Regio- and Diastereoselective Three-Component Reactions via Trapping of Ammonium Ylides with N-Alkylquinolinium Salts: Synthesis of Multisubstituted Tetra- and Dihydroquinoline Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b01664

Pd(II)-catalyzed three-component reactions via trapping of ammonium ylides with N-alkylquinolinium salts are reported. These reactions provided polyfunctional polycyclic tetrahydroquinolines or 4-substituted 1,4-dihydroquinolines in excellent yields (89-99% and 89-98%, respectively) with high regioselectivities and moderate to good diastereoselectivities (up to 95:5 dr) under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b01664

Letter
pubs.acs.org/OrgLett
Regio- and Diastereoselective Three-Component Reactions via
Trapping of Ammonium Ylides with N‑Alkylquinolinium Salts:
Synthesis of Multisubstituted Tetra- and Dihydroquinoline
Derivatives
Zhenghui Kang,† Dan Zhang,† and Wenhao Hu*
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular
Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
S
* Supporting Information
ABSTRACT: Pd(II)-catalyzed three-component reactions via
trapping of ammonium ylides with N-alkylquinolinium salts
are reported. These reactions provided polyfunctional
polycyclic tetrahydroquinolines or 4-substituted 1,4-dihydro-
quinolines in excellent yields (89−99% and 89−98%,
respectively) with high regioselectivities and moderate to
good diastereoselectivities (up to 95:5 dr) under mild reaction
conditions.
itrogen-containing heterocycles are widespread in natural
products and constitute core motifs in various bio-
display cytotoxicity against cultured lymphocytic leukemia cells
and insecticidal activity.6 Considering the significance of these
scaffolds, the continued development of efficient methodologies
to allow the synthesis of structurally diverse derivatives is of
particular importance for drug discovery.
N
logically active pharmaceutical and agrochemical products as
well as in materials science.1 Hydrogenated (iso)quinoline
derivatives, such as dihydro- and tetrahydroquinolines, are
particularly important core constituents within this broad family
owing to their pharmacological activities.1c For example (Figure
1), martinellic acid (a) was identified as a nonpeptide
Among the reported methods, nucleophilic addition of N-
activated quinolines has proved to be one of most
straightforward and versatile strategies to afford dihydro- and
tetrahydroquinoline derivatives (Scheme 1, a).7 However, the
regioselectivity of this addition may be critical because both the
C-2 and C-4 positions of N-activated quinolines are active sites.
Generally, nucleophilic additions favor the more electron-
deficient C-2 position8a of N-substituted quinolinium salts,8 but
mixtures of regioisomers have also been observed in many
cases.9 To achieve regioselective additions to the C-4 position,
an electron-withdrawing group (EWG) at the C-3 position is
required.10 Regioselective C-4 additions to quinolinium salts
without a blocked or induced substituent at the C-2 or C-3
positions are rare.11 Moreover, the low-face discrimination of
aromatic electrophiles creates another challenge in the
diastereocontrol over two contiguous stereogenic centers.10b
To accomplish nondirect regioselective C-4 additions to
quinolinium salts, we turned our attention to transient
nucleophilic intermediates with unique reactivities. Onium
ylides generated in situ from diazo compounds and alcohols/
anilines are transient nucleophilic intermediates and can be
trapped by a wide scope of electrophiles with polarized
electron-deficient double bonds (CO, CN, CC, etc.)
Figure 1. Select examples of biologically active tetrahydroquinolines.
