Oxidative Fluorination of Cyclopropylamides through Organic Photoredox Catalysis

Article abstract of DOI:10.1002/anie.202007864

We report an oxidative ring-opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the γ or δ position. Both inexpensive benzophenone with UVA light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry.

Full text of DOI:10.1002/anie.202007864

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Accepted Article
Title: Oxidative Fluorination of Cyclopropylamides via Organic
Photoredox Catalysis
Authors: Ming-Ming Wang and Jerome Waser
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Oxidative Fluorination of Cyclopropylamides via Organic
Photoredox Catalysis
Ming-Ming Wang and Jérôme Waser*[a]
Abstract: We report an oxidative ring-opening strategy to transform
cyclopropylamides and cyclobutylamides into fluorinated imines. The
imines can be isolated in their more stable hemiaminal form, with the
fluorine atom installed selectively at the or position. Both cheap
benzophenone with UV A light or organic and inorganic dyes with blue
light could be used as photoredox catalysts to promote this process.
Various fluorinated amines were then obtained by nucleophilic attack
on the hemiaminals in one pot, giving access to a broad range of
useful building blocks for medicinal chemistry.
generate
a
nitrogen-centered radical from N-halogen
aminocyclopropane III (Scheme 1D).[12] The N radical then
underwent ring-opening and radical recombination to generate -
halogenated imines isolable in their N,O-acetal form IV. However,
this approach failed in the case of fluorination.
Tremendous efforts have been devoted to the development of
site-selective fluorination methods, given the significance of
fluorinated compounds in medicine and agrochemistry.[1] Among
these methods, the formation of C(sp3)-F bonds via ring opening
fluorination of carbocycles is an attractive route.[2] While success
has been achieved in ring opening fluorination of
arylcyclopropanes (Scheme 1A),[3] cyclopropanols[4] and
cyclobutanols[4a,b] (Scheme 1B), their nitrogen-substituted
counterparts were not studied yet, despite the importance of
nitrogen-containing fluorinated drugs and agrochemicals.
Previous studies on ring-opening of aminocyclopropanes and
aminocyclobutanes focused on Donor-Acceptor systems, which
are more reactive.[5] Simple systems lacking electron-withdrawing
groups have been less exploited, with most approaches using
transition-metal catalyst for C-C activation.[6] Oxidative methods
proceeding via radical pathways constitute an interesting
alternative.[7] Zheng and co-workers demonstrated that
cyclopropylanilines and cyclobutylanilines can be oxidized to a
radical cation species I using photoredox catalysis (Scheme
1C).[8] After ring opening, the resulting iminium radical II
underwent (3+2) annulation with alkenes or alkynes. Our group
later extended this approach to cyclopropenes[9] and Stephenson
and co-workers applied it to the synthesis of 1-
aminonorbornanes.[10] They also developed an alternative
strategy involving the activation of cyclopropylimines through their
triplet excited state.[11] Our group exploited another approach
based on a Hofmann–Löffler–Freytag (HLF)-inspired reaction to
Scheme 1. Oxidative ring-opening fluorination of cyclopropanes (A).
Fluorination of cyclopropanols and cyclobutanols (B). Photoredox catalysis
enabled (3+2) annulation of cyclopropylanilines (C). 1,3-Difunctionalization of
aminocyclopropanes (D). This work: oxidative fluorination of cyclopropylamides
(E).
We envisioned that a highly oxidizing excited photocatalyst
should be able to activate cyclopropylamides via single electron
transfer (SET) oxidation to give amidium radical V (Scheme
1E).[13] After ring-opening, the formed alkyl radical could be
trapped by a fluorination reagent, and the imine stabilized as a
hemiaminal VI. Herein, we report the successful implementation
of this strategy, using either cheap benzophenone with black light
(365 nm) or organic/inorganic dyes with blue LEDs, and
Selectfluor acting as both oxidant and fluorination reagent. The
reaction is complementary to the method of Lectka for the
[a]
Ming-Ming Wang and Prof. Dr. Jérôme Waser
Laboratory of Catalysis and Organic Synthesis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (CH)
Fax: (+)41 21 693 97 00
+
synthesis of fluorinated amines (Scheme 1A, R = NR3 ),[3a] as a
reversed regioselectivity is observed for fluorination compared
with arylcyclopropanes. The obtained hemiaminals were easily
converted into diverse products by reaction with nucleophiles.
