Visible-Light-Assisted Gold-Catalyzed Fluoroarylation of Allenoates

Article abstract of DOI:10.1002/anie.201916471

A strategically novel synthetic method for the fluoroarylation of allenic ester was developed that enables the expedient construction of a host of β-fluoroalkyl-containing cinnamate derivatives. The reaction proceeds through visible-light-promoted gold redox catalysis, occurs smoothly under very mild reaction conditions, accommodates a large variety of functional groups, and more importantly allows the incorporation of fluorine and aryl groups with excellent regio- and stereoselectivity. The concomitant activation mode for both the allene motif and the hydrogen fluoride is key for the success of the reaction.

Full text of DOI:10.1002/anie.201916471

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Accepted Article
Title: Visible Light-Assisted Gold-Catalyzed Fluoroarylation of
Allenoates
Authors: Hai-Jun Tang, Xinggui Zhang, Yu-Feng Zhang, and Chao
Feng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201916471
Angew. Chem. 10.1002/ange.201916471
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Visible Light-Assisted Gold-Catalyzed Fluoroarylation of
Allenoates
Hai-Jun Tang, Xinggui Zhang, Yu-Feng Zhang, Chao Feng*
Abstract:
A
strategically novel synthetic method for the
with nucleophilc fluorination reagent. Shortly afterwards, an
inspiring work of chelation assisted palladium catalyzed
fluoroarylation of styrene derivatives was reported by Toste and
fluoroarylation of allenic ester was successfully developed, which
enables an expedient construction of a host of β-fluoroalkyl-containing
cinnamate derivatives. By resorting to visible light-promoted gold
redox catalysis, this reaction proceeds smoothly under very mild
reaction conditions, accommodates a large variety of functional
groups, and more importantly allows the incorporation of fluorine and
aryl groups in excellent regio- and stereoselectivity. The concomitant
activation mode for both allene motif and hydrogen fluoride is ascribed
as the key for the success of this reaction.
coworkers, albeit using expensive Selectfluor as the fluorination
reagent (Scheme 1a).[
3a]
Recently, our group achieved a
straightforward construction of 1,1,1-trifluoro-2-arylalkane
derivatives by resorting to palladium-catalyzed crossing coulping
of aryl iodides with in situ generated organosilver intemediate
(Scheme 1b).[ Notwithstanding the notable advancement
obtained in this direction, the reported reactions still suffer from a
sort of limitations, such as restricted reaction generality, the
employment of expensive fluorination reagents, and also the
unavoidable formation of accompanying regioisomers in some
cases. To ameliorate this situation, the development of novel
synthetic protocols for fluoroarylation reactions is still highly
desirable, especially for those that make use of cost-effective
nucleophilic fluorination reagents.
8]
The site-selective incorporation of fluorine atom into organic
molecules would bring forth a fundamental change on the
physicochemical properties of the parent molecules by
modulating conformations, enhancing metabolic stabilities, and
also strengthening the binding affinities to specific protein targets.
As such, the invention of effective synthetic methods for the
accomplishment of regioselective introduction of fluorine atom
into diverse molecular frameworks has been attracting increasing
interest in fields of medicinal chemistry and drug development.[1]
Among current state of the art for building fluorinated
architectures, the carbofluorination of π-systems, which adds one
more flexible dimension for rapid generation of molecular
complexity, is highly appealing.[2-6] Within this domain,
tremendous efforts from the synthetic community have, over the
past decade, substantially enriched the diversity of reaction type,
enabling
a
concomitant incorporation of carbon-based
functionalities such as alkyl,[2] aryl,
[3]
alkynyl,
[4]
cyano,
[5]
alkoxycarbonyl[ groups into the target molecules. By judiciously
integrating the ease of carbon radical generation, either using
transition metal catalysis or photocatalysis, with productive
fluorination techniques, considerable progress has definitely been
attained in the arena of fluoroalkylation reactions,[2f-j] although
most of the reported methods still show a heavy reliance on the
use of electrophilic fluorination reagents.[7] However, the
fluoroarylation counterpart is comparatively underdeveloped,
probably due to relative lack of efficient avenues for the easy
production of aryl radical intermediates.[3h-k]
6]
In 2013, Gouverneur and coworkers successfully developed
an intriguing intramolecular fluoroarylation protocol by taking
advantage of the activation of alkene double bond with
[
3g]
electrophilic fluorination reagent. Using AgF as the fluoro donor,
an elegant work of palladium-catalyzed fluoroarylation of allenes
was disclosed by Doyle and coworkers in the same year,[3n] which
represents a rare example of accomplishing this type of reaction
Scheme 1. Intermolecular fluoroarylation of unsaturated π systems
Enlightened by the venerable transformation of
[
9]
hydrofluorination of alkenes using HF-complexes, we envisaged
the possibility of uncovering a novel fluoroarylation protocol for
the elaboration of unsaturated π-systems through electrophilic
[
*]
H. J. Tang, X. Zhang, Y. F. Zhang, Prof. Dr. C. Feng
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, 30 South Puzhu
Road, Nanjing 211816, P. R. China
activation of double bond with aryl cation equivalents.[
10,11]
In this
E-mail: iamcfeng@njtech.edu.cn
III
regard, Ar-Au intermediates attracted our attention, whereas the
pioneering reports from the groups of Glorius , Toste and Hashmi
revealed the ease of generating such high valent gold complexes
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.2017xxxxx.
