Divinylcyclopropane-cycloheptadiene rearrangement
Encyclopedia
The divinylcyclopropane-cycloheptadiene rearrangement is an organic chemical transformation that involves the isomerization of a 1,2-divinylcyclopropane into a cycloheptadiene or -triene. It is conceptually related to the Cope rearrangement
, but has the advantage of a strong thermodynamic driving force due to the release of ring strain.
of vinylcyclopropane to cyclopentene. By the 1970s, the rearrangement had achieved synthetic utility and to this day it continues to be a useful method for the formation of seven-membered rings. Variations incorporating heteroatoms have been reported (see below).
(1)
Advantages: Being a rearrangement, the process exhibits ideal atom economy. It often proceeds spontaneously without the need for a catalyst. Competitive pathways are minimal for the all-carbon rearrangement.
Disadvantages: The configuration of the starting materials needs be controlled in many cases—trans-divinylcyclopropanes often require heating to facilitate isomerization before rearrangement will occur. Rearrangements involving heteroatoms can exhibit reduced yields due to the formation of side products.
(2)
Transition-metal-catalyzed versions of the rearrangement are known, and mechanisms vary. In one example employing rhodium bis(ethylene) hexafluoroacetylacetonate, coordination and formation of a bis-π-allyl complex precede electrocyclic ring closure and catalyst release.
(3)
(4)
In the example below, cuprate addition-elimination generates the transient enone 1, which rearranges to spirocycle 2.
(5)
Organolithiums can be employed in a similar role, but add in a direct fashion to carbonyls. Products with fused topology result.
(6)
Rearrangement after elimination of ditosylates has been observed; the chlorinated cycloheptadiene thus produced isomerizes to conjugated heptadiene 3 during the reaction.
(7)
Cyclopropanation with conjugated diazo compounds produces divinylcyclopropanes that then undergo rearrangement. When cyclic starting materials are used, bridged products result.
(8)
Substrates containing three-membered heterocyclic rings can also undergo the reaction. cis-Divinylepoxides give oxepines at elevated temperatures (100 °C). trans Isomers undergo an interesting competitive rearrangement to dihydrofurans through the intermediacy of a carbonyl ylide
and the same ylide intermediate has been proposed as the direct precursor to the oxepine product 4. Conjugated dienyl epoxides form similar products, lending support to the existence of an ylide intermediate.
(9)
Divinyl aziridine
s undergo a similar suite of reactions providing azepines or vinyl pyrroline
s depending on the relative configuration of the aziridine starting material. Divinyl thiirane
s can provide thiepines or dihydrothiophenes, although these reactions are slower than those of the corresponding nitrogen- and oxygen-containing compounds.
(10)
In the Eschenmoser synthesis of colchicine
, the rearrangement is used to form the seven-membered ring of the target.
(11)
A racemic synthesis of sirenin employs a Wittig reaction
to form the key divinylcyclopropane. Hydrogenation of the rearrangement product afforded the target.
(12)
To a cold (–78°) stirred solution of lithium diisopropylamide
(1.4–1.5 mmol/mmol of ketone) in dry THF
(4 mL/mmol of base) under an atmosphere of argon was added slowly a solution of n-butyl-trans-2-vinylcyclopropyl ketone (1.19 mmol) in dry THF
(1 mL/mmol of ketone), and the resulting solution was stirred at –78° for 45 minutes. A solution of freshly sublimed tert-butyldimethylsilyl chloride (1.6 mmol/mmol of ketone) in dry THF
(1 mL/mmol of chloride) was added, followed by dry HMPA
(0.5 mL/mmol of ketone). The solution was stirred at –78° for 15 minutes and at room temperature for 2–3 hours, and then it was partitioned between saturated aqueous sodium bicarbonate
and pentane
(10 mL and 20 mL/mmol of ketone, respectively). The aqueous phase was washed twice with pentane. The combined extract was washed four times with saturated aqueous sodium bicarbonate and twice with brine
, and then dried (MgSO4
). Removal of the solvent, followed by bulb-to-bulb distillation of the remaining oil, gave the corresponding silyl enol ether
as a colorless oil that exhibited no IR carbonyl stretching absorption. Thermolysis of the silyl enol ether was accomplished by heating (neat, argon atmosphere) at 230° (air-bath temperature) for 30–60 minutes. Direct distillation (140–150°/12 torr) of the resultant materials provided the cycloheptadiene in 85% yield: IR
(film) 1660, 1260, 840 cm–1; 1H NMR (CDCl3
) δ 0.09 (s, 6H), 0.88 (s, 9H), 0.7–2.75 (m, 14H), 4.8 (t, 1H, J = 5.5 Hz), 5.5–5.9 (m, 2H).
