Stereocontrol in the synthesis of acyclic systems: applications to natural product synthesis

8 – Chirality Transfer via Sigmatropic Rearrangements

Treatment of 3-bromo3-methyl-1-butyne (1) or 1-iodo-3-methyl-1,2-butadiene (3) with solutions of sodium azide affords 3-azido-3-methyl-1-butyne (5) which reacts already at room temperature to 1,2,3-triazoles 8–11. Structures of 5 and 8–11 are verified by independent syntheses and spectroscopic data although in part other assignments of structures have been published. The preparation of 1H-1,2,3-triazoles via propargyl azides is carried out in the presence of various nucleophiles and investigated by means of 15N-labelled starting material as well as optically active 3-azido-1-butyne (R-21). The only mechanism compatible with all results includes short-lived allenyl azides and triazafulvenes. Thus, propargyl azide 14 rearranges to allenyl azide 16 leading to triazafulvene 18 by rapid ring closure. Finally, 18 is trapped by nucleophiles to give triazole 17. The conversion of various propargyl compounds into N-unsubstituted 1H-1,2,3-triazoles 23, 41, 44, 46, 50, and 51 is effected by a one-pot procedure without isolation of 14 and turns out to be a convenient method to prepare these heterocycles.



Reaktionen Ungesattigter Azide, 6. – Synthesen von 1, 2, 3-Triazolen aus Proparglaziden durch Umlagerung der Azid-Gruppe. – Hinweise auf kurzlebige Allenylazide and Triazafulvene



In Natriumazid-Losungen setzen sich 3-Brom-3-methyl-1-butin (1) oder 1-Iod-3-methyl-1,2-butadien (3) zu 3-Azido-3-methyl-1-butin (5) um, das schon bei Raumtemperatur zu den 1,2,3-Triazolen 8–11 weiterreagiert. Unabhangige Synthesen und spektroskopische Charakterisierungen belegen die Strukturen von 5 und 8–11, fur die in der Literatur teilweise andere Strukturzuordnungen getroffen worden sind. Die Darstellung von 1H-1,2,3-Triazolen uber Propargylazide wird in Gegenwart verschiedener Nucleophile durchgefuhrt und mit Hilfe 15N-markierter Edukte sowie unter Einbeziehung von optisch aktivem 3-Azido-1-butin (R-21) untersucht. Mit allen Ergebnissen ist nur ein Mechanismus uber kurzlebige Allenylazide und Triazafulvene im Einklang. Demnach lagert sich Propargylazid 14 zu Allenylazid 16 um, das durch raschen Ringschlus zu Triazafulven 18 fuhrt; dieses wird durch Nucleophile zum Triazol 17 abgefangen. Die Reaktion diverser Propargyl-Verbindungen zu den N-unsubstituierten 1H-1,2,3-Triazolen 23, 41, 44, 46, 50 und 51 kann als Eintopf-Verfahren ohne Isolierung von 14 durchgefuhrt werden und erweist sich damit als eine bequeme Synthesemethode fur diese Heterocyclen.

Reactions of Unsaturated Azides, 6. Synthesis of 1,2,3-Triazoles from Propargyl Azides by Rearrangement of the Azido Group. – Indication of Short-Lived Allenyl Azides and Triazafulvenes

