Chemical Reviews

Chem. Rev. 1990, 90, 879-933 879 Chemical Reviews

Volume 90, Number 6 September/October 1990

Directed Ortho Metalation. Tertiary Amide and &Carbamate Directors in Synthetic Strategies for Polysubstituted Aromaticst

VICTOR SNIECKUS

Guelph- Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G 1

Received August 17, 1989 (Revised Mnuscript Received February 20, 1990)

Contents 2. 1-Naphthols 904 C. o-Formyl 905 1. Introduction 880 1. Phthalides by Reduction 905 II. Aim and Scope of the Review 880 2. 3-Hydroxyphthalides and 905 111. The Directed Ortho Metalation (DoM) Reaction 88 1 Isobenzofurans A. General Characteristics of DoM and Scope 88 1 3. Isoquinolones 908 of Directed Metalation Groups (DMGs) D. Ortho Hydroxyalkylation 908 8. Bases 882 1. Naphthoqulnones 908 C. Mechanistic Aspects 882 2. Phthalides and Derived Anthraquinones 909 D. Nature of the DM6 883 3. Polycyclic Aromatic Hydrocarbons via 915 E. Hierarchy of DMGs 884 Phthalides F. Cooperative Metalation Effects 884 4. Anthraquinones Not via Phthalides 915 G. Practical Aspects 886 5. Intramolecular Epoxycyclialkylation 917 IV. Methodological Aspects of Tertiary Amide and 887 E. Ortho Carboxylation and Acylation 917 0-Carbamate DMGs IX. Synthetic Consequences of o-Heteroatom 917 A. Aromatic Tertiary Amide 887 Introduction B. Heteroaromatic Tertiary Amide 89 1 A. o-Amino 917 C. Amide Manipulation 89 1 1. Quinolones 917 D. Aromatic Tertiary 0-Carbamate 894 2. Acridones 920 E. Heteroaromatic Tertiary 0-Carbamate 894 B. o-Thiol and o-Selenol 920 F. Carbamate Manipulation 897 C. o-Silyl 922 V. The Amide-Carbamate Connection 897 1. Protection of Aromatic Preferred 922 A. Anionic Rearrangements 897 Metalation Sites B. Benzyne Generation 898 2. Fluoride- and Electrophile-Induced Ipso 922 VI. 2,6-Dianion Equivalents 899 Desilylation VII. Iterative DoM Reactions 900 D. o-Stannyl 923 VIII. Synthetic Consequences of oCarbon 900 E. o-Boronic Acid 924 Electrophile Introduction 1. Cross-Coupling Methodology 924 A. &Methyl 900 2. Dibenzopyrones 928 1. Chain Extension 901 3. Phenanthrols and Phenanthrenes 928 2. Heteroannelation via o-Tolyl Anions 90 1 4. Remote Metalation to Fluorenones 928 3. a-Silylated o-Toluamides 902 X. DoM of Benzamides and Free Radical 929 B. o-Allyl 903 Chemistry 1. Isocoumarins 904 XI. Concluding Remarks 930 'It is with regret that I am unable to provide complementary re- XII. Acknowledgments 93 1 prints. XIII. References 93 1

0009-2665/90/0790-0879$09.50/0 0 1990 American Chemical Society 880 Chemical Reviews. 1990. VoI. 90. No. 6 Snleckus

SCHEME 1. Synthetic Approaches to Substituted Aromatics C4DYdllMb" 0.lnr" una, .. Anne ."wcnulm car*." car*..,

Victor Snieckus was born in Kaunas. Lithuania. and spent his childhood in Germany during World War II. He obtained his BSc. degree from the University of Alberta in 1959. where he was strongly influenced by R. Sandin. He studied with D. S. Noyce (M.Sc.. University of Caiifomia. Berkeley. 1961) and V. Boekekwii (Ph.D.. University of Oregon. 1965). Following a posMoctoral year with 0. E. Edwards (National Research Council. Onawa). he joined the University of Waterloo. His major research focus is in the SCHEME 2. The Directed Ortho Metalation Reaction development of new methods and strategies in organic synthesis, with increasing emphasis on biological molecules. He can be distracted from ihe laboratory by yxd Buand noncontaci hodcey. 1 2 3

I. Introductlon ence of o-halo similarly, SRNlreactions based on 1,2-disubstituted precursors;12 nucleophilic Studies on the structure, reactions, and synthesis of substitution of (r-arenehetal (Cr, Mn) tricarbonyl aromatic compounds are steeped in the history of or- complexe~;"~J~sigmatropic rearrangements;" carban- ganic chemistry since the time of KekulB's dream a ionic de novo ring constru~tion;~~cycloaddition with or century ago.'J Today, the regiospecific preparation and without small-molecule extr~sion;'~J~transformation modification of polysubstituted aromatic molecules of heterocycle^;'"'^ dearomatization-rearomatization constitute engaging fundamental problems in synthetic ta~tics.'~J'' chemistry in both industrial and academic laborator- In 1939-1940, the independent discovery by Gilman ie~.'.~Many modern synthetic targets, in particular and BebbIg and Wittig and Fuhrmanm of anisole ortho those of interest for pharmaceutical and agrochemical deprotonation by n-BuLi constituted a harbinger for preparations, either are benzenoid or incorporate key a new conceptual framework in synthetic aromatic aromatic or heteroaromatic component^.'*^ In these chemistry. These seminal results of the directed ortho endeavors, commercially available aromatic substances metalation (DoM) process initiated fundamental re- are modified in a variety of ways for a variety of pur- activity studies by GilmanZ1and, in the early 196Os, by poses by (a) functional group introduction into a mone Hauser and his students,n who also systematically ex- or disubstituted material, (b) functional group inter- panded the scope of directed metalation groups conversions, (c) attachment of chains either to existing (DMGs). The complementary technique of metal- functionality or directly onto the ring, (d) hetero- or halogen exchange, also discovered by Gil~nan*~and carbocyclic ring annelation, and (e) reduction (e.g., Wittig,% provided further impetus to this area.% In the Birch) and ring destruction (e.g., ozonolysis) to carbo- 1970s, the industrial use of alkyllithium bases as po- cyclic and acyclic derivatives. lymerization catalystsm led to their commercial avail- The initial response triggered by traditional pedagogy ability and allowed the metalation technique to he in undertaking a problem in synthetic aromatic chem- practiced widely. In 1979, the outstanding compre- istry is to apply classical electrophilic substitution? hensive review by Gschwend and Rodriguezn brought While these diverse reactions are not to be denied in timely appreciation of the potential of the DoM reac- synthetic planning, they often suffer from harsh con- tion?" The past decade has seen the evolution of this ditions and formation of mixtures of positional isomers. reaction as a significant fundamental methodology, Given the normal electrophilic substitution rules, the demanding at least "equal time" with other methods, preparation of contiguously substituted systems (1,2-, for the regiospecific construction of polysubstituted 1,2,3-, and 1,2,3,4-) can become a most demanding aromatic and heteroaromatic compounds. challenge. To aid the synthetic chemist in the fundamental task of constructing the prototype 1,Zdisub- stituted aromatics, an armamentarium of methods has II. Alm and Scope of the Revlew evolved in the interim (Scheme lh7 electrouhilic substitution via para protection-deprotectionaand metal chelati~n;~the use of u-transition-metal complexes, the This reviewB will focus on tertiary amide and 0- synthesis of which u invariably depend upon the pres- carbamate DMGs for methodological and total syn- Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 881

TABLE 1. DMGa in Synthesis: Qualitative Evaluation Z (pKJ synthetic Z (PKA synthetic carbon based" utilitvb ref heteroatom baaeda utilitvb- ref strong CON-R +++ 27, 29f N-COR (240.5) +t C CSN-R t+ d N-CO,R +++ e CONR, (37.8) t+t 29a-e OCONRZ (3782) ++ 114 CONR, (31.1)f tt f OPO(NRI2 + 139 CON(R)CH(Z)TMS, Z = H, TMS t 104, 157 OCHIOMe t++ 66, 106 tetramer t g OTHP (40.0) c, 1 27 t++ 29g OPh (38.5) + i 1 SOaR + J CH=NR ++ h S02N-R + 27 (CH2),NR2, n = 1, 2 (240.3) + 27 SOzNR (38.2) + 27 so,- t k CH(0H)CHzNRz + 27 SO,-t-Bu + 1 CN (38.1) t 49 SO-t-Bu t m moderate CF3 + 27 NR, (240.3) + 27 N=C ++ n OMe (39.0) +++ 27 ++ 84 OMe (33.0)f + f OCH=CH2 + 0 OPO(0R)p + 107

O(CH2)2X,X = OMe, NR2 + P F + 4 c1 ? r PO(NR)z + S PS(Ph)NRZ + t weak C(OTMS)=CHZ + 27 0- (240.5) + U CH(OR)p + u S- + W CHZO- +t X R t Y I $4;)I

R + 2 dJ CrC- + aa Ph + bb OpK, data in parentheses are given in ref 30 and: Fraser, R. R.; Bresse, M.; Mansour, T. S J. Chem. SOC.,Chem. Commun. 1983, 620. +++ = well proven/extensively applied; ++ = promising/requires studies in scope, application; + = inadequately tested/new/limited use. cFuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979,44,1133. dFitt, J. J.; Gschwend, H. W. J. Org. Chem. 1976,41,4029. eMuchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980,45,4758. fCr(C0) complex. Fraser, R. R.; Mansour, T. S. J. Organomet. Chem. 1986,310, C60. gKraus, G. A.; Pezzanite, J. 0. J. Org. Chem. 1979,44, 2480. il Cushman, M.; Choong, T.-C.; Valko, J. T.; Koleck, M. P. J. Org. Chem. 1980,45,5067. 'Narasimhan, N. S.; Chandrachood, P. S. Synthesis 1979, 589. JBonfiglio, J. N. J. Org. Chem. 1986,51, 2833. kFiguly, G. D.; Martin, J. C. J. Org. Chem. 1980, 45, 3728. 'Iwao, M.; Iihama, T.; Mahalanabis, K. K.; Perrier, H.; Snieckus, V. J. Org. Chem. 1989, 54, 24. "Quesnelle, C.; Iihama, T.; Perrier, H.; Aubert, T.; Snieckus, V., unpublished results. "Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. Bull. Chem. SOC. Jpn. 1984, 57, 73. "Muthakrishnan, R.; Schlosser, M. Helu. Chim. Acta 1976, 59, 13. PWada, A.; Kanatomo, S.; Nagai, S. Chem. Pharm. Bull. Jpn. 1985, 33, 1016. PGschwend, H. W.; Hamdan, A. J. Org. Chem. 1982, 47, 3652. 'Sutter, M. A.; Seebach, D. Ann. 1983, 939. "ashan, L.; Trippett, S. Tetrahedron Lett. 1983,24, 2039. "oshifuji, M.; Ishizuka, T.; Choi, Y. J.; Inamoto, N. Tetrahedron Lett. 1984,25, 553. "Posner, G. H.; Canella, K. A. J. Am. Chem. Soc. 1985,107, 2571. "Plaumann, H. P.; Keay, B. A.; Rodrigo, R. Tetrahedron Lett. 1979, 20,4921. "Figuly, J. D.; Loop, C. K.; Martin, J. C. J. Am. Chem, SOC.1989,111,654. Block, E.; Eswarakrishnan, V.; Gernon, M.; Ofori-Okai, G.; Saha, C.; Tang, K. J. Am. Chem. Soc. 1989, 211, 658. Smith, K.; Lindsay, C. M.; Pritchard, G. J. J. Am. Chem. SOC.1989, 111, 665. xUemura, M.; Tokuyana, S.; Sakan, T. Chem. Lett. 1975, 1195. Meyer, N.; Seebach, D. Chem. Ber. 1980, 118, 1304. YHarris, T. D.; Roth, G. P. J. Org. Chem. 1979, 44, 2004. "oulihan, W. J.; Parrino, V. A. J. Org. Chem. 1982, 47, 5177. Houlihan, W. J.; Parrino, V. A. J. Heterocycl. Chem. 1981, 18, 1549. "'Hommes, H.; Verkrusse, H. D.; Brandsma, L. Tetrahedron Lett. 1981, 22, 2495. Hommes, H.; Ver- kruijsse, H. D.; Brandsma, L. J. Chem. Soc., Chem. Commun. 1981, 366. bbNeugebauer, W.; Kos, A. J.; Schleyer, P. v. R. J. Organomet. Chem. 1982,228, 107.

thesis journeys in aromatic chemistry. After a brief III. The Directed Ortho Metalation (DOM) overview of general aspects of the DoM reaction, the Reaction utility and applications of tertiary amide and carbamate DMGs will be systematically and comprehensively de- A. General Characteristics of DoM and Scope veloped. Where appropriate, comparison with other of Directed Metalation Groups (DMGs) carbon-based (CONHR,oxazoline) and oxygen-based (OMOM) DMGs for synthetically equivalent operations The DoM reaction (Scheme 2) comprises the depro- will be provided. tonation of a site ortho to a heteroatom-containing 882 Cnemlcal Revlews. 1990, Vol. 90, No. 6 Snieckus

TABLE 2, Aggregation State oP Organolithium Reagents SCHEME 3 concn RLi solvent range, M species ref MeLi THF or EtBO 0.2-1.2 tetramer a n-BuLi C6HLZor PhH 0.4-3.4 hexamer b-d THF or Et,O 0.14.7 tetramer .+a, c, e, f dimer n-BuLbTMEDA ? 0.1 monomer g n-BuLLTMEDA '! high dimer g sec-BuLi C5H1b tetramer - h hexamer THF or Ego tetramer d t-BuLi n-Hex,C,H,,, 0.05-0.50 tetramer c, i or PhH sec-BuLi-TMEDA combination appears to be a most THF dimer d potent metalating agent, effecting deprotonation of "West, P.; Waack, R. J. Am. Chem. SOC. 1967, 89, 4395. Me& 1000-fold faster than the n-BuLi-TMEDA com- bMargerison, D.; Newport, J. P. Trans. Faraday SOC.1963, 59, 2058. plex.26a Increased understanding of the stability of CBrown,T. L. J. Am. Chem. SOC.1970, 92, 4664. dEastham,J. J. Am. Chem. SOC.1964,86, 1076. eQuirck, R. P.; Kester, D. E. J. Organomet. RLi-solvent as well as the effect of metal Chem. 1974, 72, C23. fSee ref 43. #See ref 26a. hFraenkel, G.; Hen- alkoxides41* and continuing evolution4 of the powerful richs, M.;Hewitt, M.;Su, B. M. J. Am. Chem. SOC.1984, 106, 225. LICKOR bases,45which have not as yet been applied 'West, P. Inorg. Chem. 1962, 1, 654. in DoM reactions, will undoubtedly influence future application in synthesis. Lithium dialkylamide~~9~~are of insufficient kinetic DMG (1) by a strong base, normally an alkyllithium basicity for the DoM reaction. However, reports of reagent, leading to an ortho-lithiated species 2. This effects of LiX on selectivity of enolization4 and success species, upon treatment with electrophilic reagents, in aromatic and heteroaromatic deprotonations using yields 1,2-disubstituted products 3. Table 1 lists the in situ trapping combinations under thermodynamic currently available repertoire of DMGs, somewhat ar- condition~~+~l(e.g., LiTMP/TMSCI)49should also be bitrarily divided into strong, moderate, and weak viewed with anticipated synthetic potential. groups,3otogether with pKa data and qualitative evaluation of use and potential in synthesis. Of the over C. Mechanistic Aspects 40 DMGs, over half, including the CONR2 and OCONR2 groups, have been introduced into synthetic Although undoubtedly simplistic, the DoM process practice since the publication of the Gschwend and may be viewed as a three-step sequence (Scheme 3): Rodriguez review.27 coordination of the (RLi), aggregate to the heteroatom-containing DMG, 4 - 5; deprotonation to give the 6. Bases coordinated ortho-lithiated species, 5 - 6; and reaction with electrophile to yield product, 6 - 7. The original The DoM process normally demands the use of suggestion52that the ortho-lithiated species 6, DMG = powerful alkyllithium ba~es~l-~,in organic solvents in OMe, is stabilized by coordination has been supported which they exhibit high solubility due to association by thermochemical data which established that proton into aggregates of defined structure, typically as hex- quench of (p-anisy1)lithium is 3.6 kcal/mol more exo- amers (in hydrocarbon solvents) or tetramers-dimers thermic than that of (o-ani~yl)lithium.~~Studies con- (in basic solvents) (Table 2). On the basis of reactiv- cerning rate enhancement of anisole deprotonation it~,~lNMR,35 X-ray structure,36 and ~alculational~~ relative to benzene,54 (T Taft relationships between studies, alkyllithiums are viewed predominantly as DMGs and partial rate factor, fortho, for base-catalyzed bridged structures of electron-deficient bonding ar- deuterium exchange,55pK, measurement^,^^ steric ef- rangements of polar multicovalent c-Li bonds which fect~,~~~~~~~and ab initio calc~lations~~~~ are all con- in solution undergo fast equilibrium carbon-lithium and sistent with the thermodynamic stabilization of an or- lithium-ligand bond exchanges as well as rapid con- tho-lithiated species 6, DMG = OMe. That complex- formational interconversions. ation is also kinetically acidifying was suggested initially In hydrocarbon solvents, alkyllithiums are thought from qualitative NMR,30-56kinetic isotope,Mand steric to react as aggregates and mixtures of aggregate or effe~t~~i~~i~~investigations. Recent crystal structure dissociated species.% Addition of basic solvents (ethers, determinations of ortho-lithiated species indicating amines, phosphines) causes dissociation by an acid-base complex tetrameric aggregates with a high degree of reaction: e.g., THF coordination to (n-BuLi), leads to lithium-heteroatom coordination61 may be taken as solvated (n-BuLi), (Table 2), and addition of Et3N to circumstantial evidence for the existence of the ortho- (t-BuLi), leads to a 50-fold acceleration in dissociation lithiated intermediate 6. to (~-BUL~),.~~Furthermore, bidentate ligands, in Using HOESY and supportive MNDO calculations, particular TMEDA, effectively break down alkyllithium Bauer and Schleyer obtained initial mechanistic evi- aggregates, forming monomers and dimers in solution dence for the formation of 2.62 In toluene at -64 "C, (Table 2), and thereby significantly increase their anisole and n-BuLi exist as a tetrameric aggregate 8 basicity.32 X-ray crystal structure data indicate that (Scheme 4). Addition of 1 equiv of TMEDA forms the these species are usually of the form (RLi.TMEDA)2 1:l n-BuLi-TMEDA dimer 9 and free anisole (no involving fourfold-coordinated lithi~m.~%~~Their en- HOESY anisole-Li interactions), which, however, does hanced basicity is illustrated by the observed quanti- not undergo ortho lithiation. This is hypothesized to tative deprotonation of benzene by n-BuLiSTMEDA occur via a low (NMR undetectable) stationary con- compared to its nonreactivity with n-BuLi alone.% The centration of species 10 whose newly available two co- Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 663

SCHEME 4 with marginal supporting evidence,5'@ although the - intervention of radicals in reactions of naphthalene with n-BuLi.TMEDA6' and anisole with lithium naphth- alides8 has been reported. The mechanism of the reaction of 6 with electrophiles to give 7 (Scheme 3) has not been investigated for any DMG. The reaction of alkyl halides with alkyllithiums has been studied extensively and shown by CIDNP experiments to proceed by a SET proces~.~~~~~On the basis of kinetic and physical measurements, Brown and co-workers have suggested that PhLi reacts as a disso-

10 ciated species.39 However, Bauer and Schleyer have demonstrated that the monomer-dimer equilibrium of PhLi is shifted completely toward dimer upon addition of 1 equiv of TMEDA.62 The evolving mechanistic studies of organic reactions that occur by SET pro- cesses70 will undoubtedly have an impact on the understanding of the conversion 6 - 7. 13 D. Nature of the DMG

SCHEME 5 For a successful deprotonation to occur, the DMG (Table 1) must exhibit the somewhat schizophrenic properties of being a good coordinating site for alkyllithium and a poor electrophilic site for attack by this strong base. A heteroatom is therefore an obligatory component of a DMG. Steric hindrance (CONEh, oxazolino, OCONEt2, P(0)NR2), charge deactivation (CON-R, CSN-R, imidazolino), or both (-NC02-t-Bu, I CHs -NCO-t-Bu) may be incorporated into the design of the 17 metalation director. On the basis of limited data on Ar - 2,4,6-(kPr)3CSH2 systems containing two competing DMGs, Gschwend and Rodriguez suggested27 the operation of either a "coordination only" or an "acid-base" (inductive) ordination sites at Li are taken up by anisole oxygen mechanism. The relative significance of coordination and agostic Li-H interactions to give 11. Irreversible and inductive effects of modern DMGs has not been deprotonation follows to give ortho-lithiated species 13 systematically correlated with fundamental Lewis and 1:l n-BuLieTMEDA species 12, both of which un- acid-base and electronic principle^.^^ Inductive effects dergo aggregation. MNDO calculations support the appear to play the major role in ortho deprotonation postulated structure 11. Thus kinetic (Li with the of fluorobenzene62and benzonitrile,72 since neither can availability of more than one coordinating site) and achive normal coordinatively stabilized ortho-lithio in- thermodynamic (ortho heteroatom coordination to Li) termediates. pK, determinations reflecting mainly in- factors appear to be significant in the DoM process. ductive effects show little variation (Table 1) and, since Similar observations were recorded for 1,2-dimethoxy- qualitative observation of variation in rates as a func- benzene and N,N-dimethylaniline but not for fluoro- tion of DMG is common, suggest that differential co- benzene. ordination under the kinetic conditions normally used Mechanistic studies by Beak38 and MeyersMon the in synthesis determines the relative metalation priori- a-deprotonation of amides and formamides, respec- ties. tively, are relevant to understanding the course of the Substituent effects on the rate of ortho deprotonation DoM reaction. For example, in the reaction of amides are also unavailable. Gschwend and Rodriguez used27 14 (Scheme 5) with RLi, stopped-flow IR spectroscopy kinetic data of rate-determining ortho metalation of has provided evidence for the intermediacy of amide- bromobenzenes as a rough but useful extrapolation of lithium reagent complex(es) 17, which may be en route substituent effects. Br, F, and CF3groups located meta to the a-lithiated species 15 and eventually to product to the deprotonation site show strong acidifying effects 16. Although the kinetics of this reaction are exceed- that parallel those observed for the corresponding ortho ingly complex, it appears that, at least in cyclohexane series.% This suggests the predominant influence of solution, amide-sec-BuLi-TMEDA complexes are in- inductive factors in the ortho deprotonation step for volved which, contrary to expectation, become more this series. On the other hand, OMe and NMe2 groups reactive with increasing number of ligands. These re- ortho to the deprotonation site show rate enhancements sults echo those of Schleyere2and McGarritp and are greater than expected on the basis of inductive effects. inferential for preequilibrium formation of the coor- To rationalize these results, a coordination component dinated species 6 (Scheme 3) by a complex-induced in the deprotonation step has been invoked. The proximity effect, a concept with broader synthetic im- acidifying effect of Ph is greater than that of OMe in plications and unifying value in organolithium chem- the meta series but almost equal to H in the ortho ist~~.~~The formation of ortho-lithiated species 6 by series. A dominant steric effect in the latter case is a radical and radical ion mechanisms has been invoked reasonable explanation for this observation. 884 Chemlcal Reviews, 1990,VOI. 90. NO. 6 Snieckus

