Intramolecular reactions of diazocarbonyl compounds
Encyclopedia
Intramolecular reactions of diazocarbonyl compounds include addition to carbon–carbon double bonds
to form fused cyclopropanes and insertion into carbon–hydrogen bonds or carbon–carbon bonds.
(typically copper
or rhodium
), α-diazocarbonyl compounds are converted to transition metal carbenes, which undergo addition reaction
s in the presence of carbon–carbon double bonds to form cyclopropanes. Insertion into carbon–carbon or carbon–hydrogen bonds is possible in substrates lacking a double bond. The intramolecular version of this reaction forms fused carbocycles, although yields of reactions mediated by copper are typically moderate. For enantioselective cyclopropanations and insertions, both copper- and rhodium-based catalysts are employed, although the latter have been more heavily studied in recent years.
(1)
of decomposition of diazocarbonyl compounds with copper begins with the formation of a copper carbene complex. Evidence for the formation of copper carbenes is provided by comparison to the behavior of photolytically generated free carbenes and the observation of appreciable enantioselectivity in cyclopropanations with chiral copper complexes. Upon formation of the copper carbene, either insertion or addition takes place to afford carbocycles or cyclopropanes, respectively. Both addition and insertion proceed with retention of configuration. Thus, diastereoselectivity may often be dictated by the configuration of the starting material.
(2)
Diazoketones containing pendant double bonds undergo cyclopropanation in the presence of copper. The key step in one synthesis of barbaralone is the selective intramolecular cyclopropanation of a cycloheptatriene
.
(3)
α,β-Cyclopropyl ketones may act as masked α,β-unsaturated ketones. In one example, intramolecular participation of an aryl group leads to the formation of a polycyclic ring system with complete diastereoselectivity.
(4)
α-Diazoesters are not as efficient as diazoketones at intramolecular cyclizations in some cases because of the propensity of esters to exist in the trans conformation about the carbon–oxygen single bond. However, intramolecular reactions of diazoesters do take place—in the example in equation (5), copper(II) sulfate is used to effect the formation of the cyclopropyl ester shown.
(5)
In the presence of a catalytic amount of acid, diazomethyl ketone substrates containing a pendant double bond or aryl
group undergo cyclization. The mechanism of this process most likely involves protonation
of the diazocarbonyl group to form a diazonium salt, followed by displacement of nitrogen by the unsaturated functionality and deprotonation. In the example below, demethylation affords a quinone
.
(6)
When no unsaturated functionality is present in the substrate, C-H insertion may occur. C-H Insertion is particularly facile in conformationally restricted substrates in which a C-H bond is held in close proximity to the diazo group.
(7)
Transannular insertions, which form fused carbocyclic products, have also been observed. Yields are often low for these reactions, however.
(8)
Insertion into carbon–carbon bonds has been observed. In the example in equation (9), the methyl group is held in close proximity to the diazo group, facilitating C-C insertion.
(9)
synthesis of sirenin. A single cyclopropane diastereomer was isolated in 55% yield after diazoketone formation and cyclization.
(10)
(see Eq. (18) below for an example). Reactions mediated by copper are typically on the order of hours, and in some cases, slow addition of the diazocarbonyl compound is necessary. Reactions should be carried out under an inert atmosphere in anhydrous conditions.
A solution of the olefinic acid (0.499 g, 2.25 mmol) dissolved in benzene (20 ml, freshly distilled from calcium hydride) was stirred at 0 °C (ice bath) under nitrogen while oxalyl chloride
(1.35 ml, 2.0 g, 15.75 mmol) was added dropwise. The ice bath
was removed and the solution was stirred at room temperature for 2 hr. The solvent and excess reagent were removed in vacuo. The resulting orange oil was dissolved in benzene
(2 x 5.0 mi, freshly distilled from calcium hydride
) under nitrogen.
This solution was added dropwise at 0 °C (ice bath) to an anhydrous ethereal solution of diazomethane
(50 ml, −20 mmol, predried over sodium metal) with vigorous stirring under nitrogen. The resulting solution was stirred at 0 °C for 1 hr and then at room temperature for 1.5 hr. The solvents and excess reagent were removed in vacuo.
