An improved Pfitzinger reaction: Eco-efficient synthesis of quinaldine-4-carboxylates by TMSCl-mediated

Article abstract of DOI:10.1016/j.tetlet.2017.08.014

We report herein an improved Pfitzinger reaction for the synthesis of highly functionalized quinaldines from 1,3-dicarbonyl compounds, isatins and alcohols mediated by TMSCl. This synthesis involves cyclization and esterification in one-step cascade process for the formation of a carboxylate (CO₂R) at the 4-position of quinaldine ring. Moreover, this procedure shows highly efficient, good functional group tolerance, operational simplicity, environment-friendly and feasibility of scale up.

Full text of DOI:10.1016/j.tetlet.2017.08.014

Accepted Manuscript
An Improved Pfitzinger Reaction: Eco-efficient Synthesis of Quinaldine-4-car-
boxylates by TMSCl-Mediated
Lingling Lu, Pan Zhou, Biao Hu, Xiang Li, Rong Huang, Fuchao Yu
PII:
S0040-4039(17)31003-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.014
TETL 49204
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 June 2017
29 July 2017
7 August 2017
Please cite this article as: Lu, L., Zhou, P., Hu, B., Li, X., Huang, R., Yu, F., An Improved Pfitzinger Reaction: Eco-
efficient Synthesis of Quinaldine-4-carboxylates by TMSCl-Mediated, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.08.014
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Graphical Abstract
An Improved Pfitzinger Reaction: Eco-efficient
Synthesis of Quinaldine-4-carboxylates by
TMSCl-Mediated
Lingling Lu,†a Pan Zhou,†a Biao Hu,a Xiang Li,b Rong Huang,c and Fuchao Yu*a
a Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650504, P.
R. China.
b Research Center for Analysis and Measurement, Kunming University of Science and Technology, Kunming,
650500, P. R. China.
c Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China

1
Tetrahedron Letters
journal homepage: www.els evier.com
An Improved Pfitzinger Reaction: Eco-efficient Synthesis of Quinaldine-4-
carboxylates by TMSCl-Mediated
Lingling Lu,†a Pan Zhou,†a Biao Hu,a Xiang Li,b Rong Huang,c and Fuchao Yu*a
a Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, P. R. China.
b Research Center for Analysis and Measurement, Kunming University of Science and Technology, Kunming, 650500, P. R. China.
c School of Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
We report herein an improved Pfitzinger reaction for the synthesis of highly functionalized quinaldines
from 1,3-dicarbonyl compounds, isatins and alcohols mediated by TMSCl. This synthesis involves
cyclization and esterification in one-step cascade process for the formation of a carboxylate (CO2R) at
the 4-position of quinaldine ring. Moreover, this procedure shows highly efficient, good functional
group tolerance, operational simplicity, environment-friendly and feasibility of scale up.
Received in revised form
Accepted
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
quinaldine-4-carboxylates
improved Pfitzinger reaction
atom- and step-economical synthesis
one-step cascade process
Introduction
Quinaldine is one of the most important methyl derivative of
quinoline, it exists in many natural products, pharmaceuticals,
physiologically active molecules, and material chemistry (Fig.
1).1 Thus, it is highly desirable to develop efficient and selective
methods for the synthesis of such highly valuable molecules.
Generally, quinaldine derivatives have been prepared by several
conventional methods (Scheme 1A), including Friedlander
−Miller reaction,3
reaction,2 Doebner
Niementowski reaction,4
and Combes reaction,5 and others.6 However, these typical
reactions were often performed under harsh reaction conditions
with high temperatures, strong acidic medium, toxic reagents and
transitionmetal mediated. To the best of our knowledge, only a
handful reports are available for the synthesis of quinaldines via
Pfitzinger reaction.7 Therefore, the development of new eco-
friendly synthetic methods for the construction of quinaldine
Scheme 1. Synthesis of quinolines.
derivatives through Pfitzinger reaction are still of great interest.
Since its discovery in 1886,8 the Pfitzinger reaction,8b
involving the condensation of isatin and carbonyl compound, has
arguably become one of the most utilized tools for the synthesis
of biologically active quinoline-4-carboxylic acids.7c,9. However,
Fig. 1. Biologically active compounds containing a quinaldine ring.
———
∗ Corresponding author. Tel.: +0086-871-65970747; e-mail: yufuchao05@126.com (F. Yu).
† L. Lu. and P. Zhou. contributed equally.