SCHEME 6 order indicated in eq 1, Scheme 7. These were extended by Beak and Brown under standardized con- <- b( - ditions but using a 4-CONEh anchor group (eq 2). This pJDMG'DMCt q;-Q' DMGzn:; order must be treated with some caution since it was DMtz established by dl incorporation in which up to 15% of 48 19' 20 isomeric deuterated species may have been undetected. Nevertheless, for the moderate and weak directors, CMG, > DMGi * a izb in absence 01 dent ladois 4-OMe and 4-C1, the metalation is overwhelmingly ortho to CONEb. Intermolecular competitions by Meyers SCHEME 7. Relative Directing Abilities of Ortho and Lutomski (eq 5) using the oxazolino anchoring Metalation Groups group invert the order of the CON-R and SOzNRz iil'am0leCular Competition groups compared to the order based on the intramolecular competition results (eq 2). However, compari- nBuLwvariouswnditlons GOMe Slocum and Jennings 1976' sons are rendered tentative by the use of different DMG Ll conditions for metalating CONR2 (sec-BuLi) and DMG = SOZNRZ,SOON-R CON R CHZNRZ> OMe > CH@IzNR2, NR2 CF,. F CON-R (HMPT) systems. This view is reinforced by SBuLVTMEDArTHFi-78'C the order in intra- and intermolecular competitions Beak and Brown 1979 1982, 198~~ DMG ~lcoNEt* (CON-R > CONR, = 5:l and l:lO, respectively) under the same condition^.^^ 3MG = CON H z CON% > ?+?&> SO~NRZ.SO& R. CHZNR~OMe CI N The intramolecular competitions of Miah and Sni- /Ab-r°CoNEtZ eckus (eq 3, Scheme 7)indicate that the OCONEt2 is s-BuLvTMED/L7HR-78'C Miah and Snieckus 1984' by far the most powerful DMG with respect to ortho 0.p-DMG Li and para CONEt, and OMOM groups. The essentially DMS = OCONEtl >> CONEtl >> OMOM > OMe CI regiospecific metalation ortho to OCONEt, in the competitions with OMOM is of synthetic value in view of mBuLi'THFl-78CC &..Zf.B" iwao et a/ 1989' the differential deprotection sensitivities of the two DMGs. The SO2-t-BuDMG has been recently evalu- Li D'IIG = OCONElz lt-BuLl1 5 SOzt-Bu > CONE12 OMOM NPBOC ated in both intra- (eq 4) and intermolecular (eq 6)

ln'eimolecular Competition competitions. While the results are again complicated by variation in conditions (t-BuLi for OCONEt2,N-t-

nBuLi'THF'.45.C Boc), SO2-t-Bu appears to outrank CONR, and perhaps Meyers and Lulomski l97ge OCONEt, in the hierarchy of metalation. Interpretation of competition results must take into account steric and inductive effects that affect aggregation and complexation of alkyllithium reagents and formation of the ortho-lithiated species. This is especially true for the intramolecular competition experiments. Although further work is required to resolve the observed inconsistencies and to quantitatively under- stand the relative hierarchy of DMGs, the available "Table 3, footnote b. *References 73 and 86. Beak, P.; Brown, results (Scheme 7)offer a guide for formulating syn- R. A. J. Org. Chem. 1979, 44, 4463. CReference117a. dTable 1, thetic strategy. footnotes 1 and m. eMeyers, A. I.; Lutomski, K. J. Org. Chem. 1979, 44. 4464. F. Cooperatlve Metalation Effects The evolving mechanistic picture of the DoM reaction A most powerful synthetic rudiment of the DoM re- summarized above suggests that solvation, alkoxide action deserving separate discussion is the cooperative doping,41in situ base-electrophile ~ystems,~~,~~~~and effect of 1,3-interrelatedDMGs in promoting metalation comple~ation~~effects will have significant future im- at their common site (19, Scheme 6). A selection of pact on the synthetic use of currently available DMGs cases illustrate the merit of this effect for the synthesis (Table 1) and the development of new ones. of contiguously substituted aromatics (Table 3). In the carbon-based DMG series, CON-R, CONEt,, and oxa- E. Hierarchy of DMGs zolino groups in a meta relationship with OR, C1, F, CH=NR, but not NMe, show exclusive metalation in The scope and limitations of achievable substitution the common site (entries 1-9). Likewise, the CH=NR patterns by the DoM reaction will be determined by an group cooperates with the OR substituent (entry 10); interplay of the incipient DMG with the nature and the same species may also be obtained from the corre- position of other DMGs and substituents that tolerate sponding 6-Li species, generated by metal-halogen ex- the RLi conditions and, ultimately, by the conversion change, a result that constitutes a rare demonstration of DMGs into other functionality. Generalized expec- of thermodynamic stability of the doubly coordinated tations for the three theoretically possible bis-DMG 2-Li species. The 1,3-CH20Li-OMOM system shows benzenoid systems 18, 19, and 20 (Scheme 6) may be good regioselectivity reversal as a function of base, formulated, although only a few systematic competition solvent, and Cr(C0)3 complexation (entries 12 and 13). studies have been carried out. In early work, using a Metalation of 1,3-related heteratom-based DMGs 4-OMe anchor group under a variety of metalation follows a parallel pattern. The N-t-Boc, NCO-t-Bu, and conditions, Slocum and Jennings suggested the rough OCONEt, groups mostly show excellent "in between" Dlrected Ortho Metalation Chemical Revlews, 1990, Vol. 90, No. 6 885

TABLE 3. Cooperative Effects of Meta-Related Directed Metalation Groups regioselectivity, % entry substrate metalation conditions electrophile yield, 90 c9:cna ref Carbon Based 1 n-BuLilTMEDA ArCHO, Ph&O 48-79 95:5 b, c THE'/-78 - -10 OC n-BuLi/THF/-75 - -10 "C ArC0,R ? 95:5 C OMe

2 sec-BuLi/TMEDA/THF/-78 OC DzO,TMSCl 90 -95:5 86 TNEt2OMe 3 Et= t-BuLi/EhO/hexane/-78 OC ICHZCHJ 35 1oo:o 66

co QOMOM 4 sec-BuLi/TMEDA/THF/-78 OC MeOD 80 95:5 86

TONEf2CI

5 sec-BuLi/TMEDA/THFI-78 OC PhCHO good 95:5 197

TONEt2F

6 sec-BuLi/TMEDA/THF/-100 "C ArCHO 60 95:5 155

Me$ CONEI, bMe 7 sec-BuLi/TMEDA/THF/-78 OC PhCHO good 595 197

Q""'"NMe, 8 qox n-BuLi/THF/-45 OC ArCHO 77-79 955 d 9 qox n-BuLi/THF/-78 OC Me1 quant 95:5 125

10 n-BuLi/THF/-78 OC DZO quant 955 e

11 n-BuLi/Et20/27 "C Ph&O 79 95:5 b

12 n-BuLi/PhH/EtzO/-78 "C ICHzCHJ 78 1oo:o 66 n-BuLi/TMEDA/EhO/-78 "C ICH2CHJ 68 1585 66

13 n-BuLi/TMEDA/EhO/-78 "C COz/ hv/CHzNz 45 2:98 f

Heteroatom Based 14 n-BuLi/THF/O "C (Mesh 82 95:5 g 4 OMe 15 t-BuLi/THF/-20 "C I(CHz)&l 26 955

QN-co,-!-BuOMe 16 n-BuLi/THF/-20 - -0 OC benzyne formation 56-89 95:5 qN--F 17 t-BuLi/THF/-70 - -25 "C benzyne formation 50-85 955 qN-m2-'-'uF 888 Chemical Reviews, 1990, Vol. 90, No. 6 Snieokus

~_____~____TABLE 3 (Continued) regioselectivity, % _.entry substrate metalation conditions electrophile yield, % cz:ctja ref 18 sec-€tuLi/TMEBA/THF/-78 'C COZ 83 67:33 114

OMe 19 sec-BuLi/TMEBA/THF/-78 "C Me1 83 955 129 Q""""'GI 20 sec-BuLi/TMEDA/THF/-78 "C TMSCl 93 DMF 30 QDamo2NMe,

21 n-BuLi/C6Hlz/0 OC ICHzCHJ 71 95:0.5 66 t-BuLi/TMEDA/EhO/-78 OC ICH,CH,I 76 10:90 66

OUYOMoM

22 t-BuLi/hexane/O OC ICHZCHJ 78 97:3 66 t-BuLi/Et,O/O OC ICHzCHzI 95 5941 66 POM0"OMe 23 n-BuLi/Et,O/reflux Me1 78 0:loo j FoMoMn-BuLi/TMEDA/C6HI4/room temp DMF 66 2838 i 0 24 n-BuLi/EtzO/reflux C02/H+ 60 95:5 27 PO'"'

OTHP 25 n-BuLi/Et20/+35 - -78 OC Me,CHCOCl 78 95:5 27. k QO"'

OMe 26 qoMen-BuLi/TMEDA/EtzO/35 "C Ph,CO 80 95:5 b NMe, 27 qoMen-BuLi/THF/-65 "C B(OMe)3/H202/HOAc 53 95:5 b, 1 28 Q' n-BuLilTHFl-65 OC 95:5 27 F "The number "4" drawn on a structure indicates that the regioselectivity should be read as C2:CI. bSlocum, D. W.; Jennings, C. A. J. Org. Chem. 1976, 41, 3653. CBaldwin,J. E.; Bair, K. W. Tetrahedron Lett. 1978, 19, 2559. dNewman, M. S.; Kanakarajan, J. J. Org. Chem. 1980, 45, 2301. eZiegler, F. E.; Fowler, K. W. J. Org. Chem. 1976, 41, 1564. fUemura, M.; Nishikawa, N.; Take, K.; Ohnishi, M.; Hirotsu, K.; Higuchi, T.; Hayashi, Y. J. Org. Chem. 1983, 48, 2349. #Table 1, footnote c. hReed, J. N.; Rotchford, J.; Strickland, D. Tetrahedron Lett. 1988, 29, 5725. 'Clark, R. D.; Caroon, J. M. J. Org. Chem. 1982,47, 2804. 'Skowronska-Ptasinska, M.; Verboom, W.; Reinhoudt, D. N. J. Org. Chem. 1985,50, 2690. *Koft, E. R.; Smith, A. B., 111. J. Am. Chem. SOC.1982, 104, 2659. 'Furlano, D. C.; Calderon, S. N.; Chen, G.; Kirk. K. L. J. Ow. Chem. 1988. 53. 3145.

regioselectivity in concert with OMe, C1, and F sub- The presence of a third DMG in 19 (Scheme 6) at C-4 stituents (entries 14-18). Analogous to results observed or C-6 that is weaker than DMGl usually does not effect with the CONEt2 (entry 7), the OCONEt2-NR2 com- the result of C-2 metalation. With the exception of bination prefers metalation at C-6 (entry 20). The most N,N-diethyl-3,5-dimetho~ybenzamide,~~such combi- systematically studied OMOM group shows a striking nations have not been systematically studied. dependence on solvent effects for both OR and NR2 meta substituents (entries 21-23). The early investi- G. Practical Aspects gated 1,3-related OR-OR and OMe-NR2 DMGs show clean metalation at the common site (entries 24-26). The inert atmosphere-low temperature-syringe The OMe-F and F-F DMG combinations (entries 27 techniques used in DoM reactions are typical of modern and 28) have not yet received wide synthetic exploita- operations in organometallic For ex- tion. ploratory experiments, the adoption of conditions based Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 887

TABLE 4. Practical Aspects of the DoM Reaction typical conditions ortho-lithiated species base solvent additive temp, 'C ref Carbon-Based Groups n-BuLi THF or Et10 none or TMEDA -78 to reflux 27

n-BuLi or sec-BuLi THF or Et20 none -45 to 0 2%

sec-BuLi THF TMEDA -78 86

n-BuLi or LDA THF none -78 a

n-BuLi THF none -78 to -20 84

n-BuLi n-hexane TMEDA reflux b

Heteroatom-Based Groups n-BuLi' THF none 0 d t-BuLie THF none -20 f

sec-BuLi THF TMEDA -78 114

n-BuLi or t-BuLi Et20 none 0-25 66

n-BuLi THF none -10 to +25 27

n-BuLi EtzO none -50 g

'Table 3, footnote e. *Table 1, footnote x. 'R = t-Bu. dTable 1, footnote c. eR = O-t-Bu. 'Table, footnote e. #Table 1, footnote q. on the prototype systems (Table 4) are advised, al- ortho-lithiated intermediate by the use of a sterically though a systematic search for the optimum conditions hindered base and that led to the discovery of syn- by variation of alkyllithiums, solvents, and complexing thetically useful conditions82for the generation of this agents invariably proves to be rewarding. In large-scale species. Table 5 shows the effect of conditions and synthesis, the conversion from more conventional routes N-substitution on the success of the tertiary benzamide to those based on use of RLi reagents may result in a DoM process. Metalation of the dimethylamide (n- significant reduction in number of operational steps at BuLi, sec-BuLi) and the diethylamide (n-BuLi, sec- a modest increase in expense. This factor coupled with BuLi (EhO),and t-BuLi) followed by D20quench leads the development of safe handling practices and low- to ketone and self-condensation products (entries 1-4 temperature techniques is leading to the greater in- and 6), although the last result was not obtained under dustrial use of organolithium chemistry.79 comparable conditions. As demonstrated by Gschwend and co-~orkers,8~ketone formation need not be synthetically unproductive since the carbinolamine formed I V. Methodological Aspects of Tertiary Amlde by n-BuLi addition to a tertiary benzamide may serve and 0-Carbamate DMGs as an in situ DMG and lead to ortho-substituted aryl ketones. A fundamental variation of this concept that A. Aromatic Tertiary Amide does not involve functional group transformation, thoroughly developed by Comins and co-workers, in- In 1973, Hauserso reported that N,N-dimethylbenz- vokes the use of carbinolamine DMGs derived from amides undergo attack by n-BuLi to give aryl butyl addition of dialkylamide nucleophiles to benz- ketones. Pursuing these observations, Beak and co- aldehydes.@ In general, ortho-lithiated dimethylbenz- workersa1 first showed that treatment of N,N-diethylamides cannot be generated except by metal-halogen benzamide with LiTMP gives N,N-diethyl-o-benzoyl- exchangea5 or with the assistance of cooperative benzamide, a result that implicated the formation of an (meta-OR DMGs) or steric hindrance (ortho-OR 888 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 5. Effect of Conditione and N-Substitution on the Tertiary Benzamide DoM Reaction Draducts. vield. %

CONR, O/WR ,?NR2 @QNR,

entry base conditions E+ COP^ ref 1 Me n-BuLi THF/O "C 70 80 2 Me sec-BuLi TMEDA/THF/-78 "C D20 14 26 86 *'i Et n-BuLi THF/-78 "C Dz0 31 86 4 Et sec-BuLi TMEDA/Et20/-78 OC D20 - 53 14 86 5 Et sec-BuLi TMEDA/THF/-78 "C DzO >90 86 6 Et t-BuLi THF/-78 "C TMSCl 9 28 5 206 i i-Pr n-BuLi, sec-BuLi TMEDA/THF/-78 "C DzO >90 86 8 i-Pr t-BuLi THF/O "C DZO 91 206 9 Et,N(Et)CH,CH,NEt, sec-BuLi TMEDA/THF/-78 "C TMSCl 75 101 lo 2.ff sec-BuLi TMEDA/THF/-78 "C TMSCl 61 a

11 Me, CHzTMS sec-BuLi TMEDA/THF/-78 "C DMF 70 157 12 i-Pr, CHzTMS sec-BuLi TMEDA/THF/-78 "C MeOD 92 a 13 Me, CH(TMSIZ t-BuLi TMEDA/THF/-78 "C MeOD 98 104

a Cuevas, J.-C.; Patil, P.; Snieckus, V., unpublished results.

DMGs) effects and at lower temperatures as demon- 6) may be used to overcome this problem. Similar strated in isolated cases (Table 6, entries 1-9). On the problems have been encountered in metalation reac- other hand, clean ortho metalation is observed for the tions of the 2-oxazolinonaphthamide, which, however, diethyl- and diisopropylamides using all three alkyl- have been turned into impressive synthetic advantage.@ lithiums (Table 5, entries 5, 7, and 8). The use of Aside from the N,N-diethyl-9-phenanthrenecarbox- sec-BuLi/TMEDA/THF/-78 "C in inverse addition amides, which are valuable in alkaloid synthesis (section mode established by Beak and BrownaGhas become the VIII.D.2), more highly condensed aromatic tertiary optimum, highly reliable conditions for ortho metala- amides have not been adequately evaluated in DoM tion. The "built-in" TMEDA benzamide (Table 5, entry reactions. 9) serves as a useful DMG and offers greater facility in Table 6 also offers an overview of the scope and hydrolysis (section 1V.C). The piperidino amide (entry diversity of electrophiles that may be introduced. 10) is moderately effective but, similar to the pyrrolido Among carbon-based electrophiles, methyl iodide has and N-methylpiperazino amides, is more useful in served as the outstanding alkylating agent (e.g., entries systems with m-alkoxy chelation or amide carbonyl 11,77,112,and 143); few examples of direct introduc- deactivating features (Table 6, entries 144-147). The tion of longer alkyl chains have been reported (entry mono'-a-TMS amide (Table 5, entry 11) requires the 12). Presumably owing to proton exchange, allylation incorporation of a steric effect (entry 12) to avoid can only be achieved by prior transmetalation to the self-condensation. Increasing the effective bulk to the corresponding softer ortho Grignard reagents (entries bis-a',a'-TMS amide (Table 5, entry 13) gives a stable, 9, 13, 42, 56, 80, and 102). For a similar reason, suc- synthetically useful ortho-lithiated species. cessful reaction with aliphatic aldehydes can only be Table 6 provides a comprehensive list of substituted achieved via the same expedient (section VIII.D.2 and aromatic amides available by the DoM reaction and Table 26). Clean hydroxyalkylation reactions occur allows evaluation of functional groups that tolerate the with aromatic aldehydes and benzophenone to give strongly basic conditions of this process. A large num- products that usually are directly transformed into ber of alkoxybenzamides, of great value in natural phthalides for ease of isolation (Table 26). o-Formyl product synthesis, have been used (e.g., entries 77-102), products or their carbinolamine precursors, invariably whereas halo (Cl, F) (entries 103, 106-108, 118, and obtained by DMF treatment, often undergo cyclization 129), amino (Table 3, entry 7), sulfur (no entries), and upon workup or chromatography to hydroxyphthalides. carbon (Table 6, entries 27, 65, and 66) substituted Steric effects of 6-substitution appear to facilitate this systems have not been extensively explored. While reaction. Hydroxyphthalides are also deliberately C-3ffiand C-4 methylbenzamides are not deprotonated formed by acid treatment for ease of isolation purposes under kinetic conditions (Table 6, entries 27, 65, and (Table 26). The oxidation state of carboxylic acid in 66), the C-2 methyl systems readily form o-toluamide the ortho position can be achieved by isocyanate (e.g., anionic species of synthetic value (section VII1.A). The Table 6, entries 71 and 87), by carbamoyl chloride (e.g., demonstrated bissilylation of such systems (entries entries 72 and 138), and, most directly, by carbon di- 30-36) as a C-CH3 protective expedient awaits broader oxide (e.g., entries 32, 58, 78, and 96) electrophiles. synthetic exploitation (Table 21). Naphthamide DoM Among heteroatom electrophiles, a large number of reactions with simple electrophiles have received limited N+ synthons have been introduced to give anthranil- use (Table 7), most work involving the bare N,N-di- amides (entries 16, 27, 36, 45, 52, 60, 66, 73, 106, 146, ethyl-l-naphthamide, which has served as a valuable and 147) and o-anilinobenzamides (entries 1,3,4,8,10, synthon for the construction of diverse polycyclic aro- 17, 18,35, and 62). The synthetic utility of the former matic hydrocarbons (PAH) (section VIII.D.3 and Table is depreciated by the difficult amide hydrolysis, while 29). The corresponding 2-naphthamide undergoes the latter serve as useful intermediates for acridones ready l-addition of RLi reagent^,^^-*^ although hin- (section IX.A.2). OH+ synthon introduction may be drance and deactivation effects (Table 7, entries 5 and achieved by direct oxygenation (entries 19, 46, 59, 99, Dlrected Ortho Metalation Chemical Reviews, 1990, VoI. 90, No. 6 889

TABLE 6. Synthesis of Ortho-Substituted Benaamides by the DoM Reactionn

entry R R E+ E yield, % ref 1 Me 3-OMe PhNMe(CN)CuLi/O, N(Me)Ph 26 193 2 Me 6-OMe Me1 Me ' 78 100 3 Me 6-OMe (CH&,N(CN)CuLi/O, N(CH,), 33 193 4 Me 6-OMe PhNMe(Cl)CuLi/O, N(Me)Ph 33 193 5 Me 6-OMe 3-MeOC6H,NH(CN)CuLil '02 NHC6H,-3-OMe 36 193 6 Me 3-OMOM ICHZCHzCl I 35 66 7 Me 3,4-OCH20 B(OMe)3/H202,H+ OH 72 193 8 Me 4,6-(OMe)2 PhNMe(C1)CuLi O2 N(Me)Ph 43 193 9 Me 4,5,6-(OMe)3 BrCH,CH=CH, l CH,CH=CH, I7 142 10 Me 4,5-OCH20, 6-OMe PhNMe(Cl)CuL$O, N(Me)Ph 48 193 11 Et H Me1 Me 77 86 12 Et H Et1 Et 70 86 13 Et H BrCH2CH=CH,b CHZCH=CH, 71 142 14 Et H HCOZEt CHO 23 156 15 Et H MeCO.Et C 35 142 16 Et H TsN3/kaBH4 NH2 40 g 17 Et H PhNMe(C1)CuLi/02 N(Me)Ph 46 193 18 Et H 2-MeOC6H,NH(CN)CuLi/Oz NHC6H4-2-OMe 50 193 19 Et H Or/H+ OH 37 d, e 20 Et H B~OMe)3/Hz02/H+ OH 56 86 21 Et H Br2' Br 93 128 22 Et H TMSCl TMS 70 130 23 Et H (t-BuS), t-BUS 88 f 24 Et H Se Se-)e 31 195 25 Et H BulSnCl SnBu3 55 197 26 Et H PPhz 197 27 Et 4-Me NHZ 82 g 28 Et 4-(CH&OTHP, 6-OMOM Me quant 141 29 Et 4-(CH,hOTHP OH 92h 141 30 Et Me 91 130 31 Et CHO 86 130 32 Et COZ C02Hi 78 130 33 Et TMSCl TMS 86 130 34 Et (MeSL SMe 76 130 35 Et PhNH(CN)CuLi/02 NHPh 48 130 36 Et 5-OMe, B-CH(TMS), TsN3/NaBH4 NH2 47 g 37 Et 3-OHj TMSCl TMS 58-62k 122 38 Et 4-OH' TMSCl TMS 62-78' 122 39 Et 6-OHj TMSCl TMS 68 122 40 Et 6-OH (i-Pr)3SiCl si(i-P~-)~ 45-41'" 122 41 Et 3-OMe Me1 Me 58 139, 208 42 Et 3-OMe BrCH2CH=CH,b CHZCH=CH2 80 142 43 Et 3-OMe DMF CHO 49" 146 44 Et 3-OMe CO2 COzH 54 146 45 Et 3-OMe TsN3/NaBH4 NH2 55 g 46 Et 3-OMe OZ/H+ OH 51 d, e 47 Et 3-OMe TMSCl TMS 65 195, 130 48 Et 3-OMe sa SH 70 195 49 Et 3-OMe BrCH2CH2Br Br 25 0 50 Et 3-OMe I2 I 62 0 51 Et 4-OMe Me1 Me 97 164 52 Et 4-OMe TsN3/NaBH4 NH2 34 g 53 Et 4-OMe Sa SH 92 195 54 Et 4-OMe Se Se-h 30 195 55 Et 6-OMe Me1 Me 88 100 56 Et 6-OMe BrCH2CH=CH,6 CHZCH=CHz 55 142 57 Et 6-OMe DMF CHO 75 146 58 Et 6-OMe coo COzH 70 146 59 Et 6-OMe OH 46 d, e 60 Et 6-OMe NH2 66-71 g 61 Et 6-OMe CN 18 193 62 Et 6-OMe NHPh 63 (54)P 193 63 Et 6-OMe SH 74 195 64 Et 6-OMe Se Se-h 32 195 65 Et 3-OMe, 4-Me Me1 Me 90 139 66 Et 3-OMe, 4-Me TsN3/NaBH4 NH2 69 g 67 Et 3-OMe, 6-OH TMSCl TMS 76 122 68 Et 2-TMS, 3-OMe sa SH 72 195 69 Et 5-OMe, 6-TMS Me1 Me 74 130 70 Et 5-OMe, 6-TMS DMF CHO 88 130 71 Et 5-OMe, 6-TMS PhNCS CSNHPh 89 130 72 Et 5-OMe, 6-TMS ClCONEtZ CONEt2 89 130 73 Et 5-OMe, 6-TMS TsN3/NaBH4 NH2 69 g 74 Et 5-OMe, 6-TMS I2 I 86 130 75 Et 5-OMe,6-TMS TMSCl TMS 80 130 76 Et 5-OMe,6-TMS (Mesh SMe 89 130 BQQ Chemical Reviews. 1990, Vol. 90, No. 8 Snleckus

