Top Curr Chem (Z) (2016) 374:24 DOI 10.1007/s41061-016-0026-2 REVIEW
Recent Advances in Inverse-Electron-Demand Hetero-Diels–Alder Reactions of 1-Oxa-1,3-Butadienes Aleksandra Pałasz1
Received: 21 December 2015 / Accepted: 11 April 2016 Ó 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 inverseelectron-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, interand 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 organocatalysts, 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-generated 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
[email protected] 1
Department of Organic Chemistry, Jagiellonian University, Ingardena 3 St, 30-060 Krako´w, Poland
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Keywords Hetero-Diels–Alder reactions 1-Oxa-1,3-butadienes Dihydropyrans Domino Knoevenagel hetero-Diels–Alder reactions Bioorthogonal cycloaddition Abbreviations Ac iBu n-Bu t-Bu (S,S)t-Bu-box [bmim][NO3] Bn BPin Bz Cb DEA DIC DMAP DMF DMSO EDDA Eu(fod)3 IBX MDO MS PCC PDC iPr TBAB TBAF TBA-HS TBDMS TBDPS TBS Tf THF
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Acetyl Isobutyl n-Butyl tert-Butyl (S,S)-tert-Butylbis(oxazoline) 1-Butyl-3-methylimidazolium nitrate Benzyl 3-Boronopinacol Benzoyl Benzyloxycarbonyl Diethylamine N,N0 -Diisopropylcarbodiimide N,N-Ddimethyl-4-aminopyridine Dimethylformamide Dimethyl sulfoxide Ethylene diammonium diacetate 6,6,7,7,8,8,8-Heptafluoro-2,2-dimethyl-3,5-octanedionato europium o-Iodoxybenzoic acid Modularly designed organocatalyst Molecular sieves Pyridinium chlorochromate Pyridinium dichromate Isopropyl tetra-n-Butylammonium bromide Tetrabutylammonium fluoride Tetrabutylammonium hydrogen sulfate tert-Butyldimethylsilyl tert-Butyldiphenylsilyl tert-Butyldimethylsilyl Trifluoromethanesulfonyl Tetrahydrofuran
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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 tetrahydropyran 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 electronrich 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 diastereoselectivity is a characteristic feature of heterocycloaddition of many substituted a,bunsaturated 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-1,3butadienes 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 diastereoselectivity of these reactions is still low. Aza-substituted dienophiles have been used more rarely than their oxygenated counterparts in the HDA reactions of 1-oxa1,3-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 semiempirical 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-1,3butadienes 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
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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 compounds 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 endoor exo-orientation of the dienophile and an (E)- or (Z)-configuration of the 1-oxa1,3-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 exoZ 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 1,3dicarbonyl 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
2
R1
H
O
R
R O
3
OR
O
H
cis - cycloadduct
H
3
OR exo-Z
2
R
2
R
H
R
O
H R1
1
O
1
R
H H R1
H
O
3
OR
3
OR exo-E
R2 H
1
R
H H
3
endo-E
H
2
R
trans - cycloadduct
O
H R2
H H
R3O H endo-Z
Fig. 1 The four different diastereoselective approaches of an alkene such as vinyl ether to 1-oxa-1,3butadiene for intermolecular HDA reaction
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H
H O
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H H
H
O
H
O cis-cycloadduct
endo-E
exo-Z H
O
H H
H
O H
H exo-E
O trans-cycloadduct
endo-Z
Fig. 2 The four different diastereoselective approaches of an alkene to 1-oxa-1,3-butadiene for intramolecular HDA reaction
method has a broad scope since a multitude of different aldehydes and 1,3dicarbonyl compounds can be used. Different examples of inter- and intramolecular HDA reactions of 1-oxa-1,3butadienes 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-Oxa1,3-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-1,3Butadienes The reactivity of heterodienes in inverse-electron-demand HDA reactions can be enhanced by introducing electron-withdrawing substituents into the 1-oxa-1,3butadiene system [34–39, 69–74]. For activation of an oxabutadiene in heterocycloadditions, a cyano group can serve especially well. Such examples are cycloadditions between propenenitriles with a cyano group at C-3 of the heterodiene
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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 4 diastereoisomers of 2-alkoxy-4-amino-3,4-dihydro-2H-pyran-5-carbonitriles in moderate yields (Scheme 1) [71]. The reactions of 2-benzoyl-3-heteroaromaticprop-2-enenitriles 5 with enol ethers 2 afforded diastereoisomeric cis 6 and trans 7 cycloadducts [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 polyfunctionalized 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.
