Te~~,fronVol 47,No Ml, pi 1765-1808.1991 oo4o-4020/91 $3 oo+ 00

F’madmGreatBmmn Pergmon Ress plc

TETRAHEDRON REPORT NUMBER 287

Rhodium (II) Catalyzed Reacliom of Maze-car bony1 Compounds*

Julian Adams and Denice M. Spero Boehrmger Ingelhetm Pharmaceuttcals Inc

90 East bdgelP.0 Box 368 Ridgefield. CT 06877 U S A

(Recerved 1 October 1990)

Contents

I Introductton ..... 1765

II Cyclopropanauon .......... 1766

III. C-H Insertron ........ 1779

IV Heteroatom-H Insertton ........ 1792

V Ylide Formatton and Reacttvtty ...... 1795

I. Introduction

The focus of thrs report deals with the use of Rh(II) complexes and thetr abrhty to catalyze a

variety of tmportant reacuons Dtazo-carbonyl compounds are tdeal substrates for Rh(II) based

catalysts and react under mrld condtttons to form what 1s probably a Fischer-type carbenotd These

carbenonls have never been observed, due to the hrgh reachvny of the putattve mtermedtate

metal-carbene. Rhodmm (II) acetate dnner 1s the prototypical catalyst for the &azo-transfer process,

although hgand mod&canons have resulted in various tmprovements for specrfic crrcumstances

(vtde mfra)

Thrs revrew wrll cover four rmportant reacttons of Rh(II) carbenes cyclopropanauon,

carbon-hydrogen bond msertton, heteroatom-hydrogen bond msertton, and yhde formatton and

subsequent mactrons. The drversrty of reacttons as welI as the umque bond formmg capabthtres 1s an

rmpressive feature of the rho&urn generated carbenes Free carbenes have long been regarded as

hrghly energehc species which have mtemstmg properttes. though of hmrted value. 111 orgamc

syntheses. Metal-carbenes m general, have generated a wealth of novel and useful reacttons. Thrs

revtew wrIl attempt to demonstrate the scope of the rh~dnun catalyzed carbene reacttons wrth a vtew

to pracucal syntheuc constructton, and brrefly address some of the mechamsnc issues whrch make

the rhodmm based catalysts useful reagents for synthettc chemotry.

1765

1766 J ADAMS and D M. SPERO

Rhodmm acetate dlmer 1s prepared by heating RhC+ 3H,O m acettc acid Other rhodmm

carboxylates may be obtamed by the analogous procedure or by hgand exchange with Rh?(OAc),

Rhodmm (II) carboxylates possess an octahedral D4 symmetry with four bndgmg carboxylates

complexed to the bmuclear rhodnun atoms This has been refemd to as the “lantern” structure The

morgamc chemistry of rhodmm (II) carboxylates has been extensively renewed by Boyer and

Robmson,lb and will not be addressed m this paper

Rhodium Acetate Duner

II. Cyclopropanation

The synthesis of cyclopropanes and the= use m Mg cleavage reactions remams an unportant

area of research m organic chemistry, and several recent reviews have explored these themes 1-4 As

mentioned m the mtroducuon, rhodium II mediated reactions of a-diazo carbonyl compounds may

result 111 ad&tion to unsaturated systems to produce 3-membered nng products The most commonly

used reacuon leads to the formation of cyclopropyl denvatlves I-hstoncally the use of various

copper catalyst.$-’ were prevalent and only the emergence of the group VIII metals m the late 1960’s

and early 1970’s challenged the efficacy of the copper based catalysts 8-12 The pioneermg work of

Belgian chemists Pauhssen, Hubert, Teyss& Anclaux and other collaborators was paramount m

ldenhfymg the rhodium (II) carboxylates as efficient catalysts for carbenoid mediated

cyclopropanauons 13-16

A systematic screening of common transihon metal complexes revealed that Rh(II) species

were the mildest and most efficient catalysts for cyclopropanauon “,I8 AU stable Rh(I1)

carboxylates, most notably Rh,(OAc),, having one coordmation site per metal, form highly reactive

complexes ~th carbenes derived from diazo precursors These carbenolds add rapidly to avadable

carbon -carbon double and mple bonds (and, as will be revlewed, are capable of smgle bond

Rhodmm(II) catalyzed reactions 1767

msemon reactions) By contrast, the tradItional copper metal catalysts which mediate the same

reacclons to varymg degrees, probably do so ma dtierent mechamsms Copper-olefm complexatlon

has been proposed to tiect the cyclopropanatton reaction Rhodmm catalysts Hrlth tbe smgle

avtiable coordmation site do not form complexes ~rlth olefms and this is mferred from the near

random chemo-selectivity observed with Qfferent olefms l’,l* The catalyst selection is crmcal smce

competing processes such as the Wolff rearrangement (seen ~nth sflver based catalysts or C-H

mseruon reachons (observed wth Pd catalysts) are also options for ol-ketocarbenes.19 Rh(II)

catalysis is documented to be very specific for cyclopropanauon

A note on the general reactton conditions is m order Catalyt~ efficiency 1s generally high,

reqmrmg l-3% catalyst (by weight) and best results are obtamed at amblent temperature (solub&y

permmmg) m non-reactive solvents such as methylene chlonde or other halogenated hydrocarbons

Reaction rates are extremely rapid and no intermediate carbenoid complexes have ever been isolated,

unhke the well known tungsten or chromium carbenolds A general correlauon of olefm react~lty

m&cates that the more electron-nch double bonds ~11 react preferentmlly ” Even ketene acetals

react with diazoacetate to give the desired cyclopropyl acetal, but only when Rh(II) was chosen for

catalysis 20 Electron deficient olefins (1 e a$ unsaturated olefms) often foul to generate

cyclopropanes, but rather form pyrazohnes Barrmg stenc factors, CIS olefins react shghtly faster

than traus olefins

scheme 1: General Cyclopropanalion Reaction

R

Coqugated dlenes and trrenes are also reactive, and cyclopropanation at the more

nucleophlhc double bond is predominant. 21-23 By the same token, acetylenes represent good

substrates for Rh(II) medmted carbene additions and lead to highly stramed (and reactive)

cyclopropenes 24 In general the coppe r catalysts foul to produce any product at all As already

mentioned, the more nucleophihc the reactmg substrate the more rapld the reaction This was

demonstrated by Petmiot et al 24 who performed a competition expernnent between 1-hexyne and

1-octene, where the cyclopropene product predominated over the cyclopropane by a ratio of 2 1

Such selectivitles amongst olefins, dlenes and tnenes have been extensively documented m

the hterature 17J8*25*26 Much of the earlier hterature addressed the intermolecular reactions with

respect to regmchemlcal and stereochemlcal aspects of cyclopropanatlon Doyle and co-workers

have conducted the most systematic mvestlgahons ~rlth regards to mechamsm and rhodmm catalyst

compansons lg.27 Doyle’s mlhal efforts confumed the supenotrty of Rh,(OAc)4 as the catalyst of

choice for cyclopropanauon, observmg superror yields under the mild reacuon condlhons

1768 J ADAMS and D M. SPERO

Nevertheless RhZ(OAc), tends to exhlblt shghtly less regloselectWy compared to copper catalysts

The reachon of ethyl dazoacetate and monosubstituted &enes was used to estabhsh a

“metal-carbene regioselechvity m&x “25 Product analysis of the competmg double bonds of the

diene gave results that were mechamstically diagnostic This exercise confiied the tendency of

Rh(II) to form reactive metal-carbene complexes with no coordmation to the reactmg olefin As

mitlally proposed by the Belgian mvesugators electron-nch olefins were more reacuve towards

cyclopropanatlon with the electrophihc ethyl acetate carbenold(Scheme 2)

