Unified Approach to (Thio)chromenones via One-Pot Friedel-Crafts Acylation/Cyclization: Distinctive Mechanistic Pathways of β-Chlorovinyl Ketones

Article abstract of DOI:10.1021/acs.orglett.6b03348

A facile synthetic method to chromenones and thiochromenones has been developed using a one-pot Friedel-Crafts acylation of alkynes with suitably substituted benzoyl chlorides. This unified approach to (thio)chromenones is readily applicable to aryl- and alkylalkynes where the stereochemically well-defined β-chlorovinyl ketone intermediates undergo distinctively different cyclization pathways. The ready availability of both starting materials, alkynes and benzoyl chlorides, coupled with the experimental simplicity makes the current synthetic method to (thio)chromenones fast, efficient, and practical.

Full text of DOI:10.1021/acs.orglett.6b03348

Letter
pubs.acs.org/OrgLett
Unified Approach to (Thio)chromenones via One-Pot Friedel−Crafts
Acylation/Cyclization: Distinctive Mechanistic Pathways of
β‑Chlorovinyl Ketones
Hun Young Kim, Eunsun Song, and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic
of Korea
S
* Supporting Information
ABSTRACT: A facile synthetic method to chromenones and
thiochromenones has been developed using a one-pot
Friedel−Crafts acylation of alkynes with suitably substituted
benzoyl chlorides. This unified approach to (thio)-
chromenones is readily applicable to aryl- and alkylalkynes
where the stereochemically well-defined β-chlorovinyl ketone
intermediates undergo distinctively different cyclization path-
ways. The ready availability of both starting materials, alkynes
and benzoyl chlorides, coupled with the experimental
simplicity makes the current synthetic method to (thio)-
chromenones fast, efficient, and practical.
synthetic versatility of β-chlorovinyl ketones,5 we devised a new
β-Chlorovinyl ketones serve as fertile ground for the develop-
ment of heterocycle synthesis.1 While the addition of acid
synthetic strategy to chromenone derivatives including flavones
and thiochromenones.
chloride to alkyne generally provides β-chlorovinyl ketones,2
Chromenones are the key constituent of numerous natural
products with various biological activities.6 The traditional
synthetic approaches include the intramolecular condensation
of o-hydroxy 1,3-diones7 and the intramolecular conjugate
addition of o-hydroxy chalcones under oxidation conditions.8
While there have been intensive synthetic efforts to develop the
efficient synthesis of chromenone derivatives, most of the
methods typically involves multistep synthesis of the precursors
to chromenones.9 For example, the intramolecular iodocycliza-
tion of alkynones,10 the intermolecular benzyne addition to
allenoic acids,11 and the Wittig reactions require the synthesis
of elaborated starting materials.12 The recent development of
C−H activation of chromenone also provides a ready access to
chromone derivatives; however, the methodology is limited to
the introduction of flavones (R2 = Ar).13 Currently, the Pd-
catalyzed cyclocarbonylation of o-iodophenols with terminal
alkynes stands out among the synthetic approaches to
chromenones in terms of ready access to starting materials
and operational simplicity.14 As a congener of chromenones,
thiochromenones also display interesting biological activities.15
Although a few direct synthetic methods to thiochromenones
exist using the Sonogashira coupling of o-haloaroyl chloride
with alkynes,16 the Ni-catalyzed reactions of thioisatins (or
thiophthalic anhydrides) and alkynes,17 and the Pd-catalyzed
carbonylative cycloaddition of 1-fluoro-2-iodobenzene with
alkynes,18 the introduction of alkyl substituents at the 2-
the stereoselective formation of (E)-β-chlorovinyl ketones still
relies on the Friedel−Crafts acylation of alkynes under the
catalysis of AlCl3 (Scheme 1).3
Scheme 1. Synthetic Utility of β-Chlorovinyl Ketones
In particular, we have recently shown that (E)-β-chlorovinyl
ketones undergo soft α-vinyl enolization more than 10−50
times faster than (Z)-β-chlorovinyl ketones in the presence of
Et3N.4 Such discrepancy in the rate of enolization could be
useful in differentiating the mechanistic pathways of stereo-
isomeric β-chlorovinyl ketones. With the aim of expanding the
Received: November 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03348
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
position remains a challenging class of thiochromenone
derivatives.
an intramolecular conjugate addition/elimination sequence.
