In-Depth Assessment of the Palladium-Catalyzed Fluorination of Five-Membered Heteroaryl Bromides

Article abstract of DOI:10.1021/acs.organomet.5b00631

A thorough investigation of the challenging Pd-catalyzed fluorination of five-membered heteroaryl bromides is presented. Crystallographic studies and density functional theory (DFT) calculations suggest that the challenging step of this transformation is

Full text of DOI:10.1021/acs.organomet.5b00631

Article
pubs.acs.org/Organometallics
In-Depth Assessment of the Palladium-Catalyzed Fluorination of
Five-Membered Heteroaryl Bromides
Phillip J. Milner,† Yang Yang,†,‡ and Stephen L. Buchwald*,†
†Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: A thorough investigation of the challenging Pd-
catalyzed fluorination of five-membered heteroaryl bromides is
presented. Crystallographic studies and density functional
theory (DFT) calculations suggest that the challenging step of
this transformation is C−F reductive elimination of five-
membered heteroaryl fluorides from Pd(II) complexes. On
the basis of these studies, we have found that various heteroaryl
bromides bearing phenyl groups in the ortho position can be
effectively fluorinated under catalytic conditions. Highly activated 2-bromoazoles, such as 8-bromocaffeine, are also viable
substrates for this reaction.
Considering the independent importance of five-membered
heterocycles and aryl fluorides in the pharmaceutical industry,
there is a surprising lack of five-membered heteroaryl fluorides
that have been prepared and studied for potential biological
activity.7 This is likely due to the limited methods available for
the fluorination of five-membered heteroarenes,8 which include
thermal9a or photochemical9b Balz−Schiemann reactions, Halex
reactions,10 electrophilic fluorinations of metalated heteroar-
enes,11 and direct fluorinations with F2.12 All of these methods
suffer from severe drawbacks in terms of safety, functional
group tolerance, generality, and/or formation of complex
mixtures of products, which limit their utility. To date, most of
the recently developed transition-metal-mediated methods for
aryl fluorination13 have seen limited application to five-
membered heteroaryl systems.14 Thus, there remains a strong
need for the development of new methods for the fluorination
of five-membered heteroarenes.
INTRODUCTION
■
Five-membered heterocycles are widely prevalent in the
pharmaceutical industry.1 For example, a number of top-selling
drugs, including raltegravier (Isentress),2 sitagliptin (Januvia),3
atorvastatin (Lipitor),4 and resperidone (Risperdal),5 contain at
least one five-membered heterocycle (Figure 1, highlighted in
We15 and others16 have explored the Pd-catalyzed cross-
coupling of (hetero)aryl halides with a metal fluoride salt
(Figure 2A) as a simple and general method for the synthesis of
(hetero)aryl fluorides. Advances in ligand (L1−L3) and
precatalyst (P1−P3, Figure 2B) design have allowed us to
convert a variety of nitrogen-containing six-membered
heteroaryl triflates15a,d and bromides15a,c into the corresponding
heteroaryl fluorides. Thus, we wondered if this methodology
could be extended to the preparation of five-membered
heteroaryl fluorides. However, previous stoichiometric and
catalytic investigations of cross-coupling reactions involving
Figure 1. Top-selling pharmaceuticals containing both a five-
membered heterocyclic core (blue) and an aryl fluoride (red).
blue). The commonality of five-membered heterocycles is due,
in part, to their enormous structural diversity and interesting
biological and electronic properties.1 Similarly, (hetero)aryl
fluorides are frequently employed in medicinal chemistry due to
their enhanced metabolic stability and membrane permeability
in comparison to nonfluorinated analogues (Figure 1, high-
lighted in red).6 Indeed, all of the drugs shown in Figure 1
contain both a five-membered heterocyclic core and an aryl
fluoride.
