Chapter 3 Three-membered ring systems

49

Chapter 3 Three-Membered Ring Systems S. Shaun Murphree

Bayer Corp., Charleston, SC, USA Albert Padwa

Emory UniversiO,, Atlanta, GA, USA

3.1

INTRODUCTION

Three-membered ring systems continue to play a pivotal role in heterocyclic chemistry. These compounds are extremely valuable substrates for the synthetic organic chemist, as versatile intermediates or as reagents with unique selectivity. Since a comprehensive review would be beyond the scope of this chapter, the following text is meant to provide a selective overview of the preparation and use of these three-membered heterocycles, drawn from the previous year's literature and with an emphasis on methodology. The organization is similar to that of previous years. 3.2

EPOXIDES

3.2.1 Preparation of Epoxides The asymmetric epoxidation of functionalized alkenes still attracts considerable attention. Synthetic chemists continue to be in search of new and improved routes to epoxides, since they provide versatile intermediates for natural product synthesis. The topic of preparative techniques for chiral epoxides is seldom broached without the mention of the Sharpless epoxidation. Indeed, the impact of this protocol cannot be overestimated, as new applications continue to be reported. For example, linear poly(tartrate ester) ligands have been used this past year to generate a solid-supported Sharpless-type catalyst <97CC 123>. Illustrations of the importance and use of chiral epoxide precursors in all aspects of synthesis abound in last year's literature. One drawback of the Sharpless technique, however, is that the requisite allylic alcohols are sometimes inaccesible or inappropriate for a particular synthetic strategy. Along these lines, Chan, Wang and Li <97TL101> have elaborated an asymmetric epoxidation of nearly symmetrical alkenes via (1,2-dialkyl)vinylsilanols 2, which are available through the regioselective addition of organocopper reagents to ethynylbutoxy-dimethylsilane (1) followed by alkylation with alkyl halides and hydrolysis of the silyl ether group. These substrates then undergo Sharpless epoxidation in fair yields and moderate ee's to give upon protodesilylation chiral cis-epoxides 4. This approach was used for the enantioselective synthesis of (+)-disparlure.

Three-Membered Ring Systems

50

I

R1,~_._/R2

Si-Ot-Bu I

=

= RwR2 0 "Si-O /\ H

H /"%i-0 \

!

2

= RwR2 0

3_

4

The premiere method for producing chiral oxiranes from non-functionalized olefins is the Jacobsen asymmetric epoxidation, which utilizes a chiral manganese salen complex as a catalyst. Since Jacobsen's first report in 1990, intensive study in this area has generated a plethora of reaction conditions and catalyst types, as well as questions regarding the mechanistic parameters. The course of the oxygen transfer itself remains a matter of much debate. Norrby and Ackermark <97AG(E)1723> maintain support for the intermediacy of a metallaoxetane species (6), which under sterically crowded conditions, could undergo homolysis of the Mn-C bond, thus rationalizing the isomerization often observed in the case of Z-alkenes.

RI'~ R2 Ph/ R3

-P

O Mn

~I1..~.,,R2

MnbR~R 2

R,,~2

II

--- MnTL"PtiR3

=

_6

"'R3

= Ph~"Ri

Z

_8

A mechanistic study of the Jacobsen asymmetric epoxidation of indene (9) under biphasic conditions has yielded some interesting results <97JOC2222>. The reaction was carried out in water/chlorobenzene using the chiral manganese salen complex 11 as a catalyst and hypochlorite as a stoichiometric oxidant. Here the reaction was shown to have an order of zero for indene and 1 for the catalyst, indicating a turnover-limiting step of catalyst oxidation. When no auxiliary ligand (i.e., 12) is used, this step occurs at the phase interface and is agitation-dependent. However, in the presence of 12, the catalyst is oxidized in the organic phase, and the overall reaction rate is increased. Thus, it appears that the axial ligand accelerates the epoxidation reaction not only by stabilizing the catalyst but also by serving as a phase-transfer agent to promote more facile catalyst regeneration.

