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Journal ArticleDOI

Synthesis of (E)- and (Z)-1-thiocyanatobuta-1,3-dienes and their Diels–Alder reaction

01 Jan 1985-Journal of The Chemical Society, Chemical Communications (The Royal Society of Chemistry)-Vol. 9, Iss: 9, pp 533-534

Abstract1-Thiocyanatobuta-1,3-dienes react with strong dienophiles to produce directly the rearranged products of type (6)via a combination of a Diels–Alder reaction with a [3,3] sigmatropic shift.

Topics: Sigmatropic reaction (64%), Diels–Alder reaction (64%), Bicyclic molecule (53%), Imide (50%), Aliphatic compound (50%)

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Published in Journal of the Chemical Society, Chemical Communications 9, 533-534, 1985
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Journal ArticleDOI
Abstract: Buta-1,3-dienyl thiocyanic acid ester reacts with acryloyl chloride in presence of Lewis acid catalysts to produce directly the rearranged product of type 3bvia a combination of a Diels-Alder reaction with a [3,3] sigmatropic shift; the 1,4-substituted cyclohexene is easily transformed into the 2-azabicyclo[2.2.2]oct-5-ene derivative 6b, which has been used as precursor for the synthesis of the Ibogamin skeleton.

17 citations


Journal ArticleDOI
01 Apr 1992-Steroids
TL;DR: Two novel series of 2-substituted estradiol derivatives have been synthesized and evaluated for uterotrophic and antiimplantation activities, finding that nuclear substitution at the C-2 position of the steroid nucleus is markedly inhibitory for estrogenic activity.
Abstract: Two novel series of 2-substituted estradiol derivatives have been synthesized and evaluated for uterotrophic and antiimplantation activities. Among the compounds tested in the rat, 2-acetylestradiol 17β-acetate (1), 2-(3'-dimethylamino-1'-propionyl)estradiol 3,17β-diacetate (7), 2-(3'-diethylamino-1 '-propionyl)estradiol 3,17β-diacetate ( 8 ), 2-(3'-piperidino-1'-propionyl)estradiol 3,17β-diacetate ( 9 ), 1'-(2-estradiol 3,17β-diacetate)-3'-diethylaminopropionyl thiosemicarbazone ( 12 ), and 1'-(2-estradiol 3,17β-diacetate)-3'-morpholinopropionyl thiosemicarbazone (14) displayed estrogenic activity. At dosages of 4 μg/rat/day, none of the tested compounds elicited antiimplantation activity. All compounds shared a similar characteristic: nuclear substitution at the C-2 position of the steroid nucleus, a property previously thought to be markedly inhibitory for estrogenic activity.

16 citations


Journal ArticleDOI
TL;DR: A pericyclic approach for the synthesis of six-membered ring structures that offers novel stereocontrolled access to cyclohexenes that are inaccessible via a direct [4 + 2] cycloaddition route.
Abstract: A pericyclic approach for the synthesis of six-membered ring structures is described. The method employs 1,3-dienes with a 1-sulfur substituent in a tandem sequence of Diels–Alder and retro-ene reactions. In this pairing of [4 + 2] cycloaddition and 1,5-sigmatropic rearrangement, 1-sulfenyl-1,3-dienes engage in Diels–Alder reactions with electron-deficient dienophiles. Subsequently, the sulfenyl group of the cycloadducts is oxidized and unmasked to form allylic sulfinic acids, which undergo sterospecific reductive transposition via sulfur dioxide extrusion. The sequence can also include an inverse electron demand Diels–Alder reaction by using a 1-sulfonyl-1,3-diene. This combination of two pericyclic events offers novel stereocontrolled access to cyclohexenes that are inaccessible via a direct [4 + 2] cycloaddition route.

15 citations


Journal ArticleDOI
Yuhang Zhou1, Lili Lin1, Xiaohua Liu1, Xinyue Hu1, Yan Lu1, Xiying Zhang1, Xiaoming Feng1 
TL;DR: A highly efficient asymmetric Diels-Alder/[3,3] sigmatropic rearrangement reaction of methyleneindolinones with 1-thiocyanatobutadienes has been realized by using a chiral N,N'-dioxide/nickel(II) complex as the catalyst.
Abstract: A highly efficient asymmetric Diels-Alder/[3,3] sigmatropic rearrangement reaction of methyleneindolinones with 1-thiocyanatobutadienes has been realized by using a chiral N,N'-dioxide/nickel(II) complex as the catalyst. A range of cyclohexenyl isothiocyanates were synthesized in high yields with excellent diastereo- and enantioselectivities. Based on mechanistic studies, a catalytic cycle with possible transition-state models were proposed to explain the process.

