1-Methoxy-3-trimethylsilyloxy-1,3-butadiene1

[59414-23-2]  · C8H16O2Si  · 1-Methoxy-3-trimethylsilyloxy-1,3-butadiene  · (MW 172.33) (E)

[54125-02-9]

(highly reactive diene for Diels-Alder reactions1a,b and hetero-Diels-Alder reactions1c)

Alternate Name: Danishefsky's diene.

Physical Data: bp 68-69 °C/14 mmHg; n20D 1.4540; d 0.885 g cm-3.

Solubility: insol H2O; sol most organic solvents.

Form Supplied in: colorless neat liquid; may contain 3-5% of 4-methoxy-3-buten-2-one. This level of purity is sufficient for most preparative purposes.

Analysis of Reagent Purity: checked easily by its 1H NMR spectrum.2,4

Preparative Methods: the diene was originally prepared from 4-Methoxy-3-buten-2-one with Chlorotrimethylsilane-Triethylamine-Zinc Chloride in benzene as shown below (68% yield, eq 1).2a A detailed experimental procedure for preparative scale work is described by Danishevsky et al. (45-50%).3 TMSCl-Sodium Iodide in acetonitrile is also a mild procedure for the preparation of this reagent (60%).4 At the present time, the most efficient method is to use TMSCl-Lithium Bromide-Et3N in THF (91%).5

Handling, Storage, and Precautions: this diene can be kept in a stoppered container without appreciable decomposition, but it is extremely moisture sensitive.

Diels-Alder Reactions.

General Aspects.

1-Methoxy-3-trimethylsilyloxy-1,3-butadiene (1) is one of the most reactive species for use in the Diels-Alder reaction and was the first example of a multioxygenated polar 1,3-diene for preparative use. More recently, analogous siloxy dienes with two or more oxygen functions have been prepared and their reactivities have been studied widely.1a,b The extremely high reactivity of this diene is illustrated by its reaction with Maleic Anhydride, in which instantaneous exothermic reaction leads to the formation of the adduct via cis-endo addition. The stereochemical course of the reaction is unambiguously determined by the isolation of the initial adduct before acidic workup (eq 2).2,3

The utility of this diene for the preparation of functionalized aromatic systems is demonstrated by the facile conversion of Dimethyl Acetylenedicarboxylate to a hydroxyphthalate (eq 3) and 1,4-Benzoquinone to an oxygenated naphthalene (eq 4).2

The second pathway leads to alicyclic compounds. In most cases, a,b-unsaturated cyclohexenones are produced. For example, treatment with a reactive dienophile such as Methacrolein or Methyl Acrylate gives the desired system (eqs 5 and 6).2,6 The important feature is that only one regioisomer is obtained by high orientational specificity of electron-donating substituents at the 1,3-positions of the diene.

The remarkable reactivity of this siloxy diene is exemplified by successful reaction with poor dienophiles such as methyl 1-cyclohexenecarboxylate, which does not give Diels-Alder adducts with ordinary dienes like butadiene. It requires more severe conditions, but the reaction gives a D1-cis-3-octalone system in good yield (eq 7); this is not very easy to access via other methods. Several other examples show the generality of this process.6

The excellent reactivity and regio- and stereoselectivity of this diene have been demonstrated, and there have been enormous numbers of publications on applications to the synthesis of various types of carbocyclic systems.

Condensed Aromatic Compounds.

Completely opposite regioselectivity is seen when juglone (eq 8) and its methyl ether (eq 9) are reacted with this diene. Directing effects, with or without chelation by the hydroxy or methoxy group, clearly explain the selectivity.7 The more polar carbonyl group, marked with an asterisk, controls the regiochemistry.

Similar regioselectivity is observed with 2,3-dichloro-5-hydroxy-1,4-naphthoquinone (eq 10),8 6,8-dimethoxy-1,4-naphthoquinone,9 and anthraquinone derivatives.10,11 These methodologies have been widely applied to the synthesis of alizarin analogs,8 daumnomycinone,12 and related anthracyclinones and their derivatives.10,11,13

Alkyl or alkoxy quinones14 also give single isomers regioselectively (eq 11), while a chloroquinone15 gives the opposite type of adduct as the sole product (eq 12).

