recent advances in inverse-electron-demand · cycloaddition reactions provide quick and economic...
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REVIEW
Recent Advances in Inverse-Electron-DemandHetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
Aleksandra Pałasz1
Received: 21 December 2015 / Accepted: 11 April 2016 / Published online: 20 April 2016
� The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract This review is an endeavor to highlight the progress in the inverse-
electron-demand hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes in recent
years. The huge number of examples of 1-oxadienes cycloadditions found in the
literature clearly demonstrates the incessant importance of this transformation in
pyran ring synthesis. This type of reaction is today one of the most important
methods for the synthesis of dihydropyrans which are the key building blocks in
structuring of carbohydrate and other natural products. Two different modes, inter-
and intramolecular, of inverse-electron-demand hetero-Diels–Alder reactions of
1-oxadienes are discussed. The domino Knoevenagel hetero-Diels–Alder reactions
are also described. In recent years the use of chiral Lewis acids, chiral organocat-
alysts, new optically active heterodienes or dienophiles have provided enormous
progress in asymmetric synthesis. Solvent-free and aqueous hetero-Diels–Alder
reactions of 1-oxabutadienes were also investigated. The reactivity of reactants,
selectivity of cycloadditions, and chemical stability in aqueous solutions and under
physiological conditions were taken into account to show the potential application
of the described reactions in bioorthogonal chemistry. New bioorthogonal ligation
by click inverse-electron-demand hetero-Diels–Alder cycloaddition of in situ-gen-
erated 1-oxa-1,3-butadienes and vinyl ethers was developed. It seems that some of
the hetero-Diels–Alder reactions described in this review can be applied in
bioorthogonal chemistry because they are selective, non-toxic, and can function in
biological conditions taking into account pH, an aqueous environment, and
temperature.
& Aleksandra Pałasz
1 Department of Organic Chemistry, Jagiellonian University, Ingardena 3 St, 30-060 Krakow,
Poland
123
Top Curr Chem (Z) (2016) 374:24
DOI 10.1007/s41061-016-0026-2
Keywords Hetero-Diels–Alder reactions � 1-Oxa-1,3-butadienes �Dihydropyrans � Domino Knoevenagel hetero-Diels–Alder reactions �Bioorthogonal cycloaddition
AbbreviationsAc Acetyl
iBu Isobutyl
n-Bu n-Butyl
t-Bu tert-Butyl
(S,S)-
t-Bu-box
(S,S)-tert-Butylbis(oxazoline)
[bmim][NO3] 1-Butyl-3-methylimidazolium nitrate
Bn Benzyl
BPin 3-Boronopinacol
Bz Benzoyl
Cb Benzyloxycarbonyl
DEA Diethylamine
DIC N,N0-Diisopropylcarbodiimide
DMAP N,N-Ddimethyl-4-aminopyridine
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
EDDA Ethylene diammonium diacetate
Eu(fod)3 6,6,7,7,8,8,8-Heptafluoro-2,2-dimethyl-3,5-octanedionato
europium
IBX o-Iodoxybenzoic acid
MDO Modularly designed organocatalyst
MS Molecular sieves
PCC Pyridinium chlorochromate
PDC Pyridinium dichromate
iPr Isopropyl
TBAB tetra-n-Butylammonium bromide
TBAF Tetrabutylammonium fluoride
TBA-HS Tetrabutylammonium hydrogen sulfate
TBDMS tert-Butyldimethylsilyl
TBDPS tert-Butyldiphenylsilyl
TBS tert-Butyldimethylsilyl
Tf Trifluoromethanesulfonyl
THF Tetrahydrofuran
24 Page 2 of 37 Top Curr Chem (Z) (2016) 374:24
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1 Introduction
Cycloaddition reactions provide quick and economic methods for the construction
of monocyclic, polycyclic and heterocyclic systems. The use of hetero-substituted
diene and dienophiles is important for the application of Diels–Alder cycloadditions
towards natural and biologically active product synthesis. Dihydro- and tetrahy-
dropyran derivatives are prevalent structural subunits in a variety of natural
compounds, including carbohydrates, pheromones, alkaloids, iridoids and polyether
antibiotics [1–8]. The abundance of carbohydrates in living cells is a reason for the
development of new synthetic procedures for the preparation of natural and
unnatural sugars. There are two synthetic routes leading to dihydropyran derivatives
via [4 ? 2] cycloadditions. The first one is the [4 ? 2] cycloaddition of the
carbonyl group of aldehydes or ketones, acting as heterodienophiles, with electron-
rich 1,3-butadienes [9–23]. The second route is the hetero-Diels–Alder (HDA)
reactions of electron-deficient a,b-unsaturated carbonyl compounds, representing an
1-oxa-1,3-butadiene system, with electron-rich alkenes. Excellent diastereoselec-
tivity is a characteristic feature of heterocycloaddition of many substituted a,b-
unsaturated carbonyl compounds. The HDA reactions of oxabutadienes also show a
high regioselectivity. These reactions have been classified as cycloadditions with
inverse-electron-demand [24]. The reviews on this topic have already been
published but they cover the literature until only 1997 [1–8, 24]. The most
comprehensive one was written by Tietze and Kettschau in Topics in Current
Chemistry in 1997 [2]. The presented review is an endeavor to highlight the
progress in the HDA reactions with inverse-electron-demand of 1-oxa-1,3-
butadienes after the year 2000.
The reactivity of a,b-unsaturated carbonyl compounds in HDA reactions is low
and the reactions must be conducted at high temperature [25–27] or under high
pressure [28–30]. The use of enol ethers as dienophiles with electron-donating
groups improves the cycloadditions but high temperature is needed and diastere-
oselectivity of these reactions is still low. Aza-substituted dienophiles have been
used more rarely than their oxygenated counterparts in the HDA reactions of 1-oxa-
1,3-butadienes. Enamines can participate in these reactions, providing entry to
highly complex molecules [31–33]. The reactivity of 1-oxa-1,3-butadiene can be
enhanced by introducing electron-withdrawing substituents [34–39]. Presence of an
electron-withdrawing group in the 1-oxadiene system lowers the lowest energy
unoccupied molecular orbital (LUMO) energy level which then can more easily
overlap with the highest energy unoccupied molecular orbital (HOMO) orbital of
the dienophile. Tietze et al. calculated the influence of various substituents on the
energy of LUMO orbitals in 4-N-acetylamino-1-oxa-1,3-butadienes using semiem-
pirical methods [40]. It was found that the energy depends on the type and position
of a substituent in the 1-oxadiene system. The cyano and trifluoromethyl groups in
the 3 position were found to have the highest influence on reactivity of 1-oxa-1,3-
butadienes in cycloadditions with enol ethers. In addition to the effect of the
substituents in the heterodiene, Lewis acid catalysts, such as ZnCl2, TiCl4, SnCl4,
EtAlCl2, Me2AlCl, LiClO4, Mg(ClO4)2, Eu(fod)3, Yb(fod)3, accelerate the HDA
Top Curr Chem (Z) (2016) 374:24 Page 3 of 37 24
123
reactions [41–53]. The choice of the Lewis acid also has influence on the
stereoselectivity of cycloadditions because this catalyst is involved in an endo or an
exo-transition structure and steric interactions are important for stereochemistry.
Inverse-electron-demand HDA reaction between a,b-unsaturated carbonyl com-
pounds and electron-rich alkenes gives an enantioselective approach to chiral
dihydropyrans which are precursors for the synthesis of carbohydrate derivatives.
To obtain optically active carbohydrate derivatives by the HDA approach, either a
chiral transformation via the use of a chiral auxiliary or a catalytic enantioselective
reaction is necessary [50–53]. Two different modes of inverse-electron-demand
HDA reactions of 1-oxa-1,3-butadienes are discussed in this paper: inter- and
intramolecular mode. The geometry of the transition structures of HDA reactions
influences the diastereoselectivity of cycloadditions. There are four different
transition states for HDA reactions of 1-oxa-1,3-butadienes, according to an endo-
or exo-orientation of the dienophile and an (E)- or (Z)-configuration of the 1-oxa-
1,3-butadiene [2]. The four transition structures for inter- and intramolecular HDA
reactions providing the two diastereomers cis and trans are showed in Figs. 1 and 2.
The orientation of the dienophile–vinyl ether, with the alkoxy group being close to
the oxygen atom in the heterodiene is called endo (Fig. 1) [2]. The opposite is called
exo. For intramolecular HDA reactions of 1-oxa-1,3-butadienes, the orientation with
the chain connecting the heterodiene and dienophile lying close to the heterodiene is
called endo (Figure 2) [2]. The cis-adduct can be formed by an endo-E or exo-
Z orientation. The trans-adduct is obtained by either an exo-E or endo-Z transition
state (Figs. 1, 2).
Tietze et al. extensively described the domino Knoevenagel hetero-Diels–Alder
reactions of unsaturated aromatic and aliphatic aldehydes with different 1,3-
dicarbonyl compounds for the synthesis of heterocycles with a pyran ring [54–68].
In the intramolecular mode, the 1-oxa-1,3-butadienes are prepared in situ by a
Knoevenagel condensation of aldehydes bearing the dienophile moiety. This
cis - cycloadductendo-E exo-Z
OR1
R2
OR3
O
R3O
H
R2
R1HH
H
O
H
H
R1 R2
HH
OR3
exo-E endo-Z
OR1
R2
OR3
O
R2
H
HR1
H
OR3
HO R2
H
R3O
R1HH
Htrans - cycloadduct
Fig. 1 The four different diastereoselective approaches of an alkene such as vinyl ether to 1-oxa-1,3-butadiene for intermolecular HDA reaction
24 Page 4 of 37 Top Curr Chem (Z) (2016) 374:24
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method has a broad scope since a multitude of different aldehydes and 1,3-
dicarbonyl compounds can be used.
Different examples of inter- and intramolecular HDA reactions of 1-oxa-1,3-
butadienes described in literature after the year 2000 are discussed below. The
usefulness of HDA reactions of oxadienes is connected with the number of bonds
which are formed in one sequence and with the fact that complex molecules can be
obtained by this method. Thus, the HDA reactions of a,b-unsaturated carbonyl
compounds are atom economic and they allow for regio-, diastereo- and
enantioselective synthesis of multifunctional pyran derivatives from relatively
simple compounds. Therefore, these cycloadditions can be potentially applied in
bioorthogonal chemistry.
2 Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
2.1 Intermolecular Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
2.1.1 Non-catalytic Intermolecular Hetero-Diels–Alder Reactions of 1-Oxa-1,3-
Butadienes
The reactivity of heterodienes in inverse-electron-demand HDA reactions can be
enhanced by introducing electron-withdrawing substituents into the 1-oxa-1,3-
butadiene system [34–39, 69–74]. For activation of an oxabutadiene in heterocy-
cloadditions, a cyano group can serve especially well. Such examples are
cycloadditions between propenenitriles with a cyano group at C-3 of the heterodiene
cis-cycloadduct
trans-cycloadduct
endo-E exo-Z
O
H
H
exo-E endo-Z
O HH
O
H
H
O
H
H
HO
H
OH
H
Fig. 2 The four different diastereoselective approaches of an alkene to 1-oxa-1,3-butadiene forintramolecular HDA reaction
Top Curr Chem (Z) (2016) 374:24 Page 5 of 37 24
123
system [71–74]. Moreover, two papers [71, 72] describe examples of cycloaddition
reaction of enaminocarbaldehydes or enaminoketones with enol ethers, leading to
4-amino-3,4-dihydro-2H-pyrans. 4-Amino-pyrans are precursors in synthesis of
3-amino sugar derivatives which are present in various antibiotics such as
gentamycin C or adriamycin. The HDA reactions of 3-(N-acetyl-N-benzylamino)-
2-formylprop-2-enenitriles 1 with enol ethers 2 yielded cis 3 and trans 4diastereoisomers of 2-alkoxy-4-amino-3,4-dihydro-2H-pyran-5-carbonitriles in
moderate yields (Scheme 1) [71]. The reactions of 2-benzoyl-3-heteroaromat-
icprop-2-enenitriles 5 with enol ethers 2 afforded diastereoisomeric cis 6 and trans 7cycloadducts [71].