9

1__0

H,,,~H t

o I

?

t-Bu

---~t-Bu CIt-Bu/-1_!1

o

Three-Membered Ring Systems

51

In addition, Katsuki and co-workers <97T9541> have shown that this axial ligand can serve as a source of chiral induction. Thus, when chromene 13 was epoxidized at 0~ in the presence of salen-Mn catalyst 15 and chiral amine ligand 16, a 30% enantiomeric excess was observed even though the catalyst itself lacked asymmetry. The results are rationalized on the basis of a preferred conformation of the catalyst-ligand complex which, in turn, influences the approach of the olefin substrate.

o2N.y o.(__

15

AcNH~

AcNH-

",~

,-'..<.~* 14

H

R3 R4

H 16

R4

15 Whatever the mechanism, this methodology is continually broadening in scope. For example, whereas unsubstituted cyclic dienes undergo epoxidation under Jacobsen conditions with moderate ee's, the attachment of a phenylsulfonyl moiety to the conjugated system increases the enantioselectivity dramatically. Thus, 2-(phenylsulfonyl)- 1,3-cycloheptadiene (17) is converted to the fused epoxide 18 in 80% yield and greater than 99% ee. The action of the sulfone functionality appears to be more electronic than steric, and placement is critical; practically no increase was observed for the corresponding 1-phenylsulfonyl cyclic dienes compared to the unsubstituted analogs <97TL5615>.

[~S02Ph 17

S02Ph 1_8

Outside the Jacobsen paradigm, other interesting examples of epoxidation techniques with general scope have also been reported. Of particular industrial interest, Noyori and co-workers <97BCSJ905> have adapted the sodium tungstate-mediated epoxidation to a system of 30% hydrogen peroxide requiring no solvents. Key to this method is the use of an (o~-aminoalkyl)phosphonic acid and a lipophilic ammonium hydrogensulfate (vs. the corresponding chloride) as a phase-transfer catalyst. The scope appears to be fairly broad, and yields are typically quite high (cf 19 --->20).

Three-Membered Ring Systems

52

Na2WO4.2H20 NH2CH2PO3H2 [CH3(nC8H17)3N]HSO4 D,

o 19

20

In like fashion, Sharpless and co-workers <97JA6189> found that catalytic methyltrioxorhenium (MTO), long recognized as an efficient epoxidation catalyst in nonaqueous systems, could be used effectively in a biphasic system with aqueous hydrogen peroxide and substoichiometric amounts of pyridine. Although the mechanistic basis is unknown, the pyridine is thought to provide a two-fold benefit: a) acceleration of the reaction by ligation with the catalyst, and b) action as an acid scavenger, thus reducing in situ product decomposition. Furthermore, in sufficient concentration, the pyridine actually increases the lifetime of the catalyst. In the special case of terminal alkenes, 3-cyanopyridine was found to provide shorter reaction times and higher yields <97CC1565>. This new process is presented as a superior alternative to the traditional MCPA conditions.

.5>o Some new square-planar cobalt(III) complexes have been prepared by the reaction of Co(C104)2.6H20 with o-phenylenebis(oxamate) derivatives 23 under aerobic conditions. These complexes have been shown to act as catalysts for the high-yield epoxidation of unfunctionalized tri- and di-substituted olefins (e.g., 24 ---) 25) under Mukaiyama conditions. Low yields are obtained with terminal olefins <97TL2377>.