Ac
N
Ac
Ph 3
NC
4
R
pressure flask, toluene
R
o
110 C, 30-96h
H
O
2
OR
O cis-3
2 2 1 R = Me, Et, iBu, n-Bu, R = H, Me R3 = H, R4 = H, Me
5
R2
OR1 2 1
R = Et, iBu Ar = 2-thienyl, 2-furyl, 4-NC-C6H4 R2 = H, Me
Ph
N
4
NC O trans-4
R 3 R 1 OR R2
Ar
Ar CH2Cl2, rt, 1-2 days
O
R 3 R2 R OR1
yield 48-77% 3 and 4 cis 3/trans 4 1.5:1 - 3.2:1
Ar NC Ph
4
NC
1
R
1
Ac
Ph
N
NC
NC 2
Ph
O cis-6
R OR1
Ph
O trans-7
yield 76-88% 6 and 7 cis 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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OR1 R2
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O
O OR3
CN
1
R
R
IBX (1.5 equiv.) DMSO/H2O (4:1), rt
2
R
8
3
CN
1
OR
R2
9
R1
O
H 3 OR
NC 11
10
2
R
1
R = Ph, Ph(CH2)2, 2-furanyl 3 4-Br-C6H4, cyclopropyl, CO2Me R = Et, nPr, nBu
yield 51-88%
2
R = H, Me, Ph, n-heptyl
Scheme 2 One-pot procedure for the conversion of b-oxonitriles 8 into dihydropyrans 11 by dehydrogenation and HDA reaction
o
O 1 R O2S
12 1
R1O2S R2
R = CF3, (CH2)4Cl 2 R = Me, Ph
ArCHO 13
Ar
NH4OAc, MS benzene, rt
R2
O
14 yield 51-94%
Ar = C6H5, 4-MeOC6H4, 4-MeC6H4, 4-BrC6H4, 2-BrC6H4, C6H5CH=CH, 2-furyl
80 C neat 3-5h
3
15
R = Et, iBu 1 R O2S 3 OR R2
Ar
O 16
3
OR
yield 96-99% cis:trans 53:47 - 64:36
Scheme 3 HDA reactions of (E)-a-perfluoroalkanesulfonyl-a,b-unsatutated ketones 14
Another example of HDA reaction of 1-oxa-1,3-butadienes is inverse-electron-demand Diels–Alder cycloaddition of sterically hindered cycloalkylidene derivatives of benzoylacetonitrile 17 and derivatives of N,N-dimethylbarbituric acid 20 with enol ethers 18 and 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-1,3dimethylpyrimidine-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 °C for 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-en2-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-oxazolidinyl)-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
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R1
n n NC
R1
o
toluene,110 C, 24h
+ Ph
NC 3
pressure flask
O
3
2
R
17
19 yield 83-91%
3
1 2 R = H, Me, R = Me, Et, iBu, R = H, Me, n = 0, 1, 2, 3
R1
n
O
n
O o
1
R
N
toluene,110 C, 24h
+ O
O
Ph
OR
18
R 2 OR
N
N
pressure flask
O
OEt
O
N
20
OEt
O 21
18
yield 78-93%
1
R = H, Me
R1 NC
1
R
toluene,110 C, 24h
+ Ph
NC
o
O
O
pressure flask
O 17
Ph
22
O 23
R1 = H, Me
yield 91-93%
O
O 1
N O
+ N
o
R
toluene,110 C, 24h
O
O
20 1
R1
R = H, Me
N O
22
O
pressure flask
N
O 24
yield 87-89%
Scheme 4 HDA reactions of sterically hindered 2-cycloalkylidene-3-oxo-3-phenylpropionitriles 17 or 5-cycloalkylidene-1,3-dimethylpyrimidine-2,4,6-triones 20 with enol ethers 18 and cyclic enol ether 22
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-electrondemand 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.
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1
1
R
R
2
O
R
N
O
1
R
2
toluene reflux 8-32h
+ R3
24
R
2
O
O
R3
O
25
N
O 3
R
O
27
26 R1 = Ph, 4-NO2-C6H4, 4-CH3O-C6H4, CH3CONH
R +
O
N
28
O
cis 27/trans 28 9:1 - (>100:1)
R2 = CN, PhSO2 R3 = Ph, Me O
O
Ar O
N
+
O
N
N
toluene reflux 8-32h
O
N
O
O
O 29
Ar O
N
O
N
30
26
N
+ O
O
Ar
N
O 31
30/31 1:0.14 - 1:1.5
Ar = Ph, 4-NO2-C6H4, 4-CH3O-C6H4
Scheme 5 Inverse-electron-demand HDA reactions of different 1-oxa-1,3-butadienes 25 and 29 with Nvinyl-2-oxazolidinone 26
2.1.2 Three-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1Oxa-1,3-Butadienes Domino Knoevenagel hetero-Diels–Alder reactions with an intermolecular cycloaddition can be performed as a three-component reaction using a mixture of a 1,3dicarbonyl compound, an aldehyde, and a vinyl ether or an enamine. Any cyclic 1,3dicarbonyl compounds such as 1,3-cyclohexanediones, Meldrum’s acid or N,NY
X 1
R 2
CbR N
O
O
Z O
34
Z
O
EDDA, toluene
O
o
ultrasound, 50 C, 15h
H
n 32
Y
X
CbR N
35
X
O
3
R
1
2
R 33 R1 = H, Me, iPr, iBu, Bn 2 3 R = H, Me R = H, Me, Et, iPr n = 0, 1, 2 Cb = benzyloxycarbonyl Y X Z O
OBn
n
OBn 3
R
Y
Z
3
R
rt, 24h
R1
N
O
Pd/C, H2, 1bar
n
H R
X O
Y
Z
N
= O
O
OBn
n
2
2
CbR N
37
O
O
3
1
R
R
36 O
N O
O
O
O
O
O
OH
Scheme 6 Domino sequence comprising Knoevenagel, inverse-electron-demand HDA reaction and hydrogenation starting from amino aldehydes 32, 1,3-dicarbonyl compounds 34, and enol ethers 33
