Revisiting Arene C(sp2)?H Amidation by Intramolecular Transfer of Iridium Nitrenoids: Evidence for a Spirocyclization Pathway

Article abstract of DOI:10.1002/anie.201808892

Two mechanistic pathways, that is, electrocyclization and electrophilic aromatic substitution, are operative in most intramolecular C?H amination reactions proceeding by metal nitrenoid catalysis. Reported here is an alternative mechanistic scaffold leading to benzofused δ-lactams selectively. Integrated experimental and computational analysis revealed that the reaction proceeds by a key spirocyclization step followed by a skeletal rearrangement. Based on this mechanistic insight, a new synthetic route to spirolactams has been developed.

Full text of DOI:10.1002/anie.201808892

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Accepted Article
Title: Revisiting Arene C(sp2)-H Amidation via Intramolecular Transfer
of Iridium Nitrenoids: Evidence for a Spirocyclization Pathway
Authors: Sukbok Chang, Yeongyu Hwang, Yoonsu Park, Yeong Bum
Kim, and Dongwook Kim
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Revisiting Arene C(sp2)H Amidation via Intramolecular Transfer
of Iridium Nitrenoids: Evidence for a Spirocyclization Pathway
Yeongyu Hwang,[a,b,+] Yoonsu Park,[a,b,+] Yeong Bum Kim,[a,b] Dongwook Kim,[b,a] and Sukbok Chang[b,a, ]
*
Abstract: Two mechanistic pathways, i.e. electrocyclization and
electrophilic aromatic substitution, are operative in most of
intramolecular CH amination reactions via metal nitrenoid catalysis.
We now report an alternative mechanistic scaffold that benzo-fused
-lactams can be obtained selectively. Integrated experimental and
computational analysis revealed that the reaction proceeds via a key
spirocyclization step followed by a skeletal rearrangement. Based on
this mechanistic insight, a new synthetic route to spiro-lactams has
been developed.
The development of selective CH oxidation is of great interest in
the synthetic and medicinal chemistry.[1] In the nitrogen-atom
transfer reactions,[2] the success is frequently dependent on
leveraging highly reactive metal-nitrenoid intermediate to the
desired transformation with effective suppression of
decomposition pathways. While a number of elegant methods
have been developed with several amino precursors including
nitrogen ylides,[3] organic azides,[4] and hydroxylamines,[5]
construction of unprotected cyclic amides has been a remaining
challenge due to the uncontrollable decomposition of
carbonylnitrene intermediates to isocyanates via the Curtius-type
rearrangement.[6] In this regard, our group recently demonstrated
that cyclopentadienyl (Cp*)-based iridium catalysts can prevent
such
a
side pathway, thus facilitating the C(sp3)H
functionalization via a closed-shell pathway.[7]
We initially hypothesized that aromatic C(sp2)H amidation
might be viable because singlet nitrenoid species could be
engaged in a two-electron process. Indeed, two mechanistic
working modes are widely accepted in the aromatic amination
reactions (Scheme 1a). Driver and co-workers proposed a 4-
electron-5-atom electrocyclization pathway in the dirhodium-
catalyzed cyclization of aryl or styryl azides,[4a,b] which exclusively
gives 5-membered aza-heterocycles.[8] Another pathway includes
an electrophilic aromatic substitution (SEAr), mainly enabled by
electron-rich substituents on the arene moiety.[9] The Falck group
reported an unique example that offers 6-membered heterocycles
with compelling evidence on the SEAr mechanism.[5b]
While we briefly communicated the viability of aromatic CH
amidation with Cp*Ir(III) catalysts in our recent report,[7] generality
of the reaction was not explored in detail and consequently, the
origin on the efficiency and selectivity was barely understood.
Describe herein is a detailed analysis on the arene CH amidation,
where a new mechanistic insight is elucidated.
Scheme 1. Identification of a spirocyclization pathway in iridium-catalyzed CH
amidation enables the construction of spiro-lactam scaffold.
