Journal of the American Chemical Society
Article
Scheme 2. (a) Stereoelectronic Features of Selected 6-endo/
formed ring (i.e., n + 1). For example, when a three-membered
ring is involved in the nucleophilic endo-tet attack, a six-
membered TS yields a seven-membered product. In analogy to
the fused TS of epoxide ring openings, where n-endo-tet
terminology is used to describe the n-size ring formation via a
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-exo Cyclizations, b) Four Possible Ways to Use Three-
Membered Rings in a Cyclization Including the Genuine
endo-tet Process in the Fused Bicyclic TS, and (c) Choice of
[
1
(n − 2).1.0] TS, we suggest calling the reactions forming an n +
size cycle as n-endo-tet (Scheme 2c).
The practical design of the “missing” type of endo-tet
cyclization is illustrated in Scheme 2c. These processes are
unlikely to be found in epoxides where the C−O bond is likely to
be broken instead of the C−Z bond for the stereoelectronic
reasons (this bond is exo relative to the forming cycle) and due
to the high electronegativity of oxygen. To coerce this elusive
cyclization to happen, one needs to tether a three-membered
cycle to the nucleophile with a sufficiently electronegative atom
Z while choosing X that cannot serve as a leaving group in
nucleophilic substitution. These considerations suggest that
both X and Z could be carbon atoms, with Z having an additional
electron-withdrawing substituent. This design logically leads to
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donor−acceptor (DA) cyclopropanes
where both a pendant
nucleophilic functionality and an acceptor group are attached at
the same “anchor” carbon atom.
For intermolecular reactions of DA cyclopropanes, a variety of
quantum mechanical methods calculated the attack “Nu···C···X”
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angles between 131° and 148°. These angles are in between
the 180° angle for the “normal” S 2 reaction and the ∼109°
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,2
Burgi−Dunitz angle for nucleophilic addition to carbonyls.
Based on these features, the endo-tet cyclizations of cyclo-
propanes should be more stereoelectronically forgiving than
endo-tet reactions of acyclic substrates.
Unlike the simple endo-tet processes, the “endo-tet” epoxide
cyclizations do form cyclic products, as one cycle is sacrificed to
make the other.
Notably, DA cyclopropanes are known to undergo a variety of
ring enlargement processes. In particular, Cloke−Wilson
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rearrangement of cyclopropyl carbonyls and imines,
However, the reactions that are generally referred to as “endo-
tet cyclizations of epoxides” are not “endo-cyclizations”
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cyclopropanecarboxylate lactonization, and related processes
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can produce five-membered heterocycles. The homo-Nazarov
according to the original Baldwin’s definition. The latter
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rearrangement and related reactions can form six-membered
would classify such reactions as exo-tet processes because the
breaking C−O bond is positioned not inside but outside of the
newly formed ring. After pointing this out, Jamison and co-
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5
rings. Formation of seven-membered cycles is also known. In
all these reactions, a nucleophile attacks the electrophilic carbon
of cyclopropane and forms a new ring, which includes all three of
the cyclopropane atoms. However, these reactions are believed
to proceed by a stepwise mechanism where the “endo” C−C
bond is broken first, and, hence, the ring forming step is not an
endo-tet cyclization. The stepwise mechanisms of all the known
literature examples illustrate that the genuine endo-tet
cyclizations of this type are very difficult and suggest that they
may be impossible. We are glad to report that the latter is not
true.
7a
workers suggested using the terms “spiro” and “fused” TSs to
distinguish between the cyclizations proceeding via the attack at
the proximal and distal carbons (Scheme 2b).
From the stereoelectronic perspective (Scheme 2a), the fused
TS in the epoxide ring openings lies in between the exo-tet and
endo-trig (not tet!) TSs. Because both 6-exo-tet and 6-endo-trig
processes are favorable according to the original Baldwin’s rules,
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the formation of pyranes via the “fused” TS is feasible (even
though the competing exo-tet cyclization is often faster) and
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found many useful applications in natural product synthesis.
In order to explore if seven-membered rings can be obtained
by 6-endo-tet cyclization of DA cyclopropanes (perhaps, one can
also call it a “6 → 7” endo-tet cyclization), we selected
cyclopropanecarboxamides with the hope to induce their
transformations to tetrahydrobenz[b]azepin-2-ones (Scheme
However, analysis of all possible reactions of cyclic precursors
suggests a fourth, so far unexplored, path corresponding to
genuine endo-tet cyclization (Scheme 2b). This path should
include the attack of a pendant nucleophile on the electrophilic
carbon of the three-membered ring via a “fused” TS where the
endocyclic atom Z, connecting the tethered nucleophile, serves
as a leaving group. Unlike the endo-tet processes in Scheme 1b,
this transformation would lead to a cyclic product because the
breaking bond is a part of a pre-existing cycle that will be merged
into the forming ring (Scheme 2c).
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c). In choosing this process, we were additionally motivated by
the known bioactivity of tetrahydrobenz[b]azepines. This
scaffold is present, for example, in benazepril, which is used to
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treat heart failure and high blood pressure, β2 adrenergic
2
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agonist zilpaterol, or vasopressin receptor antagonists
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An interesting feature of these reactions is the difference
between the number of atoms involved directly into the bicyclic
tolvaptan and mozavaptan (Figure 1). To distinguish from
a stepwise scenario, we used stereochemically defined substrates
[(n − 2).1.0] TS for the new ring formation and the size of the
as mechanistic probes for the true S 2-like processes.
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J. Am. Chem. Soc. 2021, 143, 13952−13961