Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0705 780

14. Some synthetic uses of double-bonded functional groups

715

Hydroboration-oxidation of enecarbamates with borane-dimethylsulfide complex gives reasonable yields of ˇ-hydroxycarbamates (equation 28) with some diastereoselectivity, depending upon what other functional groups are present in the starting material152.

HO

(28)

N	R	N	R
CO2 Me		CO2 Me

Asymmetric hydroboration of enamines with chiral diboranes, followed by oxidation with hydrogen peroxide, in aqueous sodium hydroxide, gives ˇ-amino alcohols in good yields and high ee (equation 29)153. The products of this reaction are useful in medicinal applications and as synthons for further synthetic elaboration.

BH

H	NR22				HO	NR22	(29)
	2			H2 O2	H	H
		THF		NaOH
R1					R1
	H					H

A range of aromatic alkenes and acrylic acid derivatives have been converted into benzyl alcohols and ˛-hydroxyalkanoic acids in good yields by a ‘reductive oxidation’ process. This reaction is accomplished by reaction with oxygen and triethylsilane with a cobalt(II) catalyst, followed by treatment with trialkyl phosphites (equation 30)154. The aromatic olefins may also be converted into the corresponding acetophenone in a modified procedure where the trialkyl phosphite is removed155. In a similar reaction 2,4-alkadienoic acids are converted into 4-oxo-2-alkenoic acids156.

				OH
R2	O2 , cat		MeO3 P	R2	(30)
R1	Et3 SiH			R1

E. Oxidative Cleavage

This is a useful route for the preparation of aldehydes and ketones from alkenes, and is covered in this section. Photosensitized oxidative cleavage of alkenes occurs in reasonable yield using p-dimethoxybenzene in the presence of oxygen (equation 31)157. The products are aldehydes or ketones depending upon substrate structure.

R1	H	R1
		O	(31)
R2	H	R2

716	Jeff Hoyle

Trans-substituted diarylalkenes undergo oxidative cleavage upon treatment by potassium permanganate in the presence of moist alumina as a solid support (equation 32)158. Under the same conditions, cyclic alkenes, with medium-sized rings, give acyclic dialdehydes (equation 33).

	Ar
Ar				ArCHO	(32)
					O
(CH2 )				(CH2 )n	(33)
	n				O

F. Other Oxidations

1. Formation of ketones and related functionalities

Phenyl vinyl sulfides undergo one-electron transfer reactions with oxygen to give reasonable yields of ˛-ketosulfides (equation 34)159.

PhS	PhS	R2
CHR2		(34)
R1	R1	O

Terminal alkenes can be selectively oxidized to aldehydes by reaction with oxygen, using a palladium-copper catalyst in tertiary butanol (equation 35)160. This reaction is contrary to the normal oxidation process which yields a ketone as the major product. The palladium(II) oxidation of terminal alkenes to give methyl ketones is known as the Wacker process. It is a very well established reaction in both laboratory and industrial synthesis161,162. The Wacker oxidation of alkenes has been used in the key step in the synthesis of the male sex pheromone of Hylotrupes bajulus (equation 36)163.

R		H	R
	O2		(35)
	Pd/Cu

O

O

	PdCl2
OP	CuCl, DMF

(36)

OP

The reaction can also be carried out under electrochemical conditions164,165. The reaction is somewhat unpredictable since in some cases the aldehyde is produced together

14. Some synthetic uses of double-bonded functional groups

717

with the ketone. However, in some cases the two products may easily be separated by recrystalization. Thus, this reaction has been used for the preparation of estratriene derivatives in up to 89% yield (equation 37)166. The stereochemistry of the lactonic bridge in this molecule is crucial to the synthetic outcome.

	O			O
		O	O
				O
	H
			H
		H
	R		Pd(OA c)2	H
			R
	H	H
			H	H

R

R

(37) Terminal olefins may be oxidatively cleaved by hydrogen peroxide, catalyzed by a palladium(0) complex, to give methyl ketones in almost quantitative yields (equation 38)167. This methodology is an alternative to the well established Wacker protocol using palla-

dium(II) complexes.

R	R
	O	(38)
Alkenylsilanes have been used	as precursors of carbonyl compounds as	depicted

in equation 39. Traditionally, the carbonyl group may be produced by epoxidation followed by an acid-catalyzed rearrangement. More recently this process has been achieved by oxygenation in the presence of N-benzyl-1,4-dihydronicotinamide, catalyzed by tetraacetylriboflavin168. The reaction has also been performed using cobalt(II) catalyzed oxygenation169. All these reactions suffer from regioselectivity problems, where the resulting ketone is unsymmetrical and specific ˛-functionalization is sought as the target molecule. This problem has been elegantly solved in a process that involves electroinitiated oxygenation of alkenylsilanes, in the presence of thiophenol (equation 40)170,171. A similar result is also obtained if the alkenylsilane is replaced by an alkenyl sulfide172.

