Construction of Diverse and Functionalized 2H-Chromenes by Organocatalytic Multicomponent Reactions

Article abstract of DOI:10.1002/ejoc.201500616

A green and efficient one-pot process for the construction of diverse and functionalized 2H-chromenes was developed by using multicomponent reactions of salicylaldehydes, alkynes (i.e., propiolate and acetylenedicarboxylates), and alcohols. This new proto

Full text of DOI:10.1002/ejoc.201500616

FULL PAPER
DOI: 10.1002/ejoc.201500616
Construction of Diverse and Functionalized 2H-Chromenes by Organocatalytic
Multicomponent Reactions
[a]
[a]
[a]
[a]
[b]
Hongyun Cai, Likai Xia, Yong Rok Lee,* Jae-Jin Shim, and Sung Hong Kim
Keywords: Oxygen heterocycles / Organocatalysis / Multicomponent reactions / Amino acids / Alkynes
A green and efficient one-pot process for the construction of
diverse and functionalized 2H-chromenes was developed by
using multicomponent reactions of salicylaldehydes, alkynes
regioselectivity, and environmentally benign nature under
mild reaction conditions. As an extension of this method,
quinoline derivatives were synthesized by replacing salicyl-
aldehyde with 2-aminobenzaldehyde, and the 2-hydroxy-
2H-chromenes prepared by this approach were also success-
fully transformed into biologically interesting coumarins
through an oxidation reaction.
(
i.e., propiolate and acetylenedicarboxylates), and alcohols.
This new protocol was achieved by using -proline as a mild
L
and green organocatalyst and offers several advantages such
as economic availability, low toxicity, ease of handling, high
Introduction
organocatalytic MCRs and the use of environmentally be-
[
9]
nign solvents and reagents are particularly attractive, be-
cause they incorporate many of the concepts and principles
of green chemistry.
Recent advances in organocatalysis have provided many
green approaches for the efficient synthesis of a wide range
[
1]
of molecules. Because of the unique characteristics of or-
ganocatalysts, their applications in organic transformations
are frequently considered.[1,2] Organocatalysts, as opposed
to protic acids and inorganic Lewis acids, have a number of
advantages such as water stability, recyclability, operational
simplicity, strong tolerance to oxygen- and nitrogen-con-
taining substrates and functional groups, and low catalyst
2
H-Chromene, a well-known privileged structural motif,
is present in a number of biologically active natural prod-
ucts and drugs and plays a key role in the regulation of
[
10]
various biopolymers. Figure 1 shows some representative
bioactive compounds that contain a 2H-chromene moiety.
Naturally occurring (+)-calanolide A (1), (+)-pseudocorda-
tolide C (2), dentatin (3), and nordentatin (4) exhibit diverse
and potent biological properties, such as anti-HIV, antitu-
mor, antiproliferative, anti-inflammatory, and antimycobac-
terial activities.
anti-HIV activity in acutely infected H9 cells (EC50
.00567 μg/mL), inhibitory activity against uninfected H9
cell growth (IC = 21.1 μg/mL), and a therapeutic index
TI) of 3710.
major cannabinoids of Cannabis sativa, and some of its an-
alogues have high therapeutic potential for the treatment of
anti-inflammatory diseases.
for inducing hypothermia and acts as an antimicrobial
agent.
found to be superior to phenylbutazone.
chromenes precocene I (7) and II (8) are well known for
their insecticidal activity and the induction of precocious
metamorphosis. They also exhibit antijuvenile hormone ac-
tivity by reducing the length of larval life in sensitive species
and preventing ovarian development in some adult in-
[
1–3]
loadings.
Amino acids, which are commercially available
and have been widely used as catalysts in a variety of or-
ganic reactions in recent years, are one of the most impor-
[
11]
(+)-Daurichromenic acid (5) has potent
[4]
tant classes of small-molecule organocatalysts. Among
=
them, l-proline and its derivatives have remarkable catalytic
0
efficiency in many reactions,[
1,2,5]
and l-proline especially
50
12]
has demonstrated distinct catalytic efficiency as well as
chemo-, regio-, and stereoselectivity in various multicompo-
nent reactions (MCRs).[ In multicomponent approaches,
complex products and biologically active molecules are syn-
thesized from simple, readily available starting materials in
a one-pot, single-step process. As a result, MCRs have
emerged as green and powerful tools for organic synthesis
[
(
Cannabichromene (CBC, 6) is one of four
6]
[
13]
Compound 6 is also useful
[
13]
In tests for anti-inflammatory activity, CBC was
[
13b]
The agerato-
[
7]
and drug discovery. By selecting different starting materi-
als, MCRs can be used to easily prepare a new class of
[
8]
compounds that may possess interesting properties. Both
[
[
a] School of Chemical Engineering, Yeungnam University,
2
14-1 Dae-dong, Gyeongsan 712-749, Korea
[
10a,10d,10e]
E-mail: yrlee@yu.ac.kr
http://display.yu.ac.kr/
sects.
Because of these important pharmacoph-
oric properties, molecules that contain the 2H-chromene
moiety have been synthesized and studied extensively.[
From the viewpoint of synthetic chemistry, the MCR is an
important strategy to extend the structural diversity of 2H-
b] Analysis Research Division, Daegu Center, Korea Basic Science
Institute,
14]
Daegu 702-701, Korea
http://www.kbsi.re.kr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500616.
