Te!&odron Leama, Vol. 34, No. 1. pp. 83% 1993 RintihGfMtBXihh

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Mn(lI9 Promoted N-O Bond Reduction of N-Hydroxy-2Azetidinones

Arun Ghoeh and Marvin J. Miller+

Depattment of Chemistry and Biochemistry

University of Notre Dam

Notre Dame, IN 46556 USA.

Abslracl: Treatment of various N-hydroxy-2-axetidinoncs with Mn(H1) acetate unexpcuedly afforded the

cotmspondmg reduced N-unsubstituted-2-atidinones in the prcscncc of hydrogen donor solvcms.

Mangancsc(III) acctatc promoted oxidation of &dicarbonyl compounds produces clcctrophilic mdicals

that have been used extensively for intramolecular cyclixation of cu-unsaturated-By1 compounds (cq

l).t &Dica&myls have also served as soutccs of elcctrophilic carbon for the formation of bicyclic g&tams

but require prior conversion to a-diax&-ketocsters~ or vicinal tricarbonyl& (Scheme 1). Direct oxidadon

of a Rdicarbonyl appended to a monocyclic L!Jactam, 3, to an intcrmaiiatc ti or cation (s) might Glitatc

straightforward cyclixation to bicyclic D-lactams (5) of current intcrcst for the synthesis of impottant

carbapcncmsandcarbacephcms.

0 0 0 0

WoAck on’ aql

cuol

1 2

Our previous studies of substituted-N-hydroxy-Rlactams6 suggested that related &dicarbonyl-

containing N-hydroxy-Wtctams 3 (R = OH) might bc especially intcrcsting substrates for Mn(IlQ oxidations.

Several m&s of reaction could be envisioned. Oxidation to g (R = OH) might induct intmmolccular trapping

by the N-hydroxy group to generate the bicyclic oxamaxin7 analog 9. Based on the pmcedented iatffmolcculu

11.21~anionic rearrangement of N-hydroxy substituted Elactams.8 9 could then bc induced to rearrange to

uicarbonyl6 and subsequently recyclize to the corresponding biiyclic Blactam 7. Altcmativcly, reaction of

the Rlactam nitrogen of an oxidixcd intermediate might produce bicyclic Wactams directly. While WC have

demonstrated that Ti(III) effectively reduces the N-O bond of N-hydroxy-2-axetidinoncs? the potential fate of

the N-O bond under presumed oxidative Mn(III) conditions was unknown.

83

84

Interestingly, when compound 10 was exposed to 200 mole 96 of Mn(OAc)~2H20 and 100 mole % of

Cu(OAckHz0 in ethanol at WC. the N-O reduced product 11 was obtained in 42% yield as the only isolable

product (eq 2). While the mechanism of the reaction is not yet clear, Mn-mediamd cleavage of the N-O bond,

presumably by a homolytic process or by alternative reduction, competes with and excludes the expected

oxidation of the E-dicarbonyl. Substitution of acetic acid for ethanol as the solvent and lowering the

temperature to 25°C gave a decreased yield (19%) of the reduced product. The use of the aprotic solvent

benzene did not give any characteristic product, but complete destruction of the g-lactam ring system. The

critical role of ethanol as the solvent may be due to its precedented function as a hydrogen atom donorlaJoJ1

Thus, if Mn(lII) fiit induces homolysis of the N-O bond to give the corresponding nitrogen radical with

concommitant generation of a Mn(lV) 0x0 species, hydrogen atom transfer from ethanol might provide the

final reduction product (11).

oe Mn(oAc),mp (200 mole 34) CnBu Cu(OAc)g~ (loo mola W) oJp OtBU

EtoH I 55% oq2 429b

10 11

Despite uncertainties about the mechanism and the low yield of this unexpected N-O bond reduction,

several other N-hydroxy &lactam derivatives were subjected to the reaction to determine its generality and

compatibility or incompatibility with other substituents. The results are summarixed in the table.**

Entry Substrate

’ op oe 3 2 11

0

O-T=

Frx

0-= N A 45

0 ‘H B 18 13

2 H 0 ,2 -OH

Fr Br 3

0 N\ 14 OH

4

5

6

BOCHN

P N 0 ‘H

17

A 53 B 12

A

A

Noohatwtertstfo

28

22

. Table: ‘AU unknom ampomds showal characteristic spectral data and exact mass rqwmmqm data. ‘V’or pmccdun A and B. see text. %olatcd yields nrc given.

