Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1497 161

24. Advances in the metathesis of olefins

1517

V. ACYCLIC MONOENES CONTAINING FUNCTIONAL GROUPS

This area has been well reviewed by Mol177. By suitable choice of catalyst almost any functional group may be tolerated in the substrate, but there must usually be one or more CH2 groups between the double bond and a functional group for productive metathesis to take place. From Table 1 it may be seen which functional groups are liable to react with particular MtDC bonds and therefore to be avoided in the substrates used with catalysts based on these metals. Table 1 does not include any reactions involving RuDC bonds; in fact they do not react with the various YDZ or Y Z functions listed. Ru-based catalysts therefore offer the widest scope for the metathesis of unsaturated compounds containing functional groups. Catalyst 19 will even bring about the metathesis of 200 equiv of oleic acid at 20° in 20 h178.

Olefinic compounds containing OH or NH2 groups destroy W- or Mo-based catalysts but metathesis is possible if these groups are first protected. For example, ω-unsaturated glucosides bearing protecting groups R will react in the presence of 12 to give boloamphiphiles (equation 16). For R D acetyl a yield of 64% is obtained at 80 °C, while for R D t-BuMe2Si the yield is 92% at 65 °C179. Equation 17 is an example of the metathesis of a protected amine (60% yield after 8 h)180.

OR
RO		O	O
2 RO						(CH2 )9 CH		CH2
		OR
		−C2 H4		12					(16)
OR
RO		O	O
RO						(CH2 )9 CH
		OR
								2
	D			8				D
2Me3CO CO NHCH2CH		CH2	!						(17)
			C		H		[Me3CO CO NHCH2CH ]2
				2		4

Perhaps surprising at first sight is the fact that the metathesis of diallylphenyl phosphane can be carried out using 12 as catalyst (equation 18.) The tungsten centre in 12 is evidently too crowded to allow its deactivation by coordination of the phosphorus atom but not so crowded as to prevent the coordination and subsequent reaction of the double bond181.

2Ph2PCH2CH	D	CH2	5 mol% 12	D	18
			!
			PhCl, 80 °C, 12h	[Ph2PCH2CH ]2

C2H4

Where there is no spacer group between the CDC bond and the functional group, productive self-metathesis does not occur, but cross-metathesis reactions with other olefins are still possible. Recent impressive examples of this are the cross-metathesis reactions of acrylonitrile (equation 19). The reaction occurs with a wide variety of R groups. For 15 different compounds the yield of the new nitrile after 3 h at room temperature is 40 90%, with the cis isomer always strongly preferred (75 90%). Only minor amounts of RCH2CHDCHCH2R are formed, and no NCCHDCHCN182. The fact that acrylonitrile

1518	K. J. Ivin

itself does not undergo metathesis must be due to the inability of [Mt]DCHCN to react with CH2DCHCN in a productive manner, though the degenerate reaction may well occur.

CH2			CHCN	8		CH2			CHCN
	+							+			(19)
				CH2 Cl2
CH2			CHCH2 R			CH2			CHCH2 R
The results of some			cross-metathesis		experiments						for a series of nitriles

CH2DCH(CH2)nCN reacting with cis-hept-3-ene are summarized in Table 4. No crossmetathesis occurs with acrylonitrile (n D 0). For n D 1, 2, 5, 8, 9 cross-metathesis products are formed in substantial amount, but for n D 3, 4 very little reaction occurs, an effect which is attributed to intramolecular coordination of the nitrile group to the metal centre in [Mt]DCH(CH2)nCN (n D 3, 4), thereby reducing its metathesis activity or causing its destruction. With n 5 the nitrile group has little influence on the reaction and its self-metathesis is preferred over that of hept-3-ene, whereas the reverse is true for n D 1, 2.

For small values of n the ability of nitriles to undergo self-metathesis depends on the catalyst. Thus for n D 1 (allyl cyanide) WCl6/Me4Sn gives only very low yields183, but WCl6/1,1,3,3-tetramethylsilane-1,3-disilacyclobutane (1/2) with 50 equiv of substrate gives a 53% yield after 10 h at 60 °C (selectivity 82%)184. For n 2 good yields are obtained with Re2O7/Al2O3/Me4Sn catalysts (selectivity >98%), and for n 5 also with WCl6/Me4Sn183.