bradykinin receptor antagonist,2 torcetrapib (b) has been
implemented in clinical trials as an anti-hypercholesterolemia
drug,3 and quinocarmycin analogue DX-52-1 (c) is an inhibitor
of epithelial cell migration.4 On the other hand, bridgehead
diazepine cores are also present in naturally occurring and
synthetic biologically active heterocycles,5 including ecteinasci-
din 743 (d), which exhibits good activity against soft tissue
sarcomas and ovarian cancer, and communesin alkaloids (e−h)
Received: June 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01664
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Organic Letters
Letter
Scheme 1. Nucleophilic Dearomatization of Quinolinium
Salts for the Synthesis of Partially Hydrogenated Quinoline
Derivatives
Table 1. Substrate Scope of Diazo Compounds 1 and
a
Anilines 2
b
c
entry
Ar1, Ar2
yield (%)
dr
1
2
3
4
5
6
7
8
9
Ph, p-BrC6H4
4b: 96
4c: 93
4d: 92
4e: 97
4f: 97
4g: 93
4h: 97
4i:96
70:30
62:38
71:29
78:22
81:19
81:19
82:18
75:25
76:24
72:28
p-Tol, p-BrC6H4
p-FC6H4, p-BrC6H4
p-BrC6H4, p-BrC6H4
m-BrC6H4, p-BrC6H4
Ph, p-Tol
Ph, p-FC6H4
Ph, m-BrC6H4
Ph, 3,4-OMeC6H3
Ph, 3,4,5-OMe C6H2
4j: 92
4k: 94
10
a
Unless otherwise indicated, all reactions were conducted on a 0.2
b
mmol scale for 3, 1/2/3 = 1.5:1.5:1. Combined yields of anti- and
syn-isomers after column chromatography isolation. Syn/anti,
determined by crude H NMR.
c
1
phenyl ring were evaluated; the reaction afforded three-
component products 4 generally in excellent yields (92−
97%) with high regioselectivities and moderate diastereose-
lectivities (62:38−81:19) (entries 1−5). Various substituted
anilines were also investigated. Anilines bearing halogen or
methyl substituents on the para- or meta-positions were
tolerated and provided the desired products in excellent yields
(93−96%) and acceptable diastereoselectivities (75:25−81:19)
(entries 6−8). Di- or trisubstituted anilines with substituents at
the meta- and para-positions were also compatible (entries 9
and 10).18
With respect to the electrophiles, various substituted
quinolinium salts from readily available quinolines were
examined (Table 2). N-Benzylquinolinium salts bearing various
substituents at the C5, C6, and C7 positions, regardless of the
electronic properties, were found to be well-tolerated and gave
the corresponding products 4 in up to 98% yields with
moderate dr value (entries 1−6). N-Methylquinolinium salts
with 6-CO2Et or 8-Me also worked and provided the products
through nucleophilic addition (Scheme 1b). Based on this
trapping process, our group has developed a series of novel
three-component reactions.12,13 In view of the unique
reactivities of these highly reactive ylide intermediates, we
envisioned that they could be utilized as efficient nucleophiles
in the dearomatization of cationic quinolinium ions, affording
an attractive method to construct multifunctional di- and
tetrahydroquinoline derivatives under mild conditions (Scheme
1b). However, owing to the short half-life of transient ylides14
as well as the low concentration of quinolinium salts in organic
solvents, trapping onium ylides with quinolinium salts is
challenging not only in the chemoselectivities of 1,2-proton
transfer and nucleophilic addition of ylides but also in the regio-
and stereocontrol of the desired trapping process.
Herein, we describe a palladium-catalyzed three-component
reaction of diazo compounds, anilines, and quinolinium salts
with regiospecific C-4 addition (Scheme 1c). In order to avoid
the two-component side reaction of anilines and quinolinium
ions, bench-stable N-alkylquinolinium salts were chosen as
substrates. Notably, when N-alkylquinolinium salts without a
substituent at the C-3 position were employed, the reaction
underwent an uncommon regioselective 1,4-conjugate addi-
tion/intramolecular cyclization sequence to give bridged
medium-ring 1,3-benzodiazepine derivatives. Actually, the
construction of medium-ring heterocycles, especially bridged
heterocycles, remains a significant synthetic challenge in
modern organic synthesis owing to entropy and ring strain.15
Initially, the reaction using quinolinium salt 3a as a substrate
did not lead to any detectable desired product 4a, probably due
to the poor solubility of 3a in CH2Cl2. After optimizations, the
optimal conditions involved the use of [PdCl(η3-C3H5)]2 as a
catalyst12c,13b,16 and the more lipophilic quinolinium salt 3b as
substrate in CH2Cl2 at 25 °C, leading to 4b in 96% yield with
70:30 dr.17
Table 2. Substrate Scope of Quinolinium Salts 3 with 1a and
a
2a
b
c
entry
3/R1
R2/X
yield (%)
dr
1
2
3
4
5
6
7
8
3c/6-Br
Bn/Br
Bn/Br
Bn/Br
Bn/Br
Bn/Br
Bn/Br
Me/I
4l: 97
4m: 92
4n: 97
4o: 98
4p: 98
4q: 96
4r: 99
4s: 96
60:40
66:34
73:27
56:44
61:39
63:37
58:42
69:31
3d/7-Br
3e/6-CO2Et
3f/6-NO2
3g/5-Br
3h/6-Me
3i/6-CO2Et
3j/8-Me
We first evaluated the substrate scope of this transformation
(Table 1). A series of substituted diazo compounds with
electron-withdrawing or electron-donating groups on the
Me/I
a−c
See Table 1.
