” (CCNU15Z-
X002and CCNU16A05002). This work was also supported by
the 111 Project B17019. We acknowledge an excellent graduate
education innovation grant from Central China Normal
University (2016CXZZ66). We thank Prof. Wei-Min Dai of
The Hong Kong University of Science and Technology for his
suggestions and dedicate this paper to him on the occasion of
his 60th birthday.
Based on the outcome of the control experiments and pre-
1
1
vious studies, a tentative mechanism for this transformation
was proposed, as shown in Scheme 5. Acetophenone 1a was
converted into phenylglyoxal 1ab via an iodination/Kornblum
oxidation sequence. Next, iminium ion 5a was formed via the
condensation of intermediate 1ab and p-toluidine 2a. Mean-
while, p-toluidine 2a could react with arylacetaldehyde to gen-
erate imine A′, which was then rapidly converted into intermediate
Scheme 5. Proposed Mechanism
REFERENCES
■
(
1) (a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223. (b) Michael, J. P.
Nat. Prod. Rep. 2008, 25, 166. (c) Michael, J. P. Nat. Prod. Rep. 1997,
1
4, 605. (d) Behenna, D. C.; Stockdill, J. L.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2008, 47, 2365. (e) Kong, L. K.; Zhou, Y. Y.; Huang,
H.; Yang, Y.; Liu, Y. Y.; Li, Y. Z. J. Org. Chem. 2015, 80, 1275.
(2) (a) Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry,
D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.;
Huang, J. H.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E.
W.; Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Shillings,
A.; Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N.
Nature 2010, 466, 935. (b) Rouffet, M.; de Oliveira, C. A. F.; Udi, Y.;
Agrawal, A.; Sagi, I.; McCammon, J. A.; Cohen, S. M. J. Am. Chem. Soc.
2
010, 132, 8232. (c) Andrews, S.; Burgess, S. J.; Skaalrud, D.; Kelly, J.
X.; Peyton, D. H. J. Med. Chem. 2010, 53, 916. (d) Lord, A.-M.;
C
DOI: 10.1021/acs.orglett.7b01686
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Mahon, M. F.; Lloyd, M. D.; Threadgill, M. D. J. Med. Chem. 2009, 52,
868. (e) Musiol, R.; Serda, M.; Hensel-Bielowka, S.; Polanski, J. Curr.
Med. Chem. 2010, 17, 1960. (f) Solomon, V. R.; Lee, H. Curr. Med.
Chem. 2011, 18, 1488. (g) Natarajan, J. K.; Alumasa, J. N.; Yearick, K.;
Ekoue-Kovi, K. A.; Casabianca, L. B.; de Dios, A. C.; Wolf, C.; Roepe,
P. D. J. Med. Chem. 2008, 51, 3466. (h) Andries, K.; Verhasselt, P.;
̈
Guillemont, J.; Gohlmann, H. W. H.; Neefs, J.-M.; Winkler, H.; Van
Gestel, J.; Timmerman, P.; Zhu, M.; Lee, E.; Williams, P.; de Chaffoy,
D.; Huitric, E.; Hoffner, S.; Cambau, E.; Truffot-Pernot, C.; Lounis,
N.; Jarlier, V. Science 2005, 307, 223.
(
3) (a) Cai, X.-F.; Huang, W.-X.; Chen, Z.-P.; Zhou, Y.-G. Chem.
Commun. 2014, 50, 9588. (b) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.;
Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536.
(
2
c) Huang, Y.-Y.; Cai, C.; Yang, X.; Lv, Z.-C.; Schneider, U. ACS Catal.
016, 6, 5747.
4) (a) Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086.
b) Doebner, O.; von Miller, W. Ber. Dtsch. Chem. Ges. 1881, 14, 2812.
c) Friedlander, P.; Henriques, S. Ber. Dtsch. Chem. Ges. 1882, 15,
572. (d) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
5) (a) Dagousset, G.; Zhu, J. P.; Masson, G. J. Am. Chem. Soc. 2011,
33, 14804. (b) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.;
(
(
(
2
̈
(
1
Zhu, J. P. J. Am. Chem. Soc. 2009, 131, 4598. (c) Ren, X. W.; Li, G. G.;
Huang, J.; Wang, W. D.; Zhang, Y. P.; Xing, G. M.; Gao, C. Y.; Zhao,
G.; Zhao, J. Z.; Tang, Z. Org. Lett. 2017, 19, 58. (d) Galvez, J.; Castillo,
J.-C.; Quiroga, J.; Rajzmann, M.; Rodriguez, J.; Coquerel, Y. Org. Lett.
