A Hypervalent Iodide‐Initiated Fragment Coupling Cascade of N‐Allylhydrazones

Abstract

Reliable bond-forming reactions that enable the union of two or more molecular fragments are essential for the efficient and convergent assembly of complex natural products or medicinal agents.[1] As part of a program aimed at developing such reactions, we have been investigating the utility of Nallylhydrazides as versatile chemical intermediates that allow for high yielding fragment coupling by way of hydrazone formation followed by a carbon-carbon bond-forming molecular rearrangement.[2] Most recently, we reported a triflimidecatalyzed rearrangement of N-allylhydrazones (the Stevens [3,3] rearrangement) [3] that allows for a "traceless" bond construction between two fragments.[2c] Prior to this development, we reported an N-bromosuccinimide (NBS)-initiated rearrangement that not only allowed for such fragment assembly but also incorporated an additional bromide atom (i.e., 1!4, Nuc = Br).[2b] We speculated that N-bromination, followed by loss of bromide, initiated the cascade sequence through diazoallene species 2 (Scheme 1). A [3,3] sigmatropic rearrangement would afford diazonium ion 3, which would react with bromide to produce the benzylic bromide 4 (Nuc = Br).We wished to widen the scope of this cascade sequence to include other nucleophiles, and were especially intrigued by the possibility of initiating the hydrazone oxidation (i.e., 1!2 in Scheme 1) with hypervalent iodine compounds (i.e., PhIX 2 where X = OAc, OTFA, OTf, etc).[4] We anticipated that the nucleophile in such a system might not necessarily be limited to the coordinated ligand on the iodine atom, providing a useful and powerful strategy to couple multiple species together (i.e., an aldehyde, an allylhydrazide, and the nucleophile).We initiated our research efforts in this new area by investigating the effects of the commercially available hypervalent iodine compounds, PhI(OAc) 2 (PIDA) and PhI-(OTFA) 2 (PIFA; OTFA = trifluoroacetate), on the hydrazone derived from the condensation of 2-naphthaldehyde and methylallyl hydrazine (i.e., 5; Scheme 2). While PIDA gave no desired product under the conditions explored, PIFA provided trifluoroacetate 6 (X = OTFA) in 43 % yield (Scheme 2 A). This low-yielding result, which could not be improved upon, provided initial evidence that hypervalent iodides were able to promote rearrangements of N-allylhydrazones. It was during an investigation of various exogenous nucleophiles that we ran the reaction between hydrazone 5 and PIFA, in the presence of methanol (10 equiv), and observed formation of the ester 6, along with competitive formation of ether 7 (Scheme 2 B). While it was possible to favor generation of the ether adduct by using methanol as the solvent, this would limit the use of this method to readily available alcohols, and would preclude the use of solid alcohols or those that are part of a more complex fragment. Therefore, we explored the use of PhI(OTf) 2 as an initiator, [5] reasoning that the much less nucleophilic triflate would not compete with the alcohol for incorporation into the substrat...

PhI(OTf)2 Does Not Exist (Yet)**

“…Syntheses of PhI(OTf) 2 and a related derivative with methyl ester groups at the 3‐ and 5‐ position have been reported by the reaction of two equivalents of trimethylsilyl trifluoromethanesulfonate (TMS‐OTf) with PhI(OAc) 2 or two TMS‐OTf with PhI=O, [3, 4, 10, 11b, 12] with the first report coming from Zhdankin using TMS‐OTf and PhI=O [13] . It was postulated that two equivalents of triflic acid may react with PhI=O to generate PhI(OTf) 2 but was found in actuality to generate 1 (Scheme 2), which could be used to generate bisiodonium salts [14] .…”

“…[2] One such derivative with an increasedo xidative capacity is PhI(OTf) 2 which has had reported use as an in situ generateds pecies in solution by severalg roups, including our own. In organic chemistry PhI(OTf) 2 has purported use in formation of hydrazones, [3] oxyaminations, [4] dizaeniums, [5] synthesis of functionalized cyclopropane rings, [6] cyclization of hydroxystilbenes or carboxylic acids, [7] functionalization of acetylenes, [8] aryl CÀHa lkylations, [9] and alpha arylations. [10] We have used it as as tarting complex to form Weiss' reagent, [PhI(Pyr) 2 ] 2 + via displacement of the triflates (Scheme 1).…”

Highly Stereoselective Metal‐Free Oxyaminations Using Chiral Hypervalent Iodine Reagents

“…mation), the more reactive PhI(OTf) 2 . [19] This step leads to a mixture of 5 a and 5 b (ratio approx. 2:1) in a much faster reaction with improved combined yields of 72 % (Table 1, entry 4).…”

Kinetic Resolution of Racemic Allylic Alcohols by Catalytic Asymmetric Substitution of the OH Group with Monosubstituted Hydrazines

“…In general, the reaction with allylic alcohols bearing a-alkyl groups and g-aryl (or heteroaryl) groups proceeded with exclusive a-selectivity and complete retention of the E-alkene geometry (entries 1-8, s factors2 1t o > 400). The racemic allylic alcohols were also efficiently resolved with s factors ranging from 128 to > 400 (entries [10][11][12][13][14][15][16][17][18][19][20].I nc ontrast, lower but still acceptable enantioselectivity was achieved when the a-substituents of allylic alcohols were aryl groups (entries9 and 22). Unlike the other cases, the allylic moiety of the p-allylpalladium intermediate generated from alcohol rac-1 i is symmetrical.…”