AU2007201132A1 - Synthesis of functionalized and unfuctionalized olefins via cross and ring-closing metathesis - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: California Institute of Technology Actual Inventor(s): Robert H. Grubbs, Arnab K. Chatterjee, John P. Morgan, Matthias Scholl, Tae-Lim Choi Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: SYNTHESIS OF FUNCTIONALIZED AND UNFUCTIONALIZED OLEFINS VIA CROSS AND RING-CLOSING METATHESIS Our Ref 796587 POF Code: 467689/104096 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- Synthesis of Functionalized and Unfunctionalized Olefins via Cross and Ring-Closing Metathesis The present application is a divisional application from Australian patent application number 2001271430 the entire disclosure of which is incorporated herein by reference.

BACKGROUND

Metathesis catalysts have been previously described by for example, United States Patents 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 reactions, but also in other metathesis reactions including cross metathesis 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 at-p 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 rearrangements, 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 -la- U M5125W56125 Di_ Speci_130307doc n o. R-N N-a .l ,CFCO,, Ph P h, P

R

h

(CF

3 oCO f v R CHr-2.4.6-CH 3 3 1 2 a R' P h 3b 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 ofolefin 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 crossmetathesis beyond a-olefms, however, Crowe et al, reported that disubstituted olefins were unreactive cross-metathesis partners with styrene using 1. Moreover, other a,13-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 a- 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 trisubstituted olefins in a stereoselective manner would be highly valuable for production of pharmaceuticals, natural products, and functionalized polymers.

1 A reference herein to a patent document or other matter which is given as prior art is not to be taken as an admission that that document or matter was, in Australia, known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims.

U: \6S512585125 Div_Spcic_130307doc

SUMMARY

0 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 i synthesis of c-functionalized or unfunctionalized olefins via intermolecular cross-metathesis and intramolecular ring-closing metathesis using a ruthenium alkylidene complex. By afunctionalized olefins, it is meant that the olefin is substituted at the allylic position.

Functional groups include, for example, carbonyls, epoxides, siloxanes, or perfluorinated 0 10 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 Ssubstituents may be selected from the group consisting of C 1

-C

2 0 alkyl, C 2

-C

20 alkenyl, C 2

C

2 0 alkynyl, aryl, Ci-C 2 o carboxylate, Ci-C 2 o alkoxy, C 2

-C

2 0 alkenyloxy, C 2

-C

20 alkynyloxy, aryloxy, C 2

-C

20 alkoxycarbonyl, Ci-C 20 alkylthio, C 1

-C

2 0 alkylsulfonyl and Ci-C 2 o 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

R

8

R

7

R

6

R

7

R

8 N NR 9 or R 8 N NR9 NX R t R 1 R L

L

wherein: M is ruthenium or osmium; X and X' are each independently an anionic ligand;

I

1 L is a neutral electron donor ligand; and, SR, R 6 R, R 8 and R 9 are each independently hydrogen or a substituent selected from the group consisting of Ci-C 20 alkyl, C 2

-C

20 alkenyl, C 2 -C20 alkynyl, aryl,

SC

i

-C

20 carboxylate, CI-C 20 alkoxy, C 2

-C

20 alkenyloxy, C 2

-C

20 alkynyloxy, aryloxy, t n 5 C 2

-C

20 alkoxycarbonyl, C 1

-C

20 alkylthio, Ci-C 20 alkylsulfonyl and Ci-C 20 alkylsulfinyl.

Optionally, each of the R, R 6

R

7

R

8 and R 9 substituent group may be substituted C with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy, and aryl which in turn may each be further substituted with one or more groups Sselected from a halogen, a Ci-C 5 alkyl, Ci-Cs alkoxy, and phenyl. Moreover, any of the catalyst ligands may further include one or more functional groups. Examples of Ssuitable 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.

The present invention also relates to a method for preparing trisubstituted olefins comprising: contacting a geminal disubstituted olefin with a terminal olefin in the presence of a metal carbene metathesis catalyst of formula XX'LL'M=CRR' to generate a trisubstituted olefin in an intermolecular olefin cross-metathesis reaction, wherein: M is ruthenium or osmium; L and L' are each, independently, any neutral electron donor; X and X' are each, independently, any anionic ligand; and R and R' are each independently selected from hydrogen or a substituent selected from the group consisting of Ci-C 20 alkyl, C 2 -C20 alkenyl, C 2

-C

20 alkynyl, aryl, C 1

-C

20 carboxylate, C 1

-C

20 alkoxy, C 2

-C

20 alkenyloxy, C 2 alkynyloxy, aryloxy, C 2

-C

20 alkoxycarbonyl, Ci-C 2 0 alkylthiol, aryl thiol, Ci-C 20 U:'5125685125 Div_Spici130307doc alkylsulfonyl and Ci-C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy, aryl, and a functional group 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, and further wherein at least one of L and L' is a substituted or unsubstituted N-heterocyclic carbene ligand.

The present invention also relates to a method for preparing di- or tri-substituted olefins comprising contacting a substituted or unsubstituted aliphatic olefin with a substituted or unsubstituted electron-deficient olefin in the presence of a metal carbene metathesis catalyst of formula XX'LL'M=CRR 1 to generate a di- or tri-substituted olefin in an intermolecular olefin cross-metathesis reaction, wherein: M is ruthenium or osmium; L and L' are each, independently, any neutral electron donor; X and X' are each, independently, any anionic ligand; and R and R' are each independently selected from hydrogen or a substituent selected from the group consisting of C 1

-C

2 0 alkyl, C 2

-C

20 alkenyl, C 2

-C

20 alkynyl, aryl, C 1

-C

20 carboxylate, Ci-C 20 alkoxy, C 2

-C

2 0 alkenyloxy, C 2

-C

20 alkynyloxy, aryloxy, C 2

-C

20 alkoxycarbonyl, C 1

-C

20 alkylthiol, aryl thiol, Ci-C 20 alkylsulfonyl and Ci-C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy, aryl, and a functional group 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, and further wherein at least one of L and L' is a substituted or unsubstituted N-heterocyclic carbene ligand.

Throughout the description and the claims of this specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.

U:\68512568S125Div_Speci_130307doc DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention generally relates to cross-metathesis and ring-closing metathesis reactions between germinal 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 carbine catalysts. The terms "catalyst" and "complex" herein are used interchangeably.

Unmodified ruthenium and osmium carbine complexes have been described in United States Patents Nos. 5,312,940, 5,342,909, 5,728,917, 5,750,815, and 5,710,298, U.S.

Application Serial Nos. 09/539,840 and 09/576,370, and PCT Publication Nos. WO 00/58322 and WO 00/15339, the contents of all of which are incorporated herein by reference. The ruthenium and osmium carbine complexes disclosed in these patents all possess metal centers that are U.65125'\85125 DivSpeci 130307doc formally in the +2 oxidation state, have an electron count of 16, and are penta-coordinated.

