Quinoline synthesis by improved Skraup-Doebner-Von Miller reactions utilizing acrolein diethyl acetal

Article abstract of DOI:10.1016/j.tetlet.2015.09.145

A robust synthetic method has been developed as an improvement to the venerable Skraup-Doebner-Von Miller reaction providing access to various quinoline products. The straightforward procedure utilizes acrolein diethyl acetal as a three-carbon annulation partner with aniline substrates in a monophasic, organic solvent-free reaction medium. Differentially substituted aniline precursors were found to be compatible with the reaction conditions and the corresponding quinoline products are isolated in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2015.09.145

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Quinoline synthesis by improved Skraup–Doebner–Von Miller
reactions utilizing acrolein diethyl acetal
⇑
Ginelle A. Ramann, Bryan J. Cowen
Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A robust synthetic method has been developed as an improvement to the venerable Skraup–Doebner–
Von Miller reaction providing access to various quinoline products. The straightforward procedure uti-
lizes acrolein diethyl acetal as a three-carbon annulation partner with aniline substrates in a monophasic,
organic solvent-free reaction medium. Differentially substituted aniline precursors were found to be
compatible with the reaction conditions and the corresponding quinoline products are isolated in mod-
erate to good yields.
Received 5 September 2015
Revised 28 September 2015
Accepted 29 September 2015
Available online xxxx
Keywords:
Heterocycle
Ó 2015 Elsevier Ltd. All rights reserved.
Skraup–Doebner–Von Miller
Acetal
Introduction
because strong exogenous oxidants are not typically required and
reaction workup procedures are straightforward. Additionally,
Substituted quinolines are ubiquitous motifs in various classes
of biologically active organic compounds. Historically, successful
medicinal application of quinoline-containing natural and syn-
thetic materials has focused on treatments for malaria.1 However,
broader application of these molecules has also been achieved. In
fact, a recent study found the quinoline moiety as a top 5 most
prevalent six-membered nitrogen heterocycle present in a data-
base of 1994 FDA approved pharmaceutials.2 In addition to pos-
sessing interesting biological activities, appropriately substituted
quinoline rings have found application as antioxidants,3 synthetic
dyes,4 and chiral small molecule catalysts.5 Thus, the development
of efficient synthetic methods for the preparation of this fused
heterocyclic ring system is a focus of many research efforts.
Recent progress in this field has included improvements to clas-
sical reactions used to prepare quinoline-containing systems and
include contributions to the Combes,6 Conrad–Limpach,7 and
Skraup8 reactions in addition to the Doebner–Von Miller,9 Fried-
lander,10 and Pfitzinger11 quinoline syntheses.12 As part of a
research program focused on the synthesis of diverse quinolines,
we became interested in the mechanistically related Skraup and
Doebner–Von Miller (DVM) protocols. Both methods utilize aniline
the reaction tolerates b-substitution on the enal reaction partner
leading to diverse quinoline products substituted at C2 if desired
(R2 in Scheme 1).
However, if quinoline products unsubstituted at C2, C3, and C4
are desired, acrolein must be used as the three-carbon enal reac-
tion partner. Drawbacks of this method include acrolein’s rela-
tively high cost13 and propensity to oligomerize under the DVM
reaction conditions (even after prolonged storage at 4 °C). This
necessitates the use of excess reagent and results in tedious
workup and purification steps to obtain the quinoline products.
In this work, we have established a straightforward and general
DVM synthesis of various quinoline products using the diethyl
acetal of acrolein as an annulation partner.14 The reactions tolerate
substitution of the aniline ring and proceed in generally higher
yields than typical DVM reactions with enal reaction partners.
We began our studies of the DVM reaction of aniline (1) and
acrolein (2; 2 equiv) in a biphasic mixture of equal volumes of
toluene and 6N hydrochloric acid (HCl) at elevated temperature.
This biphasic solvent system has been shown as advantageous
for DVM reaction efficiency.9 As seen in Table 1, these conditions
provided <10% of isolated quinoline product 3 after ca. 1 day reac-
tion time at 111 °C at either 0.50 or 0.25 M concentration (entries 1
and 2). Substituting hydrochloric acid with either a Lewis acid or
ammonium salt only provided trace amount of product in compa-
rable time frames (entries 3 and 4). Diluting the reaction mixture
and lowering the ratio of organic cosolvent gave improved results.
For example, a 3.4:1 mixture of 6N HCl/toluene under otherwise
similar conditions provided a 28% yield of quinoline (entry 5).
starting materials and either glycerol (Skraup) or
a,b-unsaturated
aldehyde (DVM) annulation partners. As depicted in Scheme 1,
acidic and thermal conditions are typically employed for each reac-
tion. The DVM process is arguably more synthetically attractive
⇑
Corresponding author. Tel.: +1 303 871 2981; fax: +1 303 871 2254.