13 citations


Journal ArticleDOI
TL;DR: The more recent discovery that 1-hydrazinodienes are amenable to chiral catalyst-controlled, enantioface-selective Diels–Alder cycloadditions, as well as the cyclohexene synthesis featuring a post-cycloaddition reductive transposition is described.
Abstract: Dienes that enable structural rearrangements in the wake of a Diels–Alder event can afford structurally unique and complex cyclohexenes that can be inaccessible by the direct cycloaddition route.[1–4] A particular problem in natural product synthesis required a substituted cyclohexene of the type 4, and we were drawn to the idea that an initial pairing of a hypothetical diene of type 1 with an activated dienophile of type 2 might be followed by a suprafacial, reductive transposition of 3 to the desired cyclohexene 4 (Scheme 1). Scheme 1 A cyclohexene synthesis featuring a post-cycloaddition reductive transposition. In principle, the Diels–Alder chemistry of Fleming’s 1-trimethylsilyl-1,3-butadiene in conjunction with a post-cycloaddition protodesilylation step offers an attractive path to a type 4 structure.[2,5] While this strategy is feasible, 1-trimethylsilyl-1,3-butadiene displays low levels of regioselectivity in cycloadditions with unsymmetrical dienophiles, and the subsequent protodesilylation step can afford mixtures of epimers when a new stereocenter is produced. Given these circumstances, we designed a 1-hydrazinodiene that allows a stepwise realization of the concept outlined in Scheme 1.[6] For example, exo cycloadduct 6 is produced by a stereospecific union of 1-hydrazinodiene 5 with diethyl maleate and subsequently converted to the isolable hydrazine derivative 7 by a palladium-catalyzed cleavage of the two allyloxy carbonyl groups in 6 (Scheme 2). By the action of a weak base (e.g., sodium acetate), compound 7 is then transformed to the desired cyclohexene 9 via the putative allylic diazene 8; the spontaneous process that transforms 8 to 9 is formulated as a retroene rearrangement with loss of molecular nitrogen.[7–9] Interestingly, if the base-induced elimination of methanesulfinic acid from 7 is conducted in CD3OD, H–D exchange occurs and the ensuing reductive transposition stereospecifically affords the deuterated cyclohexene 10. Scheme 2 The Diels–Alder and reductive transposition chemistry of a 1-hydrazinodiene. Reaction conditions: a) diethylmaleate, Et2AlCl, 23 °C, 75%; b) Pd2(dba)3, Et2NH, THF, 23 °C; c) NaOAc, MeOH, 49% over two steps; Alloc: allyloxycarbonyl. ... A growing number of examples demonstrate that 1-hydrazinodienes undergo a range of Lewis acid-catalyzed Diels–Alder reactions that are both regio- and diastereoselective as a setup for subsequent, stereospecific reductive transpositions to rearranged cyclohexenes. In this report, we describe our more recent discovery that 1-hydrazinodienes are amenable to chiral catalyst-controlled, enantioface-selective Diels–Alder cycloadditions, as well as the cycloaddition behavior of new 1-hydrazinodienes for use in chemical synthesis.[10] In our effort to merge electron-deficient dienophiles with 1-hydrazinodiene 5 with high margins of stereoselectivity, we discovered that the chiral copper(II) bis(oxazoline) catalysts of Evans and co-workers[11] mediate efficient, regioselective, and highly stereoselective Diels–Alder reactions of N-acryloyl oxazolidinones with diene 5. Unions of 1-hydrazinodiene 5 with N-acryloyl oxazolidinone 11a were best achieved in methylene chloride at room temperature in the presence of 4 A molecular sieves and 10 mol% of the freshly prepared copper(II) bis(oxazoline) catalyst. In all cases, exo cycloadduct 13a was produced as the major diastereo-isomer with varying levels of enantioselectivity. The results summarized in Table 1, reveal the impact of the identity of the group R on the chiral bis(oxazoline) ligand and the counterion on Diels–Alder diastereo- and enantioselectivity. The tert-butyl bis(oxazoline) ligand afforded excellent levels of diastereo- and enantioselectivities. While the chloride salt of the copper(II) bis(oxazoline) catalyst was unreactive, the hexafluoroantimonate and triflate salts displayed excellent reactivities. The good-to-excellent exo diastereoselectivities exhibited in these reactions are consistent with our prior observations on the stereochemical outcomes of 1-hydrazinodiene cycloadditions to Cα-unsubstituted dienophiles.[6,12] Our hypothesis is that dienophiles lacking α-substitution should undergo exo selective Diels–Alder reactions to minimize nonbonded interactions between the Lewis acid-activated carbonyl and the substituents attached to the hydrazine moiety of the diene.