Scheme 2: Diaxmcetate Addition to Mono-SusbstJtuted Diem%

Doyle and colleagues also undertook a systematic mvestlgauon of the stereoselecuvity m the

ethyl dlazoacetate cyclopropanatlon reaction *s In general the reaction tends towards little If any

select.Wy The trans Isomer predommates to a small degree (l-2.1 trans/c~s) except if a stencally

demanding group or groups mfluence the reaction outcome Trans olefins react to produce

cyclopropanes where the two substltuents derived from the olefm mamtam the trans relationship in

the cyclopropane product The same apphes to CIS substINted olefiis

Scheme 3: Stereuspedflcity of Olefin Substituents in Cyclopropanation

N$HCO,Et +

RI

trans

Rh(IU

R2

A

Rl

CO,Et

tram

R2

“lwR2 ) ma RI N2CHC02Et +

4 CO,Et

CIS CIS

1769 Rhodmm(II) catalyzed reacaons

Doyle correctly pomts out that four vanables conmbute to the resultmg reglo- and

stereochemical course of cyclopropanatlon. the transltlon metal, its associated hgands, the tizo

compound and the olefm The olefm is generally the weakest conmbutor to the stereochemical

outcome

Further mechamshc evaluation by Doyle, usmg kmeuc compebtton expenments and product

analysis, led to the comparison of the stable tungsten metal-carbene, (CO)5WCHPh, for

cyclopropanation, and the rhodmm acetate catalyzed reachon of phenyl dmzomethane.2g Though the

relative reacuvities were much faster in the tungsten catalyzed system (103-104 tnnes) the order of

olefm reactivity remamed the same as for the Rh2(0Ac), case This 1s good evidence for the

assumption of a rhodmm-carbene complex which has been extended to hold true for dlazo-carbonyl

carbenes as well

A plctonal assessment which accounts for the shght preference for the trans-cyclopropane

Isomer m mono- substituted olefins was put forth by Doyle, as shown in Scheme 4 while such an

account is reasonable, cautton must be employed 111 consldenng tis mechanism since none of the

intermediate transition states have ever been observed Nevertheless, as a point of departure, this

analysis 1s consistent with mechamsttc pnnciples and accounts for the experunental observations

Scheme 4: Doyle’s Mechanism of Cyciopropanation 29

H H H

L,M

%

OEt

H R 0

- I R H

SG H COzEt

Followmg the mmal investigations with Rh,(OAc),, Doyle et al proceeded to demonstrate

both the hgand effects on Rh(lI) and the stenc effects of the reachng dlazo carbonyl Both rhodmm

acetamlde. Rh2(NHCOCH3)4 and rhodmm pertluorobutyrate, Rh2(OCOC3F,)4 were found to affect

the trans-selectivity in the reaction of diazo-carbonyls with styrene 3o The results are summarized m

the table below

1770 J. ADAMS and D M. SPERO

Table 1: Ste~ectivity Enhancement in Catalytic Cydopropanation of Styrene

trans/c~s (yield, %)

Catalyst N&HCOOEt NzCHCOOMe(iPr)2 NZCHCONMeZ N$HCON(G’r),

~2(~~,F,), 1.1 (81) 1 1 (83) 15 (67) 12 (51)

Rh2(OAc)4 1.6 (95) 2 4 (95) 2 2 (74) 64 (53)

Rh#HCmH,), 2 1 (89) 4.4 (87) 2 4 (70) 114 (47)

The electron withdrawmg effects of the peffluorobutyrate hgaud adversely mfluences the

trans selectivity while the acetamlde catalyst enhances trans selecuvlty As well, the stenc bulkmess

of the reactmg duuo carbonyl contnbutes to the trans stereochemistry although the yields tend to

Qtmmsh Altematlvely, Callot and Metz were able to effect cis stereoselectlvity in cyclopropauatlon

with the use of bulky 2,4,6-tmuylbenzoate hgands on Rh(II) 31 A detaded account of the

stereoselechvlty m catalyuc cyclopropanatlon reacttons was recently published and includes further

stuQes mvolvmg hgand modification of the catalyst and dlazo carbonyl compounds 32

An mterestmg application of the intermolecular reaction demonstratmg the power of the

Rh(II) catalyzed cyclopropanation is the reaction of ethyl diazoacetate and furan (Scheme 5) With

furan as the solvent, rapid evolution of mtrogen ensued and a mixture of products was obtamed

Wenkert et al analyzed the products 1-4 and put forth an mterestmg mechanistic rationale to account

for their observahons In contrast to Doyle’s hypothesis, two rhodium based metallocycles 5 and 6

(differmg in their regmchemlstry) were postulated to explam the expenmental findings 33

The Merck Frosst Canada group has made use of the furan-diazo carbonyl addition chemistry

to prepare cis-trans dienes m the synthesis of the arachadomc acid metabohtes, hydroxy

eicosatetraenOic acids (HETEs) 34-36

It can, however, be concluded that the mtermolecular cyclopropanatlon reachon 1s relatively

non-selective (by today’s standards) unless particular attenhon is psud to “matchmg” the olefin, the

catalyst and the dlazo carbonyl substrates accordmgly Another potential problem arrses with the

mtermolecular reaction Due to the natme of highly reactive carbenold mtermedlates, dmenzaUon

1s often an accompanymg side reachon Typically the intermolecular reaction has been run using an

excess of the olefin substrate, often as the solvent itself Dlmenzahon can be numm1zed as well by

controllmg the rate of addlhon of the dlazo carbonyl to the reachon mixture, effectively mamtammg

a low concentration of the carbene m solution

Rhudmm(II) catalyzed ITXX~IOIU 1771

scheme 5: Reaction of Ethyl Diazoacetate with Furan

+ N,CHC02Et

CO,Et C02Et

+

C02Et

2

t t

+

COzEt

3

(332

cc

I RhLl

0

6

Et

Scheme 6: Dime&&ion of Carbenoids (a side reaction)

!!

0 WOAc),

R -

0

1772 J ADAMS and D M. SPERO

By contrast the mtramolecular reaction provides greater synthetic uttl~ty due to the geometnc

constramts of formmg the cycle and the entroplc advantages mmnmzmg the dnuenzatlon of the

carbene Several parl~cularly mterestmg demonstrattons of the carbene-olefm addltlons which

underscore the mildness and htgh spectficity of the mtramolecular process are exemphfied below

Dowd performed a cyclopropenauon followed by cyclopropanation to prepare highly stramed

rncyclo [2 1 0 02*5] pentan-3-one 737(Scheme 7)

The first to use cyclopropanauon 111 an intramolecular sense were Stork and FICIIII~* although

at the tune the more efficient Rh(lI) catalysts had not yet been described 38 In many cases the

traditional copper catalysts suffice (albeit 111 lower yield) but reactions sensmve to elevated

temperatures or Lewis acld~c me&a reqmre the use of Rh(II)

Qven the hmlted preparative utity of the mtermolecular machon. many more useful

synthetic consuuchons have been dewsed with the mtramolecula~ process We have attempted m

dus report to bghhght some of the more useful and outstandmg reactions. particularly the cases that

reqlllred the mdd Rh(II) catalysis and faded with other transition metal catalysts

Scheme 7: Fonnation of Highly Strained Cydopropanes

Cl C1CH2ECCHzCl + N&HCOO-t-Bu )

COO-t-Bu

~2WW.4 - c Cl

Followmg the work on the cyclopropanatlon of furan. Padwa3g and Wenkert33 mdependently

mvestlgated the mtramolecular process 111 some detad The mtermeQate cyclopropane was so labile

m the urnmolecular reaction that It was not observed, but its mtermediacy was mferred from the

geometry of the exocychc double bond m the product (see Scheme 8) Thus a general synthesis of

cychc 1,4-d~acyl-2,4-cls,trans butadienes (I e 8) was developed

Rhodmm(II) catalyzed reacuons 1773

Padwa expanded on thts theme usmg benxofuran cychxanons as well as reactron wttb

thtophenes.3g@ In some of these cases the mtermedrate cyclopropane was observed

spectroscopically or even Isolated. The mtramolecular reactron wrth throphenes 1s mterestmg

mechamsucally and contrasts somewhat wrth the bimolecular reactton with Qaxo carbonyls.