These catalysts are of the general formula X

RI

L

wherein: M is ruthenium or osmium; X and X' are each independently any anionic ligand; L and L 1 are each independently any neutral electron donor ligand; R and R 1 are each independently hydrogen or a substituent selected from the group consisting of C 1

-C

2 0 alkyl, C 2 -C2o alkenyl, C 2

-C

20 alkynyl, aryl, Ci-C 2 o carboxylate, Ci-C 20 alkoxy, C 2 -C2o alkenyloxy, C 2

-C

2 0 alkynyloxy, aryloxy, C 2

-C

2 0 alkoxycarbonyl, Ci-C 2 o alkylthio, Ci-C2o alkylsulfonyl and CI-C 20 alkylsulfinyl. Optionally, each of the R or R 1 substituent group may be substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy, and aryl which in turn may each be further substituted with one or more groups selected from a halogen, a CI-C5 alkyl, Ci-Cs 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 preferred catalysts used in the invention are as described above except that L 1 is an unsubstituted or substituted N-heterocyclic carbene. Preferably the N-heterocyclic carbene is of the formula:

R

6

R

7

R

6

R

7 or RN NR 9

R

8 N NR resulting in a complex of the general formula R"N NR' or RN NR" X R R 'R x1iv1 L L wherein:

R

6

R

7

R

8 and R 9 are each independently hydrogen or a substituent selected from the group consisting of Ci-C 2 0 alkyl, C 2

-C

20 alkenyl, C 2

-C

20 alkynyl, aryl, CI-C2o carboxylate, Ci-C 20 alkoxy, C 2

-C

20 alkenyloxy, C 2

-C

20 alkynyloxy, aryloxy, C 2

-C

20 alkoxycarbonyl, Ci-

C

20 alkylthio, CI-C 2 0 alkylsulfonyl and Ci-C 2 0 alkylsulfinyl. Imidazolidine ligands are also referred to as 4,5-dihydro-imidazole-2-ylidene ligands.

In preferred embodiments of the catalysts, the R substituent is hydrogen and the R 1 substituent is selected from the group consisting of Ci-C 20 alkyl, C 2

-C

20 alkenyl, and aryl. In even more preferred embodiments, the R 1 substituent is phenyl or vinyl, optionally substituted with one or more moieties selected from the group consisting of Ci-C 5 alkyl, Ci-

C

5 alkoxy, phenyl, and a functional group. In especially preferred embodiments, R' is phenyl or vinyl substituted with one or more moieties selected from the group consisting of chloride, bromide, iodide, fluoride, -NO 2 -NMe 2 methyl, methoxy and phenyl. In the most preferred embodiments, the R' substituent is phenyl or -C=C(CH 3 2 In preferred embodiments of the catalysts, L is selected from the group consisting of phosphine, sulfonated phosphine, phosphite, phosphinite, phosphonite, arsine, stibine, ether, amine, amide, imine, sulfoxide, carboxyl, nitrosyl, pyridine, and thioether. In more preferred embodiments, L is a phosphine of the formula PR 3

R

4

R

5 where R 3

R

4 and R 5 are each independently aryl or CI-Clo alkyl, particularly primary alkyl, secondary alkyl or cycloalkyl.

In the most preferred embodiments, L is each selected from the group consisting of- P(cyclohexyl)3, -P(cyclopentyl) 3 -P(isopropyl) 3 and -P(phenyl)3. L can also be an Nheterocyclic carbene. For example, L can be a ligand of the general formula: R 6 R 7 R 6 R 7 or R'N NR' R N NR 9 0. 00 wherein R 6

R

7 R 8 and R 9 are as previously defined.

In preferred embodiments of the catalysts, X and X' are each independently hydrogen, halide, or one of the following groups: C 1

-C

2 o alkyl, aryl, C 1

-C

20 alkoxNide, aryloxide, C 3

-C

20 alkyldiketonate, aryiliketonate, C 1

-C

2 o carboxylate, arylsulfonate, C 1

-C

2 o alkylsulfonate, Cjci C 20 alkylthio, C 1

-C

20 alkylsulfonyl, or C 1

-C

2 0 alkylsulfinyl. Optionally, X and X1 may be substituted with one or more moieties selected from the group consisting of C 1 -Clo akl, C 1 Cl 0 alkoxy, and alyl which in turn may each be further substituted with one or more groups selected from halogen, C 1 -C5 alkyl, C 1

-C

5 alkoxy, and phenyl. In more preferred embodiments, X and X' are halide, benzoate, Cl-C 5 carboxylate, C 1 -Cs alkyl, phenoxy, C 1 -Cs alkoxy, C 1 -Cs alkylthio, aryl, and Cj-C 5 ailkyl sulfonate. In even more preferred embodiments, X and X1 are each halide, CF 3

CO

2

CH

3

CO

2

CFH

2

CO

2

(CH

3 3 C0,

(CF

3 2

(CH

3 )CO, (CF 3

)(CI{

3 2 C0, PhO, MeO, EtO, tosylate, mesylate, or trifluoromethanesulfonate. In the most preferred embodiments, X and X' are each chloride.

In preferred embodiments of the catalysts, R6 and R(7 are each independently hydrogen, phenyl, or together form a cycloalkyl or an aryl optionally substituted with one or more moieties selected from the group consisting of C 1 -Clo ailkyl, C 1 -Clo alkoxy, aryl, and a functional group selected from the group consisting of hydroxyl, thiol, thioether, ketone, aldehyde, ester, ether, amnine, imine, amide, nitro, carboxylic acid, disulfide, carbonate, is ocyanate, carbodiirnide, carboalkoxy, carbamnate, and halogen; and R 8 and R 9 are each is independently C 1

-C

10 alkyl or aryl optionally substituted with C 1 -C5 ailkyl, Cl-Cs alkoxy, aryl, and a functional group selected from the group consisting of hydroxyl, thiol, tioether, ketone, aldehyde, ester, ether, amnine, imine, anide, nitro, carboxylic acid, disulfide, carbonate, isocyanate, carbodlimide, carboalkoxy, carbamnate, and halogen.

In more preferred embodiments, R 6 and R 7 are both hydrogen or phenyl, or R 6 and R 7 together form a cycloalkyl group; and R 8 and R 9 are each either substituted or unsubstituted aryl. Without being bound by theory, it is believed that bulkier R 8 and R 9 groups result in catalysts with improved characteristics such as thermal stability. In especially preferred embodiments, R 8 and R 9 are the same and each is independently of the formula

R'

0

R

1 wherein:

R'

I

and R 1 2 are each independently hydrogen, Ci-Clo alkyl, Ci-Clo alkoxy, aryl, or a functional group selected from hydroxyl, thiol, thioether, ketone, aldehyde, ester, ether, amine, imine, amide, nitro, carboxylic acid, disulfide, carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, and halogen. In especially preferred embodiments, R10, and R 12 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, and halogen. In the most preferred embodiments, R'1, and R12 are the same and are each methyl.

The invention discloses a novel method for the preparation of trisubstituted alkenes via intermolecular olefin cross-metathesis or intramolecular ring-closing metathesis of geminal disubstituted olefins and terminal olefins as shown in Scheme 1:

R

8

R

7 RN NR >SXiR 13 14 oL R 20R 14

S

Scheme 1 wherein X, X 1 L, R, R 6

R

7

R

8 and R 9 are as previously defined. As stated above, the use of an unsaturated N-heterocyclic carbene complex, for example one of the general formula:

R

6

R

7

R

8 N NR 9 X' R X X R'

L

wherein X, L, R, R 6

R

7

R

8 and R 9 are as previously defined, may also be used.

