Intermolecular Dehydrative [4 + 2] Aza-Annulation of N-Arylamides with Alkenes: A Direct and Divergent Entrance to Aza-Heterocycles

Article abstract of DOI:10.1021/acs.orglett.9b00233

We disclose that following activation with trifluoromethanesulfonyl anhydride, secondary N-arylamides undergo smooth intermolecular dehydrative [4 + 2] aza-annulation with alkenes under mild conditions to give 3,4-dihydroquinolines, amenable to further functionalization. Meanwhile, conditions have been established to allow divergent one pot synthesis of tetrahydroquinolines and quinolines as well as tricyclic analogues from N-arylamides.

Full text of DOI:10.1021/acs.orglett.9b00233

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intermolecular Dehydrative [4 + 2] Aza-Annulation of N‑Arylamides
with Alkenes: A Direct and Divergent Entrance to Aza-Heterocycles
Ying-Hong Huang, Shu-Ren Wang, Dong-Ping Wu, and Pei-Qiang Huang*
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P.R. China
S
* Supporting Information
ABSTRACT: We disclose that following activation with
trifluoromethanesulfonyl anhydride, secondary N-arylamides
undergo smooth intermolecular dehydrative [4 + 2] aza-
annulation with alkenes under mild conditions to give 3,4-
dihydroquinolines, amenable to further functionalization.
Meanwhile, conditions have been established to allow
divergent one pot synthesis of tetrahydroquinolines and
quinolines as well as tricyclic analogues from N-arylamides.
itrogen-containing heterocycles occupy a central position
internal alkenyl groups, for the synthesis of analogues of
Namong pharmaceuticals, agrochemicals, and functional luotonin A and (S)-14-azacamptothecin, respectively. Surpris-
ingly, to the best of our knowledge, intermolecular aza-
annulation of amides with alkenes has not been reported.
Nevertheless, the development of such intermolecular
reactions would allow a flexible and versatile construction of
nonaromatic heterocycles and thus afford the possibility for
further functionalization. Moreover, amides and alkenes are
bench-stable and widely used simple chemical feedstocks. This
gap might be ascribed to the low reactivity of N-arylimidate
generated from classical amide-activing reagents such as
Meerwein’s reagent. Moreover, the above-mentioned intra-
molecular [4+ + 2] reactions have been shown to pass through
N-arylimidate intermediates. In one recent work, we have
shown that an alkene reacted much less efficiently with an N-
arylimidate (in situ generated from a secondary amide and
Tf2O) than with the corresponding N-arylnitrilium ion (in situ
generated from a secondary amide and 1.1 equiv of Tf2O/1.2
equiv of 2-fluoropyridine combination) (yield: 51% versus
95%). Moreover, in our recently reported Tf2O/2-fluoropyr-
idine-mediated N-arylamides with alkynes, we have confirmed
that N-arylnitrilium ions instead of N-arylimidate are the
reactive intermediates. Herein, we report a divergent strategy
for the one-pot synthesis of either 3,4-dihydroquinolines,
tetrahydroquinolines, or quinolines and functionalized deriva-
tives starting from secondary N-arylamides and alkenes (Figure
1).
materials. A recent analysis of US FDA-approved drugs
revealed that 59% of unique small-molecule drugs contain a
nitrogen heterocycle.1 Heterocycloaddition/annulation be-
tween two components is the most efficient and versatile
strategy to build heterocycles because two C−C bonds or a
C−C bond and a C−X bond are formed in one pot. Thus,
development of novel heteroannulation reactions is of great
value for both medicinal chemistry and the total synthesis of
natural products.2
Since the seminal work of Ghosez,3a the direct trans-
formation of amides has emerged as an active area of research
in recent years.4−10 Although tremendous progress has been
made, the employment of amides as a partner in aza-annulation
reactions remains rare.8−10 Only the intramolecular aza-Diels−
Alder (IADA) reaction,8 dehydrative [4 + 2] aza-annulation of
enamides,9 and of N-arylamides with alkynes10 have been
reported. Among them, Fortunak’s synthesis of the indolizino-
[1,2-b]quinolin-9(11H)-one core of camptothecin was postu-
lated to pass through an intramolecular aza-Diels−Alder
(IADA) reaction between an N-arylimidate [in situ generated
from arylamide and Meerwein reagent (trimethyloxonium
fluoroborate)] and an internal alkynyl group.8a This method-
ology was improved by Yao by replacing Meerwein’s reagent
with Hendrickson’s reagent (hexaphenyloxodiphosphonium
triflate, generated in situ from 3 equiv of Ph3PO and 1.5 equiv
of Tf2O) as an amide-activating reagent.8b The concerted
IADA mechanisms have been confirmed by Yu and co-workers
by means of DFT calculations and specified as intramolecular
[4+ + 2] reactions.8d
Quinoline11 and 1,2,3,4-tetrahydroquinoline12 are two
privileged scaffolds13 of many medicinal agents, bioactive
alkaloids, coordination ligands, and functional materials.
