Does phenothiazine give a dianion on addition of two equivalents of strong base?

A careful analysis of results obtained by different authors allowed us to unravel the pathway of the metalation reaction of phenothiazine ( 1 ) by n -BuLi (2 equiv). The reaction is shown not to yield a dilithio species as believed. Electrophiles such as RCONMe 2 (R = H, Ph, 4-MeOC 6 H 4 ), RCO 2 H (R = Ph and Me) and CO 2 assist a second deprotonation


Introduction
Much is known about the structures of lithium alkyls and amides, 1 but far less about how they operate, the origin of their selectivity with aromatic substrates, and the nature of the lithiated organic compounds produced prior to workup.All crystalline organolithium salts for which an X-ray structure analysis has been successfully performed so far are dimeric, tetrameric, or hexameric aggregates, the degree of aggregation depending less upon the particular alkyllithium structure than upon solvent and added complexing or chelating agents.Structural data for ortholithiated aromatics in which the Li atom is intramolecularly coordinated to an Me 2 N or MeO group have been reported. 2Crystal structures of N,N-diisopropyl-2-lithiobenzamide-diethyl ether complex and N,N-diisopropyl-2-lithionaphthamide-THF complex are dimers. 3However, by NMR spectroscopy, these dianions when dissolved in [D 8 ]THF give at least five observable aggregates!
The fact that ortho-lithiated aromatics are found to be more or less aggregated in solution and crystals does not, of course, tell us anything about the actual reactive species and the transition state when the electrophile is added.

Results and Discussion
In this paper, the mechanism of the metalation of phenothiazine (1) is reanalyzed (Scheme 1).It is conventionally accepted that the reaction of 1 with two equivalents of n-BuLi in ether affords the lithium amide 2 which undergoes a second metalation to give the dilithio species 3. 4,5 Addition of DMF, N,N-dimethylbenzamide, 4-methoxy-N,N-dimethylbenzamide, the lithium salts of acetic and benzoic acids, and carbon dioxide leads to the C(1)-acylation products 4a-f whereas acetyl chloride, iodomethane and ethylene oxide give the N(10)-substitution products 5a-c exclusively.To explain this discrepancy in the reactivity, the authors claimed that "the site of acylation is essentially dependent on the leaving group involved in the addition".

Scheme 1
This interpretation appeared to us rather inadequate and somewhat intriguing.We found initially that under the described experimental conditions, trapping with D 2 O led to 10Dphenothiazine arising from exclusive substitution at the nitrogen atom (100% 10d 1 ).We make the following assumption, which is new and potentially valid with other substrates and electrophiles.Dianion 3 is not formed in appreciable concentration and monolithium amide 2 is the stable species present in the reaction mixture prior to addition of the electrophile.The second equivalent of n-BuLi remains to some extent on standby and the reaction follows different pathways depending on the nature of the electrophile.
The subsequent nucleophilic addition of monolithium amide 2 to DMF and amides (RCOX, X = NMe 2 , R = H, Ph, 4-MeOC 6 H 4 ) (Scheme 2), leading to tetrahedral lithium amino(dimethylamino)alkoxides 6a-c, must be at least as fast and most probably faster than quenching of n-BuLi by the electrophile.Ortho-metalation by n-BuLi directed by the lithium aminoalkoxide group 6 gives a dianionic intermediate 9a-c. 7This deprotonation presumably proceeds via a prelithiation complex (PLC) 7a-c (Complex Induced Proximity Effect (CIPE) Process) 8 which immediately precedes the formation of an eight-membered ring transition state (TS) (8a-c).Internal deprotonations have been suggested to be optimal for eight-membered rings. 9,10 uLi The regioselectivity observed indicates that this heteroatom-directed ortho-lithiation is followed by a rapid, irreversible anionic N-Fries rearrangement leading to the thermodynamically more stable (less basic) lithium amide 10.Quenching of 10 in water gives the observed 1-acyl products 4a-c.This migration presumably involves an ion pair intermediate, wherein C-N bond breaking precedes C-C bond formation. 7,11roof for the proposed mechanism is gathered by the literature (Scheme 3). 7Reaction of Nacylphenothiazines 5g,h with an excess (6 equiv) of LDA or LTMP at -78 °C gives the C1-acyl derivatives 4g,h resulting from the anionic N-Fries rearrangement of the tetrahedral intermediates 6g,h which are structurally similar to the products that arise from the reaction of monolithium amide 2 and RCOX (described in Scheme 2). 12In the published work, 7 intermolecular rearrangement was ruled out by a crossover experiment using equivalent amounts of 5g and 5h; only the intramolecular rearrangement products 4g and 4h (plus phenothiazine and 2-chlorophenothiazine), but neither of the crossover products, were obtained.The migration must be very fast since 2-chlorophenothiazines are known to readily form benzynes, even at low temperature. 13hen s-BuLi (6 equiv) is used as the base, the reaction of 5g gives the parent phenothiazine 1 and 2-methyl-1-(pyridin-3-yl)pentan-1-one (Scheme 3).Addition of the alkyllithium to the carbonyl group of 5 gives a gem-aminoalkoxide 12 which is not able to direct metalation further. 7By acidic hydrolysis, the unstable a-amino alcohol 13 is cleaved to the parent phenothiazine 1 and the ketone. 6Error!Bookmark not defined. ,14The methyl group of the in situ formed 4 or isolated 7 N-acetylphenothiazine (5a) reacts with LDA or LTMP to provide a stable lithio enolate 11. 5a is retrieved after the acidic hydrolysis.