2
Tetrahedron Letters
Table 2.
the classic chemical reaction is commonly performed in a two-
Substrate scope of the quinaldines 3.a,b
step process based on strong base and subsequently acidified
with strong acid, which can only generate quinoline-4-carboxylic
acids and is unable to obtain the quinoline-4-carboxylates
(Scheme 1B). Therfore, selective synthesis of the quinoline-4-
carboxylate motifs under mild reaction condition (strong base-
and acid-free) has remained a daunting challenge, especially
through one-step method.
Based on our previous work on isatin-based heterocycle
synthesis,10 herein we wish to report
a cyclization and
esterification in one-step cascade protocol for the synthesis of
functionalized quinaldines 3/4 via an improved Pfitzinger
reaction (Scheme 1C). The three-component cascade reaction
between readily available isatins
1
and 1,3-dicarbonyl
compounds (acetylacetone or ethyl acetoacetate) 2 in the
presence of alcohols mediated by trimethylchlorosilane (TMSCl),
generates a carboxylate (CO2R) at the 4-position of quinaldine
ring.
Result and discussion
Initially, isatin (1a) and acetylacetone (2a) were selected as
model substrates for screening the reaction conditions. (Table 1).
Firstly, various catalysts were investigated in MeOH at 60 oC for
6 h. Et3N, K2CO3, CrCl2, Bi(CF3SO3)3, AgOAc and AcOH
afforded the desired product 3a unsuccessfully (entries 1–6). To
our delight, formation of 3a was observed in reactions catalyzed
by
p-toluenesulfonic acid
(p-TSA),
HCl
and
t-
butyldimethylchlorosilane (TBSCl) (47%, 43% and 62%, entries
7–9), and TMSCl was found more efficient (66%, entry 10).
Next, the role of reaction temperature was also screened in the
presence of TMSCl in MeOH (entries 9–12). It was found that
the reaction at 60 oC still provided the best result (66%, entry 9 vs
entries 11–13). Further investigation of the catalyst amounts
showed that the reaction with 1.0 equiv TMSCl did not reach the
complete conversion (entries 14), but higher catalyst loading (3.0
equiv.) had little impact on the results (entries 15). Thus, the
Table 1.
Optimization of reaction conditions.a
a Reagents and conditions: isatins 1, (0.5 mmol) acetylacetone 2a (0.7
mmol) and TMSCl (1.0 mmol) in alcohols (3.0 mL), stirred at 60 °C for
6.0 h; b Isolated yield based on isatin 1.
reaction with 2.0 equiv. of TMSCl in MeOH at 60 °C was found
the optimal condition.
With the optimized reaction conditions in hand, the scope of
isatins were examined when alcohols act as nucleophiles. The
results summarized in Table 2. For most of the tested substrates,
showed little impact on the results, and quinaldines were isolated
Catalyst
(equiv.)
T
Time
(h)
Yield
(%)b
Entry
(oC)
1
2
Et3N (2.0)
60
60
60
60
60
60
60
60
60
60
r.t.
40
80
60
60
6
6
6
6
6
6
6
6
6
6
8
8
6
6
6
n.d.c
n.d.c
n.d.c
n.d.c
n.r.d
n.d.c
47
K2CO3 (1.0)
CrCl2 (0.5)
−75%).
in medium to excellent yields (55
Generally, strong
3
nucleophiles gave better results than weak nucleophiles (3e–3f
vs. 3a–3d, 3i vs. 3h, and 3l vs. 3j–3k), while weak nucleophiles
3g gave better results than strong nucleophiles 3a–3e. On the
other hand, electron-neutral (5-H) and halogenated (5-Br, 5-Cl,
5-F and 7-F) isatins were smoothly converted to the
corresponding products. When the substituent of isatins were
changed to strong electron-withdrawing groups (5-NO2 and 7-
CF3), the moderate yields were also obtained in certain cases
(3n−3p, 55−62%).
As shown in Table 3, the reaction is not restricted to
acetylacetone 2a, and also can work with related substrates, such
as ethyl acetoacetate 2b. The expected quinaldines were obtained
in good to excellent yields (4a−4l, 60−88%). Apparently, the
reactivity of ethyl acetoacetate 2b is higher than acetylacetone
2a, and it gave better results. Moreover, the structure of one
representative product 4j was further conclusively confirmed by
X-ray analysis (Fig. 2, CCDC 1506108).11
4
Bi(CF3SO3)3 (0.2)
AgOAc (1.0)
AcOH (2.0)
p-TSA (1.0)
HCl e
5
6
7
8
43
9
TBSCl (2.0)
TMSCl (2.0)
TMSCl (2.0)
TMSCl (2.0)
TMSCl (2.0)
TMSCl (1.0)
TMSCl (3.0)
62
10
11
12
13
14
15
66
29
53
63
46
67
a Reagents and conditions: isatin 1a (0.5 mmol) and acetylacetone 2a (0.7
b
mmol) in MeOH (3.0 mL); Isolated yield based on isatin 1a; n.d. = no
detected; d n.r. = no reaction; e 0.1 ml (1.0 M hydrochloric acid solution).
c