Qllespre and Potter have reported a stable yltde mtermedtate wtth dmxomalonate, 9, for whtch an

X-ray crystal smtcture was determmed 41 ‘llus complex does not react further to produce the

cyclopropanated throphene The authors ranonahzed this result by statmg that the two electron

wrthdrawmg esters render the yhde too stable for rearrangement. They proposed that the

dtaxoacetate addrtton to throphene may also proceed via a less stable (and not observed) yhde prtor

to cyclopropanatton Further dtscusston mgardmg the correlauon between yhde formauon and

cyclopropanatron may be found by readmg the work of Doyle 42

Scheme 8: Intramokulac Diazoketone Reaction with FUIWI

N2

-

Scheme 9: Thiophene-Malonate Ylide

I Et0 c ’

C- 2 ‘C02Et

1774 J ADAMS and D M. SPERO

In a S~ULU vem we have exammed the mtramolecular reactron on the relatively nucleophlllc

enol ether olefin m dlhydropyrans. 43 The oxa-mcychc ketone products, 10. were found to be useful

mtermediates for the synthesis of small and medmm rmg carbocycles. The sequential carbon-carbon

and oxygen-carbon bond cleavages afforded carbocychc ketones, 11, web syn-tiubsututlon The

hmit of rmg size formation was addressed ws a ws competmg C-H msertlon (Scheme 10) This

synthehc approach was employed m the total syntheses of natural products eucalyptoP and

P-chamigrene45

Scheme 10: Intramolecular Addition of Diazoketones on Dihydropyrans

Rh,OAc,

W 032)

H+/HX

X

0 X -72 HhY

Y

(CH$ - OH

n

0 ti (CH2)

n

0

1L

n= O-3

The addmon of alkyl or arylhthlum or Gngnard reagents to the carbonyl of the simplest

oxa-mcychc ketone (n=O), 10, led to carbmols, 12, which upon Lewis acid treatment (TiCI,)

provided a novel entry to cyclohexacbenes or eventually meta-subsmuted aromatic compounds 46

Another novel nng construction owing to Rh2(OAc), catalyzed cyclopropanation was

described by McKervey and used to prepare fused cycloheptatnene compounds 47 Once again, the

use of Rh(I1) 1s cntical since copper catalysis or photochemlcal methods foul The general scheme

involves the converSion of aryl prop1on1c acids to cycloheptatnenes, 13, v1a 1ntermdate fused

cyclopropanes Tetralones, 14, could be obtained by treating the cycloheptamenes with

mfluoroacetic acid 47 Doyle apphed the same reaction pathway to prepare azablcyclo [5 3 0]

decatnenones48(Scheme 12)

1775 Rhodmm(II) catalyzed rcacuons

scheme 11: Synthesis of Cyclohexadienes and m-Substituted

Aromatic Compounds

Scheme 12: Synthesis of Fused Cycloheptatrienes and Tetralones

/ OQ \ t 1 Piers et al made use of an elegant intermolecular addmon of dtazoacetate to a cyclopentane

denvative, 15, to set up a dlvmyl cyclopropane rearranagement, which afforded a unique bndged

tr~cychc construction, 17, en route to the natural product quadrone 4g Here the cyclopropanaclon

occured with high exo selectivity and the stereochemical preference was dctated by the 5,5 fused

cyclopentane substrate, 15 (Scheme 13)

One particularly novel and elegant apphcatlon of a carbenold-olefin addmon is the reachon

of the rhodmm-vmyl carbenold with dienes resultmg m a formal 3 + 4 cycloaddihon This work,

pioneered by Davies, adds a new dimension to the cyclopropanation repertoue An example of tlus

process IS the addition of dlethyl4-dlazo-2-pentendloate to furan (Scheme 14) 5o Evidence was

presented favormg a cyclopropanauon-dlvmylcyclopropane (or Cope) rearrangement based on the

endo selectivity for the carbenold addition ”

On the same theme, Davies also apphed the same methodology m an mtramolecular sense to

prepare fused 5.7 membered carbocycles and heterocycles (Scheme 15) 52+53 Once agam the

remarkable endo selectivity of the cyclopropanation accounts for the facile tandem process to afford

the observed products (I e 18)

1776 J ADAMS~II~D M SPERO

Scheme 13: Divmyl Cyclopropane Rearrangement

O’IBDMS OTBDMS s 5

8

\

I

N,CHCOOEt

) KY

C02Et

u2(OAc)4

OTBDMS

heat b

Scheme 14: Formal 3 + 4 Cycloaddition of a Vinyl Carbene to Furan

RhLn

6cLf

I CO,Et -

C02Et

Scheme 15: IntramokeuIar Tandem Cyclopropanation/Cope Reactions

Rhodmm(ll) catalyzed reactions

Another clever apphcauon by Davies allows for the synthesis of substituted furans.”

Recogmtion that &eto cyclopropenes could be formed under the nuld Rh(II) concfitions, usmg

dnuomalonates and keto-este~. led to the observed furan products. This reaction IS formally related

to a vmyl cyclopropane rearrangement. The polarizalon of the zw~tter~omc keto-olefin mtermtite,

19, serves to accelerate this process leadmg to furans (Scheme 16) 54

Seheme 16: Cydopropenation and Synthesis of Furans

R RhLn Y

II +

x

-

H 0 X

-

R 0

W

X+

Y

-

R

0 v ;_ x 19

Y I

1777

Recent examples of mtramolecular processes leadmg to unusually stramed rmg systems are

noted below (Scheme 17) 55,56 These examples further demonstrate the power of dus chemM.ry

This account IS by no means an exhaustive catalogue of all known cyclopropanat.Ions, but rather an

instructive hterature survey and cnt~al assessment of the potential for useful synthetic construchon

Chermsts 111 the future will surely wlmess further developments and apphcation of this chemistry

Scheme 17: Highly Strained Cydopropane Riq@*

0 0

cc) N2

0 0

fi@Ac),

[3 3 l]-Propellane-2,8-Qone

Rh2(oAc)4

Cyclopropanoblcyclo [3 2 11 octanone

1778 J. ADAMS and D M. SPERO

The chemistry described so far has been restncted to dmzo carbonyl ad&uons to olefms. The

extension of the Rh(II) based carbenoid ad&tions has been extended to other electron de&lent

carbenes. Druley and O’Bannon have recently made use of ethyl mtrohazoacetate and

mtrodmzomethane to form cyclopropanate alkenes 575s Once agam Rh2(OAc)., was successfully

employed where thermal or photochemical methods faded

Another mterestmg development was the report of the rhodmm catalyzed reaction of

dmzomalonate with mtnles to form oxazoles Formally one could consider a dipolar ad&hon as

proposed by Helqmst et.al.5g Nevertheless, It 1s temptmg to speculate that a 3-membered unme

species, 20, may also be possible. sunliar to the Davies synthesis of furans (Scheme 18). Precedent

for an unmo awrrdme mtermedate exists from the previous work of Hubert et aL60

Scheme 18: Preparation of Oxazoks from Dlazomalonate Addition to Nitriles

MeOqOMe + R-CN . .

N2

-

One remiumng area to explore 111 cyclopropanatlon chemistry 1s the prospect for asymmetnc

catalysis Some examples are already described usmg a copper based catalyst, but the enantiomenc

‘l-64 excesses (ee) observed have been relatively modest We have attempted to prepare choral Rh(I1)

catalysts usmg ammo acids and other choral acids but so far have been unsuccessful in obtammg

asymmetnc mductlon 65 At the hme of this wntmg we became aware of the work of Stephen Martm

(U of Texas) and Micahel Doyle (Tnmty Umverslty) who described the general reachon shown

below (Scheme 19) +% This encouraging result bodes well for future advances m thus field and may

provide addmonal useful avenues for the Rh(I1) based catalyuc cyclopropanation chemistry

Scheme 19: Asymmetric Induction Using a Chiral Rh(II) Catalyst

95% ee

Rhodmm(II) catalyzed reactions 1779

III. C-H Insetion:

Free carbenes have long been known to be capable of msertmg mto C-H bonds, although both

low yields and lack of chemical control have mitigated agamst rehable and useful synthetic

applications 67 With the advent of Rh(I1) carboxylates, the carbenouls generated from a-duuo

carbonyl compounds were found to be effective m C-H msetion under extremely mild conditions.

