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

745

using Mg metal and a trace amount of mercuric chloride524 and by electroreduction525.

CO2 Me

CO2 Me

R1

	CHO		SmI2
			R1COR2
PO		OP

OP

HO	R	2 OH
		(139)
	OP
PO
	OP

G. Wittig-type Reactions

The Wittig-type reaction is a key synthetic process by which alkene functionalities are introduced, using CO compounds as the key synthons. Thus, during the synthesis of carbohydrates, the Wittig reaction has been used as the key step for the introduction of a masked pyruvate moiety into a highly oxygenated substrate (equation 140)526. The alkene formed has E-geometry in this case. In other Wittig olefinations a mixture of E and Z isomers are often produced and this may be overcome, giving almost entirely E isomers, by photolytic irradiation527,528.

CHO

O

	OBn	O
	O		S
	+		(140)
	O	N
	N	OBn
	O

S

PPh3

O

Wittig-type reactions may also be performed intramolecularly to give cyclic alkenones in good to excellent yields. Thus bis-ˇ-ketophosphonates have been cyclized under Horner Wittig conditions to give 5-, 6- and 7-membered rings which contain a 3-phosphorylmethylene group that can be used for further synthetic elaborations (equation 141)529.

	O	O			O
(RO)2 P		P(OR)2				(141)
	n				O
O	O			n	P(OR)2
n = 1,2,3

746	Jeff Hoyle

Under very mild conditions, the Wittig-type reaction of dimesitylboron stabilized carbanions with arylketones and aldehydes yields alkenes in good yields (equation 142)530. The stereochemistry of the alkene produced may be controlled, depending upon conditions.

MeS	R	R2
	C− +					(142)
B		O	RCH		CR1R2
MeS	H	R1

Using an aldehyde as the key synthon, a reaction, which is termed an anti-Wittig reaction531, has been performed. In this process a benzyl phosphine oxide is treated with butyllithium followed by an aldehyde, to give exclusively an E-alkene in high yield (equation 143)532.

			1. BuLi	R2
	R1	POPh2		(143)
			2
			2. R CHO	R1

H. Others

Recently, there have been several reactions which do not fit into the sections above, but which are important means by which C C bonds are formed using double-bonded functional groups as the key synthons. Some of these reactions are outlined below.

Reaction of vinylboranes with secondary amines produces very good yields of allylamines (a useful functionality with antifungal properties), when the starting materials are heated in dioxane, at 90 °C, together with paraformaldehyde (equation 144)533. An intramolecular variant of this process uses a vinylsilane as the precursor534.

R1	HO	R3			R3
NH +	B		(CH2 O)n		(144)
			dioxane
R2	HO				N
				R1
					R2

Radical cyclization of 6,6-dihaloalkenes promoted by LAH in THF is a useful route to halocyclopentanes (equation 145)535,536. A small quantity of the dehalogenated alkene is also produced.

X

LiA lH4

X

(145)

THF

X

The formation of bicyclo compounds by the radical cyclization of alkenes with strategically placed phenylseleno groups, promoted by Bu3SnH, occurs in high yields and gives

14. Some synthetic uses of double-bonded functional groups

747

stereocontrolled products (equation 146)537. The reaction requires photochemical initiation and the starting materials are readily prepared by aldol condensation in the presence of PhSeH.

		O	OH
O	OH		R
	R
	Bu3 SnH	(CH2 )n	(146)
(CH2 )n	hν
	SePh		H

Hydrosilation of 1,5- and 1,6-dienes, catalyzed by a chiral neodymium complex, leads to intramolecular bond formation and results in the formation of silylated methylcyclopentanes (equation 147)538. This reaction is in stark contrast to the reaction catalyzed by group VIII complexes, which gives a range of silanes but no carbocyclic compounds539,540.

PhH2 Si

(147)

PhSiH3

Nd cat.

Finally, ring expansions of cyclic ketones are an important method for the preparation of carbocyclic systems. Diazoalkanes allow this reaction to occur and involve C C bond formation. When combined with carefully chosen organoaluminum compounds, this process can be performed in a highly stereoselective fashion (equation 148)541.

O O

CH3

CH3 CHN2

(148)

A l

R R

V. PREPARATION OF HETEROCYCLES

One of the major uses of double-bonded functional groups in organic synthesis is the preparation of heterocyclic compounds. These compounds are either target molecules of a particular synthetic sequence, or are key intermediates in organic synthesis. This section covers the synthesis of heterocyclic compounds by carbon heteroatom bond formation or by C C bond formation. Epoxidation of alkenes is not covered here, but in Section II.A. Subdivision, for ease of reading, is by ring size, for the most part.