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COMMUNICATION
through
photo-induced
denitrogenative
activation
of
revealed conducive to the reaction efficiency. After further
screening, the isolated yield of product 3aa could be promoted to
70% by using a mixed solvent of MeCN/DCE while increasing the
aryldiazonium.[11] With our continuing interest in photoredox
catalysis and fluorine chemistry,[12] herein, we would like to report
an unprecedented protocol for the fluoroarylation of allenic ester
utilizing visible light-promoted gold redox catalysis (Scheme 1c).
Several notable features regarding this transformation is worth
pointing out: i) it represented the first example of using fluoride as
a competent nucleophile in the visible light-promoted gold redox
catalysis and also a very rare case of carbofluorination protocol
without recourse to electrophilic fluorination reagents; ii) structural
motif with fluoro-containing quarternary carbon centers could be
easily accessed;[13] iii) the introduction of both fluorine and aryl
groups proceeded in a highly regio- and stereoselective manner,
with the installation of aryl group on the same side of ester
functionality.
3
amount of 2a and Et N·3HF (Table1, entry 11). Under this
conditions, the major by-product was identified as biphenyl
derivative, which was isolated in only 4% yield, along with the
generation of trace amount of aryl fluoride. It is worth mentioning
that the replacement of ester group in 1a by cyano, phenyl,
sulfone, or employment of aliphatic allenes instead, led to a
dramatic inhibition of such transformation,[16] which further
implicated the important role of ester functionality in ensuring the
success of this reaction. Further control experiment carried out
under the optimized reaction conditions but without light
irradiation, however, led to the generation of 3aa in only 5% yield
(Table1, entry 12). What needs to be emphasized is that, while 5-
endo-trig cyclization of allenoates is prevailing under gold
catalysis, no such byproduct was observed in this scenario.[
Having established the optimized reaction conditions, we
turned our attention to evaluate the reaction scope with respect to
allenoates (Scheme 2). It was found that allenoates with diverse
ester fragments were well tolerated, giving rise to the desired
products 3ba-3la in moderate to good yield. In the case of
epiandrosterone-derived allenoate 3m, the reaction proceeded
smoothly to furnish product 3ma in 55% yield. Moreover,
allenoate substrates with a variety of aromatic substituents,
differing in either electronic or steric properties, were all tolerated,
delivering the desired products 3na-3ta in moderate yields.
Interestingly, allenoate derivatives bearing single alkyl substituent
on the γ-position were also disclosed to be competent substrates,
although the reaction yields were somewhat attenuated as in the
case of 3ua. In comparison, γ,γ-dialkyl substituted allenoates 1v
and 1w were especially propitious to the fluoroarylation, probably
due to the enhanced ability to accommodate the nascent partial
positive charge when activated by gold intermediate. The superb
adaptability of γ,γ-dialkyl substituted allenoates in this
transformation further underlies the prospect of this scenario as
an expedient synthetic protocol for the assembly of structural
motif with fluoro-containing quarternary carbon centers. To further
challenge the applicability of this reaction, allenoate 1x bearing
an allyl substituent on the γ-position was examined, which
underwent fluoroarylation chemoselectively without affecting the
allyl fragment, gaving rise to the desired product 3xa in 50% yield.
Di-aryl containing allenoate such as 1z was also compatible to
this reaction, albeit affording the desired product 3za in 32% yield.