Special Issue: Gregory Hillhouse Issue
Received: July 21, 2015
© XXXX American Chemical Society
A
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Increasing the catalyst loading, reaction temperature, or
number of equivalents of AgF/KF did not change the outcome
of these reactions. For bromoazoles containing sp2-hybridized
nitrogen centers (8−12), catalyst inhibition could account for
this observation.18 Indeed, we have found that the addition of
various thiazoles and N-substituted (benz)imidazoles to the
otherwise high-yielding Pd-catalyzed fluorination of 4-(nBu)-
PhBr inhibits the desired reaction (see Table S2 in the
Supporting Information). However, 1-methyl-1H-pyrazole did
not significantly inhibit this reaction, indicating that the
unsuccessful fluorinations of 10 and 11 are not necessarily
due to catalyst inhibition. Thus, for simple five-membered
heteroaryl bromides lacking sp2-hybridized nitrogen centers
(e.g., 4−7), as well as bromopyrazoles (10 and 11), at least one
of the elementary steps of the catalytic cycle shown in Figure 2
must not be operative under the standard reaction conditions.
On the basis of previous work,15−17 we hypothesized that C−
F reductive elimination from Pd(II) was the most challenging
step in these reactions. We carried out an in-depth study of this
transformation in order to improve its efficiency. To this end,
we prepared L1-ligated oxidative addition complexes of 2-
bromothiophene (13) and 5-acetyl-2-bromothiophene (14) to
study their solid-state structures (Figure 3A).19 Although 13
and 14 proved to be unstable in solution for extended periods
of time, single crystals suitable for X-ray diffraction of both
complexes could be obtained (Figure 3B).20 Notably, these
Figure 2. (A) Catalytic cycle for the Pd-catalyzed fluorination of aryl
halides. (B) Ligands (L1−L3) and precatalysts (P1−P3) for this
reaction.
five-membered heteroaryl halides suggest that reductive
elimination is significantly more challenging in these reactions
in comparison to that with six-membered aryl halides, likely due
to the smaller size and increased electron richness of five-
membered heteroaryl groups.17 Considering the already high
kinetic barrier for C−F reductive elimination from Pd(II),16b,c
prior to this work it remained unclear if the reductive
elimination of five-membered heteroaryl fluorides was feasible
under synthetically relevant conditions. As a second challenge,
nitrogen-containing heterocycles can inhibit Pd-catalyzed
reactions by coordinating to the Pd center.15d,18 Herein, we
describe catalytic, stoichiometric, and computational studies
aimed toward determining if the Pd-catalyzed fluorination of
five-membered heteroaryl bromides is a viable transformation
with current catalyst systems.
RESULTS AND DISCUSSION
■
We began our investigation by attempting the Pd-catalyzed
fluorination of an array of five-membered heteroaryl bromides
(4−13) under the standard reaction conditions used for the
fluorination of six-membered heteroaryl bromides15a,c using
P1−P3 as precatalysts (Table 1). Unfortunately, the desired
product was not observed in any of these reactions (see Table
S1 in the Supporting Information for additional examples). In
most cases, the starting material was recovered along with trace
amounts of the corresponding reduction (Ar−H) product, as
judged by GC/MS analysis of the crude reaction mixtures.
Table 1. Selected Examples of Unsuccessful Pd-Catalyzed
a
Fluorinations of Five-Membered Heteroaryl Bromides
a
Reaction conditions: ArBr (0.10 mmol), AgF (0.20 mmol), KF (0.05
Figure 3. (A) Synthesis of oxidative addition complexes of five-
membered heteroaryl bromides 13 and 14. (B) Solid-state structures
of 13 and 14 (ellipsoids shown at 50%). (C) Comparison of the
structures of 13 and 14 with that previously reported for 15.
mmol), P1−P3 (2%), solvent (1.0 mL), 130 °C, 14 h. TBME = tert-
b
butyl methyl ether. Significant decomposition observed by 19F NMR
c
and GC/MS. PhSO2F observed by 19F NMR and GC/MS.
