Synthesis of functionalized and unfunctionalized olefins via...

Details Synthesis of functionalized and unfunctionalized olefins via... Synthesis of functionalized and unfunctionalized olefins via...

2001-06-25

2004-09-21

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C562S598000, C564S161000, C585S642000

Reexamination Certificate

active

06794534

ABSTRACT:

BACKGROUND
Metathesis catalysts have been previously described by for example, U.S. Pat. Nos. 5,312,940, 5,342,909, 5,728,917, 5,750,815, 5,710,298, and 5,831,108 and PCT Publications WO 97/20865 and WO 97/29135 which are all incorporated herein by reference. These publications describe well-defined single component ruthenium or osmium catalysts that possess several advantageous properties. For example, these catalysts are tolerant to a variety of functional groups and generally are more active than previously known metathesis catalysts. In an unexpected and surprising result, the inclusion of an imidazolidine ligand in these metal-carbene complexes has been found to dramatically improve the already advantageous properties of these catalysts. For example, the imidazolidine-based catalysts exhibit increased activity and selectivity not only in ring closing metathesis (“RCM”) reactions, but also in other metathesis reactions including cross metathesis (“CM”) reactions, reactions of acyclic olefins, and ring opening metathesis polymerization (“ROMP”) reactions.
Trisubstituted carbon—carbon double bonds are a recurring motif in a diverse array of organic molecules. In particular, the generation of olefins with electron-withdrawing functionality, such as &agr;-&bgr; unsaturated aldehydes, ketones, and esters, remains a difficult reaction in organic chemistry. Therefore, new stereoselective methods for generating functionalized trisubstituted olefins remain an ongoing challenge in the area of synthetic organic chemistry. A wide variety of methods have been investigated to date including intramolecular Claisen rearrangments, Wittig olefination, Julia couplings, Peterson olefinations, alkylation of sulfonyl hydrazones, and direct methods for the preparation of fluorinated trisubstituted alkenes. Transition metal mediated routes including hydromagnesization, hydrozirconation, and the use of organocuprates have also been reported, but often suffer from use of harsh stoichiometric reagents.
The olefin metathesis reaction has recently gained prominence in synthetic organic chemistry with the commercial availability of well-defined transition metal
catalysts, such as the molybdenum alkoxy-imido alkylidene 1 and ruthenium benzylidene 2. In particular, ring-closing olefin metathesis (RCM) reactions have been widely utilized in the construction of a diverse variety of organic molecules. Approaches to generate olefins with vinylic functionality through the use of olefin cross-metathesis have been met with limited success. The intermolecular variant of olefin metathesis, terminal olefin cross-metathesis, has received less attention in the literature due to issues of product and olefin stereoisomer selectivity. However, renewed interest in this area has led to the recent development of new methodology for the selective cross-metathesis of terminal olefins using both 1 and 2. One of these initial reports, by Crowe and Goldberg, reported that acrylonitrile participated in a cross-metathesis reaction with a variety of terminal olefins. In an attempt to extend cross-metathesis beyond &agr;-olefins, however, Crowe et al, reported that disubstituted olefins were unreactive cross-metathesis partners with styrene using 1. Moreover, other &agr;,&bgr;-unsaturated carbonyl olefins, such enones and enoic esters, were not compatible with alkylidene 1 and therefore the methodology lacked generality. Recently, the highly active ruthenium-based olefin metathesis catalyst 3a,b containing a 1,3-dimesityl-4,5-dihydro-imidazol-2-ylidene ligand was found to efficiently catalyze the ring-closing metathesis (RCM) of a variety of acyclic dienes while exhibiting excellent functional group tolerance. Because ruthenium alkylidene 3a,b displayed unique activity towards previously metathesis inactive substrates using benzylidene 2, this prompted the investigation of metathesis of &agr;-functionalized olefins. The homologation of terminal olefins with a variety of functional groups in a stereoselective manner would be a synthetically valuable transformation. In particular, the formation of tri-substituted olefins in a stereoselective manner would be highly valuable for production of pharmaceuticals, natural products, and functionalized polymers.