Although many synthetic methods have been developed for
their syntheses,11−13 flexible synthesis of 3,4-dihydroquinolines
The Fortunak−Yao methodology has been extended by
Zhang8c and Yao,8e in two examples, to intramolecular aza-
hetero-Diels−Alder reactions between N-arylimidates (in situ
generated from arylamides and Hendrickson reagent) and
Received: January 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of 3,4-Dihydroquinolines via Direct
Dehydrative [4 + 2] Aza-Annulation of N-Arylamides with
a−c
Alkenes
Figure 1. Our plan for the one-pot, divergent synthesis of diverse aza-
heterocycles by dehydrative aza-annulation of N-arylamides with
alkenes.
from simple starting materials is surprisingly limited.14 In
particular, there have been few reports of their isolation and
full characterization. Moreover, flexible, versatile, and divergent
methods for the direct construction of the three related classes
of compounds has remained elusive until now.
Very recently, we have developed a reductive alkenylation
reaction of N-(2,6-dimethylphenyl)amides 1A (Scheme 1)
Scheme 1. Our Recently Developed Reductive Alkenylation
Reaction of Amide 1A and the Discovery of a Novel
Reaction Pathway Yielding 3a from 1a
a
Reaction conditions: amide (1.0 equiv), 2-F-Pyr (1.2 equiv), CH2Cl2
(0.2 M) then −78 °C, Tf2O (1.1 equiv), 5 min, then 0 °C, 10 min.
b
Alkene (1.2 equiv), 40 °C, 2 h. See the Supporting Information for
c
the list of amides. Isolated yield.
noting that the reaction can be run on a gram scale. Indeed,
when the aza-annulation reaction of 1a with 2h was run on a
10 mmol scale, 3h was obtained in a high yield of 86%.
A secondary amide can serve as an important directing
group for C−H functionalization.15a In this regard, Wang’s
group recently reported a regioselective iodation of N-(p-
tolyl)acetamide to give iodoamides such as 1w via Pd-catalyzed
sp2 C−H bond activation in a ball mill.15b To demonstrate the
potential of our method in the transformation of functionalized
amides, the aza-annulation of N-(o-iodo-p-tolyl)acetamide
(1w) was undertaken. It proceeded smoothly to afford the
iodo compound 3j in 70% yield.
To take advantage of the imine functionality in 3,4-
dihydroquinolines, a demonstration of their synthetic utility
by a Ugi-type multicomponent reaction16 of 3k was under-
taken. Treatment of 3k with triethylamine (2.0 equiv), acetic
acid (3.0 equiv), and cyclohexyl isocyanide (c-hexNC, 9, 2.0
equiv) in trifluoroethanol afforded the desired bisamide 10 in
70% yield (Scheme 3). Furthermore, the two transformations
were merged into a one-pot reaction to yield 10 in 56% yield
from 1t.
with alkenes to yield α,β-unsaturated ketimines 8A or α,β-
enones after acidic workup.5j We discovered that when N-
phenylbenzamide (1a) was used as a substrate, a 3,4-
dihydroquinoline derivative 3a could be obtained as the
major product (Scheme 1). In light of our previous work,5j
a
quick screening of the key reaction parameter allowed us to
define the optimal reaction conditions as successive treatments
of a mixture of an N-arylamide and 2-fluoropyridine (1.2
equiv) with Tf2O (−78 °C, 5 min, 0 °C, 10 min) and an alkene
at 0 °C (then 40 °C, 2 h). The major difficulty was the
isolation of unstable 3,4-dihydroquinolines14a from the
enimine byproduct (cf. 8a, R = H). For this purpose, two
protocols were established for the isolation of 3,4-dihydroqui-
nolines (cf. Supporting Information).
