Highly efficient access to 4-chloro-2H-chromenes and 1,2-dihydroquinolines under mild conditions: TMSCl-mediated cyclization of 2-propynolphenols/anilines

Article abstract of DOI:10.1016/j.tetlet.2016.07.103

A novel and efficient TMSCl-mediated cyclization reaction of easily prepared 2-propynolphenols/anilines is developed to give 4-chloro-2H-chromenes and 1,2-dihydroquinolines in good to efficient yields. It is noted that TMSCl acts not only as a promoter in this reaction, and also as the chloro source. Both tertiary and secondary propargylic alcohols with diverse functional groups were tolerated under mild conditions. Moreover, this method can be enlarged to gram scale (yield up to 90%).

Full text of DOI:10.1016/j.tetlet.2016.07.103

Accepted Manuscript
Highly Efficient Access to 4-Chloro-2H-chromenes and 1,2-Dihydroquinolines
under Mild Conditions: TMSCl-Mediated Cyclization of 2-Propynolphenols/
Anilines
Xian-Rong Song, Ren Li, Haixin Ding, Ruchun Yang, Qiang Xiao, Yong-Min
Liang
PII:
S0040-4039(16)30971-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.103
TETL 47965
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 June 2016
24 July 2016
30 July 2016
Please cite this article as: Song, X-R., Li, R., Ding, H., Yang, R., Xiao, Q., Liang, Y-M., Highly Efficient Access
to 4-Chloro-2H-chromenes and 1,2-Dihydroquinolines under Mild Conditions: TMSCl-Mediated Cyclization of 2-
Propynolphenols/Anilines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.103
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Tetrahedron Letters
Highly Efficient Access to 4-Chloro-2H-chromenes and 1,2-Dihydroquinolines under
Mild Conditions: TMSCl-Mediated Cyclization of 2-Propynolphenols/Anilines
a
a
a
a
a
b
Xian-Rong Song, Ren Li, Haixin Ding, Ruchun Yang, Qiang Xiao* and Yong-Min Liang
a Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Key Laboratory of Organic Chemistry, Jiangxi Province, Nanchang 330013,
China
bState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
novel and efficient TMSCl-mediated cyclization reaction of easily prepared 2-
propynolphenols/anilines is developed to give 4-chloro-2H-chromenes and 1,2-Dihydroquinolines in
good to efficient yields. It is noted that TMSCl acts not only as a promoter in this reaction, and also as
the chloro source. Both tertiary and secondary propargylic alcohols with diverse functional groups
were tolerated under the mild conditions. Moreover, this method can be enlarged to gram scale (yield
up to 90%).
Available online
Keywords:
2-Propynolphenols/Anilines
4-Chloro-2H-chromenes/quinolines
TMSCl-Mediated
.
Cyclization
materials.[8] To the best of our knowledge, the direct
transformation of 2-propynolphenols to 4-chloro-2H-chromenes
has been not disclosed yet. As shown in scheme 1, 4-chloro- 2H-
Introduction
2H-chromene is a considerably significant flavonoid skeletal
structure, which widely distributes in a variety of natural
products and pharmaceutically active molecules.[1-3]
Meanwhile, in view of the potential bioactivity and
pharmaceutical activities of such compounds, as well as the
crucial position in organic synthetic chemistry, the
development of atom- and step-economical approaches for
the synthesis of benzopyran structures has attracted
considerable attentions. The general approaches for the
synthesis of functionalized 2H-chromenes include the
modification of pre-constructed of chromonone nucleus,[4]
and the cyclization of substituted phenolic propargyl ether
compounds.[5] Not long ago, Kumar and Su group reported a
mild synthesis of 4-chloro-2H-chromenes from the
Vilsmeier-type reaction of 2'-hydroxychalcones.[6] Despite
these pioneering methodologies for the synthesis of 2H-
chromenes, some of them suffered one or more
shortcomings, such as tedious procedures, harsh conditions,
limited substrates, and the unsatisfactory yields. So, it is still
desirable to develop an efficient and straightforward method
for the synthesis of functionalized 2H-chromenes in mild
conditions with broad substrates scope.
chromenes have been extensively used as valuable intermediates
for the construction of various O-heterocyclic compounds with
[9-12]
potential bioactivity.
Herein, we describe an efficient and
novel approach to access 4-chloro-2H-chromenes or 1,2-
dihydroquinolines under mild reaction conditions (Scheme 1).
Compared to the traditional strategies, our developed methods
could be conveniently operated, which may open up a new
potential application for these systems in industrial production. It
is noted that TMSCl acts not only as a promoter in this reaction,
and also as the chloro source.
Owing to the potential intrinsic reactivity of alkynols, the
tandem reaction of alkynols has recently received considerable
attention and has become powerful tool for the construction of
various carbo- and heterocyclic compounds.[7] Recently, our
group developed a tandem process to synthesize heterocyclic
building blocks by using 2-propynolphenols as the starting
Scheme 1 arious applications of 4-chloro-2H-chromenes and
our work