Tetrahydrofuran
(40 ml, freshly distilled from lithium aluminum hydride) and finely divided metallic copper powder (0.67 g) were added to the crude diazo ketone, sequentially. This suspension was vigorously stirred at reflux under nitrogen for 2 hr. The resulting suspension was allowed to stir at room temperature for an additional 14 hr. The solution was filtered into water (100 ml). The mixture was shaken vigorously for 5 min and then extracted with ether (3 x 50 ml). The combined ethereal extracts were washed with saturated sodium bicarbonate solution (4 X 40 ml), water (40 ml), and saturated sodium chloride solution (40 ml), dried (Na2SO4), and concentrated in vacuo to give 0.673 g of a crude brown oil. This crude oil was chromatographed on silica gel (67 g) in a 2-cm diameter column using 10% ether-90% petroleum ether to develop the column, taking 37-ml sized fractions. Fractions 11–16 gave 0.164 g (33%) of pure ketone product: mp 64-64.5° (from pentane); IR (CCl4) 3095 (cyclopropyl CH)
and 1755 cm−1 (CO); NMR (CCl4) δ 1.18 (s, 3H, CH3) 1.03 (9, 3H, CH3),
0.97 (s, 3H, CH3), and 0.90 ppm (s, 3H, CH3). Anal. Calcd for C15H22O: C, 82.52; H, 10.16. Found: C, 82.61; H, 10.01.
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
to form fused cyclopropanes and insertion into carbon–hydrogen bonds or carbon–carbon bonds.
Introduction
In the presence of an appropriate transition metalTransition metal
The term transition metal has two possible meanings:*The IUPAC definition states that a transition metal is "an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell." Group 12 elements are not transition metals in this definition.*Some...
(typically copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
or rhodium
Rhodium
Rhodium is a chemical element that is a rare, silvery-white, hard and chemically inert transition metal and a member of the platinum group. It has the chemical symbol Rh and atomic number 45. It is composed of only one isotope, 103Rh. Naturally occurring rhodium is found as the free metal, alloyed...
), α-diazocarbonyl compounds are converted to transition metal carbenes, which undergo addition reaction
Addition reaction
An addition reaction, in organic chemistry, is in its simplest terms an organic reaction where two or more molecules combine to form a larger one....
s in the presence of carbon–carbon double bonds to form cyclopropanes. Insertion into carbon–carbon or carbon–hydrogen bonds is possible in substrates lacking a double bond. The intramolecular version of this reaction forms fused carbocycles, although yields of reactions mediated by copper are typically moderate. For enantioselective cyclopropanations and insertions, both copper- and rhodium-based catalysts are employed, although the latter have been more heavily studied in recent years.
(1)
Prevailing mechanism
The reaction mechanismReaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
of decomposition of diazocarbonyl compounds with copper begins with the formation of a copper carbene complex. Evidence for the formation of copper carbenes is provided by comparison to the behavior of photolytically generated free carbenes and the observation of appreciable enantioselectivity in cyclopropanations with chiral copper complexes. Upon formation of the copper carbene, either insertion or addition takes place to afford carbocycles or cyclopropanes, respectively. Both addition and insertion proceed with retention of configuration. Thus, diastereoselectivity may often be dictated by the configuration of the starting material.
(2)
Scope and limitations
Either copper powder or copper salts can be used very generally for intramolecular reactions of diazocarbonyl compounds. This section describes the different types of diazocarbonyl compounds that may undergo intramolecular reactions in the presence of copper. Note that for intermolecular reactions of diazocarbonyl compounds, the use of rhodium catalysts is preferred.Diazoketones containing pendant double bonds undergo cyclopropanation in the presence of copper. The key step in one synthesis of barbaralone is the selective intramolecular cyclopropanation of a cycloheptatriene
Cycloheptatriene
Cycloheptatriene is an organic compound with the formula C7H8. This colourless liquid has been of recurring theoretical interest in organic chemistry. It is a ligand in organometallic chemistry and as a building block in organic synthesis...
.
(3)
α,β-Cyclopropyl ketones may act as masked α,β-unsaturated ketones. In one example, intramolecular participation of an aryl group leads to the formation of a polycyclic ring system with complete diastereoselectivity.
(4)
α-Diazoesters are not as efficient as diazoketones at intramolecular cyclizations in some cases because of the propensity of esters to exist in the trans conformation about the carbon–oxygen single bond. However, intramolecular reactions of diazoesters do take place—in the example in equation (5), copper(II) sulfate is used to effect the formation of the cyclopropyl ester shown.
(5)
In the presence of a catalytic amount of acid, diazomethyl ketone substrates containing a pendant double bond or aryl
Aryl
In the context of organic molecules, aryl refers to any functional group or substituent derived from an aromatic ring, be it phenyl, naphthyl, thienyl, indolyl, etc....
group undergo cyclization. The mechanism of this process most likely involves protonation
Protonation
In chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...
of the diazocarbonyl group to form a diazonium salt, followed by displacement of nitrogen by the unsaturated functionality and deprotonation. In the example below, demethylation affords a quinone
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
.