[
15]
chromenes. In this regard, the development of new multi-
5212
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5212–5220

2H-Chromenes by Organocatalytic Multicomponent Reactions
component protocols for the synthesis of new 2H- Results and Discussion
chromene-containing heterocycles has attracted consider-
able interest in recent years.[
15]
To optimize the synthesis of the 2H-chromenes, we first
examined the three-component reaction of salicylaldehyde
9a), ethyl propiolate (10a), and ethanol (11a) in the pres-
(
ence of several catalysts (Table 1). No products were formed
in the absence of a catalyst (Table 1, Entry 1). When FeCl3
(
10 mol-%) or ZnCl (10 mol-%) were employed as Lewis
2
acid catalysts in refluxing ethanol for 24 h, a trace amount
of 2H-chromene 12a was produced (Table 1, Entries 2 and
3). By using 10 mol-% of the Lewis acid catalysts, Co-
(
PPh ) Cl and InCl in refluxing ethanol for 12 h, we ob-
3
3
3
tained product 12a in only 5 and 28% yield, respectively
Table 1, Entries 4 and 5). The employment of 20 mol-% of
(
iodine did not afford 12a (Table 1, Entry 6). However, when
p-toluenesulfonic acid (PTSA, 20 mol-%) and (–)-(1R)-10-
camphorsulfonic acid [(–)-CSA] were used as Brønsted ac-
ids, 12a was produced in 45 and 62% yield, respectively
(Table 1, Entries 7 and 8). In the presence of 20 mol-% of
Brønsted bases such as triethylamine (TEA), 1,4-diazabicy-
clo[2.2.2]octane (DABCO), piperidine, pyrrolidine, and pyr-
rolidine/benzoic acid, the desired product 12a was obtained
in 27–45% yield (Table 1, Entries 9–12). With 30 mol-% of
triphenylphosphine (TPP), 2H-chromene 12a was produced
Figure 1. Representative examples of 2H-chromene-containing nat- in a low yield of 22% (Table 1, Entry 13). In contrast, 12a
ural products.
Although several methods for the synthesis of 2H-
chromenes have been reported,[
14,15]
most of these ap-
Table 1. Optimization of the reaction conditions.[a]
proaches suffer from either a limited variety of available
starting materials or the use of expensive and toxic cata-
lysts. In some cases, a multistep preparation that uses ex-
pensive metal complexes would generate of a large amount
of waste and lead to a very high environmental (E) factor
(
a useful measure of the environmental acceptability of a
[
16]
chemical process). Volatile and toxic solvents are also fre-
quently used in the reported methods. To solve these prob-
lems, general and environmentally benign methods for the
synthesis of 2H-chromenes are still in demand. Recently,
related work for the synthesis of 2H-chromenes by starting
from ortho-quinone methides or salicylaldehydes and alk-
ynes was reported by Miyabe[17a] and Pal,[17b] respectively.
As part of our ongoing studies of the development of new
methods to synthesize biologically interesting 2H-
[
18]
chromenes, we examined new multicomponent reactions
between salicylaldehydes, alkynes (e.g., propiolates and ace-
tylenedicarboxylates), and alcohols in the presence of sev-
eral catalysts. This is the first example of the synthesis of
diverse 2H-chromenes by employing an l-proline-catalyzed
one-pot, three-component reaction of salicylaldehydes with
[
9d]
alkynes and alcohols as a nucleophile and solvent
Scheme 1).
(
[
(
a] To a reaction flask was added a mixture of 9a (1.0 mmol), 10a
1.2 mmol), and the solvent (2.0 mL), and the resulting mixture was
heated in an oil bath and stirred for the corresponding reaction
time. [b] Isolated yield. [c] Benzoic acid (20 mol-%) was added.
[d] EtOH (3.0 mmol) was used.
Scheme 1. One-pot reaction for the synthesis of 2H-chromenes.
Eur. J. Org. Chem. 2015, 5212–5220
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5213

H. Cai, L. Xia, Y. R. Lee, J.-J. Shim, S. H. Kim
FULL PAPER
was not produced when the inorganic base Cs CO was were examined as bifunctional Brønsted acid and base cata-
2
3
used as the catalyst (Table 1, Entry 14). Several amino acids lysts, such as l-asparagine, l-glutamic acid, l-histidine, l-
Table 2. Three-component synthesis of 2H-chromenes from various salicylaldehydes, propiolates, and alcohols.[a]
5214
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5212–5220

2H-Chromenes by Organocatalytic Multicomponent Reactions
Table 2. (Continued)
[
[
a] Reagents and conditions: salicylaldehyde (1.0 mmol), propiolate (1.2 mmol), alcohol (2.0 mL), and l-proline (30 mol-%) under reflux.
b] Isolated yield.
isoleucine, l-proline, and l-tyrosine (Table 1, Entries 15–
0). Among these, l-proline exhibited excellent catalytic ac- as a result of the ester group on the 2H-pyran ring of 12a.
A strong IR absorption peak at 1710 cm–1 was observed
2
1
tivity, and compound 12a was obtained in the best yield In the H NMR spectrum, the two characteristic protons
85%) by using 30 mol-% l-proline (Table 1, Entry 19). In- on the 2H-pyran ring appear as two singlets at δ = 7.66
(
creasing the catalyst loading of the l-proline to 50 mol-% and 6.03 ppm, respectively. The structure of 12a was further
did not improve the yield (Table 1, Entry 23). Further confirmed by 13C NMR and HRMS analyses.
screenings of solvents and reaction temperatures indicate
To prepare a variety of 2H-chromenes derivatives, the re-
that ethanol, as reactant and solvent,[ is most suitable actions of salicylaldehydes 9b–9i, methyl and ethyl pro-
Table 1, Entries 24–29). 2H-Chromene 12a was easily iso- piolate, and a number of alcohols were then examined
lated by column chromatography and identified by spectro- (Table 2). The reactions of 2-hydroxy-5-methylbenzaldehyde
9d]
(
scopic methods.