Next, we sought the optimal amount of AlCl3 (entries 2−6)
and found that the use of 2.5 equiv of AlCl3 cleanly led to the
formation of chromenone 4a in an isolated yield of 74%.
Although we also screened other Lewis acids instead of AlCl3
(entry 7), no reaction was observed. The stereochemical
outcome of the Friedel−Crafts acylation of 1-heptyne 1b was
opposite to that of phenylacetylene 1a. Thus, upon using 1b
under otherwise identical reaction conditions the stereo-
selective formation of demethylated (E)-3b was observed
(entry 8). Further addition of AlCl3 did not alter the outcome
of the reaction, and (E)-3b was reisolated as a sole product
(entry 9). Next, we studied the role of bases upon quenching
the reaction (entries 10−14). While the formation of the
desired chromenone 4b was observed upon using an excess
amount of bases, especially KO-t-Bu, the reactions were
accompanied by multiple side products,19 making them
synthetically unviable (entry 14). Gratifyingly, we found that
the use of 1.5 equiv of Et3N could initiate the soft α-vinyl
enolization of (E)-3b, leading to the rapid formation of
chromenone 4b (entry 15).20 Finally, the combination of 1.5
equiv of Et3N and 3.0 equiv of KO-t-Bu smoothly transformed
(E)-3b to chromenone 4b in one pot with an isolated yield of
61%.
Because of the lack of direct and unified synthetic approaches
to both chromenone and thiochromenone derivatives with a
diverse substitution pattern at 2-position, we envisioned the use
of β-chlorovinyl ketones as a versatile precursor to (thio)-
chromenones. Herein, we report a one-pot synthetic approach
to (thio)chromenones using the stereospecific Friedel−Crafts
acylation of alkynes followed by an intramolecular cyclization of
in situ generated β-chlorovinyl ketones. The current approach
to (thio)chromenones signifies the conformational preferences
of stereoisomeric β-chlorovinyl ketones, the key reaction factor
for the efficient intramolecular cyclization to (thio)chromenone
derivatives.
To investigate the synthetic route to chromenones via β-
chlorovinyl ketones, we first examined the stereochemical
outcome of Friedel−Crafts acylation of alkynes with 2-
methoxybenzoyl chloride (Table 1). When phenylacetylene
Table 1. Optimization of the One-Pot Synthesis of
a
Chromenones
The optimized reaction conditions for aryl- and alkylalkynes
were further evaluated using various alkynes and benzoyl
chlorides (Scheme 2). As for the arylalkynes using 2.5 equiv of
AlCl3 (method A), the normal H2O-quenching procedure for
the Freidel−Crafts acylation reaction provided chromenones
4c−g in 65−88% yields. The reaction could be extended to
b
entry
1
MCl3 (equiv)
base (equiv)
conv (%)
Scheme 2. Scope of One-Pot Synthesis of Chromenones
c
1
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
AlCl3 (1.1)
AlCl3 (1.5)
AlCl3 (2.0)
AlCl3 (2.0)
AlCl3 (2.5)
AlCl3 (3.0)
FeCl3 (3.0)
AlCl3 (2.5)
AlCl3 (4.0)
AlCl3 (2.5)
AlCl3 (2.5)
AlCl3 (2.5)
AlCl3 (2.5)
AlCl3 (2.5)
AlCl3 (2.5)
AlCl3 (2.5)
AlCl3 (2.5)
48
d
2
50
e
3
72
f
4
78
5
100 (74)
100 (52)
6
g
7
0
h
8
0
h
9
0
10
11
12
13
14
15
K2CO3 (2.0)
NaOH (2.0)
KOH (2.0)
17
20
27
35
46
KO-t-Bu (2.0)
KO-t-Bu (10)
Et3N (1.5)
i
10
j
16
j
(1.5) + (2.0)
(1.5) + (3.0)
78
17
100 (61)
a
Reaction conditions: 1 (0.5 mmol) and 2 (0.5 mmol) in CH2Cl2 (2.5
b
mL) under argon atmosphere. Conversion by 1H NMR and, in
parentheses, isolated yield of chromenones 4 after column
c
d
e
f
chromatography. 3a (52%). 3a (50%). 3a (28%). Reaction for 7
g
h
i
j
h; 3a (22%). 1a (100%). 3b (100%). 3b (90%). Use of Et3N and
KO-t-Bu.