Preferably, the complex used is 1,3-dimesityl-4,5-dihydro-imidazol-2-ylidene ruthenium alkylidene complexes.

R

1 3 and R 14 are each independently a moiety selected from the group consisting of Ci-C 20 alkyl, C 2

-C

20 alkenyl, C 2

-C

2 o alkynyl, aryl, Ci-C 20 carboxylate, Ci-C 2 o alkoxy, C 2

-C

20 alkenyloxy, C 2

-C

2 0 alkynyloxy, aryloxy, C 2

-C

20 alkoxycarbonyl, Ci-C 2 o alkylthio, CI-C 2 0 alkylsulfonyl and Ci-C2o alkylsulfinyl. Optionally, each of the R 1 3 and R 1 4 substituent group may be substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Co alkoxy and aryl, that in turn may each be further substituted with one or more groups selected from a halogen, a C 1 -Cs alkyl, CI-C alkoxy, and phenyl. Moreover, R13 and

R

1 4 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. Further, R13 and R 14 may be a substituted or unsubstituted functional group 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 reaction in Scheme 1 results in good yields with moderate E selectivity. In addition, protected alcohols near the geminal disubstituted olefin improves reactivity for crossmetathesis.

Table 1 shows the results of studies of the use of 2-methyl-1-undecene as a unfunctionalized geminal disubstituted olefin for cross-metathesis (Table 1, Entries Substrate 4 proved to be a reactive substrate for cross-metathesis, coupling vinyldioxolane, allyl sulfone, and 1,4diacetoxy-cis-2,3-butene in good yields with moderate trans stereoselectivity. Particularly notable, allyl sulfone is a very reactive substrate for cross-metathesis (87% isolated yield, Table 1, Entry 2) using 3a,b, but yields no cross-metathesis product using 2.

Geminal Olefin Enry Substrate Terminal Olefln Product Yield EZ raio 1 67 3:1 2 4S 0^AV2_ -t 0 2 87 3.4:1 3 r(f A.O- OA. 1_ OAc 53 2.5:1 4 Y OAc Mt4 OAc 60 2.3:1 BZ3 zOAc BzO0 OAc 80 2.8:1 6 BzO OA Bz OL OAc 81 4:1 TABLE 1 Functionalized disubstituted olefins (Table 1, Entries 5 and 6) also proved excellent substrates for this reaction, and showed improved yields relative to 2-Methyl-l-undecene.

Without being bound by theory, the benzoate ester functionality may increase reactivity of the geminal olefins with the catalytic ruthenium species. In addition, maintaining a low concentration of terminal olefin homodimer also increases the cross-metathesis yields. In the reaction shown in Table 1, Entry 1, the vinyldioxolane component (3 equivalents) was added in four equal parts over a six-hour period. This maintained a low concentration of dioxolane homodimer and increased the isolated yield of cross-metathesis product by about 10 percent It should also be noted that in all reactions, the disubstituted olefin does not undergo selfmetathesis, enabling quantitative recovery of unreacted material. Protected allylic and homoallylic alcohols are also suitable under the reaction conditions.

Another aspect of the inventive method is the synthesis of functionalized olefins via intermolecular cross-metathesis and intramolecular ring-closing metathesis using a metal carbene metathesis catalyst.

-11- In exploring a variety ofgeminally disubstituted olefins in cross-metathesis, it was noted that 0 methyl methacrylate 4 participates in a novel and unexpected cross-metathesis reaction with terminal olefins 5-7 to generate the trisubstituted enoic ester in moderate yield with excellent stereoselectivity (Scheme 2): Cc, RL R' R

R'

4 (CH0 7 0TBS R 4 (CH27OBz 6 R 4 (CH 2 3 OA. 7 Scheme 2 wherein M, L, X, R 1

R

6

R

7

R

8

R

9 and R" 1 are as previously defined. Preferably, and as seen in Scheme 2, R 1 is a vinylidene. However, any of the previously described metathesis catalysts can also be used in the reaction.

The results of the cross-metathesis of a variety of a-carbonyl containing compounds can be seen in Table 2.

-12terminal cx-functionalized Isolated entry olefin olefin (equiv.) product yield(%) EIZ 1 %C 2

CH

3 TBSO A CO 2 C 75 >20:1 2 6 CO 2

C

3 C92>20: 7 2 6 CCH3 A 92 >20:1 7 'N-~CHO AcO$N-N -w O 92 >20:1 3 Ph AcO Ph 67(2.0) 99 >20:1 o 0 7 7 A 95 >20:1 0 0 TABLE 2 Particularly notable are the excellent yields attained with ketones and aldehydes (Table 2, Entry 3 In addition, the stereoselectivities of these reactions are excellent, making them synthetically practical for di- and trisubstituted olefins. Particularly notable'is the excellent yield attained with esters and aldehydes (Table 2, Entry 1 In a related result, CM of acrylic acid with terminal olefin 7 gave a quantitative yield of the cross product. This route provides a mild and efficient method for the synthesis of a variety of acrylic acids that avoids harsh reaction conditions such as oxidation of alcohols to acids and avoids the use of protecting groups on the acid moiety. In addition, in the optimization of reaction conditions, lowering reaction temperatures to about 23 to about 25 OC and reactions with no excess of one olefin partner, have also been led to successful CM. The unexpected result was that the reactions conducted at room temperature not only afford a cross product in substantial yield but also do not require an excess of one olefin partner. In the case of terminal aldehyde CM a particularly interesting and unexpected result was obtained. Due to impurities in commercially available acrolein, trans-crotonaldehyde was also investigated as an aldehyde source in CM. As demonstrated in Table 1, Entries 4 and 5, the use of crotonaldehyde is a significantly higher yielding reaction. A visible difference in the two reactions is the loss of gaseous side products ethylene (Entry 4) vs. propylene (Entry Without being bound by theory, it is proposed that the use of crotonates instead of acrylates also increase CM yields due to the catalytic intermediates involved under analogous reaction conditions.

Another inventive aspect of the invention involves the cross-metathesis of acrylamides.