To further probe the influence of the terminal substituents on the
reaction efficiency, γ-alkyl-γ-aryl-substituted allenoates were
subjected to the optimized conditions, which afforded the desired
product in good yields (3ya, 3aaa-3aea). Owing to the mild
reaction conditions employed, sensitive functional group such as
benzylic bromide in the case of 3aba is well tolerated. The
compatibility of this reaction was further showcased by the nice
applicability of cyclic γ,γ-disubstituted allenoate derivatives, which
enables a smooth construction of structural motifs with diverse
ring-containing fluoro-substituted quaternary centers (3aga-3aka).
Subsequently, the reaction generality with regard to
aryldiazonium salts was interrogated using 1v as the model
reaction partner. Specifically, halogenated aryldiazonium salts
reacted selectively to afford products 3vb-3ve, thus providing
additional handles for further derivatization through traditional
Table 1. Optimization of reaction conditions.[a]
17]
Entry
catalyst
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
DMF
fluoride
yield
48b
1
2
3
4
5
6
7
8
9
Ph
3
3
PAuCl
PAuCl
-
Et
Et
Et
Et
3
3
3
3
N·3HF
N·3HF
N·3HF
N·3HF
42b,c
Ph
NR
15b,d
NDP
NDP
NR
Ph
3
Ph
3
Ph
3
Ph
3
Ph
3
PAuCl
PAuCl
PAuCl
PAuCl
PAuCl
pyridine·HF
DMPU·HF
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
N·3HF
N·3HF
N·3HF
N·3HF
N·3HF
N·3HF
NR
XPhosAuCl
[Ph PAu]NTf
2
MeCN
MeCN
MeCN
MeCN
NR
19b
10
11
12
3
70e,f
Ph
3
3
PAuCl
PAuCl
5%e,d
Ph
[
a] Unless otherwise noted, the reaction was conducted with 1a (0.1
mmol), 2a (1.5 equiv), Et 3HF (3.0 equiv), Ph PAuCl (10 mol%),
MeCN (1.0 mL). [b] Yield was determined by F NMR with 1-iodo-4-
3
N·
3
1
9
(trifluoromethyl)benzene as internal standard. [c] Ru(bpy)
3
6 2
(PF ) (2.5
mol%) was added. [d] No blue LEDs. [e] 2a (2.0 equiv), Et
equiv), Ph
yield.
3
N·3HF (10.0
3
PAuCl (20 mol%), MeCN/DCE(0.3 mL/0.2 mL). [f] Isolated
On the basis of our hypothesis, we were pleased to find that
allenic ester 1a was the viable substrate and the reaction carried
out by irradiating a mixture of 1a with 1.5 equivalent of 2a, using
Ph
MeCN led to the formation of desired product 3aa in 48% yield
Table1, entry 1). Intriguingly, 3aa was formed in high regio- and
3 3
PAuCl, Et N·3HF as catalyst and fluorination reagent, in
(
stereoselectivity with the aryl group installed on the same side of
ester group, thus indicating that the ester functionality may, to
some extent, function as the directing group.[14] Of note, the
addition of extra photocatalyst such as Ru(bpy)
lead to further enhancement of reaction yield (Table1, entry 2).
3 6 2
(PF ) did not
[
15]
Control experiments showed that the gold catalyst was
indispensable in this transformation, whereas light irradiation was
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Scheme 2. Reaction scope. All reactions were conducted out in 0.1 mmol scale. [a] gram-scale reaction.
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coupling regimes. Meanwhile, arenediazonium substrates with
To further corroborate the alternative activation mode, the
hypothetically active Ar-AuIII complex II’ was independently
prepared using reported method.[ The finding that complex II’
not only underwent stoichiometric reaction with 1q but also acted
as effective catalyst for the reaction between 1q and 2n strongly
electron-withdrawing group such as carbonyl, CF
well suited and delivered the desired products in excellent yield
3vf-3vp). Also of note, electron-donating/neutral substitutents
3 2
, CN, NO were
19]
(
were also compatible despite somewhat attenuated reactivity
compared with that of electron-deficient ones (3vq-3vw). The
amenability of condensed arenediazonium substrate and those
embodying heterocycles in this vein further exemplified the wide
compatibility of this protocol (3vu-3vw). To further challenge the
applicability of this reaction, arenediazonium salts derived from
natural products such as L-menthol, vitamin E and estrone were
III
supports the involvement of Ar-Au intermediate (Scheme 3b, 3c).