748	Jeff Hoyle

A. Heterocycles with a Single Heteroatom

In this section, the syntheses of lactams and other nitrogen-containing heterocycles, from double-bonded functional groups, are discussed. This is an extremely important area of synthesis, especially given the present interest in developing new antibiotics to combat bacteria which are resistant to traditional treatments. In addition, a wide variety of heterocycles containing a single oxygen atom may be prepared from double-bonded functional groups, the most important of which are probably lactones. Lactones exhibit many useful properties, especially in the field of pharmaceutical synthesis. They are a very prevalent structural feature in natural products and are key intermediates in many synthetic sequences. There has been much interest and effort exerted in the development of strategies for the synthesis of these and other oxygen-containing heterocycles from doublebonded functional groups. There have been many reviews concerning the synthetic utility of lactones, for example of halolactones542 and of the synthesis of target lactones, such as macrolide antibiotics543, and the reader is referred to these sources for further details.

1. Threeand four-membered rings

This section covers the synthesis of aziridines, oxiranes, ˇ-lactams and oxetanes. Aziridines are fairly important moieties in bioactive molecules and thus new routes for their synthesis are constantly being developed. ˇ-Lactams are probably the most important heterocyclic compounds that contain a single nitrogen atom, due to their importance in penicillin and cephalosporin chemistry. Their synthesis and chemistry has received much attention and much of this work has been reviewed544. The oxygen-containing heterocycles are much less commonly synthesized from double-bonded functional groups.

6H-1,2-Oxazines (which can be readily formed from nitrosoalkenes and methoxyallene derivatives545) may be converted into aziridines by reduction with LAH. The reaction occurs in moderate yield, giving a preponderance of the cis product (equation 149)546.

R1

Ph

LiA lH4

N

R2 O O

R1

Ph

(149)

HO

N

H

Electron-deficient alkenes react with hydroxamic acids to give 2-functionalized N- arylaziridines in good yields (equation 150)547.

	R2
ArNHOCOR 1. NaH	H	EWG
R2
2.	N	(150)
H	EWG
	Ar

EWG = electron withdrawing groups

N-( -Haloalkyl) imines undergo cyclization to aziridines upon treatment with sodium borohydride in methanol548. Dibromoketimines can be readily cyclized to give (2-bromomethyl)aziridines in good yields under similar conditions (equation 151)549.

14. Some synthetic uses of double-bonded functional groups				749
N	Br		Br	(151)
	NaBH4	N

Br

N-Phthalimidoaziridines may be obtained by reaction of alkenes with N-aminophthali- mide which has been treated with lead tetraacetate (equation 152)550 554. These compounds are useful in the synthesis of ˛-hydrazino acid derivatives which are inhibitors of amino acid metabolising enzymes.

O		O		R1
	1. Pb(OA c)4			(152)
N	NH2	N	N
	2.	R2		R2
O	R1	O

The synthesis of chiral ˛-amino phosphonic acids (analogues of natural amino acids) may be accomplished from imines. The key step in this synthesis is the formation of an aziridine by reaction of a phosphonamide with an imine (equation 153)555. The reaction occurs in very good yield in THF, at 78 °C with BuLi.

Me				Me
N	O			N O
		1. BuLi
				P	H Ar
P						(153)
		2.		R
				N
N			N		H
	Cl			Me	N
Me		A r
					R

There are many routes available for the synthesis of aziridine 2-carboxylic acids, however there are few reactions which yield enantiomerically pure products. These compounds (especially those with cis-stereochemistry) are especially useful for the synthesis of bioactive molecules556. There is thus significant effort in this area of synthesis557,558, but most methods are lengthy multistep procedures. Recently, a simple, one-pot procedure, utilizing imines, has been developed for the asymmetric synthesis of cis-N-substituted aziridine-2-carboxylic acids via a Darzens-type reaction (equation 154)559.

		MeO	OLi	CO2 Me
p-TolSO
	H		R
		+		H
N					(154)
	R	Br	H	N
				SOTol-p

Treatment of aldehydes with diazomethane, in the presence of organoaluminum reagents, in dichloromethane at 78 °C, gives very good yields of oxiranes

750	Jeff Hoyle

(equation 155)560. The reaction also occurs with rhodium acetate and dimethyl sulfide as catalyst561. A wide range of oxiranes may be readily prepared using this type of methodology.

