Palladium-Catalyzed Site-Selective Fluorination of Unactivated C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.5b01710

The transition-metal-catalyzed direct C-H bond fluorination is an attractive synthetic tool toward the preparation of organofluorines. While many methods exist for the direct sp³ C-H functionalization, site-selective fluorination of unactivated sp³ carbons remains a challenge. Direct, highly site-selective and diastereoselective fluorination of aliphatic amides via a palladium-catalyzed bidentate ligand-directed C-H bond functionalization process on unactivated sp³ carbons is reported. With this approach, a wide variety of β-fluorinated amino acid derivatives and aliphatic amides, important motifs in medicinal and agricultural chemistry, were prepared with palladium acetate as the catalyst and Selectfluor as the fluorine source.

Full text of DOI:10.1021/acs.orglett.5b01710

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Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Site-Selective Fluorination of Unactivated
C(sp3)−H Bonds
Jinmin Miao,†,§ Ke Yang,‡,§ Martin Kurek,† and Haibo Ge*,†
†Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202,
United States
‡Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: The transition-metal-catalyzed direct C−H bond fluorination is
an attractive synthetic tool toward the preparation of organofluorines. While
many methods exist for the direct sp3 C−H functionalization, site-selective
fluorination of unactivated sp3 carbons remains a challenge. Direct, highly site-
selective and diastereoselective fluorination of aliphatic amides via a palladium-
catalyzed bidentate ligand-directed C−H bond functionalization process on
unactivated sp3 carbons is reported. With this approach, a wide variety of β-fluorinated amino acid derivatives and aliphatic
amides, important motifs in medicinal and agricultural chemistry, were prepared with palladium acetate as the catalyst and
Selectfluor as the fluorine source.
luorine substitution is of great interest in the fields of
Interestingly, closely related reports were published after
Fmedicinal chemistry, agricultural chemistry, and material original submission of this work.16
science.1 Fluorinated compounds affect nearly all physical and
chemical properties including stability, solubility, lipophilicity,
conformation, and bioavailability compared to the parent
molecules.2 It has been estimated that fluorine-containing
molecules account for about 25% of all pharmaceuticals and
30−40% of agrochemicals, including three of the top five best-
selling drugs in 2013.3 Furthermore, the importance of fluorine
in medical imaging technologies has also been demonstrated.4
Therefore, the selective incorporation of a fluorine atom into
biologically relevant organic molecules has continuously been
an active research area in organic chemistry over the past 40
years.5
Transition-metal-catalyzed C−H functionalization has been
extensively studied in past decades due to the avoidance of the
prefunctionalization step in this process compared to the
classical approaches.6 Within this reaction class, site-selective
direct fluorination of aromatic C−H bonds has been
documented recently via a palladium or copper catalysis.7
Despite a challenging process, transition-metal-catalyzed direct
fluorination of sp3 carbons has also been established.8 Copper,9
iron,10 manganese,11 palladium,12 silver,13 and vanadium14 have
all been demonstrated as effective catalysts in this process.
However, current studies on unactivated sp3 C−H bonds suffer
from low to moderate site selectivity. In addition, fluorination
on C−H bonds of the relatively reactive benzylic or allylic sp3
carbons is typically favored over that on unactivated sp3 bonds,
which limits the potential applications of this approach.
Inspired by the Pd-catalyzed ligand-directed C−H functional-
ization of unactivated β-sp3 carbons of amides,15 we have
investigated and report here the direct site-selective fluorination
of α-amino acid derivatives and aliphatic amides via palladium
catalysis with the assistance of a bidentate directing group.