SiR33

O

(39)

R1 R2

R1 R2

O

SiR33

R1

R2

(40)

R1	R2
	SPh

The synthesis of 4-oxo-2,5-hexadienoates (which is a functionality which has received some attention due to its presence in some anti-tumor compounds173,174) may be accomplished in high yield from isoxazolines. This reaction is performed by reaction with

718	Jeff Hoyle

molybdenum hexacarbonyl in acetonitrile water, which affords an intermediate ˇ-hydroxy ketone which is readily dehydrated by standard methodology (equation 41)175.

	CO2 Me
			R	CO2 Me
		1. Mo(CO)6		(41)
	O	2. MeSO2 Cl/TEA
	N			O

R

Peracid oxidation of alkenes, catalyzed by osmium trichloride, produces ˛-ketols which are extremely versatile synthetic intermediates. The reaction occurs for a range of monoand disubstituted alkenes (equation 42)176.

R1	R2	OH	R3
		R1	(42)
R3	H	R2	O

˛-Ketols may be formed from trisubstituted alkenes by treatment with peracetic acid, catalyzed by ruthenium trichloride in a mixed solvent system (equation 43)177. These products are very useful synthons and this functionality is the target in cortisone and adriamycin derivatives. Similar transformations have also been performed using potassium permanganate-copper sulfate178 and with isobutylaldehyde, oxygen and osmium tetraoxide, with nickel catalysts179.

R1	R3		CH3 CO3 H	R1	R3
		RuCl3		HO	(43)
		CH3 CN H2 O CH2 Cl2
R2				R2	O

˛-Diketones or ˛-hydroxyketones may also be formed from alkenes by oxidation using potassium permanganate on an inert support, which has been coated with tert-butanol180. ˛-Hydroxyketones are also formed in the osmium tetraoxide catalyzed AD of alkenes181.

2. Formation of acids and their derivatives

Aldehydes may be readily oxidized giving carboxylic acids in very good yield. This reaction has recently been performed using sodium perchlorate in aqueous acetonitrile (equation 44)182. Aldehydes may also be converted into methoxymethyl (MOM) esters, an interesting synthetic sequence that involves the initial formation of an organostanane followed by oxidation with ozone at 78 °C (equation 45)183. The ˛-alkoxyesters produced in this later reaction seem to be potentially very useful synthons for further synthetic elaboration.

	NaClO4
RCHO	!	RCOOH	(44)
	MeCN aq
	1. Bu3SnLi		(45)
RCHO ! RCOOCH2OCH3

2.MOMCl/i-Pr2NEt

3.O3/CH2Cl2

14. Some synthetic uses of double-bonded functional groups

719

Selective oxidation of thioamides into amides can be brought about by several reagents including mCPBA184,185, ozone186, phase-transfer oxidation methods187 and dimethyldioxirane188. These reactions give varying success, depending upon the substrate being oxidized.

3. Others

Oxidation of allylic alcohols with singlet oxygen has been used as a route to prepare allylic peroxides in a stereoselective fashion (equation 46)189.

OH			OH
1		HOO	(46)
	O2

Stereoselective bromination of dehydroamino acids is a useful reaction of further functionalizing such a compound. The reagent of choice is NBS and good yields are obtained under stereocontrolled conditions (equation 47)190. This reaction has been used as a key step in the synthesis of azinomycin A and B, which are valuable antitumor agents191.

MeO2 CNH

CO2 Me

MeO2 CNH

CO2 Me

1. NBS

(47)

	2. base
R	R	Br

˛-Methoxylation of an ˛,ˇ-unsaturated carbonyl compound is potentially a very useful method in the synthesis of natural products. This reaction can be readily brought about by formation of a hydrazone followed by treatment with bromine and then NaHCO3, and then aqueous acid and finally DBU (equation 48)192. Using a different hydrazone reagent, or by the initial formation of semicarbazones, ˇ-substitution is also possible193,194. Formation of an ˛-iodoenone is also easily attained by treatment of ˛,ˇ-unsaturated ketones with pyridinium dichromate (PDC) and iodine (equation 49)195.

Me

	N	OMe
	1.
		N NH2
	S	(48)
	2. Br2
O	3. MeOH/NaHCO3	O
	4. H3 O+
	5. DBU
		I
	I2	(49)
	PDC

O O

720	Jeff Hoyle

Finally, Thiele acetoxylation of quinones, by treatment with acetic anhydride and sulfuric acid, is another excellent method of introducing functionality at an alkene carbon atom, for further synthetic elaboration (equation 50)196. This reaction was recently used as a key synthetic step in the total synthesis of metachromin-A, a useful sesquiterpene quinone moiety197.

