Nucleophilic and Radical Heptafluoroisopropoxylation with Redox-Active Reagents

Article abstract of DOI:10.1002/anie.202109572

The heptafluoroisopropyl group (CF(CF₃)₂) is prevalent in pharmaceuticals and agrichemicals. However, heptafluoroisopropoxylated (OCF(CF₃)₂) compounds remain largely underexplored, presumably due to the lack of efficient access to these compounds. Herein, we disclose the practical and efficient heptafluoroisopropoxylation reactions through the invention of a series of redox-active N-OCF(CF₃)₂ reagents. These reagents were readily prepared from the oxidative heptafluoroisopropylation of hydroxylamines with AgCF(CF₃)₂. The substitutions on the nitrogen atom significantly affected the properties and reactivities of N-OCF(CF₃)₂ reagents. Accordingly, two types of N-OCF(CF₃)₂ reagents including N-OCF(CF₃)₂ phthalimide A and N-OCF(CF₃)₂ benzotriazolium salt O′ were used as OCF(CF₃)₂ anion and radical precursors, respectively. This protocol enables the direct heptafluoroisopropoxylation of a range of substrates, delivering the corresponding products in moderate to excellent yields.

Full text of DOI:10.1002/anie.202109572

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How to cite:
International Edition: doi.org/10.1002/anie.202109572
German Edition: doi.org/10.1002/ange.202109572
Fluorinating Reagents
Nucleophilic and Radical Heptafluoroisopropoxylation with Redox-
Active Reagents
Chao-Lai Tong, Xiu-Hua Xu, and Feng-Ling Qing*
Abstract: The heptafluoroisopropyl group (CF(CF3)2) is
prevalent in pharmaceuticals and agrichemicals. However,
heptafluoroisopropoxylated (OCF(CF3)2) compounds remain
largely underexplored, presumably due to the lack of efficient
access to these compounds. Herein, we disclose the practical
and efficient heptafluoroisopropoxylation reactions through
the invention of a series of redox-active N-OCF(CF3)2 reagents.
These reagents were readily prepared from the oxidative
heptafluoroisopropylation of hydroxylamines with AgCF-
(CF3)2. The substitutions on the nitrogen atom significantly
affected the properties and reactivities of N-OCF(CF3)2
reagents. Accordingly, two types of N-OCF(CF3)2 reagents
including N-OCF(CF3)2 phthalimide A and N-OCF(CF3)2
benzotriazolium salt O’ were used as OCF(CF3)2 anion and
radical precursors, respectively. This protocol enables the
direct heptafluoroisopropoxylation of a range of substrates,
delivering the corresponding products in moderate to excellent
yields.
Introduction
Fluoroalkyl ethers are valuable structural motifs in the
area of drug and agrochemical discovery (Figure 1, top),[1]
because the introduction of fluoroalkoxy group resulted in the
increased lipophilicity[2] and metabolic stability[3] compared to
non-fluorinated analogues. Consequently, tremendous prog-
ress has been made recently in the development of synthetic
method for the preparation of the simple fluoroalkyl ethers,
such as monofluoromethyl,[4] difluoromethyl,[5] and trifluor-
omethyl[6] ethers. Heptafluoroisopropyl group (CF(CF3)2) is
prominent in existing or candidate pharmaceuticals[7] and
Figure 1. Fluoroalkyl ether-containing and heptafluoroisopropylated
biologically interesting compounds.
agrochemicals[8] (Figure 1, bottom), because of its unique
properties, such as high lipophilicity, strong electron-with-
drawing effect, and large steric bulk.[2] Given the success of
both CF3 and OCF3 groups in drug and agrochemical
discovery,[9] it is reasonable to think that heptafluoroisopro-
poxyl group (OCF(CF3)2) would have potential application
for the design and preparation of bioactive compounds.
Compared to the simple fluoroalkyl ethers, the synthesis of
heptafluoroisopropyl ethers remains sparse.
