Dennis Dougherty generously agreed to become part of the team on fairly short notice. Both Matthias Scholl and Tom Kirkland (who proofread parts of this . thesis) were good comrades in the organic fraction of the group.
Introduction Schemes
- Tables
- Tables
- Tables
- Olefin Metathesis
Specifically, the nature of the acetylene substituent is investigated in the context of dienine RCM. For example, 13Enyne RCM has recently been used as a key step in the total synthesis of (-)-stemoamide.
Catalytic Ring-Closing Metathesis (RCM) of Dienynes
Construction of Fused Bicyclic [n.m.0] Systems and Effects of Acetylene Substitution*
Abstract
Introduction
The dienine 15 with an internally substituted olefin also exhibits high regioselectivity, leading to the formation of the. During the course of the dienine cyclization of 15, for example, the acetylene would react with catalyst 1 to produce the vinyl carbene species 49.
![tetrasubstituted bicyclic [4.4.0] compound 22 (entry 6, Table 1). It also represents the first](https://thumb-ap.123doks.com/thumbv2/123dok/10401073.0/32.922.191.796.119.586/tetrasubstituted-bicyclic-4-compound-22-entry-table-represents.webp)
Scheme 7
- X« H 25: X - APr
In order to investigate the reactivity of substituted dienes, several different substrates with different acetylene substituents X were synthesized and subjected to ruthenium-catalyzed diene metathesis. At the same time, the reactivity of these dienes with well-defined tungsten19 and molybdenum20 alkylidenes was investigated. Results of the RCM reactions of ruthenium alkylene 1 with compounds 24-33 are summarized in Table 2.23. The ruthenium catalyst 1 shows activity with various carbon-based substituents and invariably favors diene metathesis over the competing diene RCM.
Because no diene RCM is observed to form the cycloheptene in these reactions, the acetylenic substituents were thought to be involved in the decomposition of 1. Exposure of 29-33 to 1 in the presence of the terminal acetylene dienyne 24 or dimethyl diallylmalonate 46 led to cyclization of 24 or 46, while 29-33 remained unreacted even when a ruthenium alkylidene species was observed in the reaction mixture.23 At higher catalyst loadings, cycloheptene formation is observed (e.g. dienyne 29 where X = SiMe3 proceeds to >90% conversion of cycloheptene with 10 mol% 1 after 24 hours at The reactions of tungsten catalyst 34 and molybdenum catalyst 35 are summarized in Table 3.27 Molybdenum alkylidene 35 is the least productive catalyst, producing only a bicyclic product with the unsubstituted acetylene (X = H, compound 24, entry 1, table 3).
With the other substrates (entries 2–11), only the unreacted starting material was recovered in reaction with 35.
Catalyst 34 Catalyst 35
X-TMS 10: X-Mθ
The bromo- and iodoalkyne-dienyne substrates 32 and 33 did not cyclize under standard catalytic RCM conditions with any of the mentioned catalysts.28 However, reaction with a stoichiometric amount of ruthenium carbene I resulted in a halide exchange reaction.
Conclusions
The reaction was quenched with water (50 mL), extracted with hexanes (3 x 50 mL), dried over MgSQ, concentrated and purified by flash. The reaction mixture was then transferred via cannula to the crude ketone in 10 ml THF at -78°C. The reaction was quenched with saturated NH 4 Cl (50 mL), extracted with hexanes, dried over Na 2 SO 4 , concentrated and purified by flash chromatography (5% diethyl ether/pet. ether) to afford 340 mg (47%) of 16 as a colorless oil. .
The solution was cooled to 0°C and Et3 SiOTf (0.55 ml) was added until the reaction was complete by tlc (petroleum ether elution). The aqueous solution was extracted with EtOAc (3 x 25 mL), dried over Na 2 SO 4 and purified with silica gel. After stirring for 25 minutes, the reaction was complete as judged by tlc and was quenched by pouring into 10 ml of ice water.
The cyclization proceeds without this protection, but the reaction rate is slowed down dramatically, possibly due to intramolecules.' chelation. In solution, the reaction of 1 with 2-butene at room temperature takes place in the order of minutes, while the reaction with 2-butyne continues for hours at higher temperatures.
Tandem Ring-Opening/Ring-Closing Metathesis of Cyclic Olefinst
Because of their low strain energy, cyclohexenes were expected to be p∞r relays in ring opening/ring closing reactions. However, it was noted that conversion of a six-membered ring to two five-membered rings with simultaneous production of ethylene should be thermodynamically favorable due to the entropy change. Initial experiments with the six-link ring relay system suggested that our ring-opening-ring-closing strategy would be limited to the more strained ring systems.
The reactions of 5a, 6a and 7a gave multiple products when the reactions were carried out at concentrations close to those used for the other substrates. The failure to produce the expected bicyclics was attributed to competitive intermolecular metathesis, which was not observed in systems having high ring strain (cyclobutene or norbornene). Competitive intermolecular metathesis has previously been observed for systems in which the rate of cyclization is slower than oligomerization.17.
Scheme 3
Acyclic olefins have been shown to react via acyclic diene metathesis (ADMET)16 to produce dimers or other oligomeric species (Scheme 3). Competitive intermolecular metathesis has previously been observed for systems in which the rate of cyclization is slower than oligomerization.17. to 16% at 0.12 M). We hypothesized that oligomers are formed by intermolecular metathesis through acyclic olefins, and to reduce the ko, we prepared bis(crotyl)cycloolefin diol ethers to make acyclic olefins less active for metathesis relative to cyclic olefins. there is sufficient precedent that increased substitution on the olefin decreases the rate of olefin metathesis.2 Alkyl substitution should slow down the undesired process and allow the metathesis catalyst to react with ring opening.