2
Tetrahedron
Results and Discussion
(Me, OMe) and -withdrawing (F, Cl) substituents on either
of the two aryl groups could be tolerated and afforded the
desired products in good to excellent yields (2a 2j).
The initial exploration for the construction of 4-chloro-2H-
chromenes began by employing 2-propynolphenols 1a (0.2 mmol)
as the model substrate with TMSCl (1.5 equiv) in CH3NO2 at
50 °C for 1.0 h (Table 1, entry 1). To our delight, the desired
−
Moreover, the steric effect of substituents exerted a clear
influence on this transformation; the substituents on the
ortho-position of aryl groups gave slightly lower yields (2g).
product, 4-chloro-2,2-diphenyl-2H-chromene
(2a), was
When the substrates with two different aryl groups (R1

R2)
isolated in 87%. Subsequently, various representative
solvents were screened. And MeCN proved to be the most
efficient one, which increased the yield of 2a to 95% (Table
1, entries 2–7). When the temperature was increased to 80
°C, 2a was obtained in a lower yield (Table 1, entry 8). We
considered that a higher temperature was advantageous to
the side reaction. 79% yield of 2a was obtained at room
temperature for 4.0 h due to the relatively lower reactivity,
as expected (Table 1, entry 9). Furthermore, other
adjustments indicated that the most appropriate amount of
TMSCl was 1.5 equiv (Table 1, entries 10–11). In addition,
no better yields were obtained, when conc.HCl (12 mol/L)
was applied instead of TMSCl in this reaction (Table 1,
entry 12). Ultimately, the optimal reaction conditions for
generating 2a were determined to be the use of TMSCl (1.5
equiv) in MeCN (2.0 mL) at 50 °C for 1.0 h.
were employed under optimal reaction conditions, the
corresponding products were obtained in good to excellent
yields
(2g−2j). Furthermore, substrates with diverse
substituents (Me, Cl and Br) as the R3 group could also
readily participate in this tandem reaction to generate the
desired products in excellent yields (2l−2n). Especially, the
Table 2 Transformation of tertiary propargylic alcohols to
4-chloro-2H-chromenesa
Table 1 Optimization of the reaction conditionsa
Entry
Solvent
TMSCl
(equiv)
1.5
T[ºC ]
Yield
1
2
3
4
MeNO2
DCE
50
50
50
50
87
91
95
88
1.5
1.5
1.5
MeCN
CH2Cl2
5
6
THF
HOAc
1.5
1.5
50
50
89
91
7
1,4-dioxane
MeCN
1.5
1.5
1.5
2.0
1.2
1.5
50
80
rt
90
90
79
96
90
86
8
9b
10
11
12c
MeCN
MeCN
50
50
50
MeCN
MeCN
aUnless otherwise noted, all reactions were performed with 0.2 mmol of 1a
with TMSCl, in solvent (2.0 mL) at 50 °C. b 4.0 h. c HCl was used instead
of TMSCl.
With the optimized reaction conditions in hand, a
variety of substituted 2-propynolphenols were prepared to
investigate the scope of this tandem reaction. The
corresponding 4-chloro-2H-chromene products
(2a−2o)
were obtained in good to excellent yields (up to 97%) under
the optimal reaction conditions (Table 2). The structure of
2n was also confirmed by an X-ray diffraction (see the
Supporting Information). Firstly, various substituted tertiary
aUnless otherwise noted, all reactions were performed with 0.2 mmol of 1, 1.5
equiv of TMSCl in CH3CN (2.0 mL) at 50 °C.
reaction proceeded smoothly for the substrates with a
multiple-ring group (naphthyl group, 1k and 1o).
Unfortunately, no desired product was obtained when alkyl-
propargylic alcohols
1 were treated with TMSCl to explore
the substituents effects. In general, both electron-donating

