Synthesis of 2-alkoxy(aroxy)-3-substituted Quinolines by DABCO-promoted cyclization of o-alkynylaryl isocyanides

Article abstract of DOI:10.1021/jo1017525

Diversified 2-alkoxy- and 2-aroxy-3-substituted quinolines were synthesized from o-alkynylaryl isocyanides and alcohols and phenols promoted by DABCO, respectively. The reaction was initiated by nucleophilic addition of DABCO to isocyanide and subsequent

Full text of DOI:10.1021/jo1017525

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many others.5 Despite the great importance of 2-alkoxy-
Synthesis of 2-Alkoxy(aroxy)-3-substituted
Quinolines by DABCO-Promoted Cyclization
of o-Alkynylaryl Isocyanides
(aroxy)quinolines in medicinal chemistry, efficient ap-
proaches to their preparation are limited. One of the most
widely used methods is probably nucleophilic substitution of
2-haloquinoline derivatives with corresponding alcohols or
phenols in the presence of bases, such as K2CO3, tBuOK, or
NaH, under heating (path a, Scheme 1).6,1b,2,3 This process
can also be promoted in the presence of copper catalysts.7
The major drawback of this method is the nucleophilicity
requirement of alcohols and phenols used. For less nucleo-
philic alcohols and phenols, the yields are extremely low.1b,7b
The use of strong bases under elevated temperatures also
limits its application. Another common approach to 2-alko-
xyquinolines is alkylation of 2-quinolones (path b, Scheme 1).
Unfortunately, the selectivity between O- and N-alkylation is
always a problem. As a fact, the unwanted N-alkylation
product usually predominates.8 Copper-catalyzed coupling
of 2-quinolones with aryl halides provides the C-N bond
forming product exclusively.9 Thus, an efficient synthesis of
diversified 2-alkoxy and 2-aroxyquinolines, especially ap-
plicable to sterically demanding and/or electron-deficient
alcohols and phenols, is highly desirable.10 We report herein
a novel metal- and strong base-free synthesis of 2-alkoxy-
(aroxy)-3-aryl(alkyl)quinolines from readily accessible o-al-
kynylaryl isocyanides and various alcohols and phenols
including less nucleophilic ones in the presence of 1,4-
diazabicyclo[2.2.2]octane (DABCO) under mild conditions
(path c, Scheme 1).
In 1999,11 Ito et al reported a new access to 2,3-disubsti-
tuted quinolines through cyclization of o-alkynylaryl isocy-
anides with MeOH, Et2NH, and other carbanions as nucleo-
philes. We also developed an efficient synthesis of diversified
2-chloro-3-substituted quinolines from o-alkynylaryl isocya-
nides and tetrabutylammonium chloride under mild condi-
tions.12 We hypothesized that extension of Ito’s strategy to
other less nucleophilic oxygenated nucleophiles, such as
phenols and secondary alcohols, would lead to a general
approach to 2-alkoxy(aroxy)-3-aryl(alkyl)quinolines.
Having this idea in mind, we initiated the study with
o-(phenylethynyl)phenyl isocyanide 2a and phenol 3a as
substrates under various conditions as summarized in Table 1.
Jiaji Zhao, Changlan Peng, Lanying Liu, Yong Wang, and
Qiang Zhu*
State Key Laboratory of Respiratory Disease,
Guangzhou Institutes of Biomedicine and Health,
Chinese Academy of Sciences, 190 Kaiyuan Avenue,
Guangzhou 510530, China
zhu_qiang@gibh.ac.cn
Received September 6, 2010
Diversified 2-alkoxy- and 2-aroxy-3-substituted quino-
lines were synthesized from o-alkynylaryl isocyanides and
alcohols and phenols promoted by DABCO, respectively.
The reaction was initiated by nucleophilic addition of
DABCO to isocyanide and subsequent cycliztion, leading
to a DABCO-quinoline-based adduct as the reactive
intermediate, followed by substitution of the DABCO
moiety with oxygenated nucleophiles.
2-Alkoxy(aroxy)quinolines exist as substructures in many
medicinally interesting compounds exhibiting a wide spec-
trum of biological activities, such as antimycobacterial
tuberculosis,1 antitumor,2 antimalarial,3 antithrombin,4 and
(1) (a) Saga, Y.; Motoki, R.; Makino, S.; Shimizu, Y.; Kanai, M.;
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7502 J. Org. Chem. 2010, 75, 7502–7504
Published on Web 10/11/2010
DOI: 10.1021/jo1017525
r
2010 American Chemical Society

