Page 83 - Science

RESEARCH

ORGANIC CHEMISTRY The key intermediate is thought to be a high-
valent Ir(V)-carbonylimido species (22), which
Selective formation of g-lactams via undergoes a reductive C–N coupling to deliver
the corresponding Ir(III)-acylamido product. We
hypothesized that the half-sandwich Ir(III) com-
C–H amidation enabled by tailored plex may be able to form the acylnitrenes and
promote C–H insertion via an outer-sphere mech-
iridium catalysts anism (Fig. 1D), envisioning that catalytic C–N
coupling in these systems need not be limited to
inner-sphere mechanisms. We were encouraged
by the fact that the Cp*Ir(III) platform did not
Seung Youn Hong,* Yoonsu Park,* Yeongyu Hwang, Yeong Bum Kim, produce detectable amounts of isocyanates during
Mu-Hyun Baik,† Sukbok Chang†
other C–N coupling processes; hence, we antici-
pated that the competitive decomposition path-
Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form g-lactam rings
has traditionally been hindered by competing isocyanate formation.We report the application of way might be controlled by proper tuning of the
theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalyst.
To test these design ideas, we examined a
catalysts for suppression of this competing pathway. Modulation of the stereoelectronic
series of stoichiometric reactions with acylni-
properties of the auxiliary bidentate ligands to be more electron-donating was suggested
trene precursors (Fig. 2A), using the iridacycle
by density functional theory calculations to lower the C–H insertion barrier favoring the
I and phenyl-1,4,2-dioxazole derivatives as re-
desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones,
actants. According to the proposed reaction mech-
carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding anism, the Ir-nitrenoid intermediate should be
2
3
g-lactams via sp and sp C–H amidation with exceptional selectivity.The power of this
formed, and if an appropriate C–H bond were
method was further demonstrated by the successful late-stage functionalization of amino offered in close proximity, an insertion might oc-
acid derivatives and other bioactive molecules.
curmorereadily than theunproductivedecom- Downloaded from
position. Thus, dioxazoles bearing ortho-isopropyl
he catalytic oxidation of C–H bonds is the sence of such a method for preparing lactams is substituents were presumed to be ideal, as the
most desirable way of converting readily puzzling. In principle, carbonylnitrenes gener- weak tertiary benzylic C–Hbond of the isopropyl
available raw feedstocks to useful, value- ated in situ might allow for direct construction group may readily undergo C–Hinsertion.When
added commodity chemicals. One such re- of a cyclic amide scaffold. (o-isopropyl)phenyldioxazole 1 was treated with
F
T action highly sought after in pharmaceutical As shown in Fig. 1B, catalytic reactions are a mixture of iridium species I and NaBAr 4 ,the
as well as materials chemistry is the direct nitro- believed to proceed through a key metal-nitrenoid Ir-dioxazole adduct III was formed quantitatively,
genation of aliphatic C–Hbonds (1–4). An effec- species, which inserts into aliphatic C–H bonds asconfirmedbynuclearmagneticresonance(NMR)
tive general method for carrying out these C–N to generate the corresponding azaheterocyclic and x-ray diffraction analysis. At slightly elevated http://science.sciencemag.org/
coupling reactions is to first convert the nucleo- products. The main reason that C–Hamidation is temperature (50°C) in the presence of excess nitrile,
philic amino functionalities to more reactive, elec- ineffective for lactam synthesis lies in the intrinsic III was fully converted to the C–H insertion prod-
trophilic nitrene precursors that are subsequently instability of the putative carbonylnitrene inter- uct isoindolinone 3 with the concomitant re-
used as reaction partners in metal-catalyzed C–H mediate, which may easily decompose and form lease of a cationic iridacycle II and molecular
amination reactions (Fig. 1A). The initial demon- isocyanates via a Curtius-type rearrangement acetone. With analogous 1,4,2-dioxazol-5-one (2),