(9b), which has an electron-donating group on the benzene
Eur. J. Org. Chem. 2015, 5212–5220
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5215

H. Cai, L. Xia, Y. R. Lee, J.-J. Shim, S. H. Kim
FULL PAPER
ring, with methyl propiolate in either MeOH or EtOH af- tron-withdrawing group (EWG) on the benzene ring. For
forded the corresponding 2H-chromenes 12b and 12c in 88 example, the reaction of 9e with methyl propiolate in EtOH
and 81% yield, respectively (Table 2, Entries 1 and 2,). The gave compounds 12o and 12oЈ in 43 and 47% yield, respec-
reactions of 9b and ethyl propiolate in various alcohols such tively (Table 2, Entry 14), and the treatment of 9e with ethyl
as MeOH, EtOH, nPrOH, nBuOH, and BnOH, were also propiolate in EtOH provided 12p (37%) and 12pЈ (53%),
successful, and the corresponding 2H-chromenes 12d–12h respectively (Table 2, Entry 15). Compounds 12o and 12oЈ
were obtained in a range of 64–87% yield (Table 2, En- were readily separated by column chromatography and
1
tries 3–7). The reactivity of the alcohols in these reactions identified by analyzing the spectroscopic data. In the H
was in the order of MeOH Ͼ EtOH Ͼ nPrOH Ͼ nBuOH NMR spectrum of 12o, the two characteristic protons of
Ͼ BnOH. Encouraged by these results, reactions of the 2H-pyran ring appear as two singlets at δ = 7.51 and
2-hydroxy-4-methylbenzaldehyde (9c) and 5-fluoro-2- 5.98 ppm, respectively. In the case of 12oЈ, a broad OH sig-
hydroxybenzaldehyde (9d), which contain electron-donating nal was observed at δ = 7.24 ppm, and two singlets were
groups and, in the case of 9d, an electron-withdrawing observed at δ = 7.51 and 6.19 ppm.
group, with a propiolate in either methanol or ethanol were
attempted. In these cases, the desired products 12i–12n were of 9f, which contains both electron-withdrawing and elec-
formed in yields of 61–85% (Table 2, Entries 8–13). tron-donating groups on the benzene ring. The treatment
Interestingly, two products were also formed in the case
In contrast, two products resulted from the reactions of of 9f with methyl propiolate in EtOH afforded compounds
-bromo-2-hydroxybenzaldehyde (9e), which has an elec- 12q and 12qЈ in 31 and 42% yield, respectively (Table 2,
5
Table 3. Synthesis of 2H-chromenes from various salicylaldehydes and acetylenedicarboxylates.[a]
[
a] Reagents and conditions: salicylaldehyde (1.0 mmol), acetylenedicarboxylate (1.2 mmol), solvent (2.0 mL), and l-proline (30 mol-%)
under reflux. [b] Isolated yield.
5216
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5212–5220

2H-Chromenes by Organocatalytic Multicomponent Reactions
Entry 16). The reaction of 9f with ethyl propiolate in EtOH
provided 12r (39%) and 12rЈ (51%), respectively (Table 2,
Entry 17). Surprisingly, the reactions of salicylaldehydes
9g–9i, which contain either two halogen groups (Cl or Br)
or an NO group as a strong EWG, provided compounds
2
12s–12x in 75–93% yield, as a result of the addition of
water instead of the alcohol (Table 2, Entries 18–29). No-
tably, salicylaldehydes with a strong EWG on the benzene
ring afforded 2-hydroxy-2H-chromenes instead of 2-alkoxy-
2
H-chromenes as a result of water being more nucleophilic
[
19]
than the alcohol. These results show that substituents on
the salicylaldehydes can result in the selective introduction
of the OR or OH group to the 2H-chromene ring.
To extend the scope of this method, additional reactions
between salicylaldehydes 9a, 9e, 9f, and 9h, acetylenedicar-
boxylates, and alcohols were also investigated (Table 3). The
reaction of 9a with dimethyl acetylenedicarboxylate in re-
fluxing methanol or ethanol in the presence of 30 mol-% of
l-proline provided product 13a with an OH substituent on
the 2H-chromene ring in 86 and 88% yield, respectively
Scheme 3. Proposed mechanism for the formation of 12p and
2pЈ.
1
As an extension of this method, we examined the pos-
sibility of utilizing 2-aminobenzaldehydes instead of salicyl-
aldehydes as the starting materials to afford biologically
(Table 3, Entries 1 and 2). Similarly, the reactions between
salicylaldehydes 9e, 9f, and 9h, which have the electron-
withdrawing Br group on the benzene ring, and dimethyl or
diethyl acetylenedicarboxylate in methanol or ethanol also
provided compounds 13b–13f in 81–91% yield (Table 3, En-
tries 3–12).
[
22]
interesting quinolone derivatives.
As shown in Table 4,
the reaction of 2-aminobenzaldehyde (15a) with methyl pro-
piolate in refluxing MeOH for 7 h gave quinoline 16a in
88% yield (Table 4, Entry 1). Using other solvents such as
ethanol or toluene afforded product 16a in 91 and 75%
yield, respectively (Table 4, Entries 2 and 3). Similarly, the
reaction of 15b with methyl or ethyl propiolate also pro-
duced quinolines 16b and 16c in excellent yields (Table 4,
Entries 4–9). These results show that EtOH is a more suit-
able solvent for this type of transformation than the more
hazardous solvents methanol and toluene. Further reac-
tions of 15b with 3-methylbut-2-en-1-yl propiolate and
benzyl propiolate were successful and afforded the corre-
sponding quinolines 16d and 16e in 92 and 90% yield,
respectively (Table 4, Entries 10 and 11). Compared to
To understand the reaction process, we carried out con-
trol experiments (Scheme 2). The potential reaction inter-
mediates (Z)-14 and (E)-14 were prepared by known reac-
tions [Scheme 2, Equations (1) and (2)][20] and were treated
with MeOH in the presence of 30 mol-% of l-proline under
refluxing conditions for 24 h. The desired product 12d was
not observed [Scheme 2, Equation (3)].