When a substrate bearing reactive sp2 CH bonds was subjected
to the amidation conditions, to our surprise, a -lactam product
was obtained selectively with unexpected skeletal rearrangement
(Scheme 1b), suggesting that the operating mode is different from
the conventionally accepted pathways. Indeed, our experimental
and theoretical analysis revealed that a tandem process of
spirocyclization and subsequent structural rearrangement via
CC bond migration is operative. Based on this mechanistic
insight, a preparative method for unprotected spiro-lactams is
now established (Scheme 1c), representing the first example of
utilizing the metal-nitrenoid catalysis.
We commenced our study by subjecting a dioxazolone
substrate 1 to the CH amidation conditions with expectation of
the formation of 2 via the widely-accepted SEAr pathway (Scheme
2). However, no cyclization product was formed with the iridium
catalyst Ir1 that was the most effective for the aliphatic sp3 CH
amidation leading to 5-memberd lactams.[7] This result led us to
screen an additional array of catalysts for the sp2 CH amidation.
Pleasingly, we observed that κ2-N,O chelators exhibited
significant improvement in reactivity (Ir2 to Ir5). In particular, a
catalyst bearing 8-alkoxyquinoline ligand (Ir5) was notable, and,
moreover, the introduction of two chloro groups at the C5,7-
position in the same ligand skeleton (Ir6) resulted in even higher
catalytic reactivity in hexafluoro-2-propanol (HFIP) solvent.
[a]
[b]
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea)
Center for Catalytic Hydrocarbon Functionalizations, Institute for
Basic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: sbchang@kaist.ac.kr
[+]
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
the document.
1
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To our surprise, a careful analysis of the obtained product
including single crystal XRD indicated that it is an isomeric 6-
membered lactam (3) rather than the expected one (2).[16] This
result suggested that the present cyclization proceeds via a
pathway that is distinct to the SEAr route.[5b,9] This unexpected
outcome led us to pursue the mechanistic understanding with
subsequent investigations on the substrate scope and synthetic
applications. It is noteworthy that the facile formation of 6-
membered azacyclic compounds has been regarded as a
challenge in the metal-nitrenoid transfer chemistry.[4a,b,9,10]
Scheme 3. Possible mechanisms to account for the unexpected rearrangement.
Spiro-lactam moiety in complex IV may subsequently
undergo two distinctive skeletal rearrangements via either C−C
(red line) or C−N (blue line) bond cleavage. TS calculations
revealed that the C−C migration is kinetically favored over the
C−N bond cleavage (0.93 kcal/mol). Furthermore, more
importantly, the C−N migration is thermodynamically uphill
process, whereas the C−C rearrangement gives more stable
intermediate. The C−N migrated complex III, which is the same
intermediate via SEAr pathway, is less stable than its former
complex IV by 9.3 kcal/mol, thus making this interconversion
reversible. As soon as III is formed, the reverse reaction to IV
would proceed through IV-TSCN with only 10.0 kcal/mol of barrier.
In sharp contrast, the C−C migrated complex V is more stable
than IV by 4.3 kcal/mol, and will give the experimentally-observed
product 3 via subsequent decoordination/aromatization. This
notable thermodynamic difference would be mainly due to direct
stabilization of generating carbocation by migrated nitrogen atom
in complex V.[12] The computational analysis pinpointed that the
stability of migration intermediates are important in the selective
structural rearrangement.
Scheme 2. Catalyst optimization and key observations. Reaction conditions: 1
(0.05 mmol), Ir catalyst (5 mol %), and NaBArF (5 mol %) in HFIP (0.6 mL).
4
NMR yields of the crude reaction mixture are shown.
To rationalize the unexpected regioselectivity observed in
the initial experiment, several mechanistic scenarios were taken
into account (Scheme 3). Upon the generation of a key Ir-nitrenoid
intermediate (II),[7] the SEAr mechanism can be firstly considered
(path a), but it will give only a lactam product 2 that was not
detected in the experiment. Another generally-accepted pathway
involving electrocyclization (Scheme 1a) is also less likely, since
the required -conjugation is not allowed in this substrate.[4a,b,8,10e]
Because the obtained product 3 shows a skeletal rearrangement
in the pre-existing (phenyl-alkyl) CC bond (migrated from para-
to OMe in 1 to meta- in product 3), we proposed an alternative
pathway that can furnish this unexpected isomer.