It is also worth noting that in both catalytic and stoichiometric
experiments employing complex II’, the addition of extra AgBF
4
was required for productivity, which implicates the vital
importance of cationic character of high-valent gold complex. To
further probe the reaction profile, enantiomerically enriched ethyl
4-phenylbuta-2,3-dienoate (S)-1c (65% ee) was tested, which
afforded the desired product (S)-3ac in 52% yield and 43% ee
(Scheme 3d). This outcome reveals that the distal double bond
was functionalized through a concomitant activation mode: the
activation of allenic system by Ar-AuIII species occurred on the
side opposite to the ester group, whereas the accompanying HF
activation (through hydrogen bonding interaction with ester
functionality) as well as nucleophilic attack of fluoride happened
on the other side.[20,21] The erosion of stereochemistry in terms of
chirality transfer precludes a simply concerted process, but
instead indicates the possibility of involvement of a bent allene-
gold complex.[ Furthermore, in order to rationalize the outcome
of stereoselectivity for the generation of (E)-configuration product
in this scenario, a double bond isomerization process was
anticipated to be integral to the whole transformation. In order to
further distinguish whether the isomerization happens as part of
the catalytic cycle or as an independent process, (Z)-3alq was
added as an indicator to the reaction between 1q and 2a under
standard reaction conditions. After reaction, (Z)-3alq was
recovered without geometry perturbation, which firmly indicates
the on-cycle isomerization manifold (Scheme 3e).
tested.
Gratifyingly,
these
natural
products-derived
arenediazonium engaged in the fluoroarylation without any
complication (3vx-3vz), thus granting a higher level of mode for
creating molecular complexities. As presented in Scheme 2,
some examples provided the fluoroarylation products in only
moderate reaction yields, the generation of oligomerization side
product of allenoates was ascribed as the main reason and also
accounted for the mass balance of these transformations.
To shed more light on the reaction mechanism, a handful of
control experiments were conducted. Initially, to distinguish the
mode of activation of allenic ester, either by Au(I) or Au(III)
22]
3
species, the control experiment between 1q and Et N·3HF was
carried out in the absence of arenediazonium salt, which resulted
in no formation of anticipated hydrofluorination product, thus
virtually disfavoring the Au(I) activation scenario (Scheme 3a).[18]
Based on the experimental results, a tentatively proposed
reaction mechanism for this reaction was put forwards (Scheme
4). Initially, the Au(I) complex I undergoes light-promoted
oxidative addition with arenediazonium salt 2 to deliver the high-
valent gold complex II.[
19,23,24]
The subsequent coordination of
gold complex II with allenic ester 1 from the orientation opposite
to the ester group would lead to the formation of intermediate III.
Then, hydrogen fluoride would come in and integrate with
intermediate III through hydrogen bonding with the ester group to
Scheme 4. Proposed reaction mechanism
Scheme 3. Mechanistic studies
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Angewandte Chemie International Edition
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COMMUNICATION
afford intermediate IV, thus setting the stage for the well-
organized nucleophilic fluorination to provide alkenyl gold
complex V. Thereafter, a convenient double bond isomerization
followed by reductive elimination would give rise to the desired
product 3 while regenerating the Au(I) complex I.
In conclusion, a novel synthetic protocol for achieving
fluoroarylation of allenic ester through visible light-promoted gold
redox catalysis was successfully developed. The concomitant
activation of allene motif by high-valent gold complex and
hydrogen fluoride by hydrogen bonding with ester group, which
provides a well-organized assembly for the ensuing fluoro-
incorporation, is the key to the success of this reaction. Notably,
this transformation features high regio- and stereoselectivity,
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Ar-Au complex is demonstrated to be the active intermediate
responsible for the activation of allenic ester. Moreover, further
expanding the amenability of fluoroarylation protocol to other π-
systems is underway in our laboratory.
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H.-J. Tang, X. Zhang, Y.-F. Zhang, C.
Feng*
Page No. – Page No.
Visible Light-Assisted Gold-Catalyzed
Fluoroarylation of Allenoates
A regio- and stereoselective fluoroarylation of allenic ester through visible light-
promoted gold redox catalysis with cost-effective Et N·3HF as nucleophilic fluorine
3
source is reported. Preliminary mechanistic study reveals a concomitant activation
mode of allene motif by high-valent gold complex and hydrogen fluoride by hydrogen
bonding with ester group, enabling the otherwise challenging fluoro-incorporation.
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