p-Toluenesulfonic acid promoted annulation of 2-alkynylanilines with activated ketones: Efficient synthesis of 4-Alkyl-2, 3-disubstituted quinolines

Article abstract of DOI:10.1002/ejoc.200901257

Reactions between readily available 2-alkynylanilines and activated ketones such as ss-keto esters promoted by p-toluenesulfonic acid afford 4-alkyl-2, 3-disubstituted quinolines in good to excellent yields. The generality of substituents at the other end of the triple bond of 2-alkynylanilines makes the method a valuable approach to diversified 4-alkylquinolines, which are difficult to obtain by classical methods such as the Friedlaender reaction. Quinoline dimers can be prepared efficiently with alkyl or aryl linkers at C-4.

Full text of DOI:10.1002/ejoc.200901257

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901257
p-Toluenesulfonic Acid Promoted Annulation of 2-Alkynylanilines with
Activated Ketones: Efficient Synthesis of 4-Alkyl-2,3-Disubstituted Quinolines
Changlan Peng,[a] Yong Wang,[a] Lanying Liu,[a] Honggen Wang,[a] Jiaji Zhao,[a] and
Qiang Zhu*[a]
Keywords: Nitrogen heterocycles / Annulation / Friedländer reaction / Dimerization / Ketones
Reactions between readily available 2-alkynylanilines and
activated ketones such as β-keto esters promoted by p-tolu-
enesulfonic acid afford 4-alkyl-2,3-disubstituted quinolines
in good to excellent yields. The generality of substituents at
the other end of the triple bond of 2-alkynylanilines makes
the method a valuable approach to diversified 4-alkylquin-
olines, which are difficult to obtain by classical methods such
as the Friedländer reaction. Quinoline dimers can be pre-
pared efficiently with alkyl or aryl linkers at C-4.
unsatisfactory yields are commonly obtained. To overcome
the aforementioned drawbacks, more efficient methods such
Introduction
As a very important class of heterocyclic compounds, as modified Friedländer strategies,[9] hetero-Diels–Alder re-
quinolines, are known to display a wide range of pharmaco- action of imines,[10] and transition-metal-catalyzed reac-
logical activities, such as antimalarial,[1] antibacterial,[2] tions[11] have been developed. Although, there are numer-
anti-inflammatory,[3] antituberculosis,[4] anti-HIV,[5] and an- ous methods available for the syntheses of multisubstituted
ticancer.[6] The quinoline scaffold is also present in many quinolines, it is still a challenge to introduce a variety of
biologically active natural products, particularly in alka- alkyl groups at C-4 of the quinoline skeleton in a simple
loids.[7] Consequently, a large number of methodologies and straightforward manner.
have been developed for the syntheses of functionalized
Although the Friedländer reaction and its modifications
quinolines, such as Skraup, Doebner–von Miller, Fried- are extensively studied and widely used for the syntheses of
länder, and Combes syntheses.[8] However, many of these functionalized quinolines,[8,9] the availability of 2-amino-
methods suffer from the need of high temperatures, pro- phenylketones is limited to 2Ј-aminoacetophenones or 2-
longed reaction times, and drastic reaction conditions, and aminophenylarylketones in most cases (Scheme 1, Equa-
Scheme 1. Friedländer and indirect Friedländer synthesis of multisubstituted quinolines.
tion 1). As a result, the products are limited to 4-methyl- or
[a] State Key Laboratory of Respiratory Diseases, Guangzhou In-
4-arylquinolines. Catalytic hydration of 2-alkynylanilines to
the corresponding 2-substituted-2Ј-aminoacetophenones re-
gioselectively is known to occur in high yields owing to the
strong electron-donating ability of the ortho-amino group
(Scheme 1, Equation 2).[12] Because the reaction conditions
for the hydration of alkynes and the Friedländer reaction
stitute of Biomedicine and Health, Chinese Academy of Sci-
ences, Guangzhou International Business Incubator,
Guangzhou Science Park, Guangzhou 510663, People’s Repub-
lic of China
Fax: +86-20-3229-0606
E-mail: zhu_qiang@gibh.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901257.
818
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 818–822