1a in the presence of 1.1 equiv of AlCl3 was used, the formation
of chromenone 4a was observed in 48% yield (entry 1). The
isolation of (Z)-3a indicated the intermediacy of (Z)-3a to
chromenone 4a by a concomitant demethylation of the
methoxy group in (Z)-3a by AlCl3. Our subsequent control
reaction using (Z)-3a as the starting material to chromenone 4a
confirmed the role of AlCl3 in the demethylation followed by
B
DOI: 10.1021/acs.orglett.6b03348
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
disubstituted alkynes as well as substituted benzoyl chlorides to
give diversely substituted chromenones 4h−l. Interestingly, the
use of dimethoxy-substituted benzoyl chloride retained one
methoxy group upon use of disubstituted alkyne to give
chromenones 4m. The use of alkylalkynes again required
quenching treatment with 1.5 equiv of Et3N and 3.0 equiv of
KO-t-Bu (method B) and provided the desired chromenones
4n−q in 47−71% yields. The Friedel−Crafts acylation of
(trimethylsilyl)acetylene led to the formation of alkynone 3q
after a concomitant demethylation and desilylation by AlCl3.
The alkynone 3q only underwent cyclization upon treatment
under basic conditions, including method B.21
Scheme 4. Stereochemical and Conformational
Consideration on the Cyclization of β-Chlorovinyl Ketones
to (Thio)chromenones
Motivated by the facile synthetic routes to chromenones
from stereodefined β-chlorovinyl ketones, we employed 2-
(methylthio)benzoyl chloride 5 for the one-pot synthesis of
thiochromenones (Scheme 3). The reactions were readily
Scheme 3. Application to One-Pot Synthesis of
Thiochromenones
the validity of the non-H-bonded conformation of (E)-3 to
(thio)chromenones. However, the use of strong bases brings
about the functional group compatibility issues under strong
basic conditions, leading to (thio)chromenones in low yields.
The use of mild base, Et3N, prompts a mild α-vinyl enolization
of (E)-3 to allenes that in turn undergo a rapid cyclization to
(thio)chromenones. It is likely that the conformation of
hydroxy (or thiol)-substituted allenes effectively competes
with the H-bonded conformations;22 thus, the allene
intermediates undergo either conjugate addition followed by
alkene isomerization or hydration/hydrothiolation to give the
(thio)chromenones.
In summary, we have developed a facile and unified one-pot
synthesis to (thio)chromenones from readily available alkynes
and suitably substituted benzoyl chlorides. The divergent
reaction pathway of stereoisomeric β-chlorovinyl ketones is a
good reminder of the stereochemical as well as conformational
significance of β-chlorovinyl ketones in the subsequent reaction
pathways to important heterocycles. Our current research
efforts are directed to detailed mechanistic studies and
expanding the chemistry to other heterocyclic compounds,
and our results will be reported in due course.
applicable to aryl- and alkylalkynes, providing substituted
thiochromenones 6a−m in 63−86% yields. Notably, the
syntheses of 4H-thiopyrano[2,3-b]pyridin-4-one 6i as well as
a chloride-containing thiochromenone 6l were achieved in
good yields.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03348.
■
S
The stereochemical outcomes of the Friedel−Crafts acylation
of aryl- and alkylalkynes provide mechanistic insight into the
subsequent cyclization to (thio)chromenones. Thus, the
formation of (Z)-3 with an intact (thio)methoxy group from
arylalkynes implies that the most probable conformation of
(Z)-3a would place the carbonyl group far away from the
(thio)methoxy group (Scheme 4). The role of AlCl3 would
then be the Lewis acid to activate the carbonyl group, so the
(thio)methoxy group could initiate a conjugate addition
reaction. Once the demethylation of the oxonium (or
thionium) ion occurs, after the elimination of chloride, the
(thio)chromenones are obtained. In contrast, the formation of
(E)-3 with a hydroxyl (or thiol) group from alkyl alkynes
suggests that the most probable conformation of (E)-3 would
be the intramolecularly H-bonded conformation. The fact that
the H-bonded conformation of (E)-3 did undergo cyclization
to (thio)chromenones under the influence of bases illustrates
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kyungsoooh@cau.ac.kr.