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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 37 which 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 substituted 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 39 was 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,Ndimethylbarbituric acids 43 undergo smooth HDA reactions with enol ethers 44 to afford cis-47 and trans-48 diastereoisomers of 7-alkoxy-5-aryl-2H-pyrano[2,3d]pyrimidine-2,4-diones in excellent yields (84–95 %; Scheme 8). Cycloadducts 47 with cis-configurations were the major products. Next, three-component one-pot
Cl
Cl o
N N
O
MW, 110 C 30 min, organocatalyst A-F 20 mol%
OEt 39 Cl
N
N
N
N
N
H A
H HO B
H HO C
N
O
OEt
N
MeO
Cl 38
CHO 40
E N H D
COOH
N H
N OTMS
Cl
H HO F
41
Cl 42
OMe
Scheme 7 Microwave-assisted organocatalytic mulicomponent Knoevenagel HDA reaction
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O
OEt
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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-48 also in very good yields (87–95 %; Scheme 8). Trace amounts of compounds 49 created 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[2,3d]pyrimidines 52 and 53 were obtained in excellent yields (Scheme 9) [84]. Threecomponent 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-2oxazolidinone 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 diastereoselectivity 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. O
Ar CH2Cl2 rt, 1-5h
N O
O N
O
R2
OR1 O
N
O cis-47
R2 OR1
Ar 46 O
CH2Cl2 rt, 2-7h
CHO
N O
N
N
O
1
R
45 Ar = Ph, 4-CH3O-C6H4 4-NO2-C6H4, 2-thienyl, 2-furyl, 4-pyridinyl
OR 44
1
O
O
Ar
N
O 49
N
OR R2 O trans-48
N
H
O 2
Ar
N
N
44
43
O
Ar
R2
cis-47/trans-48 1.1:1 - 3.6:1
1
R = Me, Et, iBu 2 R = H, Me
Scheme 8 Inverse-electron-demand HDA reactions of 5-arylidene-N,N-dimethylbarbituric acids 43 with enol ethers 44. Three-component one-pot synthesis of fused uracils – pyrano[2,3-d]-pyrimidine-2,4diones cis-47 and trans-48
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Top Curr Chem (Z) (2016) 374:24
1
R
1
R
N N
X
OEt
O
R N
O
OEt
R3
N
O
N
X
2
(10 equiv.)
R2 50
O 1
N
neat, rt, 1-5h
X
3
R
O
R3
O
OEt
R
R2 cis-52 trans-53 yield 52 and 53 88-96% cis-52/ trans-53 1:1 - 3.4:1
51
R1 = R2 = H, Me X = O,S R3 = Ph, 4-MeOC6H4, 4-NO2C6H4, 4-NCC6H4, 4-ClC6H4, 4-BrC6H4, 2-thienyl, 2-furyl, 4-pyridyl O
O R1
R3CHO 54
N
X
N
trans-53
O
2
R 50 1
H2O, rt, 1-3h
51
Me
1
R
cis-52
N
X
OEt yield 52 and 53 88-96%
N
O
R2
55
OEt
cis-52/ trans-53 4.1:1 - 8.5:1
2
R = R = H, Me X = O,S R3 = Ph, 4-MeOC6H4, 4-NO2C6H4, 4-NCC6H4, 4-ClC6H4, 4-BrC6H4, 2-thienyl O R1
R3CHO
X
N
O
R2
H2O, 60oC, 1-3h 4
OR 56
50 1
R
54
N
2
O
R3
N
O
1
R = R = H, Me X = O,S R3 = Ph, 4-NO2C6H4 R4 = 4-MeO, 2-oxo-oxazolidin-3-yl
X
N R4
2
R
cis-57 yield cis-57 89-95%
Scheme 9 Solvent free HDA reactions of 5-arylidene-N,N-dimethylbarbituric acids 50 with ethyl vinyl ether 51. Three-component 50, 54 and 51 or 56 one-pot synthesis of fused uracils in water
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 cycloalkenes: 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-
123
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Page 13 of 37
24
O
4
R
O
1
P(OR )2 2
R
o
CH2Cl2, -78 C
2
O 58
1
R
59
1
R = Me, Ph R2 = H, Me 3 R = Me, Et, iPr R4 = H, Me
R 4 R 60
P(OR )2
61
O
R1 2
R
CH2Cl2, -78 C
R
2
R
62 58 1 2 R = Me, Ph R = H, Me R3 = Me, Et
3
1
R 63 O yield 43-71% endo/exo 17:1 - (>50:1) 63/64 1:1 - 14:1
P(OR )2 64
O
O
1
R1 2
o
O
O n
2
R
P(OR3)2
O
1 equiv SnCl4
3
P(OR )2
3
3
O
yield 52-77% endo/exo 2.4:1 - 47:1 60/61 2.4:1 - (>30:1)
O
R
R 4 R 2 R
0.6 equiv SnCl4
3
R
1
P(OR3)2
O
P(OR )2
P(OR3)2
O
1 equiv SnCl4 o
CH2Cl2, -78 C
R2 O 66 65 1 2 R = Me, Ph R = Me, Et R3 = H, Me n = 0, 1
2
R 1
R
yield 68-78% endo/exo 25:1 - 36:1
67
Scheme 10 Lewis acid SnCl4 promoted HDA reactions of a-ketophosphonoenoates 58 and 65 with dienes 59, 62 and 66
Ph Ph HO OH
69
3 equiv.
O O 1) DIC, DMAP, DMF, 12h, rt
70
O
O
2) filtration
O Ph
68
OMe
O O
Ph O 73
3 equiv.
