Site-Selective Tertiary Alkyl–Fluorine Bond Formation from α-Bromoamides Using a Copper/CsF Catalyst System

Article abstract of DOI:10.1002/anie.201603426

A copper-catalyzed site-selective fluorination of α-bromoamides possessing multiple reaction sites, such as primary and secondary alkyl?Br bonds, using inexpensive CsF is reported. Tertiary alkyl?F bonds, which are very difficult to synthesize, can be formed by this fluorination reaction with the aid of an amide group. Control experiments revealed that in situ generated CuF₂is a key fluorinating reagent that reacts with the tertiary alkyl radicals generated by the reaction between an α-bromocarbonyl compound and a copper(I) salt.

Full text of DOI:10.1002/anie.201603426

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603426
German Edition: DOI: 10.1002/ange.201603426
Fluorination
Site-Selective Tertiary Alkyl–Fluorine Bond Formation from
a-Bromoamides Using a Copper/CsF Catalyst System
Takashi Nishikata,* Syo Ishida, and Ryo Fujimoto
Abstract: A copper-catalyzed site-selective fluorination of
a-bromoamides possessing multiple reaction sites, such as
primary and secondary alkylÀBr bonds, using inexpensive CsF
is reported. Tertiary alkylÀF bonds, which are very difficult to
synthesize, can be formed by this fluorination reaction with the
aid of an amide group. Control experiments revealed that in
situ generated CuF is a key fluorinating reagent that reacts
2
with the tertiary alkyl radicals generated by the reaction
between an a-bromocarbonyl compound and a copper(I) salt.
Figure 1. Previous reports and the current study.
N
ucleophilic fluorination reactions using fluorides are one
[
1,6–8]
of the most important methods of forming CÀF bonds from
a highly challenging issue in fluorination chemistry.
In
[1]
carbon electrophiles, such as those with C–halogen bonds.
Although the synthesis of aryl fluorides has been studied
extensively, studies on the development of alkyl fluoride
synthesis are rare. The Finkelstein reaction is one of the
conventional choices for synthesizing primary and secondary
alkyl fluorides by nucleophilic substitution, in which an alkali
this context, we aim to achieve the copper-catalyzed site-
selective fluorination of tertiary alkyl bromides using CsF as
a low-cost fluorinating reagent (Figure 1b).
[
2]
[
3]
The Finkelstein reaction is very useful for obtaining CÀF
bonds, but tertiary alkyl–F bond formation is very difficult.
For example, primary and secondary alkyl–F bonds formed in
[
1]
[9]
fluoride MF (M = Li, Na, K, Rb, Cs) reacts with alkyl
bromide, iodide, or tosylate. However, this reaction is not
attractive for the synthesis of fluorinated fine chemicals
because a Finkelstein reaction involving an alkali fluoride is
very sensitive to water, as the fluorides have a strong tendency
to form hydrogen bonds with water molecules to decrease the
nucleophilicity of the fluoride ions. Therefore, researchers
have focused on the development of new nucleophilic and
electrophilic fluorinating reagents, such as Selectfluor, NFSI,
DAST, PyFluor, Phenofluor, Deoxo-Fluor, XtalFluor, and
Fluolead. These fluorinating reagents are very useful and
reactive, but they are also much more expensive than alkali
fluorides, and their cost might suppress further development
in fluorination chemistry for industrial purposes.
Other problems facing researchers in fluorination chemis-
try include 1) site selectivity in the fluorination reaction of
a substrate possessing more than two active reaction sites and
the presence of CsF in yields of 47 and 14%, respectively,
but tertiary alkyl–F bonds did not form (Scheme 1).
Scheme 1. Finkelstein reaction. THF=tetrahydrofuran.
Our first trial of the fluorination reaction employed
a-bromoisobutyryl carbonyl compounds (1) as model com-
pounds (Scheme 2). It is well known that the reaction of
a copper salt with 1 gives alkyl radical species by atom
transfer radical addition, atom transfer radical polymeri-
zation, and our previous tertiary alkylations of styrenes.
There have been a few examples of radical fluorination
[4]
[
10]
[11]
[12]
[
13–15]
reactions,
but the site selectivity of radical fluorination
2
) fluorination of tertiary alkyl groups with a cheap F source
reactions has not been examined. In the presence of copper-
(I)/tris(2-pyridylmethyl)amine (TPMA) or 1,10-phenanthro-
line (Phen) and CsF, the desired fluorinated product 2 was not
obtained when using either an ester or a ketone, most likely
because electron-deficient radicals are not reactive toward
(
Figure 1a). Recent progress in this field has been achieved
by Ritter and co-workers, who reported a very interesting
site-selective deoxyfluorination of aliphatic alcohols using
PhenoFluor as an electrophilic fluorinating reagent. How-
ever, the site-selective fluorination of alkyl substrates pos-
sessing primary, secondary, and tertiary alkyl–X bonds (X =
halogen, OH, boron, or another leaving group) remains
[5]
[7a,13,14]
a fluorination source.