TABLE 6 (Continued) entry R R' E+ E yield, % ref 77 Et 3,44OMe)? Me1 Me 72 146 78 Et 3,4-(OMe); cog COaH 71 146 '79 Et 3,4-(OMe), TMSCl TMS 95 130 80 Et 3,6-(OMe), BrCHzCH=CH$ CH,CH--CH, 63 142 81 Et 3,6-(OMe), DMF CHO 80 145 82 Et 5,6-(OMeh Me1 Me 97 €46 83 Et 5,6-(OMe), DMF 88 146 84 Et 5,6-(OMe), ~,~-OCH~OCGH~CHO 76 146 85 Et 5,6-(OMe), co2 77 146 86 Et 5,6-(OMe)* (C0gEt)i 88 146 87 Et 5,6-(OMe), PhNCO CONH>h 71 146 88 Et 5,6-(0Me)2 12 I 70 146 89 Et 5,6-(OMe), TMSCl TMS 65 146 90 Et 4,5-(OMe)2, 6-TMS Me1 Me 90 130 91 Et 4,5-(OMe)2, 6-TMS DMF CHO 56 130 92 Et 3,4-OCHzO Me1 Me 64 146 93 Et 3,4-OCHzO COP CO2H 54 146 94 Et 5,6-OCHzO Me1 Me 47-75 136, 146 95 Et 5,6-OCH,O Et1 Et 55 136 96 Et 5,6-OCH,O COZH 50 146 97 Et 5,6-OCHzO COC0,Et 80 146 98 Et 4,5-OCHzO, 6-OTBDMS CHO 70 119 99 Et 3,4,5-(OMe), OH 48 d 100 Et 3,4,6-(OMe)3 DMF CHO 50-56 (47)' 148a, 149a, 154 101 Et 3,4,6-(0Mel3 02/H+ OH 52 d 102 Et 4,5.6-(OMe)3 BrCH,CH=CH: CH&H=CHZ 66 142 103 Et 3-F TMSCl TMS 88 130 104 Et 5-F, 6-TMS Me1 Me 80 130 105 Et 5-F, 6-TMS DMF CHO 58 130 106 Et 3-C1 TsN3/NaBH4 NH2 31-36 i? 107 Et 3-c1 TMSCl TMS 67 130 108 Et 3-C1 DMF CHO 171 109 Et 5-C1, 6-TMS Me1 Me 89 130 110 Et 5-C1, 6-TMS DMF CHO 76 130 111 Et 6-TMS Me1 Me 91 130 112 i-Pr H Me1 Me 869 156 113 i-Pr H BrCH,CH=CH, Br 60 86 114 i-Pr H DMF CHO 909 156 115 i-Pr H TMSCl TMS 88 156 116 i-Pr 3-OMe DMF CHO 89q 156 117 i-Pr 6-OMe DMF CHO 156 118 i-Pr 641 DMF CHO 97' 156 119 i-Pr 6-TMS DMF CHO 156 120 Me, t-Bu 6-OMe Me1 Me 98 102 121 Et, CHzCHzNEt2 H Me1 Me 76 101 122 Et, CHzCHZNEt2 H DMF CHO 80 101 123 Et, CHzCHZNEtz H TMSCl TMS 75 101 124 Et, CHzCHzNEt2 H (MeSh SMe 56 101 125 Et, CHzCHzNEt2 6-OMe Me1 Me 82 101 126 Me, CHzTMS 4-OMe DMF CHO 65 157 127 Me, CH2TMS 6-OMe DMF CHO 65 157 128 Me. CH,TMS 4,6-(OMe), DMF CHO 30 157 129 Me; CHiTMS 6-C1 DMF CHO 24 157 130 Et, CHZTMS H DMF CHO 30 157 131 i-Pr, CHzTMS H DMF CHO 62 157 132 i-Pr, CHzTMS 3-OMe DMF CHO 33 157 133 i-Pr, CHzTMS 4-OMe DMF CHO 64 157 134 i-Pr, CH,TMS 6-Ph DMF CHO 55 157 135 Me, CHCTMS), H Me1 Me 91 104 136 Me, CHtTMS), H BrCHzCH=CH, CH,C H=CH2 84 104 137 Me, CH(TMS), H DMF CHO 87 104 138 Me, CH(TMS)2 H CICONEt, CONEt2 71 104 139 Me, CH(TMS)2 H Br2 Br 80 104 140 Me, CH(TMS), H Bu,SnCl SnBu, 98 104 141 Me, CH(TMS), H (t-BuS), S-t-Bu 68 104 142 Me, CH(TMS), 4-OMe DMF CHO 80 104 r7 143 --yN M e 4-OMe Me1 Me 73 101 144 9 3-OMe TMSCl TMS 72 197 145 a 3-OMe TMSCl TMS 53 197 146 a 3-OMe TsN3/NaBH4 NH2 44 197 147 3-OMOM TsN,/NaBH, NHZ 25 197 Directed OfthQ Metalation Chemical Reviews, 1990, Val. 90. NO. 6 891

TABLE 6 Footnotes (Continued) Unless otherwise indicated, sec-BuLi/TMEDA/THF/-78 'C conditions apply. o-Deuteration experiments have been omitted. With DMP as electrophile, only cases of uncyclized 6-formylated benzamides are given, Cues that lead upon workup or deliberate acid treatment to 3-hydroxyphthalides are listed in Table 26, For ortho boronation, see section 1X.E. bLi - Mg transmetalation (MgBrp2EhO) before addition of E+. e33. Methyl-3-[2-(diethylcarbamoyl)phenyl]phthalide (35%). Parker, K. A.; Koziski, K. A. J. Org. Chem. 1987, 52, 674. eDoadt, E. G.; Snieckus, V., unpublished results. 'Table 1, footnote 1. #Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1983, 24, 3795. "Isolated as the corresponding MOM derivative. Isolated as the corresponding phthalic anhydride. 'The silyloxy intermediate was prepared separately (NH(TMS)2/neat/40 "C or Et3SiC1/Et3N/PhH/reflux) or in situ (sec-BuLi/THF/-78 "C) and subjected to the standard metalation conditions. kTogether with NJV-diethyl. 3-hydroxy-6-(trimethylsilyl)benzamidewith N,N-diethyl-3-hydroxy-6-(trimethylsilyl)benzamide(5-16% ) and 3-hydroxy-2,6-bis(trimethylsilyl)benzamide (4-11%)* 'Together with NJV-diethyl-4-hydroxy-2,6-bis(trimethylsilyl)benzamide(lO-ll%). "Together with N,N-diethyl-2-(triisopropylsilyl)-6-[(triisopropylsilyl)oxy]benzamide (10-30% ). "Based on recovered starting material. OSloan, C. P. MSc. Thesis, University of Waterloo, 1986. PYield obtained with PhN(TMS)Li. q Without TMEDA. 'LiTMP/HgCI,/THF/O "C conditions. and 101) or, more reproducibly and in better yields, by (Table 30), while the 2-carboxamide allows access to a the trimethyl borate/ hydrogen peroxide method (en- variety of 2,3- and 2,3,5-substituted thiophenes (Table tries 7 and 20). The formation of such salicylamides 9) via silicon protection (section IX.C.l) and dianion is especially useful in OR-amide DMG cooperative (section VI) protocols. The corresponding furan-3- situations for the preparation of differentially func- carboxamide also undergoes tandem DoM reactions to tionalized oxygenated systems (entry 46). The inter- anthraquinones (Table 30), while the undetected anion mediate boronic acids obtained by simple hydrolysis of the 2-derivative 21 (Scheme 8) rapidly fragments to serve as productive partners in transition-metal-cata- the enyne 22 even at low temperatures owing to the lyzed cross-coupling methodologies (section 1X.E.1). electron-withdrawing effect of the amide.94 Comple- Sulfur (including Sa) (entries 23,34,48, 53, 63,68, 124, mentary DoM reactions of secondary amide and oxa- and 141), selenium (entries 24,54, and 64), phosphorus zolineg5furans and thiophenes provide greater scope, (entry 26), and tin (entries 25 and 140) electrophile although further manipulation of all systems is limited incorporation has seen few applications to date (sections by lack of mild hydrolytic conditions for these acid- IX.B,D). The normally smooth and high-yield intro- sensitive 7-deficient heterocycles. Recent studies by duction of TMSCl (e.g., entries 22, 38, 75,89, 123, and Cominsa4 on furan, thiophene, and pyrrole a-amino 145), even in cases of potential incomplete lithiation, alkoxide DMGs and by Keay= on furancarbinols is undoubtedly related to its in situ compatibility with promise to circumvent some of these difficulties. alkyllithiums.w Ortho silylation plays a useful pro- Metalation of N,N-diethylindole-2-carboxamide23 tecting group role in aromatic ring manipulations (Scheme 9) leads to 24,97 a fate analogous to that ob- (section 1X.C). Ortho silylated benzamides are also served for the corresponding furan-2-carboxamide obtained, albeit in poor yields, by ortho metalation (Scheme 8). The triazolopyridinecarboxamide 25 un- mediated oxygen to carbon silyl migration of silyloxy dergoes metalation at either C-4 (slow) or C-7 (fast); derivatives (entries 37-40). Notable among the halogen quenching with anisaldehyde gives 26.98 electrophiles introduced (entries 21,49, 50, 74,88, and Clearly, tertiary amide DoM chemistry in the heter- 139) is the absence of ortho fluorination, although new ocyclic area is in its infancy. F+ reagents are knowng1 and fluorobenzamides have themselves been metalated (entry 103 and Table 3, C. Amide Manipulation entry 5). Certain electrophiles fail in DoM reactions with tertiary benzamides,86 whereas they have been The recalcitrant nature of NJV-dialkylbenzamides to reported to be successful with secondary amidembpi and acid (e.g., stable to refluxing 16 N HC1 for 72 h) or base oxa~oline~~gDMGs. In general, most electrophiles in hydrolysis is well recognized. The synthetic use of the Table 6 serve equally well for these three DMGs. CONEtz DMG is thus seriously compromised. How- ever, anchimeric assistance by ortho-introduced elec- 8. Heteroaromatic Tertiary Amide trophiles capable of forming five- or six-membered-ring tetrahedral intermediates greatly enhances amide hy- Heterocyclic amide DoM reactions are in the early drolytic rates,% a feature that may be turned into syn- stages of development. In the pyridine series (Table thetic benefit. Thus ortho-hydroxyalkylated and - 8), the combination of diisopropylamide substrate and carboxylated products of DoM reactions may be hy- LDA or, preferably, LiTMP base is required to avoid drolyzed under relatively mild acidic conditions to give rapid self-condensation (entries 8, 19, and 26) and ad- phthalides (section VIII.D.2) and phthalic acids or an- diti~n.~~The significance of steric effects is revealed hydrides (section VII1.E). Similarly, o-allyl derivatives by comparison of dimethyl- and diethylbenzamide nu- can be cyclized to benzoisocoumarins (sections VIII.A.2 cleophiles (entries 15 and 16). A limited number of and VIII.B.l), although in some cases six-membered- electrophiles may be introduced in modest yields, al- ring formation via attack on intermediate carbonium though utility in tandem metalation to heteroanthra- ions is inhibited by the diethylamide substituent." In quinones has also been demonstrated (Table 30). In search of hydrolytic facility, Comins tested the "built- simple reactions with electrophiles, secondary amides in" TMEDA benzamide 27a (Scheme 10).'O1 The de- have comparable ~tility?~while oxazolines show dual veloped three-step sequence affords the benzoic acid 28 character of ortho metalation and addition of broader in good yield but still requires relatively vigorous hy- synthetic ~cope.~~g drolytic conditions. A milder three-step route for the N,N-Diethylthiophene-2-carboxamide and -3- preparation of 28, amenable to scale up, that takes carboxamide are useful metalation substrates. The less advantage of acid-catalyzed tert-butyl cleavage of the accessible 3-carboxamide has been used in tandem CON(Me)-t-Bu DMG 27b has been devised by Reitz.lo2 metalation sequences to obtain heteroanthraquinones In the absence of other interfering functionality, di- ES2 Chemlcal Reviews, 1999, VoI, 90, NO, 6 Snieckus

TABLE 7. Synthesis of Substituted Naphthamides'

R' CONR, R R' E+ E yield, % ref - entry 1 c-1 Et H TsN3/NaBH4 2-NHZ 74 €92 2 C-1 Et H O,iH+ 2-OH 34 b .'3 c-1 Et H PhNMe(CNKuLii0, 2-NMePh 61 193 1 c-1 Et H TMSCl 8-TMS 80 171 > c.2 Et 6-OMp Et1 1-Et 68' d 6 C-2 I-Pr 6-OMe Et1 1-Et 95e d n c-2 i-Pr H I3MF CHO 22 (C-1)' 156 10 (C-3) 8 c-2 Et 4-OMe, 6,7-OCH20 g 147 Unless otherwise specified, sec-BuLi/TMEDA/THF/-78 "C conditions apply. Table 6, footnote d. t-BuLi conditions. dBindal, R. D.; Katzenellenbogen, J. A. J. Org. Chem. 1987,52, 3182. en-BuLi conditions. f Without TMEDA. gProducts of C-1, C-3, and C-5 substitution by an unspecified E+ in unspecified yields.

TABLE 8. Synthesis of Substituted Pyridinecarboxyamides'

entry CONRz R E+ E yield, 9' ref 1 C-2 i-Pr DMF 3-CHO 35 b 7 I C-2 i-Pr PhCHO 3-PhCH(OH) b

) c-2 i-Pr PH,CO 3-Ph2C(OH) 81 b 4 C-2 i-Pr b o=o 3-q3

5 C-2 i-Pi- b 3 -Hb 6 c-2 i-Pr PhCONMe, 3-PhCO 52 b c-2 i-Pr TMSCl 3-TMS 54-64 b 6 c-2 Et 3-ccYJ 94 C

9 e-3 i-Pr DMF 4-CHO 39 b 10 C-3 i-Pr PhCHO 4-PhCH(OH) b 11 c-3 i-Pr Ph,CO 4-Ph,C(OH) 68 b 12 C-3 i-Pr b 4-

13 c-3 i-Pr b 4- Hb

14 c-3 i-Pr 4-PhCO 47 b 15 c-3 i-Pr 2-MeOC6H4C0 71d (6)e 85 16 C-3 i-Pr 4-MeOc6H4C0 98d (53P 85 17 c-3 i-Pr 3,5-(Me0)2C6H3C0 quantd 85 18 c-3 i-Pr 2,3,5-(MeO),C6H2C0 58d 85 19 c-3 Et 4-mYJ 68 C 20 c-4 i-Pr DMF 3-CHO 37 (3811 156, b 21 c-4 i-Pr PhCHO 3-PhCH(OH) b 22 c-4 i-Pr Ph,CO Ph,C(OH) 55 b 23 c-4 i-Pr b 030 3-% 24 c-4 i-Pr b O#

25 c-4 i-Pr PhCONMe, 3-PhCO 36 b 26 c-4 Et 3-cc 75 C

Unless otherwise stated, LDA/Et20/-78 "C conditions were used. * Epsztajn, J.; Berski, Z.; Brzezinski, J. Z.; Jozwiak, A. Tetrahedron Lett. 1980, 21, 4739. Epsztajn, J.; Brezezinski, J. Z.; Jozwiak, A. J. J. Chem. Res. (S) 1986, 18. cEpsztajn, J.; Bieniek, A.; Brzezinski, J. Z.; Jozwiak, A. Tetrahedron Lett. 1983, 24, 4735. dLiTMP/DME/-78 OC conditions. e Yield obtained with the corresponding N,N-diethylbenzamide electrophile. fsec-BuLi/THF/-78 "C conditions - ____~__ Directed Ortho Metalation Chemical Reviews, 1990. Val. 90, NO. 6 893

TABLE 9. Synthesis of 2,3- and 2,3,5-Substituted ThiophenecarbaxamideaO

reactant electrophile product entry R' El+ E,+ R' R2 yield, % ref 1 H TMSCl TMS H 85 94 2 H COZ COzH H 82-85b 95 (41)b7c 3 TMS Me1 TMS Me 56 123 4 TMS ClCONEt, TMS CONEt, 49 123 5 TMS (Mesh TMS SMe 68 123 6 Hd TMSCl TMSCl TMS TMS 82 94 7 Hd ClCONEt, ClCONEtz CONEtz CONEt, 82 94 8 Hd (Mesh (Mesh SMe SMe 65 94 9 Hd PhCHO PhCHO CH(0H)Ph CH(OH)Phe 48 94 10 Hd Me1 MeOH H Me 57 f 94 11 Hd (Mesh MeOH H SMe 348 94 12 Hd TMSCl MeOH H TMS 405 94 13 Hd ClCONEtz MeOH H CONEtz 381 94 14 Hd TMSCl (Mesh SMe TMS 358 94 15 Hd (Mesh TMSCl TMS SMe 305 94 16 Hd (Mesh CICONEtz CONEtz SMe 268 94 Unless otherwise indicated, sec-BuLi/TMEDA/THF/-W "C conditions apply. Using LDA/THF/-78 "C or sec-BuLi/THF/-78 OC conditions. Accompanied by the 3-COzH derivative (50%). dVia 3,5-dilithiated intermedite; see section VI. e Accompanied by 10% of 3-CH(OH)Ph product. 'Accompanied by 10-20% of starting material. g Accompanied by 25% of 3,5-disubstituted product of El+ introduction.

SCHEME 8 SCHEME 11

CONE12 1 s-BuLlfrMEDA Qc~NE~~THFi-78'C 2 E' < 21 22 E - TMS. CONE12

SCHEME 9 SCHEME 12

RBULl 0 TMS rCONEtz mCoNE,,- .. . SO2Ph (25%) SO2Ph Me 34 23 24

32 33 excessLiEIjBH aCHzOH CONEtz

@NEtzj 2 equiu LDA \ N.,/." Z.4-MeOCsH4CH0 E 35 CH(OH)QHI-~.OM~ 25 26 ported by Hauserm for a variety of amides, including the "built-in" TMEDA DMG system (Table 10).lo1 SCHEME 10 Thus in the N,N-diethyl series, lateral metalation is lor 271 1. Me1 suppressed by using PhH rather than THF as solvent, Me0 2. ElONa Me0 cONRZ 3. 6N NCI i rellux I7 d thereby leading to good yields of ketones from alkyl- (77%) * lithiums (entries 2-5) but not from Grignard reagents bMe lor27b &;; (entry 1). The piperazine amide (entry 8) is less valu- 1 TFA ireflux / 2 h 27 2. NaN02 iHOAc. AczO IO'C 28 able in view of its poor DMG properties.'O' However, 3 KOH / EIOH / 90°C a: R = El CH~CH~NEIZ (89%) both of these amide types are unreliable in forming b: R = Me. I-Bu benzaldehyde products (entries 6, 7, 9, and 10). The value of "built-in" TMEDA DMGs (entries 11-20) is ethylbenzamides may be converted into benzaldehydes thus reinforced, especially in the @(dimethylamino)- as demonstrated in the high-yield, overreduction-oxi- ethyl series (entries 11-17), in providing ortho-substi- dation sequence 29 - 30 - 31 (Scheme ll).103Pre- tuted benzaldehydes (entries 14 and 17). Although little liminary results suggest that the bis-a',a'-TMS amide exploited, amide to aryl ketone conversion has been DMG may provide a general solution to the hydrolysis achieved via intermediate a-alkoxy amine DMGs.~~ problem.lM Thus 32 (Scheme 12) is readily unmasked The introductionlo5of organolanthanum reagents for by fluoride to the dimethylbenzamide 33, which may this purpose has added a new dimension to the amide be readily reduced by standard methods to aldehyde aryl ketone conversion (Table 11). A variety of ketones 34 or alcohol 35 oxidation states. are available in excellent yield with the exception of With the aim of developing a new aryl aldehyde and those that suffer double-jeopardy hindrance from ortho ketone synthesis, Comins has systematically explored and N substituents. Reduction methods (e.g., LAH, the classical amidealkyllithium reaction originally re- Dibal, Super-Hydride) that are effective on N,N-di- BB4 Chemical Reviews, IQQQ, Val, 90, NO. 6 Snleckus

TABLE 10, Tertiary Benzamide to Ketone and Aldehyde Conversion Using RMgX and RLi Reagentsilo'

+ R3MgXorR3Li - H' benzamide product entry R1 R2 R3MgX/RSLi R' R3 yield, % 1 Me Et MeMgCl Me Me 0 2 Me Et MeLi Me Me 72 3 Me Et n-BuLi Me n-Bu 61 4 n-Bu Et MeLi n-Bu Me 55 5 n-Bu Et n-BuLi n-Bu n-Bu 62 6 Me Et SmEAH" Me H 0 m 1 n-Bu Et SMEAH" n-Bu H 0 8 n-Bu n-BuLi n-Bu n-Bu 58

SMEAH" Me H 57 9 Me -u--"Me n SMEAH" n-Bu H 0 10 n-Bu --uNMe 11 Me Me, CH2CHzNMez MeMgCl Me Me 56 12 Me Me, CH2CHzNMe2 MeLi Me Me 82 13 Me Me, CH2CHzNMe2 n-BuLi Me n-Bu 80 14 Me Me, CHzCHzNMez SMEAH" Me H 80 15 n-Bu Me, CH2CHzNMe2 MeLi n-Bu Me 77 16 n-Bu Me, CH2CHzNMez n-BuLi n-Bu n-Bu 70 17 n-Bu Me, CHzCHzNMe2 SMEAH" n-Bu H 51 18 Me Et, CHzCHzNEtz MeMgCl Me Me 38 19 n-Bu Et, CHZCHzNEt, n-BuLi n-Bu n-Bu 64 20 Me Et, CH2CHZNEt2 SMEAH" Me H 0 " Modified aluminum hydride; see: Tokoyorama, T.; Kanazawa, R. Synthesis 1976, 526.

TABLE 11. Tertiary Benzamide to Aryl Ketone Conversion spectively. The initial component of the latter reaction Using Lanthanum Triflatesl" has consequences for cross-coupling chemistry (section 1X.E). m-Methoxy (entries 27 and 28) and m-chloro (entries 35-37) systems show good C-2 regioselectivity, while m-methyl (entry 20) and m-dialkylamino (entries 22-25) substituents force metalation of the alternate site. Difficult to access o-halo-masked phenols (entries ~ ~~ ~~~ yield, 13-15) and systems containing more than one kind of R' R2 R3 (equiv) R' R3 % halogen (entry 41) may be obtained. O-Phenyl N,N- H Et Me (1.2) H Me 95 diisopropyl carbamates suffer complications in hydro- H Et Ph (2.0) H Ph 98 lytic manipulation after DoM chemistry, while the H Et n-Bu (1.2) H t-Bu 94 3-Me Et Me (1.2) 3-Me Me 92 corresponding dimethyl systems undergo rapid anionic 4-Me Et Me (2.0) 4-Me Me 98 ortho-Fries rearrangement (section V.A). Condensed 3-C1 Et Me (2.0) 3-C1 Me 95 aromatic carbamate metalation has been only briefly 3-OMe Et Me (3.0) 3-OMe Me 96 explored (Table 13) but shows excellent regioselectiv- 2-OMe Et Me (3.0) 2-OMe Me 91 ities in the l-naphthyl (entries 1-3) and 9-phenanthryl H i-Pr Me (1.0) H Me 80 2-Me i-Pr Me (1.0) NR (entries 6 and 7) series. 2-OMe, Et Me (3.0) NR In comparison with other oxygen-based DMGs 6-(2-MeC6H4) OMe,n OMOM,@OP(OR)2,1(na and OPO(NMe)2,1(nbthe carbamate has advantage in the milder metalation methylbenzamide (Scheme 12)lO4are not satisfactory conditions (Table 4) and complementarity in the basic for o- and o,o'-substituted diethy1ben~amides.l~~ conditions for hydrolysis.

D. Aromatic Tertiary O-Carbamate E. Heteroaromatic Tertiary O-Carbamate As appreciated by a glance at Table 12, electrophile All possible isomeric O-pyridyl N,N-diethyl- introduction into ortho-lithiated O-aryl N,N-diethyl carbamates undergo smooth metalation and electrophile carbamates occurs with equal efficacy and comparable quench to give a rich variety of substituted derivatives scope to that observed for the corresponding amides. that are difficult to prepare by classical substitution or Differences to note are the allylation (entry 2) and de novo pyridine construction modes (Table 14).Io8 hydroxyalkylation (entry 3) reactions, which do not The clean regiospecific 4-metalations of the 3-carbamate require transmetalation tactics. Amination and hy- are complemented by the recent preliminary results" droxylation are effected in excellent yield by the tosyl of efficient 2-deprotonation of 3-methoxypyridine using azide-borohydride reduction (entry 11) and trimethyl mesityllithium. The anionic ortho-Fries rearrangement borate/hydrogen peroxide (entry 12) procedures, re- (section V.A), iterative metalation (section VII), facile Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90. No. 6 895

TABLE 12. Synthesis of Ortho-Substituted 0-Aryl Carbamates"

R3 entry R E+ E yield, % ref 1 H Me1 Me 80 114 2 H BrCH2CH=CH2 CHzCH=CHZ 75 117a 3 H n-PrCHO n-PrCH(0H) 80 129 4 H PhCHO PhCH(0H) 90 129 5 H PhzCO PhZC(0H) 22 129 6 H DMF CHO 73 114 7 H Ac~O COMe 32 129 8 H COZ COzH 73-95 114, 118 9 H CICONEtz CONEtz 86-89 114, 118 10 H PhNCO CONHPh 80 129 11 H TsN3/NaBH, NHZ 94 b 12 H B(OMe)3/H202,HOAc OH 98 129 13 H Cl,CCCl, c1 80 129 14 H BkHzCHZBr Br 86 129 15 H 12 I 78 129 16 H TMSCl TMS 79 114 17 H (Mesh SMe 79 129 18 H (PhS), SPh 87 129 19 4-Me TMSCl TMS 83 117a 20 5-Me TMSCl TMS 77 117a 21 6-Me TMSCl TMS 54c 114 22 5-NMez DMF CHO 30 d 23 5-NMez TMSCl TMS 93 d 24 5-N(CHzCHz)Z DMF CHO 30 d 25 5-N(CHzCHZ)z TMSCl TMS 96 d 26 3-OMe Me1 Me 93' 117a 27 3-OMe COZ COzH 63 f 114 28 3-OMe 12 I 738 129 29 4-OMe Me1 Me 72 114 30 4-OMe DMF CHO 88 114 31 4-OMe COZ COzH 69 114 32 4-OMe TMSCl TMS 62 114 33 6-OMe CICONEtz CONEt, 90 117a 34 6-OMe TMSCl TMS 68 117a 35 341 Me1 Me 83 129 36 3-C1 PhCHO PhCH(0H) 81 129 37 3-C1 TMSCl TMS 89 129 38 441 COP C02H 69 118 39 4-C1 ClCONEt, CONEt2 77 118 40 6-C1 CICONEtz CONEtz 78 117a 41 6-C1 12 I 93 117a 42 6-C1 TMSCl TMS 79 117a 43 6-TMS 12 I 80 196 "All reactions were carried out under sec-BuLi/TMEDA/TMF/-78 "C conditions. *Table 6, ref g. 'Together with 2-CH2TMS derivative (26%) as an inseparable mixture. Under LDA/THF/-78 "C conditions, a mixture of 2-CHzTMS and P-CH(TMS), in a 5:l ratio and 80% yield was obtained. dTable 3, ref j. 'Combined yield with 6-Me isomer (2-Me:6-Me = 3:l). f20% 6-C09H. 827% 6-1.