Zhao et al.
JOCNote
SCHEME 1. Strategies to 2-Alkoxy(aroxy)quinolines
TABLE 2. Synthesis of 2-Alkoxy(aroxy)-3-substituted Quinolines 4a
TABLE 1. Optimization of Conditions for 2-Phenoxy-3-phenylquino-
line 4aa
entry equiv of 3a additive (equiv) temp (°C) time (h) yield (%)b
1
2
3
4
5
6
7
8
9
10
2
2
2
2
2
2
2
2
2
1
Na2CO3 (1.0)
NaH (1.0)
pyridine (1.0)
Et3N (1.0)
PPh3 (1.0)
DABCO (1.0)
DABCO (0.5)
DABCO (0.2)
DABCO (1.0)
DABCO (1.0)
25
25
25
25
25
25
25
25
40
40
24
24
24
24
24
24
24
24
14
14
0
0
0
0
0
72
35
17
71
68
aReaction conditions: 1a (0.1 mmol), POCl3 (0.15 mmol), (iPr)2NEt
(0.8 mmol), CH2Cl2 (1.0 mL), 0 °C 30 min; after workup with NaHCO3,
3a (0.1 or 0.2 mmol), additive, CH2Cl2 (1.0 mL), 25 or 40 °C; bIsolated
yield of 4a for 2 steps.
Because o-alkynylaryl isocyanides are unstable especially at
high concentration, they are used directly after dehydration
of the corresponding N-formylamide and subsequent aqueous
sodium bicarbonate workup.13 No desired cyclization prod-
uct was observed by screening of inorganic (Na2CO3, NaH)
and organic bases (pyridine, Et3N) (entries 1-4, Table 1). It
seemed that the nucleophilicity of phenoxide was not strong
enough to promote the cycloaddition reaction. Inspired by
the dual function of DABCO in Morita-Baylis-Hillman
reaction,14 acting as both a strong nucleophile and a good
leaving group, we speculated that a similar role that DABCO
could play in our proposed reaction. To our delight, a
stoichiometric amount of DABCO did promote the reaction
in the presence of 2.0 equiv of phenol and the desired
2-phenoxy-3-phenylquinoline 4a was formed in 72% overall
yield from the corresponding N-formylamide 1a at rt (entry
6, Table 1). The yield of 4a dropped dramatically when the
amount of DABCO was reduced (entries 7-8, Table 1). The
reaction time was greatly shortened at slightly elevated
temperature (40 °C) with equal yields (entry 9, Table 1).
Triphenyl phosphane, a surrogate of DABCO in Morita-
Baylis-Hillman reaction in some cases,14 cannot promote
the reaction at all (entry 5, Table 1).
aReaction conditions: 1a (0.5 mmol), POCl3 (0.75 mmol), (iPr)2NEt
(4.0 mmol), CH2Cl2 (5.0 mL), 0 °C 30 min; after workup with NaHCO3,
3a (1.0 mmol), DABCO (0.5 mmol), CH2Cl2 (5.0 mL), 40 °C; bIsolated
yield of 4a for two steps. cAdditional 1.0 equiv of Na2CO3 was added.
The generality of the reaction in terms of oxygenated
nucleophiles as well as substituents on o-alkynylaryl isocya-
nides was studied under the optimal reaction conditions
identified. The results were summarized in Table 2. In
general, electron-rich phenols (4b-c) gave better results than
less nucleophilic electron-deficient phenols (4d-g) as ex-
pected. It is noteworthy that functionalities, such as aldehyde
and nitro group, not only survive the reaction conditions but
also provide handles for further diversification. Moreover,
sterically hindered 2-isopropyl, 2-tert-butyl, and even 2,6-
dimethyl phenols furnished the corresponding substituted
2-phenoxy-3-phenylquinolines (4 h-j) in moderate to accept-
able yields. This methodology is efficient for the synthesis of
2-phenoxy-3-phenylquinolines with substituents (Me, Cl,
(13) Minozzi, M.; Nanni, D.; Zanardi, G.; Calestani, G. ARKIVO 2006,
vi, 6.
(14) For reviews, see: (a) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem.
Soc. Rev. 2007, 36, 1581. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811.
J. Org. Chem. Vol. 75, No. 21, 2010 7503