Indeed, when the crotyl ethers 5b-7b are reacted with Catalyst 1, the reactions proceed in moderate yield at concentrations comparable to those used for the other substrates (Table 3). This observation is consistent with the substitution lowering the rate of metathesis in the acyclic olefin. Olefin substitution appears to slow down the intramolecular (desired) process to a lesser extent, and the relative rate of cyclization is effectively increased to allow product formation.
Scheme 4) involves initial metathesis at the terminal olefin of the allyl group
LnRu-CHPh
That no intermediates are observed in the ring-opening/ring-closing reactions is consistent with the former mechanism. However, mechanism 2 is not ruled out; ring tension can activate the cyclic olefin and in some cases promote this mechanism. The conformational constraints imposed on the metallacyclobutane intermediate of the first intramolecular metathesis in mechanism 1 are an additional consideration.20.
The contrast in reactivity of this species between amide and ester has previously been observed in the formation of eight-membered rings. lb Supposedly 20 is able to withstand the ring. This approach has been used in the tandem ring-opening/closing metathesis of four- to eight-membered cycloolefins as well as norbomenes to produce polycyclic ethers. The relative rates of these intermolecular reactions can be lowered by running the reaction at high dilution or by increasing the substitution of the acyclic olefins involved.
Although ring-opening reactions involving six-membered rings are not well known, systems have been presented in which a cyclohexene ring is used for a metathesis relay. Flash column chromatography was performed using Silica Gel mesh) from EM Science. 21 Catalyst 1 was prepared according to published procedures. 3* trans- 1,4-Dihydronaphthalene dicarboxylic acid was prepared according to the procedure of Lyssy. 22 The metathesis reactions were carried out under an argon atmosphere. with dry, degassed solvents under anhydrous conditions.
10 ml, 120 mmol) at 0 *C was slowly added NaH (1.3 g, 56 mmol)
The reaction mixture was concentrated and purified on silica gel (10% Et2O in petroleum ether) to give the product 11 (47 mg, 85%) as a clear, colorless oil. The ether 5b was prepared similarly to 4 using crotyl bromide and cis-3,6-cyclohexenediol prepared by the Bäckvall method. Bicyclic ether 12 was obtained as a clear, colorless oil (73%) under conditions analogous to the reaction which was obtained as a clear, colorless oil (73%) under conditions analogous to the reaction.
Bicyclic ether 13 was obtained as a clear, colorless oil (57%) under conditions analogous to the reaction producing 10. Ether 7b was prepared in a manner similar to 4 using crotyl bromide and s-3,8-cyclooctenediol. prepared by Bäckvall's method. Ether 8 was prepared in a manner similar to 4 using allyl bromide and c<5-3,4-cyclopentanediol prepared by the Sharpless method from cyclopentadiene.
Bicyclic ether 15 was obtained as a clear, colorless oil (70%) under conditions analogous to the reaction that produced 10 . The ether 9 was prepared in a manner similar to 4 using allyl bromide and endo,endo-5-norbornene-2,3-dimethanol.
By exposing cyclohexene to a heterogeneous tungsten metathesis catalyst in the presence of norbornene, the propagation rate is effectively increased over that of the depropagation. A small amount (<20%) of the ring-opened 1,3-diene was observed in each of these reactions. An additional factor in the ring-opening reactions of cyclohexene-based precursors 5a and 5b is that both are cis-1,4 disubstituted, a destabilizing contribution of about 2 kcal mol-1.
Ruthenium-Catalyzed Polycyclization Reactions*
The linear precursor 4 was prepared by alkylation of 2-butyn-1,4-diol monoallyl ether anion 2 with propargyl chloride 3.11 Lithium. Palladium-catalyzed ring opening of cyclopentadiene monoepoxide with N-allyl-p-toluenesulfonamide and O-alkylation of the resulting amino alcohol with propargyl chloride 3 produced 6. Treatment of acyclic precursors containing acetylene relay units with a slightly catalytic amount of environment.
The mechanism of the polycyclizations involves initial formation of a ruthenium alkylidene which undergoes a series of intramolecular metatheses with the relay units before termination by a final ring closure. The cyclization is completed by metathesis of the vinyl carbene with the disubstituted olefin to yield product 17 and propagate alkylidene 20. The initiation and subsequent reactions of 1 are followed by observing the 'H NMR signal of the α-proton of the ruthenium alkylidene.
These observations indicate a secondary metathesis with the α-olefin byproduct of the cyclization reaction (eq 6) and are consistent with the reported reactivity of 1 with α-olefins.9*. Visualization was achieved with one or more of the following: UV light, KMnO4, phosphomolybdic acid (PMA), cerium ammonium nitrate (CAN) or p-anisaldehyde solution followed by heating.
9 A cascade of diene RCM reactions was used in the quantitative RCM of poly(l,2-butadiene) to produce a cyclopentene-based polymer. Propargyl chloride 3, instead of the tosylate, was isolated by reaction of 2 with tosyl chloride. Cyclization proceeds without this protection, but the reaction rate slows dramatically, possibly due to intramolecular chelation.
When the reaction is performed with an acyclic precursor containing two mono-substituted olefins, product formation is observed more slowly and to a lesser extent. 34; A related process involving carbene-acetylene metathesis has been reported, enyne metathesis ring closure, using tungsten and ruthenium carbene complexes, (a) Katz, T. Similarly, carbene-acetylene- metathesis the recently reported rearrangement cyclization of triynes possible to produce aromatics, an example of which is shown, (d) Peters, J.U.; Blechen, S.