1) 20 mol% Eu(fod)3, CH2Cl2, 48h, reflux 2) filtration
Ph
OH
71
Ph
1) LiAlH4, THF/Et2O, 12h, rt 2) Na2SO4 aq 3) filtration
O OH
yield 70% cis selectivity >97:3 facial selectivity 93:7
Ph O
O O
72
OMe
O O
Scheme 11 Eu(fod)3-catalyzed solid-phase HDA reaction of benzylidenepyruvate 70 with (S)-(?)-Ovinyl mandelate 71
123
24
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Top Curr Chem (Z) (2016) 374:24
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-1,3oxazolidin-2-ones 78 and unsaturated a-ketoesters 77 (Scheme 13) [88, 89]. Cycloadditions 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-b adducts 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
1
1
OR
OR
R2 2 R
2
R
Ph
5 mol% Eu(fod)3
2
O
O
3
R
O
OMe 74 1
R = Bn, t-Bu
OR O
75 R = H, Me 3 R = Me, t-Bu 2
petroleum ether reflux
O
O OMe 76
Ph OR3
O O
Scheme 12 Eu(fod)3 catalyzed HDA reaction of alkylidenepyruvate 74 with O-isopropenyl mandelic esters 75
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Page 15 of 37
1
1
2
R
R N
endo α
2
O
R o
O O
R
R
1
R
2
MeO2C
24
Eu(fod)3 5 mol%, reflux
N
cyclohexane
MeO2C
O
79 yield 57-77%
O
CH2Cl2
O 77
O
SnCl4 50 mol%, -78 C
MeO2C
O
80 yield 44-83%
MeO
2
R = H, Me, Ph
R = Ph,MeO
N
endo β
78
1
O
selectivity endo/exo for 79 and 80 80:20 - (>98:2)
MeO
Scheme 13 Lewis acid tuned facial stereodivergent HDA reactions of b-substituted N-vinyl-1,3oxazolidin-2-ones 78
b,c-unsaturated a-keto esters and amides 87 with enol ethers and sulfides 82 and 85 as 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 Me
Me
O
Me
O N
Y
R
2X - R = t-Bu, i-Pr, Bn, Ph X = OTf, SbF6
N Cu
2+
Me Y
R
10 mol% o
(MeO)2P
O
CH2Cl2, -78 C
Z 82
O 81
= O
O
OR
SEt
X
O
O
Y
Z
(MeO)2P
83
endo/exo product 1:1 - (>99:1) ee 64 - 95% yield 31-100%
R = Me, t-Bu, TBS 1
R1
R 2
2
R
[Cu((S,S)-t-Bu-box)(H2O)2](OTf)2 5 mol%
R
o
(MeO)2P
O
O 84
THF, 0 C, MS
Z 85
R1 = Me, Ph, i-Pr, OEt 2 R = H, Me
Z = OEt, SEt
(MeO)2P
O
O
86
Z
endo/exo product 16:1 - 44:1 ee 90 - 97% yield 75-98%
R
R [Cu((S,S)-t-Bu-box)(H2O)2](OTf)2 2 mol% o
YOC
Z
O 87
85
R = Me, Et, i-Pr, OMe, OEt, Ph, SBn Y = OEt, N(Me)OMe Z = OEt, SEt
THF, 0 C, MS
YOC
O
Z
88 endo/exo product 10:1 - 64:1 ee 95 - 99% yield 87-99%
Scheme 14 HDA reactions of acyl phosphonates 81, 84 and b,c-unsaturated a-keto esters and amides 87 with enol ethers and sulfides 82 and 85 catalyzed by bis(oxazoline)-Cu(II) complexes
123
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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-unsaturated 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 potential 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 inverseelectron-demand was used in synthesis of the marine neurotoxin-(?)-azaspiracid [92]. Cycloaddition between two components of the HDA reaction 95 and 96 proceeded 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 aldehydes 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
Me
Me
O
Ph
O N
R
MeO O
89
R
0.5-10 mol%
Et2O
OEt
O
Ph
2X - R = t-Bu, Ph X = OTf, SbF6
N Cu
2+
MeO
O O
90
R1 OAc 3
1
R = Ph, OEt, OBn R2 = Me, Et
[Cu(S,S)-t-Bu-box](OTf)2 10-20 mol% Et2O, rt
R
O O 92
91 de 71-99% ee 87-99% yield 93-99%
R1
R2O
OEt
93 3
R = OEt, OBn
OAc R2O
O O
R3
94 de > 99 ee 66-99.5% yield 41-76%
Scheme 15 HDA reactions of c-substituted b,c-unsaturated a-keto esters 89 and 92 with vinyl ether 90 and cis-disubstituted alkenes 93 catalyzed by bis(oxazoline)-Cu(II) complexes
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Page 17 of 37
Me Me O
O
O
EtO
Me3C
OEt
+ Me
Me 95
2+ 2 OTf
N
N
O
24
O
Cu CMe3
H2O
OH2
97
2 mol%
EtO
o
MS, Et2O, -40 C
Me
96
O
OEt
Me 98 97% ee yield 84% dr 94:6
Scheme 16 Enantioselective HDA approach to the synthon of azaspiracid
proceeded in the presence of molecular sieves MS with 5 mol% chiral catalyst 101 at 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 Cr Me
O 2
R
H 1
R N O Cr 101 O Cl 5-10 mol% (1S, 2R)
R2 1
R
+ O 99 1
OEt
R2 1
R
MS, neat, 24-120h
(10 equiv) 100
R = H, Br, Me R2 = Me, Et, i-Pr, n-Pr, n-Bu, Ph, 4-MeO-C6H4, 4-NO2-C6H4 2-NO2-C6H4, CH2OBn, CH2OTBS, CO2Et, OBz
O 102
OEt
de > 95% ee 89-98% yield 70-95%
Scheme 17 HDA reactions catalyzed by (Schiff base)Cr(III) catalyst 101. Model of one-point binding of an a,b-unsaturated aldehydes 99 to a Lewis acid center
123