However, the amide 1a under-
went the corresponding fluorination reaction to produce 2a in
19% yield. We speculated that an amide group affects the
[*] Prof. Dr. T. Nishikata, S. Ishida, R. Fujimoto
Graduate School of Science and Engineering, Yamaguchi University
2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611 (Japan)
E-mail: nisikata@yamaguchi-u.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603426.
Scheme 2. Fluorination of various carbonyl compounds.
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[
a]
fluorination step with an active fluorination species, such as
CuF . Recently, Loh reported copper-catalyzed amide-
Table 1: Fluorination of 1 under optimized reaction conditions.
2
[
16]
directed trifluoromethylation with Togniꢀs reagent.
By
controlling the acidity of the amide moiety as a directing
group, they obtained stereoselective CÀCF bonds. Similarly,
3
we expect that the nitrogen atom of the amide group plays an
important role in our fluorination reaction.
Based on our preliminary results, optimization studies
were conducted using the combination of 2-bromo-2-methyl-
N-phenylpropanamide (1a; 1 equiv) and a fluorination
reagent (1 equiv) in the presence of CuBr (10 mol%) and
2
Phen (10 mol%) in THF under nitrogen atmosphere
[a] Conducted at 808C for 23 h in THF with 10 mol% CuBr , 10 mol%
2
(
Scheme 3). We suspected that the Finkelstein reaction
PMDETA, CsF (2 equiv), and 1 (1 equiv). Yields are those of isolated
products.
2
b–e, underwent smooth fluorination in good yields, whereas
the less hindered substrates, which led to 2g and 2h, provided
low yields because primary and secondary alkyl radicals are
less stable than tertiary alkyl radicals. In this case, 2g and 2h
[
9]
are considered to form by an S 2 reaction. The p-anisyl-
N
substituted substrate gave 2 f in good yield, thus illustrating
that substrates with tertiary alkyl–Br bonds and N-aryl-
substituted amides reacted smoothly with CsF in the presence
of a copper catalyst. In contrast, N-alkyl-substituted tertiary
amides, such as the substrate leading to 2i, were not reactive.
We next evaluated functional-group compatibilities for
current fluorination using the a-bromoamides 3, which
possess either a primary or secondary alkyl–X or aryl–X
bonds (X = Cl, Br, I, OH, OTs) as a model compound
Scheme 3. Optimization. Conducted at 808C for 23 h in THF with
0 mol% Cu salt, 10 mol% ligand, F source (2 equiv), and 1a
1 equiv). Yields are those of the isolated products.
1
(
[18]
(Table 2). The reactivities of alkyl halides in the fluorina-
would proceed under our reaction conditions. We observed
that the addition of the copper catalyst was crucial for
obtaining the desired fluorinated compound 2a and the
addition of 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT)
suppressed the reaction. This result is one bit of evidence
showing that the current fluorination reaction involves
a radical reaction rather than a nucleophilic reaction. The
choice of the fluorination reagent is very important, and use
of the alkali fluoride CsF resulted in an 80% yield of 2a.
Other alkali fluorides, including LiF, NaF, and KF, were not
effective, most likely because of their solubility. We also
examined various nucleophilic and electrophilic organic
fluorination reagents, such as tetra-n-butylammonium fluo-
tion reaction generally followed the order primary carbon
center > secondary carbon center @ tertiary carbon center,
according to the S 2 reaction rule. In particular, nonfunction-
N
alized primary and secondary alkyl halides and tosylates are
[
3,6]
good substrates for S 2 nucleophilic fluorination reactions.
N
Therefore, selective fluorination of tertiary alkyl substrates
containing more than one reactive site is challenging. How-
ever, our reaction system discriminated between different
reactive alkyl–X bonds and produced the corresponding
single-fluorinated product 4 in good yields. In the fluorination
of alkyl halides, alkene formation by an E2 reaction is
[6d]
problematic,
but no alkenes were formed under our
reaction conditions. In each reaction, the selectivity was
perfect. The only challenge was the generation of the proto-
debromination products of 3, as they hindered the separation
of 4. For example, substrates possessing primary or secondary
alkyl halide moieties (3a–e) underwent fluorination only at
the tertiary alkylÀBr to produce the desired products (4a–e)
ride (TBAF), but the reactions were sluggish. CuBr was used
2
in this optimization, but other copper salts, including various
copper(I) and copper(II) salts, were not effective. Although
a copper(I) species is required to obtain an alkyl radical
[
10–12]
intermediate,
copper(II) may give a copper(I) and
[17]
2
2
copper(III) species. In this reaction, a nitrogen ligand is
also important for obtaining 2. Our investigation of reactions
with or without nitrogen ligands revealed that N,N,N’,N’,N’’-
pentamethyldiethylenetriamine (PMDETA), which possesses
three nitrogen atoms, provided the highest yields.