3
Scheme 3. Gram Scale Synthesis.
acetylacetone 2a in propyl alcohol to provide the desired
quinaldine 4c (1.13 g, 75%) as show in Scheme 3.
In terms of the reaction mechanism, we checked the pH value
of the quenched reaction system, which greatly reduced after. In
fact, HCl is less efficient than TMSCl (entry 8 vs. entry 10, Table
1). Next, the desired product 3a failed to obtain in 1.0 ml HCl
and 3a increased slightly catalyzed by 2.0 equivalent p-TSA
(54%). Based on these observations, the reaction has likely gone
through a proton acid mediated mechanism, but excess water
inhibited the reaction. To confirm that TMSCl played an
important role in the reaction, preprocessed TMSCl (dehydration
and deacidification) also was carried out in this protocol, which
found more efficient than unpreprocessed TMSCl (72% vs. 66%
(entry 10, Table 1)). Thus, it is also likely that the reaction has
experienced a TMSCl mediated mechanism. However, further
evidences are necessary to disclose the details.
Fig. 2 X-ray structure of compound 4j.
Table 3.
Substrate scope of the quinaldines 4.a,b
Conclusion
In conclusion, we developed a first improved Pfitzinger
reaction for the synthesis of highly functionalized quinaldine-
4-carboxylates, from isatins with 1,3-dicarbonyl compounds
in alcohols mediated by TMSCl. Moreover, this green
approach provided a rapidly strategy to construct molecularly
diverse quinaldine-4-carboxylate derivatives library with good
yields under mild conditions. The reaction can be scaled up to
produce grams of quinaldine-4-carboxylates. Attempts to
further understand to the reaction mechanism and applications
are underway in our laboratory.
O
Me
Br
O
O
O
O
O
OEt
Me
OEt
N
N
Me
4f
4d, 88%
, 83%
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21402070), the Personnel
Training Foundation of Kunming University of Science and
Technology (KKSY201426017, KKSY201432109) and The
Analytical & Testing Foundation of Kunming University of
Science and Technology (20150751, 20150742).
Me
O
O
O
O2N
OEt
Me
N
4j
, 64%
a Reagents and conditions: isatins 1 (0.5 mmol), ethyl acetoacetate 2b (0.7
mmol) and TMSCl (1.0 mmol) in alcohols (3.0 mL), stirred at 60 °C for
6.0 h; b Isolated yield based on isatin 1.
Supplementary data
Supplementary data (experimental procedures, characterization
data and 1H and 13C NMR spectra of the compounds) associated
with this article can be found, in the online version, at
http://dx.doi.org/xx.xxx/j.tetlet.xxxx.xx.xxx.
References and notes
Scheme 2 Synthesis of 4-carboxyl- and α-methylenation of 3-carbonyl of
quinaldine derivatives.
1
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5
An Improved Pfitzinger Reaction:
Eco-efficient Synthesis of Quinaldine-
4-carboxylates by TMSCl-Mediated
Lingling Lu,†a Pan Zhou,†a Biao Hu,a Xiang Li,b
Rong Huang,c and Fuchao Yu*a
a Faculty of Life Science and Technology, Kunming University of Science and
Technology, Kunming, 650500, P. R. China.
b Research Center for Analysis and Measurement, Kunming University of
Science and Technology, Kunming, 650500, P. R. China.
c School of Chemical Science and Technology, Yunnan University, Kunming,
650091, P. R. China
Highlights:
ꢀ
ꢀ
ꢀ
ꢀ
The first an improved Pfitzinger reaction for
synthesis of quinaldines.
It involves cyclization and esterification in one-
step cascade process.
A novel library of quinaldines in moderate to
good yields under mild conditions.
This method shows environment-friendly, easy
to operate, feasibility of scale up.
———
∗ Corresponding author. Tel.: +0086-871-65920747; e-mail:
yufuchao05@126.com (F. Yu).
† L. Lu. and P. Zhou. contributed equally.