TABLE 13. Synthesis of Ortho-Substituted 0-Naphthyl TABLE 14. Synthesis of Ortho-Substituted 0-Pyridyl and 0-9-Phenanthryl Carbamates" Carbamates"

yield, entry OCONEtz E+ E yield,%- entry OCONEtz E+ E % ref 1 C-2 Me1 3-Me 72 1 c-1 Me1 2-Me 90 114 c-2 ClCONEtt 3-CONEtz 66 2 c-1 ClCONEt, 2-CONEt, 79 117a c-2 TMSCl 3-TMS 52 (62)b 3 c-1 TMSCl 2-TMS 90 114 c-2 BrCHzCHzBr 3-Br 59 4 c-2 CICONEtz 3-CONEh 51b 117a c-2 12 3-1 68 5 c-2 TMSCl 1-TMS 17 117a c-3 Me1 4-Me 83 3-TMS 4jb 117a c-3 ClCONEtZ 4-CONEt2 64 c-3 BrCHzCHzBr 4-Br 71 c-3 TMSCl 4-TMS 69 (83)b 10 C-3 MesSnCl 4-SnMe3 82 11 C-4 Me1 3-Me 75 12 C-4 CICONEt2 3-CONEt2 69 6 Me1 IO-Me 92 200 13 C-4 TMSCl 3-TMS 67 7 TMSCl 10-TMS 88 200 Reference 108. Unless otherwise indicated, sec-BuLi/TME- "See footnote a, Table 12. addition, 20-25% of N,N-di- DA/THF/-78 "C conditions were used. bObtained under LDA/ ethyl-3-hydroxy-2-naphthamidewas obtained. THF/-78 "C conditions. 898 Chemlcal Reviews, 1990. Vol. SO. No. 6 Snieckus

TABLE 15. Synthesis of Substituted 0-Quinolyl Carbamates" ;(-y$coNEtz E

a entry OCONRz R E+ E yield, % ref 1 C-2 Et EtCHO 3-EtCHIOH) 3Obtc 116 2 c-2 Et PhCHO 3-PhCHiOH) 24b*c 116 3 c-3 Me MeCHO 4-CH(Me)NMeZd 60 116 4 C-3 Me EtCHO 4-CH(Et)NMezd 58 116 1 C-3 Me TMSCl 4-TMS 90 116 6 c-3 Et MeCHO 4-MeCH(OH) 25 116 I c-3 Et EtCHO 4-EtCH(OH) 35 116 8 c-3 Et PhCHO 40 116 Ph Y

9 C-3 Et 4-MeOC6H4CH0 4 - MeOC,H, OCONE!, 53e 116 &!rH 10 c-4 Et Me1 3-Me 75 116 11 c-4 Et EtCHO 3-EtCH(OH) 43 116 12 C-4 Et TMSCl 3-TMS 95 116 13 C-5 Me TMSCl 6-TMS 70 f 111 14 C-6 Me TMSCl 5-, I-,5,7-TMS8 75 f 111 15 C-7 Me TMSCl 8-TMS 90 f 111 16 C-8 Me TMSCl 7-TMS 40 f 111 Rz

&OH

R' RZ 17 C-3 Me PhCHO Ph NMe, 90 115 18 c-3 Me 2-MeOC6H4CH0 2-MeOC6H4 NMez 90 115 19 c-3 Me 4-MeOC6H4CH0 4-MeOC.HA NMe, 63 115 20 c-3 Me 3,4-(OMe)zC6H3CH0 3,4-(0Me)2e6H3NMei 78 115 21 c-3 Me 2-ClCSH4CHO P-CIC6H4 NMe, 65 115 22 C-3 Me 2-thienyl-CHO 2-thienyl NMe, 55 115 23 C-3 Me 2-pyridyl-CHO 2-pyridyl NMez 60 115 Unless otherwise indicated, LDA/THF/-78 "C conditions were used. bsec-BuLi/THF/-lOO "C conditions were used. Rearranged product I (R = Et (19%), R = Ph (24%)) was also isolated. dThe 3-OH quinoline derivative. 'Corresponding decarboxylated material was also obtained in variable yields. /In situ LDA/TMSCl/-78 "C conditions. gObtained in a 1:l:l ratio. ~~(i(lOCONE!r

SCHEME 14

E'2Noco& I I-BULI/ THF / .65"C, E1zNoCo

2 TMSCl

39 40 the known compatibility of LDA and TMSC1,42*60sily- lation is, with two exceptions (entries 14 and 16), cleanly hydrolysis (especially for the 2- and 4-carbamates),Io8 achieved (entries 5, 12, 13, and 15). In one of the ex- and latent DMG potential (36 - 37 - 38, Scheme 13) ceptions (entry 14), formation of mixtures may be constitute properties of the pyridyl carbamates that avoided via a metal-halogen exchange process, 39 -.+ 40 make them attractive for diverse synthetic use. (Scheme 14), at the cost of requiring the bromo- Comprehensive methoxypyridine and -quinoline quinoline precursor."' Hydroxyalkylation with aro- DoM reaction^^^^^^^*"^ complement the carbamate re- matic and aliphatic aldehydes proceeds only in mod- sults, although both DMGs have seen limited synthetic erate yields and leads to some unusual products (Table applications.29h3i 15, entries 3,4,8,9,and 17-23). Some of these products The DoM chemistry of isomeric 0-quinolyl N,N-di- 42 (Scheme 15) (entries 1, 7, and 11) have been con- methyl- and N,N-diethylcarbamates has been less div- verted into isomeric dihydrofuroquinolines 41,43, and ersely explored (Table 15). As may be expected from 44.112 Directed Ortho Metalation Chemical Reviews, 1990, Val. 90. NO. 6 897

SCHEME 15 TABLE 16. o-Hydroxy Aromatic and Heteroaromatic Amides by Anionic Ortho-Fries Rearrangement'

1, RLi/THF/-78 'c, 4 &OH 2. - rocmtemp 5 '1 CONEt2 3-OCONE12 R R6 $,,I 4-CH(OU)CHtCHa R entry reactant product yield, % ref 44 & 1 H H 2 4-Me 5-Me 70 48 3 2-Me 3-Me 70 114 SCHEME 16 4 3-Me 4-Me 48 117a 5 2-COzH 3-CO2H 37b 118 6 2-COzH, 4-C1 3-CO2H, 541 60b 118 7 2-CONEt2 3-CONEtz 30 (59)b 117a 45 46 8 2-CONEt2, 3-OH 3-CONEt2, 4-OH 75 117a 1 PG 9 2-CONEt2, 4-C1 3-CONEt2, 5-C1 42* 118 10 2-OMe 3-OMe 68 114 11 3-OMe 4-OMe 18 114 6-OMe 48 12 4-OMe 5-OMe 60 114 I 13 2,3-OCH20 3,4-OCHz0 58 119 DMG E(DMG) 14 3-OCONEtz 6-OCONEt2 86 117a 47 48 15 4-OCONEtz 4-CONEt2, 5-OH 25c 118 16 2-C1 3-C1 72 117a 17 3-C1 6-C1 71 129 Carbamate metalation has not been as yet pursued 18 4-C1 5-C1 65 114 in other heteroatomic systems, although an initial report OCONEI, OH of successful 0-fury1 phosphonate metalation may point WE12 the way.'13 19 1-OCONEtz 2$CONEtz1-OH, 2-CONEtz 71 117a F. Carbamate Manipulation 20 2-OCONEt2 48 117a 21 81d 200 Hydrolysis of tertiary O-aryl carbamates to phenols OH normally requires vigorous basic conditions;l14 in the absence of other similarly sensitive sites, LiA1H4 re- CONEI, duction followed by mild acid workup may be used. PWONEt20 0 Similar to tertiary amides, ortho-hydroxyalkylated, - 22 CONEI, 40 108 formylated, or -carboxylated carbamates suffer faster hydrolysis via anchimeric-assisted mechanisms. In the quinoline carbamate series, intermediates of such re- OH actions have been i~olated.ll~J'~J~~ OCONE1, 0 CONEt, V. The Amide-Carbamate Connection R~ RT) H A. Anionic Rearrangements 23 R=H R=H 74 108 24 R = Me R = Me 80 108 Methods for the regiospecific preparation of poly- 25 R = TMS R = TMS 60 108 substituted aromatics are considerably enhanced by the availability of the carbamate into salicylamide rear- mrNR2 rangement, 45 - 46 (Scheme 16, Table 16).l14 In this anionic equivalent of the ortho-Fries rearrangement, the 26 2-OCONRz 2-OH, 3-CONRz 60e1 111 (R = Me, Et) (R = Me, Et) carbamate 45 serves as a "carrier" of the amide into an 27 4-OCONMe2 4-OH, 3-CONMe2 80f 116 ortho site 46 from which, after suitable phenol protec- 28 5-OCONMez 5-OH, 6-CONMez 111 tion, it may oblige further DoM chemistry 48. In be- 29 6-OCONMe, 6-OH, 7-CONMez 80' 111 tween metalation of l,&related DMG substrates 47 30 7-OCONMez 7-OH, 8-CONMe2 60e 111 leading to 1,2,3-trisubstituted aromatics 48 and stra- 31 8-OCONMe2 %OH, 7-CONMez 40e 111 tegies for combinational use of amide-carbamate MGs 'Conditions: sec-BuLi/TMEDA/THF/-78 "C - room temper- are therefore conceptually possible. The 2-methyl ature (8-12 h) unless otherwise indicated. bIsolated as its methyl carbamate migrates cleanly into the ortho site (Table ether. Isolated as its dimethyl ether. Conditions: t-BuLi/ THF/-78 "C - room temperature. e Conditions: LDA/THF/-78 16, entry 3), while the corresponding 3-methyl deriva- "C room temperature or -40 "C. 'Quinolone tautomer. tive yields the 4-methyl product (entry 4) presumably - as a consequence of a steric effect. The meta-cooperative metalation effect is demonstrated cleanly by ortho-Fries rearrangement has also been observed in the carbamate (entry 14) and chloro (entry 17) DMGs; naphthyl (entries 19 and 201, phenanthryl (entry 21), surprisingly, the corresponding methoxy system shows pyridyl (entries 22-25), and quinolinyl (entries 26-31) poorer regioselectivity (entry 11). An illustration of a carbamate series. The rate of the anionic ortho-Fries double l,&carbamoyl rearrangement to a hydroquinone rearrangement is highly sensitive to N-substitution and diamide has been recorded (entry 15). The anionic temperature (Table 17) and has been shown by cross- 898 Chemical Revlews, 1999, Vol. 99, NO, 6 Snieckus

TABLE 17. Anionic Ortho-Fries Rearrangement of o-Aryl SCHEME 18 Carbamates as a Function of N-Sub~tituent"~~ OCOIIEI, pres "TR9 aOCoN'1. OCONR, {d 1 $EuLiiTMEDA_ <~coNEtE 2 iRT 2 DMF 2. Me1 3 TBSCI I Im 15o%1 CONb 55 56 4 MSCl I EIJN 57 5 DEU R temp, "C time(metalation), min product ratio yield, % Et -78 10-60 1oo:o 70 Me -78 45 0:lOO 75 Me -78 10 67:33 80 Me -95 10 1000 90

SCHEME 17

?CONE12 ?CONE12 OMe

R R R A9 50 51 a: R=H a: R s H (89%) a: R = H (59%) b: R = CI b: R - CI (77%) b: R I Ci (42%) SCHEME 19 ?H R CCONEIZ5 0 reliux OH (70%) 0 62 63 M a: R-H 52 53 b: R-TMS a: R = H (55%) a: R = H (50%)

b: R = CI (38%) b: R iCl (49%) - mJWti

54 a: R = H Ochratoxin 8 b: R = CI ochratoxin A over experiments to proceed by an intramolecular TMS mechanism.117a Nu~cONEE"71

Combinational use of amide and carbamate DoM 3 +RT 7o 69 chemistry is illustrated by the synthesis of ochratoxins ElrNOC EIlNOC Ph A and B, toxic metabolites isolated from strains of Aspergillus ochraceus and Penicillium viridicatum Ph (Scheme 17).l18 Metalation and carbamoylation of 49a Ph Ph and 49b led smoothly to compounds 50a and 50b, re- 72 156%) 73 (97% spectively, which, upon anionic rearrangement and methylation of the intermediate phenols, gave the iso- achieved by an innovative process that takes advantage phthalamides 51a and 51b. The allyl group was in- of amide stannylation to effectively increase its nu- troduced by the metalation-transmetalation sequence cleophilicity. Extensive oxygenated ring manipulation to afford 52a and 52b,which were directly treated with which includes a suprafacial allylic 0 - N transposition HC1 to effect lactonization, amide hydrolysis, and de- of 60 and terminal lactone to lactam rearrangement methylation in one pot to give the isocoumarin- gave rise to pancratistatin (61). carboxylic acids 53a and 53b in 6-14% overall yields. In contrast to the kinetic result (Table 16, entry 3), These known compounds had been previously trans- LDA deprotonation of the o-tolyl carbamate 62a formed into ochratoxin B (54a)and ochratoxin A (54b), (Scheme 19) leads to o-hydroxyphenylacetamide 63 respectively. An alternate route to 53b by direct car- (4970);"~~the yields of 63 are improved by using sily- boxylation of 49b was accomplished in low overall yield lated starting carbamate 63b.117bThe demonstrated owing to an inefficient allylation step corresponding to conversion of 63 into 64 in good yields suggests that this 51b - 52b. methodology may have general synthetic utility for Amide-carbamate DoM reactions have also been ex- difficult to access benzofuran-2-ones. ploited in the synthesis of pancratistatin (61) (Scheme 18),a phenanthridone alkaloid from Pancratium lit- B. Benzyne Generation torale showing promising antitumor activity.llg An- ionic ortho-Fries rearrangement on 55 followed by si- The discovery by Kobayashi120 that o-TMS aryl lylation afforded benzamide 56, which was metalated, triflates serve as benzyne precursors led to the devel- formylated, and subjected to chain extension and deh- opment of two routes for the generation of the syn- ydration to give the arylbutadiene 57. Cycloaddition thetically useful benzamide benzyne intermediate 68 with an acetylenic dienophile equivalent and tin hydride (Scheme 20).lZ1 Precursor isomeric TMS phenols 66 induced elimination afforded the cyclohexadiene 58. and 70 were secured by anion-induced ortho-Fries 65 Following desilylation, halolactonization to 59 was - 66 or 0 - C silicon 69 - 70 rearrangements, re- Directed Ortho Metalation Chemical Reviews, 1990,VOI. 90, NO. 6 8ee

SCHEME 21 SCHEME 22

?CONE11 CONEti

2. CaFMpCN OH '17 79 75

(79%) IE* F spectively. The latter reaction, proceeding via intra- or intermolecular paths, depending on the position of 82 the silyloxy substituent, has modest, as yet incompletely 80 81 explored, scope for the preparation of o-silylbenzamides a: E =Me (61.84%) b E = SMe(65%) (Table 6, entries 37-40).122 The triflates of 66 and 70, E: E = I(49.59%) obtained by standard procedures, upon treatment with d E = Br (M%) TBAF in the presence of an excess of appropriate di- Br E enes afford products 67a-c, 72, and 73 in good yields. In the solitary pertinent case studied (674, the reaction I I shows no regioselectivity. Using the same benzyne- iMS Br E generating conditions but in the presence of excess of 83 84 85 nucleophiles in protio, lithio, and TMS precursor forms a: E = Me (69%) b: E = SMe (65%) allows rapid access to a variety of meta-functionalized c: E= I(74%) benzamides 71. As observed by Kobayashi,120 the success of this reaction with protio nucleophiles such as MeOH is consistent with a mechanism that involves either rapid loss of OTf from a desilylated precursor or concerted formation of the benzyne. These reactions, which are under further e~ploration,'~~J~~parallel and complement observations by Meyers and co-workers on benzyne species derived from (m-chloropheny1)oxazolines under strongly basic RLi metalation conditions.lB Aside from participating in cycloaddition similar to that observed for 68, the oxazoline benzynes have been shown to react in situ with organolithiums and cuprates SCHEME 24 at either C-2 or C-3 dictated by kinetic or thermody- 1.2eglt4 sButi/TMEOA, aE' namic control conditions. The resulting anions may be GCONElz 2. El' Ei CONEtz 3. Ez' treated with electrophiles, thus providing an innovative so 81 tandem route to 1,2,3-trisubstituted benzenes. Similarly, carbamate benzynes may be generated from analogous precursors (Scheme 21).123J24 Thus d2 incorporation (95%)12' and clean disubstitution by conversion of 74 into the ortho-silylated phenol 75 electrophiles (e.g., MeI) that would expose highly acidic followed by triflation and fluoride-induced benzyne sites in potential monosubstituted intermediates formation in the presence of furan affords cycloadduct strongly suggest that the dilithiated species 78 is gen- 76 in good yields. erated in these reactions. The generation of dianion equivalent synthons may VI. 2,gDianion Equivalents be extended to phthalamides. Thus the dianion from dibromophthalamide 84, obtained analogously by bro- The successful generation of a dimetalated or higher modesilylation of 83, has been shown to react with order metalated aromatic species promoted by one or similar electrophiles to give 3,6-disubstituted products more DMGs will be dependent upon electrostatic re- 85a-c.12' The generation of the corresponding dianions pulsion, additional complexity in aggregation, and of isophthalamides and terephthalamides was impeded solubility, among other factors. Utility in synthesis has at the dibromo and bis-TMS precursor stages, respec- only recently been explored.MJ26In the context of the ti~e1y.I~~ tertiary amide DMG, the formal dilithiated species 78 In contrast to the phthalamide 84, the catechol and (Scheme 22) cannot be generated directly by double hydroquinone dicarbamates 86 and 88 (Scheme 23) DoM reaction, but may be obtained by metal-halogen undergo direct dilithiation under the standard sec- exchange from the 2,6-dibromobenzamide 77127or by BuLi/TMEDA conditions and lead, after electrophile reverse transmetalation from the dimercurial 79.128 treatment, to products 87a,b129and 89a-~,l~~respec- Compound 77 is available by double ipso bromo- tively. The evident potential for sequential introduction desilylation of 80, which, in turn, is readily accessible of two different electrophiles (87a,b) may have appli- by one-pot sequential bissilylation of N,N-diethyl- cation in these and related systems for the synthesis of benzamide; 79 is obtained from the bare benzamide 82 unsymmetrically substituted benzoquinones. under in situ trap thermodynamic conditions using the In the solitary study of a dimetalated DMG hetero- compatible LiTMP/HgC12 base-electrophile combina- aromatic system, the thiophene-2-carboxamide 90 tion. Electrophile quench of 78 leads to satisfactory (Scheme 24) has been shown to serve as a 3,5-dianion yields of otherwise poorly accessible 2,6-disubstituted equivalent and to produce, following the expected benzamides 81a,ln11za 81b,12781c,127J28 and 81d.lB High carbanion reactivity order, a variety of thiophenes with 900 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

SCHEME 27 ar F CONE!. TMs~oCoNL1& eoCoNEt2E-CONEt2 LTMshkONE~. 1 LOA 1 RLI 2 TMSCI 2 TMSCl 104 105 106 (65%) 8' E 166%) CONElz 1 cBuLt b E=CONEIz TMEDA OCONElt OCONEI,

1, sEuLiITMEDA ~s@coNE1z ;Me 1 2. TMSCl - 94

CONE12 CONE12 CONE12 COYE12 1 sBuLi ElzNOC@ ONE12 1 ~EoAS-BULI EI.NOC$J ONEb

___) SCHEME 28 TMS 2 TMSCI TMS TMS

96 97 98

111 \Chain 109 110 SCHEME 26 Exlenston

TLIS TMS Iterative metalation processes have also been demonstrated for 0-pyridyl carbamates (Scheme 27) .lo* 99 154%' ~ONEI? 100 301 Thus the 4-bromo derivative 105a (Table 14, entry 8), when subjected to known conditions for metalation of &OCONEIZ 27 ClCONElz5 BuLi I TMEDA the bromopyridine prot~type,'~~J~~afforded the 3,4,5- 3 s-BuLI, TMEDA trisubstituted pyridine 104. In a parallel series of re- 4 Me1 CONE11 actions, the intermediate isonicotinamide (Table 166% Me 105b 102 103 14, entry 7) furnished a different trisubstituted derivative 106. On the other hand, the nicotinamide 107 the same or different 3,5-substituents in modest yields (Table 14, entry 12) led to yet another variation of (Table 9, entries 6-16).94 pyridine trisubstitution (108). The final products in all three cases indicate that the last metalation occurs at C-5 irrespective of the DMG. Complementary 2- VII. Iterative DoM Reactions metalation of unsubstituted 3-methoxypyridine has Iterative DoM processes, as yet little exploited, are been achieved by using mesityllithi~m.'~~ potentially valuable for rapid access to diverse polysubstituted aromatics. The concept (92, Scheme 25) VIII. Synthetic Consequences of 0-Carbon involves sequential introduction of electrophiles that Electrophile Introduction serve as DMGs for subsequent metalation in an overall "walk-around-the-ringnregimen. The relative hierarchy Products derived from regiospecific DoM reactions of the introduced DMGz and the original DMGl dic- may be further manipulated by standard functional tates the position of the incomimg DMG3 and is a group interconversions into a variety of useful poly- repetitive consideration. Illustrative of possibilities are substituted aromatics. Of equal synthetic value is the the conversions of 93 and 96 into the polysubstituted potential, as yet in the early stages of exploration, to systems 95 and 98, respe~tive1y.l~~Metalation of 93 parlay DoM processes, via the initially introduced followed by phenyl isothiocyanate quench gave the electrophile, into chain extension, carbo- or heteroring lithiated thioamide 94, which, without isolation, was annelation, and other carbon-carbon bond-forming metalated and treated with methyl iodide to give 95 in protocols. These synthetic consequences are discussed good overall yield. Alternatively, a sequence of meta- according to the nature of the initially introduced lations on 93, involving two carbamoyl chloride and one electrophile. trimethylsilyl chloride electrophile quenches, led, via With the exception of the areas of cross-coupling isolated intermediates 96 and 97, to the hexasubstituted chemistry (section 1X.E) and anionic rearrangement aromatic 98, a highly crowded molecule with a non- (section V), few results are available for the OCONEtz planar benzene ring as established by X-ray crystallo- DMG and, as the discussion will make evident, the graphic ana1y~is.l~~ majority of synthetic applications is the exclusive do- Similarly, broader synthetic potential of iterative main of the CONRz DMG. metalations initiated by the carbamate DMG is suggested by the conversion of 99 and 102 into the tetra- A. o-Methyl substituted systems 101 and 103, respectively (Scheme 26).'17* Thus a one-pot sequence of metalation, sily- The simple expedient of methylation of an ortho- lation, metalation, and carbamoylation gave the tri- lithiated benzamide to give 109 (Scheme 28) provides substituted derivative 100, which was isolated and a handle for further electrophilic functionalization via subjected to a second metalation-carbamoylation the easily generated (usually burgundy red) 0-tolyl an- treatment to give the tetrasubstituted derivative 101. ion 110, thus offering avenues for chain extension and A similar one-pot sequence on the o-methoxy carbamate ring annelation strategies 11 1. For annelations, intro- 102 gave a different contiguously substituted aromatic duced olefinic, imine, nitrile, carboxy, and hydroxyalkyl 103. functionalities serve as electrophilic or nucleophilic sites Directed Ortho Metaiation Chemical Reviews, 1990, Vol. 90, No. 6 901

TABLE 18. Svnthesis of 3-Arvl-3.4-dih~droisocoumarins

R Z ArCHO Z Ar yield, % ref Et H PhCHO H Ph 30 (62)" 100,101 Et H 2-MeOC6H4CH0 H 2-MeOC6H4 45 100 Et H 3-MeOCaH,CHO H 3-MeOC6H4 40 100 Et H 4-MeOCiH;CHO H 4-MeOC6H4 65 100 Et H 3-PhCHzO, 4-MeOC,H3CH0 H 3-PhCHzO, 4-MeOCsH3 32 100 Et H furan-2-carbaldehyde H 2-fury1 30 100 Et H thiophene-2-carbaldehyde H 2-thienyl 30 100 Me OMe 4-MeOC6H4CH0 OMe 4-MeOCsH4 35 (46)b 100 Me OMe 3-PhCHzO, 4-MeOC6H3CH0 OMe 3-PhCHzO, 4-MeOC6H3 32 (21)b 100 Using starting benzamide, R = Me, N(Me)CH2CH2NMe2,Z = H. By a one-pot procedure from N,N-dimethyl-2-methoxybenzamide.