The photochemical reactions of different allyl aryl ethers (Scheme 3) were investigated in hydrocarbons (Chap. 3.1) and in alcoholic solvents (Chap. 3.2). The composition of the photoproducts depended very much on the nature of the solvent. Irradiation (3-95 h) of different methyl substituted allyl aryl ethers (1, 3, 5, 7 and 11) with a low pressure mercury lamp (lambda(Emiss.) = 254nm; 6 or 15 Watt) under argon (quartz vessel) resulted in the formation of 2-, 3- and 4-substituted phenols, dienones and products of consecutive reactions (Tables 1-4 and 6). The results suggested that all products were formed by homolytic cleavage of the C-O bond in the singlet state of the ethers to intermediate radical-geminates (Scheme 5) followed by radical recombination of the two fragments. No products were formed by concerted processes (Table 5, Schemes 5 and 6). Upon irradiation of allyl aryl ethers lacking alkyl substituents at position 4 (1 and 5) in protic solvents, mainly 2- and 4-allylated phenols were obtained (Tables 1 and 4); 3-allylated phenols were formed only in small amounts (0.02%). However, in aromatic hydrocarbons or cyclohexane 3-allylated phenols were obtained from 1, 5 and 11 in significant amounts (3-11%; Tables 1, 4 and 6). E.g., upon irradiation of allyl-2,6-dimethylphenyl ether (5) in toluene, the main photoproduct was 6-allyl-2,6-dimethy1-2,4-cyclohexadien-1-one (6) besides 3- and 4-ally1-2,6-dimethylphenol (23 and 24). Irradiation of 5 in methanol afforded 23 and 6 only in traces, whereas 24 was the main product. Ethers alkylated at position 4 (3 and 7) yielded 3-allylated phenols after irradiation in hydrocarbons and in methanol (Tables 2 and 3). The time independent equilibration of deuterium labelling in the allyl chain of dienone d3-6 obtained upon irradiation of 2,6-dimethylphenyl-2’, 3’, 3’-trideuterioallyl ether (2’,3’, 3’-d3-5) (cf. Table 5) demonstrated that the photolysis of aromatic allyl ethers did not occur by a [1s,3s]-sigmatropic process (cf. Chap. 3.1.4.2). For the photochemical formation of 3-allylated phenols, the following two mechanisms may be envisaged: 1. According to CIDNP measurements [12] at least one portion of the 3-allylated phenols 14, 20 and 23 is produced via a direct recombination of the triplet-geminate, which is formed from the singlet-radical-geminate via intersystem crossing (Scheme 5, pathway d). 2. Formation of 4-allyl-2,5-cyclohexadien-1-ones (III, IV and 12) could occur via a singlet-geminate (Scheme 5, pathway c). These dienones undergo photochemical excitation and give bicyclic intermediates, which after further photoexcitation are finally transformed into the 3- allylated phenols 14, 20 and 23 (cf. Scheme 6, pathway g, h and i). This path allows the formation of significant amounts of 3-allylated phenols (3- 11%) during photo-Claisen-rearrangement of allyl phenyl ethers lacking a substituent at position 4. The lifetimes of the initially formed 4-monosubstituted dienones III and IV in hydrocarbons were long enough to permit photochemical isomerization to 3- allylated phenols. In protic solvents however, a fast enolization of 3 and IV to 4-allylated phenols is expected, so that the photochemical isomerization is interrupted. The presence of bases which catalyse this heterolytic enolization further suppress the photochemical isomerization (Table 1). The very small amount (0,01- 0,1%) of 3-allylphenols, which were still formed after the irradiation of allyl aryl ethers lacking a substituent at position 4 in protic solvents or under basic conditions, must be produced by direct radical recombination within the triplet-geminate (cf. Scheme 5, pathway m and n). Free phenoxy and allyl radicals were also formed from the triplet-geminate (cf. ESR. experiments, Chap. 5). The former yielded the observed phenols after hydrogen abstraction from the solvent. A crossover experiment with tritiated ether 3’-t-3 and ether 1 suggested that recombination of free phenoxy and allyl radicals during photolysis did occur only to a very small extent (2 - 0,1%; cf. Chap. 4). The photochemical transformation of ((E)- or (Z)-2’-buteny1-2,6-dimethylphenylether ((E)- and (Z)-11, respectively) to (E)- or (Z)-6-(2’-butenyl)-2,6-dimethyl-2,4-cyclohexadien-1-one ((E)- and (Z)-26, respectively) at 7° showed, that the configurational integrity of the allyl radical was maintained (90-95%) until the recombination had occurred (Table 6).

