Efficient synthesis of secondary alkyl fluorides via suzuki cross-coupling reaction of 1-halo-1-fluoroalkanes

Article abstract of DOI:10.1021/ja504089y

Organofluorine compounds have found extensive applications in various areas of science. Consequently, the development of new efficient and selective methods for their synthesis is an important goal in organic chemistry. Here, we present the first Suzuki c

Full text of DOI:10.1021/ja504089y

Communication
pubs.acs.org/JACS
Efficient Synthesis of Secondary Alkyl Fluorides via Suzuki Cross-
Coupling Reaction of 1‑Halo-1-fluoroalkanes
Xiaojian Jiang, Sekarpandi Sakthivel, Kseniya Kulbitski, Gennady Nisnevich, and Mark Gandelman*
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel
S
* Supporting Information
Scheme 1. Proposed Conversion of Geminal 1-Fluoro-1-
Haloalkanes to Secondary Alkyl Fluorides
ABSTRACT: Organofluorine compounds have found
extensive applications in various areas of science.
Consequently, the development of new efficient and
selective methods for their synthesis is an important goal
in organic chemistry. Here, we present the first Suzuki
cross-coupling reaction which utilizes dihalo compounds
for the preparation of secondary alkyl fluorides. Namely,
an unprecedented use of simple 1-halo-1-fluoroalkanes as
3
3
3
2
electrophiles in Csp -Csp and Csp -Csp cross-couplings
allows for the formal site-selective incorporation of F-
group in the alkyl chain with no adjacent activating
functional groups. Highly effective approach to the
electrophilic substrates, 1-halo-1-fluoroalkanes, via iodode-
carboxylation of the corresponding α-fluorocarboxylic
acids is also presented. The conceptually new route to
organofluorides was used for the facile preparation of
biomedically valuable compounds. In addition, we
demonstrated that an asymmetric version of the developed
reaction for the stereoconvergent synthesis of chiral
secondary alkyl fluorides is feasible.
distant to functional groups positions. To the best of our
knowledge, geminal fluoro-haloalkanes with no adjacent func-
tional group and with β-hydrogens have not been utilized in
cross-coupling chemistry previously.5 One of the reasons might,
apparently, be a need in reliable and efficient methods for their
synthesis.6
In this paper, we report a novel and efficient method for a
straightforward and general synthesis of secondary fluoroalkanes
via unprecedented Suzuki cross-coupling reaction of geminal
dihaloalkanes. We describe the utilization of 1-halo-1-fluoroal-
kanes in catalytic cross-coupling reaction, namely Suzuki
3
3
3
alkylation (Csp -Csp bond construction) and arylation (Csp -
2
Csp bond construction) processes, which allows for a site-
selective fluorination of alkyl chain with no activating functional
group neighboring to C-F unit. Moreover, we demonstrate that
an asymmetric version of the developed reaction for the synthesis
of highly enantiomerically enriched secondary alkyl fluorides
starting from racemic 1-fluoro-1-haloalkanes is feasible. Facile
and general synthesis of electrophilic substrates, geminal 1-
fluoro-1-haloalkanes (RCHFX; X = I, Br, Cl), through the
application of the iododecarboxylation reaction, recently
developed in our group, to α-fluorocarboxylic acids is also
disclosed here.7
Recently, we reported an efficient, robust, and general
synthesis of alkyl iodides from carboxylic acids through their
simple treatment with commercially available diiododimethylhy-
dantoin (DIH) under VIS irradiation (Scheme 2).7 We now
report that α-fluorocarboxylic acids react smoothly with DIH in
dichloroethane under VIS-irradiation to generate the corre-
sponding 1-fluoro-1-iodoalkanes in high yields (Scheme 2a). The
resulting geminal fluoro-iodoalkanes (not stable under chroma-
tography conditions) can be isolated in an essentially pure form
and in high yields after a simple aqueous workup of the reaction
mixture.8 These compounds can be converted to the
corresponding more stable bromo/chloro-fluoroalkanes by
nucleophilic displacement with tetraethylammonium bromide
rganofluorine compounds have found substantial applica-
1
Otions in various areas of chemistry. Especially, the ability
of a fluorine-substituent to change the dipole moment, enhance
metabolic stability, and improve target-binding affinity of a
compound has made organic fluorides extremely important tools
in drug discovery and biomedical investigations.2 As such,
considerable efforts have been directed toward the development
of efficient synthetic strategies to prepare organofluorine
compounds.3 Notwithstanding, site-selective and general
approaches to the preparation of aliphatic C-F bonds remain
challenging. Although some approaches to secondary alkyl
fluorides exist, the majority depends on specific reactivity
enabling functional groups such as ketone, ester, nitrile, olefin
for introduction of the fluoride substituent.3,4 A general and
effective method for the site-selective incorporation of F-group at
any desired position in an alkyl chain would be a significant
scientific advance and an important complement for the
preparation of tailor-made secondary fluorides.
