Journal of the American Chemical Society
Article
Scheme 4. Extension of the Reaction Scope to Other Types of Ortho Functionalization
With the optimized conditions in hand, the scope of the
THBA formation with ortho-unsubstituted aryl iodides was then
examined (Table 2). Both electron-deficient and -rich aryl
iodides are competent coupling partners (3a−3l), though the
electron-deficient aryl iodides gave slightly better yields. Besides
meta-substituted aryl iodides, meta-, para-disubstituted ones
also reacted smoothly (3m−3r). The reaction conditions can
tolerate a wide range of functional groups, including chloro (3a),
bromo (3b), nitro (3c), trifluoromethyl (3d), ester (3e), nitrile
tile role of the alkene moiety for potential medicinal chemistry
applications. Finally, under acidic conditions, the mixture of exo-
and endo-cyclic products could be isomerized into the
thermodynamically more stable internal olefin in nearly
quantitative yield (Scheme 3C).
To explore the generality of N1 in promoting seven-
membered-ring formation with ortho-unsubstituted iodoarenes,
we examined two other ortho functionalization tactics (Scheme
4). To our delight, besides ortho amination, preliminary success
has been achieved with Catellani annulations via ortho
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(3f), terminal alkene (3k), and silyl ether (3l). Other alkene-
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tethered O-benzoyl hydroxylamines 2 were explored next. When
substituted amination reagents were employed, 3-substituted
THBAs (3s−3t) can still be afforded in good yields. Besides the
PMB protecting group, simple benzyl can be introduced in even
higher yield (3u). When using the styrene-tethered reagent,
complete selectivity of a single alkene geometrical isomer (3v)
was observed. It is likely that the conjugation and/or the
increased sterics inhibited the alkene isomerization. Finally,
ortho-unsubstituted aryl iodides derived from naphthalene (3w),
fluorenone (3x), quinoline (3y), estrone (3z), and loratadine
alkylation and ortho aminocarbonylation to give benzoan-
nulene and benzoazepin-1-one products, respectively. In
contrast, unsubstituted NBE (N2) gave much inferior results
along with forming a significant amount of NBE-containing side-
products, further confirming that the C7-bromo group is critical
to addressing the “ortho constraint” and inhibiting undesired
pathways.
X-ray Crystal Structure of Complex 11. The unique
property of the C7-bromo NBE (N1) prompted us to investigate
its exact role in the catalysis. Migratory insertion with NBEs
typically occurs in a cis, exo manner because of the predistortion
(3aa) all delivered the desired THBAs in moderate to good
12a,27
of the NBE π bond.
However, one cannot assume, a priori,
yields. These polycyclic ring-fused azepines with diverse
functional groups could be challenging to access via conven-
tional approaches.
that N1 should maintain the exo selectivity because of the
potential steric repulsion between the C7 substituent with the
Pd during the migratory insertion process. To confirm the
alkene facial selectivity of the migratory insertion step, we
synthesized pure palladium complex 11 in good yield by reacting
Synthetic applications. The utility of this method was then
evaluated. Tolvaptan, an aquaretic drug that functions as an
orally active vasopressin receptor 2 antagonist, has been used to
treat hyponatremia and autosomal dominant polycystic kidney
disease. The ketone intermediate 5 was previously prepared in
3
-iodoanisole with N1 and stoichiometric Pd(PPh3)4 in
2
seven steps; for comparison, it can now be accessed in two steps
from THBA 3a (Scheme 3 A). Note that the PMB protecting
group can be removed in high yield by treatment with TFA. Due
to the modularity of the synthesis, this approach could be
beneficial for preparing diverse tolvaptan analogues from readily
available substituted aryl iodides. In addition, the chloro group
on THBA 3a can serve as a handle to conveniently introduce
other functional groups, e.g., an aryl group (6a), via cross
couplings (Scheme 3 B); it can also be deleted through
analysis were obtained from dissolving 11 in CH Cl followed by
the addition of MeOH.The X-ray structure of complex 11 clearly
shows that the aryl ring and the palladium still remain positioned
2
2
2
4
reduction (6b). Moreover, the alkene moiety in THBA
products can undergo dihydroxylation, hydroboration−oxida-
tion, and Simmons−Smith reaction to install vicinal diol (6c),
primary alcohol (6d), and cyclopropane (6e), respectively.
Furthermore, under the Mukaiyama hydration conditions, the
alkene was converted into a tertiary alcohol (6f) and an
interesting oxa-bridged benzazepine (6f′). It is noteworthy that
these derivatizations could find their relevance in a number of
cis and exo to the norbornyl group (Figure 3, left). Interestingly,
8
the d Pd center possesses a square-planar geometry with PPh ,
3
iodide, norbornyl group, and the bromo substituent. This is in
2
8
contrast with the literature reported analogue (complex 12)
2
with simple NBE, where the η coordination with the C(5)−
C(6) π bond occupies one of the four coordination sites (Figure
3, right). Other bond lengths, such as Pd(1)−I(2), Pd(1)−
C(3), and Pd(1)−P(4) bonds, remain largely unchanged. Such
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THBA-containing bioactive compounds, implying the versa-
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997
J. Am. Chem. Soc. 2021, 143, 9991−10004