Inspired by a metal-free amination utilizing nitrenium ions to
give N-protected spiro-lactams or cyclic amides,[11] we supposed
a pathway involving iridium-mediated spirocyclization of II at the
electron-rich ipso-carbon to generate a spiro-amido intermediate
IV. Subsequent ring-expansion via either CN or CC bond
migration followed by rearomatization would provide lactam 2 or
3, respectively (Scheme 3, right side). Of note, a resultant product
from the CN bond migration will be 2, which is the same
compound that can be obtained from the direct SEAr. Given that
only 3 was exclusively obtained without detecting 2, we
speculated that the CC migration will be favored over the CN
rearrangement under the present iridium catalytic conditions.
To validate the mechanistic hypothesis, reaction energy
profiles for each working mode were evaluated by DFT
calculations. After forming a catalyst-substrate adduct I’, oxidative
decarboxylation requires 20.8 kcal/mol of activation energy to
generate Ir-nitrenoid species II. While II may traverse II-TS1 via
direct SEAr pathway with 9.7 kcal/mol of barrier (dashed lines),
spirocyclization pathway (II-TS2) to spiro-amido intermediate IV
is kinetically more accessible in 5.3 kcal/mol (bold line).
Figure 1. Reaction Energy Profiles for potential mechanisms at M06/SDD+6-
311+G**/PCM(dichloromethane)//B3LYP/Lanl2dz+6-31G** level of theory.
2
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The intermediacy of complex IV in the computational study
led us to attempt to isolate the putative spiro-lactam compound,
which itself is also of synthetic and medicinal interest.[13] We
envisaged that a dioxazolone substrate bearing para-hydroxyl in
lieu of methoxy group will allow the formation of aza-spirodienone
product based on the proposed pathway. To our delight, a
targeted spiro-lactam product 5a could be isolated in excellent
yield by using 2 mol % of Ir6 (Scheme 4). The structure of 5a was
confirmed by X-ray crystallographic analysis.[16] Again, this result
is fully consistent with our mechanistic proposal on the spiro-
lactam intermediacy (IV in Scheme 3).
To see the generality of this reaction, a range of substrates
having additional substituents were further examined under the
optimal catalytic conditions. The dearomative spirocyclization
took place in a highly efficient manner with phenol-based
dioxazolones with MeO- or Br groups (5b and 5c, respectively).
Derivatives having the same substituent at a different position
(4d) or bearing multiple substituents (4e) also underwent the
cyclization smoothly. A substrate prepared from N-protected
tyrosine was facile for the current cyclization to afford 5f in 91%
yield. Significantly, reactions of ortho-phenol or ortho-naphthol
substrates were quantitative to give the corresponding spiro-
lactams 6a and 6b, respectively. To our best knowledge, it
represents the first synthetic approach to spiro-lactams via a
metal-nitrenoid transfer process.[14] Importantly, free amides can
be directly accessed by our protocols, while most of classical
approaches require specific N-protecting groups.[11a,b]
Scheme 5. Extension to β-lactam and dispiro-indoline synthesis. Reaction
conditions: substrate (0.1 mmol), Ir catalyst (10 mol %), and NaBArF4 (10 mol %)
in HFIP (1.2 mL). [a] C6H5CF3 was used as a solvent.
Scheme 6. Substrate scope of benzo-fused -lactams with skeletal
rearrangements. Reaction conditions: substrate (0.1 mmol), Ir catalyst (2 mol %),
and NaBArF4 (2 mol %) in HFIP (1.2 mL). [a] CH2Cl2 was used as a solvent. [b]
5 Mol % catalyst was used. [c] 10 Mol % of catalyst was used.
Scheme 4. Substrate scope of dearomative spirocyclization reaction. Reaction
conditions: substrate (0.1 mmol), Ir catalyst (2 mol %), and NaBArF4 (2 mol %)
in HFIP (1.2 mL).