Stereospecific cycloaddition from the less hindered side of an epoxyanthraquinone derivative gives a single adduct, which has been converted to a daunomycinone analog (eq 13).16

Reaction with an unsymmetrically substituted spiro-ene-dione dienophile also gives primarily the adduct from attack at the less hindered face (eq 14); the product is convertible to the fredericamycin A skeleton.17

Cyclohexenones and Analogs.

As described earlier, a,b-unsaturated aldehydes and ketones are good dienophiles and the resulting polyfunctional cyclohexenones have been used for the synthesis of ajugarin I (eq 15)18 and damscones.19 The diene can even react with (trifluoromethyl)ethylenes to give the adducts regioselectively.20

Doubly activated dienophiles such as methylenemalonates,21 alkylidenemalononitriles22 and 2-trifluoromethylacrylates23 easily react with the diene to give enones and dienones (eq 16), from which the cannabinoid skeleton22 and trifluororetinal have been synthesized.23

Dienones are directly obtained using dienophiles with additional functionality such as sulfoxide (eq 17)24-26 or acetate.27 The process has been applied to the synthesis of prephenate,24,27 pretyrosines,25 and tazettine.26

Vinyl sulfones are useful dienophiles for the preparation of monocyclic cyclohexenones28,29 or phenols.30 Reactions with nitro alkenes give precursors for cyclic nitro alkenes31 and amino alcohols.32

Fused Alicyclic Ring Systems.

As discussed earlier, even cyclohexenones or cyclohexene esters are useful dienophiles and various types of adducts with fused ring systems have been synthesized from these reaction partners. For example, methyl 1,4-cyclohexadienecarboxylate gives the cis-hexalin system, which is employed for the synthesis of vernolepin (eq 18).33

This general procedure for the construction of cis-fused decalin or extended systems has been applied to the synthesis of pentalenolactone,34 both racemic and natural quassinoids, picrasin B, quassin (eq 19),35 the compactin skeleton,36 and (±)-halipanicine.37

Reactions with cyclopentene dienophiles give cis-fused hydrindenones.38,39 In the case of 3-alkoxycarbonylcyclopentadienone, the alkoxycarbonyl group is the principal substituent for controlling the orientation of the cycloaddition (eq 20).40 With the ene-dione of fused cyclopentanes, single regioisomers are produced because the carbonyl group (asterisk) is oriented out of the plane of the other conjugated enone (eq 21).41 Using an activated dioxopyrroline as the dienophile, the spirocyclic system of the Erythrina alkaloid skeleton is constructed and the synthesis of Erythrina alkaloids has been achieved (eq 22).42

Cycloaddition with 1-acetylcyclobutene gives a bicyclic adduct, which is transformed to a cyclooctadienone (eq 23).43 Exceptional stereoselectivity is also observed with bridged enones and a strained enone is a very reactive dienophile, giving the exo adduct exclusively in excellent yield (eq 24).44

Lactones are poor dienophiles under normal conditions, but, using high pressure, they smoothly afford the corresponding endo adducts (eq 25).45

On the other hand, g-lactams (eq 26) and d-lactams (eq 27) are much better dienophiles and give hydroisoindolines46 and hydroisoquinoline-type manzamine skeletons.47 Even 2,4-bis(methoxycarbonyl)furan reacts with this diene to give fused heterocycles (eq 28).48

Miscellaneous.

Danishefsky's diene reacts with strong electrophiles such as 2-methylene-1,3-cyclopentanedione to give Michael-type adducts at low temperature, but, on heating, it gives the usual cycloadduct (eq 29).49

The electron-rich enol ether moiety of the diene reacts with carbenes preferentially to give cyclopropane analogs, which afford hydroguaiazulene derivatives via Cope rearrangement (eq 30).50

Strained alkenes are useful dienophiles and tetrachlorocyclopropene reacts with the diene at ambient temperature to give substituted tropones and tropolones via bicycloheptenes (eq 31).51 Polyhalocyclobutenes give benzocyclobutenones in good yield on a preparative scale (eq 32).52

Hetero-Diels-Alder Reactions.

General Aspects.