Belgian chemists Noels et al reported the Rh(II) catalyzed C-H msertton of ethyl diazoacetate

usmg a vartety of alkane hydrocarbon solvents, at ambient tempertahu$js (Scheme 20) WMe the

overall yields were generally good, no useful regloselectivlty was seen Some preference for

secondary C-H bonds was observed with Rhz(OAc),, and mcreasmg the size of the carboxylate

hgand on rhodium (1 e 9-tnptycene carboxylate) enhanced the ratio of prunary C-H bond mser&on

Nevertheless, the intermolecular reaction has no real preparative value since mixtures of mmers are

formed 6g*70

Scheme 20: Intermolecular C-H Insertion of Hydrocarbon Solvents

0 I-WI) CH2C02Et

) \ OEt alkane

mixture of products

(2OY > 1°y)

The reahzation by Taber71 and Wenkert72 mdependently that the utihty of the carbene-metal

catalyzed C-H insetion process could be exploited in an mtramolecular sense was demonstrated in

the preparation of cyclopentanone denvatives Both groups found that the cychzation of carbenoids

denved from dlazo ketones and keto esters preferenttally formed 5-membered carbocycles This

process had been previously described ~nth copper catalysts, but once agam Rh(II) species proved to

be more selective, higher yieldmg and proceeded at amblent temperature73(Scheme 21)

The preference for 5-membered nng formahon 1s not absolute, and 1s strongly influenced by

the local stenc and electronic environment of the reactmg carbenoid Interestmgly, Taber et al

1780 J ADOS and D M. SPERO

Scheme 21: Intramolecular C-H Insertion to Cyclopentanones

Taber

Wenkert

N2

n

Rh,(OAch

published a synthesis of pentalenolactone, 21, whereby the mcychc skeleton was assembled through

a rhodmm-carbene medlated cychzatlon to form a 5-membered nng 74 By contrast, the Cane group

also constructed pentalenolactone, 21, but the key cychzauon step mvolved a C-H msemon to form a

6-membered lactone In the Cane approach, the posslblhty for 5-membered formauon exists, but the

6-membered nng 1s formed since It 1s the more stencally accessible optson ‘Ihe two successful yet

&ffenng synthetic constructions underscore the versatlhty of the intramolecular C-H msertlon

reaction (Scheme 22)

Taber and Ruckle conducted a systematic study of this reaction and concluded that the order

of reactlvlty for C-H insertion In an ahphatlc hydrocarbon was methme > methylene > methyl, which

1s consistent with the observations of the intermolecular Ractlon 76 Furthermore, It was determined

that allyhc and benzyhc C-H bond insertions were disfavored Taber ratlonaltzed that alkyl groups

are mducuvely electron donating and increase the electron density of the C-H bond, thus making tt

1781 Rho&urn(U) catalyzed Eacoons

scheme 22: Syntheses of Pentdenobctone

Taber

~co2M!EL & 0 0

Cane

COzMe

more susceptible to the electrophlhc Rh(I1) carbenold The mechamstic imphcattons of tlus have

been exploited by others and will be described later m thts chapter @de mfra)

Though little 1s known about the mechamsm for the rhodmm-carbenoid C-H mseNon

reaction, Taber offered a plausible hypothesis which accounts for preferential S-membered rmg

formation76 (Scheme 23) The fiit step reqmres the formation of a Rscher-type metal-carbene

complex, 22, at a vacant coordination site on rhodmm (a well accepted assumpaon based on the

cyclopropanatlon mechamsm) In the next step, it 1s unknown whether or not the C-H msertlon 1s a

concerted 3-bond process (mtermedlate 23) Also unknown, 1s the role of the carboxylate hgands on

the metal In any case, a hydrogen atom ends up on the rhodium@9 and the final step reqmres

P-hydnde transfer from the metal to regenerate the catalyst and afford the observed cyclopentanone

1782 J ADAMS~~~D M

Scheme 23: Mechanism of Aliphatic C-H Insertion

23 2.4 + &(OAc),

Taber et al. also detemuned that C-H insemon proceeded with retention of stereochemMy

at the reactmg carbon center and made use of this knowledege to synthesize (+)-a-cuparenone”

(Scheme 24) This enanttoselectlve process represents a general strategy for constructmg cycles

contammg quatemary centers

A further development by the Taber group demonstrated the trans selectivity of 3,4 dlalkyl

cyclopentanone subsutuents ‘* This IS sigmticant since it indicates a highly ordered transitton state

geometry whereby unfavorable ster~c mterachons are mmunized(Scheme 25)

Taber’s cyclopentanone synthesis employed a diazoketo-ester precursor, whereby the ester

functionality could be removed by hydrolysis and decarboxylation following cyclization This

Rhodmm(II) catalyzed reactions 1783

Scheme 24: Synthesis of (+)-a-Cuparenone

InserUon at C-H ~th Retention

a-cuparenone

Scheme 25: Synthesis of Trans-3,4 Dialkyl Cyclopentanones

Hb 0 0

P -3

R \

R’

provided an opportunity to explore Qsposable chrral amullarres m place of snnple esters to achieve

enanuoselective carbocycllzatlon7g (Scheme 26) This was indeed reahz.ed by the Taber group as

they prepared a naphthalene substituted (+)-camphor denvahve. 25 Excellent QastereoselectlWy

(> 80%) was observed m the C-H msertlon reaction These results suggested an ordered chaN&e

transition state whereby the bulky naphthalene moiety of the the chnal ester effectively shielded one

face of the pendant cham of the substrate The assumptton that the carbenoid ester exists m an

extended conformation duects the mode of cychzatton towards Ha This apphcatlon provides a

convenient synthesis of chmtl cyclopentanones

1784 J ADAMS and D. M SPERO

Scheme 26: Asymmetric Induction Using a Cl&al AtdIary

0 0

R

WW

OR*

‘“s R

2s dlastereoselecttvlty > 80%

Other examples of 5-membered rmg products are described m the hterature so*81 In general

polycychc systems tend to be well suited for the C-H msefion process and the stereochemical

outcome IS usually predxtable The synthesis of [4 4.5 51 fenestrane, 26, by Agosta et al illustrates

dus p~rnt!*-~ (Scheme 27) The constramts imposed by stram m the rmg system led to the predxted

result.

Scheme 27: Synthesis of [4.4.5&j Fenestrane

1 I’WOAc), D

2 reduce

Formal aromatic C-H mseruon is well documented As discussed in the cyclopropanation

section, It may not be possible to dlstmguish between dmxt C-H mseruon and apparent C-H

1785 Rhodmm(II) catalyzed reactions

msemon ansmg from an unobserved cyclopropyl mtermedlate which then rearranges to the final

product. Shown below are several examples of aromatic msetion to form mdanones. 27.85

naphtbalenes. 2t3.% fused pyrroles. 29, ~‘UXJ and 1.3 dthydrothlophene 2.2 dioxtdes, 30891~ (Scheme

28) The versat&y of dus process allows for convement preparation of a vanety of 5-membered

fused heterocycles Perhaps the most unexpected example was reported by Matsumo and co-workers

m the cychzahon of 2-dmzo-4-(4-mdolyl)-3-oxobutanoic esters, 31” Catalysis by Rhz(OAc)d gave

exclusively the 5-membered fused mdole, 32, whde reaction with Pd(OAc), afforded the

6-membered product, 33, presumably via a cationic mechamsm (Scheme 29)

The early work of Taber suggested that some stereoelectromc control exists m the C-H

msemon process The more electron nch C-H bond tends to be kmeucally more reactive This

phenomenon was also observed in our laboratory, when we first noticed the susceptlbllity towards

insetion of C-H bonds a to ether oxygens Our first expenence with this reaction mvolved the

trans-annular cycbzation of a dmzoketone appended to a tetrahydropyrau rmg, 34. which produced a

smgle product of mserhon at the 6-posttlon ether C-H, 35, and no mseruon at the ahphatlc

methylene This construction led to the total synthesis of the natural insect attractant

endo-1,3-dunethyl-2,9 dloxabicyclo[3 3 llnonane, 36 g2

Further studies in our group indicated that this selectlvlty for ether C-H bonds could be

applied to the mtermolecular reaction of ethyl dmzoacetate with ether solvents.g3 The

intermolecular reaction IS mechamsfically mstrucUve, but suffers from the same dtsadvantages

discussed previously, and holds little synthetic mterest Alternatively the mtramolecular cychzatlon

of dmzoketones denved from 2-hydroxy carboxyhc acids provided a general route to furanones. 37

(Scheme 31) The S-membered nngs were favored m the cychzauon as witnessed by the reaction of

dlazoketone, 38,m which both the 5membered and 6-membered nngs (39 and 40) are possible as

both methylenes are flanked by ether oxygens Furthermore, when we studied the cychzation of the

dlazoketone, denved from 6-benzyloxy pentanolc acid, 41, the carbon analogue, the 6-membered

nng, 42, was formed (albeit in low yield) owmg to the ether oxygen activation, and no

cyclopentanone, 43, was observed (Scheme 32)

While we were pursumg the phenomenon of ether C-H msemon, the fmdmgs of Stork and

Nakatam described a complementary C-H msetion reachon under stereoelectromc controlg4

(Scheme 33) They observed that the mducuve effects of electron withdrawing esters disfavored