Normally, heptafluoroisopropyl ethers were prepared
through nucleophilic substitution reactions with the in situ
generated heptafluoroisopropoxide anion from hexafluoroa-
cetone and metal fluoride (Scheme 1a),[10] but the reaction
was limited by the usage of the gaseous and highly toxic
hexafluoroacetone. Very recently, Ngai reported the synthesis
of heptafluoroisopropyl aryl ethers through a photocatalytic
heptafluoroisopropylation of N-aryl-N-hydroxylamides with
ICF(CF3)2 followed by an intramolecular OCF(CF3)2 migra-
tion (Scheme 1b),[11] and Hu described one example of the
heptafluoroisopropoxylation-bromination of the in situ gen-
erated aryne with BzOCF(CF3)2 prepared from hexafluoroa-
cetone (Scheme 1c).[12] Obviously, the substrate scope of
these two synthetic methods was rather narrow. Therefore,
the development of new reagents and reactions for the
preparation of heptafluoroisopropyl ethers is of high demand.
[*] C.-L. Tong, Dr. X.-H. Xu, Prof. Dr. F.-L. Qing
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Science,
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: flq@mail.sioc.ac.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202109572.
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continuing interest in oxidative fluoroalkylation reactions,[16]
we turned our attention to the oxidative heptafluoroisopro-
pylation of hydroxylamines. Very recently, we developed the
oxidative hydroheptafluoroisopropylation of unactivated al-
kenes with AgCF(CF3)2 and 1,4-cyclohexadiene (1,4-CHD)
using phenyliodine bis(trifluoroacetate) (PIFA) as the oxi-
dant.[17] On the basis of this work, N-hydroxyphthalimide
(NHPI) was chosen as the model substrate to react with the
AgCF(CF3)2, in situ generated from hexafluoropropylene and
AgF in MeCN, in the presence of PIFA (Table 1, entry 1). To
our delight, N-OCF(CF3)2 phthalimide (A) was obtained in
54% yield. Encouraged by this result, other common organic
Scheme 1. Previous synthesis of heptafluoroisopropyl ethers.
Table 1: Screening of oxidants for oxidative heptafluoroisopropylation.[a]
In 2013, our research group observed the formation of N-
trifluoromethoxy-N-phenylacetamide as a side product from
the copper-catalyzed oxytrifluoromethylation of alkenes with
CF3SO2Na and hydroxamic acid (Scheme 2a),[13] this side
product was formed from the coupling of N-hydroxy-N-
phenylacetamide and trifluoromethyl radical (CF3C). We
Entry
Oxidant
Yield [%][b]
1
2
3
4
PIFA
PIDA
m-CPBA
NBS
NFSI
54
18
38
80
6
5
6
7
selectfluor
K2S2O8
CAN
95
6
92
83
8
9[c]
selectfluor
[a] Reaction conditions: NHPI (0.2 mmol), AgF (0.4 mmol), hexafluor-
opropylene (excess, ballon, 1 atm), oxidant (0.4 mmol), MeCN (2.0 mL),
under N2, rt, 4 h. [b] Yields determined by 19F NMR spectroscopy using
trifluoromethoxybenzene as an internal standard. [c] AgF (0.3 mmol).
Scheme 2. Design of N-OCF(CF3)2 reagents.
assumed that the analogous reaction of hydroxylamines and
CF(CF3)2 radical would produce N-OCF(CF3)2 compounds
(Scheme 2b). Inspired by recent advances in the use of redox-
active N-OR reagents as alkoxy sources,[14] we anticipated
that N-OCF(CF3)2 compounds might be the promising
heptafluoroisopropoxylating reagents. Notably, to the best
of our knowledge, the radical heptafluoroisopropoxylation
reaction has not been reported yet. We envisaged that both
nucleophilic (Scheme 2c) and radical (Scheme 2d) hepta-
fluoroisopropoxylation reactions would be possible by the
alteration of the substituents on nitrogen atom of N-OCF-
(CF3)2 reagents.
and inorganic oxidants, including phenyliodine diacetate
(PIDA), meta-chloroperbenzoic acid (m-CPBA), N-bromo-
succinimide (NBS), N-fluorobenzenesulfonimide (NFSI),
selectfluor, K2S2O8, and ceric ammonium nitrate (CAN),
were examined (entries 2–8). All of them promoted this
reaction, and selectfluor was optimal to afford A in 95% yield
(entry 6). Reducing the amount of AgF resulted in a dimin-
ished yield (entry 9), probably because the in situ generated
AgCF(CF3)2 from AgF were easily consumed by side
reactions.[18]
Subsequently, a variety of hydroxylamines were evaluated
under the oxidative heptafluoroisopropylation conditions. As
shown in Scheme 3, several types of hydroxylamine substrates
underwent reaction smoothly to deliver N-OCF(CF3)2 prod-
ucts A–O in moderate to excellent yields. The structure of
compound A was confirmed by single crystal X-ray analysis.