With the optimal reaction conditions and isolation protocols
established, the scope of the reaction was examined. Scheme 2
shows that the one-pot dehydrative aza-annulation of styrene
worked well with both N-phenyl aromatic amides (1a and 1b)
and aliphatic amides, covering primary (1r), secondary (1p),
and tertiary alkanoyl (1q, 1s) amides, to give the
corresponding 3,4-dihydroquinolines 3a−f in excellent yields.
Significantly, the reaction is not limited to styrene and its
derivatives. (E)-1-Phenylbuta-1,3-diene (2f), a vinylogous
styrene, and methylenecyclohexane (2h) are also effective
olefin partners, affording 3,4-dihydroquinolines 3g and 3h in
93% and 88% yield, respectively. Interestingly, the dehydrative
annulation of 1a with bicyclo[2.2.1]hept-2-ene (norbornene,
2j) produced the polycyclic product 3i in 73% yield. It is worth
Next, we explored the synthesis of 1,2,3,4-tetrahydroquino-
lines (6) from N-arylamides (1). Given that the dehydrative
annulation of amides with alkenes yields 3,4-dihydroquinolines
(3) as the primary products, we can expect that an in situ
reduction would allow access, in a one-pot manner, to
tetrahydroquinolines (6). Indeed, after completion of the
aza-annulation reaction, methanol and NaBH4 (1.5 equiv)
were added at 0 °C, and the resulting mixture was stirred at rt
for 2 h, producing 6a as the only observable diastereomer in
89% yield (Scheme 4). The diastereoselectivity was deter-
mined as >20:1 at the limit of 1H NMR. Because both cis- and
trans-6a are known compounds,17 a comparison of their H
1
NMR data with ours allowed determination of the cis-
B
DOI: 10.1021/acs.orglett.9b00233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
annulation of ester anilide 1v with styrene yielded 6r in 78%
yield. The stereochemistries of 6b−r were determined by a
comparison of their diagnostic 1H NMR data with those of 6a
and confirmed by a single crystal X-ray diffraction analysis of
compound 6d (see the Supporting Information).
Scheme 3. One-Pot Synthesis of Functionalized 3,4-
Dihydroquinoline Derivative 10 via Tandem Dehydrative
Aza-Annulation−Ugi Three-Component Reaction
The scope of the alkene partner was next examined. The
reductive annulation reactions of p-phenyl- and p-tert-
butyldimethylsilyloxy-substituted styrene derivatives 2b and
2c reacted to give the corresponding 6s and 6t in excellent
yields (Scheme 5). Styrene bearing a sensitive acetoxy group
Scheme 5. Scope of Alkenes Used in the One-Pot Tandem
Dehydrative Aza-Annulation−Rduction Yielding
a
Tetrahydroquinolines
Scheme 4. Substrate Scope of the One-Pot Tandem
Dehydrative Aza-Annulation−Reduction Yielding
Tetrahydroquinolines
a
b
c
d
Reaction conditions: cf. Scheme 4. Isolated yield. dr >20:1. dr =
1
10:1, ratio determined by H NMR.
a
Reaction conditions: amide (1.0 equiv), 2-F-Pyr. (1.2 equiv),
CH2Cl2 (0.2 M), then, −78 °C, Tf2O (1.1 equiv), 5 min, then 0
2d also reacted smoothly to afford 6u in 83% yield. The lower
yield of 76% (6v) obtained from the reaction of p-
chloromethylstyrene (2e) might reflect the electron-with-
drawing inductive effect of the chloromethyl group. The
reductive annulations with vinylogous styrene (2f), cyclohexa-
1,3-diene (2g), methylenecyclohexane (2h), and isobutene
(2i) afforded the desired products 6w−z in good yields (80−
84%). The reaction of norbornene (2j) furnished the complex
ring system 6aa in 75% yield. More intriguingly, simple alkenes
such as hex-1-ene (2k) also reacted to give 6ab in a respectable
yield of 61%. In this case, the minor trans-diastereomer became
°C, 10 min; alkene (1.2 equiv), 40 °C, 2 h, then 0 °C, NaBH4 (1.5
b
equiv), MeOH, rt, 2 h. See the Supporting Information for the list of
c
d
amides. Isolated yields. dr >20:1.
stereochemistry for the major diastereomer of our reaction.