stration of this chemistry was reported by Breslow (Fig. 1C, left). This instability is well documented which was previously found to be a much more
in 1983 (5), wherein reactive hypervalent ylides for acyl azides that were explored as synthetic reactive substrate in other C–N forming reac-
acted as sulfonylnitrene precursors in the Fe(III)- precursors under photolytic, thermolytic (15), and tions (19), the identical lactam 3 was rapidly on March 1, 2018
or Rh(II)-catalyzed oxathiazolidine synthesis. transition-metal catalysis conditions (16, 17). As a produced even at room temperature in 5 min
Major advances were achieved in the early 2000s result, the general consensus is that acyl nitrenes with CO 2 extrusion. More important, a catalytic
when Du Bois and others found elegant ways of are unfit to serve as amide sources in C–Hinser- amount of II was found to mediate this C–Hin-
generating reactive nitrogen ylide species (6–9), tion processes (18). sertion with excellent reactivity (see fig. S4), and
which could be used to prepare a variety of amide We envisioned that this paradigm might be the formation of the lactam 3 strongly supports
products of high synthetic utility (7). In addition, challenged if the decomposition pathway could our proposal that the postulated Ir-nitrenoid
organic azides have been identified as produc- be blocked and the desired C–H amidation of the species is indeed the active intermediate and is
tive nitrene precursors to indoles (10, 11), indolines nitrenoid could be engineered to be faster (Fig. capable of rapidly activating the relatively weak
(12), andpyrrolidines (13). Recently, hydroxylamine 1C, right). Previously, we discovered that 1,4,2- C–H bond while the undesired Curtius decom-
derivatives were elegantly used as an effective han- dioxazol-5-ones, which can be readily obtained position pathway is suppressed effectively. In
dle for synthesizing aza-arenes in N-unprotected from abundant carboxylic acids, are versatile sub- contrast, when a dioxazolone bearing a flexible
form (14). Despite these advances, cyclic amides stitutes for acyl azides in related C–N coupling aliphatic chain (4) was used, a distinctively dif-
such as lactams that are valuable scaffolds in reactions (19); thus, we imagined that these sub- ferent result was obtained under the same condi-
synthetic and medicinal applications could not strates may provide a nitrene-based route to lac- tions, leading to a six-membered Ir(III)-amido
be obtained directly through a C–H amidation tam synthesis (20). Seeking to develop a catalyst species IV. Although the substrate has two ben-
strategy. Considering how successful C–Ncou- capable of C–H activation and acylnitrene for- zylic C–H bonds at the g-position, the C–H in-
pling techniques have been in general, the ab- mation while suppressing the Curtius-type deg- sertion pathway was completely suppressed, thus
radation, we were drawn to an iridium complex highlighting that the C–Ncouplingand C–Hin-
stabilized by an electron-donating cyclopentadienyl sertion pathways are in competition and that the
Department of Chemistry, Korea Advanced Institute of
Science and Technology (KAIST), Daejeon 34141, Republic ligand. Cyclometallated Cp*Ir(III) complexes are chemoselectivity is dependent on the choice of
of Korea, and Center for Catalytic Hydrocarbon widely known to facilitate C–Hactivation under the dioxazolone substrate.
Functionalizations, Institute for Basic Science (IBS), Daejeon ambient conditions. These reactions proceed via To better understand the reactivity of the Ir-
34141, Republic of Korea. an inner-sphere imido insertion into an iridium- nitrenoid species for the subsequent optimization
*These authors contributed equally to this work.
†Corresponding author. Email: sbchang@kaist.ac.kr (S.C.); carbon bond, where acyl azides or analogous of the catalysis, we carried out computer simula-
mbaik2805@kaist.ac.kr (M.-H.B.) dioxazoles serve as the nitrogen source (21, 22). tions on the three most plausible reaction pathways:

Hong et al., Science 359, 1016–1021 (2018) 2 March 2018 1of6