The ortho-Difluoroalkylation of Aryliodanes with Enol Silyl Ethers: Rearrangement Enabled by a Fluorine Effect

Article abstract of DOI:10.1002/anie.201900745

Presented herein is an intriguing effect of fluorine, and it allows difluoroenol silyl ethers to couple with aryliodanes in a redox-neutral manner to afford ortho-iodo difluoroalkylated arenes. The remaining iodide group provides a versatile platform for converting the products into various valuable difluoroalkylated arenes. The reaction shows excellent functional-group compatibility and broad substrate scope. A DFT mechanistic study suggests that the fluorine effect facilitates a subtle nucleophilic attack of the oxygen atom of enol silyl ethers onto aryliodanes, therefore leading to a rearrangement.

Full text of DOI:10.1002/anie.201900745

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Accepted Article
Title: ortho Difluoroalkylation of Aryliodanes with Enol Silyl Ethers
through a Rearrangement Enabled by a Fluorine Effect
Authors: Xin Huang, Yage Zhang, Chaoshen Zhang, Lei Zhang, Ying
Xu, Lichun Kong, Zhi-Xiang Wang, and Bo Peng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900745
Angew. Chem. 10.1002/ange.201900745
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ortho Difluoroalkylation of Aryliodanes with Enol Silyl
Ethers through a Rearrangement Enabled by a Fluorine Effect
Xin Huang+, Yage Zhang+, Chaoshen Zhang+, Lei Zhang, Ying Xu, Lichun Kong, Zhi-Xiang Wang,* Bo
Peng*
Dedication ((optional))
Abstract: Herein, we unravel an intriguing effect of fluorine which
allows difluoroenol silyl ethers to couple with aryliodanes in a redox-
neutral manner, affording ortho-iodo difluoroalkylated arenes. The
remaining iodide group provides a versatile platform for converting
the products into various valuable difluoroalkylated arenes. The
reaction shows excellent functional group compatibility and broad
substrate scope. DFT mechanistic study suggests that the fluorine
effect tunnels a subtle nucleophilic attack of the oxygen of enol silyl
ethers to aryliodanes, therefore, accomplishing a rearrangement
process.
Hypervalent iodine compounds are readily available, versatile
and environmentally benign reagents for organic synthesis.1
Chemists have devoted a substantial amount of efforts to
develop new reactions using these reagents. In particular, the
iodine(III)-mediated oxidative couplings of enol silyl ethers
(ESEs) with various nucleophiles have produced a diverse
family of α-functionalized carbonyl compounds (Scheme 1a).2,3
This type of reactions has experienced significant advances in
the past three decades. Although the mechanism still remains
elusive, the umpolung of ESEs by aryliodanes is generally
accepted as a key step in these transformations (Scheme 1a).2a-
2c
Under the oxidation effect of hypervalent iodine reagents, the
conventionally nucleophilic ESEs can react with itself or other
nucleophilic coupling partners to form the self-coupling
Scheme 1. Background and initial results.
products2e,2f or other α-functionalized carbonyls2b-2d with phenyl
iodides as wasted byproducts. In contrast to the well-established
produce α-allyl carbonyls.2b Inspired by their protocol, we
reaction pattern, we present herein a new cross-coupling
reaction between aryliodanes and difluoroenol silyl ethers
assumed that sequentially treating highly electrophilic PhI(OTf)2
(in situ generated from PhI(OAc)2/TMSOTf)6 with DFSE 2a and
allyl trimethylsilane could afford α-allylic-α,α-difluorinated ketone
(DFSEs) in which aryliodanes not only serve as an oxidant but
also act as a coupling partner (Scheme 1b).4 Accordingly, the
reaction provides a new strategy for synthesizing ortho-iodo
removing the benzoyl group via Haller-Bauer reaction.7 To our
difluoroalkylated arenes in a metal-free and redox-neutral
manner. Moreover, due to the presence of an iodide group,
3 (Scheme 1c), thus accessing C-difluoromethylated products by
surprise, in lieu of the expected product, the reaction afforded
ortho-difluoroalkylated aryl iodide 4aa in a modest yield (52%).
This intriguing switch in the reaction pathway is of great interest.
To the best of our knowledge, there have been no reports of
these compounds can further serve as synthons for accessing
biologically attractive difluoroalkylated arenes.5
Recently, Szpilman and coworkers demonstrated that
aryliodane-umpoled ESEs could be trapped by allylsilanes to
cross-coupling reactions between aryliodanes and ESEs to date.