In contrast to buffered Ti(III)-mediated reduction of N-hydroxy Blactams. which is compatible with a

variety of seositive functionality, the Mn(IIl) v fails with the Boc promted 3-amino substituted-2-

axctidinone 16 (entry 4). and gives signifmtly lower yields in the presence of a silylated hydroxyl gmup

(enay 5) and a phthalii group (entry 6). Despite these apparent limitations. the unpmedented nature of the Mn(III)-mediated N-O bond reduction merits further mechanistic study.

In a typical tea&on (Procedun A). Mn(OAc)3-2H20 (0.42 mmol) and Cu(OAc~H&l(O.21 tttmol)

wete dissolved in ethanol (2 mL) and placed in a preheated (55’C) oil-bath. N-Hydtoxy-2-axetidinone (0.21

mmol) in ethanol (1 mL) was added to the resulting greenish brown solution. After stining for 10-15 h at

55’C, the brown reaction mixture was quenched by the addition of 1 mL of water followed by a 100 r&f

solution of Na$DTA (5 mL). The resulting solution was extracted with three IO-mL portions of CH#2. The.

combined organic extracts were washed with saturated NaHCQ solution, brine and dried (NazSO4). The

residue obtained after ternoval of solvent was purified by either flash or radii chnrmatography. In procedure

B, AcOH was used insterxi of EtOH, and the maction was performed at room trmpaature.

Acknouledgmant: We are grateful to Eli Lilly and Co. for partial support of this research.

References:

1. For an authoritative background teview and comprehensive list of refetences, see: a) Snider, B. B.; Me&,

J. E.; Dombroski. M. A.; Buckman. B. 0. J. Org. Ckm. 1991,56,5544 and references cited therein. b)

Curran, D. P.; Morgan, T. M.; Schwartz, C. E.; Snider, B. B.; Dombroski. M. A. J. Am. C/tern. Sot. 1991.

113,txV.

2. a) Ratcliffe, R W.; Salxmann. T. N.; Christensen, B. 0. Ter. L&r. 1980.21.31. b) Bodunnv. C. C.;

Bayer, B. D.; Brenttan. J.; Bunnell, C. A.; Burks, J. E.; Can; M. A.; Doe&, C. W.; E&rich, T. M.; Fisher,

J. W.; Gardner, J. P.; Graves, B. J.; Hines, P.; Hoying, R. C.; Jackson, B. G.; Kinnick, M. D.; Kochert, C.

D.; Lewis, J. S.; Luke, W. D.; Moore. L. L.; Morin, J. M.. Jr., Nist, R. L.; Rather, D. E.; Sparks, D. L.;

Vladuchiik, W. C. Ter. far. 1989,30.2321. c) Evans, D. A.; Sjogren, E. B. Ter. Len. l!W, 26.3787.

3. Williams, M. A., Hsiao, C.-N.; Miller, M. J. J. Org. Ckm. 1991,56,2688.

4. Wassaman, H. H.; Han, W. T.-W. Ter. Ia, 1984,25,3743.

5. Gasparski, C.M.; Ghosh, A.; Miller, M. J. J. Org. Ckm. 1992.57.3546.

6. Miller, M. J. Act. Ckm. Res. 1%6,19,49.

7. a) Woulfe, S. R.; Miller. M. J. Ter. Mr. 1984.25.3293. b) Woulfe. S. R.; Miller, M. J. J. Med. Clan.

l!X& 28.1447.

8. Lee, B. H.; Biswas, A.; Miller, M. J. J. Org. Ckm. N&I, 51,106.

9. Mattingly, P. G.; Miller, M. J. J. Org. Ckm. 19??0,45,410.

IO. For refete& on the dative ease of hydrogen atom absaaction ftom ethanol than fnnn acetic acidz see,

a) Gilbert. B. C.; Norman, R. 0. C.; Placucci, G.; Sealy, R. C. J. Ckm. Sot., Perk.in nuns. 2 1975,885.

b) Thomas, J. K. J. Pbys. Ckm. 1967.71, 1919.

I I . The oxidation of 1-hydtoxyethyl radical to ace&ldehyde is relatively easy: Asmua, K.-D.; Bonifacic. M. Jn

Lundolr-Bomsrein New Series, Group 2; Fisher, H., Ed.; Spring Vet-lag: B&in. 1984, Vol. 13b, pp 31 l-

313.

I?. All new compounds gave satisfactory spectroscopic and analytical data.

(Received in USA 18 August 1992; accepted 6 October 1992)