Fluorine-containing amino acids have attracted considerable
attention in past decades due to the importance of these
compounds in medicinal chemistry research.17 Current
synthetic methods of these molecules primarily relied on the
nucleophilic substitution reaction, which requires preinstalla-
tion of a functional group to the C−H bonds.18 In order to
provide a direct synthetic approach for fluorinating unactivated
sp3 carbons, we began our investigation on palladium-catalyzed
fluorination of amino acid derivatives with the assistance of a
bidentate ligand. Although 8-aminoquinoline has been widely
used as a directing group for transition-metal-catalyzed C−H
functionalization, electrophilic aromatic substitution on this
moiety could be a potential problem with an electrophilic
fluorine reagent. Therefore, 2-(pyridin-2-yl)isopropyl amine19
was chosen as the directing group for fluorination of the 2-
aminobutyric acid derivative 1a (Scheme 1). Initial studies
showed that a trace amount of desired β-fluorinated product 2a
could be observed with 1-chloromethyl-4-fluoro-1,4-diazonia-
bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) as the
fluorinating reagent in dichloroethane (entry 1). To our delight,
the reaction yield was significantly improved with the addition
of stoichiometric amounts of AgOAc or Ag2CO3 (entries 3 and
4). Next, an extensive solvent screening was carried out, and the
mixture of dichloroethane and isobutyronitrile proved to be
optimal, providing 2a in 38% yield (entry 11). It was then
found that replacement of Selectfluor with another fluorinating
reagent gave no or only a trace amount of product (entries 13−
15). Further screening of the palladium catalysts showed that
Pd(OAc)2 is optimal although several other catalysts could also
Received: June 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01710
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
ab
,
Scheme 1. Optimization of Reaction Conditions
Scheme 2. Scope of Amino Acid Derivatives
a
Reaction conditions: 1 (0.30 mmol), Pd(OAc)2 (10 mol %),
Selectfluor (2.5 equiv), Ag2CO3 (2.0 equiv), Fe(OAc)2 (0.3 equiv),
b
iPrCN (300 μL), 3.0 mL of DCE, 150 °C, air, 14 h. Isolated yields.
c
d
0.25 equiv of Fe(OAc)2. Without Fe(OAc)2. PIP = 2-(pyridin-2-
yl)isopropyl.
diastereoselectivities (2a−e). In addition, the cyclic amino acid
derivative, benzyl-2-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)-
piperidine-1-carboxylate (1f), was an effective substrate,
affording the desired product 2f in 82% yield. Moreover, a
predominant preference of functionalizing β-C−H bonds over
the relatively reactive benzylic γ-C−H bonds was also observed
(2d), distinguishing this process from the current direct
fluorination methods which favor the benzylic C−H bonds.
Furthermore, phenylalanine and naphthylalanine derivatives
were also effective substrates, providing the corresponding β-
fluorinated amino acid derivatives in good yields with excellent
diastereoselectivities (2g−l). Additionally, the structure and
absolute configuration of the phenylalanine derivative L-2g
(CCDC no. 1052086) were confirmed with X-ray analysis
(Figure 1).
a
Reaction conditions: 1a (0.30 mmol), Pd source (10 mol %), F
source (2.5 equiv), Ag2CO3 (2.0 equiv), additive, solvent, 150 °C, air,
b
14 h. Yields are based on 1a, determined by 1H NMR using
dibromomethane as internal standard. 2.5 equiv of F1 were used
instead of Selectfluor. 2.5 equiv of F2 were used instead of
Selectfluor. 2.5 equiv of F3 were used instead of Selectfluor. Isolated
yield, dr = 7:1. Selectfluor = 1-chloromethyl-4fluoro-1,4-diasonia-
bicyclo[2.2.2]octanebis(tetrafluoroborate). F1 = 1-Fluoro-2,4,6-
trimethylpyridinium triflate. F2 = 2,6-Dichloro-1-fluoropyridinium
triflate. F3 = N-Fluorobenzenesulfonimide.
c
d
e
f
provide the desired product (entries 16−18). Interestingly, the
addition of Mn(OAc)2 or Fe(OAc)2 significantly improved the
reaction yield, with 0.3 equiv of Fe(OAc)2 giving the best result
(entries 19−21). As we expected, this reaction showed high site
selectivity by favoring β-C−H bonds due to the preference of
the formation of a five-membered ring intermediate in the
cyclopalladation step. Delightfully, high diastereoselectivity was
also observed by favoring the anti diastereoisomer. It is
noteworthy that only low to moderate diastereoselectivities
have been reported in previous Pd-catalyzed sp3 C−H
functionalizations of linear aliphatic α-amino acids with
relatively small functional groups, such as Me,15g OMe,18a
and OAc.20 It should be mentioned that, under the optimized
conditions, 2-(1,3-dioxoisoindolin-2-yl)-N-(quinolin-8-yl)-
butanamide with 8-aminoquinoline as the bidentate directing
group failed to provide the corresponding β-fluorinated
product.
Next, a substrate scope study of nonamino acid aliphatic
amides was carried out. As shown in Scheme 3, both linear and
α-branched aliphatic amides afforded the desired products in
With optimized conditions in hand, the scope of amino acids
was studied (Scheme 2). As expected, good yields were
obtained with linear aliphatic amino acid derivatives with high
Figure 1. X-ray crystal structure of L-2g.