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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 1Oxa-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 employing 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 inverseelectron-demand HDA reactions [103]. They developed highly enantioselective HDA reactions of electron-deficient enones 111 and aldehydes 112 by using MDO Me
105 N O Cr 1 mol% O Cl (1S, 2R)
BPin
H
O 103
OEt 104
BPin
molecular sieves, rt, 2h
O OEt 106 yield 85%
Scheme 18 Asymmetric inverse-electron-demand HDA reaction of 3-boronoacrolein pinacolate 103 and ethyl vinyl ether 104 as a key step in synthesis of several members of the styryllactone family
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Page 19 of 37
O
N
N
H
H
CF3
Ph
R
N
tBuO2C
O
24
H
R
CF3
109 16 mol%
Ph
DEA, THF, rt, 24-120h
O
tBuO2C
O
107
O
O
110
108 R = Ph, 4-Br-C6H4, 3-Br-C6H4, 2-Br-C6H4 2-F-C6H4, 4-CF3-C6H4, 4-CO2Me-C6H4, 4-NO2-C6H4, 2,6-Cl2-C6H4, 4-CH3-C6H4 3-pyridyl, Me
yield 42-82% dr 3:1 - (>20:1) ee 79-93%
Scheme 19 HDA reactions between b,c-unsaturated a-ketoesters 107 and (E)-4-phenylbut-2-enal 108 in the presence of aminocatalyst
(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 aketophosphonates 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 S Ar
H COOH
R2
N H
3
4
R 1
R
111
O
R
CHO
113
N H
NH
N
H
N
114
R2
OMe
R R4
MDO 5 mol% toluene, rt, 2-48h
112
R2 3
R1
O 115
PCC 67-80%
OH
R3 R4 R1
O 116
O
1
R = CO2Me, CO2Et, CO2iPr, P(O)(OMe)2, P(O)(OEt)2, P(O)(OiPr)2 2
R = Ph, 4-OMeC6H4, 4-MeC6H4, 4CF3C6H4, 4-ClC6H4, 2-ClC6H4, Me R3 = Me, nPr, nC10H21, Bn, iPr, Ph 4
R = H, Me
Scheme 20 MDO catalyzed HDA reactions of electron-deficient enones 111 and aldehydes 112
123
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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-1,3Butadienes with Chiral Auxiliaries Inverse-electron-demand HDA reaction between 1-oxa-1,3-butadienes and electronrich 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 119 gave 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-
O
BzO
O
O
O
PDC, MeCN, Ac2O
OH O O
O
O
O
O
o
80 C, 6h
O
O
O
O
117
O 119
118
yield 81%
NaBH4, EtOH rt, 1h
O
O O
O
O
O
H2/Pd-C, EtOH
O
o
O
40 C, 3h
O
O
O O
O HO 121
O HO 120
Scheme 21 Stereoselective synthesis of higher carbon sugar 121 from protected D-xylose 117 by HDA reaction of the a,b-unsaturated ketone 118
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Page 21 of 37
24
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 129 were 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-5ylidene 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]. Cycloadditions 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 enantiomerically pure stereoisomer was obtained in each studied cycloaddition. Analysis of R7
7
9
R
6
R
5
R
4
R5 7 R R6
1O R
O
N
O
2
R4
R
Na
122
R
R
R1
N
Ac2O, ZnCl2 24h, rt
N
3
R
3
R2 O
O
O
neat, rt 2-5 min
+ N
OR10
O
123
7
R
8
R
R
R9
R8
R9
R
R6
R5
R6
R5
R4
R
R2 O
R H
3
O
N
124 R10 = Et, iBu
R1 H
3
OR
5S
N
+ 10
O
R
2
R O H
7R
4
R
1
5R
N
8
H
7R
O
cis 125 major
N
10
OR
O
trans 126 minor
L-Xylo, L-Arabino, D-Gluco, D-Ribo L-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=H L-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAc D-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAc 1
4
6
8
2
3
5
9
7
R7
R or
7
D-Galacto, R =R =R =R =H, R =R =R =R =OAc, R =CH2OAc D-Ribo, R1=R3=R5=R7=R9=H, R2=R4=R6=R8=OAc
R9
R
R
6
R
R
R
R4
R3
R4
R3
R2 O
R1 H
R2 O
N
8 5
5R 7S
O
N
R9
O
R8
6
H +
trans 127 major
1
R H 5S
N
OR10 O
5
7S
N
O
H 10
OR
cis 128 minor D-Galacto
Scheme 22 Acetylation of C-glycosides 122 and HDA reactions of 5-ylidene derivatives 123 with enol ethers 124. Synthesis of pyrano[2,3-d]pyrimidines 125-128 with a sugar moiety
123
24
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Top Curr Chem (Z) (2016) 374:24
7
R
8
6
R
4
R
R
R
2
R O
R
N
neat, rt, 30 min
N
R6
R5
3
R
R R
1
R O
+
R
5
4
2
5R
5aS
O
O
N
O
129
123
H
R
3
R1 H
N
+
9aR
O
4
2
R O
R H
N
8
R
R
R
1
9
8
6
R
3
R
O
9
5
R
R7
R7
R 9
5S
O
O
cis-cis-(5,5a:5a,9a)-130
5aS
9aR
N
O
O
H
trans-cis-(5,5a:5a,9a)-131
1 4 5 8 2 3 6 7 9 L-Xylo, R =R =R =R =OAc, R =R =R =R =R =H 1 4 6 7 9 2 3 5 8 L-Arabino, R =R =R =R =R =H, R =R =R =R =OAc D-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAC
Scheme 23 HDA reactions of O-acetylated 1,3-dimethyl-2,4,6-trioxo-pyrimidin-5-ylidene alditols 123 with cyclic enol ether 129
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-cyclopent1-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). R 5
R
R
2
R1
X N
CH2Cl2 rt, 3 days
+ N
O
H
X
O
N Y
132
