Angewandte
Communications
Chemie
octene (2q) or cyclopentene (2r) were used. Surprisingly,
cyclohexene did not lead to the desired product. Excellent
regioselectivity was observed for the reactions with cyclo-
hexa-1,3-diene (2s), 1,2- dihydronaphthalene (2t), and 1H-
indene (2u). Acyclic internal olefins containing cis or trans
configurations, such as (E)-oct-4-ene (2v) and (Z)-but-2-ene
(2w), also provided the desired product (3av, 3aw) in good
yield. All reactions with internal alkenes were highly diaste-
reoselective and relative stereochemistry of 3aq and 3av were
unambiguously determined by X-ray crystallography, which
confirms retention of stereochemistry during the migratory-
insertion step.[20]
Finally, the scope with respect to acrylamides investigated
using vinyl cyclopentane (2a) as
a coupling partner
(Scheme 3). N-(pivaloyloxy)acrylamides containing ester
(1c), protected amine (1d), aryl (1e), and halide (1 f–1h)
groups delivered corresponding d-lactam products with good
yields and regioselectivities. 2-Methylene-N-(pivaloyloxy)-
pent-4-enamide (1i), which contains two different terminal
alkenes, gave d-lactam exclusively, presumably due to the
À
favored 5-membered rhodacycle formation after the C H
activation step.
Scheme 4. Mechanistic investigation.
À
substrate containing a C H bond and one with an analogous
[21]
À
C D bond. The reaction was conducted in an NMR tube
and the reaction progress was monitored in situ by 1H NMR.
The KIE value was calculated by comparing the initial
reaction rate (slope) of each reaction (see the Supporting
Information for details). The observed primary KIE (KH/KD)
À
value of 6.31 suggests that C H bond cleavage occurs during
the turnover limiting step. Overall, both experiments indicate
À
that C H activation is irreversible and the turnover-limiting
step when CptRhIII is used as a catalyst.
Based on previous work and our mechanistic investiga-
tion, we propose the following mechanism for the reaction
(Scheme 5). First, coordination of the acrylamide substrate to
active RhIII catalyst I generates intermediate II. At this stage,
À
turnover-limiting irreversible C H activation occurs to form
5-membered rhodacycle III. Subsequently, an alkene coupling
partner coordinates and forms 7-membered rhodacycle V
À
through regioselective migratory insertion. After C N bond
À
formation/N O bond cleavage steps, intermediate VI releases
Scheme 3. Scope with respect to acrylamides. Regioselectivity and
diasteroselectivity were determined by 1H NMR of unpurified reaction
mixture. Yield of isolated product given. [a] 5 mol% of [CptRhCl2]2.
the d-lactam product with regeneration of the active RhIII
catalyst I.
The utility of the developed method was demonstrated by
the rapid synthesis of trisubstituted piperidine 6, a potential
drug candidate for cardiovascular disorders and tumors
(Scheme 6).[22] The coupling reaction between 2-bromo-N-
(pivaloyloxy)acrylamide (1h) and N-allylmethanesulfona-
mide (2w) gives the corresponding d-lactam product (3hw)
in a single step. The aryl moiety was installed through
a Suzuki–Miyaura coupling reaction with 4-(trifluoromethyl)-
phenylboronic acid, and subsequent alkene hydrogenation
resulted in compound 5. After amide reduction and N-
acylation, trisubstituted piperidine 6 was successfully pre-
pared.
À
To obtain mechanistic insight, we first investigated the C
H activation step of the reaction (Scheme 4). The reaction
was conducted in TFE-d1 and quenched when around 50% of
the acrylamide substrate was consumed. Interestingly, the
À
reversibility of the C H activation depends on the Cp ligand
on the RhIII catalyst. When [CptRhCl2]2 was used as catalyst,
deuterium incorporation was not observed in the unreacted
À
acrylamide, which suggests C H activation is irreversible. In
the case of [Cp*RhCl2]2, the C H activation was reversible,
showing 27% deuterium incorporation on the recovered
acrylamide. Next, the kinetic isotope effect (KIE) was
measured from two separated reactions, one with a normal
À
In summary, we have developed a RhIII-catalyzed syn-
thesis of a,b-unsaturated-d-lactams from N-(pivaloyloxy)-
Angew. Chem. Int. Ed. 2020, 59, 1 – 6
ꢀ 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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