Cope rearrangement
The Cope rearrangement is an extensively studied organic reaction involving the [3,3]-sigmatropic rearrangement of 1,5-dienes. It was developed by Arthur C. Cope...
, but has the advantage of a strong thermodynamic driving force due to the release of ring strain.
Introduction
In 1960, Vogel discovered that 1,2-divinylcyclopropane rearranges to cycloheptan-1,4-diene., After his discovery, a series of intense mechanistic investigations of the reaction followed in the 1960s, as researchers realized it bore resemblance (both structural and mechanistic) to the related rearrangementVinylcyclopropane rearrangement
The vinylcyclopropane rearrangement or vinylcyclopropane-cyclopentene rearrangement is a ring expansion reaction, converting a vinyl-substituted cyclopropane ring into a cyclopentene ring. The general scope is extended by introducing heteroatoms in any of the 5 framework positions or by replacing...
of vinylcyclopropane to cyclopentene. By the 1970s, the rearrangement had achieved synthetic utility and to this day it continues to be a useful method for the formation of seven-membered rings. Variations incorporating heteroatoms have been reported (see below).
(1)
Advantages: Being a rearrangement, the process exhibits ideal atom economy. It often proceeds spontaneously without the need for a catalyst. Competitive pathways are minimal for the all-carbon rearrangement.
Disadvantages: The configuration of the starting materials needs be controlled in many cases—trans-divinylcyclopropanes often require heating to facilitate isomerization before rearrangement will occur. Rearrangements involving heteroatoms can exhibit reduced yields due to the formation of side products.
Prevailing Mechanism
The primary debate concerning the mechanism of the rearrangement centers on whether it is a concerted (sigmatropic) or stepwise (diradical) process. Mechanistic experiments have shown that trans-divinylcyclopropanes epimerize to the corresponding cis isomers and undergo the rearrangement via what is most likely a concerted pathway. A boat-like transition state has been proposed and helps explain the observed stereospecificity of the process. Whether the initial epimerization of trans substrates occurs via a one- or two-center process is unclear in most cases.(2)
Transition-metal-catalyzed versions of the rearrangement are known, and mechanisms vary. In one example employing rhodium bis(ethylene) hexafluoroacetylacetonate, coordination and formation of a bis-π-allyl complex precede electrocyclic ring closure and catalyst release.
(3)
Stereoselective Variants
Reactions of divinylcyclopropanes containing substituted double bonds are stereospecific with respect to the configurations at the double bonds—cis,cis isomers give cis products, while cis,trans isomers give trans products. Thus, chiral, non-racemic starting materials give rise to chiral products without loss of enantiomeric purity. In the example below, only the isomers depicted were observed in each case.(4)
Scope and Limitations
A wide variety of divinylcyclopropanes undergo the title reaction. These precursors have been generated by a variety of methods, including the addition of cyclopropyl nucleophiles (salts of lithium, or copper) to activated double or triple bonds, elimination of bis(2-haloethyl)cyclopropanes and cyclopropanation.In the example below, cuprate addition-elimination generates the transient enone 1, which rearranges to spirocycle 2.
(5)
Organolithiums can be employed in a similar role, but add in a direct fashion to carbonyls. Products with fused topology result.
(6)
Rearrangement after elimination of ditosylates has been observed; the chlorinated cycloheptadiene thus produced isomerizes to conjugated heptadiene 3 during the reaction.
(7)
Cyclopropanation with conjugated diazo compounds produces divinylcyclopropanes that then undergo rearrangement. When cyclic starting materials are used, bridged products result.
(8)
Substrates containing three-membered heterocyclic rings can also undergo the reaction. cis-Divinylepoxides give oxepines at elevated temperatures (100 °C). trans Isomers undergo an interesting competitive rearrangement to dihydrofurans through the intermediacy of a carbonyl ylide
Ylide
An ylide or ylid is a neutral dipolar molecule containing a formally negatively charged atom directly attached to a hetero atom with a formal positive charge , and in which both atoms have full octets of electrons. Ylides are thus 1,2-dipolar compounds...
and the same ylide intermediate has been proposed as the direct precursor to the oxepine product 4. Conjugated dienyl epoxides form similar products, lending support to the existence of an ylide intermediate.
(9)
Divinyl aziridine
Aziridine
Aziridines are organic compounds containing the aziridine functional group, a three-membered heterocycle with one amine group and two methylene groups...
s undergo a similar suite of reactions providing azepines or vinyl pyrroline
Pyrroline
Pyrrolines, also known under the name dihydropyrroles, are three different heterocyclic organic chemical compounds that differ in the position of the double bond. Pyrrolines are formally derived from the aromate pyrrole by hydrogenation...
s depending on the relative configuration of the aziridine starting material. Divinyl thiirane
Thiirane
Thiirane, more commonly known as ethylene sulfide, is the cyclic chemical compound with the formula C2H4S. It is the smallest sulfur-containing heterocycle. Like many organosulfur compounds, this species has a stench. Thiirane is also used to describe any derivative of the parent ethylene...
s can provide thiepines or dihydrothiophenes, although these reactions are slower than those of the corresponding nitrogen- and oxygen-containing compounds.