B
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complexes are among the first biaryl monophosphine-ligated
oxidative addition complexes of five-membered heteroaryl
halides that have been synthesized and characterized.21 The
solid-state structures of 13 and 14 were compared with that of
the previously reported complex L1·Pd(4-(CN)Ph)Br (15)17b
to analyze the differences that arise upon replacing a six-
membered aryl group with a smaller five-membered heteroaryl
group (Figure 3C). Consistent with our previous computa-
tional studies,17b the Ar−Pd−Br angle is significantly wider in
five-membered heteroaryl complexes 13 and 14 (13, 81.48(4)°;
14, 81.2(1)°) than in six-membered aryl complex 15
(79.03(8)°) (Figure 3C). The smaller angle in 15 in
comparison to those in 13 and 14 reflects the greater proclivity
of this complex to undergo reductive elimination.17b Notably,
only small differences were observed in the Pd−Ar and Pd−
ipso bond lengths among these complexes (Figure 3C).
Unfortunately, to date, all attempts to prepare L·Pd(Ar)F
complexes bearing five-membered heteroaryl groups have been
unsuccessful.22 Thus, we carried out density functional theory
(DFT) calculations to better understand the structure and
reactivity of these species (17−19) in comparison to that of the
analogous complex bearing a phenyl group (16); the results of
these studies are summarized in Table 2 (see the Supporting
and computational (Table 2) studies confirm that C−F
reductive elimination of five-membered heteroaryl fluorides is
an extremely challenging process and is therefore most likely
the rate-limiting step of the Pd-catalyzed fluorinations
presented in Table 1.
On the basis of this analysis, we hypothesized that ortho-
substituted heteroaryl bromides might be effective substrates
for this reaction, due to the known accelerating effect of ortho
substituents on reductive elimination.23 Indeed, DFT calcu-
lations confirm that the addition of an phenyl group adjacent to
the Pd center (19) decreases the barrier of C−F reductive
elimination substantially (21.8 kcal/mol) in comparison to 18
(25.9 kcal/mol). Therefore, we investigated the reactivity of 2-
substituted-3-bromothiophenes (Table 3), because bromothio-
phenes tend to be well-behaved in Pd-catalyzed cross-coupling
reactions.24 Unfortunately, the desired product was not
observed with a methyl group in the 2-position (20a, entry
1). The addition of an additional electron-withdrawing group to
further promote reductive elimination (20b, entry 2) was still
ineffective.25 However, the corresponding substrate substituted
with a bulky phenyl group in the ortho position furnished the
desired product 20c, albeit in modest yield (entry 3). This
finding represents one of the first transition-metal-catalyzed
fluorinations of a five-membered heteroarene. An examination
of the solvent and precatalyst employed revealed that tert-butyl
methyl ether (TBME) is generally superior to other ethereal (2-
MeTHF, cyclopentyl methyl ether, Bu2O) and hydrocarbon
(toluene, cyclohexane) solvents and that P3 is consistently
superior to P1 and P215a for carrying out this transformation.
The incorporation of various electron-withdrawing groups at
the 5-position of the heteroaryl bromide further improved the
yield of the desired product to synthetically useful levels
(entries 4−8).25 Indeed, the presence of an ester (20d),
nonenolizable ketone (20e), sulfonamide (20f), or amide
(20g) was advantageous at this position, although substrates
bearing formyl, acetyl, cyano, and nitro groups underwent
significant decomposition during the reaction (see Table S1 in
the Supporting Information). It should be noted that isolated
products were contaminated with less than 1% of the
corresponding reduction product, as judged by GC analysis
(see the Supporting Information for details). However, small
amounts (<5%) of a second fluorothiophene product, which is
likely the regioisomeric product with the fluorine adjacent to
the electron-withdrawing group, were detected in the crude
reaction mixtures.26 Consistent with this hypothesis, this side
product was not observed during the synthesis of 20h (entry
9), wherein the proposed regioisomer and the desired product
are identical compounds. Additionally the use of AlPhos (L3)
generally affords better selectivity for the desired product in
comparison to HGPhos (L2) (as shown for 20d, entries 4 and
5), which is also the case with six-membered-ring substrates.15a
In all cases except for 20f, the undesired regioisomer could be
chromatographically separated from the desired product.