Enaminocarbaldehyde 1 was found to be less reactive than propenenitriles 5 since
reactions of 5 with enol ethers 2 occurred at room temperature whereas reactions
with 1 required heating in boiling toluene.
Another interesting example of HDA reaction of 1-oxa-1,3-butadienes with vinyl
ethers was described by Klahn and Kirsch [75]. They examined dehydrogenation of
b-oxonitriles 8 by treatment with o-iodoxybenzoic acid (IBX) at room temperature
(Scheme 2). Products of the dehydrogenation–unsaturated counterparts 10 can react
in situ, undergoing rapid HDA reactions with enol ethers 9 to produce poly-
functionalized dihydropyrans 11. Cycloadducts 11 were generated in moderate to
good yields and with excellent cis-diastereoselectivity (up to[99:1).
Xing et al. described cycloadditions of fluorine-containing a,b-unsaturated
ketones 14, which are electron-poor 1-oxa-1,3-butadienes, with electron-rich olefins
15 (Scheme 3) [76]. The ketones 14 were prepared by the Knoevenagel reactions of
b-keto perfluoroalkanesulfones 12 with aromatic aldehydes 13 in presence of
ammonium acetate as catalyst.
Tetrasubstituted dihydropyrans 16 were prepared in quantitative yields. All the
products 16 were the diastereomeric mixtures.
O
NC
H
NAc
Ph
R4R3
R2 OR1O
N
OR1R2R3R4NC
AcPh
O
N
R2OR1R3R4NC
AcPh
pressure flask, toluene110oC, 30-96h
R1 = Me, Et, iBu, n-Bu, R2 = H, MeR3 = H, R4 = H, Me
1 2 cis-3 trans-4
O
NC
Ph
Ar
R2 OR1
O
Ar
OR1R2
NC
Ph O
Ar
R2OR1
NC
Ph
Ar = 2-thienyl,2-furyl, 4-NC-C6H4
5 2cis-6 trans-7
CH2Cl2, rt, 1-2 days
R1 = Et, iBuR2 = H, Me
yield 48-77% 3 and 4cis 3/trans 4 1.5:1 - 3.2:1
yield 76-88% 6 and 7cis 6/trans 7 4.5:1 - 12:1
Scheme 1 Inverse-electron-demand HDA reactions of propenenitriles 1 and 5 with enol ethers 2
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Another example of HDA reaction of 1-oxa-1,3-butadienes is inverse-electron-demand
Diels–Alder cycloaddition of sterically hindered cycloalkylidene derivatives of benzoy-
lacetonitrile 17 and derivatives of N,N-dimethylbarbituric acid 20 with enol ethers 18and cyclic enol ether 22 (Scheme 4) [77]. Spirodihydropyrans 19, dispirodihydropyrans
23, spirouracils 21, and dispirouracils 24 were prepared. The cycloaddition reactions
of 2-cycloalkylidene-3-oxo-3-phenylpropionitriles 17 or 5-cycloalkylidene-1,3-
dimethylpyrimidine-2,4,6-triones 20 with enol ethers 18 were performed in toluene
solution at reflux and the pyrans 19 and 21 were obtained in good (78–93 %) yields
(Scheme 4). The inverse-electron-demand HDA reactions between cycloalkylidene
derivatives 17 or 20 and cyclic enol ether 22 were performed in toluene solution at 110 �Cfor 24 h and the dispiropyrans 23 and 24 were obtained in good (87–93 %) yields. For all
cycloadditions, high diastereoselectivity was observed. Products were each obtained as
one enantiomerically pure diastereoisomer. Confirmation of the experimental results by
semi-empirical AM1, PM3 methods and ab initio Hartree–Fock calculations of frontier
molecular orbital energies of heterodienes (H) and dienophiles (D) has been performed.
For reaction of ethyl-vinyl ether, the energy gaps ELUMO(H)–EHOMO(D) are slightly lower
for the cycloalkylidene derivatives of N,N-dimethylbarbituric acid than for the
cycloalkylidene derivatives of benzoylacetonitrile. The reactivity of cyclic enol ether is
comparable with the reactivity of ethyl-vinyl ether [77].
The scope of intermolecular HDA reactions of 1-oxa-1,3-butadienes with
inverse-electron-demand was expanded to cycloadditions with enecarbamate [78].
Cycloadditions of 3-aryl-2-benzoylprop-2-enenitriles and 3-phenylsulfonylbut-3-en-
2-ones 25 to N-vinyl-2-oxazolidinone 26 proceeded regio- and diastereoselectively,
yielding cis 27 and trans 28 diastereoisomers of 3,4-dihydro-2-(2-oxo-3-oxazo-
lidinyl)-2H-pyrans in 37–65 % yield (Scheme 5). Cycloadducts cis-27 were the
major products. Reactions of 5-arylidene-1,3-dimethylbarbituric acids 29 with
R2
CNR1
O
OR3IBX (1.5 equiv.)
DMSO/H2O (4:1), rt
8 9
R1 = Ph, Ph(CH2)2, 2-furanyl4-Br-C6H4, cyclopropyl, CO2Me
R2 = H, Me, Ph, n-heptyl
R3 = Et, nPr, nBu
OR1
NCR2
OR3H
yield 51-88%
1110R2
CNR1
O
OR3
Scheme 2 One-pot procedure for the conversion of b-oxonitriles 8 into dihydropyrans 11 bydehydrogenation and HDA reaction
yield 51-94%
R1O2SO
R2 ArCHO
R1 = CF3, (CH2)4ClR2 = Me, Ph
Ar = C6H5, 4-MeOC6H4, 4-MeC6H4,4-BrC6H4, 2-BrC6H4, C6H5CH=CH, 2-furyl
NH4OAc, MS
benzene, rt OR2
R1O2SAr
12 1314
yield 96-99%cis:trans 53:47 - 64:36
15OR3R3 = Et, iBu80oC
neat3-5h
16O
Ar
OR3
R1O2S
R2
Scheme 3 HDA reactions of (E)-a-perfluoroalkanesulfonyl-a,b-unsatutated ketones 14
Top Curr Chem (Z) (2016) 374:24 Page 7 of 37 24
123
dienophile 26 afforded mixtures of pyrano[2,3-d]pyrimidinediones trans 30 in
50–52 % yield and products 31 resulted from an elimination of 2-oxazolidinone.
N-Vinyl-2-oxazolidinone 26 can act as a valuable dienophile in inverse-electron-
demand heterocycloaddition. This compound was found to be less reactive than enol
ethers because similar reactions of dienes 25 and 29 with enol ethers occurred at
room temperature [71, 82] whereas reactions with 26 required heating in boiling
toluene.
R3 OR2
+toluene,110oC, 24h
pressure flask
17 18
R1 = H, Me, R2 = Me, Et, iBu, R3 = H, Me, n = 0, 1, 2, 3
19yield 83-91%
O
NC
Ph
R1
n
O
NC
PhR3
OR2
R1n
R1 = H, Me
OEt
+
yield 78-93%20 21
N
N
O
OO
R1
n
toluene,110oC, 24h
pressure flaskN
N O
R1
O
O OEt
n
18
R1 = H, Me
+toluene,110oC, 24h
pressure flask
17 22R1 = H, Me
23yield 91-93%
O
NC
Ph
R1
+
yield 87-89%20 24
toluene,110oC, 24h
pressure flask
22
O
ON
N
O
OO
R1
O
NC
Ph
R1
O
N
N O
R1
O
O
O
Scheme 4 HDA reactions of sterically hindered 2-cycloalkylidene-3-oxo-3-phenylpropionitriles 17 or5-cycloalkylidene-1,3-dimethylpyrimidine-2,4,6-triones 20 with enol ethers 18 and cyclic enol ether 22
24 Page 8 of 37 Top Curr Chem (Z) (2016) 374:24
123
2.1.2 Three-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1-
Oxa-1,3-Butadienes
Domino Knoevenagel hetero-Diels–Alder reactions with an intermolecular cycload-
dition can be performed as a three-component reaction using a mixture of a 1,3-
dicarbonyl compound, an aldehyde, and a vinyl ether or an enamine. Any cyclic 1,3-
dicarbonyl compounds such as 1,3-cyclohexanediones, Meldrum’s acid or N,N-
O
R1
R2
R3 N O
O+
O
R1
NO
R2
R3
O
O
R1
NO
R2
R3
O+
toluenereflux 8-32h
25 26 27 28R1 = Ph, 4-NO2-C6H4, 4-CH3O-C6H4, CH3CONHR2 = CN, PhSO2
R3 = Ph, Me
cis 27/trans 28 9:1 - (>100:1)
N
N O
O
O
Ar
+ N O
O
26
toluenereflux 8-32h
O
Ar
NO
ON
N
O
O O
N
N
O
O
Ar
+
29 30 31
Ar = Ph, 4-NO2-C6H4, 4-CH3O-C6H4 30/31 1:0.14 - 1:1.5
Scheme 5 Inverse-electron-demand HDA reactions of different 1-oxa-1,3-butadienes 25 and 29 with N-vinyl-2-oxazolidinone 26
X ZY
O O
OBnR3
R1 O
HCbR2N n
EDDA, toluene
ultrasound, 50oC, 15h
3233
34
3637
X ZY
O O
R1CbR2NR3
OBnn
R1 = H, Me, iPr, iBu, BnR2 = H, Men = 0, 1, 2Cb = benzyloxycarbonyl
X ZY
O O=
N N
O O
O
O O O O
O
O OH
R3 = H, Me, Et, iPr
X ZY
O O
R1CbR2N
n OBnR3
35
Pd/C, H2, 1bar
rt, 24hn
X ZY
O O
N
R3
R1
H R2
Scheme 6 Domino sequence comprising Knoevenagel, inverse-electron-demand HDA reaction andhydrogenation starting from amino aldehydes 32, 1,3-dicarbonyl compounds 34, and enol ethers 33
Top Curr Chem (Z) (2016) 374:24 Page 9 of 37 24
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dimethylbarbituric acid, as well as reactive acyclic 1,3-dicarbonyl compounds, can
be employed. Tietze et al. examined the multicomponent domino Knoevenagel
HDA reactions of 1,3-dicarbonyl compounds 34 with amino aldehydes 32 and enol
ethers 33, followed by a reductive amination with the formation of betaines 37which can be precipitated from the solution in high purity (Scheme 6) [79, 80].