Zhao et al.
JOCNote
SCHEME 2. Synthesis of O-Tethered Dimeric Quinoline
In summary, an efficient approach for the synthesis of
2-alkoxy- and 2-aroxy-3-substituted quinolines, starting
from o-alkynylaryl isocyanides and various oxygenated nu-
cleophiles in the presence of 1.0 equiv of DABCO, has been
developed. A wide range of functionalities are well tolerated
under the reaction conditions. Compared with the existing
methods, the current approach features mild reaction con-
ditions and less nucleophilic phenols and alcohols applied.
A C-C bond and a C-O bond are formed sequentially from
nonquinoline-based precursors which are readily available.
DABCO triggers the reaction as a nucleophile and provides
the product as a leaving group being replaced by oxygenated
nucleophiles.
SCHEME 3. Plausible Reaction Mechanism
Experimental Section
General Procedure for DABCO Promoted 2-Alkoxy(aroxy)-3-
substituted Quinolines. POCl3 (0.75 mmol, 1.5 equiv) was added
dropwise to a solution containing o-alkynylaryl N-formylamide
1 (0.5 mmol) and diisopropylethylamine (4.0 mmol, 8.0 equiv) in
CH2Cl2 (5.0 mL) cooled in a water/ice bath under argon atmo-
sphere. The reaction was stirred at 0 °C for 30 min. The reaction
mixture was diluted with CH2Cl2 (15 mL) and washed with
saturated NaHCO3 solution three times. The organic phase was
separated and dried over Na2SO4. The CH2Cl2 solution of
o-alkynylaryl isocyanide 2 was concentrated to about 5 mL
in volume. Oxygenated nucleophile 3 (1.0 mmol) and DABCO
(0.5 mmol) were added to the above solution at rt. In some cases
as specified in Table 2, an additional 1.0 equiv of Na2CO3 was
added. The mixture was stirred at 40 °C, and the reaction was
monitored by TLC. When o-alkynylaryl isocyanide 2 had dis-
appeared, the reaction mixture was washed with water (10 mL)
and brine successively. The organic layer was dried over Na2SO4
and concentrated under vacuum. The residue was purified by
column chromatography using petroleum ether/dichloro-
methane as eluent to give the desired product 4 in 31-90%
yields.
OMe, Ac) on the 3-phenyl ring and the quinoline core (4k-p).
2-Hydroxypyridine is also a suitable nucleophile for the synthe-
sis of a heterocyclic variant of 2-aryoxy-3-phenylquinoline
4q. However, the current approach is less efficient for the
synthesis of 2-phenoxy-3-alkylquinolines (4r-s). Primary
and secondary alcohols can also act as nucleophiles to deliver
corresponding 2-alkoxy-3-phenylquinolines in moderate to
good yields (4t-aa). The presence of additional 1.0 equiv of
Na2CO3 can improve the yield dramatically in case of using
isopropanol as a nucleophile (4y), while the influence is less
significant on the formation of 4u-v, and 4x. For other
cases, either no improvement or negative effect on the yields
was observed in the presence of Na2CO3 (see Supporting
Information).
A unique O-tethered dimeric quinoline 6 was obtained
when 3-phenyl-2-quinolone 5 was applied as the nucleophile
(Scheme 2). Although the isolated yield was low due to steric
hindrance, the scaffold is difficult to be accessed via existing
methods.
2-Phenoxy-3-phenylquinoline (4a): 1H NMR (400 MHz,
DMSO): δ 8.45 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.79 (d, J =
6.8 Hz, 2H), 7.62 (t, J = 8.4 Hz, 2H), 7.45-7.54 (m, 6H), 7.25
(m, 3H); 13C NMR (100 MHz, CDCl3): δ 158.9, 154.2, 145.7,
139.0, 136.6, 129.5, 129.2, 128.3, 127.9, 127.6, 127.3, 127.0,
126.3, 125.0, 124.3, 121.6; HRMS (ESI): Exact mass calcd for
C21H16NO [M þ H]þ: 298.1232; Found: 298.1230.
A plausible mechanism is depicted in Scheme 3. Acting as a
strong nucleophile, DABCO initiates the reaction by addi-
tion of the tertiary amine to the terminal carbon of the
isocyanide moiety in 2. Cycloaddition of the resulting carb-
anion to the triple bond delivers the DABCO-quinoline-
based adduct A. The addition of oxygenated nucleophiles on
the C2 of intermediate B, forming the adduct C. Subsequent
elimination of the DABCO moiety furnishes the desired
product 4, with concurrent regeneration of the catalyst.
Although the reaction mechanism suggests that DABCO
could be regenerated, stoichiometric amount of DABCO is
needed for efficient conversion of the starting o-alkynylaryl
isocyanide 2.
Acknowledgment. We are grateful for the support of this
work by a Start-up Grant from Guangzhou Institutes of
Biomedicine and Health (GIBH) and Guangzhou Municipal
Foundation for Science and Technology (2010Y1-C241).
Supporting Information Available: General experimental
procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
7504 J. Org. Chem. Vol. 75, No. 21, 2010