The electronic properties of the substituents on the phthali-
mide scaffold (B–D) did not influence the reaction efficiency.
Furthermore, polysubstituted N-hydroxyphthalimides were
also suitable substrates. Similar hydroxylamines featuring two
carbonyl groups adjacent to nitrogen atom, such as N-
hydroxysuccinimide, N-hydroxyquinolinimide, and N-hy-
droxy-1,8-naphthalimide, were efficiently converted to the
Results and Discussion
The reported N-OCF3 reagents were prepared by the
reactions of hydroxylamines or N-O compounds with the
expensive electrophilic trifluoromethylating reagents (Togniꢀs
reagents).[14a–c,15] However, this reaction could not be extend-
ed to the synthesis of N-OCF(CF3)2 reagents, as the analogous
heptafluoroisopropylating reagents are not available. Thus, it
is highly desirable and challenging to develop new method for
the preparation of N-OCF(CF3)2 reagents. As part of our
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Scheme 4. Synthesis of N-OCF(CF3)2 benzotriazolium salts.
SCE), G (Ered = ꢀ0.96 V vs. SCE), H (Ered = ꢀ0.93 V vs.
SCE), I (Ered = ꢀ0.96 V vs. SCE), L (Ered = ꢀ0.96 V vs. SCE),
and M (Ered = ꢀ0.98 V vs. SCE) had similar reduction
potentials. The electron-donating substituent on the phthali-
mide scaffold (B) significantly decreased the reduction
potential (Ered = ꢀ1.38 V vs. SCE), whereas higher reduction
potential (Ered = ꢀ0.71 V vs. SCE) was observed in poly-
chloro-substituted N-hydroxyphthalimide (F). The reduction
potential of N-OCF(CF3)2 benzimidazole K (Ered = ꢀ0.55 V
vs. SCE) is more positive than those of common N-OCF-
(CF3)2 compounds. Notably, benzotriazolium salts M’–O’ have
the relatively higher reduction potentials.
The single-electron reduction of the redox-active N-
OCF(CF3)2 compounds would give the corresponding anionic
radical intermediates, and the subsequent fragmentation of
ꢀ
the N O bond in anionic radical species may occur in two
possible pathways, leading the formation of nitrogen radical
and OCF(CF3)2 anion (path a) or nitrogen anion and OCF-
(CF3)2 radical (path b) (Scheme 5b). To trap the possible
OCF(CF3)2 anion and OCF(CF3)2 radical, the reactions of N-
OCF(CF3)2 compounds with alkyl iodides and arenes were
investigated, respectively. Firstly, (3-iodopropyl)benzene (1a)
was chosen as the model substrate to react with N-OCF(CF3)2
compounds using copper powder as the single-electron-
transfer (SET) reductant. As shown in Scheme 5c, the
common N-OCF(CF3)2 compounds afforded the heptafluor-
oisopropyl ether 2a in moderate yields (entries 1–9), whereas
benzotriazolium salts M’–O’ did not give the desired product
(entries 10–12). These results indicated that OCF(CF3)2 anion
was generated from the common N-OCF(CF3)2 compounds,
and A and H led to superior results. As H was more
challenging to prepare, compound A was chosen as the
nucleophilic heptafluoroisopropoxylating reagent. Then, the
Scheme 3. Synthesis of N-OCF(CF3)2 reagents by the Oxidative hepta-
fluoroisopropylation of hydroxylamines. Reaction conditions: hydroxyl-
amine (1.0 mmol), AgF (2.0 mmol), hexafluoropropylene (excess, bal-
lon, 1 atm), selectfluor (2.0 mmol), MeCN (8.0 mL), under N2, rt, 4 h,
isolated yields. [a] PIFA (2.0 mmol) was used as the oxidant. [b] CAN
(2.0 mmol) was used as the oxidant.
corresponding heptafluoroisopropylated products (G–I). In
the
cases
of
3-hydroxy-1,2,3-benzotriazin-4(3H)-one
(HOOBt) and N-hydroxybenzimidazole derivative, the em-
ployment of PIFA as oxidant gave products J and K in higher
yields. Aromatic aldoxime was successfully heptafluoroiso-
propylated in the presence of CAN to provide product L in
68% yield. Finally, 1-hydroxy-benzotriazoles readily partici-
pated using CAN or selectfluor as the oxidant to furnish
products M–O in good yields.