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
With benzamide cyclopropane 1a as substrate, the combination
of benzophenone and Selectfluor under irradiation at 365 nm in
MeCN/H2O was optimal, yielding 3-fluorinated hemiaminal 2a in
74% yield (Table 1, entry 1).[14] Control experiments showed no
Supporting information for this article is given via a link at the end of
the document. Raw data for NMR, IR and MS is available at
zenodo.org, DOI: 10.5281/zenodo.3895605
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10.1002/anie.202007864
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conversion in the absence of benzophenone or irradiation (Table
1, entries 2 and 3). Only 10% of product was observed when using
NFSI as fluorinating reagent (Table 1, entry 4). 9-Fluorenone,
which is efficient for the ring-opening fluorination of
arylcyclopropanes, [3a] failed in this case (Table 1, entry 5). Other
photocatalysts such as [Ir(dF-CF3ppy)2(dtbbpy)]PF6 and Mes-Acr+
can also be utilized to achieve similar results using visible light
(Table 1, entries 6 and 7). Lower yields were obtained with
substrates containing less electron-donating substituents on the
benzene ring of the amide (Table 1, entries 8 and 9). No
conversion was observed with a strong electron-withdrawing
substituent such as a nitrobenzoyl (Table 1, entry 10) or a tosyl
(Ts) group (Table 1, entry 11). With a Boc group, no product was
isolated due to fast decomposition of the hemiaminal (Table 1,
entry 12). With a pivaloyl group, the yield dropped to 29% with
incomplete conversion (Table 1, entry 13). When mixing
cyclopropyl aniline 1h with Selectfluor, fast degradation was
observed even prior to UV irradiation (Table 1, entry 14).
We then developed one pot protocols to replace the hydroxy
group by adding nucleophiles to the reaction mixture (Scheme 2).
We focused on benzophenone as catalyst, because of its broad
availability and low prize. N,O-, N,S- or N,N- acetals can be
accessed in 39-73% yield (products 3a-f). The hemiaminal can
also be reduced by NaBH3CN, affording 3g in 83% yield. A
Petasis reaction[15] gave allylic amine 3h in 42% yield. 1,3,5-
Trimethoxybenzene afforded 3i in 69% yield while only 22% yield
of 3j was observed when using 1,3-dimethoxybenzene. With
pyrrole, C2 addition product 3k was isolated in 46% yield.
Table 1. Optimization of the reaction conditions[a]
Entry
Deviation from standard condition
Yield[b]
1
2
none
no benzophenone
74%
0
0
3
no irradiation
4
NFSI instead of Selectfluor
9-fluorenone instead of benzophenone
[Ir(dF-CF3ppy)2(dtbbpy)]PF6 with blue LED[d]
Mes-Acr+ with blue LED[e]
1b as substrate[f]
10%[c]
6%[c]
5
6
76%[c]
75%[c]
48%
7
8
9
1c as substrate[f]
43%
10
11
12
13
14
1d as substrate
0
1e as substrate
0
1f as substrate
decomposed
29%[g]
decomposed
1g as substrate
Scheme 2. Scope of nucleophiles in the one-pot ring-opening fluorination
reaction. [a]Reactions were run at a 0.30 mmol scale for 45 min, then a solution
of nucleophile (1.2 equiv.) in 0.5 mL MeCN was added and the mixture was kept
stirring at room temperature for the indicated time, Ar = p-MeO-Ph. [b]MeOH (1.0
mL, 82 equiv.) was used. [c]1,2,4-1H-Triazole (2.0 equiv.) was used. [d]1,2,3,4-
1H-Tetrazole (2.0 equiv.) was used. [e]Potassium trans-styryltrifluoroborate (2.0
equiv) was used.