The behaviour of unsaturated ethers follows a similar pattern. Thus for cis- RO(CH2)nCHDCH(CH2)nOR with n D 1, R D t-BuMe2Si or Me, no cis/trans isomerization is observed in the presence of W(DCHC6H4-OMe-2)(DNPh)([OCMe (CF3)2]2, but for n D 2 isomerization occurs quite readily185. The metathesis of o- allylphenyl propyl ether (equation 20) occurs at 22 °C with high yield (95% selectivity)186. cis-Propenyl ethyl ether and butyl vinyl ether have no CH2 spacers between the CDC and ether functions and do not undergo self-metathesis, but they are able to cross-metathesize (equation 21) to give the monoether products only188.

	CH2 CH	CH2		Re2 O7	/A l2 O3 /Bu4 Sn				CH2 CH
				−C2 H4
OPr							OPr		2(20)
	TABLE 4. The metathesis of CH2DCH(CH2)nCN with cis-
	hept-3-ene catalysed by WC16/Me4Sn at 100 °C (nitrile/heptene/
	W/Sn D 10/10/1/2)183,187
	n	Cometathesis			Self-metathesis conversion (mol%)
		conversion
		(mol%)				cis-hept-3-ene	nitrile
0		0			42		0
1		42			28		0
2		59			30		4
3		12			4		2
4		2			0		0
5		47			9		26
8		42			7		46
9		46			5		40

24. Advances in the metathesis of olefins

1519

MeCH

CHOEt

MeCH

+

CHOEt

+

Cr[

C(OMe)Ph](CO)5

(21)

BuOCH

CH2

BuOCH

CH2

In the presence of 12, allyl methyl sulphide undergoes self-metathesis leading to MeSCH2CHDCHCH2SMe (90% trans), and cometathesis with cis-but-2-ene leading to MeCHDCHCH2SMe (75% trans)189.

Vinyl chloride, like acrylonitrile, is not able to self-metathesize but will crossmetathesize with simple alkenes190,191. Both allyl chloride and allyl bromide will undergo metathesis on Re2O7/Al2O3/R4Sn with good conversion and high selectivity192,193.

Not surprisingly the metathesis of 10-nonadecen-2-one fails with W-based catalysts that

will cause the metathesis of methyl oleate194; cf. Table 1. The metathesis of allyl acetone succeeds with Re2O7/Al2O3/R4Sn as catalyst193 and the activity is increased by a factor

of 10 if the support is pretreated with triethyl borate192. Improved yields (50%) can be obtained by first protecting the keto group by reaction with Me3SiCl in the presence of Et3N in DMF to give the silylenol ether, or by reaction with ethane-1,2-diol to give the 1,3-dioxolane derivative195.

The metathesis of unsaturated esters, e.g. CH2DCH(CH2)nCOOR (n 1), can be brought about by a variety of catalysts such as (i) WCl6/Me4Sn, where it is best to add the ester before the Me4Sn196,197, (ii) Re2O7-based catalysts which are active at 20 °C, are highly selective and easily recovered198, and (iii) MoO3/SiO2 which has been

photoreduced in CO and subsequently treated with cyclopropane199,200; also by carbene complexes of W83,101,201, of Mo97,202 and of Ru178.

Vinyltrimethylsilane is reported to give good yields of the metathesis product Me3SiCHDCHSiMe3 with a number of ruthenium catalysts, e.g. Ru3(CO)12/HSiPh3 in benzene at 80 °C (75% yield of trans isomer)203 and Ru(H)(Cl)(CO)(PPh3)3 [38% yield of trans/cis (44/56) product]. With Ru(SiMe3)(Cl)(CO)(PPh3)2 as catalyst there are indications of a competing reaction in which the CDC bond of the substrate inserts into a Ru Si bond204. RuCl2(PPh3)2 is also an effective metathesis catalyst not only for vinyltrimethylsilane but also for derivatives in which some of the methyl groups have

been replaced by phenyl205 or by alkoxy groups204,206 208. The metathesis of allylsilane derivatives proceeds readily on WOCl4209 and on Re2O7/Al2O3/R4Sn210 212.