The amino aldehydes 32 were treated with the 1,3-dicarbonyl components 34 and
benzoyl enol ethers 33 in toluene in the presence of catalytic amounts of EDDA and
trimethyl orthoformate as dehydrating agent in an ultrasonic bath. The domino
reaction sequence of Knoevenagel, HDA reaction, and hydrogenation allows rapid
access to a number of N-heterocycles of different ring sizes and with different
substituents in a betaine 37.
Radi et al. described a protocol for the multicomponent microwave-assisted
organocatalytic domino Knoevenagel HDA reaction for the synthesis of substi-
tuted 2,3-dihydropyran[2,3-c]pyrazoles [81]. The reported procedure can be used
for the fast generation of pyran[2,3-c]pyrazoles with potential anti-tuberculosis
activity.
A mixture of pyrazolone 38, aldehyde 40 and 10 equiv of ethyl-vinyl ether 39was MW irradiated and heated at 110 �C in the presence of the appropriate
organocatalyst A–F (Scheme 7). The best results were obtained in the presence of
diaryl-prolinols B and C. In the absence of the catalyst the reaction did not start at
all. Using the catalyst B and t-BuOH as the solvent, the authors obtained the
cycloadducts 41 and 42 in yields (56 and 12 %, respectively) and improved
diastereoisomeric ratio (4:1) in comparison to the results previously obtained.
Inverse-electron-demand HDA reaction of 1-oxa-1,3-butadienes was used in
synthesis of the fused uracils–pyrano[2,3-d]pyrimidine-2,4-diones [82]. This group
of uracils, as a fused heterobicyclic system, constitutes an important contribution in
medicinal chemistry and a wide variety of attractive pharmacological effects has
been attributed to them [83]. First, it was examined that 5-arylidene-N,N-
dimethylbarbituric acids 43 undergo smooth HDA reactions with enol ethers 44to afford cis-47 and trans-48 diastereoisomers of 7-alkoxy-5-aryl-2H-pyrano[2,3-
d]pyrimidine-2,4-diones in excellent yields (84–95 %; Scheme 8). Cycloadducts 47with cis-configurations were the major products. Next, three-component one-pot
MW, 110oC30 min, organocatalyst A-F
NH
NH HO
NH HO
NH
COOH NH OTMS
NH HO
OMe
MeO
A B C
D
E
F
NN O OEt
Cl
Cl
NN O OEt
Cl
Cl
2414
NN
O
Cl
Cl
CHO
OEt
38
39
40
20 mol%
Scheme 7 Microwave-assisted organocatalytic mulicomponent Knoevenagel HDA reaction
24 Page 10 of 37 Top Curr Chem (Z) (2016) 374:24
123
reactions of N,N-dimethylbarbituric acid 45, aromatic and heteroaromatic aldehydes
46, and enol ethers 44 in the presence of piperidine gave uracils cis-47 and trans-48also in very good yields (87–95 %; Scheme 8). Trace amounts of compounds 49created by a trans-diaxial-elimination of the appropriate alcohol were also obtained
in these reactions.
The advantages of these reactions are: the excellent yields, short reactions
times, and the fact that cycloadditions do not require drastic conditions, but can be
carried out at room temperature. The described reactions give easy and rapid
access to both cis-47 as trans-48 diastereoisomers of uracils and pure
diastereoisomers can be very easily isolated by column chromatography. Also,
solvent-free HDA reactions of 5-arylidene derivatives of barbituric acids 50 with
ethyl vinyl ether 51 were investigated at room temperature and pyrano[2,3-
d]pyrimidines 52 and 53 were obtained in excellent yields (Scheme 9) [84]. Three-
component one-pot syntheses of fused uracils were performed in aqueous
suspensions. ‘‘On water’’ reactions of barbituric acids 50, aldehydes 54, and
ethyl vinyl ether 51 where carried out at ambient temperature, whereas the one-pot
synthesis with barbituric acids 50, aldehydes 54, and styrene or N-vinyl-2-
oxazolidinone 56 required the heating of aqueous suspensions at 60 �C(Scheme 9). Formation of the unexpected side products 55 can be explained as
the result of three-component reactions of barbituric acids and acetaldehyde which
were produced from reaction of etyl vinyl ether and water, and ethyl vinyl ether
51. Described ‘‘on water’’ cycloadditions were characterized by higher diastere-
oselectivity in contrast to reactions carried out in homogenous organic media
(dichloromethane, toluene, Scheme 9). They allowed the cis adducts 57 to be
obtained preferentially or exclusively. Green methods presented in this study avoid
the use of catalysts, the heating of reaction mixtures for long time at high
temperature, and the use of organic solvents.
NH
N
N O
O
O
Ar
R2 OR1
N
N O
O
O
Ar
CHO
R2 OR1
N
N O
O
O
Ar
OR1R2
N
N O
O
O
Ar
R2OR1
N
N O
O
O
Ar
R2
43
4445
46
cis-47 trans-48
49
44
CH2Cl2rt, 1-5h
Ar = Ph, 4-CH3O-C6H44-NO2-C6H4, 2-thienyl,2-furyl, 4-pyridinyl
R1 = Me, Et, iBuR2 = H, Me
cis-47/trans-48 1.1:1 - 3.6:1
CH2Cl2rt, 2-7h
Scheme 8 Inverse-electron-demand HDA reactions of 5-arylidene-N,N-dimethylbarbituric acids 43 withenol ethers 44. Three-component one-pot synthesis of fused uracils – pyrano[2,3-d]-pyrimidine-2,4-diones cis-47 and trans-48
Top Curr Chem (Z) (2016) 374:24 Page 11 of 37 24
123
2.1.3 Catalytic Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
with Achiral Lewis Acids
It was mentioned in the Introduction that Lewis acids accelerate the HDA reactions
of 1-oxa-1,3-butadienes [41–53]. Lewis acids can also improve regioselectivity and
diastereoselectivity of these reactions. The example of catalytic HDA reaction are
cycloadditions of a-keto-b,c-unsaturated phosphonates 58 and 65 with cycloalke-
nes: cyclopentadiene 59, cyclohexadiene 62, dihydrofuran, and dihydropyran 66,
described by Hanessian and Compain (Scheme 10) [85]. The reactions led to the
formation of the hetero-Diels–Alder products 60, 63 and 67 in addition to the
normally expected Diels–Alder cycloadducts 61 and 64. Hetero-Diels–Alder
cycloadducts with the endo product as the major isomer were the main products
in the presence of SnCl4 as a Lewis acid. The effect of substituents on
stereochemistry of these reactions can be explained by considering steric
interactions in the transition state. Increasing the bulk of the ester moiety lowered
the ratio of hetero to normal Diels–Alder products while geminal substitution
favored the product formed by HDA reaction. In the reactions of dialkyl a-
cis-52/ trans-53 1:1 - 3.4:1
N
N
R3
O
O
XR2
R1
OEt
N
N O
O
X
R1
R2
R3
OEt
50 51 cis-52 trans-53
N
N O
O
X
R1
R2
R3
OEt
yield 52 and 53 88-96%
neat, rt, 1-5h
(10 equiv.)
R1 = R2 = H, Me X = O,SR3 = Ph, 4-MeOC6H4, 4-NO2C6H4, 4-NCC6H4, 4-ClC6H4, 4-BrC6H4, 2-thienyl, 2-furyl, 4-pyridyl
N
N O
O
XR2
R1 R3CHO
OEt
H2O, rt, 1-3hcis-52
trans-53
N
N O
O
X
R1
R2
Me
OEt
yield 52 and 53 88-96%
R1 = R2 = H, Me X = O,SR3 = Ph, 4-MeOC6H4, 4-NO2C6H4, 4-NCC6H4, 4-ClC6H4, 4-BrC6H4, 2-thienyl
50 51
54
55
N
N O
O
XR2
R1 R3CHO
OR4
H2O, 60oC, 1-3h
50
54
56
N
N O
O
X
R1
R2
R3
R4
cis-57
R1 = R2 = H, Me X = O,SR3 = Ph, 4-NO2C6H4 R4 = 4-MeO, 2-oxo-oxazolidin-3-yl
yield cis-57 89-95%
cis-52/ trans-53 4.1:1 - 8.5:1
Scheme 9 Solvent free HDA reactions of 5-arylidene-N,N-dimethylbarbituric acids 50 with ethyl vinylether 51. Three-component 50, 54 and 51 or 56 one-pot synthesis of fused uracils in water
24 Page 12 of 37 Top Curr Chem (Z) (2016) 374:24
123
R4
R1 P(OR3)2
O
OR2
O P(OR3)2
O
R2
R1 R4
0.6 equiv SnCl4CH2Cl2, -78oC
R1
R2
P(OR3)2O
R4
58 59 60 61R1 = Me, Ph R2 = H, MeR3 = Me, Et, iPr R4 = H, Me
yield 52-77%endo/exo 2.4:1 - 47:160/61 2.4:1 - (>30:1)
R1 P(OR3)2
O
OR2
1 equiv SnCl4CH2Cl2, -78oC
R1 = Me, Ph R2 = H, Me R3 = Me, Et58
O P(OR3)2
O
R2
R1
R1
P(OR3)2
R2
O62 63 64yield 43-71%endo/exo 17:1 - (>50:1)63/64 1:1 - 14:1
yield 68-78%endo/exo 25:1 - 36:1
R1 P(OR2)2
O
OR2
R3O
n O P(OR3)2
O
R2
R1
1 equiv SnCl4CH2Cl2, -78oC
65 6667R1 = Me, Ph R2 = Me, Et R3 = H, Me n = 0, 1
Scheme 10 Lewis acid SnCl4 promoted HDA reactions of a-ketophosphonoenoates 58 and 65 withdienes 59, 62 and 66
3 equiv.
3 equiv.
OH O
O
O
Ph
O
O
O
Ph
OOMe
O
PhOH
O
Ph
O
OH
Ph
yield 70%cis selectivity >97:3facial selectivity 93:7
1) 20 mol% Eu(fod)3, CH2Cl2, 48h, reflux2) filtration
1) LiAlH4, THF/Et2O, 12h, rt2) Na2SO4 aq3) filtration
O
Ph
O
OMe68
69
70
71
72
73
O
Ph
O
HO
1) DIC, DMAP, DMF, 12h, rt2) filtration
Scheme 11 Eu(fod)3-catalyzed solid-phase HDA reaction of benzylidenepyruvate 70 with (S)-(?)-O-vinyl mandelate 71
Top Curr Chem (Z) (2016) 374:24 Page 13 of 37 24
123
crotonylphosphonates 65 with dihydrofuran and dihydropyran 66, the only isolable
products were heterocycloadducts with high endo/exo ratios and good yields.
Compatibility of the carrier and the linker with the Lewis acid is a main criterion
for a successful application of Lewis acid catalysts on solid supports in asymmetric
[4 ? 2] heterocycloadditions. Dujardin et al. demonstrated the usefulness of a
Wang resin-bound heterodiene benzylidenepyruvate 70 for Eu(fod)3-catalyzed
inverse-electron-demand HDA reactions with (S)-(?)-O-vinyl mandelate 71(Scheme 11) [86]. The solid-phase sequence allowed an unprecedented reuse of
the catalyst in the presence of excess dienophile in solution. Also, attempts with
ethyl vinyl ether as an achiral dienophile gave positive results.
Gong et al. examined asymmetric inverse-electron-demand HDA reaction of
trisubstituted chiral enol ether 75 derived from (R)-mandelic acid (Scheme 12) [87].