B
DOI: 10.1021/acs.orglett.7b01664
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4r or 4s in excellent yields with selectivities similar to those of
their N-Bn counterparts (entries 7 and 8). Notably, N-Bn-
quinolinium salt 3k (vide infra) containing a 3-CO2Et
substituent provided three-component product 5a without
further intramolecular annulation in 93% yield with 72:28 dr
under the standard reaction conditions (see the SI).
Scheme 2. Proposed Mechanism
To get high diastereoselectivity of reaction using N-Bn-3-
ethoxylcarbonylquinolinium salt 3k as a substrate, extensive
optimizations of reaction conditions were conducted,17 and
nonanulated product 5a was obtained in 96% yield with a
remarkably enhanced dr of 93:7 (Table 3, entry 1). The scope
Table 3. Substrate Scope of Three-Component Reaction of 1
a
and 2 with 3k
b
c
entry
Ar1
Ar2
yield (%)
dr
Scheme 3. Plausible Transition State
1
2
Ph
Ph
Ph
Ph
Ph
p-BrC6H4
p-FC6H4
p-Tol
5a: 96
5b: 97
5c: 96
5d: 97
5e: 98
5f: 97
5g: 96
5h: 97
5i: 94
5j: 89
93:7
93:7
92:8
90:10
91:9
93:7
91:9
93:7
95:5
48:52
3
4
PMP
5
Ph
6
p-BrC6H4
p-ClC6H4
p-FC6H4
m-OMeC6H4
PMP
p-BrC6H4
p-BrC6H4
p-BrC6H4
p-BrC6H4
p-BrC6H4
7
8
9
10
a−c
See Table 1.
that the H-bond between the aniline N−H functionality of
ammonium ylides and bromide of quinolinium salts, as well as a
π−π stacking10b,20 between the aromatic ring of ammonium
ylides and that of quinolinium ion, could direct the ylide
nucleophilic site to be closer to the C4-position than the C2-
position of the quinolinium ion. These interactions result in the
more stable transition state TS-I, which would lead to the syn
isomers.
In conclusion, we developed a regiospecific 1,4-conjugate
addition of readily available N-alkylquinolinium salts with
transient ammonium ylides under mild and practical conditions.
Multifunctional bridged tetrahydroquinolines and dihydroqui-
nolines derivatives were obtained from simple starting materials
in excellent yields with moderate to high diastereoselectivities.
This methodology provides a facile access to structurally
divergent hydrogenated quinoline derivatives, which is of great
potential for the establishment of compound libraries for drug
discovery. Exploration of the asymmetric version of this
transformation is currently underway in our laboratory.
of anilines 2 and diazo compounds 1 was then explored.