E-mail address: bryan.cowen@du.edu (B.J. Cowen).
http://dx.doi.org/10.1016/j.tetlet.2015.09.145
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ramann, G. A.; Cowen, B. J. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.145

2
G. A. Ramann, B. J. Cowen / Tetrahedron Letters xxx (2015) xxx–xxx
Scheme 1. Skraup and Doebner–Von Miller reactions.
Table 1
Initial optimization studies
decreased product yields (entries 4 and 5) while a longer reaction
time did not significantly increase yield (entry 6).
Having identified acrolein diethyl acetal as a robust substitute
for acrolein, the substrate scope with respect to starting aniline
was investigated. The toluidine series provided alkylated quinoline
products in modest to good yields (Table 3, entries 1–3). For exam-
ple, DVM reaction between o-toluidine (5) and acrolein diethyl
acetal was quite efficient, providing the substituted quinoline pro-
duct 6 in 83% yield (entry 1). On the other hand, p-toluidine (7)
reacted with 4 to provide a lower 36% yield of quinoline product
8 (entry 2). Interestingly, when m-toluidine (9) was subjected to
Entry
6N HCl/toluene
Concentrationa (M)
Yieldb (%)
1
2
1:1
1:1
—
—
3.4:1
6.9:1
6N HCl only
0.50
0.25
0.20
0.25
0.06
0.06
0.06
2
9
3c
4d
5
Trace
Trace
28
35
Trace
the optimized reaction conditions
a ca. 1:1 mixture of 5-
methylquinoline (10a) and 7-methylquinoline (10b) was isolated
in a combined 16% yield (entry 3). Halogenated anilines also partic-
ipated in the DVM reaction with similar efficiencies. Utilizing 2-
bromoaniline (11) in the DVM reaction with 4 provided 21% yield
6
7
a
b
c
Aniline concentration.
Isolated yields.
Reaction run with 3 equiv AlCl3 in CH2Cl2 for 24 h at 23 °C.
Reaction run with 10 mol % NH4Cl in toluene for 24 h at 50 °C.
d
Table 3
Aniline substrate scope with acrolein diethyl acetal
Decreasing the ratio of organic solvent to a 6.9:1 mixture of 6N
HCl/toluene improved the isolated yield of quinoline to 35% (entry
6). Unfortunately, removing the organic solvent entirely was detri-
mental to the reaction outcome (entry 7).
At this point, no further increase in product yield was achieved
by modifying variables such as time, concentration, or tempera-
ture. However, a significant increase in reaction efficiency was dis-
covered upon substitution of acrolein with acrolein diethyl acetal.
Running the reaction under otherwise optimal biphasic conditions
led to an isolated quinoline yield of 25% (entry 1, Table 2). This was
comparable to the reaction with acrolein (cf. entry 5, Table 1).
However, unlike the DVM reaction using acrolein, a significant
increase in product yield was now observed upon omission of
the organic cosolvent. Specifically, the product quinoline was iso-
lated in 54% yield after a reaction time of 24 h in 6N HCl (entry
2, Table 2). Diluting the reaction mixture to 0.01 M and using less
concentrated 1N HCl resulted in a similar yield but greatly facili-
tated isolation of product (entry 3). Shorter reaction times
Entry
1
Aniline
Product
Yielda (%)
83
2
3
36
16b
4
5
21
55
Table 2
DVM reaction with acrolein diethyl acetal
6
7
8
16
10
21
Entry
Concentrationa (M)
Time (h)
Yieldb (%)
1c
2
3
4
5
6
0.06
0.07
0.01
0.07
0.07
0.07
24
24
24
6
3
67
25
54
56
25
21
63
9
46
a
b
c
Aniline concentration.
Isolated yields.
Reaction run using a 3.4:1 mixture of 6N HCl/toluene.
a
Isolated yields after silica gel chromatography.
Isolated as a ca. 1:1 ratio of 10a:10b.
b
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G. A. Ramann, B. J. Cowen / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 4
as well as 4-iodoanline (17) substrates were less efficient, deliver-
ing products 16 and 18 in modest 16% and 10% yields, respectively
(entries 6 and 7). A heterocyclic aniline containing a thiazole ring
(19) has been studied in the DVM reaction with 4 providing tri-
cyclic product 20 in 21% yield (entry 8). An additional tricyclic pro-
duct was formed from reaction of 2-naphthylaniline (21) with 4
providing product 22 in 46% yield (entry 9).