Chiral 1,2,3,5-substituted tetrahydropyrans were synthesized by a three-step
sequence with a remarkable and unprecedented endo and facial stereocontrol. The
key step involved the Eu(fod)3-catalyzed HDA reaction of a trisubstituted chiral
enol ether 75 and an activated heterodiene 74. The stereoselective hydrogenation of
the heteroadducts 1-alkoxydihydropyrans 76 was optimized by using Pd on charcoal
and diisopropylethylamine, leading to a unique isomer [87].
Another example of inverse-electron-demand HDA reaction of 1-oxa-1,3-butadienes is
the [4 ? 2] acido-catalyzed heterocycloaddition between b-substituted N-vinyl-1,3-
oxazolidin-2-ones 78 and unsaturated a-ketoesters 77 (Scheme 13) [88, 89]. Cycload-
ditions afforded dihydropyrans 79 and 80 with high levels of endo and facial selectivities.
A complete reversal of facial differentiation was achieved by using a different Lewis
acid, leading to the stereoselective formation of either endo-a 79 or endo-b 80 adducts.
The endo-a adduct 79 was obtained with using Eu(fod)3 as the catalyst and endo-badducts 80 was the main product if the promoter was SnCl4 (Scheme 13) [88, 89].
2.1.4 Enantioselective Approach: Catalytic Enantioselective Hetero-Diels–Alder
Reactions of 1-Oxa-1,3-Butadienes with Chiral Lewis Acids
The catalytic enantioselective HDA reactions of 1-oxa-1,3-butadienes with chiral
Lewis acids were widely explored reactions. The chiral bisoxazoline copper(II)
complexes have been shown to be effective catalysts for inverse-electron-demand
HDA reactions. The reactions of a,b-unsaturated acyl phosphonates 81 and 84 and
O
OR1
OMe
O
R2
R2
O
O
OR3Ph
R1 = Bn, t-BuR2 = H, MeR3 = Me, t-Bu
5 mol% Eu(fod)3
petroleum ether reflux O
OR1
OMe
O
R2
O
R2
Ph
O
OR3
74 75 76
Scheme 12 Eu(fod)3 catalyzed HDA reaction of alkylidenepyruvate 74 with O-isopropenyl mandelicesters 75
24 Page 14 of 37 Top Curr Chem (Z) (2016) 374:24
123
b,c-unsaturated a-keto esters and amides 87 with enol ethers and sulfides 82 and 85as dienophiles were described by Evans et al. (Scheme 14) [90]. The products were
prepared with high diastereo- and enantioselectivity. The selectivities of reactions
exceeded 90 % even at room temperature. The synthesis of bicyclic adducts 83 in
high diasteromeric and enantiomeric excess proved that cyclic enol ethers 82 can be
excellent dienophiles. The derived cycloadducts were transformed to useful chiral
building blocks such as desymmetrized glutaric acid derivatives or highly
functionalized tetrahydropyran products. The authors examined that the high
yield 44-83%yield 57-77%selectivity endo/exo for 79 and 80 80:20 - (>98:2)
O
R1
MeO2C
R2
NO
O
O
R1
N
R2
O
O
MeO2CO
R1
N
R2
O
O
MeO2Cendo βendo α
77 7879 80
R2 = H, Me, Ph
SnCl4 50 mol%, -78oC
CH2Cl2
Eu(fod)3 5 mol%, reflux
cyclohexane
R1 = Ph,
MeO
MeO
MeO
Scheme 13 Lewis acid tuned facial stereodivergent HDA reactions of b-substituted N-vinyl-1,3-oxazolidin-2-ones 78
O(MeO)2P
O
Me
Y
Z O
Me
Y
X(MeO)2P
Oendo/exo product 1:1 - (>99:1)ee 64 - 95%yield 31-100%
Y
Z
=O O OR SEt
R = Me, t-Bu, TBS
10 mol%
CH2Cl2, -78oC
R = t-Bu, i-Pr, Bn, PhX = OTf, SbF6
CuN
O
N
O
Me Me
RR
2+
2X -
81 82 83
O(MeO)2P
O
R1
R2
Z O
R1
Z(MeO)2P
O
R2
R1 = Me, Ph, i-Pr, OEtR2 = H, Me
Z = OEt, SEt
[Cu((S,S)-t-Bu-box)(H2O)2](OTf)25 mol%
THF, 0oC, MS
endo/exo product 16:1 - 44:1ee 90 - 97%yield 75-98%
84 85 86
OYOC
R
Z
R = Me, Et, i-Pr, OMe, OEt, Ph, SBnY = OEt, N(Me)OMe
[Cu((S,S)-t-Bu-box)(H2O)2](OTf)22 mol%
THF, 0oC, MSO
R
ZYOC
Z = OEt, SEtendo/exo product 10:1 - 64:1ee 95 - 99%yield 87-99%
87 85 88
Scheme 14 HDA reactions of acyl phosphonates 81, 84 and b,c-unsaturated a-keto esters and amides87 with enol ethers and sulfides 82 and 85 catalyzed by bis(oxazoline)-Cu(II) complexes
Top Curr Chem (Z) (2016) 374:24 Page 15 of 37 24
123
diastereoselectivity for catalyzed HDA reactions is a result of the endo orientation
of dienophiles.
A highly enantioselective approach for the synthesis of optically active
carbohydrate derivatives by inverse-electron-demand HDA reaction of a,b-unsat-
urated carbonyl compounds with electron-rich alkenes catalyzed by combination of
chiral bisoxazolines and Cu(OTf)2 as the Lewis acid was also presented by
Jorgensen et al. [91]. The reaction of unsaturated a-keto esters 89 and 92 with vinyl
ether 90 and various types of cis-disubstituted alkenes 93 proceeded in good yield,
high diastereoselectivity, and excellent enantioselectivity (Scheme 15). The poten-
tial of the reaction was demonstrated by the synthesis of optically active
carbohydrates such as spiro-carbohydrates, an ethyl b-D-mannoside tetraacetate,
and acetal-protected C-2-branched carbohydrates [91].
Catalytic enantioselective HDA reaction of 1-oxa-1,3-butadiene with inverse-
electron-demand was used in synthesis of the marine neurotoxin-(?)-azaspiracid
[92]. Cycloaddition between two components of the HDA reaction 95 and 96proceeded readily using 2 mol% loadings of the hydrated copper complex 97(Scheme 16). Catalyst 97 was dehydrated with molecular sieves prior to use.
Diethyl ether was the optimal solvent for this HDA reaction (97 % ee, dr 94:6). The
desired cycloadduct 98 was isolated in 84 % yield as a single isomer.
The tridentate (Schiff base) chromium complex has been identified as a highly
diastereoselective and enantioselective catalyst in HDA reactions between aldehy-
des and mono-oxygenated 1,3-diene derivatives [93]. Jacobsen et al. examined if
use of this chiral catalyst can be evaluated for the reactions of conjugated aldehydes
[94]. The inverse-electron-demand HDA reactions of crotonaldehyde and the wide
range of a,b-unsaturated aldehydes 99 bearing b substituents and vinyl ether 100
919089de 71-99%ee 87-99%yield 93-99%
O
Ph
OEt
O
MeOO
Ph
O
MeOOEt
0.5-10 mol%
R = t-Bu, PhX = OTf, SbF6
CuN
O
N
O
Me Me
RR
2+
2X -
Et2O
949392de > 99ee 66-99.5%yield 41-76%
R3 = OEt, OBnR1 = Ph, OEt, OBnR2 = Me, Et
O
R1
R3
OAc
O
R2OR3
OAc
O
R1
O
R2O
[Cu(S,S)-t-Bu-box](OTf)210-20 mol%Et2O, rt
Scheme 15 HDA reactions of c-substituted b,c-unsaturated a-keto esters 89 and 92 with vinyl ether 90and cis-disubstituted alkenes 93 catalyzed by bis(oxazoline)-Cu(II) complexes
24 Page 16 of 37 Top Curr Chem (Z) (2016) 374:24
123
proceeded in the presence of molecular sieves MS with 5 mol% chiral catalyst 101at room temperature to provide cycloadducts 102 with excellent diastereoselectivity,
enantioselectivity, and in high yield (Scheme 17).
A dramatic improvement was observed in reactions carried out under solvent-free
conditions and excess ethyl vinyl ether 100. Usage of solvents generally resulted in
significantly lower enantioselectivity in the cycloaddition. As the steric bulk of the
alkyl group of dienophile was increased, the selectivity and reactivity decreased.
The optimal dienophile was ethyl vinyl ether. In the solid state, catalyst 101 exists
as a dimeric structure, bridged through a single water molecule and bearing one
terminal water ligand on each chromium center. Opening of a coordination site by
dissociation of the terminal water molecule for complexation of the aldehyde
substrate explains the important role of molecular sieves in these reactions [95, 96].
Asymmetric inverse-electron-demand HDA reaction of 1-oxa-1,3-butadienes was
a key step in synthesis of several members of the bioactive styryllactone family
[97]. Treatment of ethyl vinyl ether 104 with 3-boronoacrolein pinacolate 103 in the
97% eedr 94:6yield 84%
EtO
Me Me
OEt
O
O
+
95 96
OEtO
Me Me
O
OEt
98
97 2 mol%
MS, Et2O, -40oC
O
N
Me Me
NO
Me3C CMe3Cu
H2O OH2
2+OTf2
Scheme 16 Enantioselective HDA approach to the synthon of azaspiracid
5-10 mol%
R1 = H, Br, MeR2 = Me, Et, i-Pr, n-Pr, n-Bu, Ph, 4-MeO-C6H4, 4-NO2-C6H42-NO2-C6H4, CH2OBn, CH2OTBS, CO2Et, OBz
de > 95%ee 89-98%yield 70-95%
(10 equiv)99 100
101
102
(1S, 2R)
MS, neat, 24-120h+
OEtO
R2
R1
O
R1
OEt
R2
O
HR2
R1
Cr
CrClO
N O
Me
Scheme 17 HDA reactions catalyzed by (Schiff base)Cr(III) catalyst 101. Model of one-point binding ofan a,b-unsaturated aldehydes 99 to a Lewis acid center
Top Curr Chem (Z) (2016) 374:24 Page 17 of 37 24
123
presence of Jacobsen’s [(Schiff base)chromium(III)] complex 105 resulted in the
formation of cycloadduct 106 in good yield (85 %) and high enantioselectivity
(96 % ee; Scheme 18). This strategy can be applicable to the synthesis of different
stereoisomers by taking into account both isomers of mandelic acid and the different
chromium(III) complexes.
2.1.5 Enantioselective Approach: Catalytic Hetero-Diels–Alder Reactions of 1-
Oxa-1,3-Butadienes with Chiral Organocatalysts
In recent years, organocatalysis has been established as a very powerful tool for the
synthesis of functional molecules. Asymmetric versions of HDA utilizing chiral
organocatalysts have been developed. Asymmetric aminocatalytic strategies
involving HOMO activation of the dienophile constitute an important alternative
to classical LUMO-lowering pathways [98–100]. Albrech et al. developed the first
H-bond-directed inverse-electron-demand HDA proceeding via a dienamine
intermediate [101, 102]. They evaluated the organocatalytic reaction between
various b,c-unsaturated a-ketoesters 107 and (E)-4-phenylbut-2-enal 108 in the
presence of various aminocatalysts (Scheme 19). The H-bond-directing dienamine
catalyst 109 promoted the inverse-electron-demand HDA reactions.