C-H msertlon at methylenes a or even p to the ester As a result they were able to direct C-H

insertton at an unactivated methylene of a proximal ahphatlc cham to generate cyclopentanones, 44,

m a selective manner

1786 3 ADAMS andD M. SPERO

Scheme 28: Fused Aromatic Rings

R

o+ :I 0’N2

0

N2

R

/

05; I

0

\

22

OH

28

a 0

\ N

C02R

30 C02R

Rhoclmm(II) catalyzed reactions

Scheme 29: Cyclization of Indoles

1787

Scheme 30: TIIUW-AMUI~W Cyclization

a 0

0

34 35

Scheme 31: Synthesis of 2(H)-3-Furanones

-) @ 0 0 i

36

0 0

Rh2(OAd,

R CH2C12

R

(3-8 1 CldtranS~

1788 J ADAMS andD M. sPF!RO

Scheme 32: Intramolecular Cydization Ether Competition

(+bmuscarme

OBn

!?!J

OBn

Rhodmm(II) catalyzed reactions 1789

Scheme 33: Stereoelectronic Effect of Electron Withdrawing Groups

COCHN,

A (cH2&C0 Me!=% 2

n =1,2 44

45 46 2:l 47

The report of Stork and Nakatam was slgmficant to us smce we had observed that the

cycltzahon of a the dlazoketone denved from Mosher’s acid (2-methoxy-2-Wluoromethyl

phenylacettc acid) 45, led predommantly to aromatic C-H product, 46, mseNon with the moor

product, 47, artsmg from C-H insetion at the methyl ether Thts could be explamed by the mducuve

electron wtthdrawmg effect of the tnfluoromethyl group which serves to partmlly cancel the ether

acttvatton (Scheme 33)

Further studies m the preparation of unsymmetrical 2,5- dtsubstituted furanones led to the

observatton that the reachon favored the CIS dtsubstttuted Isomer g5 This appears to be the result of

kmettc control and an ordered transthon state mvolvmg the metalcarbene complex Base catalyzed

equihbratton of the product furanones provtded a thermodynamic mixture wherein the c~~/trans rauo

IS essentially 1 1 An attempt to rahonahze the results was put forth in a mechamsttc hypothesis

(Scheme 34) The proposal rehes on Taber’s ongmal mechamsm which calls for hydrogen transfer

to rhodium The electron donatmg ether oxygen faclhtates thts process, and parttctpates 111 the

transmon state by chelating the rhodium m such a way as to mmtmlze substltuent mteracttons

1790 J ADAMS~~~D M SPERO

Scheme 34: F’roposed Mechanism for Furanone synthesis

Me

In order to tighhght the useful apphcahon of our findmgs, both the furanone constructton and

the cls-selecttvlty of the C-H msertlon mediated by RhZ(OAc), were explolted m a total synthesis of

the natural product (+)-muscarmeg5 (Scheme 32)

A related C-H msertton process in which the carbene was drrected a to nitrogen was

observed by Rugglerr and co-workers m the preparation of ergohne dertva0vesg6 (Scheme 35) In

their case Cu212 was used as the catalyst to generate the carbene Here Rh,(OAc), falled to catalyze

the reachon because the metal forms strong complexes with basic mtrogens and renders the catalyst

inactive This represents a hmltahon for Rh(I1) catalyzed processes Nevertheless, the mechanism

proposed is slmllar to our hypothesis for ether activated C-H insetion, and the electron donatmg

capacity of the nitrogen lone pau directs the mode of cychzatlon Although mixtures of isomers

were obtamed, 48 and 49, mcludmg some cychzahon at an unactlvated C-H bond (9%), this reachon

further emphasizes the stereoelectronic effect of heteroatom achvabon of the C-H bond

Doyle recently described a very effective C-H insetion to prepare p-lactams, 51, from

dmzo-gketoamldes, 50, in which the nitrogen of the amide bore a bulky t-butyl or branched alkyl

subshtuent g7 The usual S-membered nng products were seen using the catalyst m dlchloromethane

at ambient temperature However, m benzene at reflux a different reachon prevaded and p-lactam,

51, was obtamed Doyle argued that the selectlvlty m the reachon is not of an electromc nature, but

1791 Rhodmm(II) catalyzed xeactlons

Scheme 35: C-H Insertion a to Nitrogen

48 91.9 49

rather that the C-H bonds m closest proxnnlty to the reachve rhodmm-carbene center led to the

preferred p- and not y-lactam products T~LS suggests a very stable anude conformation which 1s

governed by the bulky subsutuent on mtrogen (Scheme 36)

scheme 36: Synthesis of p-Lactams

0

In contrast when Doyle studied the analogous reachon using duuoesters and diazoketo-esters

no p-lactone formation was observed, but rather the normal S-membered nng leadmg to y-lactone

construcuon previuled g8 Interestmgly, hgand effects on rhodium led to dramatic regmchemlcal

preferences A competmon for C-H mscmon of dlazoester, 52, yielded product mixtures ( 53 and 54)

usmg Rh,(OAc), or Rh2(OCOC3F,)4 (Scheme 37) However when rhodium acetamide,

Rh2(NHCOCH,),, was employed as the catalyst the reaction was totally regloselecttve. These

results suggest, as m the cyclopropanauon chemistry, that the hgands on rhodmm play an Important

role in the C-H insetion process

1792 J ADAW and D M SPERO

scheme 37: Synthesis of y-L&ones

52 53 54

m2L4

~2(oAc>4 53 47

fi2(NI’=OCH,), >99 <l

The C-H mseztton chemistry of rhodmm medated carbines 1s stdl Elaclvely new and has

only received lmuted attention over the past decade It remams to be seen what future combmauons

of catalyst selection and stereoelectromc control m the reactmg substrate WIU reveal m establishmg

reglo-, stereo-, and eventually enanfio-specific control m the carbene C-H mserClon reacuon

IV. Heteroatom-H Insertion

Smce the pioneermg work of Yates on the copper-catalyzed decomposltton of dmzoketones

111 alcohols and phenol,W the mseNon of carbenes and carbenoids into hydroxyhc bonds has been

extensively mvestigated Teyssit? reported rhodium-catalyzed msetion of ethyl dmzoacetate mto the

hydroxyhc bond of sunple alcohols, 100,lol as well as unsaturated alcohols.102 In the case of ethylemc

and acetylemc alcohols there is a preference for O-H msettton over cyclopropanauon,102 and

examples a~. shown m Scheme 38

Scheme 38: O-H Insertion of Unsaturated Alcohols

N2CHC02Me

HX CH20H - HGCH20CH2C02Me + cyclopropanauon

Rh,(OAch 60% 12%

N2CHC02Et

OH - ~0cH2cC12Et + cyclopropanation

&(OAc), 68% 14%

Rhodmm(II) catalyzed reactions 1793

The mtermolecular O-H msemon of rhodmm carbenolds has been used to convert &ok to

&oxanes.lo3 I)lols treated ~nth ethyldiazoacetate and catalyuc rhodtum (II) pivalate afforded a mono

O-H msemon product Subsequent acid catalyzed lactonizauon followed by reduction yielded a

dloxane (Scheme 39)

Scheme 39: Synthesis of Dioxanes

R

x

OH N2CHCOzEt R OH 1. H+ )

x *

R OH Rh(II)pivalate R OCH$OzEt 2. reduce

The mtramolecular O-H msemon of rhodium carbenotds has been exploited to make fivelo

through eight membered oxygen contammg nngs lo5 Moody explored the rhodmm carbenold

cychzahons as a general route to oxygen, sulfur, and mtrogen contatmng nngs as shown m Scheme

40 lo5

Scheme 40: Synthesis of Lactones, Thiolactones, and Lactams

X= 0, S, N

Moderately good yields were obtamed for the formation of SIX and seven membered rmgs

The yield of cychzation to eight membered rtngs was lower due to compettng C-H msemon. When

X = sulfur, cychc SIX and seven membered thmethers were obtamed albelt 111 low yteld (30-35%) 105b

When X = tert-butyloxycarbonyl (Boc) or pivaloyl protected tutrogen only C-H msemon was

observed to afford cyclopentanones,‘05bV1e mstead of seven or eight membered rmgs The authors

propose that the fatlure of N-H msemon was probably due to the fact that the Boc or

plvaloyl-protected mtrogen 1s too hmdered and non-nucleoptic to mtercept the electrophlltc

rhodium carbenold However, the formatton of four, five and SIX membered rmgs by rhodmm

carbenoid msemon mto N-H bonds has been reported and is a &able process 104J06

1794 J ADAUS and D. M SPERO

An unportant syntheuc apphcatlon of the N-H msertton reactton was the con&u&on of

p-lactam antlblohcs. The earbest version of this reacaon was reported by workers at Merck Sharp &