23; X=O or NMe; L= ligand

~~'~OAc

~~~~'OAc

24 Another innovation involves the preparation of chiral ruthenium porphyrins of type 28, readily available from the reaction of pyrrole with enantiopure aldehydes (e.g., 26), as catalysts for the asymmetric epoxidation of unfunctionalized olefins. Using 2,6-dichloropyridine N-oxide as a terminal oxidant, good yields and enantioselectivities were observed <97JCS(P 1)2265>.

Three-Membered Ring Systems

53

R*

R*

CHO =

R*

R*

R

'k

R*

26

R*

R*

27

28

Still other alternative approaches have focused on certain types of olefinic substrates. For example, enones (e.g., 29) can be converted to the corresponding carbonyl epoxides (e.g., 31) with tetra-n-butylammonium peroxydisulfate (30) in the presence of alkaline hydrogen peroxide, where the peroxysulfate is believed to be the reactive species <97TL3009>. This conversion can also be done in asymmetric fashion with the use of immobilized poly-(L)-leucine as an "enzyme surrogate" in the presence of hydrogen peroxide under biphasic conditions, as exemplified by the preparation of epoxide 33 in excellent enantiomeric excess <97CC739>. Very high ee's can also be realized by using a lanthanoid catalyst of type 34 in combination with cumene hydroperoxide <97JA2329>. 0

0 +

~,, o-~~,-ONBu4-n n-Bu4NO-S-O9 9

29

"

0

30

o

31

o

[

@-o'

~ ( ~ L n O i - P r

The diastereoselective epoxidation of allylic alcohols (e.g., 35) has been reported to occur in the presence of zeolites, using t-butyl hydroperoxide as an oxidant, whereby a Sharpless-type transition state is invoked <97T11369>. Cycloalkenols can be converted exclusively to the corresponding cis-epoxides (e.g., 37 ~ 39) using the dianion of monoperoxyphthalic acid (MPPA) at high pH. The stereocontrol has been explained on the basis of secondary hydrogenbond stabilization in the transition state (38). This protocol is also applicable to the homoallylic analogs <97JOC3748>.

54

Three-Membered Ring Systems HO --C5Hll

.OH

HO ~~~'-C5Hll

=

2"

Ar

;

=

oIH,o..O

/

\

37 38 Chloroperoxidase (CPO) has been used to enantioselectively epoxidize m-bromo-2-methyl-1alkenes (i.e., 40), the course of which is highly dependent upon the chain length of the substrate <97JA443>.

~ B r

=

40

O ~ B r 4.1

Shi and co-workers <97JOC2328, 97JA11224> have optimized their chiral dioxirane protocol for the asymmetric epoxidation of non-functionalized trans-olefins (e.g., 44), such that the chiral ketone 42 can be used in catalytic quantities with potassium peroxomonosulfate (Oxone) as the stoichiometric oxidant. The key to preserving the lifetime of the chiral auxiliary is pH control during the reaction; the optimum range was found to be 10.5 or above, which is conveniently maintained with potassium carbonate.

o

o+

0,,,~'0/0

oO+ "

42

C6H13 ~

',, / 0

43

C6H13

,. C6H13

06H13

44

Epoxides can also be formed by a fundamentally different "C + C=O" process, whereby an ylide serves as a carbon donor. In additions of benzylsulfonium ylides to aromatic aldehydes (e.g., 47) a strong trans selectivity is observed, which is rationalized as the result of irreversible

Three-Membered Ring Systems

55

formation of the anti betaine and reversible formation of the s y n betaine <97JCS(P 1)593>. An analogous asymmetric version of this protocol employs chiral sulfimides (49) as methylidene transfer reagents. Utility of this methodology has been bolstered by the recent development of a simple new asymmetric synthesis of the requisite sulfimides <97JOC6512>.

RI~s,R2 /J

O +

Ph' -

R3CHO

46

-

Ph

r

47

NTs 9

PToI~S'Me

+

"R3

48

O

../[L.

R1

49

~,R 2

=

R2

"

50

R1

51

3.2.2 Reactions of Epoxides Perhaps the most frequently encountered reaction of the epoxide ring, whether intentional or inadvertent, is ring cleavage with nucleophiles to give the corresponding alcohol. In this arena, nicely complementing his seminal work in enantioselective epoxidation, Jacobsen has developed spin-off systems for the asymmetric ring-opening (ARO) of m e s o epoxides. For example, the (salen)Cr(III)Cl complex 52 effectively catalyzes the ARO of various five- and six-membered ring-fused m e s o epoxides (e.g., 53) with trimethylsilylazide <97JOC4197>. This methodology has been used as a key reaction for the formal synthesis of the PKC inhibitor balanol <97TL 1693>. Other types of nucleophiles can also be used; for example, epoxide 56 undergoes very efficient and highly enantioselective ring-opening with benzoic acid. In this case, the cobalt(II) catalyst 55 was found to give the best results <97TL773>.