Table 3 lists the results of the cross-metathesis of example acrylamides and terminal olefins using complex 3a: -14entry acrylamide Terminal olefin mol% 3a Product Isolated Yield of CM (EIZ) 0 5 mol% M01% M01% 0 3N

H

0 4 1 1 0

H

0 8 hNk 0 I 7 0TBS 0 CY2N 0 3

OTHP

5 mol% 0 5SM01% '1 0 1NK r0

IOH

mol% 0

H

2 N 0 TBS 39% (25:1) 83% (25:1) 77% (>20:1) 80% (>20:1) 89% (60:1) 89% (>20:1) 90% (>20:1) 97% (28:1) 100% (40:1) 87% (60:1) mol% n0 Hz 3

OTHP

mol% hI1N N 3

OTHP

5 moI% 0 Ph 2 NK 3 OTHP 0 0 0 N'3 OTHP 0 0 0 Lj 5 mol% TABLE 3 Initially, dimnethyl acrylamide (entry 1 a) was tried and a disappointingly low yield of about 39% of CM product was obtained. However, upon using higher catalyst loading, (10 mol of catalyst 1) and about 1.5 equivalents of terminal olefin, the yield was improved to about 83% (entry lb). Other substrates show good to excellent yields ranging from about 77% to about 100% with excellent diastereoselectivity (>25:1 trans:cis). IParticularly valuable is the 4 4 compatibility with Weinreb amide (entry 4) and oxazolidinone imides (entry These 0 functional groups are used widely in organic synthesis and CM provides synthons for further C-i manipulations. In particular, oxazolidinone imides are widely used in asymmetric reactions Ssuch as Michael additions, aldol, and Diels-Alder reactions. For representative examples of oxazolidinone chemistry see D. A. Evans, M. C. Willis, J. N. Johnston, Org. Lett. 1999, 1, 865. D. A. Evans, J. Bartroli, T. L. Shih, J Am. Chem. Soc. 1981, 103, 2127; b) D. A.

Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104, 1737. D. A. Evans, S. J.

Miller, T. Lectka, P. von Matt, J. Am. Chem. Soc. 1999, 121, 7559; the contents of all of Swhich are incorporated herein by reference. There is an effect of the acrylamide substituents CI 10 on the CM efficiency. Electron-donating substituents, such as alkyl groups, increase the 0 nucleophilicity of the carbonyl oxygen and lower CM yields result. Without being bound by CI theory, this may be attributed to a chelation effect on the Ru metal center and thereby lowers the overall CM reaction rate. Interestingly, where electronic contributions are similar, the chelation effect can be decreased by bulky substituents on the amide nitrogen making the carbonyl oxygen less sterically accessible (Table 3, Entry la versus Entry 2).

Other functional groups at the vinylic position were also investigated in cross-metathesis, and the results are summarized in Table 4.

entry terminal c~functionalized solated entry product yield E/Z olefin olefin (equiv.) yid B0 1 5 j BzoJo<j 38 5:1 19 22 2 5 19 (4.0)C 22 55 5:1 F F F F 3 6 CF 3 AO CF 75 2.3:1 F FF F F FF F 23 S4 6 Sl(oC 2 5 3 AO (OC2Hs 90 11:1 21 24 TABLE 4 Vinyl epoxides, such as butadiene monoxide 19 and electron-deficient perfluorinated alkenes 20 participate in cross-metathesis in moderate yields (Table 4, Entry 1-3) and represent other a-functionalized olefins that participate in CM. The addition of four equivalents ofepoxide 19 increased the yield of cross-product 22 (Table 4, Entry 2) and may be correlated to the volatility of butadiene monoxide. Vinyl siloxanes are also very good cross-metathesis partners using 3a,b (Table 4, Entry but yielded only about 36% of cross-product 24 with ruthenium benzylidene 2. These siloxanes provide useful synthons for further coupling reactions such as Suzuki-type aryl halide cross-couplings.

Finally, ring closing metathesis (RCM) reactions of substrates bearing vinyl functional groups are summarized in Table -17- S -functionalized product yield entry diene 1 0o 86 2 6 93 0O O0 4 0 ~o TABLE Six and five membered a-p unsaturated enones (Table 5, Entry 1-2) were formed in excellent yields, including the trisubstituted lactone (Table 5, Entry Also, the unprecedented ring-closing reaction of vinyl ether proceeds in good conversion to give cyclic product (Table 5, Entry Without being bound by theory, the allylic ether may be initially reacting with the catalyst followed by a fast reaction with the vinyl ether. This would minimize the formation of a stabilized Fischer-type carbene with the catalyst and allow for catalytic turnover. This is further evidenced by the inability to ring close substrates where both alkenes are vinyl ethers using catalyst 3b. In addition, larger ring structures containing a-functionalized groups can also be synthesized using the inventive method. Such afunctionalized groups include, for example, epoxides, perfluorinated olefins, and siloxanes.

Another inventive aspect of the invention is the process in which an electron deficient olefin is reacted with an aliphatic olefin or where two different sets of electron-deficient olefins are reacted with each other. In particular, the invention provides a process for preparing di- or -18-

I

tri- substituted olefins comprising contacting a substituted or unsubstituted aliphatic olefin with a substituted or unsubstituted electron-deficient olefin in the presence of a metal carbene metathesis catalyst. Substituted aliphatic olefins include any mono-, di-, or trisubstituted olefin wherein the olefin contains an alkyl group. Examples of this process can also be seen in Table 2 where the aliphatic olefin is the terminal olefin. However, the substituted olefin may also be prepared when the aliphatic olefins is an internal olefins. The invention also provides a process for preparing di- or tri-substituted olefins comprising contacting a substituted or unsubstituted electron deficient olefin with another substituted or unsubstituted electron deficient olefin in the presence of a metal carbene metathesis catalyst. The first and second electron-deficient olefins may be the same or different. Preferably one olefin is a substituted or unsubstituted styrene and the other olefin contains an a- carbonyl group, for example, an acrylate or acrylamide. Alternatively, both olefins may contain a- carbonyl group. Either or both of these electron-deficient olefins may be substituted or unsubstituted.

Substituents on the electron-deficient olefins and the aliphatic olefins may include one or more groups selected from the group consisting of C 1

-C

2 0 alkyl, C 2 -C2o alkenyl, C 2 alkynyl, aryl, Ci-C 2 0 carboxylate, Ci-C 2 0 alkoxy, C 2

-C

20 alkenyloxy, C 2

-C

2 0 alkynyloxy, aryloxy, C 2 -C2o alkoxycarbonyl, C 1

-C

2 0 alkylthio, C 1

-C

20 alkylsulfonyl and CI-C2o alkylsulfinyl. Optionally, the substituent group may be substituted with one or more moieties selected from the group consisting ofCi-Clo alkyl, Ci-Clo alkoxy, and aryl, which in turn may each be further substituted with one or more groups selected from a halogen, a alkyl, Ci-C 5 alkoxy, and phenyl. Moreover, the olefins may 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.

Styrenes are one class of electron-deficient olefins that have been examined previously in olefin cross-metathesis with early heterogeneous systems and molybdenum-based systems.

In both of these cases terminal olefins were used as the other olefin partner. In addition to examples using simple terminal olefins, it has been demonstrated that styrenes react with acrylamides in high yields with catalyst 1. The yields with styrene show a similar trend in yield (ranging from about 25% to about 87%) when comparing nitrogen substituents using catalyst 3a (Table 6).

entry acrylmideIsolated enty cryamdemot% 3a Product Yield of CM 0 0 2 yNL' 0 3N

H

0 4

N

0

H-

2 NiN.' 6QN)VN

H

0 8 Ph 2 NA)< mol% M01% 5 mo1% 5 mno1% 5 mnol% 5 M01% 5 Mo1% m0l% 5 mol% 5 mol% 0 N 0 Cy 2 N 0 0'N

HI

0 HN 'N1 0

H

0 Ph 2

N

0 0 Li 57% 62% 66% 69%* 69% 83% 87% 63% 0 0 0 )YKN" LUj TABLE 6 This reaction is valuable in that it offers the possibility of a variety of cinnamnides by crossmetathesis (CM).