Dohme. where dmzoketone, 55, was cychzed to the oxepenam, 56, with catalyhc rhodmm (II)

acetate’” (Scheme 41)

Scheme 41 Synthesis of Oxepenams

Bncom~[~)-co2Bn m2(oAc)4+

0

BncoNHzQ

0 t?02Bn

55 ss

Merck has also apphed the rhtium (II) catalyzed N-H mscruon towards the synthesis of

carbapenem rmg systems, and found thus method preferable to photochemical methods lo8

Photolyhc decomposhon of the dmzoketones gave Wolff rearranged products m addition to the

desmd N-H mseruon A rhodmm (II) catalyzed mtramolecular N-H mser&on was used as a key step

111 the total synthesis of the carbapenem tienamycm and IS even used in the commercial

manufacturmg of the druglOg~llO(Scheme 42)

Scheme 42: Synthesis of lhienamydn

wlo2B; NB~ +-3-&- SO-V2Nf-4+

H 2

co,

Thlenamycin

Synthetic approaches to l,Z&azehdmones have been mvestlgated by Moody and Pearson 111

Aza-P-lactams can be prepared m high yield from the Rh@) catalyzed decomposmon of dlazo

hydravdes (Scheme 43)

Scheme 43: Synthesis of Aza-p-LactamS

Rh,(OAc), z

Z

0

1795 Rhodmm(II) catalyzed reactions

The msemon reaction of carbenolds mto SI-H bonds to form carbon-s&on bonds IS a

synthehcally useful procedure Doyle has recently pubhshed a general procedure for the formation

of a-nlyl carbonyl compounds by the rhodmm (II) catalyzed decomposihon of duizoketones in the

presence of organos&mes112 (Scheme 44) In general the yields are high and thts methodology

offers an alternative to enolate amon displacement of chlonde from chlorosrlanes

Scheme 44: Preparation of a-Silyl Carbonyl Compounds

WOAc), R- L R

7 7. n R$H - 1

N2 =3

V. Ylide Formation and Reactivity

The reaction of carbenes with heteroatoms to form ylides has been known for many years ‘13

Recently there has been renewed mterest m these reactions due to the synthetic utity of the reactive

yhde In the following sectton the reactions of rhodmm (II) acetate denved carbenolds with oxygen,

sulfur, and nitrogen is reviewed

a) Carbonyl Yhde Formatton

The reaction of an a-ketocarbenoid with a lone pour of electrons on a carbonyl group

generates a carbonyl ylide Recently synthetic chemists have made use of the carbonyl yhde as a

l,f-dipole, trapping the reactive species with olefins, llSa acetylenes, carbonyls and hetero-multtple

bonded dlpolarophiles The Padwa group has been a major contnbutor to this area of research and

some of this work 1s reviewed below

Padwa et al have constructed a number of mtereshng nng systems using a carbonyl ybde

[2,3] cycloaddltion strategy 117 For example, oxapolycychc lactones can be synthesized by the

rhodium (ll) acetate catalyzed reaction of 1-acyl-1-dtazoacetates 114 The mtramolecular

cycloaddltlon of a mixed dlazomalonate ester, 57, with a suitably positioned oletin affords the

tr~ychc lactone, 58 (Scheme 45) In order for cychzation to occur, the dlazoacetate must have an

electron withdrawing group on the carbon bearmg the dlazo moiety In similar systems when the

electron withdrawing group 1s replaced by hydrogen, no cycloaddmon occurs, presumably because

the mtermedlate rhodium carbenoid has dlmmlshed electroptihcclty and therefore does not react with

the carbonyl to form the yhde I14

1796 J ADAMS and D M. SPERO

Scheme 45: Intramolecular Carbonyl Ylide Fommtion and 2,3 Cycloaddition

The same group also prepared unsaturated &alkoxyacyl-cll-&azoacetophenones, 59, and

mvestlgated rhodmm (II) acetate catalyzed cychzatlons Compound, 59, was treated with catalytic

rhodium (II) acetate and cycloadduct, 61, was isolated (Scheme 46) Expernnental support for the

formation of the mtermebate carbonyl yhde, 60, was provided by trappmg with dlmethylacetylene

dlcarboxylate @MAD) As seen m Scheme 46, the yhde mtermedlate IS suitably disposed for the 2

+ 3 cycloaddmon process

Scheme 46: Cyclization of Diazacetophenone Derived Ylides

COCHN, ~2(oAc), b

C02(CH2),CH=CH2

In the first two examples (Schemes 45 and 46) the tandem cychzatlon-cycloaddmon

sequence occurred with SIX membered rmg cat-bony1 yhdes Also reported are sumlar sequences

with five and seven membered rmg carbonyl yhdes ‘16 When cyclopropyl substituted diazoketone,

62, was treated with rhodium (II) acetate, the intermediate five membered rmg ylide was trapped

with DMAD to afford, 63116 (Scheme 47) Methyl propiolate, N-phenylmaleumde, ethyl

cyanoformatc and methyl propargyl ether were also used as 1.3~d~polarophlles

Scheme 47: Cyclization of Mam+Diketones with Acetylenes

0 0 0

CHN, Rh,(OAc),

0

R 37 R

I = CO,Me CO&H3

Me

62 63

1797 RhodNm(II) catalyzed reactions

The rhodmm (II) catalyzed reaction of a-dtazoketones ~th nelghbormg oxune ethers also

has been mveshgated 118 Cychzatton to the azomethme yhde occurs only d the oxnne ether exists N

such a conformation that the lone pau of electrons on Ntrogen am accessible to the carbenold The

rhodium (II) octanoate catalyzed reactton of 64 and DMAD afforded the azomethme yhde delrved

cycloadduct, 65 11* Sumlarly 66 could be converted to 67 (Scheme 48)

Scheme 48: Oxhne Ylides and 1,3 Cydoaddition

V-XzWOCHN2 WII) b

DMAD

65

OMe

+ ,OMe

Rh@I) ) q; DMAD. &zMe

0 0

b) Sulfonium Yltdes

The reaction of carbenes with the lone p;tlr of electrons on sulfur to form sulfomum ylldes 1s

finding mcreasmg ut~hty in orgaNc synthesis. ‘lg. 12’S 12’ KametaN has demonstrated the synthesis of

penicillin denvatlves utiizmg sulforuum yhdes as Ntermedlates Carbon can be introduced at the

C-4 poshon of azefidmones by employing a rhodNN-catalyzed decomposlhon reacuon of

ol-diazoNalonate120 with 4_phenylthloazetidmones, 68 lZ (Scheme 49) The formation of tbe C-4

carbon substituted azehdmone, 70, occurs through the yhde mtermehate, 69 Oxygen funcuonabty

can be mtroduced at C-4 of the azet&none by treatment of 68 wltb a-dnuoacetoacetate. In both

cases, the substltuents at C-3 and C-4 end up trans

As an extension of this work, the reaction of penicillm, 73, with the rhodmm carbenold of

p-mtrobenzyl a-dlazoacetoacetate afforded eight-membered oxa-derrvauves, 741Z (Scheme 50)

1798 J ADAMS andD M SPERO

Scheme 49: C-4 Substitution of Azetidinones

COZR

N2 <

COMe L R3

Rl

-P@ N 0 ‘R2

21

The approach of the carbene is from the less hindered p-face of the pemcillm bicyclic system The

conversion of 4-thloxo-2-azebdmones into 4-alkyhdme-2-azet.&nones has also been reported 134

A novel synthesis of 3,4-dlhydro- 1,3-thlazm-4(2H)-ones. 77, also made use of a carbene

addition-rmg expansion sequence ‘2.1 The rhodmm-catalyzed reacuon of dmzo compounds with

2-subsututed tsothmzol-3(2H)-ones, 75, afforded an intermediate sulfomum yltde. 76, which

rearranged to the six membered nng, 77 (Scheme 5 1)