Annulation of 2-Alkynylanilines with Activated Ketones
are similar (Brønsted acids or Lewis acids in polar sol- ynes,[15] which suggests that the reaction may proceed via
vents), it is viable to design a one-pot, indirect Friedländer a hydration intermediate (Scheme 1, Equation 2). Both
reaction for the synthesis of a variety of 4-alkylquinolines methyl and chloride substitutions on the aromatic ring (R1)
starting from 2-alkynylanilines, which are easily accessible have negative effects on the yields, especially when R2 is a
through Sonogashira couplings.[13]
phenyl group (Table 2, Entries 7–10). A wide range of elec-
tron-poor and electron-rich aromatics can tolerate the reac-
tion (Table 2, Entries 11–17), albeit the yield for the strong
electron-donating group OMe is low (59%; Table 2, En-
try 12). Functionalities such as bromide and carboxylic es-
ter make further modifications possible on the aromatic
ring (Table 2, Entries 13 and 17). It is noteworthy that in all
cases when R2 = TMS, the silyl group is alcoholyzed to
proton (R2 = H) in the final products (Table 2, Entries 1, 7,
and 9).
Results and Discussion
To test the idea and search for optimized conditions, the
initial attempt was carried out with 2-(1-hexynyl)aniline
(1a) and ethyl acetoacetate (2a) as substrates in refluxing
anhydrous ethanol in the presence of concentrated sulfuric
acid (0.5 equiv.; Table 1, Entry 6).[14] Gratifyingly, desired
product 3aa was obtained in 57% isolated yield. The result
encouraged us to screen different Brønsted acids for their
effectiveness in this one-pot quinoline synthesis (Table 1,
Entries 1–5). p-Toluenesulfonic acid (PTSA) monohydrate
was the acid of choice and afforded the product in excellent
yield (87%). Both catalytic (Table 1, Entry 7) and an excess
amount of PTSA (Table 1, Entries 8–10) proved to be less
effective. Altering the ratio of 2a/1a suggested that the ini-
tial ratio of 1.5 was the best (Table 1, Entries 4, 11, 12). The
reaction was much more sluggish in 95% ethanol than in
anhydrous ethanol with otherwise identical conditions (re-
sult not shown).
Table 2. p-Toluenesulfonic acid promoted annulation of 2-alk-
ynylanilines 1 with ethyl acetoacetate (2a) in ethanol.[a]
Entry 2-Alkynylanilines 1
Product 3
% Yield[b]
1
2
3
4
5
6
7
8
1b: R1 = H, R2 = TMS
3ba[c]
3ca
3da
3ea
3fa
97
89
83
80
71
88
88
60
94
55[d]
73
59
79
76
63
80
72
1c: R1 = H, R2 = tBu
1d: R1 = H, R2 = cyclohexyl
1e: R1 = H, R2 = cyclopropyl
1f: R1 = H, R2 = Bn
Table 1. Acid-promoted annulation of 2-(1-hexynyl)aniline (1a)
with ethyl acetoacetate (2a) in ethanol under various conditions.[a]
1g: R1 = H, R2 = Ph
3ga
3ha[c]
3ia
1h: R1 = Me, R2 = TMS
1i: R1 = Me, R2 = Ph
9
1j: R1 = Cl, R2 = TMS
1k: R1 = Cl, R2 = Ph
3ja[c]
3ka
3la
10
11
12
13
14
15
16
17
1l: R1 = H, R2 = p-tolyl
1m: R1 = H, R2 = 4-MeOC6H4
1n: R1 = H, R2 = 4-BrC6H4
1o: R1 = H, R2 = 4-ClC6H4
1p: R1 = H, R2 = 3-ClC6H4
1q: R1 = H, R2 = 2-ClC6H4
1r: R1 = H, R2 = 4-EtOOCC6H4
3ma
3na
3oa
3pa
3qa
3ra
Entry
Acid (equiv.)
Ratio 2a/1a
% Yield of 3aa[b]
1
2
3
4
5
6
7
8
TMSCl (1.0)
conc. HCl (1.0)
TFA (1.0)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
2.0
38
33
13
87
43
57
71
82
74
74
66
80
[a] Conditions: Heating
a
solution of 2-alkynylanilines
1
(0.5 mmol) and ethyl acetoacetate (2a; 0.75 mmol) in anhydrous
ethanol (5 mL) with p-toluenesulfonic acid monohydrate
(1.0 equiv.) in anhydrous ethanol to reflux for 15 h. [b] Isolated
yield. [c] R2 = H. [d] Another 1.0 equiv. of PTSA was added after
15 h, and the mixture was stirred for another 5 h.
PTSA (1.0)[c]
CF3SO3H (1.0)
conc. H2SO4 (0.5)
PTSA (0.5)[c]
PTSA (1.2)[c]
PTSA (1.5)[c]
PTSA (2.0)[c]
PTSA (1.0)[c]
PTSA (1.0)[c]
The scope of substrates was further explored by focusing
on activated ketones, and the results are summarized in
Table 3. Compatible yields were obtained when ethyl benzo-
ylacetate (2b) and ethyl butyrylacetate (2d) were used, which
introduced diversity at C-2 of the quinolines with aryl and
long-chain alkyl groups (Table 3, Entries 1–4, 7). A wide
range of activating groups other than carboxylic ester such
as amides (Table 3, Entries 9–11), p-toluenesulfonyl
9
10
11
12
[a] Conditions: Heating a solution of 2-(1-hexynyl)aniline (1a;
0.5 mmol) and ethyl acetoacetate (2a) in anhydrous ethanol (5 mL)
with acids for 15 h. [b] Isolated yield. [c] p-Toluenesulfonic acid