Yet another inventive aspect of the invention is the use of styrenes as CM partners, in particular with catalysts 3a or 3b. Some previous art has demonstrated limited reactivity of styrenes in CM using 2 such as trialkloxysilanes. In addition, the reaction allyl glycosides

G

with a variety of para-substituted styrenes have been investigated with 2. However, prior to the invention, an extended scope of styrenes has not been investigated with catalyst 3a,b or terminal olefins. A novel aspect of the invention is the reaction between an a-functionalized olefin with a substituted or unsubstituted styrene, wherein the substitution on the styrene occurs on the aromatic or olefinic carbons, or both. As styrenes are electron-deficient olefins, a substituted styrene can include any of the substituent groups listed above for the electrondeficient olefins. In particular, reactions with a variety of substituted styrene and acrylates yielding Heck-type reaction products were synthesized by olefin metathesis (Table 7).

R

0

R

13 0" Entry 1 2 3 4 6 7 8 9 11 12 13

H

R

4 4-CH 3

R"

4 4-t-Bu

R

14 2,4- Dimethyl

R

1 4 4-Ph

R

1 4 4-CHO

R'

4 4-Oac

R

1 4 4-NOz

R

1 4 4-C1

R

4 4-Br

R

14 2-F R" 2-C1

R

1 4 2-Br R" CH 3 R 3 CH 2

CH

3

R'

3

CH

2

CH

3

R'

3 CH2CH3 3 CH 2

CH

3

R'

3 CH2CH 3 R 3 CH 2

CH

3

R'

3

CH

3 R3= CH 3

R'

3

CH

2

CH

3

R

1 3

CH

2

CH

R3 CH 2

CH

3 R 3= CH 2

CH

3 Acrylate equiv. Isolated Yield 2 92 2 99 1.1 99 2 87 2.2 90 2 83 1 88 2 89 2 94 2 98 2 72 2 62 2 49 E/Z Ratio >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 TABLE 7 Of particular note is the use of ortho-substituents that are previously unprecedented (Table 7, Entries 4, 11-13). In addition, a variety of reactive functional groups such as nitro groups and benzaldehydes are amenable to the reaction conditions. Without being bound by theory, it is suspected that an even wider range of substituents can be used on the styrene segment of the coupling strategy. Two important additions to the reaction are the use of a,P-unsaturated -21ketones and aldehydes to styrenes. Further, yet another unexpected result of the invention is that the corresponding stilbene may also be used in the reactions and demonstrates the reversibility of the cross-metathesis reactions. For example, when using a substituted styrene with an a-functionalized olefin, the by-product, stilbene, can be reacted with a-functionalized olefins to form more cross-product (Table This has been undiscovered in the styrene cross-metathesis literature with any homogeneous catalysts. In addition, without being bound by theory, it is proposed that the use of J3-methylstyrene instead of acrylates will also increase CM yields due to the catalytic intermediates involved under analogous reaction conditions.

Stilbene Functionalized olefin (equiv.) Product Isolated Yield E/Z ratio E/Z ratio ~A

N

0,Pc (2 eq.) N .EO (2 eq.) 0 EtO 0 EtO -'11 >20:1 >20:1 EtOA'N (2 eq.) (2 eq.) (1 eq.) >20:1 >20:1 >20:1 AC OAc N 0 2 N eq.

eq.) >20:1 TABLE 8 Further, it was determined that in the cross-metathesis with styrenes, rapid formation of stilbenes were followed by productive cross-metathesis. However, a new class of styrenes was found to form stilbenes slowly and allowed for the formation of selective crossmetathesis products with terminal olefins. Examples of these styrenes are listed in Table 9: -22- Styrene Terrnal olelin Styrene: -olefln Product THPO1 THPO ~uh Isolated CM Yield 47% AcO~-

ACO

OBAco OBz NJ OBz TABLE 9 A point to note is that ortho-substitutions in Table 9, Entries 2 and 3 represent selective CM reactions and that the homoallylic substitution in Entry 4 also directs selective CM.

In the previously mentioned reactions with ca,-unsaturated carbonyl containing compounds, mechanistic studies indicated that the reactions described in Table 2 and 3 are produced predominantly via a ruthenium carbene species of the terminal olefm component, followed by a quick reaction with an electron-deficient component, such as an acrylate. However, it was determined that, in fact, a variety of reactions could be performed where the resting ruthenium carbene state lies with electron-deficient component. This allows a much wider range of products available by cross-metathesis. Table 10 lists some example results: -23- Entry Substrate Product' Isolated yield 0 0 1 87% 0 0 0 3 xYozxo<X 94% JQ0 0 0 nhxj n-hexyl n-hexyl 77% o 0 6 0 0 00 0 TABLE In addition to dimerizations, these reactions can also be applied to the reaction of acrylates with 1, 1-geminally disubstituted as summnarized in Table 11: entry Carbene Precusor Cross-partner Product Isolated yield 1 O 1 41% 2 O- O- 41% 3 O 83% 3 ^o' 1 68 3 o 0 6 XO O 7 HO) HO 83% 0 J 099% TABLE 11 Similar to the styrenes, the substitution can also occur on the olefinic carbons. The gem substitution can occur on the terminal or a- functionalized olefin.

Finally, a variety of reactions used allylic substituted terminal olefin with acrylates in crossmetathesis. For example the cross-metathesis of methyl acrylate and allyl alcohol proceeded in about 92% isolated yield with the reaction conditions listed in Table 2. In addition, a double CM reaction was accomplished with 1,5-hexadiene and four equivalents of acrylate in about 91% yield. Homoallylic substitution, such as ester groups and free hydroxyl groups, is also tolerable to the reaction conditions.

SThe following examples show the cross-metathesis and ring-closing metathesis of a variety of electron-deficient olefins employing ruthenium alkylidene 3a,b. These examples are merely 5 illustrative and are not intended to limit the scope of the invention.

EXAMPLE 1 SRepresentative Procedure of Preparation of Ruthenium Alkylidene 3a,b:

O

A 250-mL flame-dried round bottom flask equipped with a magnetic stirbar was charged with 1,3-dimesityl-4,5-dihydro-imidazolium tetrafluoroborate (3.08 g, 7.80 mmol, 1.6 equiv.) and dry THF (30 mL) under nitrogen atmosphere. A solution of potassium tertbutoxide (0.88 g, 7.80 mmol, 1.6 equiv.) in dry THF (30 mL) was slowly added at room temperature. The reaction mixture was allowed to stir for 1/2 hour and was then slowly transferred to a 500-mL flame-dried Schlenk flask containing a solution of RuC12

(=CH=C(CH

3 2)(PCp3) 2 (3.50 g, 4.88 mmol, 1.0 equiv.) in dry toluene (200 mL). This mixture was stirred at 80 0 C for 15 min, at which point the reaction was complete as indicated by 'H NMR. The reaction mixture was filtered through a glass frit under argon and all volatiles were removed under high vacuum. The residue was recrystallized three times from anhydrous methanol (40 mL) at -78 0 C to give 3 as a pinkish-brown microctystalline solid (2.95 g) in 77% yield: 'H NMR (400 MHz, C6N, PPM) 8 19.16 (1H, d, J= 11 Hz), 7.71 (1H, d, J= 11 Hz), 6.89 (2H, 6.62 (2H, 3.36-3.24 (4H, 2.80 (6H, 2.54 (6H, 2.41- 1.26 (27H, br 2.20 (3H, 2.02 (3H, 1.06 (3H, 0.90 (3H, 3'P NMR (161.9 MHz, CA, ppm) 8 28.05; HRMS (FAB) calcd for C4,H6,C12NZPRu [M+j 784.2993, found 784.2963.

