Fluorine Effects on Group Migration via a Rhodium(V) Nitrenoid Intermediate

Article abstract of DOI:10.1002/anie.201708505

An unprecedented rhodium(III)-catalyzed hydroarylation of α,α-difluoromethylene alkynes with N-pivaloxyl aroylamides through sequential C?H activation and aryl migration is detailed herein. A large array of α,α-difluoromethylene alkynes and N-pivaloxyl aryl amides were amenable to this transformation, thus providing a novel synthetic protocol for the construction of difluorinated 2-alkenyl aniline derivatives in high yields and with excellent regioselectivity. Notably, unique fluorine effects were found to underlie the thus unconventional reaction manifold.

Full text of DOI:10.1002/anie.201708505

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Accepted Article
Title: Fluorine Effects on Guiding Group Migration via Rh(V) Nitrenoid
Intermediate
Authors: Cheng-Qiang Wang, Yu Zhang, and chao feng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708505
Angew. Chem. 10.1002/ange.201708505
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Fluorine Effects on Guiding Group Migration via Rh(V) Nitrenoid
Intermediate
Cheng-Qiang Wang, Yu Zhang and Chao Feng*
Abstract: An unprecedented Rh(III)-catalyzed hydroarylation of α,α-
difluoromethylene alkynes with N-pivaloxyl aroylamides through
sequential C−H activation and aryl migration was detailed herein. A
large array of α,α-difluoromethylene alkynes and N-pivaloxyl
aroylamides were well amenable to this transformation, providing a
novel synthetic protocol for the construction of difluorinated 2-
alkenylaniline derivatives in high yields and excellent regioselectivity.
Notably, the unique fluorine effects were uncovered to underlie the
thus unconventional reaction manifold.
substituent. It is worth noting that previous reports have revealed
N-pivaloyloxyl amides as the privileged substrates for C−H
activations,[ which engage alkynes in [4+2] annulation reactions
via alkenyl group migration and protonation almost without
exception (Scheme 1a).[ Experimental endeavors substantiate
that the introduction of fluorine atoms adjacent to the alkyne group
has engendered dual roles in such transformation: i) inducing the
polarization of alkyne functionality, which in turn guarantee the
otherwise nontrivial regioselective migratory insertion in the case
of unconjugated alkyne substrates; ii) the induction effect of
12]
13]
fluorine substituents detracts from the migratory aptitude of
alkenyl moiety in the key Rh(V) nitrenoid intermediate,[14] thus
favoring the competing aryl group migration. Of note, the unique
fluorine effects being explicitly capitalized upon underpin the
feasibility of this fundamentally novel synthetic transformation
Fluorine-containing organic compounds constitute a rich resource
for discovering lead candidates that possess unique
[
1]
physiochemical and biological properties. Consequently, the
development of new synthetic methods for the introduction of
fluorinated fragments into organic molecules is gaining increasing
attention from the synthetic community,[2] however, the
inconsistent reactivity profile of fluorinated reagents with that of
the non-fluorinated congeners should not be underappreciated.[3]
The fluoroalkylation reaction, which allows a direct incorporation
of fluorine-containing alkyl fragments, proves to be a fertile
domain for the expedient construction of organofluorine
molecules.[ Continuing efforts in this direction have eventually
(
Scheme 1b). It is also worth mentioning that despite the boom of
[15]
chelation assisted C−H bond functionalizations, reactions that
integrate the ensuing elaboration of otherwise inert directing-
groups via skeletal rearrangement or reorganization remain far
less developed.[14c,16] Nevertheless, the accomplishment of such
strategy would not only be of synthetic importance but bring forth
new insight and far-reaching influence to the C−H activation
chemistry.
4]
led to
a
plethora of direct C−H bond fluoroalkylations.[5]
Notwithstanding the advance obtained, the majority of efforts
have been paid to the fluoroalkylation of arene derivatives with
little attention being drew to the development of novel synthetic
strategies that entail easy access to alkenyl fluoroalkane
architectures.[
6]
As an important class of structural motifs that found
widespread use in synthetic chemistry, ortho-alkenylated aniline
derivatives and their preparation have attracted considerable
attention from organic chemists.[7] The well-known Suzuki,
Mizoroki-Heck couplings, Fujiwara-Moritani reaction, directing
group assisted dehydrogenation coupling and hydroarylation of
alkyne represent the main current strategies.[8-11] While
synthetically enabling, prominent limitations with respect to these
protocols still remain, such as the requirement of substrates pre-
functionalization, stoichiometric amount of external oxidants
and/or harsh reaction conditions. Therefore, the development of
novel and efficient synthetic protocols which allow the
straightforward access to these structural motifs is still highly
desirable. Herein, we would like to report the first example of
fluorine effects induced skeleton rearrangement associated
hydroarylation of internal alkynes, a scenario that not only nicely
fulfills those synthetic demands but more importantly elicits an
unprecedented reactivity divergence engendered by the fluorine
Scheme 1. The dichotomy of group migration in Rh(V) nitrenoid intermediate.