in moderate to good yields. Although C(sp )ÀBr and C(sp )ÀI
bonds are also good reaction sites for catalytic fluorina-
[
2,19]
tion,
the substrates 3h–j underwent fluorination without
2
2
loss of the C(sp )ÀBr and C(sp )ÀI bonds (4h–j). The
substrate 3k, which possesses a tertiary alkyl–OH, is a good
[
5]
Before attempting site-selective fluorination of alkyl
bromides containing two or more reactive bonds, we the
examined monobrominated substrates 1 to assess their basic
reactivities under our optimized reaction conditions
substrate for electrophilic fluorination, and the OH group
did not affect the reaction. The limitation of our reaction
system was observed in the reactions of 3 f and 3g, which
possess iodide and tosyl group moieties, respectively. Both the
fluorination of the tertiary alkyl–Br bond and the bromina-
(
Table 1). The sterically hindered substrates, which led to
2
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[
a]
2
Table 2: Site-selective fluorination tests with model compounds 3.
in 68% yield, whereas 4i and 4n, possessing C(sp )ÀBr bonds,
underwent Suzuki and Heck coupling reactions to produce
the corresponding arylated and 1-alkenylated products,
respectively (6 and 7). These results show that our fluorina-
tion reaction is a powerful technique for synthesizing
fluorinated building blocks.
We next conducted the following control experiments
(Scheme 5: 1) A radical capture test with BHT: The fluori-
nation reaction was inhibited by the addition of BHT, and
indicated that this reaction may involve a radical species.
1
Scheme 5. Control experiments. [a] Yields were determined by H NMR
analysis.
Indeed, we detected alkylated BHT species in the reaction of
1
a with BHT. 2) Copper fluoride effect: A stoichiometric
[
a] Conducted at 808C for 23 h in THF with 10 mol% CuBr , 10 mol%
2
amount of CuF was used instead of CsF as the fluorination
PMDETA, CsF (2 equiv), and 1 (1 equiv). Yields were determined by
2
1
H NMR spectroscopy and GPC. [b] Yield of fluorobrominated product.
c] Yield of product isolated after flash column chromatography.
reagent in the fluorination reaction of 1a. The product 2a was
not obtained when 10 mol% PMDETA was used, but it was
obtained in 33% yield when 150 mol% PMDETA was used.
Excess PMDETA is required to generate an active catalyst,
namely, the copper(I)/PMDETA complex, which is very
[
tion of CÀI and CÀOTs bonds with in situ generated CsBr
[
10,11]
proceeded to form the fluorobrominated product in 28 and
important for generating alkyl radicals from 1a.
When
6
6% yields, respectively. We next examined multibrominated
10 mol% PMDETA was used, no reaction occurred because
most of the PMDETA ligated to the copper(II) species rather
than to the copper(I) species. The fluorination reaction of 1a
with CuF also occurred in the absence of CuBr catalyst
substrates possessing various carbon functionalities on the
carbonyl a-position (3l–o). As demonstrated in the reaction
described above, sterically hindered substrates with tertiary
alkyl–Br bonds also selectively allowed the fluorination
reaction to afford the corresponding products (4l–o) in
moderate to good yields.
The obtained fluorinated products 4, possessing various
active functional groups, were easily converted into a wide
range of derivatives using conventional organic reactions
2
2
(28%). Although copper(I) species are required to generate
alkyl radical species from 1a, CuF2 may generate active
copper(I) species with concomitant formation of copper-
[
17]
(III).
The reaction of a-bromoester in the presence of
a stoichiometric amount of CuF and the reaction with the
2
tertiary amide 1 (Table 1; 2i) did not give the desired product,
likely reflecting that the amide group may act as a directing
group. The importance of the amide NH is also supported by
the reaction leading to 2i. Since it is difficult to coordinate the
(
Scheme 4). The compound 4e reacted with NaI to produce 5
[
16]
tertiary amide group to copper species, NH is required.
From the above results, the catalytic cycle of our copper-
catalyzed fluorination reaction includes, at least, 1) a radical
generation step and 2) a fluorination step involving the alkyl
radical species generated from 1 and CuF (Scheme 6). In the
2
first step, the reaction of a copper salt with 1 gives the alkyl
radical species A. The resulting alkyl radical species react
with CuF , which is generated from the reaction of CuXBr
2
and CsF, with the aid of an amide group (B). Then, the desired
product 2 is obtained with concomitant formation of a copper-
(I) species to complete the catalytic cycle. This cycle would be
a new copper-catalyzed site-selective radical fluorination
reaction.
Scheme 4. Utilities of the fluorinated building blocks. DMF=N,N-
dimethylformamide, dppf=1,1’-bis-(diphenylphosphino)ferrocene.
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Received: April 7, 2016
[
17] a) X. Ribas, D. A. Jackson, B. Donnadieu, J. Mahꢃa, T. Parella, R.
Xifra, B. Hedman, K. O. Hodgson, A. Llobet, T. D. P. Stack,
Revised: May 1, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Fluorination
A picky copper: A copper catalyst system
enables the site-selective fluorination of
multi-brominated tertiary-alkyl com-
pounds with the aid of an amide group.
As the fluorination reagent, inexpensive
T. Nishikata,* S. Ishida,
R. Fujimoto
&&&& — &&&&
Site-Selective Tertiary Alkyl–Fluorine
Bond Formation from a-Bromoamides
Using a Copper/CsF Catalyst System
CsF is used, and CuF was found to be
a reactive intermediate.
2
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!