The cis-selectivity implies a trans-attack of a hydride, namely,
from the face opposite to the phenyl group in 3,4-
dihydroquinoline 3a, which avoids steric hindrance.
The substrate scope was investigated by examining both the
acyl and N-aryl moieties of amides. As can be seen from
Scheme 4, N-phenylbenzamide derivatives bearing either an
electron-donating or an electron-withdrawing group at the
para-position of either the benzoyl moiety or the N-phenyl ring
reacted smoothly to yield the corresponding products 6b−l in
78−94% yields. Interestingly, tetrahydroquinolines 6m−p were
prepared in excellent yields (91−94%) from aliphatic amides.
To take advantage of the good chemoselectivity of the
reaction, annulation reactions of functionalized N-arylamides
were investigated. Subjecting bromoanilide 1u to reaction with
styrene afforded 6q in 82% yield. The one-pot reductive
1
observable in the H NMR (dr = 10:1).
Next, we envisaged a two-step construction of a bis-
quinoline ring system. Thus, subjecting 6q to Pd-catalyzed
Buchwald−Hartwig reaction18 afforded 7a smoothly in almost
quantitative yield (Scheme 6, a). It is remarkable that, starting
from simple materials, this pentacyclic compound was built in
just two steps and with an overall yield of 82%. Alternatively,
upon treatment with sodium hydride, 6r was converted to the
tricyclic lactam 7b in 80% yield (Scheme 6, b). Moreover,
when 4-chloro-N-phenylbutanamide 1x was employed as a
C
DOI: 10.1021/acs.orglett.9b00233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
haloalkyl-substituted quinoline derivative 4e was prepared in
good yield.
Scheme 6. Two-Step (a, b) and One-Pot (c) Construction of
Tricyclic Systems from Secondary N-Arylamides
In summary, the first intermolecular dehydrative [4 + 2] aza-
annulation of secondary N-arylamides with alkenes has been
achieved. The methodology displayed wide scope for both
amide and alkene partners allowing the efficient one-pot,
divergent construction of a broad array of substituted 3,4-
dihydroquinolines, tetrahydroquinolines, quinolines, and re-
lated polycyclic heterocycles. Taking advantage of the mild
reaction conditions, good regio- and chemoselectivity, and
good functional group tolerance, annulation products were
further elaborated into diverse polycyclic heterocycles in one-
pot reactions (tandem annulation and reductive cyclization)
from amides.
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.9b00233.
substrate, the reductive annulation proceeded in tandem with
cyclization to produce the tricyclic system 7c directly in 91%
yield (Scheme 6, c). Similarly, the one-pot tandem reaction of
5-chloro-N-phenylpentanamide (1y) afforded the hexahydro-
1H-pyrido[1,2-a]quinoline 7d in 92% yield. To our delight,
electron-deficient p-bromostyrene (2l) also served as an
effective nucleophilic partner in the tandem reaction with 1y,
producing the tetracyclic compound 7e in 83% yield.
Finally, we addressed the synthesis of quinolines. For this
purpose, a one-pot aza-annulation reaction of an N-arylamide
with an alkene and in situ oxidation of the resulting 3,4-
dihydroquinoline was envisaged, and 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) was selected as a mild oxidant. By
employing 2 equiv of DDQ, the desired one-pot reaction of 1b
with styrene (2a) proceeded smoothly to afford quinoline 4a
in 86% yield (Scheme 7). With p-phenylstyrene (2b) as the
Experimental details, including procedures, syntheses,
and characterization of new products; 1H and 13C NMR
spectra (PDF)
Accession Codes
CCDC 1855805 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pqhuang@xmu.edu.cn.
ORCID
Scheme 7. One-Pot Tandem Dehydrative Aza-Annulation−
Oxidation Yielding Quinolines
Pei-Qiang Huang: 0000-0003-3230-0457
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support provided by the National
Natural Science Foundation of China (21332007 and
21472153), the National Key R&D Program of China (grant
No. 2017YFA0207302), and the Program for Changjiang
Scholars and Innovative Research Team in University
(PCSIRT) of Ministry of Education. We thank Dr. Jian-
Liang Ye for assistance in interpreting the NOESY spectrum.
a
Reaction conditions: amide (1.0 equiv), 2-F-Pyr (1.2 equiv), CH2Cl2
(0.2 M), then, −78 °C, Tf2O (1.1 equiv), 5 min, then 0 °C, 10 min;
b
DEDICATION
alkene (1.2 equiv), 40 °C, 2 h, then 0 °C, DDQ, rt, 2 h. See the
■
c
Supporting Information for the list of amides. Isolated yields.