substituted propargylic alcohol 1
reaction.
Encouraged by the above results, the reactions of
secondary propynols were also examined under the
optimized reaction conditions (Table 3). Some
p
was employed in this
In addition, some representative 2-propynolanilines 5a-
5f were also investigated under the optimal conditions, and
the corresponding products 4-chloro-2H-quinolines were
obtained in good to excellent yields (Table 4). 1,2-
Dihydroquinolines are important organic synthetic
intermediates for pharmaceuticals, antimicrobials, and
biologically active compounds.[13]
representative substrates 3a−3h smoothly transformed into
the corresponding mono-phenyl substituted 4-chloro-2H-
chromenes in good to excellent yields (4a
−
4h). And the
Noticeably, an obvious advantage of our developed
reaction system is that this reaction could be scaled-up to
gram quantities. When substrate 2-propynolphenol 1a (1.0
g) was performed under the optimal reaction conditions, the
corresponding product 2a was obtained in a high yield to
90%, which might provide a potential application in organic
synthesis industrial production (Scheme 2).
electronic properties of the substituent (R1) exerted a clear
influence on this transformation. Substrates with electron-
rich moieties on R1 showed better results than those with
electron-withdrawing ones in this transformation (3e vs 3f).
Table 3 Transformation of secondary propargylic alcohols into
4-chloro-2H-chromenesa
Scheme 2 Scale-up experiment
Moreover, the synthetic application of the 4-chloro-2H-
chromene products was demonstrated by an array of
palladium-catalyzed cross-coupling reactions (Scheme 3). [14]
Suzuki-Miyaura coupling of 2b with arylboronic acid
proceeded by using L1 as the ligand to yield
7 in good
yields (Scheme 3a). The products 2b also underwent
Sonogashira coupling with 4-methoxyphenylacetylene by
using L2 as the ligand to provide
8 in moderate yields
(Scheme 3b).
aUnless otherwise noted, all reactions were performed with 0.2 mmol of 3, 1.5
equiv of TMSCl in CH3CN (2.0 mL) at 50 °C.
Table 4 Transformation of 2-propynolanilines into 4-chloro-
a
2H- quinolines
Scheme 3 Synthetic application
On the basis of the above detailed investigation and
previous reports,[15]
a
plausible mechanism of this
transformation is shown in Scheme 4. Firstly, propargylic
alcohol is converted to the propargylic cation in the
presence of TMSCl, which would then undergo
mesomerism to produce the allenic cation . Then the
allenic substitution occurs by the attack of the chloro anion,
resulting in intermediate . Intermediate could then be
protonated to give intermediate , which is attacked by the
1
A
a
B
aUnless otherwise noted, all reactions were performed with 0.2 mmol of 5, 1.5
equiv of TMSCl in CH3CN (2.0 mL) at 50 °C. Ns = p-Nitrobenzenesulfonyl.
Ms = Methanesulfonyl.
C
C
D

4
Tetrahedron
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Scheme 4 Proposed mechanism.
In conclusion, we have developed a novel and highly
efficient method for the construction of 4-chloro-2H-
chromenes and -1,2-Dihydroquinolines via a TMSCl-
mediated cyclization reaction of propargyl alcohols. This
reaction performed smoothly with a C−Cl bond and a
C−O/N bond constructed concurrently under mild conditions
in very high yields (up to 97%). It is noted that TMSCl acted
as not only a promoter, and also the chloro source in this
reaction. In addition, this reaction system could be enlarged
to gram scale in an excellent yield to 90% under very mild
conditions, which might provide a potential application in
the organic synthesis for industrial production.
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We acknowledge the Jiangxi Science & Technology Normal
University
and
the
Education Department of Jiangxi Province (GJJ150806) for
financial support. We also thank the National Science
Foundation (NSF21462019) for financial support.
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Supplementary Material
Supplementary data associated with this article can be found in the online
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Highly Efficient Access to 4-Chloro-2H-
chromenes and 1,2-Dihydroquinolines under
Mild Conditions: TMSCl-Mediated
Leave this area blank for abstract info.
Cyclization of 2-Propynolphenols/Anilines
Xian-Rong Song,a Ren Li,a Haixin Ding, a Ruchun Yang,a
a
b
Qiang Xiao* and Yong-Min Liang
or altere

6
Tetrahedron
Highlights
TMSCl-mediated synthesis of 4-chloro-2H-chromenes and 1,2-
•
Dihydroquinolines.
•
Both tertiary and secondary propargylic alcohols with diverse
functional groups were tolerated.
• TMSCl acts not only as a promoter in this reaction, and also as
the chloro source.
•
This method can be enlarged to gram scale (yield up to 90%).