In this respect, geminal fluoro-haloalkanes A constitute highly
attractive starting materials for such a method (Scheme 1).
Indeed, a catalytic carbon-carbon bond formation via selective
functionalization of the C-X bond of A, i.e., a cross-coupling
reaction, would result in a facile and flexible synthesis of
secondary alkyl fluorides B. If successful, it would allow for a
formal site-selective fluorination of simple alkyl chain at the
Received: April 24, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja504089y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 2. Generation of Geminal Fluoro-Haloalkanes via
Iododecarboxylation Process
Table 1. Optimization of Cross-Coupling Conditions
(TEAB) and tetrabutyl ammonium chloride (TBAC), respec-
tively (Scheme 2b). All 1-fluoro-1-haloalkanes presented herein
(Tables 2, 4, and 5) were prepared by this approach, starting
from the corresponding α-fluorocarboxylic acids, in a selective
manner and high yields.8 This method, for the first time, allows
an access to 1-fluoro-1-haloalkanes from simple carboxylic acids.9
Having an efficient synthetic access to an array of geminal
fluoro-haloalkanes in hand, we examined their use as electro-
philes in the Suzuki cross-coupling reaction. We relied on the
substantially different dissociation energy of C-X (X = I, Br, Cl)
and C-F to enable selective activation of the C-X bond with an
appropriate metal catalyst.10 The seminal work of Fu et al. has
made Suzuki Csp -Csp cross-couplings of alkyl halides a main-stay
in contemporary organic chemistry.11 Gratifyingly, adopting this
chemistry and optimizing the reaction conditions for Suzuki
cross-coupling of 1-fluoro-1-haloalkanes with alkyl BBN, we
were able to prepare the desired secondary alkyl fluorides with
high selectivity and yields.
a
1a (0.3 mmol), 2a (0.6 mmol), NiCl2·glyme (0.03 mmol), ligand
3
3
(0.036 mmol), KOt-Bu (0.42 mmol), i-BuOH (0.6 mmol) in 3 mL
solvent. Isolated yield. n.r. = no reaction.
b
Table 2. Scope of Geminal Bromo-Fluoroalkanes for the
Catalytic Synthesis of Secondary Alkyl Fluoride
a
Although useful for coupling reactions (vide infra), 1-fluoro-1-
iodoalkanes are less stable than their bromo- and chloro-analogs.
Therefore, optimization of the reaction parameters was carried
out using 1-bromo-1-fluoroalkanes as starting materials. The
optimal conditions for Ni-catalyzed cross-coupling of 1-bromo-
1-fluoroalkanes with alkyl-9-BBN to generate secondary alkyl
fluoride, as well as factors influencing this reaction, are presented
in Table 1. We found that a Ni(II) catalyst and a diamine ligand
are necessary for the cross-coupling process (compare entries 1−
3). Utilizing other sources of Ni(II) or Ni(0) instead of NiCl2·
glyme leads to somewhat lower yields (entries 5−7). While 4 is
comparable to ligand 3 in terms of yield, ligand 5 proved to be
less effective (entries 8 and 9). Using other solvents, e.g.,
diisopropyl ether or THF, results in slight decrease in yield
(entries 10 and 11). The inferior yield is also observed when
lower loadings of Ni catalyst and ligand, as well as changes in their
ratio, are employed (entry 12).