R
R5
R4
R
1
2
X
N N
O
X
H
Y
134 NF
133
1
R O
N
O N
3
R O
R OH
R O
O
8
3
R
2
R
6
5
R
4
R
R O
O
R
3
9
R
R
6
R
4
8
R
R
R6
X
9
8
R
R7
7
7
R 9
134
N
O
X
H
N
H 134 DI
Y
yield 73-87% 1 4 6 7 9 2 3 5 8 L-Arabino, R =R =R =R =R =H, R =R =R =R =OAc, X=Me X = H, Me 1 4 5 8 2 3 6 7 9 L-Xylo, R =R =R =R =OAc, R =R =R =R =R =H, X=Me Y-NH = 4-MeC6H4-NH, 4-MeOC6H4-NH, 4-NO2C6H4-NH 6 9 7 1 4 5 8 2 3 NH NH NH D-Gluco, R =R =R =R =H, R =R =R =R =OAc, R =CH2OAc, X=Me NH 8
2
3
6
9
7
D-Gluco, R1=R4=R5=R =H, R =R =R =R =OAc, R =CH2OAc, X=H 7
Me
1 4 6 8 2 3 5 9 D-Galacto, R =R =R =R =H, R =R =R =R =OAc, R =CH2OAc, X=Me
Me
Me
Me Me
Me
Me
Me Me
Me
OH
O
N
Scheme 24 HDA reactions of alditols 132 with dimedone enamines 133. Synthesis of fused uracils chromeno[2,3-d]pyrimidine-2,4-diones 134
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24
Both reactions 136 with 135 and 137 with 135 provided respectively pyrans 138 and 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 1Oxa-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 1,3dicarbonyl 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 oxabutadienes 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
CH3CN, 85 C, 48h
o
OP
CH3CN, 85 C, 48h
54%
C H
R
N O
58%
O
Ph
N
C
135
S
Ph
H
P = TBDPS
N
O
137 N N O 139
H R Ph
dr > 95:5
R
136 O
O OP
S
N
OP
N
S
N
R
O
H S Ph 138 dr > 95:5 for (+)-zincophorin
Scheme 25 HDA reactions of chiral enone 135 with chiral allenamides 136 and 137. The key step in synthesis of the C1-C9 subunit of (?)-zincophorin
123
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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 141 yielded 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 147 and 148 were prepared with a high degree of chemoselectivity by the application of microwave irradiation. These reactions offers an easy access to pyrano[3,2c]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 macrocycle 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 151 involves the formation of intermediate 155. Dimerization of hydroxyamide 152 by
O
O PhS(O)n 1
R
CHO O
140 n = 0, 1, 2 R1 = Me, Ph
R2
EDDA, MeCN rt 3
R
141 R2 = Me, Ph R3 = Me, H
PhS(O)n
toluene or xylene
PhS(O)n
142
O2 R
R3
O H
reflux, 10-24h
R1
H
R1
3
R O R2 143
cis/trans 2.5:1 - (>100:1)
Scheme 26 Domino Knoevenagel intramolecular HDA reactions of sulfenyl, sulfinyl and sulfonyl activated methylene compounds 140 with 2-alkenyloxy aromatic aldehydes 141. Synthesis of polycyclic 2H-pyran derivatives 143
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24
A
A
O
O
O C
CHO
B
144 OH
O
EtOH, reflux, 4-8h or Microwave Irradiation (MI) 10-150s
C
O
B O
145
O
146 A
O
without MI: yield 40-75% 147/148 55:45 - 80:20
O
A
O
H B
with MI: yield 74-92% 147/148 79:21 - 95:5
H
O H
O
B O
C
148
C
O
O
147
H
Scheme 27 Microwave accelerated domino Knoevenagel intramolecular HDA reactions of 4-hydroxy coumarin and its benzo-analogues 144 with O-prenylated aromatic aldehydes 145
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-1,3butadienes–tandem transetherification-intramolecular HDA reaction. Heterodienes were obtained in situ by a transetherification under thermal conditions from balkoxy-substituted a,b-unsaturated carbonyl compounds bearing an electron-withdrawing substituent and d,e-unsaturated alcohols [112]. This tandem reaction proceeded stereoselectively to afford trans-fused hydropyranopyrans. Next, chiral Grubbs' second gen. cat. (1-5 mol%)
O
O
CH2Cl2
O
O
O
O
O O
o
CH2Cl2, 50 C 6h, 80%
OH
O
152
OH
153
Me O
151 OH
HO
NMe2
NMe2
NMe2 Grubbs' second gen. cat. (5 mol%)
O
O
O
150 OH
NMe2
O
O
O
149 OH
O
Me
O
O
O
TBDMSCl imidazole, DMAP
O
O
CH2Cl2 reflux, 6h, 87%
O
NMe2 O
O O
O RO
OH
154
OR
R = TBDMS 2-Propenyl magnesium bromide o
THF, -15 C, 0.5h, 83%
O
O Me O
O 151
OH
TBAF, THF rt, 12h, 85%
O
O
156
O
O
O
O
OR
O
O Me
Me
O RO
O
O
O O
HO
Me
Me
Me
O RO
155
OR
Scheme 28 Synthesis of macrocycle 151 by sequential cross metathesis and HDA reaction
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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]. The O-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 furopyranopyrans 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 Knoevenagel reaction of O-propargylated salicylaldehyde derivatives 172 and barbituric acids 173 with yields between 75 and 94 %. Intramolecular HDA reactions were O MeO
R2
R2
CO2Me
Chiral Cat. 10 mol%, rt transetherification