In most of the cycloadditions of 107 and 108, good yields and high regio- and
stereoselectivities were obtained. High stereoselectivities were observed by employ-
ing a bifunctional squaramide-containing aminocatalyst 109. The authors postulated
that dienamine intermediate is formed by condensation of aminocatalyst 109 with the
a,b-unsaturated aldehyde 108, and the next heterodiene 107 in s-trans conformation is
recognized by the catalyst. Two cycloreactants 107 and 108 are activated through
H-bond interactions and are positioned to facilitate the cycloaddition step.
Most recently, there was considerable interest in applying self-assembled
organocatalysts/modularly designed organocatalysts (MDO) in catalytic reactions.
Zhao et al. demonstrated that MDO self-assembled from proline derivatives and
cinchona alkaloid derived thioureas are highly efficient catalysts for inverse-
electron-demand HDA reactions [103]. They developed highly enantioselective
HDA reactions of electron-deficient enones 111 and aldehydes 112 by using MDO
O
BPin
H OEt O
BPin
OEt
1 mol%
(1S, 2R)
molecular sieves, rt, 2h
CrClO
N O
Me
yield 85%103 104
105
106
Scheme 18 Asymmetric inverse-electron-demand HDA reaction of 3-boronoacrolein pinacolate 103 andethyl vinyl ether 104 as a key step in synthesis of several members of the styryllactone family
24 Page 18 of 37 Top Curr Chem (Z) (2016) 374:24
123
(Scheme 20). Quinidine and (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid
(OHIC) are both poor catalysts for the inverse-electron-demand HDA reactions
between aldehydes and electron-deficient enones. However, forming MDO by their
self-assembly with cinchona alkaloid-derived thioureas can improve the efficiency,
reactivity and stereoselectivity of these catalysts. Various aldehydes 112, including
long-chain and branched aldehydes, were found to be excellent substrates for the
MDO-catalyzed HDA reactions (Scheme 20).
The high yield and enantioselectivity of the reactions was restored (up to 95 %
yield and 95 % ee). The ester alkyl group of b,c-unsaturated a-ketoesters 111 has
almost no influence on either the reactivity or enantioselectivity. Similarly, the
substituent on the phenyl ring of the enones 111 has minimal effects on the
reactivity and the asymmetric induction of these reactions. b,c-Unsaturated a-
ketophosphonates 111 may also be applied in these reactions if a higher loading of
the precatalyst modules (10 mol%) is used. The authors proposed a plausible
transition state on the basis of the product 116 stereochemistry and the MDO
structure [103]. They showed that the aldehyde 112 reacts with the OHIC moiety of
the MDO to form an (E)-enamine. Next, the thiourea moiety of the MDO forms
OtBuO2C
R Ph
O107 108 110
OO
N
CF3
CF3
H
N
NH
H 109
DEA, THF, rt, 24-120hO
R
Ph
OtBuO2C
R = Ph, 4-Br-C6H4, 3-Br-C6H4, 2-Br-C6H42-F-C6H4, 4-CF3-C6H4, 4-CO2Me-C6H4,4-NO2-C6H4, 2,6-Cl2-C6H4, 4-CH3-C6H43-pyridyl, Me
yield 42-82%dr 3:1 - (>20:1)ee 79-93%
16 mol%
Scheme 19 HDA reactions between b,c-unsaturated a-ketoesters 107 and (E)-4-phenylbut-2-enal 108 inthe presence of aminocatalyst
O
R2
R1
R3 R4
CHO OR1 OH
R3R2
R4 PCC67-80%
OR1
R3R2
R4
O
R1 = CO2Me, CO2Et, CO2iPr, P(O)(OMe)2, P(O)(OEt)2, P(O)(OiPr)2
R2 = Ph, 4-OMeC6H4, 4-MeC6H4, 4CF3C6H4, 4-ClC6H4, 2-ClC6H4, MeR3 = Me, nPr, nC10H21, Bn, iPr, PhR4 = H, Me
111 112 115 116
toluene, rt, 2-48h
MDO 5 mol%113
114NCOOH
H
H H
N
NH
OMe
N
S
Ar
NH
Scheme 20 MDO catalyzed HDA reactions of electron-deficient enones 111 and aldehydes 112
Top Curr Chem (Z) (2016) 374:24 Page 19 of 37 24
123
hydrogen bonds with the enone 111 and directs to enamine from the front. The
attack of the enone 111 onto the Re face of the enamine in an endo transition state
leads to the formation of the observed (4S, 5R)-product 116.
2.1.6 Enantioselective Approach: Hetero-Diels–Alder Reactions of 1-Oxa-1,3-
Butadienes with Chiral Auxiliaries
Inverse-electron-demand HDA reaction between 1-oxa-1,3-butadienes and electron-
rich alkenes represents one of the most direct approaches for the synthesis of
optically active carbohydrate derivatives. To obtain optically active dihydropyrans
derivatives by the HDA approach, either a catalytic enantioselective reaction or a
chiral transformation via the use of a chiral auxiliary is necessary. The
enantioselective HDA reaction requires chiral 1-oxa-1,3-butadienes or optically
active alkene. The HDA reaction of the a,b-unsaturated ketone 118 prepared in situ
from protected D-xylose 117 was used as the key step for the synthesis of a C10
higher carbon sugar 119 in a one-pot multi-step route (Scheme 21) [104].
Two molecules of a,b-unsaturated ketone 118 undergo the HDA reaction affording
the 10 carbon sugar 119. Reduction and catalytic hydrogenation of cycloadduct 119gave stereoselectively a single product 121 in an excellent yield.
Recently, it was shown that fused uracils, such as pyrano[2,3-d]pyrimidines with an
aryl substituent at carbon C(5) in the ring system can be efficiently synthesized by HDA
reactions of 5-arylidene derivatives of barbituric acids with vinyl ethers [82]. To
increase the potential pharmacological activity of the fused uracil, a sugar moiety can be
introduced instead of an aryl group at the C(5) position of pyrano[2,3-d]pyrimidine.
Therefore, 5-ylidene barbituric acids bearing the carbohydrate substituent were
constructed. A convenient and efficient procedure for the preparation of fused uracils
containing a sugar moiety was described [105]. The reaction sequence was:
Knoevenagel condensation of unprotected sugars and barbituric acid in water,
acetylation of C-glycosides and HDA reaction. The cycloaddition reactions of O-
yield 81%
OOH
BzO
OO
PDC, MeCN, Ac2O
80 oC, 6h
117
O
OO
O
118
OO
OO
O
OO
O
119
NaBH4, EtOH rt, 1h
OO
OO
O
HOO
O
120
OO
OO
O
HOO
O
121
H2/Pd-C, EtOH
40oC, 3h
Scheme 21 Stereoselective synthesis of higher carbon sugar 121 from protected D-xylose 117 by HDAreaction of the a,b-unsaturated ketone 118
24 Page 20 of 37 Top Curr Chem (Z) (2016) 374:24
123
acetylated 1,3-dimethyl-2,4,6-trioxo-pyrimidin-5-ylidene alditols 123, representing an
1-oxa-1,3-butadiene system, with enol ethers 124 were performed in the absence of
solvent at room temperature for 2–5 min and enantiomerically pure cis and trans
diastereoisomers of pyrano[2,3-d]pyrimidines 125–128 with an alditol moiety were
obtained in good 80–87 % yields (Scheme 22). It is worth noting that barbituric acid
5-ylidene alditols 123 are extremely reactive because they underwent smooth HDA
reactions at a temperature of -80 �C as well as at room temperature. Observed
diastereoselectivity of the HDA reactions of 123 and 124 changed in the range from
6.6:1 to 2.1:1. Cycloadducts cis were the major products in all reactions except those of
D-galactose derivatives (Scheme 22). The inverse-electron-demand HDA reactions of
O-acetylated 5-ylidene derivatives 123 with a tenfold excess of cyclic enol ether 129were performed in solvent-less conditions at room temperature for 30 min, and
pyrano[30,20:5,6]pyrano[2,3-d]pyrimidines 130 and 131 were obtained in good
76–78 % yields (Scheme 23). O-Acetylated 1,3-dimethyl-2,4,6-trioxo-pyrimidin-5-
ylidene alditols 123 can act as active heterodienes in HDA reactions and their use in
cycloadditions allows preparation of the enantiomerically pure diastereoisomers of
pyrano[2,3-d]pyrimidines with a sugar moiety.
In the field of pericyclic reactions, the development of new cycloreactants is a
continuous challenge. Dimedone enamines were applied as new dienophiles in HDA
reactions with inverse-electron-demand of 1-oxa-1,3-butadienes [106]. Cycloaddi-
tions of barbituric acid 5-ylidene alditols 132, representing a 1-oxa-1,3-butadiene
system, with dimedone enamines 133 were performed in dichloromethane at room
temperature for 3 days, and fused uracils–chromeno[2,3-d]pyrimidine-2,4-diones
134 were prepared in good (73–87 %) yields (Scheme 24). Only one enantiomer-
ically pure stereoisomer was obtained in each studied cycloaddition. Analysis of
122 minor
+
OR10
L-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=HL-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAcD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAcD-Galacto, R1=R4=R6=R8=H, R2=R3=R5=R9=OAc, R7=CH2OAcD-Ribo, R1=R3=R5=R7=R9=H, R2=R4=R6=R8=OAc
N
N OO
R2 R1R4 R3R6 R5
R8R9R7
O
123 124R10 = Et, iBu
N
NO
O
O
Na
O
R2
R5
R6 R1
R4
R3
R7
7R
major
N
N OO
R2 R1R4 R3R6 R5
O
R9 R8
OR10
R7
H
H
trans 126cis 125
5S
7R
N
N OO
R2 R1R4 R3R6 R5
O
R9 R8
OR10
R7
H
H+5R
L-Xylo, L-Arabino, D-Gluco, D-Ribo
or
Ac2O, ZnCl224h, rt
neat, rt2-5 min
5R
minormajortrans 127 cis 128
+N
N OO
R2 R1R4 R3R6 R5
O
R9 R8
OR10
R7
H
H5S
7S
N
N OO
R2 R1R4 R3R6 R5
O
R9 R8
OR10
R7
H
H7S
D-Galacto
Scheme 22 Acetylation of C-glycosides 122 and HDA reactions of 5-ylidene derivatives 123 with enolethers 124. Synthesis of pyrano[2,3-d]pyrimidines 125-128 with a sugar moiety
Top Curr Chem (Z) (2016) 374:24 Page 21 of 37 24
123
proton nuclear magnetic resonance ( 1H NMR) and two-dimensional (2D) NMR
spectra allowed for the determination that cycloadducts 134 exist in solution as a
mixture of the neutral form 134 NF and dipolar ion 134 DI. The prepared fused
uracils, possessing both amine and enol functional groups, share amphiprotic
properties and are zwitterions in solid state. Important for biological interaction,
groups such as different sugar moieties, enol moieties and different amino groups
can be introduced into fused uracil systems by this simple HDA reaction. It was also
shown that different alkenes can be used as dienophiles towards barbituric acid
5-ylidene alditols 132; for example, styrene or 1-amino-2-thiocarbamoyl-cyclopent-
1-ene [106].