1h as substrate
[a]Reaction conditions: 0.30 mmol scale for 45 min. [b]Yield of isolated product.
[c]Yield determined by 1H NMR using CH2Br2 as internal standard. [d]With 1 mol%
[Ir(dF-CF3ppy)2(dtbbpy)]PF6 and 1.5 equiv. Selectfluor for 1 h. [e]With 2 mol% 9-
mesityl-10-methylacridiniumperchlorate (Mes-Acr+) and 1.5 equiv. Selectfluor
for 3 h. [f]Reaction run for 4 h. [g]Reaction run for 10 h and product 2g converted
to an indole adduct to simplify purification.
The addition of indole provided 3l in 67% yield. Upon scaling up
this reaction to 10 mmol, 1.86 grams (57% yield) of 3l were
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10.1002/anie.202007864
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obtained. Indoles bearing a N-methyl or a 2-phenyl group
provided the corresponding products 3m and 3n in 64 and 67%
yield. With 3-methyl indole, 3o and 3p resulting from C and N
alkylation were isolated in 65% yield in 2:1 ratio. 4-Fluoro indole
was well tolerated, giving 3q in 57% yield. Indoles bearing
electron-donating substituents like methoxy (3r) and methyl (3s),
as well as electron-withdrawing substituents like a chloro (3t) and
an ester groups (3u) at the C5 position gave yields ranging from
45% to 69%. A methyl (3v), a CF3 (3w) and a bromo (3x) group at
C6 or a methyl at C7 position (3y) led to product formation in 50-
66% yield.
(hydride, indole or pyrazole) for the second step. When using 3-
phenyl aminocyclobutane 4f, 5f resulting from selective C1-C2
bond cleavage next to nitrogen was obtained in 63% yield, while
C3-C4 bond cleavage was observed only in traces by 19F NMR in
the reaction mixture. With cyclopropylbenzene (6) oxyfluorinated
product 7 was isolated in 63% yield, with the same regioselectivity
as previously observed for aminofluorination (Scheme 4).[3] This
shows that selectivity for ring-opening is substrate controlled and
not originating from our different reaction conditions.
We then examined the scope of aminocyclopropanes and
aminocyclobutanes (Scheme 3). When using 2-methyl substituted
aminocyclopropane 4a (d.r.= 4:1), 5a was isolated as a mixture of
two diastereoisomers in a 1:1 ratio. With 2-phenyl substituted
aminocyclopropane 4b, 5b was obtained in 90% yield after
reduction by NaBH3CN. When using bicyclic compound 4c, a
mixture of two diastereoisomers in a ratio of 1.4:1 was isolated in
60% yield. 2,2-Difluoro aminocyclopropane 4d afforded
trifluoromethyl hemiaminal 5d in 68% yield.
Scheme 4. Oxy-fluorination of cyclopropylbenzene (6).
In order to better understand the mechanism, we performed
several control experiments (Scheme 5). When the trans and the
cis isomers of 4a were submitted separately to the reaction
conditions, the same diastereomeric ratio was observed for
product 5a, supporting the formation of
a ring-opened
intermediate (Scheme 5, equation 1). When adding TEMPO, we
obtained product 8 in 13% yield and recovered 84% 1a,
suggesting that a primary alkyl radical was formed (Scheme 5,
equation 2). In order to exclude initiation by hydrogen atom
transfer (HAT) to form a neutral amidyl radical, we tested the
reaction of N-cyclopropyl-4-methoxy-N-methylbenzamide (9).
Products 11 and 12 were obtained, resulting probably from the
hydrolysis of unstable hemiaminal intermediate 10 (Scheme 5,
equation 3). Attempts to synthesize
a
N-fluorinated
aminocyclopropane corresponding to 1a were unsuccessful,[16]
and an independently synthesized N-fluoro amide did not react
under our reaction conditions (See Supporting Information for
details).[17] This makes N-H fluorination as a first step highly
improbable.