OH
157
158 R1
- MeOH
1
R
R2 R2
O
CO2Me
1
R 1 R
O 159
R1 = H, Me R2 = H, Me
O
O N
R
Cu
2+ 2X
N R
Chiral Cat. 10 mol% CH2Cl2, rt, 1 - 96 h MS
-
R = t-Bu, X = OTf R = t-Bu, X = SbF6 R = Ph, X = SbF6
2
R R2
O
H
1
R R1
CO2Me O
160 H
160 yield 75 - 83 % ee 3 -98 %
Scheme 29 Catalylic enantioselective tandem transetherification-intramolecular HDA reaction of methyl (E)-4-methoxy-2-oxo-3-butenoate 157 with d,e-unsaturated alcohols 158
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Page 27 of 37
O
O
O
24
O
AcONa 3 equiv., AcOH
H
80oC, 6.5 h
R
O
R
H O
R
164 O O
O yield 82 %
R AcONa 3 equiv., AcOH 80oC, 5 - 6 h
O
O
163 O
162 O
H
O O
H
O O
165 O
R = H, Me
O O yield 80-82 %
H
O Me
O
Me
O 161
O
N
O AcONa 3 equiv., AcOH 80oC, 8.5 h
N
Me
N
O Me
166 O
O H
N
167
O O
O O yield 72 %
O H
O 1
R
R1 2 168 R
AcONa 3 equiv., AcOH
H
R2
80oC, 5 - 6 h
O
169
R1 = R2 = Me R1 = Me, R2 = OMe
O
O O
O O yield 70-79 %
O H
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
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 OCHO
CHO K2CO3 Br
OH
DMF, rt
O
171
1
R 170
R1 172 R1
R1 = 5-Br, 5-NO2, 3-MeO, naphthaldehyde
R1 D
O R2 O
R2
CHO
N
H 2O N
173 R2
O
O
O
O 1
R
i or ii
O
172 2
i: R = H, 10% HCl 2 ii: R = Me, 20% (NH4)2HPO4
O
C
2
CuI 40 mol%
N N
O
R2 174
R
6-28 h, H2O, reflux
O
N
A
B
N
O
R2
175
O
yield 70-84%
Scheme 31 Synthesis of O-propargylated aldehydes 172 and fused uracils - oxa-helicene derivatives 175 by intramolecular HDA reaction
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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 endoE-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-1,3butadienes 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
O
O
O
CuI 30 mol%/Et3N 100 mol%
H
O O
O
MeOH, reflux, 4 h
167 OH R
O yield 75%
178 O O
R
R CuI 30 mol%/Et3N 100 mol%
H O
O
O O
O
N
Me
Me
N
N
O
O CuI 30 mol%/Et3N 100 mol%
176
MeOH, reflux, 4.5 h
Me
O H
N
O O
Me
Ar
O
Me N
N
O O yield 85%
182 O
181 O
N
O O yield 84-90 %
180 O
Me O
O
H
MeOH, reflux, 3.5-4 h
O 179 R = H, Me
O
O
R
CuI 30 mol%/Et3N 100 mol% MeOH, reflux, 4.5-5.5 h
183 O Ar = C6H5, 4-MeC6H4, 4-FC6H4, 3-ClC6H4
Ar
H
N
184
O
O
O O
yield 75-80 %
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
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24
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 Opropargylated salicylaldehydes with some active methylene compounds [119]. 2.2.3 Two-Component Domino Knoevenagel Hetero-Diels–Alder Reactions of 1Oxa-1,3-Butadienes with Intramolecular Cycloaddition in Water or SolventFree 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-1,3butadienes with intramolecular cycloaddition in water as the solvent are described below. Moghaddam et al. examined domino Knoevenagel HDA of 4-hydroxydithiocoumarin 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-hydroxydithiocoumarin 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 2
2
R
R
O 2
R
CHO ZnO 10 mol%, MeCN
O
3h, reflux
N
S
O
S
185 1
R = Me, Et, Ph
R1
N
1
R
186 R2 = H, Br, OMe, NO2
187
N
1
R
S 188
yield 85-95%
Scheme 33 ZnO-catalyzed synthesis of indole-thiopyrano-chromene derivatives 188 via domino Knoevenagel intramolecular HDA reactions
123
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Top Curr Chem (Z) (2016) 374:24 X
X
X
O
O
ZrO2-NP 20-40 mol%, rt
O O
CHO
189
190
O H
189 =
O
O 191 O
O
O
Me
N
N
O
N
O
O
H
N
O
N O
192
O
N O
O
O
solvent base
O
O
Ar Ar = C6H5, 3-ClC6H4
O Me 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
Scheme 34 Domino Knoevenagel- HDA reactions of O-propargylated salicylaldehydes 190 with active methylene compounds 189 in the presence of ZrO2-nanopowder
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-3formylquinolines 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-1,3butadienes (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 214 or 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
OH R2
CHO O
+
O R3
O R1 193
S
S S
194 1 R = H, OMe R2 = H, Br, NO2 3
R = Me, Ph
S
S H2O, 3h reflux
S R3
O R2
R2
S
H
H O O 1
R
195
O
1
R
196
O
O 2 R3 R H +
S
H
H O R1
H R3
O
197
total yield 60-90% 196/197 4:96 - 97:3
Scheme 35 Synthesis thiochromone-annulated thiopyranocoumarins 196 and 197 by domino Knoevenagel HDA reaction
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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 solventfree one-pot procedure in the presence of tetrabutylammonium-hydrogensulfate (Scheme 38) [125].