In honor of the 120th birthday of the late Professor Dr. Ming-
Long Huang.
olefin partner, the reaction afforded 4b in 77% yield. The one-
pot reaction also displayed good chemoselectivity and
functional group tolerance. As can be expected from our
previous results, not only halo groups in the amide moiety but
also an acetoxy group in the olefin moiety survive the reaction.
Ketoamide derivative 1g reacted selectively at the amide group
to give keto-quinoline derivative 4d in 62% yield. Similarly, ω-
REFERENCES
■
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257.
(2) For a powerful aza-[3 + 3] annulation reaction developed by
Hsung, see: (a) Buchanan, G. S.; Feltenberger, J. B.; Hsung, R. P.
Curr. Org. Synth. 2010, 7, 363. (b) Gerasyuto, A. I.; Ma, Z.-X.;
Buchanan, G. S.; Hsung, R. P. Beilstein J. Org. Chem. 2013, 9, 1170.
D
DOI: 10.1021/acs.orglett.9b00233
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) Ghosez’s [2 + 2] cycloaddition of alkenes with keteniminium
ions generated in situ from tert-amides has been established as a
standard method for the synthesis of cyclobutanones: (a) Falmagne,
J.-B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L. Angew. Chem., Int.
Ed. Engl. 1981, 20, 879. For a recent application, see: (b) Schmid,
M.; Grossmann, A. S.; Wurst, K.; Magauer, T. J. Am. Chem. Soc. 2018,
140, 8444.
(c) Dai, X.; Cheng, C.; Ding, C.; Yao, Q.; Zhang, A. Synlett 2008,
2008, 2989. (d) Liang, Y.; Jiang, X.; Yu, Z.-X. Org. Lett. 2009, 11,
5302. (e) Liu, G.-S.; Yao, Y.-S.; Xu, P.; Wang, S.; Yao, Z.-J. Chem. -
Asian J. 2010, 5, 1382.
(9) (a) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc.
2007, 129, 10096. (b) Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan,
Z.-H. Chem. Commun. 2012, 48, 8105. (c) Gilmore, C. D.; Allan, K.
M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558. (d) Wu, J.-C.; Xu,
W.-B.; Yu, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015, 137, 9489.
(10) (a) See ref 9a. (b) Kong, L.; Yu, S.; Zhou, X.; Li, X. Org. Lett.
2016, 18, 588. (c) Li, L.-H.; Niu, Z.-J.; Liang, Y.-M. Chem. - Eur. J.
2017, 23, 15300. (d) Ye, J.-L.; Zhu, Y.-N.; Geng, H.; Huang, P.-Q. Sci.
China: Chem. 2018, 61, 687.
(11) For a review on the synthesis of quinolines, see: (a) Ramann,
G. A.; Cowen, B. J. Molecules 2016, 21, 986. For selected examples,
see: (b) Sarode, P. B.; Bahekar, S. P.; Chandak, H. S. Tetrahedron Lett.
2016, 57, 5753. (c) Chen, X.; Qiu, S.; Wang, S.; Wang, H.; Zhai, H.
Org. Biomol. Chem. 2017, 15, 6349. (d) Phanindrudu, M.; Wakade, S.
B.; Tiwari, D. K.; Likhar, P. R.; Tiwari, D. K. J. Org. Chem. 2018, 83,
9137. (e) Jiang, W.; Wang, Y.; Niu, P.; Quan, Z.; Su, Y.; Huo, C. Org.
Lett. 2018, 20, 4649. (f) Ahmed, W.; Zhang, S.; Yu, X. Q.; Yamamoto,
Y.; Bao, M. Green Chem. 2018, 20, 261. See also refs 8−10.
(12) For recent reviews on the synthesis of tetrahydroquinolines,
(4) For reviews, see: (a) Huang, P.-Q. Huaxue Xuebao 2018, 76,
357. (b) Kaiser, D.; Bauer, A.; Lemmerer, M.; Maulide, N. Chem. Soc.