The application of stereoselective inverse-electron-demand HDA reaction of
1-oxa-1,3-dienes and chiral allenamides in natural product synthesis was described
by Song et al. [107]. They used this reaction as a key step in synthesis of the C1–C9
subunit of (?)-zincophorin (Scheme 25).
neat, rt, 30 min
O
129
+
L-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=HL-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAcD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAC
123
N
N OO
R2 R1R4 R3R6 R5
R8R9R7
O
+
trans-cis-(5,5a:5a,9a)-131cis-cis-(5,5a:5a,9a)-130
9aR5aS
5RN
N OO
R2 R1R4 R3R6 R5
O
R9 R8R7
OH
H
9aR5aS5SN
N OO
R2 R1R4 R3R6 R5
O
R9 R8R7
OH
H
Scheme 23 HDA reactions of O-acetylated 1,3-dimethyl-2,4,6-trioxo-pyrimidin-5-ylidene alditols 123with cyclic enol ether 129
134 NF
N
N OO
X
X
R2 R1R4 R3R6 R5
R8R9R7
O
132 134
N
N OO
X
X
R2 R1R4 R3R6 R5
R8R9R7
O OH
NH Y
O
NH
Y
+
133
CH2Cl2rt, 3 days
yield 73-87%L-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAc, X=MeL-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=H, X=MeD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAc, X=MeD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAc, X=HD-Galacto, R1=R4=R6=R8=H, R2=R3=R5=R9=OAc, R7=CH2OAc, X=Me
X = H, MeY-NH = 4-MeC6H4-NH, 4-MeOC6H4-NH, 4-NO2C6H4-NH
MeMe
NH
MeMe
NH
MeMeMe
MeNH
MeMe
NH
OHNO
134 DI
N
N OO
X
X
R2 R1R4 R3R6 R5
R8R9R7
O O
NH Y
H
Scheme 24 HDA reactions of alditols 132 with dimedone enamines 133. Synthesis of fused uracils -chromeno[2,3-d]pyrimidine-2,4-diones 134
24 Page 22 of 37 Top Curr Chem (Z) (2016) 374:24
123
Both reactions 136 with 135 and 137 with 135 provided respectively pyrans 138and 139 in 58 and 54 % yields, as single isomers, after heating in a sealed tube at
85 �C for 48 h in acetonitrile as the solvent (Scheme 25).
2.2 Intramolecular Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes
2.2.1 Two-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1-
Oxa-1,3-Butadienes with an Intramolecular Cycloaddition
The domino Knoevenagel intramolecular hetero-Diels–Alder reaction is one of the
most powerful synthetic routes for the synthesis of various heterocycles and natural
products. This reaction can be used in dihydropyran synthesis [54–68]. In
intramolecular cycloaddition, the 1-oxa-1,3-butadienes are prepared in situ by
Knoevenagel condensation of aldehydes possessing the dienophile moiety and a 1,3-
dicarbonyl compound. A lot of different aldehydes and 1,3-dicarbonyl compounds
such as barbituric acids, Meldrum’s acid, 1,3-cyclohexanedione, dimedone,
4-hydroxycoumarin, indiandiones, pyrazolones, or isooxazolones can be used.
Cis-fused cycloadducts are the main products in intramolecular HDA reactions of
oxabutadienes obtained from aromatic aldehydes [54, 55]. Reactions of oxabuta-
dienes derived from aliphatic aldehydes result in the trans-fused cycloadducts [56,
57]. In recent years, intramolecular HDA reactions of 1-oxa-1,3-butadienes have
been used widely in numerous reactions in organic synthesis due to their economical
and stereo-controlled nature. These reactions allow the formation of two or more
rings at once, avoiding sequential chemical transformations. Therefore, the scope of
the intramolecular HDA reactions of 1-oxadienes was expanded recently. The
influence of an electron-withdrawing group at C-3 in 1-oxa-1,3-butadienes on the
intramolecular HDA reaction was studied. First, the influence of cyano, carbonyl,
and ethoxycarbonyl groups was examined [108]. Next, it was demonstrated that
O
OP
P = TBDPS135
C
NH
N
Ph
O
R
S
CH3CN, 85oC, 48h58%
136137
138139
CH3CN, 85oC, 48h54%
O HN
N
O
Ph
OPS
R
C
NH
N
Ph
OR
S
O HN
N
O
Ph
OP
S
R
dr > 95:5dr > 95:5for (+)-zincophorin
Scheme 25 HDA reactions of chiral enone 135 with chiral allenamides 136 and 137. The key step insynthesis of the C1-C9 subunit of (?)-zincophorin
Top Curr Chem (Z) (2016) 374:24 Page 23 of 37 24
123
sulfur-containing substituents incorporated into 1-oxa-1,3-butadienes positively
influence the results of the cycloaddition. The intramolecular HDA reactions of
sulfenyl-, sulfinyl-, and sulfonyl-activated methylene compounds 140 with
2-alkenyloxy aromatic aldehydes 141 were conducted (Scheme 26) [109].
Knoevenagel condensations of 1-(phenylsulfenyl)-, 1-(phenylsulfinyl)-, and
1-(phenylsulfonyl)-2-propanones 140 with 2-alkenyloxy aromatic aldehydes 141yielded the corresponding condensation products 142 which in turn underwent
intramolecular HDA reactions during heating in boiling toluene or xylene
(Scheme 26). Cis-fused 2H-pyran derivatives 143 were the major products. An
increase of the reactivity and a decrease of the diastereoselectivity of the HDA
reactions were observed in order: PhS derivative, PhSO2 derivative and compounds
containing PhSO group [108, 109].
The most widely used 1-oxa-1,3-butadienes in intramolecular HDA reactions are
usually those where the double bond is placed between the symmetrical 1,3-dicarbonyl
compounds. Shanmugasundaram et al. studied the heterocycloaddition in which the
alkene part was flanked by a keto carbonyl and a lactone carbonyl [110]. The reactions
of 4-hydroxy coumarin and its benzo-analogues 144 with O-prenylated aromatic
aldehydes 145 were examined (Scheme 27). Pyrano fused polycyclic compounds 147and 148 were prepared with a high degree of chemoselectivity by the application of
microwave irradiation. These reactions offers an easy access to pyrano[3,2-
c]coumarin 147 which is a structural element of many natural products.
Chemoselectivity was achieved with the reduction in reaction time because the
cycloadducts 147 and 148 formed in the ratios ranging from 79:21–95:5 when the
reactions were carried out under microwave irradiation for 10–150 s. Reactions of
unsymmetrical 1,3-diones 144 with citronellal were also described [110].
Surprising formation of a 2,3-dihydro-4H-pyran containing 14-membered macro-
cycle 151 by sequential olefin cross metathesis and a highly regiospecific intramolecular
HDA reaction of 1-oxa-1,3-dienes was described by Prasad and Kumar (Scheme 28)
[111]. They studied the reaction of a hydroxydienone 149 derived from tartaric acid with
Grubbs’ second generation catalyst. Presence of the unprotected hydroxyl group in the
hydroxyenone led to the formation of macrocycle 151. Protection of the hydroxyl group
resulted in the ring-closing metathesis product 150.
The authors made the experiment to show that obtaining macrocycle 151involves the formation of intermediate 155. Dimerization of hydroxyamide 152 by
PhS(O)n
OR1
CHO
O
R2 R3
O
OR1
PhS(O)n
R2 R3
O
OR1
PhS(O)n
R2R3
H
HEDDA, MeCN
rt
toluene or xylene
reflux, 10-24h
n = 0, 1, 2R1 = Me, Ph
cis/trans 2.5:1 - (>100:1)
140 141 341241R2 = Me, PhR3 = Me, H
Scheme 26 Domino Knoevenagel intramolecular HDA reactions of sulfenyl, sulfinyl and sulfonylactivated methylene compounds 140 with 2-alkenyloxy aromatic aldehydes 141. Synthesis of polycyclic2H-pyran derivatives 143
24 Page 24 of 37 Top Curr Chem (Z) (2016) 374:24
123
olefin cross metathesis with Grubbs second generation catalyst gave the bis-amide
153 (Scheme 28). Protection of the two hydroxyl groups in 153 as the bis-silyl ether
154 and then the reaction with 2-propenylmagnesium bromide resulted in formation
of the macrocycle 156. Deprotection of the silyl ethers in 156 furnished the
macrocycle 151 in 85 % yield. These studies represent the first example of a tandem
olefin cross metathesis HDA reaction sequence.
Wada et al. developed a new type of intramolecular HDA reaction of 1-oxa-1,3-
butadienes–tandem transetherification-intramolecular HDA reaction. Heterodienes
were obtained in situ by a transetherification under thermal conditions from b-
alkoxy-substituted a,b-unsaturated carbonyl compounds bearing an electron-with-
drawing substituent and d,e-unsaturated alcohols [112]. This tandem reaction
proceeded stereoselectively to afford trans-fused hydropyranopyrans. Next, chiral
C
144 145146
147
without MI: yield 40-75%147/148 55:45 - 80:20
with MI: yield 74-92%147/148 79:21 - 95:5
O O
OO
H
H
A
B
148
O O
OH
A
B
O
CHO
CEtOH, reflux, 4-8h orMicrowave Irradiation (MI) 10-150s
O O
O O
A
B
C
O O
O OH
H
A
B
C
Scheme 27 Microwave accelerated domino Knoevenagel intramolecular HDA reactions of 4-hydroxycoumarin and its benzo-analogues 144 with O-prenylated aromatic aldehydes 145
149
O
O
O
OH
O
O
O
OH
Grubbs' secondgen. cat. (1-5 mol%)
CH2Cl2
151
O
O
O
HO OH
O
O
MeO
Me
150
O
O
O
OH
NMe2
O
O
O
NMe2
OH OH
O
NMe2
O
OGrubbs' secondgen. cat. (5 mol%)
CH2Cl2, 50oC6h, 80%
TBDMSClimidazole, DMAP
CH2Cl2reflux, 6h, 87%
O
O
O
NMe2
RO OR
O
NMe2
O
O
R = TBDMS
TBAF, THFrt, 12h, 85% O
O
O
RO OR
O
O
MeO
Me
152 153 154
155
2-Propenyl magnesium bromideTHF, -15oC, 0.5h, 83%
156
O
O
O
RO OR
O
O
MeO
Me
151
O
O
O
HO OH
O
O
MeO
Me
Scheme 28 Synthesis of macrocycle 151 by sequential cross metathesis and HDA reaction
Top Curr Chem (Z) (2016) 374:24 Page 25 of 37 24
123
Lewis acid catalysts were used in this new type of transformation. Wada et al.
examined the catalytic asymmetric tandem transetherification-intramolecular HDA
reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate 157 with d,e-unsaturated
alcohols 158 (Scheme 29) [113]. The optically active catalyst derived from the
(S,S)-tert-Bu-bis(oxazoline) and Cu(SbF6)2 in presence of molecular sieves was a
highly effective Lewis acid catalyst. The trans-fused hydropyranopyran derivatives
160 were prepared in yields up to 83 % and with high enantiomeric excess up to
98 %. In order to prevent the acid-induced cyclization, molecular sieves were used
as a dehydratation agent.
