Synthesis of 4,5-fused tricyclic quinolines via an acid-promoted intramolecular Friedel-Crafts allenylation of aniline derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.10.010

A novel method for synthesizing 4,5-fused tricyclic quinoline derivatives based on an acid-promoted intramolecular Friedel-Crafts allenylation of anilines. Using aryl group-substituted propargyl alcohol derivatives with a meta-substituted N-Boc aniline unit as substrates, a four-step reaction sequence involving an acid-promoted intramolecular Friedel-Crafts allenylation of anilines, an acid-promoted intramolecular C-N bond formation, deprotection of the Boc group, and air oxidation proceeded in a single pot, producing the corresponding 4,5-fused tricyclic quinoline derivatives in 31-84% yield.

Full text of DOI:10.1016/j.tetlet.2014.10.010

Tetrahedron Letters 55 (2014) 6726–6728
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Synthesis of 4,5-fused tricyclic quinolines via an acid-promoted
intramolecular Friedel–Crafts allenylation of aniline derivatives
⇑
Yuta Suzuki, Tetsuhiro Nemoto, Shun-ichi Nakano, Zengduo Zhao, Yuta Yoshimatsu, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method for synthesizing 4,5-fused tricyclic quinoline derivatives based on an acid-promoted
intramolecular Friedel–Crafts allenylation of anilines. Using aryl group-substituted propargyl alcohol
derivatives with a meta-substituted N-Boc aniline unit as substrates, a four-step reaction sequence
involving an acid-promoted intramolecular Friedel–Crafts allenylation of anilines, an acid-promoted
intramolecular C–N bond formation, deprotection of the Boc group, and air oxidation proceeded in a sin-
gle pot, producing the corresponding 4,5-fused tricyclic quinoline derivatives in 31–84% yield.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 29 August 2014
Revised 30 September 2014
Accepted 3 October 2014
Available online 13 October 2014
Keywords:
Cascade reaction
Friedel–Crafts reaction
Heterocycle
Quinoline
Synthetic method
Functionalized quinoline rings are ubiquitous in a wide variety
of biologically active natural products and pharmaceuticals. An
efficient synthetic method for quinoline derivatives is therefore
in high demand in the fields of organic synthesis and medicinal
chemistry.1 The 4,5-fused tricyclic quinoline framework is present
in various bioactive molecules, such as kuanoniamines (cytotoxic
activity),2a and exatecan (topoisomerase I inhibitor),2b and is an
attractive structural motif for scaffolds in drug design (Fig. 1). Effi-
cient construction of a 4,5-fused tricyclic quinoline skeleton, how-
ever, remains a challenging task in organic synthesis.3
delocalized cationic species V, and subsequent deprotection and
oxidation would produce the corresponding 4,5-fused tricyclic
quinoline derivatives (Scheme 1(b)). Herein, we report a novel
method for synthesizing 4,5-fused tricyclic quinolines based on
an acid-promoted intramolecular Friedel–Crafts allenylation of
anilines.
Our investigation began with the model substrate 1a (Table 1).
We first examined the reaction using 3 equiv of trifluoroacetic acid
(TFA) as an acid promoter in CH2Cl2 (0.05 M) at room temperature.
Substrate 1a was gradually consumed, and the desired product 2a
was obtained in 12% yield, accompanied by the isolation of N-Boc
dihydroquinoline derivative 3a in 50% yield (entry 1). The amount
of TFA remarkably affected the reactivity (entries 1–4). When the
reaction was performed using 15 equiv of TFA in CH2Cl2 under
air, the desired cascade reaction proceeded smoothly to give 4,5-
We recently focused on the development of a novel cascade
process for synthesizing fused-polycyclic indoles4 and hydroquin-
olines5 based on an acid-promoted intramolecular Friedel–
Crafts-type reaction using phenol derivatives as substrates. When
aryl group-substituted propargyl alcohol derivatives with
a
para-substituted phenol unit I were utilized as substrates, an intra-
molecular ipso-Friedel–Crafts allenylation of phenols proceeded in
the presence of an acid promoter, providing aryl group-substituted
allenyl spirocyclohexadienones II that could be transformed into
various fused heterocycles via sequential bond forming/cleaving
reactions (Scheme 1(a)). The present reaction mode can be
extended to the synthesis of 2,3-fused bicyclic ortho-allenyl ani-
lines IV using meta-substituted aniline derivatives III as sub-
strates.6 We hypothesized that an acid-promoted six-membered
ring formation would proceed sequentially from IV through a
Figure 1. Examples of bioactive molecules with a 4,5-fused tricyclic quinoline
skeleton.