We also investigated whether additional ortho substitution
could further promote C−F reductive elimination (entries 10−
12). Bromothiophenes bearing additional methyl (20i, entry
10) or phenyl (20j, entry 11) groups adjacent to the bromine
atom produced diminished yields in comparison to the
corresponding substrate lacking substitution at the 4-position
(20h, entry 9). Likewise, the presence of a bulky 1-naphthyl
group in the ortho position impeded the formation of 20k
(entry 12). The sluggish reactivity of these extremely hindered
substrates is likely due to slow oxidative addition of the aryl
Table 2. Computationally Determined Parameters for L3·
a
Pd(Ar)F Complexes 16−19
a
Energies were calculated at the M06/6-311+G(d,p)-SDD/SMD-
(toluene) level of theory with geometries optimized at the B3LYP/6-
b
31G(d) level. ΔG⧧ values were determined at 25 °C. Ground-state
values.
Information for optimized ground- and transition-state geo-
metries). Consistent with our initial hypothesis, the barrier to
C−F reductive elimination was calculated to be 7.0 kcal/mol
higher in energy for the 2-thienyl-substituted complex 17 (27.7
kcal/mol) in comparison to phenyl-substituted complex 16
(20.7 kcal/mol), suggesting that reductive elimination is on the
order of 100000 times slower in the former case. Additionally,
the ground-state Ar−Pd−F angle was wider in 17 (82.3°) than
in 16 (80.7°), which corroborates the X-ray crystallographic
findings in Figure 3C. Notably, the calculated Pd−F bond
lengths are in line with those that have been observed
experimentally for other Ln·Pd(Ar)F complexes.16d The barrier
to reductive elimination for the corresponding 3-thienyl
complex 18 was 1.8 kcal/mol lower than for 17, which is also
consistent with previous experimental and theoretical
findings.17c,d Taken together, these crystallographic (Figure 3)
C
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a
Table 3. Pd-Catalyzed Fluorination of 2-Substituted 3-Bromothiophenes
b
c
entry
product
R1
R2
R3
conversn, %
yield, % (α:β)
1
2
3
4
20a
20b
20c
20d
20d
20e
20f
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
Me
Ph
H
H
n/d
n/d
45
n/o
CO2Me
H
n/o
22 (>50:1)
80 (>50:1)
91 (10:1)
91 (26:1)
CO2Me
CO2Me
C(O)Ph
SO2NEt2
C(O)NEt2
Ph
95
d
5
95
6
98
e
f
7
100
100
95
93 (30:1)
f
8
20g
20h
20i
94 (>50:1)
9
80
10
11
12
Ph
n/d
n/d
n/d
20
20j
Ph
n/o
n/o
20k
1-naphthyl
H
a
Reaction conditions unless specified otherwise: ArBr (0.10 mmol), AgF (0.20 mmol), KF (0.05 mmol), P3 (2%), TBME (1.0 mL), 130 °C, 14 h.
b
c
n/d = not determined. n/o = not observed. Determined by GC. Yield determined by 19F NMR comparison to an authentic sample unless
otherwise noted. P2 was used in place of P3. Toluene as reaction solvent. Isolated yield, 0.50 mmol scale.
d
e
f
bromide to the active L3·Pd(0) species. Overall, these studies
revealed that only 3-bromothiophenes bearing both phenyl
groups in the ortho position and electron-withdrawing groups
on the thiophene ring provide synthetically useful yields, which
is consistent with our hypothesis that C−F reductive
elimination is the challenging process in this transformation.
We next attempted to extend these findings to other five-
membered heteroaryl bromides bearing ortho phenyl sub-
stituents (Table 4). Consistent with the results highlighted in
Table 3 (compare 21b to 20h and 21c to 20c) are consistent
with the DFT calculations in Table 2, which show that
reductive elimination of 3-thienyl groups is easier than that of
2-thienyl groups, as well as with literature precedent.17c,d
Notably, in the case of 21a, 4% of the corresponding reduction
product was isolated along with the desired aryl fluoride.