monohydrate was used.
With the optimized conditions identified, the scope of 2- (Table 3, Entry 8), ketone (Table 3, Entries 5 and 6), and
alkynylanilines 1 was first examined with the activated cyanide (Table 3, Entry 12) all worked well. Consequently,
ketone ethyl acetoacetate (2a; Table 2). In general, alkyl the diversity at C-3 of the quinolines was largely expanded.
substituents R2 (Table 2, Entries 1–5) give better yields than Unfortunately, unactivated ketones such as acetophenone
aryl ones (Table 2, Entries 11–17). This result agrees with failed to give the desired product under the optimized con-
the outcome of PTSA-catalyzed hydration of arylalk- ditions.
Eur. J. Org. Chem. 2010, 818–822
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C. Peng, Y. Wang, L. Liu, H. Wang, J. Zhao, Q. Zhu
Table 3. p-Toluenesulfonic acid promoted annulation of 2-alkynylanilines 1 with activated ketones 2 in ethanol.[a]
SHORT COMMUNICATION
.
Entry
Anilines 1
Ketones 2
Product 3[c]
% Yield[b]
1
2
3
4
5
6
7
8
9
10
1a
1b
1g
1n
1a
1b
1b
1b
1b
1b
2b:
2b
2b
2b
2c:
2c
2d:
2e:
2f:
2g:
R3 = Ph, R4 = CO2Et
R3 = Me, R4 = CH3CO
3ab
3bb
3gb
3nb
3ac
3bc
3bd
3be
3bf
91
99
73
66
77
99
94
70
91
98
R3 = nPr, R4 = CO2Et
R3 = Me, R4 = p-Ts
R3 = Me, R4 = CONH2
R3 = Me, R4 = CONHPh
3bg
11
1b
2h:
3bh
87
12
1b
2i:
R3 = Ph, R4 = CN
3bi
92
[a] Conditions: Heating a solution of 2-alkynylanilines 1 (0.5 mmol) and activated ketones 2 (0.75 mmol) in anhydrous ethanol (5 mL)
with p-toluenesulfonic acid monohydrate (1.0 equiv.) in anhydrous ethanol to reflux for 15 h. [b] Isolated yield. [c] R2 = H in the case
where 1b was used.
The current strategy can be applied to the synthesis of
To determine the mechanism of this one-pot quinoline
quinoline dimers linked at C-4 as shown in Scheme 2. Sym- synthesis, the results of a stepwise hydration of 1a and the
metric substrates 4 and 5 can be accessed easily by double subsequent Friedländer reaction of the corresponding hy-
Sonogashira couplings of 1,6-heptadiyne and 1,4-diethyn- dration product 8 promoted by PTSA and H2SO4 were
ylbenzene with 2.5 equivalents of 2-iodoaniline, respec- compared side by side (Scheme 3). Both acids promoted the
tively.[16] Under the standard reaction conditions, desired hydration of 1a with almost equal effectiveness. Although
quinoline dimer 5 with a linear alkyl chain linkage was ob- PTSA was more effective than H2SO4 (95% vs. 82%) in the
tained in good yield. A similar yield was achieved for 7 with Friedländer reaction of 8 and 2a, their difference in the one-
a 1,4-benzylic linker. This unprecedented dimeric quinoline pot reaction was much more significant (87% vs. 57%). The
synthesis will inspire us to prepare more derivatives and to presence of 2a in the one-pot procedure must play an im-
explore their potential biological activities and other prop- portant role, leading the reaction to different pathways with
erties.
the use of different acids.
Scheme 3. Hydration of 2-(1-hexynyl)aniline (1a) and Friedländer
reaction of 1-(2-aminophenyl)hexane-1-one (8) promoted by PTSA
and H2SO4.
We propose the reaction pathways and rationalize the in-
fluence of the two acids on the yields as depicted in
Scheme 4. In the presence of PTSA, 1a is hydrated to 8
first (path a1), and then enamine B is formed with ethyl
acetoacetate (2a; path a2) before cyclization and dehy-
dration to furnish the final product. In the case of H2SO4
Scheme 2. Synthesis of dimeric quinolines with alkyl or aryl link-
ages at C-4.
820
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Annulation of 2-Alkynylanilines with Activated Ketones
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In summary, we have demonstrated a convenient and sin-
gle-step procedure for the conversion of readily available 2-
alkynylanilines and activated ketones into the correspond-
ing 4-alkylquinolines. The tolerance of a wide range of
functionalities on both substrates gives complementary ac-
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of a variety of 4-alkylquinolines. Dimeric quinolines with
potential biological interest can also be synthesized ef-
ficiently from symmetric 2-alkynylanilines.
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Received: November 4, 2009
Published Online: January 4, 2010
822
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Eur. J. Org. Chem. 2010, 818–822