Ando and co-workers have mvestlgated the reaction of cyclic disulfides with carbenes to

afford 1 ,Z&thlanes, or desulfurtzatlon products if the dlsulfide and the carbene are stertcally

hindered 125 In most cases the authors used CuCl to catalyze carbene formation, however, some

examples employed rhodmm (II) acetate and the results dtd not depend on the method of carbene

generation In general, the yields for the desulfurrzation reacttons are approximately 30% The

yields for the S-S mseNon products are typically greater than 65%

Rhodmm(II) catalyzed reactions 1799

Scheme 50: Ring Expansion of Penidllimi

H

COzR

Me C02R

N2

Rh20W,

Scheme 51: Synthesis of DihydIxAhhzinones

Me

R R +

It 1s well known that sulfomum yhdes are isolable when stabtized by two electrons

wlthdrawmg groups 121*126 Stable cychc sulfomum yhdes are less well known although some have

been prepared by the treatment of cychc sulfomum salts ~th base. 127 Stable cyclic sulfomum yhdes

formed via a carbene route have been reported by DavieslB and MoodylB Moody demonstrated

that 111 the presence of catalec rhodmm (II) acetate the dmzosulfide, 78, gave the stable yhde, 79, m

24% yield (Scheme 52). Further heating m toluene effected a Stevens type [ 1,2]-rearrangement to

the thlapyrone, 80

Thlophenes react with dlazomalonates under rhodium (II) acetate catalysis to give

thlophenmm methylides 130 ImtAly, copper catalysis was mvesttgated as the means for genemtmg

the carbene but these reachons were lmprachcally slow, typtcally takmg eight days at reflux with

incomplete reaction 130 In contrast the rhodium (II) acetate reactions are complete m 18h at room

1800 J ADAMS~~~D M SPERO

Scheme 52: Sulfonium Ylides and Stevens Reanangement

0 m@Ad,

S I

C02Et

\Pll

28

0

C02Et

Ph

!B

temperature Otto Meth-Cohn found that 2.5&chlorothtophenes reacted ~rlth Qazoketones to yield

yhdes which reatiy underwent thermal rearrangement to give oxathmcmes 131

Intramolecular versions of tiophemum yhde formation have also been reported m the

hterature 132 Rhodmm (II) acetate catalyzed decompostuon of the Qazo compound, 81. gave

cychzed 83 as the maJor product, presumably arrsmg from a Stevens rearrangement of yhde,

82133(Scheme 53) In addmon, the C-H mseruon product, 84, was Isolated 11125% yield

c) Oxomum Ylides

Oxonmm yhdes have been postulated as mtermedtates when diazo compounds decompose m

the presence of 2-phenyl-l,3-&oxolsne,135 styrene o~ldes,‘~~ allyhc ethers,13’ ahphatlc ethers,138.13g

allyhc acetals,lN oxetanes141 and furans 142 Carbenoids react wtth the oxygen of epoludes143 and

sulfoxldes144 effectmg transfer of oxygen to the carbene center Oxomum yhdes have also been

generated by deprotonatton’” and desdylauon 145 of oxomum ions and they are mvolved m the

zeohte catalyzed conversion of methanol to ethylene146

Johnson has deslgned ahphatic, alkoxysubshtuted hazoketones and ut&zed theu rhodunn

(II) acetate decomposlhons to yteld cycloalkanones 147 The presence of an mtermebte oxomum

yltde was proposed An example of tis work is shown m Scheme 54 Diazoketone, 85, was

decomposed m the presence of rhodium (II) acetate to form cyclobutanone, 87, and cyclooctenone,

89 When the methyl subshtuted diazoketone, 86, was SubJected to the reactton condmons the

resultmg cyclobutane, 88, was formed 111 high tiasteroselectivlty (97 3) with the CIS vlcmal methyl

groups of the cyclobutanone nng as the maJor diastereolsomer

Rhodmm(II) catalyzed xeactlons 1801

scheme 53: Thiophenlum YIldes

0

sl

I- C-H insertion

CO,Me MeOzC 0

P

Pumng148 has reported results on the mtramolecular generation of allybc oxomum yhdes and

tbelr subsequent [2,3]-szgmatroplc rearrangement to @ve five-, six-, and eight- membered oxygen

heterocycles In a generalized scheme dmxoketone. 90, was treated with rhodium 0 acetate to form

au allyhc oxomum yhde, 91, which underwent a [2.31-slgmatroplc rearrangement to form an oxygen

contimng nng, 92 (Scheme 55)

In the majortty of examples the htghest ytelds were obtamed when R=C02R1 Altemattve

pathways avalable to the carbenold (e g , C-H msertlon, cyclopropanation and dlmenzauon) were

muumlzed by the kmeuc preference for five-membered nng formation Furanones are formed 111

very good yields (93-W. whereas pyranone formation occurs m modest yield (95-W) due to

competmg C-H msemon (Scheme 56)

Padwa has also observed that for the formation of SIX-membered rmgs, C-H msertlon can be

competitive wtth yhde formation and subsequent [2,3] sigmatroplc rearrangement 149 In ad&tion he

1802 J ADAMS andD M SPERO

Scheme 54: J.ntmmokcdar Cyclhation of Oxonium Ylides

a R=H

@i R=Me

\ Oil0 f , a R=H

@ R=Me

Scheme 55: Allylie Oxonimn YUde

0

@ R=H

noted that the replacement of ally1 substituted oxygen with sulfur resulted m pnmanly yhde dewed

products Moody has also studied the [2,3]-rearrangements of S-ally1 sulfomum yhdes to form

six-membered nngs 12g

Rhodmm(II) catalyzed n?acnons 1803

Scheme 56: Synthesis of Furanones and Pyrmms

0 0

C02Me

w

d) Intermolecular Reactions of Carbenes with Allyhc Hetero Compounds

Intermolecular reacttons of rhodmm carbenolds with allyhc hetero compounds ate Hndely

recogmzed The [2,3]-sigmatropic rearrangement of S-ally1 sulfomum ylldes. generated by the

reaction of a dmzoketone and an ally1 alkyl sulfide, has been stu&ed by Takano lx) In a typxal

procedure allylphenylsulfide, 97, and dlazo compound, 98. were heated to reflux m toluene in the

presence of rhodmm (II) acetate to form the intermediate sulfomum yhde, 99, which underwent 2,3

sigmatropic rearrangement to form 100 (Scheme 57)

Scheme 57: Interrnokcular Ylide Formation with Allylic Sulfides

Ry&x Y

G31 R -

-R G

SPh

x Y

J ADAMS andD M SPERO

With simple alkyl ally1 sulphldes, [2,3]-slgmatropic rearrangement was the maJor pathway

However with more complex systems, such as 2-vmyl derrvatlves of 1.3~d~tiuane and 1,Zditiolane.

ehmmatton reactions of the mtermediate yhdes was compettuve with [2.3]-sigmatroplc

rearrangement 140

Ally1 acetals underwent yhde generauon m rhodmm (II) acetate catalyzed reactions with

dmzoesters to form 25Qalkoxy44kenoates by 12.31~slgmatroplc rearrangement. 140 Competmg

cyclopropanation. and 111 some cases Stevens rearrangements, occurred The product dlstnbutlons

were dependent on the catalyst, dlazo compound, acetal and temperature

Metal catalyzed decomposition of dlazoesten m the presence of ally1 hahdes can afford

halomum yhdes, but cyclopropanatlon IS competitive with yhde generauon and Earrangement

Compeutton between cyclopropanation and yhde generation can be mampulated by varymg the

nucleophihclty of halogen m the reactant ally1 halide. Reactions with ally1 to&de resulted solely 111

the product from [2,31-slgmatroplc rearrangement, whereas cyclopropanation occured predommantly

with ally1 chlorrde 150bz1 Catalyst selection was also Important: Cu catalysis afforded more

complex reacuon mixtures due to C-Br bond cleavage Another method of mcreasmg the relattve

yield of yhde denved product was through the use of rhodmm (II) perfluorobutyrate 151

In summary, the chemistrypf yhde formation resultmg from Rh(II) catalyzed dtazo-carbonyl

decomposition IS very nch and dtverse. allowmg for many novel synthettc appllcahons

