Organic Letters
Letter
fully in THF. Importantly, scale-up of these reactions proved to
be facile, with 6aa, 6ab, and 6bc being formed in equal or
increased yield on a 3 mmol scale.
Scheme 5. Mechanistic and Isotopic Labeling Studies
Reactions of 3-substituted tether 5e also proved to be
successful, with high regiocontrol for the linear allylated
intermediate combining with high E selectivity to yield a single
stereoisomer. However, attempted reactions of disubstituted
allyl acetate 5f were less successful, with only the allylated
diene intermediate being obtained. This likely reflects
increased steric demand, where the phenyl substituent of the
E-alkene would need to adopt an unfavorable endo-cyclic
position in the transition state.
The cycloaddition step was seen to occur under conditions
substantially milder than those of similar IMDA reactions.
On the basis of this and the preceding results, the
mechanism can be proposed (Scheme 6). Initial additive-
14
Indeed, substrates lacking an activated dienophile (i.e., 12a−c)
reacted at 70 °C, and we chose to investigate this further. As
Scheme 6. Proposed Mechanism
t
observed above, Bu system 12a proved to be less reactive than
amide 12c (k = 6.8 × 10−
6
s
−1
vs k = 5.5 × 10
−5 −1
s
at 75 °C).
assisted, Pd-catalyzed C−N cleavage of 2 leads to the
formation of a π-allyl Pd intermediate 7. This species then
undergoes direct β-hydride elimination, even in the absence of
additional base, to form intermediate diene 20. What follows is
likely to be a standard Tsuji−Trost mechanism between 20
and allyl acetate 5, with the added base present serving to
ensure sufficient levels of reactive free amine 20. The lack of a
significant KIE associated with this process, as determined by
competition (i.e., between 17 and 2a), is consistent with the
first step (C−N cleavage) being turnover-limiting. This low
KIE value necessarily means that a reversible β-hydride
Figure 1. Eyring plots and thermodynamic parameters for the Diels−
Alder cyclization to form 6aa and 6ca.
16
largely controlled by the enthalpy of activation, with a 20 kJ
elimination cannot be ruled out. The resulting N-allylated
product 12 then undergoes cycloaddition to form product 6,
the rate of which is controlled by the aziridine and allyl
substituents. Although a Pd-catalyzed elimination/intermolec-
−
1
mol difference between 12a and 12c. While it is unclear
whether this increase is due entirely to electronic factors or
includes an additional conformational element, both values
appear to be low when compared with those known for other
17
ular DA process has been reported previously, to the best of
1
5
IMDA reactions. Further attempts to explore the impact of
the dienophile activation proved not to be possible due to
appreciable formation of 6ab even at 20 °C, again emphasizing
the facile nature of this IMDA process.
our knowledge, this is the first example of a sequential Tsuji−
18,19
Trost/IMDA cascade.
Given our previous discussion of the importance of a high
3
3
sp content within drug discovery programs, we undertook a
short study to diversify products 6 using routine trans-
formations (Scheme 7). For example, in a telescoped oxidative
cleavage/reductive amination sequence, compound 6aa was
efficiently transformed into tetracyclic amino ester 21,
possessing orthogonal protection for further functionalization.
Alternatively, selective and sequential ester hydrolysis/amide
formation gave 22 in a 47% yield overall, demonstrating
potential for efficient two-dimensional amide library formation.
In conclusion, we have shown that stereodefined tetracycles
6 can be formed in only two steps from simple pyrroles,
through initial photochemical conversion to aziridines 2. These
13
was prepared and subjected to the reaction conditions;
however, diene 13a was not observed, ruling this out as a
potential intermediate (Scheme 5). Deuterated substrate 17
was also subjected to the reaction conditions, leading to the
formation of 18 by cleavage of a single C−D bond. The kinetic
isotope effect associated with this process was investigated
through a competition reaction with 17 and 2a, which showed
4
988
Org. Lett. 2021, 23, 4986−4990