(6)
When no unsaturated functionality is present in the substrate, C-H insertion may occur. C-H Insertion is particularly facile in conformationally restricted substrates in which a C-H bond is held in close proximity to the diazo group.
(7)
Transannular insertions, which form fused carbocyclic products, have also been observed. Yields are often low for these reactions, however.
(8)
Insertion into carbon–carbon bonds has been observed. In the example in equation (9), the methyl group is held in close proximity to the diazo group, facilitating C-C insertion.
(9)
Synthetic applications
Intramolecular cyclopropanation of a diazoketone is applied in a racemicRacemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
synthesis of sirenin. A single cyclopropane diastereomer was isolated in 55% yield after diazoketone formation and cyclization.
(10)
Typical conditions
Diazo compounds may be explosive and should be handled with care. Very often, the diazocarbonyl compound is prepared and immediately used via treatment of the corresponding acid chloride with an excess of diazomethaneDiazomethane
Diazomethane is the chemical compound CH2N2. It is the simplest of diazo compounds. In the pure form at room temperature, it is a extremely sensitive explosive yellow gas, thus it is almost universally used as a solution in diethyl ether...
(see Eq. (18) below for an example). Reactions mediated by copper are typically on the order of hours, and in some cases, slow addition of the diazocarbonyl compound is necessary. Reactions should be carried out under an inert atmosphere in anhydrous conditions.
Example procedure
(11)A solution of the olefinic acid (0.499 g, 2.25 mmol) dissolved in benzene (20 ml, freshly distilled from calcium hydride) was stirred at 0 °C (ice bath) under nitrogen while oxalyl chloride
Oxalyl chloride
Oxalyl chloride or ethanedioyl dichloride is a chemical compound with the formula 2. This colourless, sharp-smelling liquid, the diacid chloride of oxalic acid, is a useful reagent in organic synthesis...
(1.35 ml, 2.0 g, 15.75 mmol) was added dropwise. The ice bath
was removed and the solution was stirred at room temperature for 2 hr. The solvent and excess reagent were removed in vacuo. The resulting orange oil was dissolved in benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
(2 x 5.0 mi, freshly distilled from calcium hydride
Calcium hydride
Calcium hydride is the chemical compound with the formula CaH2. This grey powder reacts vigorously with water liberating hydrogen gas. CaH2 is thus used as a drying agent, i.e. a desiccant....
) under nitrogen.
This solution was added dropwise at 0 °C (ice bath) to an anhydrous ethereal solution of diazomethane
Diazomethane
Diazomethane is the chemical compound CH2N2. It is the simplest of diazo compounds. In the pure form at room temperature, it is a extremely sensitive explosive yellow gas, thus it is almost universally used as a solution in diethyl ether...
(50 ml, −20 mmol, predried over sodium metal) with vigorous stirring under nitrogen. The resulting solution was stirred at 0 °C for 1 hr and then at room temperature for 1.5 hr. The solvents and excess reagent were removed in vacuo.
Tetrahydrofuran
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...
(40 ml, freshly distilled from lithium aluminum hydride) and finely divided metallic copper powder (0.67 g) were added to the crude diazo ketone, sequentially. This suspension was vigorously stirred at reflux under nitrogen for 2 hr. The resulting suspension was allowed to stir at room temperature for an additional 14 hr. The solution was filtered into water (100 ml). The mixture was shaken vigorously for 5 min and then extracted with ether (3 x 50 ml). The combined ethereal extracts were washed with saturated sodium bicarbonate solution (4 X 40 ml), water (40 ml), and saturated sodium chloride solution (40 ml), dried (Na2SO4), and concentrated in vacuo to give 0.673 g of a crude brown oil. This crude oil was chromatographed on silica gel (67 g) in a 2-cm diameter column using 10% ether-90% petroleum ether to develop the column, taking 37-ml sized fractions. Fractions 11–16 gave 0.164 g (33%) of pure ketone product: mp 64-64.5° (from pentane); IR (CCl4) 3095 (cyclopropyl CH)
and 1755 cm−1 (CO); NMR (CCl4) δ 1.18 (s, 3H, CH3) 1.03 (9, 3H, CH3),
0.97 (s, 3H, CH3), and 0.90 ppm (s, 3H, CH3). Anal. Calcd for C15H22O: C, 82.52; H, 10.16. Found: C, 82.61; H, 10.01.