H, " ~ H t-Bu~,~~ O ~ O ~ t-Bu t-Bu

t-Bu

52

52

O 53

N~~'"OTMS 54

Three-Membered Ring Systems

56

t-Bu ~

~~

o'M'o

t-Be

t-Bet-Be55

~_ HO

O

OCOPh

For organometallic nucleophiles, the enantioselectivity must be controlled in a slightly different fashion. For example, treatment of cyclohexene oxide (58) with a combination of an external chiral ligand (i.e., 59) and an organolithium in the presence of boron trifluoride gave the corresponding alcohol 60 in up to 47% ee. In this case, the ligation of 59 to the nucleophile imparts enantioface differentiation <97T 10699>.

Ph MeO [~O

+ PhLi

Ph 59

OMe ,.

.,OH Ph

Vinylepoxides (e.g., 61) undergo TsOH-catalyzed aminolysis regioselectively at the allylic position to give vicinal amino alcohols (e.g., 62) in generally high yields, although the reaction is sensitive to steric bulk about the epoxide nucleus <97TL2027>.

~O

B n O ~ 61

OH

- BnOv~ ~ NH2 62

The regiochemical outcome of certain epoxide ring-openings can also be controlled by remote polar functionalities, as observed in the semirigid branched O-benzyl pyranosidic oxiranes 63 and 66. Upon treatment with various nucleophiles, the trans-epoxide 63 gives a mixture of products resulting from C-3 and C-4 attack (64 and 65, respectively). Under chelation control, however, the proportion of C-4 product is increased, presumably via a chelated bidentate species (68) involving the endocyclic oxygen of the epoxide, which locks in an otherwise unfavorable conformation. Interestingly, the cis-oxirane 66 yields exclusively the corresponding C-4 product (67), regardless of the reaction conditions. This result is rationalized on the basis of steric crowding about the metal in the requisite bidentate structure 69 <97GC79>.

Three-Membered Ring Systems

Me_:~~OBn

M ~ ~ . OBn

57

Me.,. O

OBn

+

_

OH

63

x

64

Me~OBn

O Bn

O

x

M+, O"" '"O M ' Oe ~'~ x~an

M+

BnO"'~ o~V ~.~ x@

It is often desirable to employ some hydride equivalent as a nucleophile to convert epoxides to simple alcohols (i.e., reductive cleavage). Toward this end, racemic epoxides 70 can be regioselectively reduced to an enantiomerically enriched mixture of stereoisomeric alcohols 71 by treatment with zirconium tetrachloride-sodium borohydride in the presence of L-proline as a

RI,.~H R2

NaBH4/ZrCl4/ L-Proline = RI.~__~ OH.,,, R3

R2

R3

70

chiral auxiliary <97SC1731>. In certain cases, use of hydride reagents fail to give satisfactory results. For example, treatment of epoxy alcohol 72 with a variety of hydride donors (including RedA1) gave only the 1,2-diol instead of the desired 1,3-isomer 76. A novel work-around was developed by using a Cp2TiCl-cyclohexa-l,4-diene system, which effects a regioselective epoxide ring-opening reaction in an anti-Markovnikov fashion to give the stereotriad 76. The mechanism is believed to involve homolytic cleavage of the epoxide to give intermediate 74; the ensuing critical hydrogen atom abstraction to give 75 is not yet clearly understood, but is probably conformation-dependent <97JCS(P 1) 1257>.

58

Three-Membered Ring Systems

Me RI--~R2 OH

Me RI'--.~~, R2 OH OH

72

76

i

t

RI rMe R2 19

Me

o.~.o

H CP2

73

I

RI"~R2 O Ivo ''1]"

Cp2

74

75

Nucleophilic ring-opening reactions can also take place intramolecularly, as exemplified in the epoxy-Ramberg-B~icklund reaction. This is a novel variant of the classical RambergB~icklund protocol in which cz,13-epoxysulfones 77 undergo base-catalyzed conversion into a range of substituted mono-, di-, and tri-substituted allylic alcohols 79. The reaction proceeds by abstraction of the active sulfone hydrogen distal to the epoxide moiety, followed by intramolecular epoxide cleavage to give an intermediate thiirane dioxide (78), which then ejects SO2 by cheletropic elimination. The highest yields are obtained using lithium t-butoxide in THF <97TL3055>.

~. R ~ R2 S 02 R4R5

.~1 ~::~3 R2 02 S R4

77

R1

R3

R4 R5

78