[
22]
other reported methods,
this protocol provides a facile
and green synthetic approach to synthesize various quinol-
ines by starting from commercially available 2-aminobenz-
aldehydes and alkyl propiolates.
To examine the usefulness of this approach, the conver-
sion of the synthesized compounds 12pЈ, 12s, and 12u into
biologically interesting coumarins was then attempted by
employing an oxidation reaction (Scheme 4). Compounds
1
2pЈ, 12s, and 12u were treated with pyridinium chloro-
Scheme 2. Mechanistic investigations.
chromate (PCC) in refluxing dichloromethane for 5–10 h to
give coumarins 17a, 17b, and 17c in 98, 92, and 86% yield,
respectively.
On the basis of the above mechanistic investigations, a
plausible mechanism for the formation of 12p and 12pЈ was
then proposed (Scheme 3).[
6b,15g,15h,21]
The starting material
9e was treated with the catalyst to give intermediate I,
which was attacked by in situ generated 3-aminoalkenoate
II, prepared from l-proline and ethyl propiolate, to provide
intermediate III. Intramolecular cyclization of III furnished
intermediate IV, which underwent a subsequent elimination
process to give V and l-proline. Finally, nucleophile
attack of V by EtOH or H O provided 12p and 12pЈ,
2
respectively.
Scheme 4. Application for the synthesis of coumarins 17a–17c.
Eur. J. Org. Chem. 2015, 5212–5220
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5217

H. Cai, L. Xia, Y. R. Lee, J.-J. Shim, S. H. Kim
FULL PAPER
Table 4. Synthesis of quinolines from 2-aminobenzaldehydes and propiolates.[a]
[
a] Reagents and conditions: 2-aminobenzaldehyde (1.0 mmol), the propiolate (1.2 mmol), solvent (2.0 mL), and l-proline (30 mol-%),
heated at reflux. [b] Isolated yield.
the required time. After completion of the reaction as indicated by
TLC (hexane/EtOAc, 10:1, v/v), the solvent was evaporated, and
Conclusions
A new and efficient green procedure was successfully de- the residue was purified by flash column chromatography on silica
veloped for the regioselective synthesis of highly function- gel (hexane/EtOAc, 15:1, v/v) to give 2H-chromenes 12 and 13.
alized 2H-chromenes by using the one-pot three-component
reactions of salicylaldehydes, electron-deficient alkynes, and
General Procedure for the Synthesis of Quinolines 16: To a solution
of 2-aminobenzaldehyde 15 (1.0 mmol) and the propiolate
alcohols along with l-proline as an environmentally benign (1.2 mmol) in solvent (2.0 mL) was added l-proline (30 mol-%) at
organocatalyst. A variety of diverse and functionalized 2H- room temperature. The reaction mixture was heated at reflux for
chromenes were produced from different starting materials the required time. After completion of the reaction as indicated by
TLC (hexane/EtOAc, 10:1, v/v), the solvent was evaporated, and
in good to excellent yields. As an extension of this method,
the residue was purified by flash column chromatography on silica
gel (hexane/EtOAc, 15:1, v/v) to give quinolines 16.
General Procedure for the Synthesis of Coumarins 17:[23] To a solu-
2 2
tion of the 2-hydroxy-2H-chromene (0.50 mmol) in CH Cl
various quinoline derivatives were prepared by two-compo-
nent reactions of 2-aminobenzaldehyde and terminal alk-
ynes. Also, the synthesized 2-hydroxy-2H-chromenes were
further transformed into biologically interesting coumarins
through a PCC oxidation. Efforts to explore applications in
medicinal chemistry are currently underway in our labora-
tory.
(
5.0 mL) was added pyridinium chlorochromate (3.0 mmol,
6.0 equiv.) at room temperature, and the mixture was heated at re-
flux for several hours. After completion of the reaction as indicated
by TLC (hexane/EtOAc, 4:1, v/v), the mixture was cooled to room
temperature and diluted with EtOAc. The mixture was quickly
passed through a short pad of silica gel (EtOAc). The filtrate was
concentrated under reduced pressure to give the crude product,
which was purified by flash column chromatography on silica gel
Experimental Section
General Procedure for the Synthesis of 2H-Chromenes 12 and 13:
To a solution of salicylaldehyde 9 (1.0 mmol) and the alkyne
(
hexane/EtOAc, 4:1, v/v) to afford coumarins 17.
Supporting Information (see footnote on the first page of this arti-
room temperature. The reaction mixture was heated at reflux for cle): Experimental details for 2H-chromenes 12a–12x and 13a–13f,
(1.2 mmol) in alcohol (2.0 mL) was added l-proline (30 mol-%) at
5218
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5212–5220

2H-Chromenes by Organocatalytic Multicomponent Reactions
quinolines 16a–16e, coumarins 17a–17c, complete characterization
of these compounds, and copies of H and C NMR spectra.
Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001, 123, 5260–5267.
a) Y.-Q. Wang, Y. Zhang, K. Pan, J. You, J. Zhao, Adv. Synth.
Catal. 2013, 355, 3381–3386; b) S. N. Rao, D. C. Mohan, S.
Adimurthy, Org. Lett. 2013, 15, 1496–1499; c) P. Prasanna, S.
Perumal, J. C. Menendez, Green Chem. 2013, 15, 1292–1299;
d) D.-J. Cheng, S.-K. Tian, Adv. Synth. Catal. 2013, 355, 1715–
1
13
[5]
Acknowledgments
1718; e) H. Wang, L. Li, W. Lin, P. Xu, Z. Huang, D. Shi, Org.
Lett. 2012, 14, 4598–4601; f) S. Indumathi, S. Perumal, J. C.