⇑
Corresponding author. Tel./fax: +81 43 226 2920.
E-mail address: y-hamada@faculty.chiba-u.jp (Y. Hamada).
http://dx.doi.org/10.1016/j.tetlet.2014.10.010
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Suzuki et al. / Tetrahedron Letters 55 (2014) 6726–6728
6727
Scheme 1. Background and reaction design of this work.
Table 1
Optimization of the reaction conditions
Entry
Acid (equiv)
Concd (M)
Time (h)
Yielda (%)
Scheme 2. Experiments for elucidating the reaction pathway.
1
2
3
4
5
6
7
TFA (3)
TFA (8)
0.05
0.05
0.05
0.05
0.1
16
16
3
3
3
12 (50)b
60
TFA (15)
TFA (25)
TFA (15)
TFA (15)
TsOHÁH2O (3)
76 (75)c
75
fused tricyclic quinoline 2a in 76% yield (75% isolated yield) (entry
4). The results were less satisfactory, however, when the reaction
concentration was either increased or decreased (entries 5 and
6). The use of more acidic TsOHÁH2O resulted in a messy reaction
(entry 7). Thus, we selected the conditions in entry 3 as optimum
for this cascade reaction.
After determining the optimal reaction conditions, we investi-
gated the scope and limitations of the developed cascade process
(Table 2).7 In addition to model substrate 1a (entry 1), aryl
67
74
Messy
0.025
0.05
12
3
Determined by 1H NMR analysis of the crude sample. Triphenylmethane was
used as an internal standard.
a
b
Isolated yield of 3a.
Isolated yield of 2a.
c
Table 2
Substrate scope
Entry
Product
X
Y
R1
R2
R3
Time (h)
Yielda (%)
1
2
3
2a
2b
2c
2d
2e
2f
2g
2h
2i
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
C(CO2Me)2
NTs
Me
Me
Me
Me
Me
Me
Me
Me
OMe
F
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
3
3
3
18
18
4
3
3
75
53
62
60
69
84
79
82
75
53
31
Me
OMe
Cl
Br
H
H
H
H
H
4b
5b
6
H
OMe
Me
H
H
H
7
8
9
3
6
18
10
2j
2k
H
H
11b
Me
H
H
a
Isolated yield.
Reaction concentration = 0.025 M.
b

6728
Y. Suzuki et al. / Tetrahedron Letters 55 (2014) 6726–6728
Scheme 3. Proposed reaction mechanism.
group-substituted propargyl alcohol derivatives with an electron-
donating group or an electron-withdrawing group on the ortho-
position (1b–e), meta-position (1f and 1g), or para-position (1h)
of the aromatic ring were applicable to this cascade process and
4,5-fused tricyclic quinoline derivatives 2b–h were obtained in
53–84% yield (entries 2–9). Introduction of a methoxy group (1i)
or fluorine group (1j) on the anilinic aromatic ring was also toler-
ant to this reaction, affording the corresponding products 2i and 2j
in 75% yield and 53% yield, respectively. Furthermore, when N-Ts
tethered compound 1k was used as a substrate, the desired prod-
uct 2k was obtained in 31% yield.8
To gain insight into the reaction mechanism of this cascade pro-
cess, we performed the following experiments (Scheme 2). When
compound 1a was reacted with 8 equiv of TFA in CH2Cl2 at 0 °C
for 15 min, ortho-allenyl aniline derivative 4a was obtained in
30% yield. Both 3a and 4a were transformed into 2a under the opti-
mal reaction conditions in 88% yield and 85% yield, respectively.
Moreover, when 4a was treated with 3 equiv of TFA in CH2Cl2 for
3 h at room temperature, 3a was isolated in 43% yield. These exper-
imental data led us to propose a reaction pathway for this cascade
reaction (Scheme 3).
First, substrate 1a reacts with TFA to give propargyl cation
intermediate A. An intramolecular Friedel–Crafts allenylation of
the meta-substituted aniline proceeds, providing 2,3-fused bicyclic
ortho-allenyl aniline derivative 4a. After the generation of delocal-
ized cationic species B by protonation of the allene, the six-mem-
bered ring formation occurs sequentially to give N-Boc
dihydroquinoline derivative 3a. Finally, deprotection of the N-Boc
group in the presence of TFA, followed by air oxidation of the dihy-
droquinoline unit,9 affords 4,5-fused tricyclic quinoline 2a.