Rev. 2018, 47, 7899. (c) Sato, T.; Yoritate, M.; Tajima, H.; Chida, N.
Org. Biomol. Chem. 2018, 16, 3864. (d) Kaiser, D.; Maulide, N. J. Org.
Chem. 2016, 81, 4421. (e) Sato, T.; Chida, N. J. Yuki Gosei Kagaku
Kyokaishi 2016, 74, 599. (f) Ruider, S. A.; Maulide, N. Angew. Chem.,
Int. Ed. 2015, 54, 13856. (g) Pace, V.; Holzer, W.; Olofsson, B. Adv.
Synth. Catal. 2014, 356, 3697. (h) Sato, T.; Chida, N. Org. Biomol.
Chem. 2014, 12, 3147. (i) Pace, V.; Holzer, W. Aust. J. Chem. 2013,
66, 507. (j) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96.
(5) For selected examples on reductive alkylation of amides, see:
(a) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew.
Chem., Int. Ed. 2010, 49, 3037. (b) Shirokane, K.; Kurosaki, Y.; Sato,
T.; Chida, N. Angew. Chem., Int. Ed. 2010, 49, 6369. (c) Vincent, G.;
Guillot, R.; Kouklovsky, C. Angew. Chem., Int. Ed. 2011, 50, 1350.
(d) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4,
228. (e) Xiao, K.-J.; Wang, A.-E; Huang, P.-Q. Angew. Chem., Int. Ed.
2012, 51, 8314. (f) Jaekel, M.; Qu, J.; Schnitzer, T.; Helmchen, G.
Chem. - Eur. J. 2013, 19, 16746. (g) Shirokane, K.; Wada, T.; Yoritate,
M.; Minamikawa, R.; Takayama, N.; Sato, T.; Chida, N. Angew.
Chem., Int. Ed. 2014, 53, 512. (h) Nakajima, M.; Wada, T.; Yoritate,
M.; Minamikawa, R.; Sato, T.; Chida, N.; Oda, Y.; Shirokane, K.
Chem. - Eur. J. 2014, 20, 17565. (i) White, K. L.; Mewald, M.;
Movassaghi, M. J. Org. Chem. 2015, 80, 7403. (j) Huang, P.-Q.;
Huang, Y.-H.; Geng, H.; Ye, J.-L. Sci. Rep. 2016, 6, 28801. (k) Zheng,
J.-F.; Hu, X.-N.; Xu, Z.; Cai, D.-C.; Shen, T.-L.; Huang, P.-Q. J. Org.
Chem. 2017, 82, 9693. (l) Wang, A.-E; Yu, C.-C.; Chen, T.-T.; Liu, Y.-
P.; Huang, P.-Q. Org. Lett. 2018, 20, 999. (m) Antropow, A. H.;
Garcia, N. R.; White, K. L.; Movassaghi, M. Org. Lett. 2018, 20, 3647.
(n) Yang, Z.-P.; He, Q.; Ye, J.-L.; Huang, P.-Q. Org. Lett. 2018, 20,
4200. (o) Fan, T.; Wang, A.; Li, J.-Q.; Ye, J.-L.; Zheng, X.; Huang, P.-
Q. Angew. Chem., Int. Ed. 2018, 57, 10352.
see: (a) Munoz, G. D.; Dudley, G. B. Org. Prep. Proced. Int. 2015, 47,
̃
́
179. (b) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Chem. Rev.
2011, 111, 7157. For selected recent examples, see: (c) Li, H. Y.;
Horn, J.; Campbell, A.; House, D.; Nelson, A.; Marsden, S. P. Chem.
Commun. 2014, 50, 10222. (d) Xie, M.-S.; Chen, X.-H.; Zhu, Y.; Gao,
B.; Lin, L.-L.; Liu, X.-H.; Feng, X.-M. Angew. Chem., Int. Ed. 2010, 49,
3799.
́
(13) (a) Lopez, A. E. Quinolines: Privileged Scaffolds in Medicinal
Chemistry. In Privileged Scaffolds in Medicinal Chemistry: Design,
̈
Synthesis, Evaluation; Brase, S., Ed.; Royal Society of Chemistry,
London, 2015; Chapter 6. (b) Goli, N.; Mainkar, P. S.; Kotapalli, S.