VI. THE CARBONYL OLEFINATION REACTION

Before considering ring-closing metathesis (RCM) it is convenient to discuss the carbonyl olefination reaction because this is sometimes an important adjunct to RCM. This reaction, e.g. equation 22, is like a Wittig reaction in which the MtDC bond takes the place of a PDC bond. It is important both as a means of effecting clean termination of living ROMP reactions when initiated with Ti, Mo or W complexes, and as a convenient means of converting CDO groups into olefinic groups. While ketones can be used to terminate living Ti and W carbenes, they do not react so readily with Mo carbenes, except when carrying a ˇ- or -hydroxy substituent, in which case the reaction becomes very stereoselective; e.g. E/Z > 99/1 for the product of reaction 23 in benzene at 20 °C. This effect is thought to be caused by coordination of the hydroxy substituent to the metal centre in the intermediate metallacycle11.

[Mt]DCHR C R1R2CDO ! [Mt]DO C RCHDCR1R2

(22)

1520	K. J. Ivin
O
	O
	Me3 CO
		O
(30)	(31)	‘Cp2Ti CH2’
		benzene 25 °C

	TiCp2	90 °C
		TiCp2
Me3 CO		Me3 CO
(33)		(32)
O		O
90 °C
		O
		H
		•
Me3 CO		H
		(35)
(34)

ether −40 ° to 25 °C ‘C p2Ti CH2’

H

•
(36)	H

SCHEME 3. Synthesis of (š)- 9 12 -capnellene involving metathesis reactions 31 ! 33, 33 ! 34, and 35 ! 36 facilitated by the Tebbe reagent ‘Cp2TiDCH2’

	24. Advances in the metathesis of olefins		1521
OH	O	OH	CMe2 Ph
	8 (R = Ph)

		(23)
	C6 H6 , 20 °C
Me		Me

The analogous reaction, using the tungsten analogue 8W of the molybdenum complex 8 in toluene, is stereoselective at 78 °C (E/Z > 99/1), but less so at 20 °C (E/Z D 89/11). The stereoselectivity is not so high when the HO group is replaced by PhCH2O or MeCOO, or if the HO group occupies the ˛- or -positions. This suggests that the hydroxyl group is the only Lewis base functionality that is small enough or basic enough to coordinate strongly to the highly sterically hindered metal centre11. In passing it should be noted that living ruthenium carbene complexes are unreactive towards both aldehydes and ketones but can be terminated by stoichiometric metathesis with ethyl vinyl ether109 and other strained or functionalized olefins213.

The complex 8W (R D Me) can also be used in a stoichiometric metathesis sequence to effect the ring closure of unsaturated ketones so as to form 1-substituted cyclopentenes, cyclohexenes and cycloheptenes in good yield, e.g. equation 24. The CDC bond reacts first to give [W]DCH(CH2)3CO(CH2)O(CH2)3Ph, which then undergoes an internal carbonyl olefination reaction13.

O(CH2 )3 Ph	8W(R = Me)	(24)
O		O(CH2 )3 Ph

The same strategy has been used in the total synthesis of (š)- 9 12 -capnellene (36) from dimethyl- -butyrolactone (30), the key steps of which are shown in Scheme 3. The Tebbe reagent is used to cleave the CDC bond in 31 to give 33 via 32, immediately followed by the carbonyl olefination reaction to give 34. This is then transformed to 35 by standard procedures and finally converted to 36, again using the Tebbe reagent. This synthesis of 36 is the first to achieve the formation of all four asymmetric centres in a single step. The overall yield is 20%214,215.

The WCl6-assisted condensation polymerization of conjugated ketones such as benzylideneacetophenone (37) proceeds through the formation of oligomeric ketones PhCO(CHDCPh)nCHDCHPh which can be detected (n D 1 6) in the early stages of the reaction216; see also elsewhere217 222. By analogy with reaction 24 it is likely that the polymerization proceeds via alternate metathesis reactions of the CDC and CDO bonds with tungsten carbene species formed from the reactants (equations 25 and 26).

[W]

CHR

[W]

CHR

+

+

PhCCH

CHPh

P hCCH

CHP h

(25)

O

O

(37)

[W]

O

[W]

O

+

PhCCH +

CCH

CHPh

PhCCH

CCH

CHPh

(26)

Ph

O

O

Ph

(37)

1522	K. J. Ivin
	VII. ACYCLIC DIENE METATHESIS (ADMET)
Dienes can	undergo olefin metathesis reactions of two types: (i) intermolecular and

(ii) intramolecular, as illustrated by the reactions of hexa-1,5-diene and octa-1,7-diene, equations 27 and 28, respectively.