RCHO + CH2 N2		O	R	(155)

Due to the increasing resistance of bacteria to ˇ-lactams, new syntheses and novel structural variants are continuously being sought562,563. Some recent examples are described below.

ˇ-Lactams may be synthesized from N-protected ˇ-tosylethyl (TSE) imines by reaction with ˛-bromoesters, in the presence of zinc and HgCl2 (equation 156)564. The TSE group is readily removed by stirring with t-butoxide for a few hours.

Ph	R1
R1 CO2 Me	Ph
	R2

N	R2		Zn		(156)
		Br	HgCl2		N
TSE				O	TSE

The Staudinger reaction565, the cyclization of an imine with an acyl halide, in the presence of base, is an extremely useful method of ˇ-lactam preparation. In this reaction it is possible to get asymmetric induction by use of chiral auxiliaries in either starting material. However, a chiral auxiliary attached directly to the imine nitrogen is generally more useful since, if it is removed, it allows for a greater range of useful products. With this strategy in mind, diastereomeric cis-lactams have been prepared in good yields (equation 157)566,567. Replacing the imine with an azine gives good yields of N-imino- ˇ-lactams568. Imines also react with esters, upon treatment with t-butoxide, to give good yields of ˇ-lactams (equation 158)569 571.

R1				2		R1					R2
				R
			+	N	Me						(157)
									N
O		Cl				O					Me
					1-naph
											1-naph
R2				EtO2 C		R4	R3
					R4						R2
							(158)
	N	R1		R3					N
						O
											R1

The so-called ‘ene-type’ ˇ-lactams are an important group of compounds which contain a ˛-alkylidene side chain in the lactam moiety, and which are also useful both as antibiotics and as synthetic intermediates. A recent simple synthesis of these compounds has been

14. Some synthetic uses of double-bonded functional groups

751

reported in which imines are reacted with the lithium enolates of 3-(dialkylamino) esters (equation 159)572,573. Dehydroamination is affected by treatment with silica gel in toluene or methyl iodide in methanol followed by DBU in benzene. The resultant ˇ-lactams are produced in good overall yields.

					R4
				R3	N
R1	R3	R4		R1	R5	R1	R5
	+	N	LDA				(159)
			THF	N			N
N
	R5	CO2 Me
R2				2	O	2	O
				R		R

The palladium-catalyzed carbonylation reaction of allyl diethyl phosphate, in the presence of imines, gives either cis- or trans-3-vinyl-ˇ-lactams, in high yields and in a stereoselective fashion (equation 160)574,575. The reaction is a [2 C 2] cycloaddition process which occurs under simple and mild conditions and has significantly more potential than the reaction of imines with ketenes (due to the more forcing conditions that are usually required to form the ketene intermediates). This reaction, however, only proceeds in low yield if the allyl phosphate is replaced with allyl acetate576.

		R1			R1
			i-Pr2 NEt		(160)
			CO, Pd cat.
	N	OPO3 Et2			N
				O
		R2			R2

ˇ-Lactams are also prepared in a highly stereoselective fashion, in good yields, by

treatment of imines with titanium enolates of 2-pyridylthioesters (equation 161)577 580 and similar compounds581,582.

R1	R2			R2	R1
N	+		TiCl4		(161)
			Et3 N		N
	O	SPy		O
Ph					Ph

The Paterno Buchi reaction for the formation of oxetanes by a photochemical [2 C 2] process, from an alkene moiety and a carbonyl-containing compound, is a well-established synthetic route583. Reaction of benzaldehyde with a range of silyl enol ethers, under photolytic conditions, gives rise to oxetanes in reasonable yields and with excellent regioselectivity and some diastereoselectivity, the latter of which parallels the bulkiness of the R group (equation 162)584,585. Other workers have also performed this type of reaction with excellent regio-586 or stereocontrol587 590, or both591,592. One notable reaction of the latter type is an internal [2C 2] reaction which occurs in very high yield and a syn:anti

752				Jeff Hoyle
ratio of 2.1 (equation 163)593.
	O		R				O
					hν
		+					R	(162)
Ph		H	TMSO			Ph	OTMS
Ph		O			Ph		O
	O	N	iPr	hν	Me	O N iPr		(163)
Me	Me	O			Me		O

2. Fiveand six-membered rings

Fiveand six-membered heterocycles, containing either a nitrogen or oxygen atom, and in particular pyrrolidine rings, are very important in natural products synthesis. There are many methods by which all these compounds may be synthesized and new routes to this target are constantly being sought.

