Dual C-F, C-H Functionalization via Photocatalysis: Access to Multifluorinated Biaryls

Article abstract of DOI:10.1021/jacs.5b13450

Multifluorinated biaryls are challenging to synthesize and yet are an important class of molecules. Because of the difficulty associated with selective fluorination, this class of molecules represent a formidable synthetic challenge. An alternative approach to selective fluorination of biaryls is to couple an arene that already possesses C-F bonds in the desired location. This strategy has been regularly utilized and relies heavily on traditional cross-coupling strategies that employ organometallics and halides (or pseudohalides) in order to achieve the coupling. Herein we report conditions for the photocatalytic coupling via direct functionalization of the C-F bond of a perfluoroarene and C-H bond of the other arene to provide an expedient route to multifluorinated biaryls. The mild conditions and good functional group tolerance enable a broad scope, including access to the anti-Minisci product of basic heterocycles. Finally, we demonstrate the value of the C-F functionalization approach by utilizing the high fluorine content to systematically build complex biaryls containing between two and five C_aryl-F bonds via the synergistic use of photocatalysis and S_NAr chemistry.

Full text of DOI:10.1021/jacs.5b13450

Communication
pubs.acs.org/JACS
Dual C−F, C−H Functionalization via Photocatalysis: Access to
Multifluorinated Biaryls
Sameera Senaweera and Jimmie D. Weaver*
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078, United States
*
S Supporting Information
Scheme 1. Strategies To Access Fluorinated Biaryls
ABSTRACT: Multifluorinated biaryls are challenging to
synthesize and yet are an important class of molecules.
Because of the difficulty associated with selective
fluorination, this class of molecules represent a formidable
synthetic challenge. An alternative approach to selective
fluorination of biaryls is to couple an arene that already
possesses C−F bonds in the desired location. This strategy
has been regularly utilized and relies heavily on traditional
cross-coupling strategies that employ organometallics and
halides (or pseudohalides) in order to achieve the
coupling. Herein we report conditions for the photo-
catalytic coupling via direct functionalization of the C−F
bond of a perfluoroarene and C−H bond of the other
arene to provide an expedient route to multifluorinated
biaryls. The mild conditions and good functional group
tolerance enable a broad scope, including access to the
anti-Minisci product of basic heterocycles. Finally, we
demonstrate the value of the C−F functionalization
approach by utilizing the high fluorine content to
systematically build complex biaryls containing between
Scheme 2. Photocatalytic C−F Functionalization
two and five C −F bonds via the synergistic use of
aryl
photocatalysis and S Ar chemistry.
N
luorinated biaryls are an important class of molecules with
stable catalytic intermediates and leading to sluggish catalyst
turnover. If all of these issues are circumvented, the method must
contend with a C−F regioselectivity issue, since polyfluorinated
arenes contain multiple C−F bonds. In this work (approach D),
we sought to form a new biaryl C−C bond directly from a C−F
bond of the fluoroarene and a C−H bond of the arene partner. It
was expected that realizing this goal would provide rapid access
to new fluorinated chemical space.
1a,b
1c,d
F
many examples in drugs,
agrochemicals,
functional
1e,f
materials such as liquid crystals, organic light-emitting diodes
1
g,h
1i
(
OLEDs), water-splitting sensitizers, and electron transport
1
j,k
materials. While cross-coupling methods have made biaryls
generally accessible, currently far fewer methods exist that lead to
the important class of partially fluorinated biaryls. The synthesis
of fluorinated biaryls has been approached from several
directions. One method is traditional cross-coupling of a
fluorine-containing arene possessing either a halogen or an
organometallic group with a partner substituted with a
While the synthetic advantages of the dual C−F, C−H biaryl
formation are manifold, achieving such a goal would require
solutions for the aforementioned issues. Photocatalysis has been
shown to be capable of reductive cleavage of Ar−X groups, i.e.,
2
complementary reactive group (approach A, Scheme 1).