However, it should be noted that Maulide and coworkers
reported an elegant protocol for the cross-coupling of aryl
sufloxides with enol silyl ethers.8 In addition, Shafir and
coworkers accomplished α-(ortho-iodo)arylation of carbonyls
with activated aryliodanes.4e,4f
[*]
X. Huang, Y. Zhang, L. Zhang, Y. Xu., L. Kong, Prof. Dr. B. Peng*
Key Laboratory of the Ministry of Education for Advanced Catalysis
Materials, Zhejiang Normal University
Jinhua 321004, China
E-mail: pengbo@zjnu.cn
C. Zhang, Prof. Z. Wang
School of Chemical Sciences, University of the Chinese Academy of
Sciences
Beijing 100049, China
Intrigued by the unexpected discovery, we switched our
efforts to the reaction of PhI(OAc)2 1a with DFSE 2a. Through
optimization of the reaction conditions, including the aryl source,
electrophilic activator, temperature, and solvent (see SI 2.1 for
more details), we found that the reaction of PhI(OAc)2/TMSOTf
with DFSE 2a at -78 °C produced 4aa with the best yield (83%)
(eq 1). The experimental results suggested that the
E-mail: zxwang@ucas.ac.cn
These authors contributed equally to this work
[+]
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nature of the corresponding multi-fluorinated ketone. Similar
polyfluorinated ketone hydrates has been reported in the
literatures.12a The formation of 5ah could be attributed to the
partial detrifluoromethylation of 4ah∙H2O.12b In view of the
synthetic versatility of the carboxylic group,13 we simply treated
the reaction mixture with aqueous KOH to convert ketone
hydrate 4ah∙H2O to carboxylic acid 5ah. As a consequence, 5ah
was obtained as the sole product in synthetically useful yield
(62%).
To understand how the fluorine effect in 2a enabled the
reaction, we performed DFT calculations to characterize the
pathway for the reaction of PhI(OTf)2 6 with 2a (see SI 3.1 for
computational details). On the basis of the calculation results,
we tentatively propose a reaction mechanism as illustrated by
the simplified pathway in Figure 1a (see the Supporting
Information 3.2 for the complete pathway). To begin with, 2a
undergoes nucleophilic attack on PhI(OTf)2. The OI attack via
TS1 is more favorable than the C=CI attack via TS1a and
difluoromethylene group of DFSE 2a could play a critical role in
switching the reactivity of 2a.9 Thus, we examined the non-
fluorinated and mono-fluorinated ESEs 2b-2e (eq 1). In
agreement with our expectation, no desired products 4ab-4ae
could be obtained from the reactions.10 Furthermore, as shown
in eq 2, we considered the substitution effects of Ph group in 2a
with electron donating groups nBu(2f) and OMe(2g) and
electron withdrawing group CF3 (2h), note that 2h can be readily
prepared from HFIP (hexafluoroisopropanol).11 2h furnished
trace amount of desired product under standard conditions.
Through optimization(see SI 2.2 for more details), we identified
the optimum conditions (-78 °C for 5 min and then -50 °C for 2 h),
under which the reaction gave the best yield of 4ah (52%) along
with small amount of α,α-difluoroacetic acid 5ah (15%) (eq 2).
Notably, the expected ketone product 4ah was obtained as its
hydrate (4ah∙H2O). This was due to the highly electrophilic
Figure 1. a, Free energy profile for the reaction of 2a with PhI(OTf)2, along with relative free energies in kcal mol-1. Additional results are given in SI 3.2. b.
Comparing the energetic preference of the two nucleophilic attacking modes. See SI 3.4 for the optimized structures of transition states and intermediates. c.
HOMOs of 2a and 2b, along with NBO charges in e.
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results in IM1 with a IOTMS bond length of 2.47Å. Subsequently,
IM1 rearranges to IM3 via TS2. The rearrangement breaks the
IOTMS bond and forms a new C-C bond between ortho-carbon
of PhI(OTf)2 and terminal carbon of 2a, which is similar to a
[3,3]-sigmatropic rearrangement. The rearrangement alters a
ortho sp2 carbon in IM1 to a sp3 carbon in IM3. Consistently, our
intramolecular kinetic isotope effect (KIE) study (eq 3) indicates
that the reaction of d-1a under the standard conditions exhibits
inverse isotope effect,14 giving a mixture of 4aa/d-4aa in a ratio
fluorine atoms in 2a are substantially involved in its HOMO,
which decreases the -electron density of the C=C bond of 2a,
thus weakens its nucleophilicity and disfavors the C=CI attack.