The fluorinations of ortho-substituted benzofused heteroaryl
bromides (22 and 23) afforded similar results. Although 3-
bromo-2-phenylbenzo[b]thiophene underwent fluorination
only sluggishly, furnishing an inseparable mixture of starting
material and 22a, the corresponding benzo[b]furan underwent
clean fluorination to give 22b in high yield. The higher
reactivity of benzofurans (22b) in comparison to benzothio-
phenes (22a) likely reflects the stronger inductive electron-
withdrawing effect of the O atom in the benzofuran ring.17c,d,27
Unfortunately, the corresponding 3-bromo-N-sulfonylindole
did not undergo fluorination to provide 22c. Consistent with
our studies concerning non-benzo-fused bromothiophenes
(Tables 3 and 4), the corresponding 2-bromobenzo[b]-
thiophene bearing an ortho phenyl group provided only a
low yield of 23 under the reaction conditions.
Table 4. Additional Pd-Catalyzed Fluorinations of Ortho-
a
Substituted Five-Membered Heteroaryl Bromides
We also examined the Pd-catalyzed fluorination of
bromoazoles with phenyl groups in the ortho position (24−
26, Table 4). Low yields of the desired product were observed
with both ortho-substituted 4- (24a,b) and 5-bromothiazoles
(25). Thiazoles inhibit the desired reaction, which likely
explains the observed decrease in reactivity in comparison to
thiophenes (see Table S2 in the Supporting Information). As in
previous cases, increasing the catalyst loading did not
significantly improve the yield of these reactions. Additionally,
none of the desired product was observed with more electron
rich 4-bromo-1H-pyrazoles substituted with a phenyl group in
the ortho position (26a,b), regardless of the nitrogen
protecting group (for additional examples, see Table S1 in
the Supporting Information).
a
Reaction conditions unless specified otherwise: ArBr (0.10 mmol),
AgF (0.20 mmol), KF (0.05 mmol), P3 (2%), TBME (1.0 mL), 130
b
°C, 14 h. n/o = not observed. Isolated yield, 0.50 mmol scale.
c
Contaminated with 4% of the corresponding reduction product.
d
Yield determined by 19F NMR comparison to an authentic sample.
e
f
Toluene as reaction solvent. Determined by GC.
Table 3, only 2-bromothiophenes bearing an electron-with-
drawing group in the 5-position afforded a high yield of the
desired product (21a), while those substituted with an electron-
neutral phenyl group (21b) or lacking substitution at this
position (21c) were less reactive (Table 4). The overall lower
yields obtained for these substrates in comparison to those in
To overcome the generally poor reactivity of bromoazoles,
we also attempted the fluorination of electron-deficient 2-
bromo-1,3-azoles (Table 5). In these cases, significant
formation of side products occurred using TBME as the
reaction solvent, and so these reactions were carried out in
D
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a
Table 5. Pd-Catalyzed Fluorinations of 2-Bromo-1,3-azoles
EXPERIMENTAL SECTION
■
General Procedure for Pd-Catalyzed Fluorination Reactions.
In a nitrogen-filled glovebox, an oven-dried screw-cap reaction tube
equipped with a stir bar was charged (in this order) with silver fluoride
(26 mg, 0.20 mmol, 2.00 equiv), additive (0.05 mmol, 0.50 equiv),
P1−P3 (4.0 mg, 2%), aryl bromide (0.10 mmol, 1.00 equiv), and
solvent (1.0 mL). The tube was capped, removed from the glovebox,
and placed in an oil bath that had been preheated to 130 °C, and the
mixture was vigorously stirred for 14 h. (Caution! Perform behind a
barrier such as a blast shield!) At this time, the tube was cooled to
room temperature, and 1-fluoronaphthalene (20 μL, 1.55 equiv) was
added. The reaction mixture was analyzed directly by 19F NMR.
Afterward, the reaction mixture was filtered through a silica gel plug,
eluted with EtOAc, and analyzed by GC (or GC/MS).
a
Reaction conditions unless specified otherwise: ArBr (0.10 mmol),
AgF (0.20 mmol), KF (0.05 mmol), P3 (2%), toluene (1.0 mL), 130
b
°C, 14 h. n/o = not observed. Yield determined by 19F NMR
c
comparison to an authentic sample. <5% yield observed in the
absence of P3. Isolated yield, 0.50 mmol scale. Significant
d
e
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00631.