Having well understood the details on the amidation pathways,
scope of the substrates bearing substituents other than a hydroxyl
group was next investigated (Scheme 6). Various phenyl
substituents, such as alkoxy, alkyl, and halide groups, were all
compatible, and provided corresponding benzo-fused -lactams
via the analogous tandem process of spirocyclization and
following the CC bond migration (12a12c). However, the
reaction with CF3 substituent (11d) was not successful, possibly
due to its electronic property. The cyclization was found to be
selective in that a more electron-rich phenyl was reacted
exclusively (12e). On the other hand, when a methyl group is
substituted at the ortho-position, the cyclization gave a mixture of
two isomeric products 12f and 12f’ (1:1.2), suggesting that
competing pathways (direct SEAr or CN bond migration) might
The present procedure was further extended to the formation
of 4-membered spiro-lactams (Scheme 5a). Indeed, we were
pleased to observe that the highly strained spiro--lactam 8 with
10 mol % of the catalyst. Of note, a 5-membered cyclic amide that
can be formed via a direct SEAr pathway was not detected in the
present reaction. The current procedure was found to be
successfully applied to the reaction of indole derivatives (Scheme
5b). In this case, highly condensed dispiro-indoline products were
isolated under the identical conditions (10ab), and their
structures were confirmed by X-ray crystallographic analysis.[16]
These structurally unique compounds are likely formed via an
analogous dearomative spirocyclization followed by dimerization
of the resultant intermediate, although the dimerization
mechanism is remained elusive at the present stage.
3
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be simultaneously operative in a specific type of substrates (vide
infra). A sterically congested substrate having triphenyl moiety
underwent the cyclization without difficulty leading to 12g in
excellent yield. Naphthylethyl dioxazolone was also efficiently
amidated to afford tricyclic dihydroquinolinone (12h). Reaction of
ortho-bromo-substituted phenylethyl dioxazolone proceeded in
satisfactory yield (12i). Significantly, an analogous pathway is
likely operative in a 5-membered cyclization of 11j, and a skeletal-
rearranged indolinone product 12j was obtained in moderate yield.
It needs to be emphasized that this result is consistent with the
observation of the 4-membered spirocyclization (7 in Scheme 5a).
Keywords: CH amidation
rearrangement • iridium catalysis
•
spiro-lactams
•
skeletal
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Scheme 7. Substrates scope without skeletal rearrangement. Reaction
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[7]
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regioisomers 3 and 14a (1.2:1). These products can be formed
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substituted substrate 13b showed a similar product distribution
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In conclusion, we have elucidated the mechanistic details of
iridium-catalyzed arene CH amidation. Experimental and
computational analysis revealed that the reaction proceeds via a
tandem process of spirocyclization and following CC bond
migration instead of widely accepted pathways. Based on the
mechanistic findings, a highly efficient Ir-catalyzed synthetic route
to spiro-lactams and benzolactams is now developed for the first
time. This preparative process is anticipated to find its utility in
synthetic and medicinal chemistry.
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Acknowledgements
This research was supported by the Institute for Basic Science
(IBS-R010- D1). Single crystal x-ray diffraction experiments of
compound 3, 8, and 10a were performed at the BL2D-SMC in
Pohang Accelerator Laboratory with synchrotron radiation.
[15] See the Supporting Information for details
[16] CCDC 1859413 (3), 1859414 (5a), 1859411 (8), 1859416 (10a),
1859415 (10b), 1859410 (12i), and 1859412 (12j) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
4
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Entry for the Table of Contents (Please choose one layout)
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Yeongyu Hwang, Yoonsu Park, Yeong
Bum Kim, Dongwook Kim, and Sukbok
Chang*
Page No. – Page No.
Title
Revisiting Arene C(sp2)H Amidation via
Intramolecular Transfer of Iridium
Nitrenoids: Evidence for a
Spirocyclization Pathway
A tandem process of spirocyclization and subsequent skeletal rarrangement
was elucidated as a working mode in the Ir-catalzyed arene C(sp2)H amidation of
phenylalkyl dioxazolones. This mechanistic insight led us to develop an Ir-catalzyed
efficient and selective synthetic route to spiro-lactams and benzolactams.
.
5
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