Functionalization diazo insertion

Excess diazomethane has been used to convert phenols to methyl ethers in the presence or absence of acids . Employment of transition metal derivatives, typically Rh2(OAc)4 and recently CHsReOs , allows one to react functionalized diazo compounds in an intramolecular or intermolecular 0-aUtylation (equation 13). The stability of diazo compounds derived from active methylene compounds toward OH insertion was compared... 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

The diazo function in compound 4 can be regarded as a latent carbene. Transition metal catalyzed decomposition of a diazo keto ester, such as 4, could conceivably lead to the formation of an electron-deficient carbene (see intermediate 3) which could then insert into the proximal N-H bond. If successful, this attractive transition metal induced ring closure would accomplish the formation of the targeted carbapenem bicyclic nucleus. Support for this idea came from a model study12 in which the Merck group found that rhodi-um(n) acetate is particularly well suited as a catalyst for the carbe-noid-mediated cyclization of a diazo azetidinone closely related to 4. Indeed, when a solution of intermediate 4 in either benzene or toluene is heated to 80 °C in the presence of a catalytic amount of rhodium(n) acetate (substrate catalyst, ca. 1000 1), the processes... 

Ring enlargement via an insertion of a carbene generated in the a-position to the ring is an established method and has also been applied to the synthesis of oxepins. The ()3-allylpalladium chloride catalyzed decomposition of substituted ethyl diazo(4/7-pyran-4-yl)acetates in benzene at room temperature gives ethyl oxepin-4-carboxylates 1 in excellent yield.190 The ester function can be replaced by the phosphonate group and other P = 0-functions (see Houben-Weyl,... 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

The use of rhodium(II) acetate in carbenoid chemistry has also been extended to promoting intramolecular C/H insertion reactions of ketocarbenoids 277,280,280 ,). From the a-diazo-P-ketoester 305, highly functionalized cyclopentane 306 could thus be constructed in acceptable yields by regiospecific insertion into an unactivated... 

One of the key steps in building the fused ring involves the reaction of the activated acetoacetate methylene group in that compound with toluenesulfonyl azide to give the diazo intemediate (12-1). Treatment of that product with rhodium acetate leads to a loss of nitrogen with the consequent formation of carbene (12-2) this inserts into the adjacent amide N—H bond to form a five-membered ring and thus the carbapenem (12-3) [15]. The first step in the incorporation of the thioenol function consists in the conversion of the ketone to the enol phosphate derivative... 

Regioselective introduction of an ester functionality into the /3-position of SCBs can be accomplished by means of an Rh2(OAc)4-catalyzed C-H insertion reactions of a-diazo esters <1998JOC422, 1979ZOB2776> (Scheme 58). The reaction proceeds cleanly to give the products in excellent yields. 

Novel methods for functionalizing piperidines at the 3- and 4-positions were also introduced. Mete and co-worker synthesized 3-diazo-piperidin-2-one and characterized its reactivity in transition-metal catalyzed reactions, particularly H-X insertion reactions and cyclopropanation reactions <02T3137>. Christoffers and co-workers developed an asymmetric Michael addition reaction with a chirally modified 4-piperidone-enamine. They were able to create a quaternary carbon center in >95% de and elaborate the compound on through classical means to the functionalized piperidine 107 (Scheme 21) <02EJ01505>. 

Caibene reagents also functionalize alkanes. Triplet CH2 adds unselecdvely to alkane C—bonds. The product mixture obtained from n-pentane was found to be 48% n-hexane, 3S% 2-methylpentane and 17% 3-methylpentane, so that addition to a primary C—bond appears to be favored. Monochloro-methylcarbene, CHCl, is less reactive and more electrophilic and so the normal tertiary > secondary > primary selectivity pattern was observed. Ethoxycarbonylcarbene, formed on fdiotolysis of the corresponding diazo compound, inserts rather unselectively in to alkane C—H bonds to give the ethoxycarbo-nylmethyl derivatives in ca. 50% yield. Transition metals, such as copper(II) or rhodium(I). also usefully catalyze the insertion of carbenes into alkane C—bonds. 

The first case of an mrramolecular C-H carbenoid insertion was reported by Cane and Thomas in 1984 [12], with the special diazoacetate 17 forming the spirocyclic 5-lactone 18 in 45 % yield according to eq. (8). Doyle et al. recognized that this is a general methodology for the synthesis of y-butyrolactones [16], The reactivity of the C-H bond toward carbene insertion is increased in the vicinity of an ether functionality. Thus, the 3(2H)-furanone 20, as a useful building block in the total synthesis of (+)-muscarine, results in 40% yield from the diazo precursor compound 19 [17],... 

The time-resolved method was applied to another photodissociation reaction [124], Upon the photoexcitation of diazo compounds (Fig. 16), nitrogen is dissociated to yield the singlet carbenes. In alcoholic solvents such as methanol, the O—H bond is inserted into the carbene part quickly (within 40 ps for diphenylcarbene), and an ether is formed. The AH and AV values for the ether formation from DPDM in methanol were measured by the time-resolved method. A similar TG signal to the DPCP case was observed after the excitation of DPDM in methanol. The signal rises within 50 ns after the excitation and decays monotonously. The time profile of the signal was found to be expressed well with a tri-exponential function... 

More recent approaches include a rhodium(II)-catalyzed intramolecular insertion reaction to form the hve-membered heterocycle. Reformatsky-imine addition of 4-bromo-4,4-difluoroacetoacetate with aldimines gave b-amino-y.y-difluoroacetoa-cetates 67 that were readily converted to the key diazo intermediates 68 through the action of tosyl azide and molecular sieve. Rhodium(II)-catalyzed intramolecular insertion followed by aromatization through loss of HF gave the functionalized pyrroles 69 (Fig. 3.29). 

The requisite bis-Boc-protected 4-bromotryptamine 1459 was available in four steps from 4-bromoindole (Scheme 1.374). The other component of the biaryl coupling, the boronic acid 1460, was prepared from 2-(allyloxy)-bromobenzene. Suzuki coupling of 1459 and 1460 proceeded in excellent yield to afford 1461, which was elaborated to the ot-diazo-p-ketoester 1462. It required some experimentation to prepare 1462. Dirhodium(II) acetate-catalyzed N-H insertion of 1462 with (5)-benzyloxycarbonylvalinamide, followed by cyclodehydration, gave 1463, albeit in low overall yield (13%, two steps). Nonetheless, the authors had prepared a highly functionalized 4-aryltryptamine analog that could serve as a precursor to construct the B, E, and H rings. 

Similar to the ether substrates mentioned above, both cyclic and acyclic N-protected amines could be converted into their corresponding ortho-C—H bond functionalization products via the insertion of metal carbenoids derived from Rh catalysts and donor/acceptor diazo compounds. Thking Af-Boc-protected pyrrolidine 48 as an example (Scheme 1.15), Rh2(S -DOSP)4 catalyzed the decomposition of methyl phenyldiazoacetate la and converted the Af-Boc-pyrrolidine 48 into the corresponding C—H bond insertion product 49 in 72% yield, 94% ee, and 92% de. Furthermore, the C2-symmetric amine 50 could be formed in 78% yield and 97% ee under altered reaction conditions. Further investigation demonstrates that this intermolecular C—H bond insertion could also be applied in the kinetic resolution of 2-substituted pyrrolidine 51. The corresponding C—H bond insertion reaction proceeded smoothly, and subsequent treatment with TFA delivered the deprotected product 52 in high diastereo- and enantioselectivity (45% yield, 91% ee, >94% de). " ... 

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