ꢀ
To enrich the type of N-OCF(CF3)2 reagents, we attempt-
ed to prepare the cationic N-OCF(CF3)2 reagents from
compounds A–O. Among these reagents, N-OCF(CF3)2
benzotriazoles M–O successfully underwent methylation with
MeOTf to give the corresponding benzotriazolium salts M’–
O’ in high yields (Scheme 4). The structure of M’ was also
confirmed by X-ray crystallographic analysis.
With the N-OCF(CF3)2 compounds A–O and M’–O’ in
hand, their redox reactivities were then evaluated by cyclic
voltammetry studies (see the Supporting Information). The
selected reduction potentials of N-OCF(CF3)2 compounds
were shown in Scheme 5a. Compounds A (Ered = ꢀ0.97 V vs.
C H heptafluoroisopropoxylation of benzene (3a) with the
N-OCF(CF3)2 compounds was explored under photocatalytic
conditions (Scheme 5d). This photoredox catalysis reaction
was significantly affected by the reduction potentials of the N-
OCF(CF3)2 compounds. In general, N-OCF(CF3)2 with more
positive reduction potential furnished the heptafluoroisopro-
poxylated product 4a in higher yield (entries 2–6). Accord-
ingly, benzotriazolium salt O’ represents as an ideal radical
heptafluoroisopropoxylating reagent. Notably, both of A and
O’ were bench stable and thus stored under ambient
conditions for several months without noticeable decompo-
sition. Furthermore, the differential scanning calorimetry
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ꢀ
Scheme 5. a) Reduction potentials of N-OCF(CF3)2 reagents; b) N O bond redox fragmentation; c) Trapping of OCF(CF3)2 anion. Reaction
conditions: 1a (0.1 mmol), N-OCF(CF3)2 reagent (0.12 mmol), Cu (0.1 mmol), DMF (1.0 mL), 808C, 12 h. [a] Yields determined by 19F NMR
spectroscopy using trifluoromethoxybenzene as an internal standard; d) Trapping of OCF(CF3)2 radical. Reaction conditions: 3a (0.3 mmol), N-
OCF(CF3)2 reagent (0.1 mmol), Ru(bpy)3(PF6)2 (0.001 mmol), MeCN (1.0 mL), rt, 1 h. [b] Yields determined by 19F NMR spectroscopy using
trifluoromethoxybenzene as an internal standard.
(DSC) analysis revealed that reagent A does not decompose
in the range of 40–3008C, whereas the thermal decomposition
of reagent O’ was observed at 1888C.
yield of 2a was observed in the presence of 0.5 equivalent of
Et4NI (entries 10–12). We reasoned that iodide anion in situ
generated from the nucleophilic heptafluoroisopropoxylation
reaction of alkyl iodide was further used as the activator for
the formation of OCF(CF3)2 anion.