Zur Photochemie von Allylaryläthern. 55. Mitteilung über Photoreaktionen

Rearrangements of (2′-Propinyl)cyclohexadienols and -semibenzenes



The acid-catalyzed dienol-benzene rearrangement of 3- and 5-methyl-substituted (2′-propinyl)cyclohexadienols has been investigated. Treatment of the dienols with CF3COOH in CCl4 yields allenyl- and (2′-propinyl)benzenes via [3,4]- and [1,2]-sigmatropic rearrangements, respectively. The reaction with H2SO4 in Et2O leeds to a mixture of allenyl-, 2′-propinyl-, 3′-butinyl- and (2′,3′-butadienyl)benzenes (Scheme 3). The latter are products of a thermal semibenzene-benzene rearrangement (cf. Scheme 9). The corresponding semibenzenes have been prepared by dehydration of the cyclohexadienols with H2SO4 or POCl3 (Schemes 6 and 7). Under acidic conditions, the p-(2′-propinyl)semibenzenes 33–35(Scheme 8) undergo [3,4]- and [1,2]-sigmatropic rearrangements to give again allenyl- and (2′-propinyl)benzenes, whereas the thermal rearrangements to the 3′-butinyl- and (2′,3′-butadienyl)benzenes (Scheme 9) involves a radical mechanism. In contrast, the o-(2′-propinyl)semibenzene b(Scheme 7) leads to (2′,3′-butadienyl)benzene 32via a thermal [3,3]-sigmatropic rearrangement.

Umlagerungsreaktionen von (2'-Propinyl)cyclohexadienolen und -semibenzolen

On the Stereochemistry of the Aromatic Claisen Rearrangement. Thermal Rearrangement of erythroid and threoid ortho-Dienones.



Erythro- and threo-1-methyl-1-(1′-methyl-2′-propynyl)-2-oxo-1,2-dihydronaph-thalene (erythro- and threo-6) as well as erythro- and threo-2,6-dimethyl-6-(1′-methyl-2′-propynyl)-cyclohexa-2,4-dien-1-one (erythro- and threo-8) were obtained together with the corresponding aromatic ethers 5 and 7 by alkylation of 1-methyl-2-naphthol and 2,6-dimethyl-phenol, respectively in alcoholic potassium hydroxide solution with 1-methyl-2-propynyl p-toluenesulfonate (Scheme 2). The diastereoisomeric dienones 6 and 8 were easily separated by column chromatography on silica gel and its relative configuration at C(1) or C(6) and C(1′) deduced from the chemical shifts in their 1H-NMR.-spectra (Table 1). Hydrogenation of 6 and 8 using Lindlar catalyst yielded the corresponding erythro- and threo-configurated (1′-methyl-2′-propenyl)-dienones 10 and 13, respectively (Scheme 3) the thermal rearrangement of which were studied. The following results were obtained: threo-10 rearranged in benzene at 85–105° preferentially via a chair-like (C) transition state to yield 99,5% (E)- and 0,5% (Z)-(2′-butenyl) 1-methyl-2-naphthyl ether ((E)- and (Z)-14; ΔΔG(C/B) = −4,0 kcal/mol). On the other hand, erythro-10 when heated at 105-125° in benzene gave 84,7% (E)- and 15,3% (Z)-14, i.e. in this case a boat-like (B) transition state is favoured (G(C/B) = + 1,3 kcal/mol) (Scheme 5 and Table 2). The thermal rearrangement of dienones 13 led to the corresponding ethers 12 as well as p-allyl-phenols 11. Thus, heating of threo-13 at 20–42° in cyclohexane resulted in the formation of 2,5% of ether 12, consisting of 98% of the (E)- and 2% of the (Z)-isomer, and 97,5% of (E)-11 which contained, at a maximum, 0,5% of the (Z)-isomer, (Scheme 6 and Table 3). This means that both rearrangements occurred with a strong preference of the C transition state (G (C/B, phenol) = −3,3 kcal/mol). On the contrary, erythro-13 when heated at 42–68° in cyclohexane yielded a 3:2 mixture of ether 12 and phenol 11(Scheme 6). The ethereal part consisted of 88,0% of the (E)- and 12,0% of the (Z)-isomer which again shows that the B geometry predominated in the erythro transition state leading to the ether (G (C/B)= + 1,3 kcal/mol). In the phenolic part 36–40% of the (E)-isomer and 64–60% of (Z)-isomer were found which means that in the para-Claisen rearrangement of erythro-13 the C arrangement is only slightly favoured (ΔΔG (C/B)= −0,36 kcal/mol).

Tammo Winkler

Papers

Zur Stereochemie der aromatischen Claisen‐Umlagerung. Thermische Umlagerung von erythroiden und threoiden ortho‐Dienonen