B
DOI: 10.1021/acs.orglett.5b01710
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Organic Letters
Letter
ab
,
Scheme 3. Scope of Aliphatic Amides
Scheme 5. Synthesis of D-2g
(Figure 2). Coordination of amide 1 or 3 to a palladium species
followed by a base-promoted ligand exchange process produces
a
Reaction conditions: 3 (0.30 mmol), Pd(OAc)2 (10 mol %),
Selectfluor (2.5 equiv), Ag2CO3 (2.0 equiv), Fe(OAc)2 (0.75 equiv),
b
MeCN (400 μL), 3.0 mL of DCE, 150 °C, air, 14 h. Isolated yields.
c
d
e
3.0 equiv of Selectfluor. 0.2 equiv of Fe(OAc)2. Without Fe(OAc)2.
f
0.5 equiv of Fe(OAc)2. PIP = 2-(pyridin-2-yl)isopropyl.
Figure 2. Proposed catalytic cycle of β-fluorination.
good yields under modified reaction conditions (4a−l).
Similarly, functionalization of β-C−H bonds was favored over
the relatively reactive benzylic γ- or δ-C−H bonds (4d and 4e).
As expected, high diastereoselectivity was also observed with α-
branched aliphatic amides (4g−l). Furthermore, it was found
that the current process favored functionalization of β-C−H
bonds of the sp3 carbons over γ-C−H bonds of the sp2 carbons,
indicating that formation of a five-membered ring intermediate
is preferred to the six-membered ring intermediate in the
cyclopalladation step (4k and 4l).
To further demonstrate the synthetic utility of this
fluorination method, removal of the protecting and the
directing group PIP was carried out, and the corresponding
products were obtained in good yields (Scheme 4).
the palladium complex A. Subsequently, cyclometalation of the
palladium complex A occurs to generate the intermediate B via
a C−H bond activation process. Oxidative addition of the
intermediate B with Selectfluor provides the palladium(IV)
species C, which then gives rise to the final product 2 or 4 via
reductive elimination followed by ligand dissociation.22
Although the exact role of Ag2CO3 in the reaction is not
clear, it is believed that this species participates in the ligand
exchange and subsequent C−H bond cleavage steps by acting
as a base, and also possibly promotes the oxidative addition of
Selectfluor to the intermediate B. On the other hand, the role
of Fe(OAc)2 in the reaction could be the promotion of
releasing Pd(II) species from the intermediate D.
Scheme 4. Removal of Protecting Group and Directing
Group
In summary, the palladium-catalyzed ligand-directed highly
site-selective fluorination of amino acid derivatives and aliphatic
amides was developed via an sp3 C−H bond functionalization
process. This reaction showed high diastereoselectivity and
good functional group compatibility. Additionally, a great
preference for functionalizing the C−H bonds of β-sp3 carbons
over those of relatively reactive γ-sp2 or benzylic sp3 carbons
was observed. As mentioned earlier, current methods for the
direct fluorination of unactivated sp3 carbons suffer from poor
site selectivity, incompatibility with benzylic carbons, and low
diastereoselectivity in many cases. Therefore, this reported
process provides a complementary and advantageous approach
to access fluorine-containing organic molecules. The detailed
mechanistic study of this transformation is currently underway
in our laboratory.
In addition, no apparent racemization of the α-chiral center
was observed during the fluorination of the D-2-(1,3-
dioxoisoindolin-2-yl)-3-phenyl-N-(2-(pyridin-2-yl)propan-2-
yl)propanamide (D-1g) (Scheme 5).
On the basis of the above obtained results and the previous
reports,7,12b,21 a plausible reaction mechanism is proposed
C
DOI: 10.1021/acs.orglett.5b01710
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical data for products, NMR
spectra of products. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01710.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: geh@iupui.edu.
Author Contributions
§J.-M.M. and K.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Xuesong Wu (Indiana University Purdue University
Indianapolis) for his valuable discussion on this project. We
gratefully acknowledge Indiana University-Purdue University
Indianapolis and NSF CHE-1350541 for financial support. We
are also grateful for financial support from the Robert A. Welch
Foundation (D-1361, USA), NSFC (No. 21332005), and the
Jiangsu Innovation Programs (P. R. China).
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