EXAMPLE 2 Representative Procedures for the Formation of Trisubstituted Olefinic Products: a) 2-methyl-l-undecene (110 piL, 0.5 mmol) and 5-hexenyl-1-acetate (170 pL, mmol) were simultaneously added via syringe to a stirring solution of 3 (20 mg, 0.024 mmol,

I

4.8 mol in CH 2 C1 2 (2.5 mL). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 ml and purified directly on a silica gel column (2x10 cm), eluting with 9:1 hexane:ethyl acetate.

Clear oil was obtained (83 mg, 60% yield, 2.3:1 trans/cis as determined by relative intensity of alkene 3 C peaks at 125.0 and 124.2 ppm). H NMR (300 MHz, CDC13, ppm): 5.08 (1H, t, J= 2.0 Hz), 4.04 (2H, t, J= 6.0 Hz), 2.03 (3H, obs 2.01-1.91 (2H, 1.69-1.59 (2H, m), 1.56 (3H, obs 1.47-1.05 (16H, broad 1.05-0.84 (3H, t, J= 6.8 Hz) 13 C NMR (75 MHz, CDCl 3 ppm): 171.7, 136.7, 136.4, 150.0, 124.2, 123.3, 65.1, 40.3, 32.5, 32.3, 30.2, 29.9, 28.8, 28.6, 28.5, 28.0, 26.7, 23.2, 21.5, 16.4, 14.7. Rf= 0.35 EXAMPLE 3 Representative Procedure of Preparation of Product in Table 2, Entry 1: 9-Decen-l(tert-butyldimethylsilane)-yl (165 iL, 0.51 mmol) and Methyl methacrylate (110 pl, 1.00 mmol) were added simultaneously via syringe to a stirring solution of 3 (21 mg, 0.026 mmol, 5.2 mol in CH 2 C1 2 (2.5 ml). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to ml and purified directly on a silica gel column (2x10 cm), eluting with 9:1 hexane:ethyl acetate. Viscous oil was obtained (123 mg, 72% yield, trans/cis as determined by relative heights at 143.2 and 143.1 ppm of 3 C NMR spectra) and is representative of all the reactions in this table.

Reaction at room temperature: For example, in the reaction in Table 2, Entry 2 the reaction is conducted as follows: To a solution of 3a in CH 2 C1 2 (0.2 M) at 23-25 °C was added sequentially by syringe hexene (1 equiv) and methyl acrylate (1.05 equiv). The flask placed under a flow of nitrogen, and the reaction mixture was allowed to stir at the 23-23 °C temperature range and was maintained at that temperature for 12 h. The black reaction mixture was concentrated to mL by rotary evaporation. The resulting residue was purified by silica gel chromatography (2x10 cm, 9:1 hexane:ethyl acetate), affording cross-product in 92% isolated yield.

-27- EXAMPLE 4 Representative Procedure for Reactions in Table 3: To a flask charged with amide (1.0 equiv) in CH 2 C1 2 (0.2 catalyst 1 (0.05 equiv in

CH

2 C12) was added by cannulation followed by addition of terminal olefin (1.25 equiv) via syringe. The flask was fitted with a condenser and refluxed under argon for 15 hours. TLC analysis was used to monitor the reactions. After the solvent was evaporated, the product was purified directly on a silica gel column to provide products as either viscous oils or white solids. A slight modification was made for the reaction on Table 3, Entry lb where equivalents of terminal olefm were used and a higher catalyst loading was used (10 mol%).

These conditions increase the CM yields for all of the reactions described Table 3.

EXAMPLE Representative Procedure of Preparation of Product in Table 4, Entry 1: The reaction was conducted by analogy to the reactions mentioned above: 9-Decen-l-yl benzoate (145 ptl, 0.52 mmol) and butadiene monoxide (160 l.d, 1.98 mmol) and were added simultaneously via syringe to a stirring solution of 3a,b (21 mg, 0.027 mmol, 5.0 mol in

CH

2

C

2 (2.5 ml). The flask was fitted with a condenser and refluxed under nitrogen for 12 hours. The reaction mixture was then reduced in volume to 0.5 ml and purified directly on a silica gel column (2x10 cm), eluting with 20:1 hexane:ethyl acetate. Clear oil was obtained mg, 55% yield, 5:1 trans/cis as determined by relative integrations of iH peaks at 5.94 and 5.75 ppm). The only difference in experimental procedure is in Entry 2 where two additional equivalents (4 equivalents total) of butadiene monoxide are added via a syringe pump over 12 hours. All of the reaction yields can be optimized with this change in the procedure.

EXAMPLE 6 Representative Procedure of Preparation of Product in Table 5, Entry 3: -28- A 250 mL oven-dried round bottom flask equipped with a stir bar was charged with CH 2

CI

2 (156 mL), mixed ether diene (1.00 g, 7.80 mmol, I equiv.) and catalyst 3b (331 mg, 0.42 mmol, 0.05 equiv.). The reaction mixture was refluxed overnight at which time the 1H NMR indicated complete disappearance of the starting material. CH 2 C2 was distilled off at ambient pressure and the product was purified by bulb-to-bulb distillation to yield the product as colorless oil (382 mg, 3.78 mmol, 49% yield). The only difference for the reactions in Table 4 entries 1 and 2 are that reaction purification is by column chromatography in 10:1 hexanes:ethyl acetate eluant. Evaporation of solvent yielded products as clear oils.

EXAMPLE 7 Representative Procedure for Reactions in Table 6: The same general procedure was used for all of the entries and is as follows: To a flask charged with amide (1.0 equiv) in CH 2 Cl2 (0.2 catalyst 3a (0.05 equiv in CH 2 C12) was added by cannulation followed by addition of styrene (1.9 equiv) via syringe. The flask was fitted with a condenser and refluxed under argon for 15 hours. The reaction is monitored by TLC analysis. After the solvent was evaporated, the product was purified directly on a silica gel column. The only deviation from this procedure is in Table 6, Entry Ib where 0.1 equivalents of catalyst 3a are used instead of 0.05 equivalents that is used in the rest of the reactions.