Synthetic Applications
The earliest observation of a cycloheptadiene via the title rearrangement was made by Baeyer in his synthesis of eucarvone from carvone hydrobromide. Mechanistic studies revealed that the rearrangement did indeed proceed via a concerted, Cope-type mechanism.(10)
In the Eschenmoser synthesis of colchicine
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
, the rearrangement is used to form the seven-membered ring of the target.
(11)
A racemic synthesis of sirenin employs a Wittig reaction
Wittig reaction
The Wittig reaction is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide....
to form the key divinylcyclopropane. Hydrogenation of the rearrangement product afforded the target.
(12)
Typical Conditions
Typically, the rearrangement is carried out just after the formation of the divinylcyclopropane, in the same pot. Heating is sometimes necessary, particularly for trans substrates, which must undergo epimerization prior to rearrangement. With enough energy to surmount activation barriers, however, the isomerization is usually very efficient.Example Procedure
(13)To a cold (–78°) stirred solution of lithium diisopropylamide
Lithium diisopropylamide
Lithium diisopropylamide is the chemical compound with the formula [2CH]2NLi. Generally abbreviated LDA, it is a strong base used in organic chemistry for the deprotonation of weakly acidic compounds. The reagent has been widely accepted because it is soluble in non-polar organic solvents and it...
(1.4–1.5 mmol/mmol of ketone) in dry THF
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
(4 mL/mmol of base) under an atmosphere of argon was added slowly a solution of n-butyl-trans-2-vinylcyclopropyl ketone (1.19 mmol) in dry THF
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
(1 mL/mmol of ketone), and the resulting solution was stirred at –78° for 45 minutes. A solution of freshly sublimed tert-butyldimethylsilyl chloride (1.6 mmol/mmol of ketone) in dry THF
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
(1 mL/mmol of chloride) was added, followed by dry HMPA
Hexamethylphosphoramide
Hexamethylphosphoramide, often abbreviated HMPA, is a phosphoramide having the formula [2N]3PO. This colorless liquid is a useful polar aprotic solvent and additive in organic synthesis.-Structure and reactivity:...
(0.5 mL/mmol of ketone). The solution was stirred at –78° for 15 minutes and at room temperature for 2–3 hours, and then it was partitioned between saturated aqueous sodium bicarbonate
Sodium bicarbonate
Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...
and pentane
Pentane
Pentane is an organic compound with the formula C5H12 — that is, an alkane with five carbon atoms. The term may refer to any of three structural isomers, or to a mixture of them: in the IUPAC nomenclature, however, pentane means exclusively the n-pentane isomer; the other two being called...
(10 mL and 20 mL/mmol of ketone, respectively). The aqueous phase was washed twice with pentane. The combined extract was washed four times with saturated aqueous sodium bicarbonate and twice with brine
Brine
Brine is water, saturated or nearly saturated with salt .Brine is used to preserve vegetables, fruit, fish, and meat, in a process known as brining . Brine is also commonly used to age Halloumi and Feta cheeses, or for pickling foodstuffs, as a means of preserving them...
, and then dried (MgSO4
Magnesium sulfate
Magnesium sulfate is a chemical compound containing magnesium, sulfur and oxygen, with the formula MgSO4. It is often encountered as the heptahydrate epsomite , commonly called Epsom salt, from the town of Epsom in Surrey, England, where the salt was distilled from the springs that arise where the...
). Removal of the solvent, followed by bulb-to-bulb distillation of the remaining oil, gave the corresponding silyl enol ether
Silyl enol ether
Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen terminus to an organosilicon group....
as a colorless oil that exhibited no IR carbonyl stretching absorption. Thermolysis of the silyl enol ether was accomplished by heating (neat, argon atmosphere) at 230° (air-bath temperature) for 30–60 minutes. Direct distillation (140–150°/12 torr) of the resultant materials provided the cycloheptadiene in 85% yield: IR
Infrared spectroscopy
Infrared spectroscopy is the spectroscopy that deals with the infrared region of the electromagnetic spectrum, that is light with a longer wavelength and lower frequency than visible light. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic...
(film) 1660, 1260, 840 cm–1; 1H NMR (CDCl3
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
) δ 0.09 (s, 6H), 0.88 (s, 9H), 0.7–2.75 (m, 14H), 4.8 (t, 1H, J = 5.5 Hz), 5.5–5.9 (m, 2H).