[
*] C.-Q. Wang, Y. Zhang, Prof. Dr. C. Feng
Institute of Advanced Synthesis (IAS), School of Chemistry and
Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials (SICAM)
Initially, the model reaction between N-pivaloyloxyl
benzamide 1a and gem-difluoromethylene alkyne 2a was tested.
After extensive screening of reaction parameters, we found that
Nanjing Tech University
30 South Puzhu Road, Nanjing 211816, P. R. China
4
aaa could be generated in 92% isolated yield when using 2 mol%
E-mail: iamcfeng@njtech.edu.cn
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[
RhCp*Cl
MeOH (3a) at ambient temperature. The structure of compound
aaa was confirmed by X-ray analysis.[18] With the optimal
2 2
] and 30 mol% CsOPiv as the catalyst system in 0.2 M
[
17]
4
reaction conditions in hand, the substrate scope of alcohols was
investigated. Most saturated aliphatic alcohols were able to be
integrated into the desired products in good to high yields (4aaa-
i
4
aah), except PrOH which afforded compound 4aae merely in 40%
yield even at elevated temperature probably because of the steric
hindrance (Scheme 2). Besides, alcohols bearing alkenyl groups
also proved to be good candidates for this conversion (4aai-4aaj),
which indicates the high functional group compatibility of this
procedure. To our delight, alcohols containing heterocycles, such
as furan and tetrahydrofuran, were also amendable to this
protocol, delivering 4aak and 4aal in 71% and 72% yield,
respectively. Interestingly, product 4aam as well as a trace
amount of difunctionalization product were generated when
ethane-1,2-diol was employed. Moreover, methoxyl, ester and tri-
substituted amine were also well tolerated in this transformation
(4aan-4aap). Of note, chiral 2-methylbutan-1-ol performed well to
afford the desired product 4aaq in 77% yield.
Scheme 3. Reaction scope of N-pivaloyloxyl amides and alkynes. Unless
otherwise noted, the reactions were carried out at room temperature using 1
(0.1 mmol), 2 (0.12 mmol), [Cp*RhCl
2 2
] (0.002 mmol), CsOPiv (0.03 mmol) in
3a (MeOH) (0.5 mL) for 12 h and the isolated products were listed. [a] Reaction
temperature was 80 °C. [b] Reaction temperature was 50 °C. [c] [4+2]
annulation product was formed in 33% yield.
Scheme 2. Reaction scope of alcohols. Unless otherwise noted, the reactions
were carried out at room temperature (28 °C) using 1a (0.1 mmol), 2a (0.12
*
mmol), [Cp RhCl
2
]
2
(0.002 mmol), CsOPiv (0.03 mmol) in 3 (ROH) (0.5 mL) for
12 h and the isolated products were listed. [a] Reaction temperature was 80 °C.
3
when 1n containing a p-CF group was employed, the reaction
resulted in the generation of the desired product 4naa in 38%
yield and [4+2] annulation product 5na in 33% yield.[17,19] In
addition, when meta-substituted substrates were employed,
reactions occurred selectively at less hindered site (4caa, 4eaa,
The reaction generality of N-pivaloyloxyl amides and α,α-
difluoromethylene alkynes were subsequently examined
Scheme 3). It was found that a broad range of N-pivaloyloxyl
amides bearing electron-releasing groups at meta- or para-
position were well tolerated, and the corresponding products were
isolated in modest to excellent yields (4baa-4haa). Amides
equipped with alkene or alkyne moieties also turned out to be
proper candidates, giving products 4jaa and 4kaa in moderate
yields. Electron-deficient N-pivaloyloxyl amides (1l-1p) afforded
the desired products in slightly diminished yields. Surprisingly,
(
4iaa, 4jaa, 4oaa, 4qaa-4saa). As expected, Br and I were well
tolerated, enabling further elaboration through conventional
cross-coupling reactions. Furthermore, potentially bioactive
indole derivative was also compatible and afforded 4raa in 55%
yield. What particularly worth mentioning was that estrone-
derived substrate 1s worked nicely and provided 4saa in 80%
yield, indicating the applicability of this protocol to the late-stage
modification of complex molecules. With respect to the alkyne
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reaction partner, most of the gem-difluoroalkyne derivatives listed
in Scheme 3 engaged in such transformation smoothly and a wide
variety of functionalities including alkyl, ether, ester, acetal,
hydroxyl, phthalimidyl all proved to be nicely accommodate, which
corroborates the generality of this transformation. It also needs to
point out that aryl alkyne was also amenable to this reaction, albeit
with somewhat diminished reaction efficiency as the formation of
Based on the experimental results, a plausible mechanism
was proposed in Scheme 5. Initially, the coordination of amide 1
with active Rh(III) catalyst would trigger ortho C−H bond cleavage
to form the five-membered rhodacycle I. Subsequently, the Rh−C
bond of cyclic complex undergoes regioselective insertion into the
alkyne 2, delivering the seven-membered rhodacycle II, wherein
the regioselectivity profile hinges upon the inherent polarity of α,α-
difluoromethylene alkyne 2. Then, the migration of OPiv from N to
Rh through a five-membered ring transition state yields the Rh(V)
nitrenoid intermediate III.[20] At this juncture, two competing
reaction pathways could be envisioned: i) the conventional
avenue delivers the [4+2] annulation product 5 via intermediated
VI which arises from alkenyl group migration (path b); ii) the
dearomative ipso-attack of arene group affords cationic
intermediate IV, which is labile to alcohol nucleophilic addition
induced rearomatization through C−C bond cleavage to afford six-
membered rhodacycle V. The ensuing protodemetalation of V
product
4aoa.