EXAMPLE 8 Representative Procedure for Reactions-in Table 7: To a flask charged with ethyl vinyl ketone (1.0 equiv) in CH 2 Cl 2 (0.2 catalyst 3a (0.05 equiv in CH 2 C2) was added by cannulation followed by addition of styrene (1.9 equiv) via syringe. The flask was fitted with a condenser and refluxed under argon for 15 hours. The reaction is monitored by TLC analysis. After the solvent was evaporated, the product was purified directly on a silica gel column to yield cross-metathesis product in quantitative yield and characterized exclusively as the trans isomer by 'H-NMR. The reactions described in Table 7 were conducted under the same reaction conditions with the equivalents of acrylates as listed in the table.

EXAMPLE 9 Representative Procedure for Reactions in Table 9: The reaction conditions are analogous to those in Table 7. The ratios of styrene to terminal olefin are listed in Table 9.

EXAMPLE Representative Procedure for Reactions in Table An analogous set of reaction conditions are employed for acrylate dimerization in entries 1-4.

To a solution of 3a (5 mol in CH 2 C12 (0.4M) at room temperature was added the appropriate acrylate by syringe. The flask was fitted with a reflux condenser under a flow of nitrogen and the reaction mixture heated to 40 OC and was maintained at that temperature for 3 h. The black reaction mixture was cooled to room temperature and then was concentrated to 0.5 mL by rotary evaporation. The resulting residue was purified by silica gel chromatography (2x10 cm) to yield fumarate dimers as exclusive trans isomers by 'H-NMR.

For Table 10 Entries 5-7, the identical reaction conditions to those listed above apply, except that the substrate concentration was lowered to 0.05M in CH2C12 from 0.4M. Without being bound by theory, this change in reaction conditions is attributed to a more expedious bimolecular catalyst decomposition pathway of ketone carbenes versus ester carbenes.

EXAMPLE 11 Representative Procedure for Reactions in Table 11: There are three sets of reaction conditions used in these reactions. For Table 11 Entries 1-2, a flask charged with catalyst 3a (0.05 equiv), a,P-unsaturated ketone (1 equiv) and oc,punsaturated ester (2 equiv) were added via syringe. The flask was fitted with a condenser and refluxed under argon for 3 hours. TLC analysis is used to monitor the reaction. After the solvent was evaporated, the product was purified directly on a silica gel column. For Table 11 Entries 3-5, analogous reactions are used, except that the 1,1-disubstituted olefin is used in excess by 4 equivalents relative to the acrylate component. In addition, the products from these reactions were isolated as a 2 to 1 ratio of trans:cis diastereomers and were determined by 'H-NMR nOe determination. Finally, for Table 11 Entries 6-7, identical reaction conditions are used as for Entries 1-5 except that the methylenecyclohexane is added in a 2 equivalent excess relative to the acrylate cross-partner.

-31-

Claims (33)

1. A method for preparing trisubstituted olefins comprising: contacting a geminal disubstituted olefin with a terminal olefin in the presence of a metal carbene metathesis catalyst of formula XX'LL'M=CRR' to generate a trisubstituted olefin in an intermolecular olefin cross-metathesis reaction, wherein: M is ruthenium or osmium; L and L' are each, independently, any neutral electron donor; X and X' are each, independently, any anionic ligand; and R and R' are each independently selected from hydrogen or a substituent selected from the group consisting of Ci-C 2 0 alkyl, C 2 -C 2 o alkenyl, C 2 -C 20 alkynyl, aryl, Ci- C 20 carboxylate, Ci-C 20 alkoxy, C 2 -C 2 o alkenyloxy, C 2 -C 2 0 alkynyloxy, aryloxy, C 2 -C 2 0 alkoxycarbonyl, C 1 -C 20 alkylthiol, aryl thiol, Ci-C 2 0 alkylsulfonyl and C 1 C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy, aryl, and a functional group 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, and further wherein at least one of L and L' is a substituted or unsubstituted N-heterocyclic carbene ligand.

2. The method of claim 1 wherein the catalyst is of the formula: R 6 R 7 R 6 R 7 R 8 N NR 9 R 8 N NR 9 Xi R Xi R M M SR R L or L wherein: M is ruthenium or osmium; X and X 1 are each, independently, any anionic ligand; L is a neutral electron donor ligand; and, -32- U:WS1251685125 Div_Specie_130307 do R, R 6 R 7 R 8 and R 9 are each independently hydrogen or a substituent selected from the group consisting of CI-C 2 0 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, C 1 C 20 carboxylate, C 1 -C 2 alkoxy, C 2 -C 2 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, C 1 -C 20 alkylthiol, aryl thiol, CI-C 20 alkylsulfonyl and C 1 C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, C 1 -Clo alkoxy, aryl, and a functional group 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, and further wherein R6 and R may be taken together to form a cycloalkyl or aryl ring.

3. The method of claim 2, wherein: M is ruthenium; L is selected from the group consisting of phosphine, sulfonated phosphine, phosphite, phosphinite, phosphonite, arsine, stibine, ether, amine, amide, imine, sulfoxide, carboxyl, nitrosyl, pyridine, and thioether; and, X and X' are each independently hydrogen, halide, or a substituent selected from the group consisting of C 1 -C 20 alkyl, aryl, Ci-C 20 alkoxide, aryloxide, C 3 -C 20 alkyldiketonate, aryldiketonate, C 1 -C 20 carboxylate, CI-C 2 0 arylsulfonate, C 1 -C 20 alkylsulfonate, C 1 -C 20 alkylsulfonate, C 1 -C 20 alkylthiol, aryl thiol, C 1 -C 2 0 alkylsulfonyl and CI-C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of CI-Clo alkyl, C 1 -C 0 lo alkoxy, aryl, and halide.

4. The method of claim 3, wherein: M is ruthenium; X and X' are each independently selected from the group consisting of halide, CF 3 CO 2 CH 3 CO 2 CFH 2 CO 2 (CH 3 3 CO, (CF 3 2 (CH 3 )CO, (CF 3 )(CH 3 2 CO, PhO, MeO, EtO, tosylate, mesylate, and trifluoromethanesulfonate; L is a phosphine of the formula PR 3 R 4 R where R 3 R 4 and R 5 are each independently aryl, CI-C 1 o alkyl, or cycloalkyl; R is hydrogen; and, -33 UW6851268512Div_Spci,_1303074o r R' is phenyl or vinyl, optionally substituted with one or more moieties selected from the group consisting of Ci-C 5 alkyl, Ci-Cs alkoxy, phenyl, and a functional group 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 method of claim 4, wherein: X and X' are each chloride; L is selected from the group consisting of -P(cyclohexyl) 3 -P(cyclopentyl) 3 -P(isopropyl)3, and -P(phenyl) 3 and, R' is phenyl or-C=C(CH 3 2

6. The method of claim 5, wherein R 6 and R 7 together form a cycloalkyl or an aryl.

7. The method of claim 5, wherein R 6 and R 7 are the same and are hydrogen or phenyl.

8. The method of claim 5, wherein R 8 and R 9 are each independently a substituted or unsubstituted aryl.

9. The method of claim 5, wherein R 8 and R 9 are each independently of the formula Rl0 RI2 Rl wherein R1 0 and R 12 are each independently hydrogen, Ci-Clo alkyl, Ci-Clo alkoxy, aryl, or a functional group selected from hydroxyl, thiol, thioether, ketone, aldehyde, ester, ether, amine, imine, amide, nitro, carboxylic acid, disulfide, carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, and halogen.