After the appropriate heptafluoroisopropoxylating re-
agents A and O’ were identified, we further explored their
applications in nucleophilic and radical heptafluoroisopro-
poxylation reactions. Initially, we focused on the reaction of
alkyl electrophiles and reagent A. It was found that OCF-
(CF3)2 anion was formed from the reduction of reagent Awith
copper powder, other reductants were then screened (Sche-
me 6a, for details see the Supporting Information). No
desired product was observed in the presence of zinc or iron
powder (entries 2 and 3). Cuprous salts, such as CuCl, CuI,
and CuOAc, also accelerated this reaction, but 2a was
obtained in lower yields than that with copper powder
(entries 4–6). To our surprise, the employment of Et4NI as
an activator gave 2a in 60% yield (entry 7). Switching Et4NI
to Et4NBr or Et4NCl decreased the yield of 2a (entries 8 and
9). These results suggested that OCF(CF3)2 anion was formed
from the activation of reagent A with halides.[19] Further
screening of the amounts of Et4NI revealed that the highest
Besides alkyl iodides, other alkyl electrophiles including
bromide, mesylate, and tosylate were also amenable to the
heptafluoroisopropoxylation reaction under slightly modified
conditions (Scheme 6b). Notably, a stoichiometric amount of
Et4NI was required for alkyl mesylate and tosylate, as these
substrates did not yield activators for the formation of
OCF(CF3)2 anion. Alkyl dibromide 1c and secondary alkyl
iodide 1d reacted smoothly, furnishing the desired products in
good yields, respectively. However, the reactions of tertiary
alkyl halides failed to give any desired products. With regard
to the functional group tolerance, a diverse array of functional
groups such as aldehyde (1e), ketone (1 f), ester (1g), a,b-
unsaturated ester (1h), nitro (1j), amide (1j), ether (1k), and
aryl halides (1l–n) were compatible with the reaction
conditions. Furthermore, substrates bearing heterocycles
including furan (1p), thiophene (1q), pyridine (1r), thiazole
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Scheme 6. a) Screening of additives; b) Substrate scope of nucleophilic heptafluoroisopropoxylation with reagent A. Reaction conditions:
1 (0.6 mmol), A (0.72 mmol), Et4NI (0.3 mmol), DMF (4.0 mL), 808C, 12 h, isolated yields. [a] A (0.9 mmol). [b] A (0.9 mmol), Et4NI (0.9 mmol).
[c] A (1.8 mmol), Et4NI (0.6 mmol). [d] A (1.2 mmol), Et4NI (0.6 mmol).
(1s), benzothiophene (1t), quinolinone (1u), coumarin (1v),
carbazole (1w), and purine (1x) were converted to the
corresponding products in high yields. Finally, this protocol
was successfully applied to heptafluoroisopropoxylation of
complex compounds derived from amiodarone (1y), lomita-
pide (1z), and estrone (1aa).
Compared to the alkyl halides, alcohols are more readily
available. Inspired by the recent advances in deoxyfluoroal-
kylation of alcohols,[20] we next explored the deoxyhepta-
fluoroisopropoxylation of alcohols with reagent A. After
simple optimization of the reaction conditions (see the
Supporting Information), it was found that the combination
of the respective activation of alcohols with PPh3/ICH2CH2I
and reagent A with Et4NI was successfully applied to
deoxyheptafluoroisopropoxylation reactions (Scheme 7). A
diverse array of benzyl (5ab–aj), allyl (5ak), propargyl (5al),
primary (5am–an) and secondary (5d) alcohols were smooth-
ly converted to the corresponding heptafluoroisopropyl
ethers in moderate to excellent yields. Unfortunately, tertiary
alcohols were not suitable substrates for this reaction. The
mild conditions allow the tolerance of common functional
groups. Furthermore, heterocycles such as benzothiophene
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cetone hydrate intermediate was generated and then involved
in this reaction.
Having demonstrated the nucleophilic heptafluoroisopro-
poxylation reactions with reagent A, we next turned our
attention to the radical heptafluoroisopropoxylation with
reagent O’. As shown in Scheme 9, various (hetero)arenes
ꢀ
were subjected to the photoredox catalysis C H heptafluor-
oisopropoxylation reactions to give the desired products in
moderate to excellent yields. In general, electron-rich (het-
ero)arenes afforded higher yields than electron-deficient
(hetero)arenes. Arenes (3b–j) featuring different substitution
patterns (mono-, di-, and tri-substitution) and functional
groups (electron-rich, -natural, and -withdrawing groups)
participated in this reaction without any difficulty (Sche-
me 9a). Heteroarenes including thiophene (3k–n), pyrazole
(3o–t), imidazole (3u), thiazole (3v,w), 1,2,3-triazole (3x),
indazole (3y), benzothiophene (3z,aa), quinoxaline (3ab),
pyrazolo[3,4-b]pyridine (3ac), imidazo[1,2-b]pyridazine
(3ad,ae), and [1,2,4]triazolo[4,3-b]pyridazine (3af) were
readily converted to the heptafluoroisopropoxylated products
(4k–af) in moderate to excellent yields (Scheme 9b). The
structures of compounds 4t and 4u were confirmed by single
crystal X-ray diffraction analysis.