Anilines with various substituents at the para- and meta-
positions also led to 5b−e in excellent yields (96−98%) with
good dr (entries 2−5). Substituted diazo compounds also
proceeded well and provided 5f−i in 94−97% yields with up to
95:5 dr (entries 6−9), while that with a methoxy group at the
para-position of the phenyl ring resulted in a considerable
decrease in the dr value (48:52) (entry 10).19
A mechanism for the three-component reaction was
proposed (Scheme 2) according to the control experiments
(see the SI) and previous investigations.12,13 First, [PdCl(η3-
C3H5)]2 decomposes diazo compounds 1 to form electrophilic
palladium carbene intermediates I, which react with anilines 2
to give palladium-associated ammonium ylide intermediates II
and their enolate counterparts III. Then the resulting ylide
intermediates II or III are immediately trapped by quinolinium
salts 3 via 1,4-conjugate addition to provide 1,4-dihydroquino-
lines 5, along with HX (X = Br, I), and regenerate the
palladium catalyst. At last, the enamine moiety of 1,4-
dihydroquinolines 5 (R2 = H) are further protonated by the
released HX to form iminium intermediates IV, which undergo
intramolecular nucleophilic cyclization involving the amino
group to afford the bridged product 4. Notably, 1,4-
dihydroquinolines 5 (R2 = CO2Et) cannot undergo further
intramolecular annulation due to the stabilization of the
enamine moiety by the electron-withdrawing ester group.
The excellent regioselective outcome of this trapping process,
as well as the diastereoselective control, could be rationalized
according to the models shown in Scheme 3. It was proposed
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.7b01664.
Crystallographic data for syn-4p (CIF)
Crystallographic data for anti-4p (CIF)
Crystallographic data for syn-5a (CIF)
Crystallographic data for anti-5a (CIF)
Experimental procedures and characterization data for
new compounds including NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b01664
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
W. H. J. Am. Chem. Soc. 2011, 133, 8428. (c) Zhang, D.; Zhou, J.; Xia,
F.; Kang, Z.; Hu, W. Nat. Commun. 2015, 6, 5801. See reviews:
(d) Guo, X.; Hu, W. Acc. Chem. Res. 2013, 46, 2427. (e) Zhang, D.;
Hu, W. Chem. Rec. 2017, DOI: 10.1002/tcr.201600124.
(13) For MCRs via the trapping of zwitterionic intermediates, see:
(a) Qiu, H.; Li, M.; Jiang, L.-Q.; Lv, F.-P.; Zan, L.; Zhai, C.-W.; Doyle,
M. P.; Hu, W.-H. Nat. Chem. 2012, 4, 733. (b) Zhang, D.; Qiu, H.;
Jiang, L.; Lv, F.; Ma, C.; Hu, W. Angew. Chem., Int. Ed. 2013, 52,
13356. (c) Jia, S.; Xing, D.; Zhang, D.; Hu, W. Angew. Chem., Int. Ed.
2014, 53, 13098.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: whu@chem.ecnu.edu.cn.
ORCID
Dan Zhang: 0000-0003-0200-8527
Wenhao Hu: 0000-0002-1461-3671
Author Contributions
†Z.K. and D.Z. contributed equally.
(14) Xue, J.; Luk, H. L.; Platz, M. S. J. Am. Chem. Soc. 2011, 133,
1763.
Notes
(15) (a) Mondal, S.; Paira, R.; Maity, A.; Naskar, S.; Sahu, K. B.;
Hazra, A.; Saha, P.; Banerjee, S.; Mondal, N. B. Tetrahedron Lett. 2011,
52, 4697−4700. (b) Luo, C. S.; Huang, Y. J. Am. Chem. Soc. 2013, 135,
8193.
(16) (a) Xiao, Q.; Zhang, Y.; Wang, J. B. Acc. Chem. Res. 2013, 46,
236. (b) Xia, Y.; Zhang, Y.; Wang, J. B. ACS Catal. 2013, 3, 2586.
(17) For the detailed optimization of reaction conditions, see the
Supporting Information.
(18) For additional examples (4t−x), see the Supporting
Information.
(19) For additional examples (5k−n), see the Supporting
Information.
(20) (a) Jones, G. B. Tetrahedron 2001, 57, 7999. (b) Li, Z.;
Mukhopadhyay, S.; Jang, S.-H.; Bredas, J.-L.; Jen, A. K. Y. J. Am. Chem.
Soc. 2015, 137, 11920. (c) Buisine, E.; de Villiers, K.; Egan, T. J.; Biot,
C. J. Am. Chem. Soc. 2006, 128, 12122. (d) Kawabata, T.; Nagato, M.;
Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169. (e) Birman, V.
B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from NSFC (21332003).
■
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Org. Lett. XXXX, XXX, XXX−XXX