79

The analogous reaction with heteroatoms is well known; for example, a secondary aminoepoxide of type 80 will undergo rearrangement to a hydroxyaziridine (i.e., 81) via an aza-

O R Z-~'~ N" H

~ HO.,....~N_R

80

R20 RI,'~,~ SR3 82

R2

85

81

R2.0LA 1 R I ~ s +-R3

R2 OH = R I ~ J ~ " Nu SR3

83

I R2.0LA 1 N(R3)2 = R1~ + -R3 R3

R2 OH Rl-~-.r~. Nu N(R3)2 87

Three-Membered Ring Systems

59

Payne reaction. Recent methodology takes advantage of the same anchimeric activity in optically active 2,3-epoxy sulfides and 2,3-epoxy amines (82 and 85), whereby treatment with Lewis acid induces rearrangement to the corresponding thiiranium and aziridinium ions (83 and 86) as reactive intermediates which react efficiently with a variety of nitrogen-based nucleophiles to give functionalized hydroxy sulfides (84) or hydroxy amines (87) <97SL11>. Another twist on the classical aza-Payne rearrangement involves the treatment of aminoepoxides (e.g., 88) with magnesium bromide etherate in dioxane. Here, these traditional aza-Payne precursors undergo a regioselective bromination with concomitant ring-opening to give a [3-halohydrin (89), followed by a rate-determining cyclization to give the corresponding 3hydroxyazetidine (90). The reaction proceeds with a net retention of configuration, being the product of two inversions <97TL6059>.

Br R~--,~

--

NH R,

R'

R/~"~ NHR' OMgBr

=

R--~ OH

A halogenation/ring-opening sequence is also central to a protocol for the 1,3-transposition of primary allylic alcohols to give optically active secondary and tertiary allylic alcohols 97. The key reaction in this methodology involves the treatment of hydroxyepoxides 91, obtained from the Sharpless epoxidation of the corresponding primary allylic alcohols, with a mixture of triphenylphosphine, iodine, imidazole, 2,6-1utidine, and water. In this one-pot reaction, the series of steps involved proceeds by 1) transformation of the primary alcohol into the iodide (93) by the action of phosphine complex 92, followed by 2) rearrangement to the masked allylic alcohol (96) induced by the phosphine hydroxyiodide 94. This reaction is unsuccessful when secondary epoxy alcohols are used <97TL4675>.

Ph3p~imidazolyI R b' H 91

ph3p~,OH R d 93

H

0 Ph3P-O H 0 H

96

OH g7

--

95

The previous example illustrates a frequently encountered epoxide ring-opening mode, namely the [3-elimination. Indeed, this reaction is of general importance, and can be induced by base- and acid-catalyzed routes, as well as homolytic sequences. For example, Singh and coworkers <97T1855> have found that the lithium diethylamide (LDEA)-induced rearrangement of

CH2

Three-Membered Ring Systems

60

cyclic epoxides (e.g., 98 --~ 99) proceeds with higher yields in the presence of lithium t-butoxide, which is believed to disrupt aggregation of the base. In the case of oxiranylcarbinyl radicals (100), [3-elimination can occur via either C-O cleavage or a C-C pathway to give oxygen-based or carbon-based radicals (101, 102), respectively. Marples and co-workers <97TL3599> have shown that the C-C bond cleavage is reversible, and that it can occur even when no products of C-C scission are observed. This mechanism has been implicated in the radical epimerization of certain epoxides. In any event, Molander and Losada <97JOC2935> have used the radical ring-opening of epoxides to advantage in a new sequential reductive coupling process promoted by samarium(II) iodide. For example, treatment of ketoepoxide 103 with SmI2 in methanol leads to a cascade epoxide ring opening and ketyl radical olefin cyclization to give the cis-l,3-cyclohexanediol 109 in good yield and high diastereoselectivity.

O" R2~R1

=

101

100

103

iOi \ / O H

a~

= R 2 ~./ O ~

R2,~Z~,~ R1

102

104

105

H O- Sm Ill

H O- Sm Ill

~ =

HO R

~ R

~

R 9

107

106

R1

108

_.~.,,Me HO Me 109

In addition to 13-elimination, epoxides are also known to undergo rearrangement to a carbonyl group, and this reactivity can be synthetically useful as well. For example, Kita and co-workers <97JOC4991> have used a novel acid-promoted rearrangement of cyclic c~,13-epoxy acylates (e.g., 110) for the stereoselective synthesis of spirocyclanes (e.g., 111), a technique which is

OBz 110

0

Bz

111