It should be noted that for some unsuitable heteroarenes
ꢀ
such as pyridines, C H trifluoromethylated byproducts were
observed. This result indicated that the OCF(CF3)2 radical
Scheme 7. Deoxyheptafluoroisopropoxylation with reagent A. Reaction
conditions: 5 (0.6 mmol), A (0.9 mmol), PPh3 (0.72 mmol), ICH2CH2I
(0.72 mmol), Et4NI (0.6 mmol), DMF (4.0 mL), 808C, 12 h, isolated
yields.
could undergo b-fragmentation to generate CF3 radical.[21,22]
This C H heptafluoroisopropoxylation protocol exhibits high
levels of regioselectivity. For heteroarenes (3l–r,t,y–af) bear-
ing multiple potential reaction sites, only one regioisomer that
OCF(CF3)2 group connected to the more electron-rich carbon
was observed. The high regioselectivity could be attributed to
the electrophilic character[14b,c,23] and steric hindrance of
ꢀ
(5ao), indole (5ap), and 1,3-benzodioxole (5aq) posed no
problem during this deoxyheptafluoroisopropoxylation pro-
tocol.
ꢀ
To further expand the synthetic utility of reagent A, we set
out to investigate its reactivity with alkenes. As shown in
Scheme 8a, the reaction of styrene 6a with reagent A and 1,3-
diiodo-5,5-dimethylhydantoin (DIDMH) in the presence of
Et4NI regioselectively afforded the iodoheptafluoroisopro-
poxylated product 7 in moderate yield. However, the
analogous bromoheptafluoroisopropoxylation with 1,3-dibro-
mo-5,5-dimethylhydantoin (DBDMH) failed to give the
desired product. To our surprise, when unactivated alkene
6b was subjected to the iodoheptafluoroisopropoxylation
conditions, an unexpected cyclic ketal 8 was formed as the
major product (Scheme 8b). We reasoned that hexafluoroa-
OCF(CF3)2 radical. Furthermore, C H heptafluoroisopro-
poxylation of unsymmetrical bi(hetero)arenes (3ag-ao) was
examined (Scheme 9c). As expected, these reactions oc-
curred selectively on the electron-rich (hetero)arenes. The
structures of products 4ai, 4al, and 4an were also confirmed
by X-ray crystallographic analysis.
In addition to the (hetero)arene substrates, alkenes could
also be employed in the radical heptafluoroisopropoxylation
reactions. The reaction of unactivated alkene 6c and reagent
O’ in the presence n-Bu3SnH under photoredox catalytic
conditions afforded the corresponding hydroheptafluoroiso-
propoxylated product 9 in moderate yield (Scheme 10a).
Furthermore, a cascade heptafluoroisopropoxylation/cycliza-
tion of N-benzoylacrylamide 10 yielded the heptafluoroiso-
propoxylated isoquinolinedione (11) in 62% yield (Sche-
me 10b). To the best of our knowledge, the radical fluoroal-
koxylation of alkenes has rarely been reported.[24]
Finally, the late-stage heptafluoroisopropoxylation of the
existing and commercially available pharmaceuticals and
argochemicals was investigated (Scheme 11). For instance,
treatment of Idebenone, Ru58841, and Ospemifene with
reagent A under the standard deoxyheptafluoroisopropoxy-
lation conditions afforded the heptafluoroisopropoxylated
products 12–14 in moderate to high yields. On the other hand,
ꢀ
the C H heptafluoroisopropoxylation of Procymidone and
Fenclorim with reagent O’ under photoredox catalytic con-
Scheme 8. Reactions of alkenes with reagent A and DIDMH.