ORCID
Kyungsoo Oh: 0000-0002-4566-6573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korea government (MSIP)
■
C
DOI: 10.1021/acs.orglett.6b03348
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(17) (a) Inami, T.; Baba, Y.; Kurahashi, T.; Matsubara, S. Org. Lett.
2011, 13, 1912−1915. (b) Inami, T.; Kurahashi, T.; Matsubara, S. Org.
Lett. 2014, 16, 5660−5662.
( N R F - 2 0 1 5 R 1 A 5 A 1 0 0 8 9 5 8 a n d N R F -
2015R1C1A2A01053504).
(18) Shen, C.; Spannenberg, A.; Wu, X.-F. Angew. Chem., Int. Ed.
2016, 55, 5067−5070.
REFERENCES
■
(19) Among other unidentifiable products, the formation of hydrated
products was observed.
(1) For reviews, see: (a) Pohland, A. E.; Benson, W. R. Chem. Rev.
1966, 66, 161−197. (b) Gooßen, L. J.; Rodríguez, N.; Gooßen, K.
Angew. Chem., Int. Ed. 2009, 48, 9592−9594.
(2) For recent examples, see: (a) Gandeepan, P.; Parthasarathy, K.;
Su, T.-H.; Cheng, C.-H. Adv. Synth. Catal. 2012, 354, 457−468.
́
(b) Cano, R.; Yus, M.; Ramon, D. J. Tetrahedron 2013, 69, 7056−
(20) The formation of allenyl ketone intermediates was not observed
upon treating the purified (E)-3b with Et3N. Instead, the formation of
chromenone 4b was observed from (E)-3b in 85% yield.
(21) The use of AlCl3 did not effect the cyclization of alkynone 3q
under the method A conditions.
(22) The fact that the soft α-vinyl enolization of (E)-3b prompts the
direct formation of chromenone 4b suggests that the intermediate,
hydroxyallenyl ketone, might readily undergo the cyclization to
chromenone under slightly basic/neutral conditions. The β-chlor-
ovinyl ketones derived from 1,2-dialkylalkynes failed to provide (thio)
chromenones, possibly due to the lack of α-hydrogen for the soft vinyl
enolization to give allenyl ketone intermediates.
7065. (c) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc.
2012, 134, 1268−1274. (d) Kashiwabara, T.; Tanaka, M. Adv. Synth.
Catal. 2011, 353, 1485−1490. (e) Wang, B.; Wang, S.; Li, P.; Wang, L.
Chem. Commun. 2010, 46, 5891−5893. (f) See ref1a.
(3) (a) Benson, W. R.; Pohland, A. E. J. Org. Chem. 1964, 29, 385−
391. (b) Oh, K.; Kim, H.; Cardelli, F.; Bwititi, T.; Martynow, A. M. J.
Org. Chem. 2008, 73, 2432−2434.
(4) Kim, H. Y.; Li, J.-Y.; Oh, K. J. Org. Chem. 2012, 77, 11132−
11145.
(5) For the previous contributions from our group, see: (a) Kim, H.
Y.; Li, J.-Y.; Oh, K. Angew. Chem., Int. Ed. 2013, 52, 3736−3740.
(b) Kim, H. Y.; Rooney, E. O.; Meury, R. P.; Oh, K. Angew. Chem., Int.
Ed. 2013, 52, 8026−8030. (c) Kim, H. Y.; Oh, K. Org. Lett. 2014, 16,
5934−5936. (d) Kim, H. Y.; Lee, S.; Kim, S.; Oh, K. Org. Lett. 2015,
17, 450−453. (e) Kim, H. Y.; Oh, K. Org. Lett. 2015, 17, 6254−6257.