Aminophenol Subtract Scope with 4
Diversification of the substrate scope was next investigated by
incorporating phenolic groups into the starting materials (Table 4).
The hydroxyquinoline products obtained from such DVM reactions
are known to be metal chelators with a variety of applications.15 As
such, 2-aminophenol (23) smoothly underwent the annulation
reaction to deliver 8-hydroxyquinoline (24) in 41% isolated yield
(entry 1). Better results were obtained with 2-amino-4-methylphe-
nol (25) and 2-amino-5-methylphenol (27) delivering products 26
and 28 in 58% and 50% yields, respectively (entries 2 and 3). Fluo-
rinated derivatives were good reaction partners as well with 5-flu-
oro-2-aminophenol (29) delivering the corresponding quinoline
product 30 in 42% yield (entry 4). The regioisomer 6-fluoro-2-
aminophenol (31) was as efficient (43% yield of product 32, entry
5), with the 4-fluoro-2-aminophenol (33) isomer less so (18% yield
of product 34, entry 6). Chlorination was also tolerated with 4-
chloro-2-aminophenol (35) reacting with 4 to provide quinoline
36 in 49% yield (entry 7). Alternatively, starting with 4-aminophe-
nol (37) reduced overall efficiency leading to product 38 in 23%
yield (entry 8). The 4-methoxyphenol derivative 39 performed
similarly in the DVM process to give quinoline 40 in 27% yield
(entry 9).
Entry
1
Aniline
Product
Yielda (%)
41
2
58
3
4
5
50
42
43
The mechanistic details of the Skraup and DVM reactions have
been the subject of much investigation and debate in the litera-
ture.16 Most recently, Denmark and coworkers proposed that a
conjugate addition–fragmentation mechanism was operative
when b-disubstituted carbonyl substrates were employed in the
reaction.17 This proposal was supported with careful crossover
experiments using 13C-labeled substrates. While Denmark studied
ketone derivatives, if applied to b-disubstituted enals their mecha-
nism would begin with reversible conjugate addition with the ani-
line to deliver intermediate 41 (Scheme 2). Next, irreversible
fragmentation to imine 42 and acetaldehyde (43) would be fol-
lowed with recombination by condensation through the enamine
tautomer of 42. The product of this recombination, 44, would be
subject to conjugate addition of aniline to give 45 which would
then cyclize to deliver the dehydroquinoline product 46 and
aniline.
6
7
18
49
8
9
23
27
a
Isolated yields after silica gel chromatography.
Since the current system employs acrolein derivatives unsubsti-
tuted at the b-position, the fragmentation as proposed by Denmark
would be unproductive because the analogous enamine required
of quinoline product 12 (entry 4). Starting with 2-bromo-4-fluo-
roaniline (13), quinoline product 14 was isolated in 55% yield fol-
lowing the DVM reaction (entry 5). The difluorinated aniline 15
Scheme 2. Proposed mechanism for the DVM reaction with b-disubstituted carbonyl compound.
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4
G. A. Ramann, B. J. Cowen / Tetrahedron Letters xxx (2015) xxx–xxx
Scheme 3. Proposed mechanism for the DVM reaction acrolein diethyl acetal.
for recombination is inaccessible. Hence, conjugate addition to the
protonated acrolein (or oxocarbenium ion18) would deliver 47 that
would be followed by direct dehydrative ring closure to give 48
(Scheme 3A). Oxidative aromatization would then provide the pro-
duct quinoline 49. Alternatively, we cannot rule out the formation
of anil 50 first through a condensation reaction which then can
undergo conjugate addition from aniline to give 51 (Scheme 3B).
Ring closure, aniline elimination, and oxidative aromatization
would then deliver the product.
In conclusion, we have identified an operationally simple
method for efficient DVM annulations using the diethyl acetal of
acrolein. Products are isolated in modest to good yields, and the
reaction tolerates a range of different functional groups including
alkyl groups, halogens, phenols, and heterocycles. New fluorinated
quinolines may have applications in medicinal chemistry, while
novel hydroxyquinoline products prepared herein are predicted
to have interesting metal binding activity.
References and notes
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We thank the University of Denver for generous startup funds
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Supplementary data
General experimental procedures and copies of 1H NMR and 13
C
NMR spectra for quinoline products 14, 16, 18, 20, 26, 28, 30, 32,
and 34 are available online. Additionally, copies of 1H NMR spectra
for known quinoline products 3, 6, 8, 10a + 10b, 12, 22, 24, 36, and
38 are also available online.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
145.
17. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668–1676.
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