This work was supported by the National Research Foundation of
Korea (NRF) with a grant funded by the Korea government
Menéndez, J. Org. Chem. 2010, 75, 472–475.
[
6] a) L. Fu, W. Lin, M.-H. Hu, X.-C. Liu, Z.-B. Huang, D.-Q.
Shi, ACS Comb. Sci. 2014, 16, 238–243; b) M. Li, B. Zhang,
Y. Gu, Green Chem. 2012, 14, 2421–2428; c) A. Kumar, M. K.
Gupta, M. Kumar, Green Chem. 2012, 14, 290–295; d) A. Khal-
afi-Nezhad, S. Sarikhani, E. S. Shahidzadeh, F. Panahi, Green
Chem. 2012, 14, 2876–2884; e) M. Fridén-Saxin, T. Seifert,
L. K. Hansen, M. Grøtli, M. Erdelyi, K. Luthman, Tetrahe-
dron 2012, 68, 7035–7040; f) G. Bhaskar, Y. Arun, C. Balachan-
dran, C. Saikumar, P. T. Perumal, Eur. J. Med. Chem. 2012, 51,
(MSIP) (NRF-2014R1A2A1A11052391) and the Nano Material
Technology Development Program (2012M3A7B4049675). This
work was also supported by the Priority Research Centers Program
through the National Research Foundation (NRF) of Korea
funded by the Ministry of Education (2014R1A6A1031189).
[
1] a) C. M. R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 2014,
14, 2390–2431; b) A.-N. Alba, X. Companyo, M. Viciano, R.
1
7
9–91; g) S. M. Rajesh, B. D. Bala, S. Perumal, J. C. Menéndez,
Rios, Curr. Org. Chem. 2009, 13, 1432–1474; c) A. Dondoni,
A. Massi, Angew. Chem. Int. Ed. 2008, 47, 4638–4660; Angew.
Chem. 2008, 120, 4716; d) P. I. Dalko, L. Moisan, Angew.
Chem. Int. Ed. 2004, 43, 5138–5175; Angew. Chem. 2004, 116,
Green Chem. 2011, 13, 3248–3254; h) T. Indumathi, V. S. J.
Ahamed, S.-S. Moon, F. R. Fronczek, K. J. R. Prasad, Eur. J.
Med. Chem. 2011, 46, 5580–5590; i) H.-F. Jiang, J.-H. Li, Z.-
W. Chen, Tetrahedron 2010, 66, 9721–9728; j) H. Jiang, R. Mai,
H. Cao, Q. Zhu, X. Liu, Org. Biomol. Chem. 2009, 7, 4943–
5
248; e) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001,
40, 3726–3748; Angew. Chem. 2001, 113, 3840.
4
953; k) B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am.
[
2] a) U. Scheffler, R. Mahrwald, Chem. Eur. J. 2013, 19, 14346–
Chem. Soc. 2002, 124, 827–833.
14396; b) S. Meninno, A. Lattanzi, Chem. Commun. 2013, 49,
3821–3832; c) P. Kumar, N. Dwivedi, Acc. Chem. Res. 2013,
46, 289–299; d) P. Renzi, M. Bella, Chem. Commun. 2012, 48,
6881–6896; e) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011,
44, 1156–1171; f) A. T. Biju, N. Kuhl, F. Glorius, Acc. Chem.
[
7] a) M. B. Gawande, V. D. B. Bonifacio, R. Luque, P. S. Branco,
R. S. Varma, Chem. Soc. Rev. 2013, 42, 5522–5551; b) J. Ale-
man, S. Cabrera, Chem. Soc. Rev. 2013, 42, 774–793; c) A.
Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083–
3135; d) C. de Graaff, E. Ruijter, R. V. A. Orru, Chem. Soc.
Res. 2011, 44, 1182–1195; g) S. G. Ouellet, A. M. Walji,
D. W. C. MacMillan, Acc. Chem. Res. 2007, 40, 1327–1339; h)
S. J. Connon, Chem. Eur. J. 2006, 12, 5419–5427; i) W. Notz,
F. Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004, 37, 580–
Rev. 2012, 41, 3969–4009; e) N. Isambert, M. d. M. S. Duque,
J.-C. Plaquevent, Y. Génisson, J. Rodriguez, T. Constantieux,
Chem. Soc. Rev. 2011, 40, 1347–1357; f) B. B. Toure, D. G.
Hall, Chem. Rev. 2009, 109, 4439–4486; g) D. M. D’Souza,
T. J. J. Müeller, Chem. Soc. Rev. 2007, 36, 1095–1108; h) D. J.
Ramón, M. Yus, Angew. Chem. Int. Ed. 2005, 44, 1602–1634;
Angew. Chem. 2005, 117, 1628.
5
4
91; j) K. N. Houk, B. List, Acc. Chem. Res. 2004, 37, 487–
87.
[
3] a) J.-W. Xie, M.-L. Xu, R.-Z. Zhang, J.-Y. Pan, W.-D. Zhu,
Adv. Synth. Catal. 2014, 356, 395–400; b) L. Xia, H. Cai, Y. R.
Lee, Org. Biomol. Chem. 2014, 12, 4386–4396; c) C. J. Whit-
eoak, A. H. Henseler, C. Ayats, A. W. Kleij, M. A. Pericas,
Green Chem. 2014, 16, 1552–1559; d) R. Alonso, T. Bach, An-
gew. Chem. Int. Ed. 2014, 53, 4368–4371; Angew. Chem. 2014,
[
[
[
8] a) S. Brauch, S. S. van Berkel, B. Westermann, Chem. Soc. Rev.
2
013, 42, 4948–4962; b) M. Shiri, Chem. Rev. 2012, 112, 3508–
3
549; c) V. Estévez, M. Villacampa, J. C. Menéndez, Chem.