2CH2	D	D	CH2	!	[CH2	D	CH CH2	D	C	C2H4	(27)
		CH CH2 2CH						2CH ]2
					C2 H4 +						(28)

The linear product of reaction 27 can undergo further metathesis condensation reactions, eventually leading to high polymer. This is known as ADMET (acyclic diene metathesis) polymerization, to be discussed in Section VIIB. Ring-closing metathesis reactions (RCM), such as reaction 28, occur with great readiness whenever the product is a 6-membered ring. They are also often favoured for the production of 5-, 7- and 8-membered rings, depending on the nature, number and location of any substituents. The formation of much larger rings can also be achieved by imposing conformational restraints on the bonds lying between the two CDC bonds; examples are given later. Whether polymer or cyclic compound is formed from any given diene is usually determined by thermodynamic rather than kinetic factors. When the standard free energy of polymerization of the cyclic compound is close to zero, a high concentration of substrate will favour polymer formation, while low concentration will favour the formation of the cyclic compound. For a discussion of the thermodynamics of polymerization of cyclic compounds, see Ivin223.

A. Ring-Closing Metathesis (RCM)

This reaction has become a powerful tool for the synthesis of numerous cyclic compounds including many which are biologically active; see the recent reviews by Schmalz224 and Grubbs225. Here we shall give examples of various classes of compound which undergo this reaction or can be made in this way.

1. Hydrocarbons

The RCM of (C)-ˇ-citronellene (38, 2,6-dimethylocta-2,7-diene) in toluene (0.75 M), induced by 8, proceeds quantitatively at 20 °C to yield isomerically pure (S)-3- methylcyclopentene (39); see equation 29226. The same result can be achieved with trans-WOCl2(OC6H3-Br2-2,6)2/Et4Pb as catalyst78. This is a remarkable improvement on the previous, very difficult synthesis of this compound. In concentrated solution in toluene (5 M), 39 undergoes ROMP when initiated by 8 at 30 °C226. (S)-4- methylcyclohexene can be made in a similar way, as can 3,3-dimethylcyclohexene and

2-methylcyclohexene78.

Me

Me

Me

(38)

0.1 mol% 8

p-xylene 25 °C

(29)

Me

(39)

24. Advances in the metathesis of olefins

1523

RCM is also possible between pairs of double bonds contained in the side chains of polymers, for example atactic 1,2-polybutadiene (40); see equation 30. The reaction proceeds to 90% conversion in 30 min and then much more slowly to 97% conversion in 200 min. The first stage corresponds to the random reaction of adjacent double bonds in the chain, leaving 13.5% of isolated vinyl groups. These react more slowly by secondary metathesis with the double bonds in the neighbouring cyclopentene rings, thereby causing the vinyl group in effect to move along the chain until it meets another isolated vinyl group with which it can undergo RCM. The product (41) contains two types of repeat unit, trans and cis, according to whether the reacting dyad was r or m, giving rise to distinct olefinic 1H NMR signals227a.

r

m

(40)

(30)

CH2 Cl2 , 35 °C 1 9

trans		cis
•	CH2 •	•	CH2
	(41)

2. Ethers and sulphides

Some side-chain and ring ethers that have been prepared by RCM are shown below. Latterly the carbene catalysts, particularly 19 and 8, have been used to obtain these compounds in high yields (mostly 70 95%). Re2O7-based catalysts or trans- WOCl2(OAr)2/Et4Pb are also quite effective.

	R
R		R		R
R = PhCH2 O [1] R = t-BuMe2 SiO [2-4]		R = PhCH2 O [1]	R = PhCH2 O [2]
R = i-Pr3 SiOCH2 [4]
R
	O	O
		R1		R2
R	R	R2	R1	O
R = PhCH2 O [5]	R = H [6,11]	R1 = Me		R1 = PhCH2
	R = C7H15 [4]	R2 = Ph [7]		R2 = Ph[1]
	R = Ph [3,7]

	1524		K. J. Ivin
			R	Ph	R
			O	O
	R	O		R	O
		R = Pr [1]	R = H [3,8]	R = Me [7]	R = Ph [9]
		R = PhCH2 [1]	R = Me [8]	R = PhCH2 [1]
			R = Ph [3,7,8]
			O	O
		R		R
		O	O	O
		R = Ph [7]	R = Ph [7]	[10]
			R = PhCH2 [3]	O

O [10]

Refs. [1]2 2 8 , [2]13 , [3]2 2 7b, [4]78 , [5]2 2 7c, [6]2 2 7d, [7]2 51, [8]2 2 7e, [9]2 2 7f, [10]2 3 8 , [11]2 6 2

If the precursor dienes have vinyl end-groups, ethene is eliminated in the metathesis reaction, but it is sometimes advantageous to use a precursor with one or two propenyl end-groups, eliminating propene or but-2-ene in the metathesis reaction. An example is shown in equation 31, the final stage in the synthesis of the protected precursor (42) of Sophora compound I, the antifungal phytoalexine isolated from the aerial part of Sophora tomentosa L228.