a
The optimized reaction conditions allow the efficient Suzuki
cross-coupling of a wide variety of 1-bromo-1-fluoroalkanes with
alkyl boranes (Table 2). Entries 1−4 show that by alternating the
length of the alkyl unit in the substrate, the C-F motif can be
selectively placed at any desired position in the chain of the
product. This ability to introduce a C-F unit at a completely
unactivated position in the alkyl chain underscores the power of
this method. Remarkably, the reaction is efficient, despite the
presence of potentially eliminable β-hydrogens in the starting
material. The 1-bromo-1-fluoroalkanes can be decorated with a
diverse array of functional groups. For instance, the reaction
tolerates amides, sulfonamides, carbonyls, ethers, and esters
(entries 7−11). In cases of amides and sulfonamides, catalyst
NiBr2·diglyme gives higher yields than NiCl2·glyme (entries 10,
11). In all cases the secondary alkyl fluorides are obtained in high
yields.
1 (0.5 mmol), 2b (1.0 mmol), NiCl2·glyme (0.05 mmol), 3 (0.06
mmol), KOt-Bu (0.7 mmol), i-BuOH (1.0 mmol) in 5 mL solvent.
b
c
Isolated yield. NiBr2·diglyme as catalyst, 4 as ligand, iPr2O as solvent.
A wide range of alkyl boranes is compatible with our method,
which provides an additional illustration of the versatility of this
approach to fluoroalkanes (Table 3). While symmetrically
substituted trialkylboranes proved highly efficient in the reaction
(entry 7), we continued to focus on alkyl-9-BBN for obvious
synthetic reasons. We found that 9-BBN-based alkyl nucleo-
philes bearing functional groups such as aryls, ethers, esters, and
amines participated in the reaction to furnish the desired cross-
coupling products in high yields (entries 2−6, 9−10).
Interestingly, triaryl boranes are also compatible with this
methodology, which provides access to formation of C-F units by
B
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Journal of the American Chemical Society
Communication
the starting material that partially poisons the Ni catalyst (entries
1−3). Indeed, employment of 1-fluoro-1-bromoalkane in this
reaction with controllable addition of the trace amounts of iodine
leads to the reduced yields. In the case of the 1-fluoro-1-chloro-
alkanes, the difficulty of cleaving the stronger C-Cl bond may
account for the slightly lower yield (entries 2, 5−16).12
Table 3. Scope of Organoboranes for the Catalytic Synthesis
of Secondary Alkyl Fluorides
a
The present method can be applied to the synthesis of
biochemically valuable fluorinated compounds. For example,
spirolaxine derivative 9 is reported to exhibit antibacterial
activity.13 We prepared its fluorinated analog 10, in a facile
manner by Ni-catalyzed cross-coupling of the 1-fluoro-1-
bromoalkane 1g and alkyl-BBN 2o in 71% isolated yield
(Scheme 3a). We arbitrarily choose to introduce the fluorine at
Scheme 3. Syntheses of 10 and 12
a
1a (0.5 mmol), 2 (1.0 mmol), catalyst (0.05 mmol), 3 (0.06 mmol),
b
KOt-Bu (0.7 mmol), i-BuOH (1.0 mmol) in dioxane (5 mL). Isolated
yield. R3B as organo borane source, 1b as substrate, 4 as ligand, iPr2O
c
as solvent.
3
2
Csp -Csp bond formation. For example, Ph3B reacts smoothly
with substrate 1b to produce 6s in 89% yield (entry 8).
The protocol is not limited to 1-bromo-1-fluoroalkanes as
starting materials. 1-Fluoro-1-iodoalkanes (7a−c) and 1-chloro-
1-fluoroalkanes (8a−e) can also serve as electrophiles to furnish,
after cross-coupling, secondary fluoroalkanes in moderate to
good yields (Table 4). We speculate that the lower yields
observed for 1-fluoro-1-iodoalkanes, compared to their 1-fluoro-
1-bromo-counterparts, may be due to trace amounts of iodine in
C(4) of the alkyl chain of 9. However, all other possible
fluorinated analogues of 10 should be accessible using the same
strategy. Consequently, this method constitutes a strategic entry
to prepare biologically active compounds that are fluorinated at
preselected alkyl positions.