Nevertheless, optunum utdity of these processes reqmres analysis of the reacting substrates, the

catalyst employed and the reaction conditions, smce the reacuon pathways of yhde mtermedmtes are

numerous

Rhodmm(II) catalyzed reactions 1805

(a) Wong, H.N.C.; Hon, M., Tse, C., Yip, Y.; Tanko, J ; Hudhcky, T. them Rev (1989). 89, 165 (b) Boyer, E.B.; Robmson, S.D. Coordmatwn Chtmstry Rev (1983) 50.109. Ed. Lever, A B P., Elsemer, Amsterdam-oxford-New York Brookhart, M., Studabaker, W B Chem Rev (1987) 87.411 Maas. G Topics zn Current Chemstry. Vol 137, Sprmger-Verlag, Berlm Hadelberg, 1987 Doyle, M P them Rev. (1986),86,919. Knmse, W “Carbene Chemistry”. 2nd ed., Academtc Press, New York, 1971. ~116 Marchand. A.P.. MacBrockway. N Chem Rev (1974) 74.431. Jones Jr., M.; Moss, R A., Eds., “Carbenes”, Vol. 1. Whey, New York, 1973 Armstrong, R K .Z. Org Chem (1966) 31.618 McBee. E T , Calundann, G.W ; Hodgm, T J Org. Chem (1966) 31,426O. Werner, H , &chards, J H. J Am. Cheer. Sot. (1968) 90,4976. Montam, I , Yammamoto. Y., Homsb, H .Z Chem Sot , Chem Commun (1969) 1457 K&mam, K., Hlyama, T , No&, H. Tetrahedron Lett (1974) 153 1 Pauhssen, R , Hubert, A J ; Teyssl P. Tetrahedron Letz (1972) 1465 ;;;ssen, R , Rennlmger H., Hayez E , Hubert, A J , Teyssd, P Tetrahedron I&. (1973)

Pauhssen, R ; Hayez, E , Hubert, A.J., Teyssd, P Tetrahedron Z.&r (1974) 607. Hubert, A J .Noels, A.F , Anaaux, A J Teyssn?. Synthesrs (1976) 600 Anclaux, A.J , Hubert, A.J , Noels, A F 695

Petuuot, N , Teyss& P J Org Cheer (1980) 45,

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Belg

zeyt, N , Anclaux, A J , Noels, A F , Hubert, A J Teyss& P Tetrahedron Leti (1978)

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J ADAMS~~~D M SPERO

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1807 Rhcdmm(II) catalyzed reactions

91 92 93

98 99 100

101 102

103 104 105

106 107 108 109

110

111

112 113

114 115 116 117 118 119 120 121 122 123 124 125 126

127

128 Davies, H &I L ; Cnsco, L.V.T Tetr&edrdn Lett (i987) 28; 37 1.’ 129 Moody, C J , Taylor, R J Tetrahedron Lett (1988) 29,6005

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(b) Moody, C J , Pearson,

aza-analogues of B_lactam antlbtottcs see For an attempted approach to the

(1984) 49,113 Taylor, E C ; Davies, H M L J. Org Chem.

Baghen, V , Doyle, M.P , Taunton, J , Claxton, E E J Org Chem., (1988) 53,6158 Ibata, T ; Hamaguchl, M Tetrahedron Lett (1974) 4475 Ibata. T.. Toyoda. J Bull them Sot Jpn (1985) 1787 Taylor, K G Tetrahedron (1982) 38, 159 Dean, D C , Krumpe, K E , Padwa, A J Chem. Sot , Chem Commun (1989) 921 Gallon , A , Ova&a, D , Kapon, M , Bien, S Tetrahedron (1982) 38.1477. Padwa, A , Chum, R.L , Hombuckle, S F , Zhl, L Tetrahedron Lett (1989) 30,301 Padwa, A , Stull, P.D Tetrahedron L&t (1987) 28,5407 Padwa, A , Dean, D C. J Org Chem (1990) 55,405 Doyle, M P Chem. Rev. (1986) 86,919 Maas, G Tap Curr Chem (1987) 137,75 Ando, W.,Acc Chem Res (1977) 10.179 Kametani, T , Kanaya. N ; Mochlzti, T ; Honda, Heterocycles (1982) 19(6), 1023 Kametani, T ; Kanaya, N , Mochizulu, T , Honda, T Tetrahedron Lett. (1983) 24,221 Crow, W D : Gosnev. I, Grmiston. R A J Chem. Sot Gxnmun (1983) 643 Ando, W , I&man&&, Y.. Takata,.T Tetrahedron Lett. (1985) 26‘(42),-5187 Ando. W , Yagihara, T , Tozune, S , Imiu, I , Suzukt, J , Toyama. T ; Nakrudo. S , Mtgta, T .Z Org Chem (1972) 37.1721. Hart, M , Kataoka, T , Shtmlzu, H , Kataoka, M , ToNo~~. A , tishlda, M Tetrahedron L&t. (1983) 24,3733 Herr, M , Kataoka, T , S~INIZU, H , Inm, E , Tomoto, A ldld (1982) 25, 2597 Hon. M.. Kataoka. T . Shtmlzu. H . Tomoto. A Ibid 11981) 22.3629

1808 J ADOS andD M SPERO

130. Gillespie, R J.; Murray-Rust, J , Murray-Rust, P ; Porter, A.E.A. J them Sot. Chum Commun. (1978) 83. Gdlespre, R.J.; Porter, A.E.A J Chem Sot. Perkm Trans Z (1979) 2624

131 Met&Cohn, 0.; Vuormen, E. J. Chem Sot Chem Commurt. (1988) 138 132 Storflor, H.; Skramstad, J Acru Chetnica Scuuuinuvrcu (1986) B40.303 133 Storflor, H., Skramstad, J.; Nordenson, S. .Z. Chem Sot Cheer Gxaamn. (1984) 208 134. 135

Bachi, M.D.; Goldberg, 0.; Gross, A.; Vaya, J. J. Org. cheat. (1980) 45.1481 Guts&, D.C., Hrllman, M. J. Anr C&em. Sot. (1954) 76,2236

136 Nozakt. H , Takaya, H ; Noyon, R. Tebuhedron Z&.(1%5) 2563. 137 Ando. W., Yagiham, T , Kondo, S ; Nakayama, K; Yamato, H.. Nakatdo. S.; Mrgrta, T. J.

Org Chem (1971) 36,1732. (b) Ando, W , Kondo S ; Nakayama, K.; Iclubort. K, Kohoda, H.; Yamato, H.; Ima, I.; Nakatdo, S.; Migita, T. J. Anr C&em Sot. (1972) 94.3870.

138 Iwamura. H , Imahashr, Y , Kushnla. K , Aoki, K., Satoh, S Bull Chem Sot Jp (1976) 49, 1690

139 140 141

142

143

:z

146

147 148 149 150

151

_-_ _ Olah, GA.; Doggwerler, H.; Felberg, J.D J Org Chem (1984) 49.2116. Doyle, M.P.; Griffm, J H.; Chum, M.S ; van Leusen, D J Org. Chem. (1984) 49, 1917 Friedrich, K.; Jansen,D ; Kumse, W , Tetrahedron Left. (1985) 26,193 Kumse, W , Cmem, P V. Tetrahedron Len 0985) 26, 197. Saltykova, L.E.; Vasdvnski, A.E.; Shostakovski, V M., Nefedov, O.M. In. Akaa! Nauk, SSSR Ser. Khnn., (1988) 4,842. Nefedov, 0.M ; Vasibntskt, A.E.; Zlatkma, V.L., Yuflt, D.C.; Struchkov, Y T ; Shostakouskt, V M ibid (1988) IO,2340 Martin, M F , Ganem, B Tetrahedron L&t. (1984) 251 Ebbmghaus. C F , Momssey, P , Rosa& RL. Z. Org. Chem (1979) 44.4697 Olah, G.A , Doggweder. H., Fe&erg, J D Z. Org Chem. (1984) 49.2112. Olah. GA., Doggweder, H , F&erg, J.D. Frohlich, S. .Z. Org. Chem (1985) 50.4847 Olah, G A ; Doggweder, H ; Felberg, J D ; Frohhch, S., Grrdina, M J.; Karpeles, R.; Keumt, T., Inaba, S , Ip, W.M.; Lammertsma, K.; Salem, G.; Tabor, DC J Am Chem Sot. (1984) 106,2143. Mole, T J Cqtal (1983) 84,423. Roskamp, E.J.; Johnson, CR. J Am Chem Sot. (1986) 108.6062 Pnrung, M.C.; Werner, J.A. .Z. Am Chem Sot. (1986) 108.6060 Padwa, A , Hombuckle, S.F , Fryxell, G.E., Stull, P D. .Z. Org Chem. (1989) 54,817 Takano, S , Tomna. S , Takahasht. M , Ogasawara, K Chemrstry Letters (1987) 1569 (b) ~or;nnilar studies see Doyle, M.P., Tamblyn, W.H , Bagherr, V J Org Chem (1981) 46,

Doyle, M P. Act Chem. Res.(1986) 19.348