SCHEME 29 SCHEME 30

Me0 Me0

1 I-BuLIlLDA 2 CtCH2CsH,-4-OMem (74%) 112 OMe 115 116 117 1 TFA 2 NaNqI HOAc I Ac20 3 KOH 4 BBr, I CH& 1.78% Wd 114 OH for cyclization by amide participation. This partly confers a chameleon character to the CON& in that it originally withstands attack by potent RLi reagents. Complementary routes are available from o-tolyl sec- SCHEME 31 ondary amide^,^^^^^ oxaz~lines,~~ga-amino alkoxides,u and esters,133although the last species, while widely used, clearly cannot be derived via initial DoM chemistry. As documented below, a large body of literature 120 (32% overall) attests to the synthetic value of the o-tolyl tertiary amide anion 110. Me? FI HP x

1. Chain Extension OH (45%) With the exception of ethylation (Table 6, entry 12), introduction of long chains into ortho-lithiated N,N- 122 123 diethylbenzamides has not been reported, perhaps due to intervention of elimination reactions. The less basic o-tolyl anion is recommended for such processes as il- prepared for use in a naphthoquinone ring construct lustrated by the short synthesis of lunularic acid 112 (Scheme 36). - 113 - 114 (Scheme 29) using the more easily hy- An alternate annelation method leading to the same drolyzed CON(Me)-t-Bu DMG.lo2 ring system at a different oxidation state 123 (Scheme 31) may be achieved via amide alcohol intermediate 2. Heteroannelation via 0-Tolyl Anions 121.100J01A typical sequence" of some generality (Table 18) begins with a rare case of an N,N-di- The carboxylation of the o-tolyl anion of 116 (Scheme methylbenzamide 120 metalation followed by methyl- 30), obtained from the benzamide 115, leads to the ation, a second metalation, and treatment with 0- homophthalic acid amide 117.134 This overall two- benzylisovanillin in a one-pot process to give amide carbon chain extension, not achievable directly by alcohol 121 in modest overall yield. Compound 121 is treatment of 116 with ethyl a-bromoacetate, can also also available by condensation of the intermediate o- be carried out in a one-pot procedure and provides toluamide with the appropriate benzoate ester followed convenient access to the homophthalic anhydride 118, by sodium borohydride reduction. Base-induced cy- previously available by a classical route in nine steps clization to 122 followed by deprotection affords and low overall yield. The heteroring annelation phyllodulcin (123),a natural product with a sweetness product 118 served as one component for a convergent index 400 times that of sucrose. Base hydrolysis of the and abbreviated synthesis of the phthalide isoquinoline tertiary amides was necessitated by the derailment of alkaloids cordrastine I (119a) and cordrastine I1 (119b), the synthesis to a stilbene derivative under the standard which also embodied a key bromohomophthalic anhy- TsOH-catalyzed conditions. This problem appears to dride-phthalide a-carboxamide rearrangement. 5- be circumvented by the use of the TMEDA-like DMG Methoxyhomophthalic anhydride has been similarly (Table 18).101A single case of condensation of lithiated 902 Chemical Reviews, 1990. Vol. 90, No. 6 Snieckus

SCHEME 32 LI

0 0 124 125 (26

SCHEME 33

Me 1 1.DA

197 RN fi=Me TM5 ,,p

SCHEME 35 N,N-dimethyl-2-methoxy-6-methylbenzamidewith an aliphatic aldehyde has been re~0rded.l~~ N-Heteroring annelation using imine electrophilic partners has been demonstrated and applied to alkaloid synthesis by Clark and Jahangir (Schemes 32-35, Ta- bles 19 and 20).136J37In this rapid heteroring construct related to several other methods of isoquinoline synthesis,138o-toluamides 124 (Scheme 32) are condensed with a variety of aromatic and aliphatic imines to give satisfactory yields of 3-substituted isoquinolones 126 (E = H) via the 4-lithiated species 125. Among the derivatives available by this procedure are functionalized amine (Table 19, entries 7 and €9, spiro (entry 161, and fused (entries 17 and 18) systems. In contrast to the acid-mediated synthesis of isocoumarins (Table 18), This convergent synthesis illustrates the use of the this route involves amide participation as an electro- o-tolyl amide anion as a lynchpin for the C/D rings of philic site in what appears to be a stepwise process. As compounds 142 and the amide as a terminal electrophile a consequence of the generation of the 4-lithiated for heteroannelation. species 125 (formed by proton exchange with the in situ N-Heteroring annelation to the a-lithiated o-tolu- generated LiNEt,), quench with electrophiles other amide synthon may be achieved by use of nitrile elec- than a proton source leads to 3,4-disubstituted products trophiles as demonstrated in the instructive synthesis 126 (E = alkyl), thereby adding a valuable feature to of the potent antitumor antibiotic fredericamycin A this heteroannelation method. The scope of this ste- (148)(Scheme 37).140 Thus starting with simple indan reospecific tandem reaction has been explored (Table 143 or dihydroisocoumarin 146 precursors, intermedi- 20) and extended to heterocyclic analogues (127.-+ 128, ates 144 were prepared, which, upon LiTMP-induced Scheme 33).137 Instructive applications of this metho- condensation with diethoxyacetonitrile, produced 145 dology for the construction of protoberberines (Table in good yield on a multigram scale. Conversion into the 19, entries 17 and 18),a benzophenanthridine alkaloid silyl anion 147 followed by coupling with an appropriate (129 + 130 - 131 - 132, Scheme 34),136aand a pro- naphthalene anhydride set the stage for the successful posed common biosynthetic intermediate (133 + 134 .-+ completion of the total synthesis of fredericamycin A 135 + 136 - 137, Scheme 35)136bfor these two classes (148). The heteroannelation tactic has also been used of natural products have been demonstrated. In the last for the construction of the isoquinolone 151, initiated case, the inability to obtain 136 by the tandem se- by a comprehensive DoM approach on 149 and in- quence, presumably owing to decreased acidity of the volving the intermediate 150, with the same target C-4 hydrogens, necessitated the use of the %ethyl molecule as a starting material 133. Condensation of o-tolyl amide anions 139 (Scheme 3. a-Silyated 0-Toluamides 36)139with homophthalic anhydride 138 leads to adducts 140 in a reaction that embodies overtones of po- The a-silylated o-toluamides 153a,b (Scheme 38) are lyketide biogenesis.'" Since both reacting partners may formally o-tolylamide anion synthons through the ex- be prepared by DoM, the overall process has consid- pediency of fluoride ion. As demonstrated by several erable scope. Sequential Claisen-aldol condensation, examples, TBAF-induced carbodesilylative hydroxyla- base-catalyzed aerial oxidation, and amide hydrolysis tion on the a-silyl o-toluamides 153a,available in high on 140 afford the hydroxynaphthoquinones 141 in good yield from precursors 152, gives products 154a-d in overall yields. The pendant quinone hydroxy group good ~ie1ds.l~~Since this process is carried out under presumably assists the hydrolysis step under these essentially neutral conditions, it complements the direct relatively mild ~0nditions.l~~These compounds were chain extension of the anion derived from 152 with converted into pyranonaphthoquinones, one of which benzaldehyde to give 154 and may be valuable for the (142) was shown to be identical with the antibiotic preparation of substituted systems that cannot tolerate WS-5995A isolated from Streptomyces auranticolor. strongly basic conditions. a-Bromination of derivatives Directed Ortho Metalation Chemical Reviews, 1990, Voi. 90, No. 6 003

TABLE 19. Synthesis of 3-Substituted 3,4-Dihydro-l(2H)-isoquinolones

entry R R' R2 yield, % ref 1 H Ph CHoPh 55 137 2 TM% a 137 3 Me 56 137 4 C6Hll 42 137 5 n-Bu 42 137 6 C6H11 48 137 7 CH2CH2NMe2 37 137 8 24 137 -CNCHIPh 9 3,4-(MeO),C6H3 Me 37 137 10 3,4-OCH,OC6H, Me 47 137 11 3,4-OCHzOCsH3 Me 136b 12 3,4-OCHzOCsH3 Me lob 136a 13 2-vinyl-4,5-OCHzOC6Hz Me 61 b 14 4-pyridyl Me 30 137 15 C6H11 Me 44 137 16 44 137 n -0uN # 0pu0 0~3 OR^

N&TOV &OR'

0 17 R3 = R4 = Me 43 137 18 R3 + R4 = CH2 59 137 " Obtained after cyclization (TsOH/xylene/reflux) of initially isolated open-chain intermediate. Byproduct from tandem reaction, 129 - 131 (Scheme 34).

TABLE 20. Synthesis of 3,4-Disubstituted SCHEME 36 3,4-Dihydro-l(2H)-isoquinolones -

R' CONE12 OMe R' 140 138 139 R' Rz R3 yield, % 8: H H H 86 b' H OMe H 93 C: OMB OMe H 61 d. OMe OMe Me 80

Me Me1 Me1 H H 45 136b 1 NaOMelMeOH Me1 Me OCH20 62 137 Ndrellux 2 10XNaOH n-BuI n-Bu OCHzO 68" 137 air OH 3 15%aqHClOi R' 0 OH 0 CH2=CHCHzBr CHzCH=CHz OCHzO 51 137 n"a.lll/ 1"",",cnDI_ ".".".,, PhCHzCl CHzPh OCHZO 59 137 141 142 WS.5995A CICHzTMS CH,TMS OCH20 58 137 TMSCl TMS OCHzO 32 137 BrCH,CH(OMe), CH,CH(OMe), OCH20 54 136a of electrophile quench (Table 21)." Fluoride-induced desilylation to contiguously substituted aromatics with "Using n-BuBr and n-BuC1 gave yields of 53% and 59%, re- diverse functionality concludes this methodology, which spectively. has been applied (Table 29, entries 3 and 4; Scheme 62) and deserves further attention. 153a is also possible (section VIII.C.2). Fluoride-me- B. o-Allyl diated Peterson olefination may be effected on the equally accessible u,u-disilylated o-toluamide 153b with N,N-Diethyl-o-allylbenzamidesmay assume either an aromatic aldehyde leading to a stilbene derivative cationic 158 (Scheme 39) or anionic 159 annelation 157. The reduced counterpart of the monosilylated modes. In the former, the amide is internally hydro- amide 153a is useful as an o-quinodimethane precursor lyzed by anchimeric assistance from the developing 155 to the tetralin 156.130 a',a'-Disilylated derivative carbocation; in the latter, it reveals its chameleon 153b undergoes further kinetic metalation at aromatic electrophilic character which is not granted to RLi C-6 rather than methine site as evidenced by products reagents. 904 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

SCHEME 37 TABLE 21. Silicon Protection Route to 6-Substituted 2-Tol~amides'~~ 1 sBuLiTMEDA 2 CICONEII E E

OMOM 0 OMOM

TMS TMS '70 E ~Ivield. E vield."I YO D 94 SMe 96 Me 81 TMS 83 CHO 78

TABLE 22. Synthesis of I-Naphth~lsl~~

2 equiv of MeLi THFi-78 'C + momtemp

reactant product entry R' R2 R' yield," % 1 H Et H 86 (65) 2 3-OMe Et 5-OMe 90 (58) 3 4-OMe Et 6-OMe 64 4 6-OMe Et 8-OMe 35 (16) a 6-OMe Me 8-OMe 81 6 3,6-(OMe), Et 5,8-(OMe)* 77 (37) 7 4,6-(OMe), Et 6,8-(OMe), 62 'Yields in parentheses are for reactions using 2.2 equiv of LDA.

SCHEME 40 0 CONRz 1 SBULI ' TMEDA 2 MpBryZEt20 * =-& 157 )d R' ~rdR' R' 162 160 161 OM R' Ylew vn

Ri iMe El a: H 93 b: 6-OH 75 SCHEME 39 c:S-OMe 49 d: 5-OH 16 e 6 7.iMe0)~- 8-OH 27

SCHEME 41 &-ecz+ &NE12 1. Isocoumarins MeLi f'. MeLi 163 THFI-7BeC+RT ,a (35%) t65 (50%) a: Z=Me o-Allylbenzamides 16 1 (Scheme 40), readily prepared b: Z-mS from the parent 160 by the ortho metalation- transmetalation technique, are converted into substituted isocoumarins 162 under acid-catalyzed condi- this anionic carboannelation reaction provides rapid and tion~.'~~The vigorous conditions of this reaction lead, regiospecific assemblage of several significant oxygen- in part, to demethylation but this result has, at times, ated naphthols. The operation of a steric factor is ev- advantage in that two natural products, mellein (162b) ident from comparison of yields of products from di- and kigelin (162e),are directly formed. The synthesis ethyl- and dimethylamides (entries 4 and 5), although of ochratoxin (Scheme 17) demonstrates the application it appears not to have a detrimental effect for a number of this cyclization to a more complex system. Secondary of oxygenated cases. The o-crotyl derivative 164a toluamide~~~~!~and o-tolyl oxazoline~~~ghave been (dotted bond) (Scheme 41), prepared by Ni-catalyzed adapted for similar ring construction. cross coupling, allows access to 2-methyl-1-naphthol 163 while the (trimethylsily1)allyl counterpart 164b, ob- 2. 1-Naphthols tained by metalation-silylation of the parent system, affords 1-(diethy1amino)naphthalene (165),a product In contrast to the nature of the above isocoumarin of an intramolecular amide Peterson olefination. A ring closure, the electrophilic character of the tertiary useful, potentially general, adjunct to this method is the amide in o-allylbenzamides is manifested in a methyl- regiospecific preparation of oxygenated naphtho- lithium-induced regiospecific construction of 1-naphthol quinones as illustrated by the conversion of 167 derivatives (Table Although not thoroughly (Scheme 42) into both 166 and 168 (juglone acetate) in evaluated in scope and mechanistically ambiguous,143 unoptimized yields. Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 905

SCHEME 42 SCHEME 45 Me0 0 MOO OH 0 OAC

@-@-@(31%) (91%)

Me0 0 Me0 0 176 177 178 166 167 168 SCHEME 46 SCHEME 43 R OH Me0 OH 0 / 1. .CH$Oz’ LRW02wZo 2. TsOH/ PhMa / reflux a::179 CHO 3. BBr3 / CHZCIZ/ -78°C 180 0 181 0 OMG CONR,. CobJHR, OX, 169 170 \COzH - 2 H. SOzPh, CN ais0 C&R -

SCHEME 44

1. 2 TSOH I PhMe CHO (91%) 1RjSiCI OM0 OM0 171 172 1

oMe OH 0

1.DbilCH$12/654:, MeONa I/ 2 2NHCI -(70%) 184 OSiRl 185 0 186 0 (75%) 1 OM1 173 three-step process 176 - 177 - 178 (Scheme 45, Table 26, entries 1-4).146 Analogous sequences have been effected via DoM chemistry of secondary amidesBb and oxaz~lines.~gJ~~This general and invariably high-yield protocol is particularly valuable for the preparation of 174 175 (Daunomycinone) oxygenated phthalides, useful synthons for natural products, which have been previously available only by tedious and inefficient routes.14s C. o-Formyl 2. 3-Hydroxyphthalides and Isobenzofurans The NJV-diethyl-o-formylbenzamidesynthon, readily available in a variety of substitution patterns (Table 6), The easily achieved, acid-driven cyclization of o- may, in principle, partake in the large body of funda- formyl DMG aromatics 179 (Scheme 46) to 3- mental carbonyl chemistry. The expedient of anchim- hydroxyphthalide 180 has served as the basis for the erically assisted hydrolysis to 3-hydroxyphthalide de- development of several new important annelation rivatives has dominated the utility of o-formylbenz- methods. The hydroxyphthalides are usually converted amides in synthesis (section VIII.C.2); however, chain into carbanion-activating derivatives 181 which proceed extension by an acetic acid dianion 169 - 170 (Scheme by metalation (182)and condensation (183)with Mi- 43)144is a simple illustration of further synthetic po- chael acceptors to give quinones 185. In this sequence, tential. Compound 170 represents isoochracinic acid, the 3-hydroxyphthalide synthon 180, easily available a rare phthalide natural product isolated from the in a variety of substitution patterns (Table 26, entries parasitic fungus Alternaria kikuchiana which is re- 46-54), acts as a 1,4-dipole equivalent 186.149The as- sponsible for black spot disease on Japanese pears. sumed two-step anionic process in the conversion 182 Similarly, chain elongation via Grignard reagents - 183 is synthetically equivalent to a (4 + 2)~cyclo- (Schemes 18, 44) has been exploited. The efficient addition 184 - 185, the 3-(silyloxy)isobenzofuran 184 construction of the A/B ring synthon 174 (Scheme being generated by an in situ silicon trap of the am- 44)14 of the antitumor antibiotic daunomycinone (175) bident anion 182.I5O The contribution of benzamide was initiated by the incorporation of a four-carbon DoM chemistry to these two types of protocols is in- Grignard into the o-formylbenzamide 171. The dicated in Schemes 47-51 and Schemes 52-54, respec- phthalide 172, resulting from subsequent acid-catalyzed tively. cyclization, was partially reduced and carefully hydro- A convergent synthesis of the 7-deoxy-7-epimethox- lyzed to give the hemiacetal 173, which upon intramo- ydaunomycinone derivative 192 (Scheme 47) 149b com- lecular aldol condensation furnished 174 in 38% overall mences with the hydroxyphthalide 188, obtained in yield. satisfactory yield from the anisamide 187. Conversion into the corresponding sulfone 189 and condensation 1. Phthalides by Reduction with the quinone monoketal 190 led directly to the tetracyclic product 191. Cosmetic modification gave the As a consequence of the inconvenience and poor re- daunomycinone derivative 192 in good overall yield. In producibility of tertiary benzamide DoM reactions with a synthesis of the antiprotozoal pigment bikaverdin various sources of formaldehyde, the preparation of (196) (Scheme 48),149aa more highly oxygenated C-3-unsubstituted phthalides has been pursued by the phthalide sulfone 194 was coupled with the chromone 906 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

SCHEME 51

1 nBuLi THFI.100'C

2 ClCONEIi (90%) Bl 3 I.BuLi 4 OMF (96%) 5 TMSCNiKCN 21 3 18-c.6 214 6 HOAcJCH2=C(OMe)Me Camphor sunonic acid (84%)

Me0 0 OH OMe Me0 0 OMe :Me '3' 152

SCHEME 48 216 217 (Granamn)

Me0 (27%) OH OMe 193 194 195

Me0 OMe OH 0 218 219 220 196 (Blkaverd!n' X Y Vdd.% ab Yield s:CH H 87 0 r b:CH OMe 78 12 b: 81 SCHEME 49 c:COMe H 80 10 c: 85 d: N OMe 38 8 d 80

SCHEME 50

SCHEME 53 0 OMe OMe o 201 202 203 (Zqanein dimethyl elheii Y@OMe 2' ':;:byFTMSCI b [ r#OMe] 0 .78"C+RT O OMe TMSO ow 223 224

225 .7B°C+RT 2 SI02 (62%)

226

SCHEME 54 +@y-(y@JoCI 2 ti' ,"VII 1. oBuLVTMEDA e:0 370, TCIFI.7R°C OMe 0 OMe Me OM 210 211 212 Me+ Me0 CONE12

oxi- 227 193 to give the annelated product 195, which was (80%)onc@om 228 dized and demethylated to complete the brief synthesis OM of 196. 3-Cyanophthalides appear to be even more effective 1,4-dipole equivalents (186). In a comprehensive study, Biehl and co-workers have demonstrated a rapid construction of anthraquinones 200 (Scheme 49)15' by base-mediated condensation of 3-cyanophthalides 198, readily available from benzamides via the corresponding 230 231 (Reslstomycin) hydroxy derivatives 197, with benzynes derived from haloaromatic precursors 199. A variety of alkoxy, al- site. A selection of natural products and natural dehyde, and condensed anthraquinones are available product precursors available by this protocol from sim- by this reaction, whose regioselectivity is dictated by ple 3-cyanophthalides and haloaromatics is shown in methoxy substituents ortho to the incipient benzyne Scheme 50 201 + 202 - 203 (ziganein dimethyl ether), Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 907

TABLE 23. Reaction of N,N-Diisopropyl-2-(diazomethy1)benzamideswith Dienophileslw

method 2 e(m#'OH (see Scheme 55) dienophile R Z yield, % A H2C=CHC02Me i-Pr H 52' B H2C=CHC02Me Et H 44 C H,C=CHCO,Me i-Pr H 55 A (Z)-Me02CCH=CHC02Me i-Pr P-C02Me 75' B (Z)-Me02CCH=CHC02Me Et a,P-CO,Me 27:40b A (E)-Me02CCH=CHC02Me i-Pr a-COzMe 430" B (E)-Me02CCH=CHC02Me Et a-C02Me 44 C (Z)-Me02CCH=CHC02Me i-Pr P-C02Me 51 A Me02CC=CC02Me i-Pr COzMe 49,"d 2a4e B Me02CC=CC02Me Et COzMe 71d A CH,=CHCON(Me)Ph i-Pr H 56O A CH2=CHS02Ph i-Pr H 39c C CH2=CHS02Ph i-Pr H 46 i-Pr (E)-CH=CHMe 6cf A -cogt A * 33," 44c 4 HO Using Cu(acac), catalyst. bN,N-Diethyl-2,3-bis(methoxycarbonyl)naphthalene(17 %) byproduct. Using Rh,(OA& catalyst. The aromatized (-H2) product was obtained. e30 mol % of Cu(acac), was used. 'The regioisomer from addition at the a,b-double bond was obtained (35%) as a separable &:trans = 21:13 mixture.