Soc. Rev. 2010, 39, 4402–4421; d) E. Ruijter, R. Scheffelaar,
R. V. A. Orru, Angew. Chem. Int. Ed. 2011, 50, 6234–6246; An-
gew. Chem. 2011, 123, 6358; e) D. Tejedor, F. Garcia-Tellado,
Chem. Soc. Rev. 2007, 36, 484–491.
126, 4457; e) L. Xia, Y. R. Lee, Org. Biomol. Chem. 2013, 11,
5254–5263; f) Z.-Y. Wang, W.-T. Wong, D. Yang, Org. Lett.
2013, 15, 4980–4983; g) Y. Kong, R. Tan, L. Zhao, D. Yin,
9] a) A. E. Díaz-Álvarez, J. Francos, P. Croche, V. Cadierno, Curr.
Green Chem. 2014, 1, 51–65; b) K. Shanab, C. Neudorfer, E.
Schirmer, H. Spreitzer, Curr. Org. Chem. 2013, 17, 1179–1187;
c) G. Imperato, B. König, C. Chiappe, Eur. J. Org. Chem. 2007,
Green Chem. 2013, 15, 2422–2433; h) B.-C. Hong, P. Kotame,
J.-H. Liao, Org. Biomol. Chem. 2011, 9, 382–386; i) S. Takiz-
awa, N. Inoue, S. Hirata, H. Sasai, Angew. Chem. Int. Ed. 2010,
4
9, 9725–9729; Angew. Chem. 2010, 122, 9919.
1
049–1058; d) C. Capello, U. Fischer, K. Hungerbühler, Green
Chem. 2007, 9, 927–934; e) R. A. Sheldon, Green Chem. 2005,
, 267–278; f) J. M. DeSimone, Science 2002, 297, 799–803.
[
4] a) V. Resch, C. Seidler, B.-S. Chen, I. Degeling, U. Hanefeld,
Eur. J. Org. Chem. 2013, 7697–7704; b) C. G. Kokotos, Org.
Lett. 2013, 15, 2406–2409; c) L.-W. Zhao, H.-M. Shi, J.-Z.
Wang, J. He, Chem. Eur. J. 2012, 18, 15323–15329; d) Q.-X.
Guo, Y.-W. Liu, X.-C. Li, L.-Z. Zhong, Y.-G. Peng, J. Org.
Chem. 2012, 77, 3589–3594; e) H. Yang, M. W. Wong, J. Org.
Chem. 2011, 76, 7399–7405; f) J.-Y. Fu, Q.-C. Yang, Q.-L.
Wang, J.-N. Ming, F.-Y. Wang, X.-Y. Xu, L.-X. Wang, J. Org.
Chem. 2011, 76, 4661–4664; g) D. B. Ramachary, Y. Vijayen-
dar Reddy, J. Org. Chem. 2010, 75, 74–85; h) D. B. Ramachary,
K. Ramakumar, V. V. Narayana, Chem. Eur. J. 2008, 14, 9143–
7
10] a) W. E. Khafagi, E. M. Hegazi, BioControl 2004, 49, 517–536;
b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
2003, 103, 893–930; c) L. J. V. Galietta, M. F. Springsteel, M.
Eda, E. J. Niedzinski, K. By, M. J. Haddadin, M. J. Kurth,
M. H. Nantz, A. S. Verkman, J. Biol. Chem. 2001, 276, 19723–
19728; d) G. E. Pratt, R. C. Jennings, A. F. Hamnett, G. T.
Brooks, Nature 1980, 284, 320–323; e) G. T. Brooks, G. E.
Pratt, R. C. Jennings, Nature 1979, 281, 570–572.
9
147; i) D. B. Ramachary, M. Kishor, Org. Biomol. Chem. [11] a) P. Zheng, S. Somersan-Karakaya, S. Lu, J. Roberts, M. Pin-
2
008, 6, 4176–4187; j) I. Ibrahem, W. Zou, Y. Xu, A. Córdova,
gle, T. Warrier, D. Little, X. Guo, S. J. Brickner, C. F. Nathan,
B. Gold, G. Liu, J. Med. Chem. 2014, 57, 3755–3772; b) F.
Saadat, S. Sardari, B. Maleki, Mol. Inf. 2013, 32, 802–810; c)
Y.-Y. Chan, C.-H. Li, Y.-C. Shen, T.-S. Wu, Chem. Pharm. Bull.
2010, 58, 61–65; d) C. Ito, M. Itoigawa, M. Ju-ichi, N. Sakam-
oto, H. Tokuda, H. Nishino, H. Furukawa, Planta Med. 2005,
71, 84–87; e) A. Sunthitikawinsakul, N. Kongkathip, B. Kong-
kathip, S. Phonnakhu, J. W. Daly, T. F. Spande, Y. Nimit, C.
Napaswat, J. Kasisit, C. Yoosook, Phytother. Res. 2003, 17,
Adv. Synth. Catal. 2006, 348, 211–222; k) K. Inomata, M. Bar-
ragué, L. A. Paquette, J. Org. Chem. 2005, 70, 533–539; l) A.
Córdova, W. Zou, I. Ibrahem, E. Reyes, M. Engqvist, W.-W.
Liao, Chem. Commun. 2005, 3586–3588; m) H. Sundén, M.
Engqvist, J. Casas, I. Ibrahem, A. Córdova, Angew. Chem. Int.
Ed. 2004, 43, 6532–6535; Angew. Chem. 2004, 116, 6694; n) A.
Córdova, H. Sundén, M. Engqvist, I. Ibrahem, J. Casas, J. Am.
Chem. Soc. 2004, 126, 8914–8915; o) K. Sakthivel, W. Notz, T.