Activated hetero-alkenes such as carbonyls and imines with electron-withdrawing substituents react with the diene under pyrolytic conditions to give dihydropyrones (eq 33)53-55 and dihydropyridones, respectively (eq 34).54,56,57 In these cases, however, reactions are limited only to special hetero-alkenes.

A major generalization of this heterocycle synthesis has been achieved by the reaction of hetero-alkenes with the diene in the presence of Lewis acid catalysts. In these cases, even hetero-alkenes without activating groups can react under mild conditions to give the corresponding heterocycles (eqs 35 and 36).58,59

The most common catalyst is Zinc Chloride, but ZnBr2, MgCl2, MgBr2, BF3 etherate, TiCl4, and alkylaluminum chlorides are also useful. In some cases, even the lanthanide reagent Eu(fod)3 can catalyze the cycloaddition to give cyclic acetals,60 and partial asymmetric induction is observed using Eu(hfc)3 as a catalyst (eq 37).61

A mechanistic survey has revealed that this hetero-Diels-Alder reaction proceeds mainly via a pericyclic pathway with endo addition, but an aldol-type stepwise process is also followed and the ratio varies with the Lewis acid used.62

Oxygen Heterocycles.

Hetero-Diels-Alder reactions of chiral aldehydes give substituted dihydropyrones with high diastereoselectivity and Cram products are formed exclusively or predominantly. In the case of a-alkoxy or a-amino aldehydes, excellent selectivities are achieved (eqs 38-40).63,64 The diastereoselectivity of the reaction with a protected serine-aldehyde is influenced by the amount of Lewis acid employed (eq 41).65 Because of this high stereoselectivity and since the resulting multifunctionalized pyrone derivatives can be converted to various oxygen heterocycles, a number of natural products, especially carbohydrates and analogs, have been synthesized by this method. The following are representative examples: spiroacetals (Mus musculus pheromone64a and avermectins66); hexoses (fucose and daunosamine67); unusual sugars (tunicaminyluracil,68 octosyl acid A,69 and galantinic acid70); C-glycosides (papulacandins71).

Even remote chiral centers afford rather high diastereoselectivity, giving the desired isomers as major products; these are convertible to mevinolin and pravastatin (eq 42).72

Nitrogen and Sulfur Heterocycles.

As mentioned earlier, dihydropyridones and arylquinolizinones are readily prepared (eq 43).73 Reaction with triazolediones without a catalyst gives pyridazine derivatives.74 The diene reacts with in situ formed thioaldehydes without a catalyst to give thiopyranones (eq 44).75

Miscellaneous.

Extremely polar hetero-alkenes react smoothly with the diene to give heterocycles. For example, reaction with nitrosobenzene at 0 °C gives substituted oxazinones (eq 45).76 Phosphabenzenes are prepared by the reaction with chlorophosphorus ylides formed in situ (eq 46).77 Arsabenzene is formed using the arsine ylide.78 Reaction with singlet oxygen yields cyclic peroxides.79

Asymmetric Synthesis.

Asymmetric Diels-Alder reactions with dienophiles containing a chiral auxiliary usually give adducts with high diastereoselectivity. For example, reaction with a nitro alkene having a chiral sulfoxide gives the hydrindenone with 95% ee after elimination of the sulfoxide.80 In the case of 5-(-)-menthyloxy-5H-furanone, the reaction gives two diastereomers via both endo and exo attack, but diastereofacial selectivity is exclusive (eq 47).81 Reaction with O-b-D-glucosyljuglone gives a single adduct (eq 48); this is a versatile precursor for optically active anthracyclinones.82

In the hetero-Diels-Alder reaction, the imine derived from D-galactosylamine gives the (S)-adduct preferentially, from which (S)-anabasin is obtained.83 Imines of optically active amino acids give substituted pyridones with high diastereoselectivity (eq 49).84

Catalytic asymmetric hetero-Diels-Alder reactions using chiral acyloxyboranes85 or oxazaborolidines86 give substituted hydropyranones and hydropyridones with ca. 70-95% ee (eqs 50 and 51).

Related Reagents.

1-Acetoxy-1,3-butadiene; 2-Methoxy-1-phenylthio-1,3-butadiene; 1-Trimethylsilyloxy-1,3-butadiene; 2-Trimethylsilyloxy-1,3-butadiene.


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Takeshi Kitahara

The University of Tokyo, Japan



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