	O				OAc
					OAc
		A c2	O		(50)
		H2 SO4
MeO	R			MeO	R
	O				OAc

III. REDUCTION

The reduction of double bond-containing functionalities, especially alkenes and carbonyl compounds, is an important methodology used in synthetic elaboration. In this section the stereocontrolled reduction of aldehydes, ketones and CDN-containing compounds and the catalytic hydrogenation of alkenes are covered, among other reductions. The emphasis here is placed on stereocontrolled reactions.

A. Reduction of Ketones and Aldehydes to Alcohols

The production of alcohols by the reduction of aldehydes and ketones is probably one of the most useful and fundamental steps in the synthetic chemist’s arsenal. Although there are many well developed methods for the reduction of ketones and aldehydes to alcohols, there is still much interest in developing new or improved methodologies which are milder and can be brought about under special conditions, especially in the presence of other reducible functional groups. Of particular interest to the modern synthetic organic chemist are the aldehyde and ketone reductions which are accomplished in an enantioselective fashion. Advances in this field up to 1992 have been the subject of a review by Singh198. The present section covers very recent work in this area.

1. Using hydride transfer and related reagents

This section covers the reduction of aldehydes and ketones, in complex molecules using hydride transfer reagents. Many of these are complex reagents designed specifically for particular reactions. LAH has been used for the reduction of cyclopropyl ketones199. Trialkyltin moieties in the cyclopropane ring cause diastereoselective reduction to occur (equation 51).

Bu3 Sn	H		Bu3 Sn	H	+	Bu3 Sn	H
Bu3 Sn	R		Bu3 Sn		R	Bu3 Sn	R (51)
	O			HO			HO
					17:1

Enantiomerically pure ˛-hydroxy esters may be prepared by the stereoselective reduction of the corresponding ˛-keto esters, by LiAlH(OCEt3)3 in THF in the presence of chiral

14. Some synthetic uses of double-bonded functional groups

721

borneol auxiliaries200. The auxiliaries may be easily removed under mild, saponification conditions, giving the free acid as the final product.

The synthesis of 3-hydroxy-2-methyl esters and amides in a stereoselective manner is a challenge which needs to be met due to the prevalence of these moieties in natural products201. This has been accomplished by using sodium borohydride, catalyzed by manganese(II) chloride or by tetrabutylammonium borohydride (equation 52)202,203.

O	O		OH	O		OH	O
		NaBH4			+
		cat					(52)
R	OMe		R	OMe	R		OMe

The synthesis of ˛0-amino allylic alcohols is particularly difficult, yet this functionality is important in natural products (such as sphingosine) or as a synthon for further elaboration to amino sugars. In synthetic studies of this moiety204, the corresponding enones, with adjacent stereocenters, have been efficiently reduced to the allylic alcohol in quantitative yields and in both a regiocontrolled (1,2) and a stereocontrolled fashion (equation 53). The syn:anti ratio of the product depends upon the hydride reductant and solvent being utilized. A 4:1 ratio was obtained with L-selectride and a 1:6 ratio obtained by the use of DIBAL in toluene.

		HO		R
O	R	N	Boc	syn
		O
		H−		(53)
N	Boc	HO		R
O
		N	Boc	anti
		O

Potassium tetracarbonylhydridoferrate is a hydride transfer agent that may be used

to reduce ketones selectively in high ketone is produced.

R1

O

R2

yields (equation 54)205. With diketones a hydroxy

R1

KHFe(CO)4	OH	(54)

MeOH

R2

Allylic alcohols have also been obtained in excellent (90%) yields by reduction of enones with diisopropoxytitanium(III) tetrahydroborate (equation 55)206. The reaction

722	Jeff Hoyle

occurs in only a few minutes, in dichloromethane at 20 °C.

O		HO
R2	(i-PrO)2 TiBH4	R2	(55)
	CH2 Cl2
R1		R1

˛-Ketoesters and ˛-methoxycarbonylimino esters may be efficiently reduced, with good enantioselectivity, by the use of C-4 methylated NADH model compounds in the presence of magnesium perchlorate (equation 56)207. This reaction may also be brought about, in good yield and with up to 87% ee, by catalytic hydrogenation with Pt/Al2O3 and a chiral catalyst208.

	R	1. NA DH model /Mg(ClO4 )2	R
	O		O	(56)
		2. H2 O
	X		H XH

X = NCO2 Me or O

The reduction of aldehydes and ketones to alcohols by tri-n-butyltin hydride gives a yield of up to 95% when carried out in the presence of silica gel209 or Lewis acids210.