7
Alternatively, methods characterized by the use of less-
Ar−X to Ar−H. In 2014 we showed that catalytic amounts of
3
functionalized molecules (i.e., H on one or both partners)
fac-Ir(ppy) in the presence of light and an amine reductant
3
4
have also been developed (approach B). Typically, activated
result in highly efficient hydrodefluorination (HDF) (eq 1 in
multifluorinated arenes are derived from the C−F bond in one to
Scheme 2) with excellent regioselectivity and functional group
8
5
a
5b,c
three steps, i.e., C−F to C−H to C−halogen
to C−
tolerance, suggesting that it might provide a novel route for
5
d,e
direct C−F functionalization. Indeed, in 2015 we showed that
the same reactive intermediate could be intercepted with an
alkene (eq 2), which then underwent a subsequent reduction of
organometallic. Consequently, efforts have been made in the
area direct C −F functionalization, which have been focused
6
Ar
primarily on overcoming the difficulties associated with C−F
functionalization (approach C). Among these challenges, C−F
bonds tend to be both kinetically and thermodynamically robust,
and they often form strong metal−fluoride bonds, resulting in
Received: December 24, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b13450
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Journal of the American Chemical Society
Communication
Table 1. Optimization of the Reaction Conditions
Table 2. Reaction Scope with Limiting Perfluoroarene
conv. to
time
(h)
a
entry
modification
1a:1a′ 1a (%)
b
1
2
3
4
5
6
7
8
9
none
5:1
1:2
3:1
47/73
3/19
3/19
3/19
3/19
4/15
5/19
2/17
2/17
2/17
21
b
b
DMF instead of MeCN
22/31
58/58
DMSO instead of MeCN
DCM, THF instead of MeCN
Cat A instead of Ir(ppy)3
c
c
na
na
b
b
6:1
10/52
47/66
<5
Et N instead of DIPEA
4:1
3
without DIPEA
na
b
b
DIPEA (0.5 equiv)
DIPEA (3.0 equiv)
6:1
22/79
40/61
3:1
10
11
12
13
14
iPr Nn-hept instead of DIPEA
< 5%
2:1
2
b
arene−H (1.2 equiv)
arene−H (3.0 equiv)
0 °C, arene−H (3.0 equiv)
57
66
75
71
17
b
3.5:1
6:1
17
b
19
b
0 °C, arene−H (2.4 equiv), DIPEA (0.4 13:1
24
equiv), KHCO (1.2 equiv)
3
1
1
1
1
5
6
7
8
same as 14 with no DIPEA
same as 14 with no fac-Ir(ppy)3
in air
na
na
na
na
1
24
24
19
19
d
nd
11
in the dark
nd
a
a
Determined by 19F NMR analysis. Reaction complete. <20% conv.
to undesired products. Not detected.
b
c
The reaction mixture was degassed by bubbling with Ar for 10 min.
b
d
The yield is for the isomer shown. The minor regioisomers (meta and
c
ortho) were not separated, assigned, or counted for yield. The yield is
the total for the separated isomers.
9
the presumed alkyl radical. We were curious whether the
incipient radical formed as a result of C−C bond formation could
Table 3. Reaction Scope with Limiting Arene−H
9
be oxidized rather than reduced, leading to an alkene. In view of
their propensity to regain aromaticity after temporary loss, arenes
were a logical place to start, since we could use rearomatization to
our advantage to help facilitate the oxidation (eq 3).
10
From the outset, several obvious challenges associated with
the desired reaction were apparent (eq 3): the need to achieve an
11
oxidation of int-a under reducing conditions, the regioselec-
tivity of the C−C coupling event with respect to the Ar−H bond,
and competing HDF. Oxidation of int-a could occur prior to
deprotonation (eq 3a) or afterward (eq 3b). The dominant path
may depend the natures of both arene partners. Nonetheless, we
began our investigation with conditions that had facilitated
8
HDF using pentafluoropyridine with the addition of 6 equiv of
trimethoxybenzene, which removed the possibility of re-
gioisomers (Table 1, entry 1). We were pleased to see that the
desired C−C-coupled product was indeed formed as the major
product in reasonable yield along with a significant amount of the
HDF product. By optimization we hoped to increase the yield
and simultaneously decrease the amount of the arene−H
coupling partner. A survey of solvents (entries 2−4) showed
that both DMF and DMSO provided the desired product, albeit
in lower yields than MeCN, while DCM and THF resulted in low
yields of only undesired products. Next, we screened photo-
catalysts for the ability to influence the product ratio and yield
a
The reaction mixture was degassed by bubbling with Ar for 10 min.
14
it led to byproducts stemming from N-perfluoarylation, which
were substantially decreased by the use of more sterically
cumbersome diisopropylethylamine (DIPEA). Varying the
amount of amine revealed two key features (entries 8−10).