In addition, considering the C=CI attack, the fluorine effect
switches the Coulomb interaction between the terminal carbon
and positively-charged iodine (Q=1.46e) of PhI(OTf)2 from
attraction in 2b to repulsion in 2a (see Figure 1c for charge
population), which also disfavors the C=CI attack.
The mechanistic study suggests that the favorable assembly
of 62/38. Finally, rearomatization of IM3 affords the product 4aa. of the rearrangement precursor (i.e. IM1) via OI attack is
Overall, the reaction was predicted to have a rate-determining
barrier of 10.9 kcal mol-1 for assembling the rearrangement
precursor IM1 and is highly exergonic by 80.1 kcal mol-1. The
energetic results explain why the reactions could take place at
low temperature. The predicted rate-determining step agrees
with the intermolecular kinetic isotope effect study (eq 4), the
equal rates of 1a and d-1a indicating that the rearrangement
step is the product-determining step rather than the rate-
determining step of the whole transformation.14b,15
The pathway initiated by C=CI attack via TS1a suffers a
kinetically facile SN2 process that prevents the pathway from
producing 4aa (see SI 3.3).
To gain insight into how the fluorine effect in 2a favors OI
attack over C=CI one, Figure 1c compares the electronic
structures of 2a and 2b. Compared to 2b, the pz orbitals of
crucial for the reaction. Indeed, as compared in Figure 1b, the
derivatives (2b-2g) of 2a all have TS1-like transition states
higher than corresponding TS1a-like ones, which agrees with
our experimental results of no desired products.
Recently, Shafir et al. reported an unconventional Claisen
rearrangement in their study of ortho-propagylation of
bis(acyloxy)iodoarenes,4b encouraging us to reexamine the
present rearrangement. IM3 has the CI bond length equal to
that (2.09Å) in IM1 and two distant OTf- groups, suggesting that
IM3 had better be represented by the resonance structure
IM3RE1 with iodine(I) rather than IM3RE2 with iodine(III).
Supportively, the Wiberg bond index (1.08) of C-I bond in IM3 is
only slightly greater than that (0.99) of the bond in IM1. Thus,
the rearrangement proceeds in accompany with the reduction of
Scheme 2. Ortho C-H difluoroalkylation of aryliodanes with enol silyl ether 2a. [a] Unless otherwise noted, the reactions were performed with aryliodanes 1 (0.5
mmol) under the optimized conditions. [b] 10 mmol of 1a was used in the reaction. [c] Corresponding aryl iodides were recovered in 47%, 49% and 77% yields
from the reactions of 1m, 1o and 1j’ respectively. [d] TMSOCOCF3 was used instead of TMSOTf.
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of the reaction was demonstrated by a gram-scale synthesis of
4aa (76%, 2.70 g). Remarkably, functional groups including aryl
halides (4da, 4ea, 4va, 4wa, 4xa, 4za, 4a’a, and 4f’a), a nitro
group (4ia), a ketone (4ma), esters (4na-4sa), benzylic halides
(4ka, 4la), an unsaturated ester (4pa), a nitrile (4ua), and even
an amine (4ra) were all nicely tolerated in the reaction, most of
which could be challenging for conventional aromatic
difluoroalkylation processes.5 These tolerated functionalities
provided diverse platforms for the further elaboration of products,
which increased the synthetic utility of this reaction (vide infra).
It’s also impressive that stereochemistry has little influence on
the reaction. Reactions with hindered substrates (1t-1x)
proceeded smoothly to afford the desired products (4ta-4xa) in
good yields. Interestingly, meta-methyl-substituted aryliodane 1b’
furnished a mixture of ortho-difluoroalkylated products (4b’a) in
a 1/2 ratio. In sharp contrast, aryliodane 1c’ bearing a meta-
methoxyl group exclusively gave the less congested product
(4c’a) in a good yield (61%). To our delight, both naphthalene
(1e’ and 1f’) and thiophene (1g’ and 1h’) derivatives were also
found to be suitable for the reaction. However, pyridine 1i’ and
pyrazole 1j’ were not tolerated. This was probably due to the
relatively high nucleophilicity of N-heteroarenes which might
quench the electrophilic aryliodine(III) species in the reaction.
The reaction scope in use of 2h as difluoroalkylation reagent
was also investigated under the optimum conditions (Scheme 3).