Yadav et al. presented the synthesis of carbohydrate analogues, cis-fused chiral
polyoxygenated (tricyclic, tetracyclic, and pentacyclic) heterocycles by domino
Knoevenagel intramolecular HDA reactions [114]. TheO-prenyl derivative of a sugar
aldehyde 161 derived from D-glucose underwent reactions with 1,3-diones 162, 164,
166 and 168 in presence of sodium acetate in acetic acid at 80 �C (Scheme 30). The
reactions were highly stereoselective affording exclusively cis-fused furopyranopy-
rans 163, 165, 167 and 169 in 70–82 % yields. The authors suggested that the
cycloadditions proceeded in a concerted manner via an endo-E-syn transition state.
2.2.2 Catalytic Intramolecular HDA Reaction of 1-Oxa-1,3-Butadienes and Alkynes
Due to the lower reactivity of alkynes in comparison to the corresponding alkenes,
no HDA reaction of 1-oxa-1,3-butadienes with alkynes has been reported. Recently,
different Lewis acids have provided new opportunities for various catalytic alkyne
reactions. Some of the most frequently used transition metal catalysts are
copper(I) compounds. Khoshkholgh et al. studied the intramolecular HDA reaction
of 1-oxa-1,3-butadiene and an alkyne in the presence of CuI [115]. The Williamson
reaction of propargyl bromide 171 and salicylaldehydes 170 afforded compounds
172 (Scheme 31). The 1-oxa-1,3-butadienes 174 were prepared through Knoeve-
nagel reaction of O-propargylated salicylaldehyde derivatives 172 and barbituric
acids 173 with yields between 75 and 94 %. Intramolecular HDA reactions were
CO2Me
O
MeO OHR1 R1
R2 R2
157 158- MeOH
CuN
O
N
O
RR
2+
2X - R = t-Bu, X = OTfR = t-Bu, X = SbF6R = Ph, X = SbF6
R1 = H, MeR2 = H, Me
Chiral Cat. 10 mol%, rt transetherification
160 yield 75 - 83 % ee 3 -98 %
159
160
O
O
R2
R2
R1R1
CO2Me
Chiral Cat. 10 mol%CH2Cl2, rt, 1 - 96 hMS
O
O
R2
R2
R1R1
CO2MeH
H
Scheme 29 Catalylic enantioselective tandem transetherification-intramolecular HDA reaction ofmethyl (E)-4-methoxy-2-oxo-3-butenoate 157 with d,e-unsaturated alcohols 158
24 Page 26 of 37 Top Curr Chem (Z) (2016) 374:24
123
carried out in the presence of CuI (40 mol%) and water as the solvent and
tetracyclic uracils 175 were prepared in 70–84 % yields. The authors explained that
the initial step of cycloaddition was probably the formation of a p-complex with CuI
since copper(I) salts can act as a p-electrophilic Lewis acid. This complexation of
alkyne increases activity toward an 1-oxa-1,3-butadiene system (Scheme 31).
Yadav et al. developed a novel method for the synthesis of sugar-annulated
tetracyclic- and pentacyclic-heterocycles in a single-step operation [116]. The O-
O
O
O
162
168
169
O
R1
OR2
R1 = R2 = MeR1 = Me, R2 = OMe
O
O
R
R
R = H, Me
164
N
N O
O
O
Me
Me166
O
O
H
O
O
O
161
AcONa 3 equiv., AcOH 80oC, 6.5 h
AcONa 3 equiv., AcOH 80oC, 8.5 h
AcONa 3 equiv., AcOH 80oC, 5 - 6 h
AcONa 3 equiv., AcOH 80oC, 5 - 6 h
O
O O
OO
OOH
H
163
O O
OO
O
H
R1 O
R2
H
O O
OO
OOH
R
R
H
165
N
N
O O
OO
OOH
O
Me
H
Me
167
yield 82 %
yield 80-82 %
yield 72 %
yield 70-79 %
Scheme 30 Domino Knoevenagel HDA reactions of sugar aldehyde 161 with 4-hydroxycoumarin 162,cyclohexa-1,3-dione or dimedone 164, 1,3-dimethylbarbituric acid 166 and 1,3-diones 168
6-28 h,
BrK2CO3
DMF, rt
CHO
OHR1
CHO
OR1
H2Oi or ii
N
N
O
OO
R2
R2
O
R1R1 = 5-Br, 5-NO2, 3-MeO, naphthaldehyde
i: R2 = H, 10% HClii: R2 = Me, 20% (NH4)2HPO4
N
N
O
OO
R2
R2
O
R1
A B
C
D
N
N
O
OO
R2
R2
CHO
OR1
170 171 172
173 174 175172
CuI 40 mol%
H2O, reflux
yield 70-84%
Scheme 31 Synthesis of O-propargylated aldehydes 172 and fused uracils - oxa-helicene derivatives 175by intramolecular HDA reaction
Top Curr Chem (Z) (2016) 374:24 Page 27 of 37 24
123
propargyl derivative of a sugar aldehyde 176 derived from D-glucose undergoes
smooth domino Knoevenagel intramolecular HDA reactions with 1,3-diketones 177,
179, 181 and 1-aryl-pyrazol-5-ones 183 in the presence of CuI/Et3N in refluxing
methanol (Scheme 32).
Furopyranopyrans 178, 180, 182 and 184 were prepared in 75–90 % yields. The
authors assumed that these cycloadditions proceed in a concerted way via an endo-
E-syn transition state [116]. Acyclic 1,3-diketones such as acetyl acetone and ethyl
acetoacetate can’t be used in the reaction.
Another example of catalytic intramolecular HDA reaction of 1-oxa-1,3-
butadienes and an alkyne is domino Knoevenagel intramolecular HDA reaction
of indolin-2-thiones 185 and O-propargylated salicylaldehyde derivatives 186 in the
presence of ZnO (Scheme 33) [117].
The major advantage of this reaction is the fact that pentacyclic indole
derivatives 188 can be isolated by filtration from the reaction mixture. This method
also has advantages such as the use of commercially available, non-toxic and
inexpensive ZnO as catalyst, low loading of catalyst, and high yields of products.
Balalaie et al. described domino Knoevenagel intramolecular HDA reactions of
O-propargylated salicylaldehyde 190 with active methylene compounds 189 in the
presence of ZrO2-nanopowder (NP) as a Lewis acid in ionic liquid and different
organic solvents (Scheme 34) [118]. The reactions were carried out for different
active methylene compounds 189 such as barbituric acid, N,N-dimethyl barbituric
acid, indandione, Meldrum’s acid, and pyrazolone.
The solutions of aldehyde 190 and appropriate 1,3-dicarbonyl compound 189, ZrO2
and base in ionic liquid or organic solvent were stirred for 5–40 min at room temperature
O
OH
O
167 178
O
O
H
O
O
O
176
O
O
R
R
R = H, Me179 180
N
N O
O
O
Me
Me
181 182
NN
OAr
Me
Ar = C6H5, 4-MeC6H4, 4-FC6H4, 3-ClC6H4
183yield 75-80 %
O
O O
OO
OOH
O O
OO
OOH
R
R
N
N
O O
OO
OOH
O
Me
Me
184
yield 75%
yield 84-90 %
yield 85%
O O
OO
O
HN
N
Me
Ar
CuI 30 mol%/Et3N 100 mol%
MeOH, reflux, 4 h
CuI 30 mol%/Et3N 100 mol%
MeOH, reflux, 3.5-4 h
CuI 30 mol%/Et3N 100 mol%
MeOH, reflux, 4.5 h
CuI 30 mol%/Et3N 100 mol%
MeOH, reflux, 4.5-5.5 h
Scheme 32 Domino Knoevenagel HDA reactions of sugar aldehyde 176 with 4-hydroxycoumarin 167,cyclohexa-1,3-dione or dimedone 179, 1,3-dimethylbarbituric acid 181 and 1-aryl-pyrazol-5-ones 183
24 Page 28 of 37 Top Curr Chem (Z) (2016) 374:24
123
and desired products were obtained in 80–95 % yields. The best results were obtained
for 5-nitro-O-propargylated salicylaldehyde and 1-butyl-3-methylimidazolium nitrate
[bmim][NO3] as the reaction medium. Balalaie et al. also used ionic liquid [bmim][NO3]
in the presence of 30 mol% CuI in the domino Knoevenagel HDA reactions of O-
propargylated salicylaldehydes with some active methylene compounds [119].
2.2.3 Two-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1-
Oxa-1,3-Butadienes with Intramolecular Cycloaddition in Water or Solvent-
Free
Water is the solvent of choice for nature to carry out syntheses of complex organic
molecules. Water is a clean, inexpensive, environment friendly reaction medium.
Therefore, the choice of water as the solvent for organic reactions in the laboratory
synthesis is obvious. However, water as a solvent was ruled out from organic
reactions. It has been changed in 1980 by the pioneering work of Breslow and
Rideout, who demonstrated that Diels–Alder reactions of water-soluble reagents
would be greatly accelerated in aqueous solution [120]. In 2005, Sharpless et al.
demonstrated that the Diels–Alder reaction of the water-insoluble reactants showed
substantial rate acceleration in aqueous suspension over homogeneous solution
[121, 122]. Some examples of domino Knoevenagel HDA reactions of 1-oxa-1,3-
butadienes with intramolecular cycloaddition in water as the solvent are described
below. Moghaddam et al. examined domino Knoevenagel HDA of 4-hydroxy-
dithiocoumarin 194 and O-acrylated salicylaldehyde derivatives 193 in water
(Scheme 35) [123]. Pentacyclic heterocycles 196 and 197 were formed by a
catalyst-free method in good yields and with high regio- and stereo-selectivity.
Aldehydes 193 underwent the Knoevenagel condensation with 4-hydroxy-
dithiocoumarin 194 in water at reflux to give the intermediates 195 in which two
different heterodiene fragments were presented. The thiocarbonyl group of the
thioester 195 reacted as heterodiene. The cycloadducts were obtained as a mixture
of cis- and trans-isomers. The authors observed the influence of the substituent R2
on reaction diastereoselectivity. The trans-isomer 196 was the main product for
some reactions whereas for others, the products 197 were formed with the
predominance of the cis-isomers (Scheme 35).
The importance of quinoline and its fused derivatives prompted Baruah and Bhuyan
to study the domino Knoevenagel intramolecular HDA reactions of 3-formyl quinoline
NR1
S
OR2
NS
O
R1
R2
R1 = Me, Et, Ph R2 = H, Br, OMe, NO2 yield 85-95%
185 186 187 188
NR1
S
CHO
O
R2
ZnO 10 mol%, MeCN3h, reflux
Scheme 33 ZnO-catalyzed synthesis of indole-thiopyrano-chromene derivatives 188 via dominoKnoevenagel intramolecular HDA reactions
Top Curr Chem (Z) (2016) 374:24 Page 29 of 37 24
123
containing a dienophile moiety [124]. Appropriate 1-oxa-1,3-butadienes were prepared
from acetanilides 198 by treatment with Vilsmeier reagent (Scheme 36).
To introduce the dienophile in compound 201, the reactions of 2-chloro-3-
formylquinolines 199 with alcohol 200 in presence of aqueous sodium hydroxide
under phase transfer catalytic conditions were used. Domino Knoevenagel HDA
reactions of 201 and active methylene compound 202, 204 and 206 in presence of
piperidine at room temperature in water gave the cis fused penta or hexacyclic
pyrano[2,3-b]quinoline derivative 203, 205 or 207 with high yield (70–80 %) and
diastereoselectivity ([99 %). The products were isolated by filtration in the pure
form from aqueous medium.