First, both a reduction and an oxidation occur in the same
reaction, which begs the question of whether the amine might
just serve as an initiator. While the amine does demonstrate
1
2
(
entry 5); while a subtle improvement in product ratio was
observed, the reaction was noticeably slower. Next, we evaluated
both the structure of the amine and its loading as reaction
13
parameters (entries 6−10). While Et N worked reasonably well,
3
B
DOI: 10.1021/jacs.5b13450
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3. Utility of C−F Functionalization To Access Complex Multifluorinated Biaryls
a
b
The reaction mixture was degassed by bubbling with Ar for 10 min. The yield is for the isolated product. The regioisomeric ratio (rr) was
1
determined by H NMR analysis of the isolated product.
superstoichiometric activity (entry 8), the reaction becomes
inefficient. Second, too much amine results in increased amounts
of the HDF product 1a′. We previously showed that the use of
less-soluble amines could retard the rate of photocatalytic
limiting reagent and using excess perfluoroarene (Table 3). We
were pleased to see that the reaction worked under these
conditions and allowed the formation of fully substituted biaryls.
Trisubstituted pyrimidines underwent addition to give the C−H-
coupled product (18a−21a). Tetrasubstituted pyrroles also
coupled with the expected C−F selectivity (22a and 23a) to give
biologically relevant pentasubstituted pyrroles (e.g., see Lipitor),
suggesting that it may be possible to use this method to
accomplish late-stage modifications of biologically active
molecules. 19a−21a, in which substitution of the C−Cl or C−
Br bond occurs, indicate a halogen fragmentation pattern
consistent with that of radical anion fragmentation observed by
Bunnett and Rossi (i.e., I > Br > Cl > F). This selectivity is
both an inherent limitation and an opportunity to build
complementary regioisomers. Importantly, use of the fluorinated
arene in excess protects the bromine of product 21a from
subsequent reduction of the C−Br bond, providing the
opportunity for further elaboration by other methods. In general,
the biggest limitation of the method is the use of arene−H
compounds that are either highly substituted or polarized, as this
reduces the number of isomers that are formed.
1
5
reduction. However, in this case, less-soluble iPr Nn-hept
2
(
entry 10; 0.15 M max conc. in MeCN vs 1.3 M for DIPEA, both
at rt) dramatically slowed the reaction. Next, we looked at the
effect of reducing the amount of trimethoxybenzene in hopes
that we could approach near-stoichiometric ratios (entries 11 and
12). As expected, diminishing the amount of arene−H led to
increased amounts of 1a′. Next, we investigated the effect of
temperature. We were pleased to see that dropping the
temperature led to an improved 1a:1a′ ratio (entry 12 vs 13).
Finally, we suspected that the amine plays two roles: as a
reductant that initiates the C−F fragmentation and as a base to
scavenge the HF formed in the reaction. In order to address this,
18
19
we added KHCO (entry 14), which allowed us to simulta-
3
neously lower the loadings of both the amine and trimethox-
ybenzene and achieve the best 1a:1a′ ratio. Finally, controls were
run (entries 15−18) and indicated the necessity of light, catalyst,
and amine as well as the sensitivity toward air.
Using the conditions from Table 1, entry 14, we evaluated the
scope of the reaction (Table 2). We were pleased to see that good
to modest yields could be obtained with electron-rich arenes and
a variety of perfluoroarenes (1a, 9a−17a) as well as with
acetophenones (2a), pyrroles (3a), and nitriles (4a). The ability
of the perfluoroaryl radical to form highly congested C−C bonds
In addition to the esoteric reasons to develop C−F
functionalization chemistry, it also has the potential to be the
most rapid and versatile method for accessing multifluorinated
arenes, which would be useful in discovery chemistry efforts
involving fluorinated aromatics. Specifically, it starts with
readily available perfluorinated arenes that have all of the
difficult-to-install fluorines at the desired positions. The
challenge then becomes selective functionalization of the
unwanted fluorines to build the desired molecule. To
demonstrate this concept and its feasibility, we started with
commercially available perfluoroarenes and subjected them to a
20
(
5a and 6a) is noteworthy. The Minisci reaction is commonly
16
employed to functionalize basic heterocycles. Interestingly, we
observed anti-Minisci selectivity (7a and 8a), likely because the
basic heterocycle is not protonated under these conditions as is
typical in the Minisci reaction. Substrates 11a and 12a suggest
that the method can be used to access extended aryl systems and
that even moderately acidic protons are tolerated under the
reaction conditions. 13a indicates that the second site of
photocatalytic C−F functionalization occurs ortho to the nitrile.
series of both photocatalytic and S Ar functionalizations. This
N
allowed us to rapidly obtain multifluorinated benzoates and
pyridines that would be very difficult to synthesize by any other
method, thus allowing access to new fluorinated chemical space
(Scheme 3). Addition of a Meldrum’s acid derivative followed by
decomposition in the presence of a nucleophile gave a near-
quantitative yields of the products of α-perfluoroarylation (24a
14a shows the preference for the 3-Cl fragmentation over that of
the fluorines, allowing access to complementary regioisomers.