Modified tin hydrides have also been employed for this reduction211 213. For example, ˛,ˇ-epoxyketones may be reduced, in excellent yields, in a selective manner to give the anti epoxy alcohol as the major product, by reaction with Bu2SnFH214 and similar tin hydrides215 (equation 57). A similar anti -selectivity is obtained upon reduction of ˛-alkoxy ketones216.

	O			O	O
		Bu2 SnFH		+
R1			R1		R1	(57)
	R2			R2	R2
O			OH		OH
			anti		syn

Tin hydrides that are internally activated have also proved extremely useful for the mild reduction of a wide range of ketones containing alkoxy, halogen and alkyne groups (equation 58)217. Careful choice of solvent is needed in order to eliminate halogen reduction.

		NMe2
R	Br	R	Br
		SnMe2 H	(58)
	O		OH

Rhodium(I) catalyzed asymmetric hydrosilation of ketones is an excellent route to chiral alcohols in reasonable chemical yields. The reaction occurs by treatment of alkyl

14. Some synthetic uses of double-bonded functional groups

723

aryl ketones with diphenylsilane at 0 °C (equation 59)218. Similar reactions have been performed using lithium hydride/trimethylsilyl chloride as the hydrosilation reagent219 and using a chiral titanium complex as the catalyst220. Reaction of 2,2,4,4-tetramethyl-1,3- cyclobutanedione with hydrosilanes, catalyzed by rhodium(I) complexes, results in either one or two carbonyl groups being reduced, to the alcohol, depending upon the silane employed221. This reaction can be controlled to give either the cis-diol or the trans-diol exclusively. The three products resulting from this reaction are shown in equation 60. Other metals and their complexes also catalyze the reduction of diketones222 224.

Ar

1. Ph2 SiH2 , Rh(I) cat

O

2. HCl/MeOH

R

Ar

* OH

(59)

R

O	OH	OH	OH
	+	+	(60)
O	O	OH	OH

2. Using boron-containing reagents

Enantioselective reduction of ketones can be accomplished by the use of BH3 and catalytic quantities of chiral oxazaborolidines, in THF at low temperature225 236. The enantiomer produced depends upon the choice of reducing agent (see, for example, equation 61), and in most cases the alcohol is produced in high enantiomeric excess. This reaction has been used as the key step of enantioselective synthesis of a dopamine D1 agonist237, which has found use in the treatment of Parkinson’s Disease. The reaction is successful in the presence of halogens and sulfur and nitrogen atoms238 242, thus making this particular reduction procedure very useful in the elaboration of more complex molecules. Imines243,244, imides245 and oximes246 may also be reduced by this mild methodology. Borane reduction of ketones may also be catalyzed by ˇ- hydroxysulfoximines giving enantioselectivity of up to 93%247.

H	OH			O			H	OH
RL	RS	Ph	Ph	RL RS	Ph	Ph	RL	RS
		H			H
								(61)
			O		N	O
		N
		B			B
		R			R

Cyclic ketones may be reduced by thexylchloroborane-dimethyl sulfide (ThxBHCl.SMe2) and the related bromo and iodo compounds, in a stereoselective manner (equation 62)248. The selectivity increases with increasing halogen size. These reagents give much better selectivity than many of the more traditional ones, such as ThxBH2.

724	Jeff Hoyle
O	OH

1. RBHX.SMe2

(62)

2. NaOH/H2 O2

The enantioselective reduction of ketones using oxazaborolidine-borane complexes is a useful synthetic route to chiral alcohols (equation 63). Additives such as simple alcohols have been found to enhance the enantioselectivity of the process, and the reaction has been used in the large-scale synthesis of an important drug with anti arrhythmic properties249.

	1. i-PrOH
O	2. H3 B−SMe2	*	OH

3.Ph

Ph

(63)

N O

B

BH3

CH3

4. MeOH

Directed asymmetric reduction of a ketone has been brought about by the use of an intramolecular homochiral boronate ester250. The latter was readily introduced at a hydroxyl group in the molecule and has allowed the production of the enantiomeric alcohol, from the ketone by use of BH3-complex as the reductant (equation 64). The boronate ester may be readily removed by treatment with hydrogen peroxide sodium hydroxide, using standard methodology. Other similar reductions have also been reported251 253.

	O	O
R	OH	R	B O
			O
			(64)
	OH		OH
R	B O	R	OH
	O

Finally, it is noteworthy that Lewis base adducts of gallane (LGaH3) reduce cyclic ketones, enones and ˛-haloketones to the corresponding alcohols in excellent yields254. These reagents show some promise as a new extension of the boron-type reductions of carbonyl compounds.