[13] Table 1 Chiral copper(II) bis(oxazoline)-catalyzed Diels–Alder cycloadditions of diene 5 with N-acryloyl oxazolidinone 11a.[a] Having identified the (S,S)-(−)-2,2′-isopropylidene-bis(4-tert-butyl-2-oxazoline) chiral ligand and the hexafluoroantimonate counter ion as key components of an effective chiral catalyst, we examined a variety of β-substituted N-acryloyl oxazolidinones in asymmetric Diels–Alder reactions with 1-hydrazinodiene 5 (Table 2). Table 2 Chiral catalyst-controlled, asymmetric Diels–Alder cycloadditions of diene 5 to β-substituted N-acryloyl oxazolidinones 11a–l.[a] Although there was some variation in reaction times, all of the unions leading to exo cycloadducts 13a–l displayed diastereomer ratios of greater than 20:1 and enantiomer ratios ranging from 21–99:1. Evans’s copper(II) catalyst 14 is clearly capable of mediating cycloadditions of diverse, β-substituted N-acryloyl oxazolidinones to diene 5 with high margins of stereoselectivity. To further increase the scope of this chemistry, we leveraged our previously described method[6] to achieve syntheses of an expanded set of hydrazinodienes with diverse substitution patterns. Thus, from simple α,β-unsaturated aldehydes and monoallyloxycarbonyl (Alloc) hydrazine, 1-hydrazinodienes 15–18 (Table 3) were synthesized in three steps[14] and employed in asymmetric Diels–Alder reactions with α,β-unsaturated imides 11a, 11b, 11 f, and 11l. Table 3 Chiral catalyst-controlled, asymmetric Diels–Alder cycloadditions of additional 1-hydrazinodienes.[a] Qualitatively, these new hydrazinodienes were judged to be comparable with respect to reactivity, although dienes 16 and 18 reacted more slowly in relation to the others. All of these chiral catalyst-directed cycloadditions were regioselective and afforded exo cycloadducts 19a–k in good to excellent yields and with diastereomer ratios greater than 20:1. The major, exo diastereomers were also produced with high levels of enantioselectivity. X-ray crystallographic analysis confirmed the relative and absolute stereochemical configurations of cycloadduct 19a; this analysis was fully consistent with the prior observations of Evans and co-workers[11] on how the architecture of the dienophile-copper(II) BOX complex imparts high levels of stereoface selectivity in Diels–Alder reactions.[15] In the wake of the asymmetric Diels–Alder events, it was straightforward to execute the desired reductive transpositions to rearranged cyclohexenes (Table 4). Thus, the Diels–Alder adducts arising from diene 5 and the four dienes shown in Table 3, were smoothly transformed to the isolable hydrazine derivatives 20a–h by mild, palladium(0)-catalyzed cleavages of the Alloc protecting groups. The reductive transpositions to cyclohexenes 21a–h were subsequently achieved by warming solutions of compounds 20a–h in methanol to 50°C. Through a retroene-like rearrangement[7] of a putative allylic diazene intermediate, molecular nitrogen is expelled, the alkene is shifted to a new position within the six-membered ring, and a new stereochemical relationship is established in this pivotal step. Table 4 Deprotections and reductive transpositions of selected Diels–Alder products.[a] In the presence of Lewis acids, 1-hydrazinodienes undergo efficient [4+2] cycloadditions with fumarate and maleate esters, as well as α,β-unsaturated aldehydes, ketones, and imides. To gain some insight into the relative reactivity of 1-hydrazinodienes, the HOMO Eigenvalues for 1-dimethylamino-3-tert-butyldimethylsilyloxy-1,3-butadiene,[16] 1-methoxy-3-trimethylsilyloxy-1,3-butadiene,[17] 1-hydrazinodiene 5,[6] and isoprene were calculated as −0.172, −0.190, −0.207, and −0.226, respectively, by the method of Gaussian 03 B3LYP at the 6-31G(d) level of theory.[18] By this analysis, the HOMO energy of 1-hydrazinodiene 5 was judged to be less than the HOMO energies of the synergistic dienes of Rawal and Kozmin[16] and Danishefsky and Kitahara,[17] but greater than that of isoprene. As a class, the 1-hydrazinodienes have value in synthesis because they are easily constructed, amenable to efficient and highly stereoselective Diels–Alder reactions with a variety of dienophiles, and enable mild, post-cycloaddition rearrangements to new cyclohexenes that would likely by challenging to produce by alternative methods of synthesis. Our efforts to further extend the utility of 1-hydrazinodienes in organic synthesis are continuing.

13 citations