Eur. J. Org. Chem. 2015, 5212–5220
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5219

H. Cai, L. Xia, Y. R. Lee, J.-J. Shim, S. H. Kim
FULL PAPER
1
101–1103; f) D. A. Eiznhamer, T. Creagh, J. L. Ruckle, D. T.
M. T. Duarte, L. F. Veiros, P. M. P. Gois, Tetrahedron 2010, 66,
2736–2745; f) J. S. Yadav, B. V. Subba Reddy, S. K. Biswas, S.
Sengupta, Tetrahedron Lett. 2009, 50, 5798–5801; g) Y. Mats-
uya, K. Hayashi, A. Wada, H. Nemoto, J. Org. Chem. 2008,
73, 1987–1990; h) D.-Q. Xu, Y.-F. Wang, S.-P. Luo, S. Zhang,
A.-G. Zhong, H. Chen, Z.-Y. Xu, Adv. Synth. Catal. 2008, 350,
2610–2616.
Tolbert, J. Giltner, B. Dutta, M. T. Flavin, T. Jenta, Z.-Q. Xu,
HIV Clin. Trials 2002, 3, 435–450; g) S. Kawaii, Y. Tomono,
K. Ogawa, M. Sugiura, M. Yano, Y. Yoshizawa, C. Ito, H.
Furukawa, Anticancer Res. 2001, 21, 1905–1911; h) T. C.
McKee, R. W. Fuller, C. D. Covington, J. H. Cardellina II, R. J.
Gulakowski, B. L. Krepps, J. B. McMahon, M. R. Boyd, J.
Nat. Prod. 1996, 59, 754–758; i) T.-S. Wu, S.-C. Huang, T.-T. [16] a) B. H. Lipshutz, S. Ghorai, Green Chem. 2014, 16, 3660–
Jong, J.-S. Lai, C.-S. Kuoh, Phytochemistry 1988, 27, 585–587;
j) T.-S. Wu, H. Furukawa, J. Nat. Prod. 1982, 45, 718–720; k)
M. T. Flavin, J. D. Rizzo, A. Khilevich, A. Kucherenko, A. K.
Sheinkman, V. Vilaychack, L. Lin, W. Chen, E. M. Greenwood,
T. Pengsuparp, J. M. Pezzuto, S. H. Hughes, T. M. Flavin, M.
Cibulski, W. A. Boulanger, R. L. Shone, Z. Q. Xu, J. Med.
Chem. 1996, 39, 1303–1313.
3679; b) R. A. Sheldon, Chem. Soc. Rev. 2012, 41, 1437–1451;
c) C. Jiménez-González, C. S. Ponder, Q. B. Broxterman, J. B.
Manley, Org. Process Res. Dev. 2011, 15, 912–917; d) S.
Bertelsen, K. A. Jørgensen, Chem. Soc. Rev. 2009, 38, 2178–
2189; e) N. Noshiranzadeh, A. Ramazani, Synth. Commun.
2007, 37, 3181–3189; f) R. A. Sheldon, Green Chem. 2007, 9,
1273–1283.
[
12] Y. Kashiwada, K. Yamazaki, Y. Ikeshiro, T. Yamagishi, T. Fu- [17] a) E. Yoshioka, H. Tamenaga, H. Miyabe, Tetrahedron Lett.
jioka, K. Mihashi, K. Mizuki, L. M. Cosentino, K. Fowke,
2014, 55, 1402–1405; b) S. N. Singh, R. Bopanni, S. Jayaprak-
ash, K. V. Reddy, M. A. Ashfaq, K. S. Kumar, M. Pal, RSC
Adv. 2014, 4, 24870–24873.
S. L. Morris-Natschke, K. H. Lee, Tetrahedron 2001, 57, 1559–
1563.
[
13] a) C. E. Turner, M. A. Elsohly, J. Clin. Pharmacol. 1981, 21,
[18] a) X. Li, Y. R. Lee, Org. Biomol. Chem. 2014, 12, 1250–1257;
b) T. N. Poudel, Y. R. Lee, Org. Biomol. Chem. 2014, 12, 919–
930; c) A. Idhayadhulla, L. Xia, Y. R. Lee, S. H. Kim, Y.-J.
Wee, C.-S. Lee, Bioorg. Chem. 2014, 52, 77–82; d) L. Xia, Y. R.
Lee, Helv. Chim. Acta 2013, 96, 644–650; e) E. J. Jung, B. H.
Park, Y. R. Lee, Green Chem. 2010, 12, 2003–2011; f) L. Xia,
Y. R. Lee, Synlett 2008, 1643–1646; g) Y. R. Lee, L. Xia, Tetra-
hedron Lett. 2008, 49, 3283–3287; h) Y. R. Lee, X. Li, J. H.
Kim, J. Org. Chem. 2008, 73, 4313–4316; i) Y. R. Lee, L. Xia,
Synthesis 2007, 3240–3246.
2
83–291; b) P. W. Wirth, E. S. Watson, M. ElSohly, C. E.
Turner, J. C. Murphy, Life Sci. 1980, 26, 1991–1995.
[
14] a) Y. Xia, Y. Xia, Y. Zhang, J. Wang, Org. Biomol. Chem. 2014,
12, 9333–9336; b) N. D. Paul, S. Mandal, M. Otte, X. Cui, X. P.
Zhang, B. de Bruin, J. Am. Chem. Soc. 2014, 136, 1090–1096;
c) S. A. Patil, R. Patil, L. M. Pfeffer, D. D. Miller, Future Med.
Chem. 2013, 5, 1647–1660; d) R. G. Soengas, H. Rodríguez-
Solla, A. M. S. Silva, R. Llavona, F. A. A. Paz, J. Org. Chem.