204 + 205 - 206 (chrysophanol dimethyl ether), 204 SCHEME 55 + 207 - 208 (islandicin trimethyl ether) + 209 (digitopurpone trimethyl ether). In addition, the coupling of 210 and 211 leads to 212, a valuable intermediate for 232 233 234

4-demethoxydaunomycinone. 1 S-BULI 2 TMSCl The total synthesis of granaticin (217) (Scheme 51),152 13NBS an antibiotic with powerful and diverse biological activity, incorporates a complex cyanophthalide 214, available from the aryl bromide 213 by a six-step sequence which was initiated by incorporation of the tertiary amide DMG by a metal-halogen exchange- carbamoylation (ClCONEh) process. Disciplined conditions for the condensation of 214 with the furan enone ' NRz /

215 gave 216, which was converted into the natural R = Et. iPr product 217 by a series of equally carefully executed EWG I eleciron withdrawing gmup OH steps. 238 The utility of Diels-Alder cycloaddition to in situ 239 generated 3-(silyloxy)isobenzofurans (184 - 185, Scheme 46) is illustrated by a procedure for rapid benzofuran intermediate derived by benzamide DoM aromatic ring annelation (Scheme 52).163 Thus chemistry for the total synthesis of the aptly named phthalides 218, available by benzamide DoM metho- antibiotic resistomycin (231) (Scheme 54).165Cooper- dology, provided mixtures of cycloadducts 219a-d, ative imine-amide DMGs in 227 promoted regiospecific which upon acid treatment were smoothly aromatized lithiation and condensation with 228 to afford 229. to the naphthols 220a-d in high yields. In a non- Special conditions of iodoacetic acid-pyridine led to the DoM-mediated application of this method, phthalide cycloadduct 230, which, in several steps, was trans- 221, prepared via metal-halogen exchange, was con- formed into resistomycin (231). verted into the aryl naphthalide lignan diphyllin (222). A tertiary amide DMG based generation of 1- The Diels-Alder approach has also been used for the aminoisobenzofurans 238, R = i-Pr (Scheme 55),lM construction of the spiroindandione 226 (Scheme 53),'" allows the construction of a variety of dihydro- a model for fredericamycin A (148, Scheme 37). The naphthalene derivatives (Table 23). The undetectable cyanophthalide 223, derived by DoM chemistry from species 238 were generated by DoM chemistry from the the appropriate benzamide, was deprotonated and si- pivotal o-formylbenzamide 232 via the easily accessible lylated to give 224, whose solution NMR spectrum at diazomethyl (235), imidate salt (236), and bromo(tri- room temperature could be recorded. Treatment with methylsily1)methyl (237) intermediates. These were the enedione 225 at low temperatures gave the fre- treated with reactive dienophiles under copper or rho- dericamycin A model 226 in good yield. In an elegant dium catalytic (method A), LiTMP (method B), and and instructive study, Keay and Rodrigo used an iso- CsF (method C) conditions, respectively, to give prod- 908 Chemical Reviews, 1990, Voi. 90, No. 6 Snieckus

TABLE 24. Synthesis of 2-Isoquinolones from a'- and u',a'-Silylated Benzamides

A' overall R' RZ yield, 70 ref SCHEME 59

H H i-Pr H i-Pr 44 157 CONR2 1 S~ULVTMEDA H 3-OMe i-Pr 5-OMe i-Pr 26 157 H 4-OMe i-Pr 6-OMe i-Pr 49 157 ZOHC&SPhTHFI.78'C GSPh 3 ShLl H 6-OMe Me 8-OMe Me 46 157 LIO LI H 250 251 4,6-(OMe), Me 6,8-(OMeI2 Me 23 157 0 ';I. H 6-Cl Me 8-C1 Me 20 157 IB~YN mCP0A QSph

H 6-Ph i-Pr 8-Ph i-Pr 51 157 0, TMS H Me H Me 36 104 4 equiv ti202 HOAC R TMS 4-OMe Me 6-OMe Me 21 104 252 253 a n=r b n=2 SCHEME 56 on 2UboMe TMSO$ R' 0 OH R' 0 OMe

2 EI3N Me R2 Me 0 0 254 255 a: 186% b' 184"% c 1811:

"@), ~MSO~oMeOEI ~~oM~Rz~oMe

sph 2 EIiN " '/ R' 0 O2 R' 0 OH R' 0 OEl 258 256 257 SCHEME 57

F! TMS 0 n

245 on a Z=H and 247, the former being readily converted into the b Z=Th!S '''ilatter by acid treatment.lU Preliminary results on both substpates promise generalization (Table 24). Fur- thermore, the reactivity of 245a,b as amide dipole-sta- ucts 239. Ring annelation using diethylamides 235, R bilized carbanion equivalents in lateral condensation = Et, gives products in low yields. Although substituted and 1,&dipolar cycloaddition protocols has been dem- benzamide precursors 232 have been only briefly in- ~nstrated.'~J~'This coupled with the ready transfor- vestigated, the cycloaddition provides good scope for mation of 245b into other functionality (Scheme 12) the preparation of non-aromatic ring functionalized provides a new focus for DoM-mediated chemistry. systems 239, including some condensed and heterocyclic As an early indication of the additional utility of analogues (241 - 240 and 242; 243 - 244; Scheme o-formylbenzamides, the simple imine derivative 248 56).lS6 (Scheme 58) has been converted into 3-phenyl-4- hydroxyisoquinoline (249).158 3. Isoquinolones D. Ortho Hydroxyalkylatlon The development of cy'- and a',cy'-silylated tertiary carboxamide DMGs has provided a rational basis for 7. Naphthoquinones a fluoride-induced intramolecular carbodesilylative route to isoquinolines 247 (Scheme 57, Table 24).104J57 The previously encountered (Scheme 41) chameleon Clean metalation-formylation of a'-silylated benzamide character of the tertiary amide DMG is further evi- 245a cannot be achieved without competing self-con- denced in the general synthesis of naphthoquinones densation of the ortho-lithiated species unless a steric (Scheme 59).159 A variety of benzamides 250 were effect (R2 = i-Pr) or ring deactivation (R' = OMe) sequentially ortho metalated under standard conditions, (Table 6, entries 126, 128, and 129) is incorporated in treated with 3-(phenylthio)acrolein, and a-metalated the precursor. On the other hand, the corresponding to give transient dianions 251, which, upon warming to cy',a'-disilylated 245b (and a variety of other ortho- room temperature, led to products 252. Good yields of functionalized products) may be obtained in high yields alkoxy-substituted (pheny1thio)naphthoquinones (Table for R2= Me (Table 6, entries 135-142). Treatment of 25) may be obtained by this regioselective tandem 245a with CsF leads to the hydroxydihydroiso- metalation process, although use of o-methoxy (entries quinolones 246, which by acid-catalyzed dehydration 10-12), naphthalen-l-amide (entry 13), and m-fluoro furnish product 247.15' The same conditions applied (entry 3) derivatives gives lower yields presumably due on the disilylated substrates 245b result in intramo- to steric hindrance effects in the former two cases and lecular Peterson olefination to afford mixtures of 246 competitive benzyne formation in the latter sample. Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 909

TABLE 25. Synthesis of 2-(Phenylthi0)-1,4-naphthoquinones~~~

R2$C0NR2 + gSPh - R3 R4 OHC ..+4fPhR3 R4 0

amide product yield, entry R R1 R2 R3 R4 % 1 Et H H H H 59 2 Et H H Me H 66 3 Et H H F H 33 4 Et H H OMe H 66 5 Et H H H OMe 58" 6 Et H OMe H OMe 52 7 Et H H OMe OMe 52 8 Et H H OCHPO 49 9 Et H Me H OMe 530 10 Me OMe H H H 22 11 Me OMe H OMe H 31 12 Me OMe H H OMe 46" 13 Et CH=CH-CH=CH H H 21 14 CONE1, 44

*sph

0 15 CONEt, 0 63

*"h

" Yield after Aa?O oxidation.

Potential extension of this methodology to heterocyclic (Table 26, entries 8-12) are rapidly available by this quinones is indicated by entries 14 and 15. tactic. Comparable routes are known by secondary Removal of the phenylthio a-metalation director may amide29hpiand o~azoline~~gDoM technology. A solitary be achieved by sequential treatment of 252 with attempt to induce optical activity by the reaction of MCPBA and BU~S~H.'~~However, more significant is (S)-O-methyl-N-methylbenzoylleucinolwith l-naphth- its use in controlling the regiochemistry of subsequent aldehyde was unsuccessful.73 In contrast, optically ac- Diels-Alder reaction.160 Thus a variety of naphtho- tive oxazolines serve as excellent chiral auxilliaries in quinone sulfoxides or sulfones 253a,b, readily obtained numerous preparative applications.29gAs summarized from 252, have been shown to undergo cycloaddition below, phthalides derived from tertiary benzamides are with vinylketene acetals to give, after base-catalyzed useful intermediates for a variety of more highly con- aromatization, anthraquinones 254 and 255. In this densed systems such as anthraquinones (Schemes 61, comprehensive study, Iwao demonstrated that sulf- 62, and 64; Tables 28 and 301, heterocyclic quinones oxides and sulfones 253a,b show greater regioselectivity (Schemes 65 and 66), anthracyclinones (Scheme 63), and rate of reaction compared to the corresponding several classes of alkaloids (Schemes 68-70), and poly- sulfides. For example, the naturally occurring anthra- cyclic aromatic hydrocarbons (PAH) (Scheme 72, Table quinones pachybasin (254a), phomarin 6-methyl ether 29). (254b), and emodin 6,8-dimethyl ether (254c) were Classical approaches to unsymmetrically oxygenated obtained in high yield together with small amounts of anthraquinones 263 and 264 (Scheme 60) initiated from corresponding methyl ethers 255a, 25513, and 255c, re- phthalic acids and phenols by double Friedel-Crafts spectively. Similarly, the cycloaddition of sulfones reactions are, as illustrated for a specific bond construct, 256a-c with a cyclic vinylketene acetal produced an- plagued by lack of regiocontrol (initial Friedel-Crafts thracyclinone analogues 257a-c and 258a-c in some- step 259 + 260 - 261 + 262), inefficiency (electron- what lower yields but good selectivities favoring phenols withdrawing benzoyl substituent in 261 and 262 in the 257. second Friedel-Crafts step), and ambiguity (potential Hayashi rearrangement of the equilibrating acylium 2. Phthalides and Derived Anthraquinones ions corresponding to 261 and 262). According to DoM retrosynthetic analysis (illustrated only for 263), four Hydroxyalkylation of ortho-lithiated benzamides modes of initial coupling of two appropriately substi- followed by anchimerically assisted161 acid-catalyzed tuted and usually readily accessible lithiated benzamide cyclization constitutes a convenient entry into 3-sub- (267, 269) and benzaldehyde (268, 270) partners are stituted phthalides (Tables 26 and 27). A diverse and eminently feasible; the productive dissections a and b extensive group of 3-arylphthalides (Table 26, entries focus on the regiospecific positioning of the bond to ring 17-34; Table 27), heterophthalides (Table 26, entries A (+265,266), thus avoiding the ambiguity in the first 63-74), and, by transmetalation, 3-alkylphthalides Friedel-Crafts step of the classical approach. Although 910 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 26. Synthesis of Phthalides and Phthalic Anhydrides from Ortho-Lithiated Tertiary Aromatic Amides"

substituent entry R' R2 c-4 c-5 C-6 C-7 yield. % ref 1 H H OMe H H H 93 146 2 H H H H H OMe 97 146 3 H H H H OMe OMe 90 146 4 H H OMe OMe H OMe 44 148a I 0 OMe H H H 70-80 146 6 0 OMe OMe H H 70 146 I 1 Me H H H H H 61b 142 8 n-Pr H H H H H 64* 142 9 n-Pr H OMe H H H 59* 142 10 n-Pr H H H H OMe 60b 142 11 n-Pr H OMe H H OMe 756 142 12 Me Me H H H H 54 86 13 Me 2-(CONEt,)C6H4 H H H H 35 142 i4 PI1 H H H H H 48, 50, 56 86, 101, 130, 153 15 Ph H H OMe H H 153 16 Ph H OMe OMe H H 49,74 87, 130 17 3-MeC6H, H H OMe H H 5 163 18 4-MeC6H, H H OMe H H 11 163 19 4-MeOC6H4 H H H H H 153 20 3-MeOC6H4 H H H Me OMe 76 162 21 4-MeOC6H4 H H Me H OMe 45 160 22 2,5-(MeO)2C6H3 H OMe OMe OMe H 21 159 2 a 3,5-(Meo)*C6H3 H H OMe H Me 51' 164 24 2,5-(Me0)2-4-MeC6H2 H OMe H H H 68 162 25 2,5-(MeO),-4-MeC6H2 H H H H OMe 62 162 26 2,5-(MeO),-4-MeCsHz H OMe H OMe H 64 162 2: 2,5-(MeO),-4-MeC6H2 H OMe H H OMe 63 162 28 3,4-(Meo),C6H3 H H H H Me 65' 130 29 1-naphthyl H H H H H 20 87 30 2-naphthyl H H H H H 22 164 31 1-naphthyl H H H H Me 58c 164 32 %naphthyl H H H H Me 52c 164 33 9-phenanthryl H H H H H 24 87 34 9-phenanthryl H H H H Me 63 164 35 2-(NCH2Ph)pyrrolyl H H H H H 89 175 36 2-fury1 H H H OMe OMe 75 169 37 2-pyridyl H H H H H 88b 142 38 l-[6,7-(Me0)2-isoquinolyl] H H H OMe OMe 173 39 Ph Ph H H H H 65 86 40 Ph Ph H OXd H H 46 86 '11 Ph Ph H CONHMe H H 7e 86 42 Ph Ph H CONEt, H H 20e 86 43 Ph Ph H C1 H H 60 86 44 Ph Ph H S0,NHMe H H 41 86 45 Ph Ph H SO,NEt, H H 21 86 46 OH H H H H H 80 101 4;' OH H OMe H H H 54 f, 151 48 OH H OMe OMe H OMe 47, 81 149a, 154 49 OH H OMe H H H 54 f, 148b, 151 50 OH H H H H OMe 39, 61 149b, 151 51 OH H H Me H OMe 39 151 52 OH H OMe H OMe H 40 151 5 3 OH H F H H H (15 f 54 OH H H H H F 10 148b 55 COzH H H H OMe OMe 72 146 56 CO,H H H H OCH,O 37 146 5i H H H H H 77 168

58 H H H H H 70 182

59 x H H H H H 93 183 Directed Ortho Metalation Chemical Reviews, 1990, Voi. 90, NO. 6 911

TABLE 26 (Continued) substituent entry R' R2 c-4 c-5 C-6 c-7 yield, 70 ref H H H H H 22 (50)g 176 H t-Bu H H H 39 179

62 H H H H H 80' 184

0 63 R' = Ph; R2 = H 64 R' + R2 = (CHJ4 65 R' + R2 = (CH,), 66 R' = RZ = Ph

67 R1 = Ph; R2 = H 68 R' + R2= (CH2)4 69 R' + R2 = (CH,), 70 R' = RZ = Ph

71 R1= Ph; R2= H i k 72 R' = 4-MeOC6H,; R2 = H 153 73 R' + R2 = (CHZ), j k 74 R' + R2 = (CHZ), j k 75 R1 = R2 = Ph 51' k Unless otherwise noted, N,N-diethylbenzamide starting materials were employed. The phthalides resulted from spontaneous cyclization of intermediate alcohol amides upon workup or chromatography or upon deliberate treatment with acid. *Table 6, footnote b. 'Fluoride desilylation of the unisolated CH(TMS)? intermediate prior to acid-catalyzed cyclization. d5-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl). e Obtained from a competitive metalation reaction of a 1:l mixture of N-methylbenzamide and N,N-diethylbenzamide. The yield was improved to 55% of a 3:l mixture of products of entries 42:41. entries 42:41. fMorrow, G.W.; Swenton, J. S.; Filippi, J. A.; Wolgemuth, R. L. J. Org. Chem. 1987,52, 713. #Yield obtained with the apdideuterated 2,3-dihydrophenalen-l-one.Yield of the benzoic acid obtained by Zn-Cu/KOH reduction of the phthalide. ' N-[2-(Diethylamino)ethyl]-N-ethylbenzamidestarting material. jN,N-Diisopropylamide starting material. Table 8, footnote b. the second bond formation to ring C is carried out by The synthesis of desoxyerythrolaccin trimethyl ether Friedel-Crafts technology and is therefore dictated by (278) (Scheme 62)lM involves a similar strategy but normal electronic substitution rules, regioselectivity illustrates the silicon protection of reactive o-methyl may be decided by appropriate choice of benzaldehyde hydrogens in toluamide 275 for the construction of this reactant. Furthermore, the Hayashi rearrangement is peri-methyl anthraquinone. Thus a,a-disilylation of precluded by use of intermediate benzyl benzoic acids 275, prepared by DoM, furnished 276, which upon obtained from amide alcohol intermediates 265 and 266. metalation, condensation with 3,5-dimethoxybenz- This strategy, which is also viable via secondary am- aldehyde, and, without isolation of intermediates, ide29hliand oxa~oline~~gDMG protocols, has been ap- CsF-mediated desilylation and cyclization gave the plied to the synthesis of anthraquinones, including phthalide 277. A simple three-step conversion afforded several natural products (Table 28).159J60J62-165Early the trimethyl ether of the natural product 278 in 51% illustrations are delinated in Scheme 61.'@ Metalation overall yield. The use of the silicon protection tactic of 271 followed by condensation with an appropriate for simpler systems has also been demonstrated (Table benzaldehyde and TsOH cyclization afforded phthalide 26, entries 23, 28, 31, and 32). 272, which upon hydrogenolysis and mild Friedel-Crafts Similarly, ketone 285 (Scheme 63), a key intermediate cyclization led to the anthracenol 273. Chromium in several syntheses of daunomycinone, has been pre- trioxide oxidation to the corresponding anthraquinone pared by a route that is initiated from 279 and 282 by followed by selective deprotection afforded either amide DoM tactics and that converges into the catenarin (274a)or erythroglaucin (274b). Significantly, phthalide 281.'@ Thus treatment of lithiated 279 and acidic methyl hydrogens in aldehyde and, in certain aldehyde 282, which are interrelated by DoM reactions, cases, amide (e.g., soranjidiol, Table 28) components are with aldehydes 280a,b and lithiated 283, respectively, tolerated in the metalation-condensation stages of this led, after TsOH cyclization, to the phthalides 281a,b route. in good overall yields. Standard manipulation provided 912 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 27. Synthesis of Phthalides from Ortho-Lithiated SCHEME 60 Naphthamides 0

&$OH, OR, CI or ,anhydride -k @R I II I RO Lewis OR 0 Acid 1 260 259

OR entry R' R2 yield, YO ref I. ambiguous 1 Ph H 81 87 bonds 2 Ph Me 71 176 in F-C approach 3 1-naphthyl H 81, 67 87, 176 RO 0 OR 4 2-naphthyl H 70 87, 176 261 OR 5 1-naphthyl Me 52 176 6 2-naphthyl Me 58" 176 7 2-pyridyl H 80 175 8 2-(NCH2Ph)pyrroly1 H 89 175 9 Ph Me 72" 177 5,8-(OMe), RO 0 OR RO OR rf 0 263 264

0 OR

10 50b 180 CONRz '' 11 30 (52)* 176 R' q+ RO 0 OR RO OR 266 12 70 182 265

13 87 183

267 268 269 270

lowed by a regioselective selenohydroxylation to give 289. Oxidation and deselenylation yielded X-14881C 14 66' 152 (290a), which was demethylated (AlC1,) to ochromycinone (290b),thus concluding these short syntheses (21% overall yields). Phthalide-mediated routes to anthraquinones may be extended to heterocyclic analogues as shown by the 15 24 87 synthesis of the cytotoxic furanonaphthoquinone 295 (Scheme 651." Thus treatment of lithiated benzamide 291 with furfural (292) and cyclization afforded the 0 furanophthalide 293 in good yield. Zinc chloride pro- 8 moted acylation at the highly reactive furan 2-position followed by protection gave the ketal 294, which was " Yield of corresponding benzoic acid obtained after Zn-Cu/ converted into the unnamed natural product 295 by KOH reduction of the phthalide. bYield obtained with the (Y,(Y- dideuterated indan-1-one. Overall yield from amide after treat- standard steps. ment of o-CHO intermediate with Me,SiCN, KCN-18-c-6;HOAc; The synthesis of the rare azaanthraquinone bostry- CH2=C(OMe)Me, camphorsulfonic acid. coidin (301) (Scheme 66) involves analogous steps but also illustrates an interesting pyridine methylation reaction.170 Although 4-silylation of the methylnicotin- the anthraquinone 284, which upon epoxidation and amide 296a was achieved under sec-BuLi/TMEDA/ acid-catalyzed rearrangement afforded the anthra- THF/-78 "C condition^,"^ metalation using LiTMP cyclinone 285. Syntheses of this class of antitumor followed by dimethylben~amidel~~or ben~aldehydel'~ antibiotics via analogous convergent approaches in- quench led to products of lateral substitution, e.g., 297. volving the secondary amide DMG have been report- This result necessitated the introduction of the methyl ed.'67 group at a later stage in the synthesis. Optimized A maximum convergence approach is also portrayed metalation of 296b using LiTMP followed by conden- by the synthesis of the "angular" anthracyclinone an- sation with an appropriate NJV-dimethylbenzamide,a tibiotics X-14881C (290a)and ochromycinone (290b) reaction of some generality (Table 8, entries 6 and isolated from several strains of Streptomyces (Scheme 14-18), afforded the keto amide 298. Regioselective 64).lM Thus treatment of the metalation-interrelated 2-methyl group introduction was achieved via the N- tetralin derivatives 286 and 287 with appropriate ani- oxide of 298 involving an acetoacetic ester synthon samides followed by acid-induced cyclization afforded which suffers hydrolysis, decarboxylation, and deacy- the phthalide 288. The first route involving the use of lation in the last acid-catalyzed step. The resulting the CHzOLi DMG proved to be the more efficient one. product 299 was reduced and cyclized to furnish the Standard conversion into an anthraquinone was fol- phthalide 300, which was conventionally manipulated Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 913

TABLE 28. Synthesis of Anthraquinones from Ortho-Lithiated Tertiary Benzamides via Phthalide Intermediates 0

substitution overall name c-1 c-2 c-3 c-4 c-5 '2-6 c-7 C-8 yield, % ref islandicin OH Me H OH OH H H H 41" 162 digitopurpone OH H Me OH OH H H H 39" 162 er ythroglaucin OH Me H OH OH H OMe H 22 162 catenarin OH Me H OH OH H OH H 29 162 cyanodontin OH Me H OH OH H H OH 23 162 soranjidiol H H OH H H H Me H 21 162 desoxyerythrolaccin OH H OH H H OH H Me 61" 164 H Me H H H OMe H H 163 H H Me H H OMe H H 163 OH H Me H H H OMe H 11 160 emodin OH H Me H H OH H OH 38" 165 7-hydroxyemodin OH H Me H H OH OH OH 37b 165 helminthosporin OH H Me H OH H H H 23 165 chrysophanol OH H Me H H H H OH 3 5c 165 " Yield of trimethyl ether. *Yield of tetramethyl ether. Yield of dimethyl ether.

SCHEME 61 SCHEME 63 ,. OM OR

CONE12 I Me0 I Me0 OMS Me0 279 280 271 OHC 272 6Me I R=Me 1 sBuLvTMEDA b R-CHzOMe 3 TsOHlPhMe 12DMF OMe reflux ?MOM 281 (63%) I: R-Me

b: R ICH2CMe OH OM0 1 Pd/C,Hz HOAclSS'C Me0 OMe 2 TFAWCHCI) 282 283 (92%) Me0 OM OH 0 OH 0 OMe 273 274 a: R = H (Catenarin) b: R = Me (Ery3hroglaucin) 312 ZNCuTFAAiCHpCl2K2COdMeOHIalrKWPY VV..) (54%) -g$@-@yJo Me0 0 OMB Me0 0 SCHEME 62 284 285 TMS

&cONEt2 21 TMSClsBuLiI SCHEME 64

3 sSuLi I TMEDA 2 OMe Me0 4 TMSCI Me0 275 (75%) 276

3 CSF 4 TSOH (51%) 1 Pequlv nEuLtTMEDA \ / 1 sBuLlrrMEDA 1 ZWOH 2TFAA CONE12 IEtzOIRT 3 CrOs GINEt2 Me0 OMe (72%) Me0 OMe Me0 3 TsOHIIoVrellux Me0 0 (i7%) 3 287 TsOHlToVrellux 277 270 (Desoxyerythrolaccin 4 trimethyl ether) (W4

Meb 288 into the antibiotic bostrycoidin (301). 1 ZnilO% NaOHl In a further application of pyridine amide DoM, the reflix 2 TFAAJCH2CI2/rellux conformationally rigid analogue of the tricyclic anti- /3 02Kriton BIMeOHIRl depressant imipramine (306) (Scheme 67) was prepared lTSOHICH2CIzIRT by condensation of metalated nicotinamide 302 with the N'NSePh (85% overall) dibenzazepine carbaldehyde 303, which was also obtained by DoM hemi is try.''^ Surprising difficulty was encountered in the hydrolysis of the initial product 304 2 Ph3SnH (48%) or the corresponding diisopropylamide, which was sim- Me0 0 RO 0 ilarly secured. However, hydrogenolysis of 304 in acetic 289 290 acid followed by P0Cl3treatment gave the lactam 305, a:b: R = MeH (Ochromyc8mne) (X-14881C) 914 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

SCHEME 65 SCHEME 68

COralaSIlne I 1 9BuLUTMEDA Meow t Coidrasline 11 isee SCHEME 30, 2 292

Meo& CONEt2 3 H0.Q

175%) 0 291 292 293 +EIrNOC OMe OMe 307 cHo-o.OMe 0 OMe n 308 309

SCHEME 69

294 295 Q

SCHEME 66

313 314 315

SCHEME 70 Me? Me0

1 sBuLiflMEDA 2 pyridine.2 CHO

Me0 316 317

a: HetAr = 2-pyridyl (72%) b: HelAr = 2.1NCH~Ph)pyrrolyl(639:! (lor 317br 1 Zn'Cu