3 Application of Inverse-Electron-Demand Hetero-Diels–Alder Reactions 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 200 TBAB R
R DMF/POCl3
50% NaOHaq
CHO
R
OH
80oC NHCOCH3 198 R = H, Me
N 199
CHO
Cl
N 201
O
O Me O
O Me
O
202
N N
H N O 203 yield 76 - 80%
O
Me
H2O, rt, 3h N
O
O
H
O
204
CHO N
Me
N
H
R
O
R
N
O
H
R
H
O
H2O, rt, 3h
201 R = H, Me
N H
Ph
N N N
N H2O, rt, 4h N
O
O
205 yield 70 - 75%
Me
206
N
Ph
Me
O
H
R
H
H N
O
207 yield 74 - 80%
Scheme 36 Synthesis of 3-formyl quinoline 201 containing dienophile moiety. Domino Knoevenagel HDA reactions of 201 and active methylene compounds 202, 204 and 206
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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-1,3butadienes 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. oQuinone 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. oQuinolinone quinine methide 226 was prepared from 8-(hydroxymehyl)-2methylquinolin-7-ol 225 without use of catalyst and UV light. Cycloreactants 226 210 R
R
NH
CHO
DMF/POCl3
K2CO3 DMF
Me
80oC NHCOCH3 208 R = H, Me
N 209
R
CHO
Cl
N 211
O Me
N
N Me
Me
N
O Me O R
CHO
O N
212 N
O
H2O, rt, 5h
O
H
R
N
H
H
N
Me
N
214 yield 65 - 70%
Me
Ph
N N N 211 R = H, Me
N
Me
Me
Me 213
N N
O
H2O, rt, 6h
O
H
R
H
N
Ph
H
N
N Me
215 yield 52 - 55%
Scheme 37 Synthesis of 3-formyl quinoline 211 containing dienophile moiety. Domino Knoevenagel HDA reactions of 211 and active methylene compounds 212 and 213
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24 R1 N N
Me
O 2
R
ZnO 25 mol% TBA-HS 25 mol%
3
R
R2
219 yield 71-80% R1 N N
2 3 R = H, NO2 R = H, Me
O
N R2
R1
ZnO 25 mol% TBA-HS 25 mol%
216
neat, 160oC, 4-6h
R1 = Ph, 3-Cl-C6H4, 4-Me-C6H4
R3 3 R
O
217
R
N O
H
neat, 160oC, 2-3.5h
3
2
R
R
O Me
O
Me
2
Me 2
R
O
Me
O 2
R
218
O
2
R = H, NO2
2
R 220 yield 65-77%
Scheme 38 Domino Knoevenagel HDA reaction of 2-(alkenloxy)- and 2-(alkynyloxy)acetophenones 217 and 218 with pyrazolones 216. Synthesis of chromeno-fused pyrazoles 219 and 220
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 226 and 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-didehydrodibenzo[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. OH OH 221
1
1
R
hv H 2O
R2
O 222
R3 223
R1, R2 = H, R3 = OCH3 R1, R2 = H, R3 = OCH2OH R1 = H, R2 = CH3; R3 = H
R O
R2 R3
224 yield 94-100%
1 2 R = n-BuH, R = H; R3 = CH3 1
2
R , R = CH3, R3 = morpholine
Scheme 39 HDA cycloadditions of photochemically generated o-naphthoquinone methides 222 with vinyl ethers or enamines 223
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OH N
OH
S 37oC
N
O
H 2O
N S
225
226
OH
O
OH
227
228
yield 92%
Scheme 40 HDA cycloaddition of o-quinolinone quinine methide 226 and vinyl thioether 227 under physiological conditions OH N
S
OH
N S
225
OH
O
OH H2O/CH3CN 1:1, 37oC
227
228
N N
N
N3
229
230
231
Scheme 41 HDA reaction of 225 with 227 and SPAAC of 229 with 230 proceeded simultaneously without interfering with each other
4 Conclusion This review article is an effort to summarize recent developments in inverseelectron-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-oxabutadienes 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-
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electron-demand cycloaddition of 1-oxa-1,3-butadienes and will encourage scientists 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, distribution, 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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