Scheme 3. Scope of multi-substituted aminocyclopropanes and
aminocyclobutanes in the ring-opening fluorination reaction. Ar = p-MeO-Ph.
See supporting Information for detailed reaction conditions.
Scheme 5. Mechanistic investigations.
With aminocyclobutane 4e, a series of products 5ea-5ec was
obtained in 56-64% yield, by simply adding different nucleophiles
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Based on these results and literature precedence, a first
speculative reaction mechanism can be proposed (Scheme 6).
Photo-excited ketones such as benzophenone (BP) in their triplet
state can initiate processes such as hydrogen atom transfer
(HAT),[18] triplet energy transfer (EnT)[19] and single electron
transfer (SET).[20] By comparing the reduction potentials of
cyclopropylamide 1a, Selectfluor and triplet state benzophenone
substituting the hydroxy group with diverse nucleophiles. Based
on the simple reaction procedure and the structural diversity of
nitrogen- and fluorine-containing building blocks obtained, we
believe that this methodology will be useful in synthetic and
medicinal chemistry.
(BP3*), neither Selectfluor (E1/2red = +0.33 V)[21,22] nor triplet state
Acknowledgements
BP*/BP-
benzophenone (E1/2
= +1.27 V)[23] are able to oxidize
red
cyclopropylamide 1a (measured E1/2 = +1.67 V). However,
Selectfluor or the Selectfluor-derived radical cation (I, E1/2
We thank the Swiss National Science Foundation (SNSF, grant
nos. 200021_165788 and 200020_182798) and EPFL for
financial support. We thank Dr. Luca Buzzetti, Dr. Zhikun Zhang
and Ms. Stephanie Amos from ISIC EPFL for helpful discussion.
We thank Mr. Bastian Muriel from our laboratory for the synthesis
of compound 1h.
red
=
+0.79 V)[24] could oxidize triplet state benzophenone (BP3*, E1/2
BP+/BP3* = -0.62 V) to the benzophenone radical cation BP+, which
is oxidizing enough to convert 1a to radical cation intermediate III
(E1/2BP+/BP = +2.37 V). For [Ir(dF-CF3ppy)2(dtbbpy)]PF6, a similar
catalytic cycle could be proposed when considering its redox
Ir(III)*/Ir(II)
Ir(III)*/Ir(IV)
properties (E1/2
Ir(IV)/Ir(III)
= +1.21 V, E1/2
= -0.89 V and E1/2
Keywords: aminocyclopropanes • ring-opening • photoreaction •
fluorination • benzophenone
= +1.69 V).[21] For the stronger oxidizing Mes-Acr+ dye
(E1/2red = +2.06 V),[25] another mechanism may be operative. After
SET oxidation, III would undergo ring opening to form IV, followed
by radical fluorination with Selectfluor and nucleophilic addition of
water to the iminium to yield 2a. The reversal of regiochemistry
observed compared to the work of Lectka can be tentatively
attributed to the low stability of III leading to ring-opening, whereas
the radical cation obtained from arylcyclopropanes is more stable
and undergoes first nucleophilic addition.
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Scheme 6. Speculative reaction mechanism.
In summary, we have developed a strategy for the ring-opening
fluorination of cyclopropylamides and cyclobutylamides using
cheap benzophenone as organophotoredox catalyst. The
hemiaminal products can be converted to other building blocks by
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Angewandte Chemie International Edition
COMMUNICATION
Ming-Ming Wang and Jérôme Waser*
Page No. – Page No.
Oxidative
Fluorination
of
Cyclopropylamides
via
Organic
Photoredox Catalysis
Make it shine: We report
a
photocatalyzed ring-opening fluorination of
cyclopropylamides and cyclobutylamides. Both cheap benzophenone with UV A light or
organic and inorganic dyes with blue light could be used to promote this process. Various
fluorinated amines were then obtained by nucleophilic attack on the formed hemiaminals
in one pot, giving access to a broad range of useful building blocks for medicinal chemistry.
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