Baruah and Bhuyan also studied the HDA reactions for other 1-oxa-1,3-
butadienes (Scheme 37) [124]. These compounds possessing diene and dienophile
moieties were prepared from aldehydes 209 by treatment with N-allyl methyl amine
210 in presence of K2CO3. Obtained products 211 on treatment with 212 or 213 in
presence of piperidine in water at room temperature afforded the cycloadducts 214or 215 in 52–70 % yields.
Parmar et al. used alkenyl- and alkynyl-ether-tethered ketones instead of
aldehydes to extend the substrate scope in domino Knoevenagel intramolecular
CHO
O
X
189 190
NN O
Ar Ar = C6H5, 3-ClC6H4
O
O
solvent = MeCN, H2O, EtOH, MeOH, t = 360 - 2400 min, 192 yield 75-90% solvent = [bmim][NO3], t = 2 - 75 min, 192 yield 81-95 %X = H, 5-Me, 5-NO2, 5-Cl
solvent = MeCN, H2O, EtOH, MeOH, [bmim][NO3]base = DMAP, Et3N
189 = N
N
O
OO
H
H
N
N
O
OO
Me
Me
O
O
O
O
O
O
191 192
X
OO
O
X
O
OOZrO2-NP 20-40 mol%, rtsolventbase
Scheme 34 Domino Knoevenagel- HDA reactions of O-propargylated salicylaldehydes 190 with activemethylene compounds 189 in the presence of ZrO2-nanopowder
H2O, 3h
refluxR1 = H, OMeR2 = H, Br, NO2
R3 = Me, Ph 195O
S
O
O
R2
R1
R3S
CHO
O R3
R2
R1
O
S
OH
S
+
193 194
total yield 60-90% 196/197 4:96 - 97:3
O
S
S
OH
H
R3
H
O
R2
R1
O
S
S
OH
H
HR3
O
R2
R1
+
196 197
Scheme 35 Synthesis thiochromone-annulated thiopyranocoumarins 196 and 197 by dominoKnoevenagel HDA reaction
24 Page 30 of 37 Top Curr Chem (Z) (2016) 374:24
123
HDA reactions of 1-oxa-1,3-butadienes. They synthesized dihydropyran derivatives
219 and 220 as single stereoisomers with a tertiary ring junction carbon by solvent-
free one-pot procedure in the presence of tetrabutylammonium-hydrogensulfate
(Scheme 38) [125].
3 Application of Inverse-Electron-Demand Hetero-Diels–AlderReactions of 1-Oxa-1,3-Butadienes in Bioorthogonal Chemistry
For chemical biologists, discovering new reactions which can expand the toolbox of
bioorthogonal chemistry is a current challenge. Development of new orthogonal
methods for labeling in the biosystems is still continued, although effective
bioorthogonal reactions such as copper-free click chemistry have been developed
[126]. Reactions which can be used in bioorthogonal click chemistry should meet
the requirements: high reactivity and selectivity of reagent functional groups,
chemical stability in aqueous solutions in vivo, biocompatibility and high reaction
N
CHO
O
ROH
TBAB50% NaOHaq
198 199
200
201
N
N
O
OO
Me
Me
N O
R
O
NN
H
H
O
O
Me Me
OO
N O
R
OH
H
O
NN
Me
O Ph
N O
R
OH
H
NN
Me
Ph
202
203 yield 76 - 80%
N
H
H2O, rt, 3h
N
H
H2O, rt, 3h
N
H
H2O, rt, 4h
204
205 yield 70 - 75%
206
207 yield 74 - 80%
N
CHO
O
R
201
R
NHCOCH3
R = H, Me
N
CHO
Cl
RDMF/POCl380oC
R = H, Me
Scheme 36 Synthesis of 3-formyl quinoline 201 containing dienophile moiety. Domino KnoevenagelHDA reactions of 201 and active methylene compounds 202, 204 and 206
Top Curr Chem (Z) (2016) 374:24 Page 31 of 37 24
123
rate under physiological conditions [127–130]. Bioorthogonal ligations have been
widely used in biomedical research since they can selective labels of biomolecules
in living systems. Some of inverse-electron-demand HDA reactions 1-oxa-1,3-
butadienes developed in recent years fulfill the criteria of click chemistry compiled
by Sharpless [131, 132] and, in the future, can be used as bioorthogonal
cycloaddition. There is only one example in the literature of application of
inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes in bioorthogonal
chemistry. Lei et al. described a new bioorthogonal ligation by click HDA
cycloaddition of in situ-generated o-quinolinone quinone methides and vinyl
thioethers [133]. High selectivity and the fact that this cycloaddition can proceed
smoothly under aqueous conditions make it suitable for bioorthogonal chemistry. o-
Quinone methides represent an 1-oxa-1,3-butadiene system which can undergo
quick and selective inverse-electron-demand HDA cycloadditions. It is important
that generation of the o-quinone methides can’t be conducted in harsh reaction
conditions because it could be harmful for the organism cells. HDA cycloadditions
of photochemically generated o-naphthoquinone methides 222 with vinyl ethers or
enamines 223 as dienophiles were described by Arumugam and Popik (Scheme 39)
[134–136]. They used ultraviolet (UV) light to generate 1-oxa-1,3-butadienes 222.
Li et al. optimized both reaction partners to make the reaction suitable for
bioorthogonal ligation [133]. Introduction of more electronegative nitrogen into a
heterodiene system 221 improved its reactivity and hydrophilicity (Scheme 40). As
dienophile was used small and chemically stable in vivo vinyl thioether 227. o-
Quinolinone quinine methide 226 was prepared from 8-(hydroxymehyl)-2-
methylquinolin-7-ol 225 without use of catalyst and UV light. Cycloreactants 226
N
CHO
N
R
Me208 209
210
211
NHMe
K2CO3 DMF
N
H
H2O, rt, 5h
N
H
H2O, rt, 6h
N
N
O
OO
Me
Me
212
N
CHO
N
R
Me211N
N
Me
O Ph
213
N N
R
O
NN
H
H
O
O
Me Me
Me214 yield 65 - 70%
N N
R
OH
H
NN
Me
Ph
Me215 yield 52 - 55%
R
NHCOCH3
R = H, Me
N
CHO
Cl
RDMF/POCl380oC
R = H, Me
Scheme 37 Synthesis of 3-formyl quinoline 211 containing dienophile moiety. Domino KnoevenagelHDA reactions of 211 and active methylene compounds 212 and 213
24 Page 32 of 37 Top Curr Chem (Z) (2016) 374:24
123
and 227 underwent HDA cycloaddition under physiological conditions (37 �C,
H2O). The authors used this bioorthonogal cycloaddition for labeling of proteins and
imaging of taxol derivatives inside live cells.
Li et al. proved that HDA cycloaddition of o-quinolinone quinine methide 226and vinyl thioether 227 can be utilized for labeling of multiple biomolecules in
complex living systems when it is combined with other methods [137]. When
cycloreactants 225 and 227 were combined with 5,6-didehydro-11,12-didehy-
drodibenzo[a,e]cyclooctene 229 and (azidomethyl)benzene 230 in a mixture of
H2O/CH3CN at 37 �C, only products 228 and 231 were obtained, and no cross
reaction products were prepared (Scheme 41). 1,3-Dipolar cycloaddition of azide
230 and alkyne 229 is widely used in bioorthogonal ligation as strain-promoted
azide alkyne cycloaddition (SPAAC). The results indicated that these two ligations
proceeded simultaneously without interfering with each other.
It seems that some of the HDA reactions described in Chapter 2 can be used in
bioorthogonal chemistry in the future because they are selective, non-toxic, and can
function in biological conditions taking into account pH, an aqueous environment,
and temperature.
216
R2
R2O
O
NN
Me
H
R3
R3
R1
Me
R2
R2O
O
NN
Me
R1
MeN
N
Me
O
R1
R2
R2
O
O
R3
R3
R2
R2
O
O
217
218
219
220
R1 = Ph, 3-Cl-C6H4,4-Me-C6H4
R2 = H, NO2 R3 = H, Meyield 71-80%
yield 65-77%
ZnO 25 mol%TBA-HS 25 mol%
neat, 160oC, 2-3.5h
ZnO 25 mol%TBA-HS 25 mol%
neat, 160oC, 4-6h
R2 = H, NO2
Scheme 38 Domino Knoevenagel HDA reaction of 2-(alkenloxy)- and 2-(alkynyloxy)acetophenones217 and 218 with pyrazolones 216. Synthesis of chromeno-fused pyrazoles 219 and 220
224O
R1
R3R2
OH
OH hv
H2OO R2 R3
R1
221 222 223R1, R2 = H, R3 = OCH3
R1, R2 = H, R3 = OCH2OHR1 = H, R2 = CH3; R3 = H
yield 94-100%
R1 = n-BuH, R2 = H; R3 = CH3
R1, R2 = CH3, R3 = morpholine
Scheme 39 HDA cycloadditions of photochemically generated o-naphthoquinone methides 222 withvinyl ethers or enamines 223
Top Curr Chem (Z) (2016) 374:24 Page 33 of 37 24
123
4 Conclusion
This review article is an effort to summarize recent developments in inverse-
electron-demand HDA reactions of 1-oxa-1,3-butadienes. Some of the papers
related to the inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes
found in the literature clearly demonstrate the importance of this transformation
which opened up efficient and creative routes to different natural products
containing six-membered oxygen ring systems. This type of cycloaddition is today
one of the most important methods for the synthesis of dihydropyrans which are the
key building blocks in carbohydrate derivative synthesis. Especially, the domino
Knoevenagel HDA reactions have been frequently applied for the synthesis of
natural products. The main advantage of the inverse-electron-demand HDA reaction
of oxabutadienes is formation of dihydropyran derivatives with up to three
stereogenic centers in one step from simple achiral precursors. This transformation
characterizes the huge diversity, excellent efficiency, high regioselectivity,
diastereoselectivity, and enantioselectivity observed in many cases. In recent years,
the use of chiral Lewis acids, chiral organocatalysts, new heterodienes, or new
dienophiles have given enormous progress. Recently, HDA reactions of 1-oxabu-
tadienes conducted without a solvent or in water were developed and the results
suggested that the presented green methods may displace other methods that use
various organic solvents and that are performed at high temperature. Application of
inverse-electron-demand HDA reactions of 1-oxa-1,3-butadienes in bioorthogonal
chemistry is still challenging because there is only one example of this
bioorthogonal cycloaddition in the literature. The author of this review sincerely
hopes that this article will stimulate future research in bioorthogonal inverse-
N OH
OH
37oC
H2O
N O
SOH
N O
SOH
622522 227 228 yield 92%
Scheme 40 HDA cycloaddition of o-quinolinone quinine methide 226 and vinyl thioether 227 underphysiological conditions
N OH
OH
N O
SOH
225 227 228
SOH
N3
229 230 231
H2O/CH3CN 1:1, 37oC
NN
N
Scheme 41 HDA reaction of 225 with 227 and SPAAC of 229 with 230 proceeded simultaneouslywithout interfering with each other
24 Page 34 of 37 Top Curr Chem (Z) (2016) 374:24
123
electron-demand cycloaddition of 1-oxa-1,3-butadienes and will encourage scien-
tists to design novel bioorthogonal ligations.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, dis-
tribution, and reproduction in any medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were
made.
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