2
013, 78, 12831–12836; e) G. Maiti, R. Karmakar, U. Kayal,
R. N. Bhattacharya, Tetrahedron 2012, 68, 8817–8822; f) K.
[19] a) D. B. Ramachary, R. Sakthidevi, Chem. Eur. J. 2009, 15,
4516–4522; b) G.-L. Zhao, Y.-L. Shi, M. Shi, Org. Lett. 2005,
7, 4527–4530.
Bera, S. Sarkar, S. Biswas, S. Maiti, U. Jana, J. Org. Chem.
2011, 76, 3539–3544; g) P. N. Moquist, T. Kodama, S. E.
Schaus, Angew. Chem. Int. Ed. 2010, 49, 7096–7100; Angew.
Chem. 2010, 122, 7250; h) D. Bello, J. Ruiz-Rodríguez, F. Al-
bericio, R. Ramón, R. Lavilla, Eur. J. Org. Chem. 2010, 5373–
[20] a) Y. Sarrafi, M. Sadatshahabi, K. Alimohammadi, M.
Tajbakhsh, Green Chem. 2011, 13, 2851–2858; b) L.-Q. Lu, F.
Li, J. An, J.-J. Zhang, X.-L. An, Q.-L. Hua, W.-J. Xiao, Angew.
Chem. Int. Ed. 2009, 48, 9542–9545; Angew. Chem. 2009, 121,
9706.
5379; i) R. S. Menon, A. D. Findlay, A. C. Bissember, M. G.
Banwell, J. Org. Chem. 2009, 74, 8901–8903; j) A. R. Katritzky,
R. Sakhuja, L. Khelashvili, K. Shanab, J. Org. Chem. 2009, 74,
[21] a) L.-C. Feng, Y.-W. Sun, W.-J. Tang, L.-J. Xu, K.-L. Lam, Z.
Zhou, A. S. C. Chan, Green Chem. 2010, 12, 949–952; b) O.
Abillard, B. Breit, Adv. Synth. Catal. 2007, 349, 1891–1895; c)
R. K. Gupta, M. V. George, Tetrahedron 1975, 31, 1263–1275.
[22] a) R. P. Pandit, Y. R. Lee, RSC Adv. 2013, 3, 22039–22045; b)
J. Han, L. Li, Y. Shen, J. Chen, H. Deng, M. Shao, X. Lu, H.
Zhang, W. Cao, Eur. J. Org. Chem. 2013, 8323–8329; c) X.-Y.
Liu, Y.-P. Xiao, F.-M. Siu, L.-C. Ni, Y. Chen, L. Wang, C.-M.
Che, Org. Biomol. Chem. 2012, 10, 7208–7219; d) T. Chanda,
R. K. Verma, M. S. Singh, Chem. Asian J. 2012, 7, 778–787; e)
S. Cai, J. Zeng, Y. Bai, X.-W. Liu, J. Org. Chem. 2012, 77, 801–
807; f) B. Madhav, S. N. Murthy, K. R. Rao, Y. V. D. Nageswar,
Helv. Chim. Acta 2010, 93, 257–260; g) J. B. Hendrickson, R.
Rees, J. F. Templeton, J. Am. Chem. Soc. 1964, 86, 107–111.
[23] a) W. Yao, Y. Wu, G. Wang, Y. Zhang, C. Ma, Angew. Chem.
Int. Ed. 2009, 48, 9713–9716; Angew. Chem. 2009, 121, 9893;
b) M. Rueping, E. Sugiono, E. Merino, Angew. Chem. Int. Ed.
2008, 47, 3046–3049; Angew. Chem. 2008, 120, 3089; c) M.
Rueping, E. Merino, E. Sugiono, Adv. Synth. Catal. 2008, 350,
2127–2131.
3
9
062–3065; k) X.-L. Sun, Y. Tang, Acc. Chem. Res. 2008, 41,
37–948; l) L.-Z. Dai, Y.-L. Shi, G.-L. Zhao, M. Shi, Chem.
Eur. J. 2007, 13, 3701–3706; m) L.-W. Ye, X.-L. Sun, C.-Y. Zhu,
Y. Tang, Org. Lett. 2006, 8, 3853–3856; n) M.-J. R. P. Queiroz,
A. S. Abreu, P. M. T. Ferreira, M. M. Oliveira, R. Dubest, J.
Aubard, A. Samat, Org. Lett. 2005, 7, 4811–4814; o) N. Ishi-
zuka, K.-i. Matsumura, K. Sakai, M. Fujimoto, S.-i. Mihara,
T. Yamamori, J. Med. Chem. 2002, 45, 2041–2055; p) S. A.
Ahmed, X. Sallenave, F. Fages, G. Mieden-Gundert, W. M.
Müller, U. Müller, F. Vögtle, J.-L. Pozzo, Langmuir 2002, 18,
7096–7101; q) K. A. Parker, T. L. Mindt, Org. Lett. 2001, 3,
3875–3878; r) Q. Wang, M. G. Finn, Org. Lett. 2000, 2, 4063–
4065.
[
15] a) F. Yang, Z. Wang, H. Wang, H. Zhang, H. Yue, L. Wang,
RSC Adv. 2014, 4, 25633–25636; b) L. Chandrasekhara Rao,
H. M. Meshram, N. Satish Kumar, N. Nageswara Rao, N. Ja-
gadeesh Babu, Tetrahedron Lett. 2014, 55, 1127–1131; c) W.
Qian, A. Amegadzie, D. Winternheimer, J. Allen, Org. Lett.
2
013, 15, 2986–2989; d) E. Yoshioka, S. Kohtani, H. Miyabe,
Angew. Chem. Int. Ed. 2011, 50, 6638–6642; Angew. Chem.
Received: May 13, 2015
Published Online: July 17, 2015
2011, 123, 6768; e) N. R. Candeias, P. M. S. D. Cal, V. André,
5220
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 5212–5220