■
decomposition observed by 19F NMR and GC/MS.
S
toluene. Although 2-bromothiazole did not provide the desired
product (27a) under the reaction conditions, the addition of a
phenyl group adjacent to the nitrogen center led to a low yield
of 27b. As shown with bromothiophenes (20d−g, Table 3; 21a,
Table 4), the presence of an electron-withdrawing group on the
thiazole ring was crucial for the isolation of 27c in synthetically
useful yield. Notably, less than 5% of 27b,c was observed in the
absence of P3, ruling out the possibility of a background Halex
process. Although simple N-substituted 2-bromo-1H-imida-
zoles underwent decomposition (28a) or no reaction (28b)
under these conditions, we found that the more activated 8-
bromocaffeine could be efficiently converted to 29 in high
yield; again, only trace amounts of 29 were observed in the
absence of catalyst. Additionally, none of the corresponding
reduction product was detected in the purified samples of 27c
and 29 (see the Supporting Information for details). It should
be noted that benzo-fused 2-bromoazoles, such as 2-
bromobenzothiazole and 2-bromo-1-methyl-1H-benzimidazole,
underwent significant fluorination in the absence of catalyst,
reflecting their proclivity toward Halex processes (not shown).
Nevertheless, this methodology may be attractive for the
synthesis of 2-fluoroazoles bearing electron-withdrawing
groups.
Full procedural and spectroscopic data (PDF)
Solid-state structure of 13 (CIF)
Solid-state structure of 14 (CIF)
Cartesian coordinates for the ground-state structures of
16−19 and the corresponding C−F reductive elimi-
nation transition-state geometries (XYZ)
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.L.B.: sbuchwal@mit.edu.
■
Notes
The authors declare the following competing financial
interest(s): MIT has patents on some of the ligands and
precatalysts used in this work, from which S.L.B. and former
coworkers receive royalty payments.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institutes of Health under award number GM46059.
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National
Institutes of Health. P.J.M. thanks the National Science
Foundation for a predoctoral fellowship (2010094243). P.J.M.
also thanks Amgen for an educational donation, for which we
are grateful. One of the X-ray diffractometers used in this work
was purchased with the help of funding from the National
Science Foundation (Grant CHE 0946721). Dr. Peter Mueller
(MIT) is acknowledged for solving the X-ray structures of 13
and 14. Dr. Aaron Sather (MIT) is acknowledged for helpful
discussions, assistance with this manuscript, and the generous
donation of P3. We thank Prof. Peng Liu (University of
Pittsburgh) for help with computational studies. Calculations
were performed at the Center for Simulation and Modeling at
the University of Pittsburgh.
CONCLUSION
■
By systematically studying substituent effects on the fluorina-
tion of five-membered heteroaryl bromides, we were able to
identify a number of five-membered heteroaryl fluorides that
could be prepared in synthetically useful yields with a catalyst
system based on L3. In particular, electron-deficient and ortho-
substituted benzo[b]thiophenes, ortho-substituted benzo[b]-
furans, and highly activated 2-bromo-1,3-azoles are viable
substrates for this reaction.28 Despite these advances, the scope
of this reaction remains limited, especially with respect to
bromoazoles. Although our previous work in this area15d,17a,b
suggests that increasing the steric bulk of the ligand could
potentially help overcome these problems, it is probable that a
more fundamental change to the reaction, such as a change in
mechanism, transition-metal catalyst, or ligand architecture may
be needed to access a broader scope of five-membered
heteroaryl fluorides. Given the potential importance of five-
membered heteroaryl fluorides in medicinal chemistry, this
transformation remains an active area of research in our group.
DEDICATION
■
Dedicated to the memory of Professor Gregory L. Hillhouse:
brilliant chemist, great person and friend.
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elimination. Further study of this phenomenon is required.
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evaluated, but most underwent significant decomposition under the
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F
DOI: 10.1021/acs.organomet.5b00631
Organometallics XXXX, XXX, XXX−XXX