applicable to the preparation of optically active compounds of this type. A similar rearrangement is the first step in an organoaluminum-promoted cyclization of olefinic epoxides (e.g., 112), whereby the initially formed aldehyde (113) undergoes a highly stereoselective Lewis

Three-Membered Ring Systems

61

acid-catalyzed intramolecular ene reaction to give the methylenecyclohexane 114 in the presence of methylaluminum bis(4-bromo-2,6-di-t-butylphenoxide (MABR). This strategy is proposed as a route for the stereoselective synthesis of various terpenes <97BCSJ707>.

H

~ M e

H

"AI /\ ~ 112

0H

113

114

Another mode of useful reactivity in the epoxide series occurs via the oxiranyl anion. For example, Mori and co-workers <97JA4557> have used three different sulfonyl-stabilized oxiranyl anions of type 115 to construct three of the four heterocyclic rings in their synthesis of hemibrevetoxin B (116). In similar fashion, ~-stannylepoxides (e.g., 117) can be induced to stereoselectively cross-couple with various reactive electrophiles in the presence of Cu2S <97SL481>. When a leaving group is situated vicinal to the nascent oxiranyl anion, elimination ensues to provide an allene oxide (e.g., 120), itself a highly strained and reactive species, which has been shown to undergo a variety of novel chemical transformations. In the case of the enantiomerically enriched epoxide 119, treatment with sodium methoxide in THF provides the corresponding o~-alkoxyketone 121 via 120 with net stereochemical inversion at the epoxide and without significant racemization <97TL897>.

R1~ S O 2 T o l R2 Li 115

OH2

HOHoMe -

OHC

<.. ] 11__fi

"'~~'S ~'-..v Br Ph nBu3 H 117 SiMe3 n-C10H21~~-.,../O OMs 119

%

NaOMe

.~.~?~ H Ph" ~ ~'v"'% H 118

O 1

,- nC10H21 "-,.L~c H2 120

n'C1~

O ~Me OMe 121

Finally, when an olefinic moiety is appended to an epoxide nucleus, the corresponding oxiranyl anion can exhibit carbenoid-like reactivity, as demonstrated by the intramolecular cyclopropanation reaction of 13,y-unsaturated epoxide 122. Treatment with phenyllithium first

Three-Membered Ring Systems

62

produces the highly strained tricycloheptane 124, which hydrolyzes to the spiro cyclopropane 125 in a completely stereospecific fashion <97TL4071>.

Me~ O

PhU

~oLi

122

123

1

OH 124

OH 125

Occasionally, it is desirable to completely remove the epoxide functionality from the substrate. Toward this end, a novel deoxygenation protocol has been reported for the conversion of o:,[3-epoxy ketones (e.g., 126) to the corresponding enones using thiourea dioxide (127) as a reducing agent under phase transfer conditions.

H~N~_s,O R1~ R3 a2" o~-R4

H2N+ O 127 =

126

3.3

R1 R3 R2~R 4 O 128

AZIRIDINES

3.3.1 Preparation of Aziridines

Two common approaches for the construction of the aziridine nucleus are: 1) addition of a carbon center onto a C=N double bond, and 2) addition of a nitrene onto an olefinic moiety. In the area of the former type of approach, two new heterogeneous catalysts have been prepared by exchanging a montmorillonite K10 clay with dilute solutions of RhCI3 and Mn(NO3)3, respectively. These catalysts are effective for the synthesis of trans-aziridines (e.g., 131) from imines (e.g., 129) and methyl diazoacetate <97CC1429>.

+ N2CHCO2Me 129

C I \ ~ H H 'CO2Me 13__!

130

Another example of the "C + C=N" pathway involves the addition of stabilized sulfonium ylides onto N-tosylimines. This is operationally a straightforward procedure under phasetransfer conditions <97TL7225>, and the use of a chiral auxiliary allows the preparation of enantiomerically enriched aziridines, as illustrated by the reaction of N-sulfonylimine 132 with chiral sulfonium propargylide 133 to give the chiral aziridine 134 <97AG(E)1317>. Me

sv~

..SiMe3

.SiMe3

R1N2== N--Ts R~1= H I

133

Ts

134

Three-Membered Ring Systems

63

As for the second type of approach, the transition-metal mediated nitrenoid transfer to olefins represents a very concise route to the aziridine structure; very often, however, an excess of the olefinic subsrate is required for preparatively useful yields. In this arena, Andersson and coworkers <97TL6897> have studied the copper-catalyzed aziridination of olefins using [N(arenesulfonyl)imino]phenyliodinanes (136) as nitrene precursors, and have reported on conditions which give good to excellent yields of aziridines 137 without the constraint of having to use an excess of alkene.