First, the scalability of the reaction was demonstrated by a
successful gram-scale synthesis of 5ah (58%, 1.73 g). A variety
of aryliodanes 1 could be transformed to corresponding α,α-
difluoroacetic acids 5 with this protocol. Substrates bearing para-
electron-donating groups (1b and 1c) afforded desired products
(5bh and 5ch) in good yields. However, para-halogenated
aryliodanes (1d and 1e) proved to be problematic substrates
since no expected products (5dh and 5eh) could be isolated
from these reactions. Similar to the reactions using 2a as a
nucleophile (Scheme 2), meta-methylated phenyliodane 1z
furnished a 1/2 mixture of regio-isomers 5zh, whereas meta-
methoxyl-substituted 1a’ exclusively afforded less congested
Scheme 3. Ortho C-H difluoroalkylation of aryliodanes with enol silyl ether 2h
General reaction conditions: 1 (0.5 mmol), TMSOTf (2.0 equiv), 2h (2.0 equiv),
DCM (0.1 M), -78 °C, 5 min then -50 °C, 2 h. [a] 10 mmol of 1a was used in
the reaction.
iodine(III) to iodine(I), as illustrated by the curl arrows in TS2,
which is different from
a
classical [3,3]-sigmatropic
rearrangement. In line with the concomitant reduction, the NBO
charge on iodine decreases significantly from 1.42 (compared to
1.46 in PhI(OTf)2) in IM1 to 0.84 in TS2 to 0.48e in IM3 and the
dearomative rearrangement is exergonic by 29.8 kcal mol-1.
Next, we evaluated the reaction scope with various
aryliodanes. As shown in Scheme 2, the reaction could be
successfully applied to a wide range of aryliodanes, producing a
large number of difluoroalkylated arenes 4. First, the scalability
Scheme 4. Elaboration of the coupling products 4.
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Retailleau, A. Panossian, F. R. Leroux, G. Masson, J. Org. Chem. 2017,
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5a’h. Pleasingly, naphthalene (1b’ and 1c’) and thiophene (1d’
and 1e’) derivatives produced the desired products in modest to
good yields.
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To demonstrate the usefulness of this reaction, we further
elaborated products 4 and 5 as illustrated in Scheme 4. Simple
treatment of 4aa and 4fa with KOt-Bu produced
difluoromethylated phenyl iodides 6a and 6b, respectively, in
good yields.7 The carboxylic group of 5ah was converted to a
new C-F bond giving trifluoromethylated phenyl iodide 7 in 51%
yield.16 The synthetic utility of 7 has been demonstrated by Ritter
and coworkers in the synthesis of an anti-inflammatory drug,
Flunixin.17a Not surprisingly, the iodide group, one of the best
leaving groups, could be readily transformed into other
functionalities including SAr, Ar, Bpin, allyl, vinyl, and alkynyl
groups. Among them, the C-S bond formation of 4da and Suzuki
coupling of 4sa directly delivered the difluoromethylated analogs
of two drugs, Tetrasul17b and Felbinac17c, respectively. Notably,
the successful synthesis of 8 bearing a Bpin moiety ortho to a
difluoromethyl group paves
a
way for coupling the
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In summary, we have disclosed an intriguing fluorine effect
which enables a rearrangement which couples aryliodanes with
difluoroenol silyl ether 2a in a redox-neutral manner, leading to
ortho-iodo difluoroalkylated arenes which can serve as
difluorination reagents. Notable features of the reaction include
its remarkably low temperature (-78 °C) and short reaction time
(< 5 min), which allow the process to tolerate a diverse array of
functionalities. The key for the success of the reaction is that the
fluorine effect favors the nucleophilic attack of the O atom of
DFSE 2a on PhI(OTf)2 over C=C attack, thus enabling a
selective assembly of the rearrangement precursor for coupling.
We anticipate that this work will stimulate more interests and
efforts on the development of difluoroalkylation reactions using
the newly discovered fluorine effect.
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Acknowledgements ((optional))
This work is supported by Zhejiang Normal University and
NSFC-21502171, 21773240. S. E. Denmark (UIUC), A. A.
Thomas (MIT) and J. Hu (SIOC) are thanked for helpful
discussions.
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Keywords: fluorine effect• hypervalent iodine •
difluoromethylation • rearrangement reaction
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Xin Huang, Yage Zhang, Chaoshen
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Kong, Zhi-Xiang Wang,* Bo Peng*
Page No. – Page No.
ortho Difluoroalkylation of
Aryliodanes with Enol Silyl Ethers
through a Rearrangement Enabled by
a Fluorine Effect
An intriguing effect of fluorine in difluoroenol silyl ether distinguishes it from other
enol silyl ethers by enabling its cross-coupling with aryliodanes, which represents
the first iodide-remaining cross-coupling of enol silyl ethers via rearrangement.
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