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ꢀ
Scheme 9. C H heptafluoroisopropoxylation of (hetero)arenes with reagent O’. Reaction conditions: 3 (1.8 mmol), O’ (0.6 mmol), Ru(bpy)3(PF6)2
(0.06 mmol), CH3CN (4.0 mL), blue LEDs, rt, 30 min, isolated yields. [a] Yields and regioselectivity were determined by 19F NMR spectroscopy
using trifluoromethoxybenzene as an internal standard.
ditions gave the desired products 15 and 16 in good yields,
respectively.
a dihedral angle (q) of 7.58. In the cases of OCF(CF3)2-
substituted heterocycles (4t, 4u, 4al, and 4an), the dihedral
=
The X-ray single-crystal diffraction analysis of compounds
4t, 4u, 4ai, 4al, 4an, and 15 (Figure 2) clearly depicts that
OCF(CF3)2-substituted (hetero)aromatics possesses interest-
ing conformation, which might find useful applications in
medicinal chemistry. The OCF(CF3)2-substituted arenes (4ai
and 15) preferably adopt a conformation in which the
OCF(CF3)2 moiety lies in the plane orthogonal to the
aromatic ring (q = 79–858), analogously to OCF3-substituted
arenes.[25] This unique conformation is in striking contrast to
the behavior of nonfluorinated ArOCH(CH3)2,[26a] in which
the OCH(CH3)2 group is in plane of the aromatic ring with
angle (q) of C C-O-CF(CF3)2 bond is between 57–788. This
striking molecular structure is probably due to the influence
of the electron-withdrawing CF(CF3)2 group on the neighbor-
ing oxygen lone pairs and the steric interaction between the
CF(CF3)2 group and the ortho substituents of the heteroar-
omatics. Furthermore, ArO-CF(CF3)2 bond (1.32–1.38 ꢁ) is
generally shorter than ArO-CH(CH3)2 bond (1.44–1.45 ꢁ),[26]
which could be attributed largely to the negative hyper-
conjugation (nO!s*C-F).
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Scheme 10. Heptafluoroisopropoxylation of alkenes with reagent O’.
Conclusion
Scheme 11. Late-stage heptafluoroisopropoxylation with N-OCF(CF3)2
We have reported the development of a series of redox-
reagents. [a] Reaction conditions: alcohol (0.6 mmol), A (0.9 mmol),
PPh3 (0.72 mmol), ICH2CH2I (0.72 mmol), Et4NI (0.6 mmol), DMF
(4.0 mL), 808C, 12 h, isolated yields. [b] Reaction conditions: arene
(1.8 mmol), O’ (0.6 mmol), Ru(bpy)3(PF6)2 (0.06 mmol), CH3CN
(4.0 mL), blue LEDs, rt, 30 min, isolated yields.
active N-OCF(CF3)2 reagents for heptafluoroisopropoxyla-
tion reactions. These reagents are conveniently prepared
through oxidative heptafluoroisopropylation of hydroxyl-
amines. Among the reagents tested, N-OCF(CF3)2 phthali-
mide A was selected and applied in the nucleophilc hepta-
fluoroisopropoxylation of alkyl halides, deoxyheptafluoroiso-
propoxylation of alcohols, and iodoheptafluoroisopropoxyla-
tion of alkenes. On the other hand, N-OCF(CF3)2 benzotria-
zolium salt O’ demonstrated excellent reactivities in the
radical heptafluoroisopropoxylation of (hetero)arenes and
alkenes. The synthetic utility of this protocol was well
demonstrated by the late-stage heptafluoroisopropoxylation
of pharmaceuticals and argochemicals. We are optimistic that
these new N-OCF(CF3)2 reagents and related reactions will
find use in medicinal and biological chemistry.
Figure 2. ORTEP drawings of compounds 4t, 4u, 4ai, 4al, 4an, and 15 (ellipsoids set at 30% probability).
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Acknowledgements
National Natural Science Foundation of China (21991211) is
greatly acknowledged for funding this work.
Conflict of Interest
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The authors declare no conflict of interest.
Keywords: conformation · heptafluoroisopropoxylation ·
nucleophilic reactions · radical reactions · redox-active reagents
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Accepted manuscript online: August 19, 2021
Version of record online: && &&
,
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Research Articles
Fluorinating Reagents
Redox-active heptafluoroisopropoxylating
reagents were conveniently prepared
from the oxidative hepta-
fluoroisopropylation of hydroxylamines,
and then were successfully used for the
synthesis of a series of alkyl(aryl) hepta-
fluoroisopropyl ethers.
C.-L. Tong, X.-H. Xu,
F.-L. Qing*
&&&& — &&&&
Nucleophilic and Radical
Heptafluoroisopropoxylation with Redox-
Active Reagents
&&&&
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ꢀ 2021 Wiley-VCH GmbH
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These are not the final page numbers!