2 ''?'KoH1pyCHzNz 3 HzlPIIHOAc SCHEME 67 (68%) t (lor 3178) 1 Zn,Cu 10% KOHlpy 2 HZIP1IHOAc-HCI Me0 ,_"" 3 Xyleneirellux 318 319 (4756) 302 303 a.n=l a: n = 1 (antoline) EliNOC b ?=2 b' n = 2 !crypIopleurine)

the nicotinic acid 312, which upon benzylic metalation, carbonation, and esterification afforded the diester 313. Nonstereoselective bromohydrin formation, 314, was later recouped when both of the corresponding debro- 305 306 minated products were converted into sesbanine (315) cis IianS = 5 ' (12.5% overall yield). An abbreviated synthesis of the phenanthroindol- a sequence that likely proceeds via a phthalide inter- izidine and -quinolizidine alkaloids antofine (319a) and mediate. Unexceptional steps led to the target molecule cryptopleurine (319b) was achieved by using the com- 306 as a separable cis-trans mixture. mon phenanthrenecarboxamide 316 as starting material Concurrent with a DoM approach to the phthalide (Scheme 70).175 Metalation of 316 followed by con- isoquinoline alkaloids cordrastine I and I1 (Scheme 30), densation with pyridine-2-carbaldehyde and N- a second, more direct, synthesis was also formally benzylpyrrole-2-carbaldehydeand TsOH cyclization achieved by simple condensation of the isoquinoline- afforded the phthalides 317a and 317b, respectively, in carbaldehyde 307 (Scheme 68) with the ortho-lithiated good yields. These were subjected to sequential C-0 species derived from 308 to give, after acid-catalyzed bond hydrogenolysis and heterocyclic ring hydrogena- cyclization, phthalide 309 (also Table 26, entry 38).173 tion with slight additional procedural variation to give Following careful experimentation in pyridine- lactams 318a and 318b, which were reduced to antofine carboxamide metalation, Iwao devised an innovative (319a) and cryptopleurine (319b), respectively. The synthesis of the antileukemic pyridinecarboximide N-methoxymethylpyrrole phthalide corresponding to sesbanine (315) (Scheme 69).174 The spirophthalide 311 317b, obtained in 72% yield, proceeded smoothly was secured by metalation of the diisopropylnicotin- through the Zn/Cu hydrogenolysis stage but suffered amide 310 in preference to the corresponding diethyl- hydrogenolytic OMe cleavage during pyrrole ring cat- amide (e.g., Table 8, entries 8 vs 9-11), followed by alytic reduction, thus thwarting this approach. The condensation with 3-cyclopentenoneand acid-mediated five-step heteroannelation process was generalized to cyclization. Chemical hydrogenolysis usefully com- prepare the condensed lactams 320,321,323, and 324 pleted the circumscribed amide "hydrolysis" to afford in modest to good yields from the ortho-lithiated amide Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 915

SCHEME 71 SCHEME 73 4 U-N

R R' R' 0 OLI 330 331 332 320 0 FONEIz /rr 321 O'LI' 0

333 334 335

Thus condensation of the indanone 325a with the lithiated species of naphthamide 326 followed by acid- catalyzed cyclization afforded the spirophthalide 327 323 324 in low yield. In contrast, under the same conditions, the a,a-dideuterated indanone 325b gave the product SCHEME 72 327 in substantially improved yield. This marked isotope effect, which evidently attenuates proton exchange, has also been used to enhance the yields of analogous condensation reactions (Table 29, entries 14 and 17-21). Hydrogenolysis of phthalide 327 led to 328, which was 325 326 327 converted into 3-methylcholanthrene (329) in excellent I: R-H b: RID overall yield. The regiospecific and efficient preparation of peri- methyl-substituted benz[a]anthraquinones (Table 29, entries 3 and 41, using silicon protection of methyl 328 329 groups of o-toluamides (Table 21), invites broader application of this tactic. 322 and respective pyrrole- or pyridine-Zcarbaldehyde 4. Anthraquinones Not via Phthalides precursors (Scheme 71).175 Tandem benzamide DoM processes may be used to 3. Polycyclic Aroma tic Hydrocarbons via Phthalides effect one-pot regioselective synthesis of anthraquinones (Scheme 73).87 In this sequence of potential broader The facile and generally high-yield condensation of application for other DMGs, the initial ortho-lithiated ortho-lithiated benzamide with aromatic aldehydes benzamide (330)-benzaldehyde (331, X = H) conden- provides a general principle for the regiospecific con- sation to give intermediate 332, X = H, is followed by struction of polycyclic aromatic hydrocarbons (PAH). a second metalation that takes advantage of the pres- In view of the significant environmental presence of this ence of the CH20Li DMG to give 333. Although met- class of carcinogenic substances, the development of alation ortho to the more powerful amine DMG un- regiospecific syntheses that avoid isomeric mixtures and doubtedly occurs, equilibration of anions is assumed, extended handling of intermediates is of considerable with cyclization to an anthracene diphenolate 334 merit. Application of the amide DMG has led to the constituting a driving force for the overall reaction. rapid and efficient preparation of a variety of PAH Aerial oxidation to the anthraquinone 335 is a well- (Table 29) of value in analytical, metabolism, and documented process. The success of this reaction using carcinogenicity studies. Thus condensation of simple acetophenone or benzophenone as the carbonyl reac- lithiated N,N-diethylbenzamides, N,N-diethylnaphth- tant~~~does not preclude an alternate mechanism in- amides, and, in one case, the "built-in" TMEDA benz- volving benzylic deprotonation of 332, X = H, and cy- amide (entry 26) with aryl aldehydes or ketones, nor- clization. On the other hand, 333 is the likely species mally readily obtained by classical electrophilic (e.g., in the more efficient tandem DoM metal-halogen ex- Villsmeier) substitution, leads to the following PAH: change involving intermediate 332, X = Br.las benz[a]anthraquinones (entries l-4),lMJ7' whose re- In spite of mechanistic uncertainty, this method has duction to the corresponding PAH is well documented, considerable synthetic utility for the rapid construction benz[a]anthrancenes (entries 5 and 6),176J77dibenz- of complex anthraquinones, including diverse hetero- [ajlanthrancenes (entries 7-10),176J78 dibenz[a,h]- cyclic analogues (Table 30). Illustrative of scope and anthracenes (entries 11 and benzo[a]pyrenes generality is the synthesis of a variety of substituted and (entries 13-15),'76-179 cholanthrenes (entries condensed anthraquinones (entries 1-20), thus consti- 16-21),176JwJ81benzo[a]fluoranthene (entry 22),IB2na- tuting an alternate abbreviated route to PAH deriva- phtho[2,1-~]fluoranthene (entry 23),lE2 1,12- tives (section VIII.D.3). Significant improvement in methylenebenz [ a]anthracene (entry 24) ,lE3 1,14- yields is observed when the second metalation is carried methylenedibenz[a,h]anthrancene (entry 25),lB3and out with excess sec-BuLi (entry 2) or by the metal- dibenz[e,k]acephenanthrylene (entry 26).'@ halogen exchange'& (entries 5-15 and 18) processes. The preparation of 3-methylcholanthrene (329) The latter is of course dependent upon the convenient (Scheme 72)'76 is representative but also illustrates the availability of the o-bromoaldehyde precursor. Using advantage of deuteration of a-carbonyl sites to diminish the non metal-halogen exchange tactic, methoxy-sub- proton exchange in strong-base-mediated processes. stituted benzaldehydes give modest yields of products 916 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 29. Synthesis of PAH Quinones and PAH via Phthalidesn Entry Aromatic ACHO or ArCOAr Product Yield, Yo Ref Amide Overall

&C0NEt2 OHC-, Y 9

1 X=Y=Br 1 -CHO R1 = Br, R2 =H 22 127,171 2 X=Y=Br 2-CHO R1=H,R2=Br 33 127,171 3 X = CH(TMS)2, Y = H 2-CHO R1 5: Me, R2 = H 31 164 4 X = CH(TMS)2, Y = H 2-CHO R1 = H, R2 = Me 43 164

C&O @// , R1 Me Me

5 R1=H ~1 =R~=H 54 176 6 R1 =OMe R1 = OMe, R2 = Me 31 177

"'QCONEt2 0 8 R2

7 R'=H R~=H 176 8 R1=H R2 = Me 176 9 R1 =OMe R2 = H 178 10 R1=OMe R2 = H 178

EtzNOC@ &o

11 R=H R=H 50 176 12 R=Me R=Me 35 176

""Q 0 CONEt2 :Q? 13 R1=H R2 = H R1 =H 15 176 14 R'=H R2 = D R1 =H 35 176 15 R1 =t-Bu R2 = H R' =t-BU 34 179

R2 a0R3 R3 R* HR1\\ 4

16 R1=H R2= Me, R3= H R2=Me,R1=R4=H 23 176 17 R1 =ti R2= Me, R3= D R2=Me,R1=R4=H 40 176 18 R1=H R2 = Me, R3 = D R1=H,R2=R4=Me 36 180 19 R1 =H R2 = H, R3 = D R1= R2= R4= H 25 180 20 R1 = OMe R2 = H, R3= D R1=OH,R2=R4=H 17 181 21 R1 = OMe R2 = H, R3= D R1 =OH, R2= H, R4=Me 22 181

22 182 QCONE12 og

23 EbNOC-8 182 Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90,No. 6 017

TABLE 29 (Continued) Entry Aromatic ArCHO or ArCOAr Product Yield,% Ref Amide Overall K 24 0 &\\\ 10 103 CONEt2 / \I

25 @CONE,, 37 103

26 (&.F!NEt2 0

a All metalations were carried out under sec-BuLi/TMEDA/THF/-78 OC conditions.

SCHEME 74

2 47% HI I MeOH 3 SnCIfiCI-HOAc 0 (40%) ’ Me Me0 336 337 stereoselectively and has some generality (Table 31).lg1 (entries 2 and 3), while methyl groups are poorly tol- This reaction, for which the Parham metal-halogen erated (entry 4). N,N-Diethyl-l-naphthamideis a exchange analogue leads via 5-exo-tet modes useful reactant (entries 16-18) but the corresponding to dihydrobenzofurans in acceptable yields (entries 1-4 2-naphthamide is a poor partner (entry 19), most likely and 6 and 7). Steric impedance to cyclization is ob- due to nucleophilic addition of the alkyllithium.88 The served in 0-substituted epoxide (entry 5), although the preferred formation of a linear anthraquinone using a formation of the requisite anion was confirmed by naphth-2-carbaldehyde by a DoM process is clearly TMSCl quench. Bis(epoxycyclialky1ation) (entry 8) improved by incorporating a metal-halogen exchange cannot be achieved, and corresponding 6-exo-tet ring step (entry 14). closure (entry 9) proceeds in lower yield. Coupling of aromatic or heteroaromatic amides with heterocyclic aldehydes provides access to a variety of E. Ortho Carboxylation and Acylation heterocyclic quinones, some of which are new and others of which have been previously prepared only by tedious Although DoM-mediated ortho carboxylation of and inefficient routes (entries 21-34). Although fu- benzamides and 0-aryl carbamates proceeds well (Table rancarbaldehyde (entry 221, thiophenecarbaldehyde 6, e.g., entries 58, 78, and 85; Table 12, entries 8 and (entries 21 and 23-26), and indolecarbaldehyde (entries 31), acylation with acid chlorides or esters is, with one 32-37) give useful yields of products, pyridinecarb- exception (diethyl oxalate, Table 6, entries 86 and 97), aldehyde (entries 27-3O)Ia7 is a poor coupling partner, not a useful synthetic process.lW The demonstration undoubtedly due to competing nucleophilic attack by of smooth acylation of metalated pyridinecarboxamides alkyllithium in the second metalation step. A similar using N,N-dimethylbenzamides (Table 8, entries 14-18) explanation may be responsible for the low yields of suggests that the use of these electrophiles for the azaellipticine quinones from reactions with a pyrrolo- corresponding benzamides should be explored. The pyridinecarbaldehyde (entries 38-44).lM A one-pot viability of introduction of a new DMG by carbamoy- assemblage of the ellipticine alkaloid skeleton (entries lation using CICONEtz has been amply documented 35-37) allows the achievement of a very short synthesis (Schemes 25 and 26). of the alkaloid itself, 336 - 337 (Scheme 74).87 Standard sec-BuLi/TMEDA metalation of N,N-diethylbenzamide followed by warming to room temper- XI. Synfhetlc Consequences of o-Heteroatom ature also affords anthraquinone (74%).87 This po- Introduction tentially general reaction, which presumably proceeds via an ortho-lithiated benzophenone intermediate, has A. o-Amino been effected under LDA conditions to prepare a sym- metrical dipyridoquinone (entry 31).la9 1. Quinolones 5. Intramolecular Epoxycyclialkylation The availability of anthranilamides 338 (Scheme 75) by the TsN3/NaBH4method (Table 6, entries 27, 36, Although intermolecular condensation of ortho-lith- 45, 52, 60, 66, 73, 106, 146, and 147) and the demon- iated N,N-diethylbenzamides with epoxides fails,86the stration of the electrophilic character of the CONEt, corresponding intramolecular process may be achieved group (Scheme 41) led to the development of a new 918 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 30. Synthesis of Anthraquinones by the Tandem DoM Reaction

Entry Amide Aldehyde Product Yield, % Ref CondaA B C

i7m26 )gb (BPH CoNEt2 a 0 h5 4' 1 no subst no subst no subst 43 87 2 no subst 2-OMe 1-OMe 10 55 87,123 3 no subst 4-OMe 2-OMe 28 87 4 no subst 4-Me 248 15 15 65b87, 123,185 5 3,4-(OMe)2 no subst 1,2-(OMe)2 70 185 6 5-OMe, 2-OMOM no subst 1-OMe, 4-OMOM 66 185 7 2-TMS, 3,4-(OMe)2 no subst 1-TMS, 2,3-(OMe)2 58 185 8 3-OMe 3,4-OCH20 1-OMe, 6,7-OCH20- 70 185 9 3,4-(OMe)2 3,4-OCH20 1,2-(OMe)2, 6,7-OCH20- 68 185 10 4-CONEt2 3,4-OCH20 2-CONEt2, 6,7-OCH20- 60 185

OHC(Bolq R

11 no subst 1-CHO no subst 49 53 75 87,123,185 12 4-OMe 1-CHO, 2-Br 9-OMe 73 185 13 2-CONEt2 1-CHO, 2-Br 11-CONE12 50 185

-0

2- 32-

0 14 no subst 2-CHO no subst 39c 61 87,185 15 4-OMe 2-CHO 3-OMe 70 185

CONE12 16 d 1-CHO @ 10 87 00

CONEt;! 17 a 2-CHO 87 CONEt2 Q@R / 18 d 1-Br, 2-CHO 62 185 0

19 mcoNEt22-CHO 62 87 0

20 OHC \ 87 0"""Et2 g

21 35 87 ON Et2 + OHC 0 0 Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 919

TABLE 30 (Continued)

Entry Amide Aldehyde Product Yield, % Ref CondaA B C Me0 0 Me0 22 MeO@CONEt2 Meow 15 169 OHC 0

CONEt2 Q 37 87 OHC 0

25 QCONEt2 OHC Q&S 77 87 0 0

OHC QqpNH 20 87 26 NHYONEt2 0 R‘ 0 CYCoNEt2OHC nmN ..R2 0 27 2-OMe R’ = OMe, R2 = H I87 28 3-OMe R1=H,R2=OMe 187 R’ 0

OHC R2 0 29 2-OMe R1 =OMe,R2=H 10 187 30 3-OMe R1 = H, R2 = OMe 187

31 CYCoNEt2N ‘&N god 189 0

32 EtNOC WCH0& 44 87 PhJ PhJo

33 EbNOC 20 87 Ph’ PhJo

34 N N 67 87 EhNOC 0 WCHO PhJ PhJo

35 R = CH20Me 26 87 36 R=Me 76 87 37 R = CH2Ph 40 87 920 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 30 (Continued) Entry Amide Aldehyde Product Yield, Yo Ref CondaA B C

38 no subst no subst 4 188 39 4-OMe 9-OMe 4 (ele 188 40 3-OMe 10-OMe 12 (36)e 188 41 2,5-(OMe)2 7,10-(OMe)2 20e 188 42 3,4,5-(OMe)3 8,9,1O-(OMe)3 40e 188 43 3,5-(OMe)2 8,1O-(OMe)n 5 70 188 44 2-OMe 7-OMe 90 188 Conditions A: (1) equiv sec-BuLi/TMEDA/THF/-78 OC/l h; (2) ArCHO; (3) 1 equiv sec-BuLi/TMEDA/l h; (4) - room temperature (5) H+. Conditions B: Same as conditions A except for step 3, in which 4 equiv sec-BuLi/TMEDA was used, and step 5, Cr08/HOAc. Conditions C: Same as conditions A; (2) ArCHO; (3) t-BuLi; (4) - room temperature; (5) H,O/O,. bFrom reaction of 4-MeC6H4CONEh with 2-BrCBH4CH0. Benz[o]anthracene-7,12-dione(5%) was also isolated. Conditions: 3 equiv of LDA in THF-HMPA/-78 OC. The corresponding isonicotinamide also gave the same product in unspecified yield. e Two equivalents of the diethylbenzamide was used. general method for the regiospecific construction of TABLE 31. Tertiary Amide DoM-Induced 4-quinolones 340.'% Thus compounds 338 were readily Epo~ycyclialkylation'~~ converted into imines 339, which, without purification, Et 2 N were treated with LDA to afford 4-quinolones 340. As &"?he gi 1. s-BuLi/TMEDA1.5 equiv gleaned from Table 32, 2-substituted (entries 1-5), an- OH 2. -78°C +RT nelated (entry 7), and condensed (entry 10) products 0 have been obtained in good to excellent yield. Unsym- metrical imines undergo cyclization from the less ste- Entry Epoxide Product yield, % rically hindered incipient azaallyl anion (entries 2, 3, R' R2 R3 R1 R2 R3 and 6). The formation of methoxy-substituted quino- I HHH HHH 67 lones (entries 8 and 9) by this mild modification of the 2 HMeH H Me H 60 von Niementowski reaction is of particular synthetic 3 HPhH H Ph H 64 4 H Me Me H Me Me 66 significance. 5 MeHH Me H H 0 2. Acridones 53 The demonstration of oxidative coupling of ortho- Me0 Me0 lithiated benzamides with anilido cuprates to form N-arylanthranilamides (Table 6, entries 1, 3-5, 8, 10, 17, 18, and 35) served as the basis for the general re- 7 65 giospecific synthesis of acridones (Table 33).lg3 A va- H riety of methoxy-substituted N-H and N-Me acridones have been prepared from N,N-dimethyl- or N,N-di- O$'N&O& 0 qkN&f0H0 3Ea ethylamide precursors, mainly under vigorous hepta- fluorobutyric acid conditions. Naturally occurring acridones have been synthesized (entries 1,7,and 8) in EhNoC yields that compare favorably with those obtained by 9 a$ E'N&soH0 32 classical Ullmann- or benzyne-basedlg4protocols. a Three equivalents of sec-BuLi/TMEDA was required. B. o-Thiol and o-Selenol The conveniently prepared thiosalicylamides (Table SCHEME 76 6, entries 48, 53, 63, and 68) undergo lithium isopropylcyclohexylamide (L1CA)-mediatedcondensation with benzynes, derived in situ from halobenzenes, to R2 21 PhRvTHFLICATHF 20°C78 C *&R1 form thioxanthan-9-ones (Table 34).lg5 All four isom- 341 342 eric monomethoxy thioxanthenones (entries 1,3,5,and

7)as well as some dimethoxy (entries 2, 4, 6, 8) and a R' G2= h 140%). b: R' = H Rz = OMe (22%) c: GI = OMe G2 = H (4Zs% trimethoxy (entry 9) derivatives are obtained by taking advantage of the regioselective benzamide DoM reaction and the polarization effect of the OMe group in benzyne intermediates. Entry 10 illustrates an inter- directing the cycloaddition. The 2-, 3-, and 4-methoxy esting albeit low-yield case of this type of heteroanne- regioisomers cannot be prepared from the correspond- lation using a thiosalicylate. ing condensation of methyl thiosalicylate owing to the By an analogous process, several relatively unknown unfavorable OMe polarization effect in the requisite selenoxanthen-9-ones 342 (Scheme 76) have been pre- Dlrected Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 021

TABLE 32. Synthesis of 4-Quinolone Derivatives from Anthranilamide~~~~

1 R1=H MeCOMe A R1 = H, R2 t Me 55 (45)b 2 R1 -H MeCOEt A R1=H,R2=Et 95 3 R1=H MeCO(CH2)4Me A R1 = H, R2 = (CH2)dMe 93 4 R1=H MeCOPh A R' = H, R2= Ph 70 5 R1=H MeCOC02Et A R1 H, R2 - CO2Et 64

6 R1 =H A 58 H

7 R1=H 00 B 70 H 8 R1 = 3-OMe MeCOMe A R1 = 8-OMe, R2 = Me 95 9 R1 = 6-OMe MeCOMe C R1 = 5-OMe, R2 = Me 73 CONEt2 10 MeCOMe B pe00 a4 "Conditions A 0 OC - room temperature, 8-12 h. Conditions B: reflux, 8-12 h. Conditions C: reflux, 3 h. *Yield using the Nfl-di- methylanthranilamide.

TABLE 33. Synthesis of Acridones from N-Phenylanthranilamides

Entry Anthranilamide Condition@ Acridone Yiekl,% Ref R R1 X Y R1 X Y

1 Et Me H H Me H H 32 193 2 Et H H 2-OMe H H 4-OMe 58 193 Et H 6-OMe H H 8-OMe H 80 193 Me Me 6-OMe H Me 8-OMe H 95 193 Me H 6-OMe 3-OMe H 8-OMe 3-OMe 95 193 Me Me 3-OMe H Me 5-OMe H 25 193 Me Me 4,6-(OMe)2 H Me 6,8-(OMe)2 H 79 193 Me Me 4,5-OCH20, H Me 6,7-OCH20, H 61 193 6-OMe 8-OMe 9 Et H 6-Me H B H 8-Me H 50 130

0 0 10 B % 85 193 N Me Me " Conditions A POC18/PhMe/reflux/10 h. Conditions B: heptaflurobutyric acid/reflux/24-27 h. Conditions C: CF,CO,H/reflux/GO h. Conditions D: HC02H/reflux/60 h. 922 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 34. Synthesis of Thioxanthan-9-ones from Thiosali~ylamides~~~

Entry Thiosalicylamide Halobenzene Thioxanthanone Yield, % R1 X R2 R1 R2

1 3-OMe Br H 4-OMe H 60 2 3-OMe Br 2-OMe 4-OMe 8-OMe 37 3 4-OMe Br H 3-OMe H 90 4 4-OMe Br 2-OMe 3-OMe 8-OMe 45 5 5-OMe Br H 2-OMe H 50 6 5-OMe Br 2-OMe 2-OMe 8-OMe 38 7 6-OMe Br H 1-0Me H 65 8 6-OMe Br 2-OMe l-OMe 8-OMe 61 9 6-OMe CI 2,5-(MeO)z 1-OMe 5,8-(Me0)2 65 10 Methylthiosalicylate Br 2-CONEtg 1-CONE12 H 22

a Conditions: (1) 1 equiv of thiosalicylamide/3 equiv of lithium isopropylcyclohexylamide (LICA)/THF/-78 "C; (2) -, -20 "C/2 equiv of halobenzene/THF; (3) - room temperature.

TABLE 35. Silicon Protection Route to Polysubstituted Benzamideslso

gi____tCsF/DMF R2@i RZ TMS R' R'

Entry Product Yield, % R' R2 E SCHEME 78

1 OMe H Me 85 2 OMe H CHO 76 3 OMe H CONE12 73 3 CSFDMF 4 OMe H SMe 82 4 TSOH 5 OMe H I 93 346 6 OMe OMe D 65 a: R CI (32%) b: R F (40%) 7 OMe OMe Me 87 - - 8 CI H D 90 9 CI H CHO 80 10 F H D 95 aromatics 345. Such a sequence has been achieved for 11 F H Me 90 the ortho-silylated m-methoxy- (Table 35, entries 1-7), m-chloro- (entries 8 and 9), and m-fluorobenzamides (entries 10 and 11) and briefly explored in the synthesis 12 75 of chloro and fluorophthalides, 346 - 347 (Scheme 78).I3O The former illustrates mainly the preparation of 1,3,5-functionalized systems at different oxidation states, while the latter sequence indicates potential for pared from the corresponding diselenides 341 (Table the preparation of specifically substituted PAH (section 6, entries 24, 54, and 64).Ig5 VIII.D.3). c. 0-Sllyl 2. Fluoride- and Electrophie- Induced Ipso Desilylation 1. Protection of Aromatic Preferred Metalation Sites ortho-Silylated benzamides may also be used in fluoride-mediated condensation with aromatic alde- The cooperative effects of 1,3-interrelated DMGs hydes to give, after acid treatment, modest yields of (Table 3) allow conceptualization of silicon protection phthalides, 348 - 349 (Scheme 79).130 Although as yet (343, Scheme 77) of the in between site in order to insufficiently investigated in terms of substituent ef- achieve further DoM reactions (344, DMGl more pow- fects, this mild carbodesilylation process accommodates erful than DMG2) and, eventually, deprotection as a groups that, owing to preferential metalation or po- general three-step procedure to diverse polysubstituted tential benzyne formation (e.g., 348c) would not be Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 923

SCHEME 79 SCHEME 81

357 348 349

a: E - R‘ - R2 - H (48%); b: E - ti R’ - R2 = OMe (49%): e: E = Me. R’ - CI, Rz - H (45%)

SCHEME 80

E NE12 E NEtz 358 359 a: R’ * R2- H;b: R’ = H, R2 - Me;e: R’ - R2 I Me RZ Jy: =JyO CsFIDMF, R’ R‘ Po” 3s 361 TMSO 0 OMe I I &Me I:E - Me, R’ R2 - H (69%):b: E Ma. R’ ICI. R’ IH (81%): 361 362 e: E - H. R‘ = Rz IWe (8%): d: E - Ma. R’ - R2 IWe (95%)

SCHEME 82 - Br M00 (SCHEMEM)) L(.Q 352 353 354 I:R‘ = NOZ,Rz H (76%) OM. - w b: R‘ -H,R2 - NO, (19%)

(51%) 2. 365 (94%) tolerated by the strongly basic DoM conditions, thus 3. TtOH precluding the synthesis of analogous products by the latter method (compare Schemes 62 and 82).