PhI=NSO2Ar

Rl,~__~R2 H

SO2ph Rl~R2

136

R3

H

135

R3 137

The addition of Grignard reagents onto chiral azirenes (e.g., 138) has been used for the highly stereoselective preparation of unsymmetrical 3,3-disubstituted aziridine-2-carboxylate esters (e.g., 139), themselves useful precursors for the synthesis of unnatural [3-substituted o~-amino acids <97JOC3796>. Organometallic reagents can also engage in nucleophilic attack on the aziridine nucleus, which Bergmeier and Seth <97JOC2671> use to advantage in their synthesis of monosubstituted alkyl aziridines (141) starting from the chiral tosylated derivative 140, a reaction which occurs without the loss of optical purity.

~.,,CO2R Ph

Me

H

=

138

CO2R

Ph'~/H H

139

TsO~~INT s

R2CuLi TsN"~R

140

141

Finally, some rather interesting but esoteric methyleneaziridines (e.g., 143) have been prepared via the 1,2-dehydrobromination of 2-(bromomethyl)aziridines 142 under carefully controlled conditions <97JOC2448>.

(

R

N

142

( =

R

N

143

(

R

N

144

3.3.2 Reactions of Aziridines

In strict analogy to their oxygen-containing counterparts, aziridines are prone to attack by a variety of nucleophiles, a process which can be harnessed for synthetic utility. Crotti and coworkers <97T1417> have studied the ring-opening behavior of certain bicyclic aziridines under standard and chelating conditions; their findings are in keeping with those obtained from similar epoxides systems (vide supra), namely that the course of the aziridine cleavage can be strongly influenced by the reaction conditions and the topography of the substrate. For example, when

Three-Membered Ring Systems

64

the two bicyclic aziridines 145 and 148 undergo nucleophilic attack under standard conditions, a strong C-1 preference is observed. In the former system, the C-2 position is believed to be deactivated towards nucleophilic attack due to the electronic effect of the pyransidic oxygen; in the latter, the observed selectivity is presumably due to the predominance of the more stable conformer 148a, in which the benzylic group assumes an equatorial attitude. Introduction of a chelating metal into the reaction system causes an enhancement of C-1 selectivity in the case of 145, yet a complete crossover is observed for the benzylic derivatives 148. In both cases, the role of the metal is thought to be in the formation of a bidentate chelate structure (i.e., 146 and 150) which further stabilizes the already low-energy intermediate 146 in the first series, but which coordinates with the benzylic oxygen in the latter case (i.e., 150) to lock in an otherwise disfavored conformation, leading to C-2 products (151).

~INPR 1

/ M+....(~.pR1 ~N

Ha

O/~bNHbNNxR1 145a

O

146

~

147

Ha Hb

145b

(~ pR1 N

BnO R2

BnO R2

148a

NHR 1 149 X

IT M +l,

148b

150

151

The ring-opening of a bicyclic aziridine is also the key step in a novel synthesis of vicinal amino alcohols (154) from allylic alcohols. In this protocol, the thermolysis of an azidoformate (152) results in the formation of a nitrene which is captured intramolecularly to generate the strained bicyclic system 153. The methylene carbon of the aziridine ring proved to be very susceptible to ring opening providing intermediate oxazolidinones, which on hydrolysis, yielded substituted amino alcohols <97JOC4449>.

Three-Membered Ring Systems o

65

oH

O~N3

O =\ R/

R~ S / 152

E

=-

R

X NH2

153

154

The aziridine nucleus can also be activated towards nucleophilic attack by attaching electronwithdrawing substituents to the nitrogen atom, as illustrated by the chiral N-tosylaziridine 2carboxylate esters 155, which undergo a highly stereoselective ring opening upon treatment with lithium aluminum hydride. In this case, the attack of hydride causes inversion of configuration and is directed by the hydroxyl group. This sequence is presented as an efficient asymmetric synthesis of o~-alkyl-[3-amino acids <97TL5139>. In a similar vein, the p-nitrophenyl-sulfonyl (nosyl) group is also a useful activating group for ring-opening reactions. Nosyl aziridines 158 are highly reactive electrophiles towards a variety of nucleophiles and do not exhibit competing SNAr reactivity; furthermore, the resultant nosylamide adducts 159 can be cleaved under mild conditions <97TL5253>.