RO

OR

O	O
O	Me

12 mol% 8

(31)

C6 H6 , 60 °C, 2 h

Me − MeCH	CHMe	RO
O		O

OR

O

(42) R = CH2 Ph, yield 85%

24. Advances in the metathesis of olefins

1525

Substituted unsaturated pyrans prepared by RCM using 19 as catalyst can be immediately submitted to zirconium-catalysed kinetic resolution of the racemic product at 70 °C. This provides a new route to medicinally important agents containing 6-membered cyclic ethers. A one-pot synthesis can give 63% conversion with >99% enantiomeric purity229.

The complex 12 catalyses the RCM of diand tri-substituted ω-unsaturated protected glucose and glucosamine derivatives yielding bicyclic carbohydrate-based compounds containing 12and 14-atom rings230.

Diallyl sulphide also undergoes RCM in the presence of 12 at 50 80 °C to give 2,5- dihydrothiophene (43) in up to 88% yield (equation 32). The reaction can be conducted without the use of a solvent189.

			12		(32)
	S	80	°C, 3 h	S

−C2 H4

(43)

3. Alcohols, aldehydes, acids, esters and ketones

The ruthenium carbene catalyst 19 is capable of effecting RCM of dienes bearing alcohol, aldehyde or carboxylic acid functions, with remarkably high yields (equation 33).

X		X X		Yield
	2 mol% 19		CH2 OH	88% (33)
	20 °C, 1 h		CHO	82%
			COOH	87%

The cyclopentene ester derivatives 44 and 45 are both readily obtained by the RCM of diallyl precursors using W-based catalysts78,231. Likewise, the 16-membered unsaturated lactone 46 can be made according to equation 34232. Tsuji233 gives a similar example.

COOEt

COOEt

H

COOEt

(44)

(45)

CH2

CH(CH2 )8 C

O

WCl6 /Me4 Sn

CH2

+

CH(CH2 )8 C

O

(34)

CH2

CH(CH2 )4 O

80 °C

CH2

CH(CH2 )4 O

(46)

The ketones 47 49 can be made in good yield (55 95%) by RCM of the appropriate diallyl compounds using 8 as catalyst234. If the spacing between the two CDC bonds in the reactant is increased to ten bonds, then ADMET polymerization is the preferred reaction at normal concentrations. However, by working at 10 3 M it is possible to favour the RCM of oleon (50), equation 35, to give civetone (51) (musk odour) with a yield of up to 14%235. This method of preparation of 51 has the advantage that the metathesis reaction

1526	K. J. Ivin
	Me	Me
	Me
	COPh
	O	O
	Me
	Me
	Me	Me
(47)	(48)	(49)

can be carried out at room temperature and the catalyst is re-usable after regeneration.

	Me(CH2 )7CH	CH(CH2 )6 CH2		Me(CH2 )7CH
		O	Re2 O7/A l2 O3 -SiO2 /
			Bu4 Sn, hexane 20 °C
				Me(CH2 )7CH
	Me(CH2 )7CH CH(CH2 )6 CH2
	(50)			(35)
				CH(CH2 )6 CH2
		+				O
				CH(CH2 )6 CH2
				(51)
	The synthesis	of some hydroazulenes such as 51a by		reaction 35a, catalysed by

CH3ReO3/SiO2 Al2O3236, or better still by 19237, has been reported. Such ring systems occur in many natural products of pharmacological interest.

O O

CH3 ReO3 /SiO2 - A l2 O3

(35a)

or 19

(51a)

4. Rings containing N

Many 5-, 6-, 7- and 8-membered ring compounds containing nitrogen in the ring have been prepared by RCM using the same catalysts as for the ethers; see Section VII.A.2. Some examples are given below.

				O	O
N	Ph	N		N	N
				OBut	CF3
		R	Ph
				R	R
[1]		R = H, Me [2]		R = H, CH2 OH [3,4]	[2,3,5]