S.; Ummanni, T. K. R.; Chandrasekhar, S. Bioorg. Med. Chem. Lett.
2017, 27, 1714.
(14) (a) It was noted that 3,4-dihydroquinolines are unstable:
Adam, G.; Andrieux, J.; Plat, M. M. Tetrahedron Lett. 1983, 24, 3609.
For the synthesis of 3,4-dihydroquinolines as salts, see: (b) Cacchi, S.;
Palmieri, G. Tetrahedron 1983, 39, 3373. (c) Moustafa, A. H.; Hitzler,
M. G.; Lutz, M.; Jochims, J. C. Tetrahedron 1997, 53, 625.
(15) (a) Zhu, R.-Y.; Farmer, M. E.; Chen, Y.-Q.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2016, 55, 10578. (b) Liu, Z.; Xu, H.; Wang, G. W.
Beilstein J. Org. Chem. 2018, 14, 430.
(6) For catalytic reductive alkylation of amides, see: (a) Gregory, A.
W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. Chem. - Eur. J.
2015, 21, 111. (b) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015,
17, 1696. (c) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.;
Sato, T.; Chida, N. J. Am. Chem. Soc. 2016, 138, 5246. (d) Huang, P.-
Q.; Ou, W.; Han, F. Chem. Commun. 2016, 52, 11967. (e) Tan, P. W.;
Seayad, J.; Dixon, D. Angew. Chem., Int. Ed. 2016, 55, 13436.
(f) Slagbrand, T.; Kervefors, G.; Tinnis, F.; Adolfsson, H. Adv. Synth.
̈
(16) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(17) (a) Ueda, M.; Kawai, S.; Hayashi, M.; Naito, T.; Miyata, O. J.
Org. Chem. 2010, 75, 914. (b) Tan, Y.-J.; Zhang, Z.; Wang, F.-J.; Wu,
H.-H.; Li, Q.-H. RSC Adv. 2014, 4, 35635.
́
Catal. 2017, 359, 1990. (g) Fuentes de Arriba, A. L.; Lenci, E.;
(18) (a) Marion, N.; Navarro, O.; Mei, J.-G.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (b) Surry, D.
S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
Sonawane, M.; Formery, O.; Dixon, D. Angew. Chem., Int. Ed. 2017,
56, 3655. (h) Xie, L.-G.; Dixon, D. J. Chem. Sci. 2017, 8, 7492.
(i) Trillo, P.; Slagbrand, T.; Tinnis, F.; Adolfsson, H. Chem. Commun.
2017, 53, 9159. (j) Liu, X.-Q.; Hsiao, C.-C.; Guo, L.; Rueping, M.
Org. Lett. 2018, 20, 2976. (k) Ou, W.; Han, F.; Hu, X.-N.; Chen, H.;
Huang, P.-Q. Angew. Chem., Int. Ed. 2018, 57, 11354. (l) Takahashi,
Y.; Yoshii, R.; Sato, T.; Chida, N. Org. Lett. 2018, 20, 5705.
(m) Trillo, P.; Slagbrand, T.; Adolfsson, H. Angew. Chem., Int. Ed.
2018, 57, 12347.
(7) For umpolung of the α-position, see: (a) Tona, V.; de la Torre,
́
A.; Padmanaban, M.; Ruider, S.; Gonzalez, L.; Maulide, N. J. Am.
Chem. Soc. 2016, 138, 8348. (b) Kaiser, D.; de la Torre, A.; Shaaban,
S.; Maulide, N. Angew. Chem., Int. Ed. 2017, 56, 5921. (c) Shaaban, S.;
Tona, V.; Peng, B.; Maulide, N. Angew. Chem., Int. Ed. 2017, 56,
10938. (d) de la Torre, A.; Tona, V.; Maulide, N. Angew. Chem., Int.
Ed. 2017, 56, 12416. (e) de la Torre, A.; Kaiser, D.; Maulide, N. J.
Am. Chem. Soc. 2017, 139, 6578. (f) Kaiser, D.; Teskey, C. J.; Adler,
P.; Maulide, N. J. Am. Chem. Soc. 2017, 139, 16040.
(8) (a) Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N.
J.; Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37, 5679.
(b) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett. 2007, 9, 2003.
E
DOI: 10.1021/acs.orglett.9b00233
Org. Lett. XXXX, XXX, XXX−XXX