R~A;e H N Ts

LAH > O2Me

.H2

-

H N ",,,(3' Ts

155

156

R/"~"~_. O H Me 157

NO2

0

R

)J

so2

Nu

NsNH

N N x/ N 158

159

Various functionalized aziridines can undergo some interesting and useful chemistry. For example, ot-carbonyl aziridines (160) can be smoothly ring-opened upon treatment with samarium iodide. This reaction proceeds via familiar radical anion formation (161) followed by rearrangement to give the [3-amino carbonyl 163 <97T8887>. Vinylaziridines 164 undergo a highly stereoselective aza-[3,3]-Claisen rearrangement to give seven-membered lactams 165 <97JA8385>. Methyleneaziridines 166 provide enamines 167 when treated with methyl chloroformate in dichloromethane at room temperature <97TL5887>.

R

N[~

~ R1 160

=

R1

R 161

=

R

S

R1 16__._22

R1

RNH 163

Three-Membered Ring Systems

66

al

R3 __~

=

o

R

164

H R2,~R1

R3

165

O R2 MeO2CCI MeO,~N.~H1

H2CJ\

H2C'~ CI

166

3.4

167

DIOXIRANES

3.4.1 Preparation of Dioxiranes Perhaps the most commonly used dioxirane for preparative purposes is dimethyldioxirane (DMD, 168), which is readily available, usually as a solution in acetone. For certain applications, however, it is desirable to have other available forms of the reagent. Toward this end, a recent report <97T8643> describes a procedure for obtaining an acetone-free DMD preparation, as well as highly concentrated solutions in various halogenated solvents.

,,# O-O

168 Dimesityldioxirane (171) has been prepared via the oxidation of dimesitylcarbene (170), which in turn was derived from photolysis of the corresponding diazo compound (169). This dioxirane was obtained as a colorless, crystalline material and was characterized by spectroscopy and X-ray diffraction <97JA7265>.

N2

169

hv__

02

170

O

:-

17"1

3.4.2 Reactions of Dioxiranes Dioxiranes in general and DMD in particular are very efficient as oxygen insertion reagents at carbon centers, and are often capable of effecting transformations under mild conditions that

Three-Membered Ring Systems

67

otherwise require a fairly aggressive reagent system. For example, the benzylic methylene group of the isochroman 172 is oxidized quantitatively by one equivalent of DMD at room temperature to provide the corresponding isocoumarin 173 <97T9755>. O

172

3.5

173

OXAZIRIDINES

3.5.1 Preparation of Oxaziridines Chiral N-sulfonyloxaziridines are useful reagents for the asymmetric synthesis of sulfoxides, selenoxides, and other substrates. Davis and co-workers <97JOC3625> have reported the first example of an e x o - c a m p h o r y l s u l f o n y l o x a z i r i d i n e 175, prepared by the M C P B A oxidation of camphor imine 174 in the presence of potassium hexamethyldisilazide. This compound was then studied in various asymmetric oxidation applications.

S'O N ~O

N"SO2 174

175

3.5.2 Reaction of Oxaziridines Dmitrienko and co-workers < 9 7 J A l 1 5 9 > have reported an anomalous reaction of 2phenylsulfonyl-3-aryloxaziridines ( 1 7 7 ) with indoles to give an u n e x p e c t e d 1,3oxazolidinolindole ring system 179 rather than the indole epoxide. The mechanism is thought to proceed via a zwitterionic intermediate (cf. 178), and represents an interesting example of a mode of reactivity for these reagents other than the traditional direct oxygen transfer. H

o"4" , R1

SO2 R

176

3.6

177

ItL.

N-SO R

R

,

R1

F11

178

179

REFERENCES

97AG(E)1317 97AG(E)I723 97BCSJ707 97BCSJ905

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68 97CC 123 97CC739 97CC 1429 97CC 1565 97GCI79 97JA443 97JA l 159 97JA2329 97JA4557 97JA6189 97JA7265 97JA8385 97JA 11224 97JCS(PI)593 97JCS(PI)1257 97JCS(P1)2265 97JOC2222 97JOC2328 97JOC2448 97JOC2671 97JOC2935 97JOC3625 97JOC3748 97JOC3796 97JOC4197 97JOC4449 97JOC4991 97JOC6512 97SC 1731 97SL l 1 97SL48 l 97T1417 97T 1855 97T8643 97T8887 97T9541 97T9755 97T 10699 97T11369 97TL 101 97TL773 97TL897 97TL 1693 97TL2027 97TL2377 97TL3009 97TL3055 97TL3599 97TL4071 97TL4675 97TL5139

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69

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