In conclusion, we developed a novel synthetic method for
4,5-fused tricyclic quinoline derivatives based on an acid-pro-
moted intramolecular Friedel–Crafts allenylation of anilines. Using
Acknowledgments
This work was supported by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan, JSPS Research Fellowship for Young Scien-
tists (Y.S.), and Chiba University.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
010.
References and notes
1. For reviews on the synthesis of quinolines, see: (a) Jones, G. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, A. R., Eds.; Pergamon: New York,
1984; Vol. 2, p 395. Part 2A; (b) Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.;
Panchal, S. N.; Patel, H. D. RSC Adv. 2014, 4, 24463.
2. (a) Carroll, A. R.; Scheuer, P. J. J. Org. Chem. 1990, 55, 4426; (b) Pommier, Y. Nat.
Rev. Cancer 2006, 6, 789.
3. For examples of the stepwise construction of 4,5-fused tricyclic quinoline
skeletons, see: (a) Bishop, M. J.; Ciufolini, M. A. J. Am. Chem. Soc. 1992, 114,
10081; (b) Ciufolini, M. A.; Shen, Y.-C.; Bishop, M. J. J. Am. Chem. Soc. 1995, 117,
12460; (c) Gellerman, G.; Rudi, A.; Kashman, Y. Tetrahedron Lett. 1992, 33, 5577;
(d) Kitahara, Y.; Mochii, M.; Mori, M.; Kubo, A. Tetrahedron Lett. 2000, 41, 1481.
4. (a) Yokosaka, T.; Nemoto, T.; Hamada, Y. Chem. Commun. 2012, 5431; (b)
Yokosaka, T.; Nakayama, H.; Nemoto, T.; Hamada, Y. Org. Lett. 2013, 15, 2978; (c)
Yokosaka, T.; Kanehira, T.; Nakayama, H.; Nemoto, T.; Hamada, Y. Tetrahedron
2014, 70, 2151.
5. (a) Yokosaka, T.; Shiga, N.; Nemoto, T.; Hamada, Y. J. Org. Chem. 2014, 79, 3866;
(b) Nakano, S.; Kakugawa, K.; Nemoto, T.; Hamada, Y. Adv. Synth. Catal. 2014,
356, 2088.
6. For examples of acid-promoted Friedel–Crafts allenylation of aromatic rings,
see: (a) Ishikawa, T.; Okano, M.; Aikawa, T.; Saito, S. J. Org. Chem. 2001, 66, 4635;
(b) Ishikawa, T.; Manabe, S.; Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004, 6,
2361; (c) Huang, W.; Shen, Q.; Wang, J.; Zhou, X. J. Org. Chem. 2008, 73, 1586.
7. General procedure (Table 2, entry 1). To a stirred solution of 1a (48.5 mg,
0.0952 mmol) in CH2Cl2 (1.90 mL) at room temperature was added
trifluoroacetic acid (0.106 mL, 1.43 mmol), and the resulting solution was
stirred under air at the same temperature. After 3 h, the reaction was quenched
with sat. aq NaHCO3 at 0 °C and the mixture was extracted with AcOEt. The
organic layer was washed with brine, dried over Na2SO4, and then concentrated
in vacuo. The obtained residue was purified by flash column chromatography
(SiO2, hexane/AcOEt = 5/1) to give 2a (26.8 mg, 75% yield) as white solid.
8. When a non-substituted propargyl ether derivative was used as a substrate, only
deprotection of the Boc group occurred under the optimized reaction conditions.
This result indicates that an aryl substituent is necessary for the generation of
the cation intermediate.
aryl group-substituted propargyl alcohol derivatives with
a
meta-substituted N-Boc aniline unit as substrates, a four-step
reaction sequence involving an acid-promoted intramolecular
Friedel–Crafts allenylation of anilines, an acid-promoted intramo-
lecular C–N bond formation, deprotection of the Boc group, and
air oxidation proceeded in the presence of TFA, producing the cor-
responding 4,5-fused tricyclic quinoline derivatives in 31–84%
yield in a single pot process. To the best of our knowledge, this is
the first example of a cascade reaction for synthesizing 4,5-fused
tricyclic quinoline derivatives from aryl group-substituted propar-
gyl alcohol derivatives with a meta-substituted aniline unit. Fur-
ther studies are in progress to examine the pharmacological
activity of these quinoline derivatives.
9. When the reaction was performed under an argon atmosphere, intermediate C
was detected in the NMR analysis of the crude sample. This intermediate was
transformed into 2a during the silica gel column purification.