Table 4. 1-Fluoro-1-Iodo/Chloroalkanes in the Catalytic
Synthesis of Secondary Alkyl Fluorides
a
As an additional example of the utility of our method, we have
prepared 11-fluorotetradecanoic acid 12 which exhibit inhibitory
activity of Δ11 desaturase.14
This compound is straightforwardly and efficiently synthesized
by catalytic cross-coupling of 1-bromo-1-fluoroester 1i and
propyl BBN followed by a subsequent hydrolysis of the resulting
ester 11 (Scheme 3b).
The secondary alkyl fluorides described above were all
prepared as racemic mixtures. However, a stereoconvergent
synthesis of enantiomerically enriched secondary alkyl fluorides
may be envisioned if a suitable chiral catalyst is identified.
Delightfully, preliminary studies show that this is feasible. Thus,
we were able to prepare the chiral secondary alkyl fluorides 14
possessing stereogenic C-F center by the cross-coupling of
racemic sulfonamides 1l−p and organoborane 2c using Ni
catalyst and chiral ligand 13 with high enantioselectivity (91%
ee), albeit with modest yield (Table 5). Further studies are
required in order to improve efficiency and extend a scope of this
transformation.
In conclusion, we have established the first Suzuki cross-
coupling reaction that utilizes geminal dihaloalkanes as starting
materials for the efficient and general synthesis of secondary
fluoroalkanes. Moreover, we have demonstrated, for the first time
that simple 1-fluoro-1-haloalkanes with no adjacent functional
groups can be powerful electrophiles for the cross-coupling
a
1 (0.5 mmol), 2b (1.0 mmol), catalyst (0.05 mmol), 4 (0.06 mmol),
b
KOt-Bu (0.7 mmol), i-BuOH (1.0 mmol) in 5 mL iPr2O. Isolated
yield.
C
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Journal of the American Chemical Society
Communication
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Table 5. Enantioselective Catalytic Synthesis of Secondary
Alkyl Fluoride
a
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Reactions were carried out with substrate 1 (0.2 mmol), 2c (0.4
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(0.28 mmol), i-BuOH (0.4 mmol) in i-Pr2O (4 mL). Yields are
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3
2
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processes. A wide array of 1-fluoro-1-haloalkanes is now available
by the efficient methodology for their synthesis, which is
reported in this work. The developed cross-coupling method
employing these geminal dihalo compounds represents a
conceptually new approach for the preparation of a variety of
secondary alkyl fluorides possessing β-hydrogens and having no
adjacent activating functional groups. Using this approach, site-
selectively fluorinated analogs of bioactive molecules as well as
known C-F containing compounds with interesting biomedical
properties can be facilely prepared. Direct asymmetric catalytic
stereoconvergent synthesis of enantioenriched secondary alkyl
fluorides from the racemic mixture of 1-fluoro-1-haloalkanes
proved feasible and is currently under further investigation in our
laboratories.
(7) Kulbitski, K.; Nisnevich, G.; Gandelman, M. Adv. Synth. Catal.
2011, 353, 1438.
(8) See SI.
(9) Conversion of HOOC(CF2)3COOH to X(CF2)3X with XeF2 and
X2 (X = Cl, Br) was reported: Brel, V. K.; Uvarov, V. I.; Zefirov, N. S.;
Stang, P. J.; Caple, R. J. Org. Chem. 1993, 58, 6922.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(10) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
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(12) The oxidative addition/abstraction process may be the rate-
limiting step in the Ni-catalyzed cross-coupling reaction with alkyl
chlorides: Lin, X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680.
(13) Dekker, K.; Inagake, T.; Gootz, T.; Kaneda, K.; Nomura, E.;
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AUTHOR INFORMATION
Corresponding Author
chmark@tx.technion.ac.il
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from German-Israeli Project Cooperation
(DIP) and KAMIN program of the Industry, Trade and Labour
Ministry is acknowledged.
(14) Abad, J. L.; Villorbina, G.; Fabrias
865.
̀
, G.; Camps, F. Lipids 2003, 38,
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