The method of claim 9, wherein RI R 1 and R 12 are each independently hydrogen, methyl or isopropyl. -34- U ~851565125 DIv_Specie_130307doc

11. The method of claim 1, wherein the terminal olefin is of the formula: ^^R4 wherein R 1 4 is selected from the group consisting of Ci-C 2 0 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, C 1 -C 20 carboxylate, Ci-C 20 alkoxy, C 2 -C20 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, Ci-C 20 alkylthio, Ci-C 20 alkylsulfonyl and Ci-C 20 alkylsulfinyl; and wherein R 1 4 is substituted or unsubstituted.

12. The method of claim 11, wherein R 1 4 is substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, C 1 -Clo alkoxy and aryl, wherein the moiety is substituted or unsubstituted.

13. The method of claim 12, wherein the moiety substitution is selected from the group consisting of halogen, a CI.C 5 alkyl, Ci-C 5 alkoxy, and phenyl.

14. The method of claim 11, wherein R 14 contains one or more functional groups, wherein the functional group is 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 method of claim 11, wherein R 1 4 is a functional group 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, wherein the functional group is substituted or unsubstituted.

16. The method of claim 1 wherein the geminal disubstituted olefin is of the formula R 1 3 wherein R 13 is selected from the group consisting of C 1 -C 20 alkyl, C 2 -C 2 0 alkenyl, C 2 -C 2 0 alkynyl, aryl, carboxylate, Ci-C 20 alkoxy, C 2 -C 2 0 alkenyloxy, C 2 -C 20 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, C 1 -C 20 alkylthio, Ci-C 2 0 alkylsulfonyl and Ci-C 20 alkylsulfinyl; and wherein R 1 3 is substituted or unsubstituted. U:I85125685125 Div Spcie_130307doc

17. The method of claim 16, wherein R 13 is substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy and aryl, wherein the moiety is substituted or unsubstituted.

18. The method of claim 17, wherein the moiety substitution is selected from the group consisting of halogen, a Ci-Cs alkyl, Ci-C 5 alkoxy, and phenyl.

19. The method of claim 16, wherein R 13 contains one or more functional groups, wherein the functional group is 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 method of claim 1, wherein the geminal disubstituted olefin is of the formula R13 wherein R 13 is a functional group 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, wherein the functional group is substituted or unsubstituted.

21. The method of claim 1, wherein the disubstituted olefin is a substituted or unsubstituted a-functionalized olefin.

22. The method of claim 21, wherein the a-functionalized olefin is a substituted or unsubstituted acrylamide.

23. The method of claim 21, wherein the a-functionalized olefin is selected from the group consisting of a substituted or unsubstituted acrylate, vinyl ketone, and vinyl aldehyde. -36- U:'85125165125 Div_Spccic_130307doc

24. The method of claim 1, wherein the trisubstituted olefin is prepared at room temperature.

A method for preparing di- or tri-substituted olefins comprising contacting a substituted or unsubstituted aliphatic olefin with a substituted or unsubstituted electron-deficient olefin in the presence of a metal carbene metathesis catalyst of formula XX'LL'M=CRR' to generate a di- or tri-substituted olefin in an intermolecular olefin cross-metathesis reaction, wherein: M is ruthenium or osmium; L and L' are each, independently, any neutral electron donor; X and X' are each, independently, any anionic ligand; and R and R' are each independently selected from hydrogen or a substituent selected from the group consisting of Ci-C 20 alkyl, C 2 -C 2 0 alkenyl, C 2 -C 2 o alkynyl, aryl, Ci-C 20 carboxylate, Ci-C 2 0 alkoxy, C 2 -C 20 alkenyloxy, C 2 -C 2 0 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, Ci-C 2 o alkylthiol, aryl thiol, Ci-C 20 alkylsulfonyl and Ci-C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of Ci-Clo alkyl, Ci-Clo alkoxy, aryl, and a functional group 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, and further wherein at least one of L and L' is a substituted or unsubstituted N-heterocyclic carbene ligand.

26. The method of claim 25, wherein the metathesis catalyst is of the formula R 6 R 7 R 6 R 7 RN NR 9 RN NR 9 x R xi R M M L or L wherein: M is ruthenium; -37- U W125'685125 Div_Speci._130307do J. X and X' are each independently selected from the group consisting of halide, CF 3 CO 2 CH 3 CO 2 CFH 2 CO 2 (CH 3 3 CO, (CF 3 2 (CH 3 )CO, (CF 3 )(CH 3 2 CO, PhO, MeO, EtO, tosylate, mesylate, and trifluoromethanesulfonate; L is a phosphine of the formula PR R 4 R where R 3 R 4 and R 5 are each independently aryl, CI-Clo alkyl, or cycloalkyl; R is hydrogen; and, R6, R, and R 9 are each independently hydrogen or a substituent selected from the group consisting of CI-C 2 0 alkyl, C 2 -C 20 alkenyl, C 2 -C 2 0 alkynyl, aryl, C 1 -C 2 0 carboxylate, C 1 -C 20 alkoxy, C 2 -C 2 0 alkenyloxy, C 2 -C 2 0 alkynyloxy, aryloxy, C 2 -C 2 0 alkoxycarbonyl, C 1 -C 2 0 alkylthiol, aryl thiol, CI-C 2 0 alkylsulfonyl and CI-C 20 alkylsulfinyl, the substituent optionally substituted with one or more moieties selected from the group consisting of C 1 -Clo alkyl, CI-Clo alkoxy, aryl, and a functional group 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, and further wherein R 6 and R 7 may be taken together to form a cycloalkyl or aryl nring.

27. The method of claim 25, wherein the aliphatic olefin is a mono-, di- or trisubstituted olefin.

28. The method of claim 25, wherein the aliphatic olefin is substituted one or more groups selected from the group consisting of CI-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 2 0 alkynyloxy, aryloxy, C 2 -C 20 alkoxycarbonyl, CI-C 20 alkylthiol, C 1 -C 20 alkylsulfonyl and CI-C 20 alkylsulfinyl, wherein the substituent is substituted or unsubstituted.

29. The method of claim 28, wherein the substituent group is substituted with one or more moieties selected from the group consisting of CI-Clo alkyl, CI-Clo alkoxy, and aryl, wherein the moiety is substituted or unsubstituted.

The method of claim 29, wherein the moiety is substituted with one or more groups selected from a halogen, a C 1 -Cs alkyl, CI-Cs alkoxy, and phenyl. 38 U\685125W5125 Div_Spcie_130307doc

31. The method of claim 25, wherein the aliphatic olefin includes one or more functional groups selected from the group consisting of hydroxyl, thiol, thioether, Sketone, aldehyde, ester, ether, amine, imine, amide, nitro, carboxylic acid, disulfide, t 5 carbonate, isocyanate, carbodiimide, carboalkoxy, carbamate, and halogen. C

32. The method of claim 25, wherein the aliphatic olefin is 1-hexene and the electron- deficient olefin is methyl acrylate.

33. A product whenever prepared by the method of any one of claims 1 to 32. -39- U:%6851256S~125 Div_Spcic 130307doc