(6) For selected reviews, see: (a) Kosmider, B.; Osiecka, R. Drug Dev.
Res. 2004, 63, 200−211. (b) Teillet, F.; Boumendjel, A.; Boutonnat, J.;
Ronot, X. Med. Res. Rev. 2008, 28, 715−745. (c) Talhi, O.; Silva, A. M.
S. Curr. Org. Chem. 2012, 16, 859−896. (d) Kumazawa, Y.; Takimoto,
H.; Matsumoto, T.; Kawaguchi, K. Curr. Pharm. Des. 2014, 20, 857−
863.
(7) For selected examples, see: (a) Okombi, S.; Schmidt, J.; Mariotte,
A.; Perrier, E.; Boumendjel, A. Chem. Pharm. Bull. 2005, 53, 1460−
1462. (b) Chee, C. F.; Buckle, M. J. C.; Rahman, N. A. Tetrahedron
Lett. 2011, 52, 3120−3123. (c) Zhao, J.; Zhao, Y.; Fu, H. Org. Lett.
2012, 14, 2710−2713.
(8) For selected examples, see: (a) Lorenz, M.; Kabir, M. S.; Cook, J.
M. Tetrahedron Lett. 2010, 51, 1095−1098. (b) Du, Z.; Ng, H.; Zhang,
K.; Zeng, H.; Wang, J. Org. Biomol. Chem. 2011, 9, 6930−6933.
(c) Sashidhara, K. V.; Kumar, M.; Kumar, A. Tetrahedron Lett. 2012,
53, 2355−2359.
(9) For a recent reviews, see: (a) Gaspar, A.; Matos, M. J.; Garrido, J.;
Uriarte, E.; Borges, F. Chem. Rev. 2014, 114, 4960−4992. (b) Tome, S.
M.; Silva, A. M. S.; Santos, C. M. M. Curr. Org. Synth. 2014, 11, 317−
341.
(10) For selected examples, see: (a) Zhou, C.; Dubrovsky, A. V.;
Larock, R. C. J. Org. Chem. 2006, 71, 1626−1632. Using TfOH, see:
(b) Yoshida, M.; Fujino, Y.; Doi, T. Org. Lett. 2011, 13, 4526−4529.
(11) Chai, G.; Qiu, Y.; Fu, C.; Ma, S. Org. Lett. 2011, 13, 5196−5199.
(12) For selected examples, see: (a) Kumar, P.; Bodas, M. S. Org.
Lett. 2000, 2, 3821−3823. (b) Das, J.; Ghosh, S. Tetrahedron Lett.
2011, 52, 7189−7194.
(13) For selected examples, see: (a) Kim, K.; Choe, H.; Jeong, Y.;
Lee, J. H.; Hong, S. Org. Lett. 2015, 17, 2550−2553. (b) Lee, J.; Yu, J.;
Son, S. H.; Heo, J.; Kim, T.; An, J.-Y.; Inn, K.-S.; Kim, N.-J. Org.
Biomol. Chem. 2016, 14, 777−784.
(14) For selected examples, see: (a) Liang, B.; Huang, M.; You, Z.;
Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70,
6097−6100. (b) Awuah, E.; Capretta, A. Org. Lett. 2009, 11, 3210−
3213. (c) Yang, Q.; Alper, H. J. Org. Chem. 2010, 75, 948−950.
(15) For examples, see: (a) Wang, H.-K.; Bastow, K. F.; Cosentino,
L. M.; Lee, K.-H. J. Med. Chem. 1996, 39, 1975−1980.
(b) Dekermendjian, K.; Kahnberg, P.; Witt, M.-R.; Sterner, O.;
Nielsen, M.; Liljefors, T. J. Med. Chem. 1999, 42, 4343−4350.
(c) Kataoka, T.; Watanabe, S.; Mori, E.; Kadomoto, R.; Tanimura, S.;
Kohno, M. Bioorg. Med. Chem. 2004, 12, 2397−2407.
(16) Fuchs, F. C.; Eller, G. A.; Holzer, W. Molecules 2009, 14, 3814−
3832.
D
DOI: 10.1021/acs.orglett.6b03348
Org. Lett. XXXX, XXX, XXX−XXX