Ipso bromodesilylation of ortho-silylated benzamides OMe (77%) H.0 OM9 using bromine leads to o-bromobenzamides,350 - 351 Moo 366 367 (Erflhmlaccin (Scheme 8O).l3O Although well-known and mechanis- l~lramethylether) tically documented, this electrophilic reaction of aryl- silanes has enjoyed limited synthetic application in spite of the promise of achieving substitution patterns that Both silicon protection and ipso bromodesilylation constitute far from trivial problems in classical elec- serve as guiding principles in the synthesis of erythro- trophilic aromatic substitution. 2,6-Bis ipso bromo- laccin tetramethyl ether (367) (Scheme 82).lM Thus desilylations of benzamides (Scheme 22) and carba- treatment of 363 with the benzaldehyde 365 in the mates” have also been reported. While as yet unde- presence of CsF followed by TsOH cyclization gave the fined in scope, interesting limitations that may also be phthalide 366 in modest yield. On the other hand, by of synthetic value are seen from comparison of these taking advantage of extremely fast alkyllithium-induced results with transformations 353 into 352 and 354. The metal-halogen exchange compared to o-tolyl methyl high-yield formation of 354 is indicative of the over- deprotonation, the bromobenzamide 364 provided, after riding directing effect of the methoxy group” while the condensation with 365 and acid treatment, 366 in al- generation of 352a and 352b favoring the former most quantitative yield. Unexceptional steps led to 367 productlg7suggests a steric effect of TMS to the larger in 65% overall yield, thus completing the most efficient nitronium electrophile. synthesis of this penultimate precursor of the naturally Intramolecular versions of the fluoride-mediated occurring anthraquinone. carbodesilylation processes provide regiospecific routes to 7-methoxyindanol derivatives (360a-c, Scheme 81).lO3 D. o-Stannyl Benzaldehyde 355, obtained in three steps from the corresponding amide (Scheme ll), was converted by ortho-Stannylated benzamides and 0-aryl carba- standard procedures involving Wittig chemistry and mates, readily obtained by DoM processes (e.g., Table reduction via 356a-c into 357a-c. Cyclization using 6, entries 25 and 140; Table 14, entry lo), represent CsF afforded modest yields of 7-methoxy-1-indanols synthetic connections to the excellent Stille transi- 360a-c. Under similar conditions, a more complex case, tion-metal-catalyzed cross-coupling regimen.” Thus the keto ester 361, was transformed into the lactone 369a (Scheme 83) has been converted into 368 and 370a 362.1g8 These cases illustrate a mild methodology that using aryl triflatem and bromide” coupling partners, overrides the textbook example of normal Friedel- respectively; similarly, 369b gave 370b.lB As a further Crafts reactivity and suggest broader utility for carbo- link, the biphenyl 372, obtained from the o-stannyl and heteroannelation. As a complementary method, the a,a-disilyl amide 371 by cross coupling, has been bromo acids 359, readily accessible from 356 by ipso transformed in modest yield into the dibenzazocinone bromodesilylation, have been convertedlWin somewhat 373 using an intramolecular Peterson o1efination.lM higher overall yields into the 7-methoxy-1-indanones The known fast rate of electrophile-induced ipso des- 358 by the metal-halogen exchange initiated Parham tannylation of arylstannanes has been adapted in the cycliacylation reaction.lM regiospecific iodination (374) and acylation (376) of the 924 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

SCHEME 83 SCHEME 85 for 3na, b PdC,3MFlL~Cl 1 RLIITMSCI 9 phenanthryl OTf Pd%G 2 BBr3 aoMG 6 Arh (76%1 SnMe3 Ph for3 3770,H‘ d * (Ho12a~Pd(PPh3)JNa&03 * 368 369 370 377 1 RLI/B(OM~)~ 378 379 2 H- a DMG=CGYEli b DMG=OCONElZ

DMG DMG

380 381 3,‘ ‘40%1 DMG - I: CONR2. b: WONEt2, c: OMOM. d: NH 1-BOC

CSF DMF 90-c @Yo

tin 0-pyridyl carbamate 375 (Scheme 84).loS Gener- bMe alization of such synthetically useful processes for am- PdC!NaHCO ide, carbamate, and other DMGs may be anticipated. EIzNOCO OCONEI, E. o-Boronic Acid OMe 390

1. Cross-Coupling Methodology The ready availability of ortho-DMG arylboronic acids either by metalation-boronation or by metala- (entries 11 and 12), phenyl-9-phenanthryl (entry 13), tion-silylation-ipso borodesilylation sequences, 377 - and phenyl-heteroaryl (entries 14-17) systems are ac- 378 (Scheme 85) provides a synthetic link to the Suzuki cessible in high yields. A solitary case of coupling with cross-coupling protocol.201 Although the boronic acids benzyl bromide has been recorded (entry 18),but allyl 378a-d may be characterized as their diethanolamine and vinyl bromides have not yielded the expected adducts, they are normally coupled directly as crude products.202 foams with aryl bromides under PdO catalysis, in one Although requiring further investigation in scope, of several different solvent systems, to afford a variety coupling reactions of phenyl 0-carbamates provide of biaryls with carbon- and heteroatom-DMGs 379 in products in lower yields (entries 28 and 29) perhaps due high yield^.^^^^^^ Furthermore, iteration of this process to competing hydrolysis under the mild base-catalyzed via the biarylboronic acids 380 allows access to similarly conditions. functionalized m-terphenyls 381.203 Benzamide 2-aryl-6-boronic acids (380, Scheme 85), In the context of tertiary amide 377a and carbamate prepared by identical metalation-boronation sequences, 377b arylboronic acids, procured by either indicated undergo efficient cross coupling with substituted phenyl tactic, this sequence has considerable scope for the (Table 36, entries 30, 31,33, and 34), naphthyl (entries synthesis of unsymmetrical biaryls and heterobiaryls 32, 35, and 36), and phenanthryl (entry 37) bromides (Table 36). Thus a variety of biphenyl-2-carboxamides to give diverse amide m-terphenyls. The observed good with methyl (entries 2-5 and lo), methoxy (entries 6-8), to excellent yields of these products suggest that aryl carboxamido (entries 4 and 9), and chloro (entry 5) steric hindrance effects, clearly evident in the twisted substituents have been obtained. Steric hindrance ap- orientation of the 1,2,3-substituents (X-ray structure pears not to be a major factor for the formation of of entry 32),m are not detrimental to the cross-coupling 2,2’-disubstituted systems (entries 2-6 and 8) unless one process. Similarly, high yields of carbamate m-ter- of the ortho groups is exceedingly bulky in the aryl phenyls are obtained (entries 38-40), which also suggest bromide coupling component (entry 9). Of the number that, in comparison to the formation of the corre- of methoxy-substituted boronic acids that participate sponding biaryl systems (entries 28 and 29), carbamate in this reaction (entries 19-26), those leading to the hydrolysis under the basic reaction conditions is ste- formation of a 2,2’,6’-trisubstituted system (entry 22), rically impeded. a differentiated oxygenated derivative (entry 25), and Iterative application of the DoM boronation-cross others derived by inversion of the boronic acid (non- coupling process has led to the assemblage of highly DoM origin) and bromo functions in the coupling functionalized m-tetraphenyls and mixed m- and p- partners (entries 24 and 27) may be of specific synthetic tetraphenyls (Scheme 86).205 Thus cross coupling of value. Furthermore, unsymmetrical phenyl-naphthyl the biphenylboronic acid 382 with the o-bromophenyl Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90,No. 6 925

TABLE 36. Cross-Coupling of Benzamide and 0-Aryl Carbamate o-Boronic Acids with Aryl Bromides

N(CPr)p

1 202 '

2 81 200

NEtp 4 $: Bra 77 200,208 B(0H)z Me CONEt2 Me ' CONE12

5 $: Braci@& 85 200,208 B(W2 Me 0 Me CI

6 202

Me0

200,208

d: Br@ 200,208 ' B(0H)p Me '

202 OMe OM e

13 209

14 e& 92 202 026 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 36 (Continued)

15 90 202

80 202

87 202

a3 202

Me0 NE12 Me0 NEI2 19 85 200,208 \ Me ' Me0 NEt2 20 Me0 NE12 64 206

Me0

21 B8 207 OMe OMe-.

22 23 200,208

Me0 Me NE12

98 200,208 23 Me0d' ' B(OH)2 Me Me,%Me ' c'

24 76 207

Me0 NE12

25 Me$p: Brn 75 207 0 0 B(oH)z MOMO MOMO Me0 N(kPr)p MeowOMe0 N(iPr)Z BrQMeo% 74 207 26 Me0 OMe ' B(OH)2 OMe Me0 ' OMe

207

Et2NOCO 0 52 203 Br 28 bBioH'2\ Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 927

TABLE 36 (Continued)

EW Boronic Add Aryi Bromide Produd Y~ld,~/~Ref EtzNOCO 29 Br 40-55 202,203 OMe

203

209

32 2(33

CON(CPr)2

33 4 80 209 OMe Me0 \ OMe

2Q3

a4 209

81 209

78 209

07 2a3

75 203

80 200

carbamate 383 gave the expected product 34, R = Metalation-boronation gave the boronic acid 389, which MOM (31%),and, surprisingly, the phenol 384, R = H served a pivotal position for cross coupling with bromo (41%). With 384, R = MOM, a second sequence of carbamates 383 and 390 to afford, in low yields, the metalation, boronation, and cross coupling with 385 led tetraphenyl387 and the azapyridotetraphenyl391, re- to the m-tetraphenyl 386. Alternatively, anionic or- spectively. tho-Fries rearrangement (section V.A) on 384, R = The connection between the DoM and the Suzuki MOM, followed by acid hydrolysis and etherification cross-coupling reactions provides an entry into highly of the intermediate diphenol gave the m-terphenol388, functionalized biaryls, m-teraryk, and tetraaryls whose which now reveals a site for para cross coupling. generality, scope, and regioselectivity allow anticipation 928 Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

TABLE 37. Synthesis of Dibenzo[b,d]pyran-6-ones

4% 1. -78OCBBrS/CH& +RT

xi5" '5' 2. HOAc .\; 4' ref'ux Me 3' Y 2 'Y

Entry Biaryl Amide Dibenzopyrone Yield, Oh Ref R X Y X Y

1 r-Pr H H 89 202 2 Et 3-OMe H 79 206 3a Et 3,4-(OMe)2 H 8 2b 207 4 CPr H 3',4'-(OMe)2 71 207

2 Et 3-OMe 4'-OMe 62 207 6 Et 4-OMe 4'-OMe 47 207 7 /-Pr 3,4-(OMe)2 3'4'-(OMe)2 70 207 8 Et 4,5-(OMe)2 3'4-(OMe)2 75 207

9 92c 202 EbNOCO N

10 P 205 CONEt2

"The 2'-OMOM derivative was used. bThe order of reactions with BBr, and HOAc was inverted. 'Obtained under 2 N HCl/reflux conditions. of broad application for the synthesis of polyaryls with TABLE 38. Synthesis of 9-Phenanthrols from Biaryls" interesting properties. NE1 z 0. 2. Dibenzopyrones The simple two-step conversion of 2-methoxy-2'- carboxamidobiphenyls, efficiently obtained by the 65 4 cross-couplingtactic (Table 36), into dibenzopyranones (Table 37) constitutes a new general synthesis of this Enlry Biaryl Phenanthrol Yield, % class of heterocy~les.~~~~~~"~~~Good to excellent yields of highly oxygenated dibenzopyrones (entries 1-8) have no subst no subst 92 (98)a 3-OMe 6-OMe 92 been obtained, including two heterocyclic analogues 4-CONEt2 2-CONEl2 (entries 9 and 10). 78 4'-CI 2-CI 96 3. Phenanthrols and Phenanthrenes 6-OMe 5-OMe 92 5-OMe, 4-CI &OMe, 2-CI 93 The conversion of 2-methyl-2-carboxamidobiphenyls 4-NO2 NR into 9-phenanthrols (Table 38) defines a further ex- 5'-N02 NR ploitation of the DoM-cross coupling connection.200 This high-yield process, based on the vinylogous ther- 90 modynamic acidity of the 2-methyl hydrogens, shows good versatility for the regiospecific preparation of methoxy (entries 2, 5, and 6),carboxamido (entry 31, Yield using the corresponding diisopropylamide. and chloro (entries 4 and 6) phenanthrols but fails for nitro derivatives (entries 7 and €9, presumably because of the incompatability of nitro aromatics and LDA. Pschorr, Ullmann, and the more recent Mallory phen- Peri-substituted (entry 5) and condensed (entry 9) anthrene methodologies. phenanthrols have also been obtained. Access to the 4. Remote Metalation to Fluorenones parent hydrocarbons via triflate intermediates, 392 - 393 (Scheme 87),200p208provides additional scope to this Examination of the X-ray crystallographic structure method which is favorably competitive with the classical of a m-terphenyl (Table 36, entry 32)204and consider- Directed Ortho Metalation Chemical Reviews, 1990, Vol. 90, No. 6 929

TABLE 39. Synthesis of Fluorenones by Remote Metalation206~208~m

Entry m-Terphenyl Fluorenone Yield, %

4 2-pyridyl Ph

5 3-pyridyl Ph

6 1-Naphthyl 1-Naphthyl

7 2-(6-OMe)naphthyl 2-(6-OMe)naphthyl 53a'b

8 9-phenanthryl 9-phenanthryl &g -phenanthryl 34aJJ

0 0 #Yield from the diisopropylamide. * t-BuLi/THF/O "C - room temperature conditions. 'LDA/THF/O "C - room temperature conditions. dYield from the the diethylamide.

SCHEME 87 SCHEME 88 .#",.

392 393 394 395 396 a: R=H 1: R-H (67%) b R-2CI b R-2U (Wh) c: R-We c: R-COMB (93%) readily available m-terphenyls (Table 36, entries 30-37) d: R - 8-We d: R-l-OMe (97%) is feasible and generalization is anticipated. ation of the role of complex induced proximity effects X. DoM of Benzamides and Free Radical in amide reactions6s led to the discovery of a remote Chemistry metalation-induced synthesis of fluorenone derivatives, 394 - 395 - 396 (Scheme 88).206~208~209The regiose- Although a variety of OMe- and OMOM-substituted lectivity of this process (395) will be dependent in part, bromoaryl allyl ethers 398a,b (Scheme 89), available by upon the relative acidities of the remote hydrogens in the DoM reaction, undergo smooth radical-induced ring the Ar' and Ar2 moieties. On the basis of preliminary closure to give a series of benzene annelated furans observations (Table 39), rapid regiospecific access to a 399,210including aflatoxin synthons,211the correspond- variety of substituted (entries 1-3), heterocyclic (entries ing carboxamide 398c suffers dehalogenation to 401a 4 and 5), and condensed (entries 6-8) fluorenones from in high yield. A tin deuteride mediated experiment on SSO Chemical Reviews, 1990, Vol. 90, No. 6 Snieckus

SCHEME 89 SCHEME 91 Et DMG DMG

RiR2 !30-91%) R' R2 39 I 398 [X=Br I) 399 406 407 a DAG = OMe b DUG = OMOM c DMG = CONE12 a: R' = R2 = H, b: R' = R2 = Me c: R' + R2 = !CH2)2 d: R' = R2 ICH2)i e' R' = H. R2 = Ph 1: R' = TMS R2 = H

El El commercial status as a result of necessity in the industrially important anionic polymerization.26 The timely review by Gschwend and Rodriguez27in 1979 stimulated synthetic chemists to fresh conceptualization 400 401 in aromatic chemistry from the surprisingly large and, SCHEME 90 to that time, scattered body of accumulated knowledge on DoM processes. In the past decade, the promise of the DoM reaction has been realized in significant and diverse applications in academic and industrial laboratories on micro- and #+Ri A' macroscale operations. Although the reaction may be 402 403 ripe for inclusion into undergraduate texts, the current limited mechanistic understanding62and continuing accumulation of new DMGs (Table 1) with their in- herent new synthetic vistas forces the admission that goBu3SnH AlBN i PhH eR'/ NVR* the DoM process is still in a highly evolutionary stage. reflux Br (" > !45-70%) 0 Mechanistic62and str~ctural~~.~~insight into organo- R' R* lithiums and their reactions will allow the formulation 404 405 of new, industrially more convenient, conditions for the DoM reaction, the discovery of new DMGs, and the a: R' = R2 E Me, R3 = H, b: R' = R2 = Me R3 = Ph c: R' = R2 =Me, R3 = CO2EI d. R' I R2 = (CH& R3 iH. e: R' + R2 I(CH2,3 R3 = H 1: R' iR2 - R3 = H further rational design of new synthetic pathways in aromatic chemistry. The above comments are pertinent to the areas of 398c gave 401b (>95% dl content), thus implicating the benzamide and 0-aryl carbamate DoM reactions. While formation of an a-amidoyl radical via a 1,5-hydrogen amide metalations have been significantly exploited in atom transfer process, 397 - 400, which supersedes the synthesis, corresponding carbamate reactions are at normally rapid 5-exo-trig ring closure. On the basis of early stages of development. The limited results in this observation, a new method for heteroannelation to DoM reactions of heterocyclic systems may be amelio- an aromatic ring has been developed (Scheme rated by the development of new compatible base/ Thus application of the tin hydride method to com- electrophile combinations. Consideration of amides and pounds 404a-f, available from 402 by a sequence of carbamates in combination and with other DMGs raises DoM (402 - 403), ipso halodesilylation, and standard a multitude of retrosynthetic combinations and per- Wittig procedures (403 - 404), led to diastereomeric mutations invariably of considerable, and, at times, mixtures of dihydroisoquinolone derivatives 405a-f in unique, value for the preparation of polysubstituted modest to good yields. The success of this reaction is aromatics. The use of amide DMGs in electrophilic dependent upon rapid 1,5-hydrogen atom transfer and reaction modes subsequent to DoM chemistry has been 6-exo-trigring closure relative to ring-C0 bond rotation barely initiated. The anionic ortho-Fries rearrangement of the incipient a-amidoyl radical and bimolecular of the carbamate DMG not only provides migratory quench by tin hydride. Intermolecular interception of functionalization methods for aromatics but also opens the a-amidoyl radical by electron-deficient alkenes has new doors for further DoM reaction of the migrated also been demonstrated, 406 - 407 (Scheme 91). amide. The generation of dianionic species of both These early results suggest the development of a new DMGs invites the development of new concepts in class of intra- and intermolecular carbon-carbon aromatic ring functionalization. The establishment of bond-forming reactions, connected to DoM chemistry, connections between the amide or carbamate DoM which proceed via radical intermediates generated by process and other modern synthetic methods, illustrated 1,5-hydrogen atom transfer processes at normally un- by cross coupling and free radical reactions, will con- reactive sites. tinue to enhance the power of the methodology. The complex induced proximity effect concept@will XI. Concludlng Remarks undoubtedly play a role in the further general development of DoM chemistry. Early indications in its Discovered 50 years ago by Gilmanlg and Wittig,20the value are evident in remote metalation of biaryl (Table DoM reaction began its rise to prominence by the 39) and annulene amides.213 In a general context of systematic studies of Hauser and his school in the late amide and carbamate DMGs, this effect may stimulate 1950~.~~7~Early mechanistic st~dies~~,~~@v~provided the discovery of new metalation processes that would additional stimulus. The accelerating pace of applica- create a greater interplay between aliphatic and aro- tion became evident only after alkyllithiums reached matic areas of chemistry. This path would naturally Directed Ortho Metabtion Chemical Reviews, 1990, Vol. 90, No. 6 931 lead to the next evolutionary stage of the DoM reaction 1983, 39, 3373; (Cu, Hurtley reaction): Bruggink, A.; McKillop, A. Tetrahedron 1975,31,2607;Smidrkal, J. Col- as a tool for organic synthesis. For, as in any scientific lect. Czech. Chem. Commun. 1982, 47, 2140; Aalten, H. L.; endeavor, "le dernier mot n'est certainement pas encore van Koten, G.; Goubitz, K.; Stam, C. H. Organometallics 1989,8, 2293. dit et l'avenir nous rgservera encore bien des (11) Colquhoun, H. M.; Holton, J.; Thompson, D. J.; Twigg, M. surprise^''.^^^ V. New Pathways for Organic Synthesis; Plenum: New York, 1984 (a) 44 (b) 33. (12) Rwi, R. A.; De &si: R. 8.ACS Monograph 178; American XII. Acknowledgments Chemical Society: Washington, DC, 1983. (13) Blagg, J.; Davies, S. G.; Goodfellow, C. L.; Sutton, K. H. J. Chem. Soc., Chem. Commun. 1986, 1283. Chung, Y. K.; I heartily thank all students whose joy in discovery, Williard, P. G.; Sweigart, D. A. Organometallics 1982, I, 1053. dedication, insight, and skillful experimentation over (14) Claisen: Parker, K. A.; Casteel, D. A. J. Org. Chem. 1988,53, the past decade has provided the harvest of results on 2847; Bender, D. R.; Kanne, D.; Frazier, J. D.; Rapoport, H. J. Org. Chem. 1983, 48, 2709; Kaufman, K. D.; Erb, D. J.; the benzamide and carbamate DoM chemistry. I ded- Blok, T. M.; Carlson, R. W.; Knoechel, D. J.; McBride, L.; icate this article to those who have been, those who are Zeitlow, T. J. Heteroc cl. Chem. 1982, 19, 1051. Hetero- here, and those who will come. Our work has been Cope: Blechert, S. He$. Chim. Acta 1985,68,1835. Fries: Lewis, J. R.; Paul, J. G. J. Chem. SOC.,Perkin Trans I 1981, supported by NSERC Canada, Merck Frosst, Imperial 770. Sommelet-Hauser: Ito, Y.; In Nozaki, H., Ed. Current Oil, and the Ministry of Environment (Ontario) to Trends in Synthesis; Pergamon: London, 1981; 169 Shirai, whom I am grateful. N.; Sato, Y. J. Org. Chem. 1988,53,194;Inoue, E.; Ikeda, H.; Sato, S.; Horie, K.; Ota, T.; Mi amoto, 0.;Sato, K. J. Org. The award of the 1989 Chaire Noelting at l'Universit6 Chem. 1987,52, 5495; Lee, T.-J; Holtz, W. J. Tetrahedron de Haute Alsace, Mulhouse, France, provided the Lett. 1983, 24, 2071. (15) (a) For an excellent, unique review, see: Baumfield, P.; tranquility for word processing the first draft of this Gordon, P. F. Chem. SOC.Rev. 1984, 13, 441. (b) From p- DoM article. Most appropriately, Prof. M. E. Noelting dicarbonyl systems: Harris, T. M.; Harris, C. M.; Kuzma, P. (1851-1922), almost a contemporary of Kekul6, had a C.; Lee, J. Y.-C.; Mahalingan, S.; Gilbreath, S. G. J. Am. Chem. SOC.1988,110,6186 and references therein; Yamagu- keen interest in aromatic structure and contributed chi, M. J. Synth. Org. Chem. Jpn. 1987,10,969Katagiri, N.; significantly to aromatic dye chemistry. I am grateful Kato, T.; Nakano, J. Chem. Pharm. Bull. Jpn. 1982,30,2440; to Professor J.-P. Fleury for the invitation and Professor Barton, D. H. R.; Dressaire, G.; Willis, B. J.; Barrett, A. G. M.; Pfeffer, M. J. Chem. SOC.,Perkin Trans. I 1982, 665; J. Streith and other colleagues and students for pro- Chan, T.-H.; Prasad, C. V. C. J. Org. Chem. 1986,51, 3012 viding the ambiance and stimulating teaching envi- and references therein. (c) From isoxazoles (masked P-di- carbonyls): Auricchio, S.; Ricca, A.; Vajna de Pava, 0. J. Org. ronment. This article would still be gestating as a Chem. 1983,48,602. (d) Chromium carbenes: Dotz, K. H. diskette draft were it not for the perspicacity of Barb An ew. Chem.,Int. Ed. Engl. 1984,23,587; Wulff, W. D.; Xu, Weber (manuscript) and the perfection of Claude Y.%. J. A m. Chem. SOC.1988,110,2312 and references cited therein. Quesnelle (graphics, tables). (16) From carbocycles: Rippol, J. L.; Rouessac, A.; Rouessac, F. Tetrahedron 1978,34,19: From heterocycles: Boger, D. L,.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic XII I. References Synthesis; Academic: New York, 1987; p 312 ff. Co(Cp), [2 + 2 + 21 cycloadditions: Vollhardt, I-?.P. C. In Linberg, Franck, H. G.; Stadelhofer, J. W. 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