2014, 16, 4126. (e) Min, C.; Sanchawala, A.; Seidel, D. Org. Lett. 2014,
16, 2756. (f) Bunescu, A.; Wang, Q.; Zhu, J. P. Org. Lett. 2014, 16,
1756.
(
6) (a) Liu, J.; Wang, Y. X.; Yu, L. L.; Huo, C. D.; Wang, X. C.; Jia, X.
D. Adv. Synth. Catal. 2014, 356, 3214. (b) Liu, J.; Liu, F.; Zhu, Y. Z.;
Ma, X. G.; Jia, X. D. Org. Lett. 2015, 17, 1409. (c) 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. (d) Richter, H.; GarcíaManchen
Org. Lett. 2011, 13, 6066.
̃
o, O.
(
(
7) Gao, Q. H.; Liu, S.; Wu, X.; Wu, A. X. Org. Lett. 2014, 16, 4582.
8) (a) Tang, S.; Wu, X. D.; Liao, W. Q.; Liu, K.; Liu, C.; Luo, S. Z.;
Lei, A. W. Org. Lett. 2014, 16, 3584. (b) Petronijevic, F. R.; Nappi, M.;
́
MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 18323. (c) Allen, A.
E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260. (d) Skucas,
E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 9090.
(
e) Stevens, J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135,
1756. (f) Ikeda, M.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int.
Ed. 2010, 49, 7289. (g) Sunden, H.; Ibrahem, I.; Eriksson, L.; Cordova,
A. Angew. Chem. 2005, 117, 4955. (h) Ibrahem, I.; Cordova, A. Angew.
1
́
́
́
Chem., Int. Ed. 2006, 45, 1952. (i) Donadío, L. G.; Galetti, M. A.;
Giorgi, G.; Rasparini, M.; Comin, M. J. Org. Chem. 2016, 81, 7952.
(
j) Wang, S.-N.; Li, X.-M.; Liu, H.-W.; Xu, L.; Zhuang, J.-C.; Li, J.; Li,
H.; Wang, W. J. Am. Chem. Soc. 2015, 137, 2303. (k) Ding, Q.-P.; Wu,
J. Org. Lett. 2007, 9, 4959. (l) Colbon, P.; Ruan, J. W.; Purdie, M.;
Xiao, J. L. Org. Lett. 2010, 12, 3670.
(
9) (a) Wu, X.; Geng, X.; Zhao, P.; Zhang, J. J.; Gong, X. X.; Wu, Y.
D.; Wu, A. X. Org. Lett. 2017, 19, 1550. (b) Gao, Q. H.; Liu, S.; Wu,
X.; Zhang, J. J.; Wu, A. X. J. Org. Chem. 2015, 80, 5984.
(
10) C-acylimine 5b would easily release arylamine via hydrolysis,
and then arylamine could react with phenylacetaldehyde to promote
enamine formation.
(
11) (a) Wu, Y. D.; Geng, X.; Gao, Q. H.; Zhang, J. J.; Wu, X.; Wu,
A. X. Org. Chem. Front. 2016, 3, 1430. (b) Wu, X.; Gao, Q. H.; Geng,
X.; Zhang, J. J.; Wu, Y. D.; Wu, A. X. Org. Lett. 2016, 18, 2507. (c) Yin,
G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan, Y. J. Org. Lett. 2006,
8, 2245.
(
12) (a) 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. (b) Li, Q. J.; Fan, A.
L.; Lu, Z. Y.; Cui, Y. X.; Lin, W. H.; Jia, Y. X. Org. Lett. 2010, 12, 4066.
(
1
c) Zhang, C.; Zhang, L. R.; Jiao, N. Adv. Synth. Catal. 2012, 354,
293.
13) (a) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756.
b) Yang, G. M.; Jia, Q. F.; Chen, L.; Du, Z. Y.; Wang, J. RSC Adv.
(
(
2
015, 5, 76759.
D
DOI: 10.1021/acs.orglett.7b01686
Org. Lett. XXXX, XXX, XXX−XXX