SUMMARY
The invention generally relates to the cross-metathesis and ring-closing metathesis reactions between geminal disubstituted olefins and terminal olefins, wherein the reaction employs a Ruthenium or Osmium metal carbene complex. Specifically, the invention relates to the synthesis of &agr;-functionalized or unfunctionalized olefins via intermolecular cross-metathesis and intramolecular ring-closing metathesis using a ruthenium alkylidene complex. By &agr;-functionalized olefins, it is meant that the olefin is substituted at the allylic position. Functional groups include, for example, carbonyls, epoxides, siloxanes, or perfluorinated alkenes and represent functional groups that make the olefin electron deficient by resonance or inductive effects. These functionalized olefins can be substituted or unsubstituted. Such substituents may be selected from the group consisting of C
1
-C
20
alkyl, C
2
-C
20
alkenyl, C
2
-C
20
alkynyl, aryl, C
1
-C
20
carboxylate, C
1
-C
20
alkoxy, C
2
-C
20
alkenyloxy, C
2
-C
20
alkynyloxy, aryloxy, C
2
-C
20
alkoxycarbonyl, C
1
-C
20
alkylthio, C
1
-C
20
alkylsulfonyl and C
1
-C
20
alkylsulfinyl. Further, the functional group or substituent can be selected from the group consisting of hydroxyl, thiol, thioether, ketone, aldehyde, ester, ether, amine, imine, amide, nitro, carboxylic acid, disulfide, carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, and halogen. The catalysts preferably used in the invention are of the general formula
wherein:
M is ruthenium or osmium;
X and X
1
are each independently an anionic ligand;
L is a neutral electron donor ligand; and,
R, R
1
R
6
, R
7
, R
8
, and R
9
are each independently hydrogen or a substituent selected from the group consisting of C
1
-C
20
alkyl, C
2
-C
20
alkenyl, C
2
-C
20
alkynyl, aryl, C
1
-C
20
carboxylate, C
1
-C
20
alkoxy, C
2
-C
20
alkenyloxy, C
2
-C
20
alkynyloxy, aryloxy, C
2
-C
20
alkoxycarbonyl, C
1
-C
20
alkylthio, C
1
-C
20
alkylsulfonyl and C
1
-C
20
alkylsulfinyl. Optionally, each of the R, R
1
R
6
, R
7
, R
8
, and R
9
substituent group may be substituted with one or more moieties selected from the group consisting of C
1
-C
10
alkyl, C
1
-C
10
alkoxy, and aryl which in turn may each be further substituted with one or more groups selected from a halogen, a C
1
-C
5
alkyl, C
1
-C
5
alkoxy, and phenyl. Moreover, any of the catalyst ligands may further include one or more functional groups. Examples of suitable functional groups include but are not limited to: hydroxyl, thiol, thioether, ketone, aldehyde, ester, ether, amine, imine, amide, nitro, carboxylic acid, disulfide, carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, and halogen. The inclusion of an imidazolidine ligand to the previously described ruthenium or osmium catalysts has been found to dramatically improve the properties of these complexes. Imidazolidine ligands are also referred to as 4,5-dihydro-imidazole-2-ylidene ligands. Because the imidazolidine-based complexes are extremely active, the amount of catalysts that is required is significantly reduced. The inventive method allows for an efficient one-step formation of functionalized trisubstituted olefins under mild reaction conditions and further demonstrates the utility of olefin metathesis in organic synthesis.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention generally relates to cross-metathesis and ring-closing metathesis reactions between geminal disubstituted olefins and terminal olefins employing ruthenium alkylidenes. More particularly, the invention relates to the synthesis of unfunctionalized or functionalized trisubstituted and vicinally disubstituted olefins via intermolecular cross-metathesis and intramolecular ring-closing metathesis using imidazolidine based ruthenium and osmium carbene c

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