Scheme 3
The reaction of the lithium salts of acetic and benzoic acids (RCO 2 Li, R = Me, Ph) under the conditions reported in Scheme 1 is believed to proceed similarly by the indicated conversion to the Fries rearrangement product 10d,e, via the prelithiation complex 7d,e (Scheme 2).The doubly charged geminal dilithio dialkoxide group C(OLi) 2 was recently reported to direct orthometalation in the fluorenone series. 15With carbon dioxide, the reaction leads to 10Hphenothiazine-1-carboxylic acid (4f) by CO 2 -migration when the mixture is allowed to warm up to room temperature.Katritzky reported convenient procedures for the regiospecific metalation of nitrogen-containing heterocycles in which an in situ formed N-carboxylate activates the subsequent C-lithiation step. 16n agreement with our previous comments, N-substitution products 5b and 5c are formed when iodomethane and ethylene oxide are the electrophiles (Scheme 1). 17Only one equivalent of n-BuLi is required for the metalation of N-methylphenothiazine 14 (Scheme 4).The sulfur atom exerts a stronger acidifying effect in its ortho position.Addition of lithium acetate followed by hydrolysis furnished the 4-acetyl derivative 15 (20%).o-Aminobiphenyls and derivatives 18 reported by Narasimhan to undergo remote lithiation upon treatment with n-butyllithium in ether presumably react similarly.
Anomalies in reactivity have appeared to exist in the literature for a number of reactions of organolithiums with electrophiles.For instance, when dibenzodioxin is allowed to react with 2 molar equiv of tert-butyllithium at -30 °C and quenched with CO 2 followed by esterification, a good yield of the 1,9-diester is obtained, suggesting that a 1,9-dianion might have been generated under these conditions (Scheme 5). 19However, when the electrophile is changed to iodomethane, only 1-methyldibenzodioxin is isolated, indicating that at this temperature only monometalation occurs to any appreciable extent.It was suggested that in the special case of quenching with CO 2 the initially formed 1-carboxylate salt is able to direct a subsequent deprotonation of the 9position during the quench.We have recently shown that treatment of 4-fluorobenzoic acid using 6 equiv of LTMP at -50 °C followed by addition of elemental iodine or dimethyldisulfide provides 4-fluoro-3-(iodo/methylthio)benzoic acids, along with 4-fluoro-3,5-bis(iodo/methylthio)benzoic acids, suggesting the formation of 3-lithio and 3,5-dilithio intermediates (Scheme 6). 20,21However deuteration (D 2 O) and carboxylation (CO 2 ) result in the formation of only 3-deutero-4fluorobenzoic acid and 4-fluorobenzene-1,3-dioic acid with no detectable 3,5-bisdeutero-4fluorobenzoic acid and 2-fluorobenzene-1,3,5-tricarboxylic acid.A sequential process involving a rapid intraaggregate lithiation through a transient QUADAC (QUAsi DiAnion Complex) 22 was postulated to explain the unusual reactivity of Me 2 S 2 and I 2 in these transformations. 20

Scheme 6
The considerable current interest of both the structure and synthetic application of apparent aromatic dianion compounds demands a careful reappraisal of much of the existing data.The principle of parsimony (Ockham'razor) which underlies all scientific modelling and theory building, admonishes us to choose from a set of otherwise equivalent models of a given phenomenon the simplest one.However, « Everything should be made as simple as possible, but not one bit simpler » (Albert Einstein). 5a