Comparison of 15a and 16a demonstrates that both the 2- and 4-
8
,9,17
21
positions of the perfluorobenzoate system are accessible.
and 26a). Photocatalytic arylation then desymmetrized the
Hexafluorobenzene, devoid of electron-withdrawing functional
groups, which would facilitate reduction, also undergoes
arylation (17a). In general, the scope is broad in terms of the
fluoroarene while the arene−H benefits from substitution or
polarizing functional groups.
molecules (15a and 14a). The total fluorine content could then
be reduced to generate hard-to-access difluorinated arenes (25a)
and heteroarenes (27a). The regiochemistry of the HDF appears
to be dominated by the electronics, i.e., proximity to the electron-
withdrawing functional group, but other competing influences
lead to the formation of regioisomers. On radical anions of
benzene systems, halogen fragmentation is preferred at the
Next, we investigated the scenario in which the arene−H
would be the more valuable coupling partner by making it the
C
DOI: 10.1021/jacs.5b13450
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Journal of the American Chemical Society
Communication
position opposite of a substituent, which we believe gives rise to
the minor isomer of 25a. Hydrogen bonding may be an even
stronger influence on the selectivity, as the amide is essential to
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In conclusion, we have generated and utilized the perfluoroaryl
radical generated by the photocatalyst fac-Ir(ppy) , blue light,
̈
e, S.; Masters, K.-S. J. Fluorine Chem. 2015, 179,
3
and an amine to form a new C−C bond via dual C−F, C−H
functionalization. This allows access to a wide array of
multifluorinated biaryls. From a synthetic perspective, this
reaction has the potential for significant impact given the
single-step coupling of such broadly accessible starting materials,
the mild conditions, and the functional group tolerance of the
method. From a mechanistic perspective, we have shown that the
perfluoroaryl radical is capable of adding to π systems of a wide
range of arenes, including some that give anti-Minisci selectivity,
followed by oxidation and rearomatization. Given these initial
findings, we expect that this chemistry will facilitate inves-
tigations of new fluorinated chemical space and therefore enable
a number of research efforts.
(
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nig, B. ACS Catal. 2016,
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1
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b13450.
■
(
2
*
S
2014, 136, 16986. (c) McNally, A.; Prier, C. K.; MacMillan, D. W. C.
Science 2011, 334, 1114. (d) Narayanam, J. M. R.; Stephenson, C. R. J.
Chem. Soc. Rev. 2011, 40, 102. (e) Nguyen, J. D.; D’Amato, E. M.;
Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem. 2012, 4, 854.
Experimental procedures and additional data (PDF)
(
8) Senaweera, S. M.; Singh, A.; Weaver, J. D. J. Am. Chem. Soc. 2014,
AUTHOR INFORMATION
Corresponding Author
Jimmie.weaver@okstate.edu
Notes
The authors declare the following competing financial
interest(s): The authors hold a patent, United States Serial No.
2/043,650, concerning the structure and method for the
136, 3002.
■
(
(
9) Singh, A.; Kubik, J. J.; Weaver, J. D. Chem. Sci. 2015, 6, 7206.
10) The first step of the reaction is transfer of an electron to the
*
perfluoroarene. Reductive and oxidative quenching are nearly equally
endothermic (0.17−0.16 V vs SCE) in the case of pentafluoropyridine,
DIPEA, and Ir(ppy) . Extrusion of F is likely an irreversible step that
could drive the reaction. With other less-reducible perfluoroarenes,
reductive quenching is likely operative. See ref 9 for more discussion.
(
photoexcited Ir(ppy) * (−2.012 V vs SCE) are strongly reducing.
Oxidative quenching would produce Ir(ppy)3 (0.738 V vs SCE), which
could most likely oxidize int-A. However, because of their low
concentrations, this would be a statistically unlikely event.
−
3
6
−
11) Both the reduced Ir(ppy)3 species (−2.245 V vs SCE) and
Meldrum’s acid adducts.
3
+
ACKNOWLEDGMENTS
■
The reported results were made possible in total or in part by
funding from the Oklahoma Center for the Advancement of
Science and Technology (Award HR-14-072). We gratefully
acknowledge NIH NIGMS (GM115697) for financial support of
this work and thank JID for help in editing the manuscript.
(
12) More photocatalysts were screened but none gave better results
(see the Supporting Information for details).
(13) More amines were screened but none gave better results than
DIPEA (see the Supporting Information for details).
(
14) The 19F NMR shifts are consistent with those of other N-
substituted tetrafluoropyridines observed in our lab, which have been
observed to undergo N-arylation followed by dealkylation. No further
attempts were made to characterize this product.
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DOI: 10.1021/jacs.5b13450
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