Whereas
reaction
between
α,α,α-
trifluoromethylene alkyne 2p and amide 1a afforded the desired
product 4apa in 83% yield, no reaction occurred by using mono-
fluorine substituted alkyne 2q as reaction partner.[17]
To gain deep insight into the reaction mechanism, a series of
control experiments were carried out (Scheme 4). Competing
experiment between amide 1b and pentadeuterated counterpart
1
b-d
would be involved as the rate-determining step. The incorporation
of 75% deuterium at the vinylic position of product 4aaa-d was
observed when the model reaction was conducted with CD
as reaction solvent, implicating the involvement of
5
led to a KIE value of 4.2, indicating that C−H bond cleavage
4
3
OD
a
allows the formation of product 4 accompanied by the
regeneration of active Rh(III) catalyst (path a). The overwhelming
production of aryl migration product 4 is attributed to the inherent
property of fluorine substituent which results in the attenuation of
the magnitude of alkenyl group migration, considering from both
its electronic and steric effects. Furthermore, the electronic effect
of the substituent on the aryl of amide substrate closely correlating
to the reaction efficiency is also in nice accordance with the
proposed reaction mechanism.
protodemetallation step at the vinylic carbon atom. [17] In order to
distinguish whether the Lossen-rearrangement occurs before or
after the C−H bond activation step, methyl phenylcarbamate 1t
was subjected to the standard reaction conditions with 2a, which,
however, resulted in only starting materials recovery (eq. 1). In
addition, no rearrangement of 1a occurred in the absence of 2a.[17]
It was also found that the conventional [4+2] annulation product,
such as 5aa, could not be transformed into the desired
hydroarylation product under standard conditions, which firmly
precludes its intermediacy in the catalytic cycle (eq. 2). To further
probe the role of fluorine effects in this intriguing transformation,
an extra couple of experiments were examined. The reference
reaction between amide 1a and alkynone 2r afforded only the
normal [4+2] annulation product 6ar, with no hydroarylation
product being observed (eq. 3). The contrasting outcomes of
chloro- and fluoro-based alkyne substrates engaged reactions
further substantiated involvement of fluorine effects in this
reaction (eq. 4).
Scheme 5. Proposed reaction mechanism.
In summary, by taking advantage of Rh(III)-catalyzed C−H
activation of N-pivaloyloxyl aroylamides, a straightforward and
efficient protocol for the synthesis of difluorinated 2-alkenylaniline
derivatives was developed. The fluorine substituents in alkyne
substrates were revealed to be essential for diverting the reaction
sequence from conventional avenue, thus securing the
aforementioned
Lossen-rearrangement
associated
hydroarylation process. Moreover, this reaction proceeds under
mild and oxidant-free reaction conditions with a wide spectrum of
functionalities being well accommodated. Additionally, the
intriguing role of fluorine effects in this transformation provides a
Scheme 4. Mechanistic studies.
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Keywords: C-H bond activation• rhodium • hydroarylation •
fluorine effects • Lossen-rearrangement
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C.-Q. Wang, Y. Zhang, C. Feng*
Page No. – Page No.
Fluorine Effects on Guiding Group
Migration via Rh(V) Nitrenoid
Intermediate
By taking advantage of Rh(III)-catalyzed hydroarylation of α,α-difluoromethylene
alkynes with N-pivaloyloxyl aroylamides, a straightforward and efficient protocol for
the regiospecific synthesis of difluorinated 2-alkenylaniline derivatives was
developed. The fluorine substituents in alkyne substrates were revealed to play an
essential role in diverting the reaction sequence from conventional avenue, thus
securing the nontraditional Lossen-rearrangement associated hydroarylation
process.
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