-Lactams may be formed by intramolecular reaction of an alkene with an amidyl radical (equation 164)594,595. The radical is formed from the N-(phenylthio) amide by treatment with Bu3SnH. If the molecule has a second, strategically placed alkene moiety, tandem cyclizations occur to give either pyrrolizidinones (equation 165) or 3,4-benzo- indolizidinones (equation 166)596. In all cases, yields were very good to excellent.

	Bu			Bu		Bu
O	N		O	N.	O	N
		SPh	Bu3 SnH			(164)
					X
O	N	X		N		(165)
			O
				O
O					N
						(166)
	N
Ph	X

14. Some synthetic uses of double-bonded functional groups

753

Cyclization of N-allylic ˛-chloro-˛-thioacetamides, catalyzed by Ru complexes, gives rise to five-membered lactams (equation 167). This reaction has been used as a key step in the synthesis of several natural products597. Other similar Ru-catalyzed cyclizations have been used to prepare 2-pyrrolidinones598,599. This methodology is preferable over the equivalent Bu3SnH-mediated radical cyclization600,601 when a halogen atom is required in the target molecule.

Cl

N

SR

O SR

RuCl2 (PPh3 )3

(167)

N Cl

2-Pyrrolidinones with a chiral C-5 atom have been prepared in a very simple, one-pot synthesis, by treatment of N-alkoxycarbamoyl -amino ˛,ˇ-unsaturated carboxylates with Mg in methanol (equation 168)602. The products are formed in 87 95% yield, with high optical purity (96 99% ee). Since this -lactam is very important, as an intermediate and target in the synthesis of natural products, this simple reaction is a very useful addition to the synthetic chemist’s arsenal. Most other preparations of this target usually lead to racemic mixtures603 606.

R3 O2 CHN

					R2
R1	R2	CO2 R4	O	N	(168)
					R1

H

Alkyl and aryl isocyanates (and ketenes) can be used in a [6C 2] cycloaddition process, promoted by chromium(0) species under photolysis, to give useful bicyclo compounds (equation 169)607. In this process the yields are 20 45%, which is a great improvement over other attempts at metal-mediated [6 C 2] cycloaddition reaction608 610.

X	O	N
NCO
		X
hν			(169)
	H	H

Cr(CO)3

X = CH2 or NCO2 Me

An interesting [3 C 2] cycloaddition reaction, of imines with TMS allyl esters catalyzed by Pd complexes, has been developed and produces pyrrolidine rings in good to excellent yields under mild conditions (equation 170)611.

Ts

Ts

N

+ X

TMS

R

	Pd	N
		(170)
	cat
		R

754	Jeff Hoyle

Another synthesis of pyrrolidines, in this case with high enantioselectivity, has seen several enones with a chiral alkoxy or amino substituent in the -position react with azomethine yields (derived from glycine imine derivatives) upon treatment with DBU/AgOAc

(equation 171)612 614. This reaction may also be done using other alkene-containing substrates615,616.

		CO2 Et			O
						R1
R1
			DBU
+	N					(171)
			A gOA c
O
				R2	N	CO2 Et
R2
					H
The catalytic ring-closing	metathesis of functionalized				dienes is an important

means of preparing heterocyclic and carbocyclic compounds. Both ruthenium617 and molybdenum618 620 carbene complexes catalyze this process, giving good to excellent yields of cyclized products. In this way dihydropyrroles, dihydrofurans and larger oxygencontaining heterocycles can be produced (viz equations 172 and 173). A wide range of oxygenated functional groups can be tolerated in the diene.

Boc

	Boc
N	N
Ru			(172)
complex
	Ph
O
Ph	Ru	O	(173)
O	O
	complex

Reductive amination of 2,5- and 2,6-hexanedione moieties, with ammonia and primary amines in the presence of sodium cyanoborohydride, gives 5- and 6-membered rings with some diastereoselectivity (equation 174)621. As the bulk of the nitrogen substituent is increased, so greater amounts of cis-pyrrolidines and trans-piperidines are produced. This methodology has been exploited in the synthesis of azasugars from dicarbonyl sugars622. A similar synthesis may also be performed using other reducing agents623 626.

	n		n
	RNH2	+
			(174)
n	N	N
	R	R

n = 1,2