Pd(OAc)2-catalyzed regioselective aromatic C-H bond fluorination

Article abstract of DOI:10.1039/c3cc42220h

A novel Pd(OAc)₂-NFSI-TFA system was developed for the highly selective ortho-monofluorination directed by diverse aryl-N-heterocyclic directing groups e.g., quinoxaline, pyrazole, benzo[d]oxazole, and pyrazine derivatives. A Pd(ii/iv) catalytic cycle was proposed based on the ESI-MS/MS studies. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc42220h

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Pd(OAc)2-catalyzed regioselective aromatic C–H bond
fluorination†
Cite this: Chem. Commun., 2013,
49, 6218
Shao-Jie Lou, Dan-Qian Xu,* Ai-Bao Xia, Yi-Feng Wang, Yun-Kui Liu, Xiao-Hua Du
and Zhen-Yuan Xu*
Received 27th March 2013,
Accepted 21st May 2013
DOI: 10.1039/c3cc42220h
www.rsc.org/chemcomm
A novel Pd(OAc)2–NFSI–TFA system was developed for the highly
selective ortho-monofluorination directed by diverse aryl-N-hetero-
cyclic directing groups e.g., quinoxaline, pyrazole, benzo[d]oxazole,
and pyrazine derivatives. A Pd(II/IV) catalytic cycle was proposed
based on the ESI-MS/MS studies.
Scheme 1 Aryl-N-heterocycle directed C–H bond fluorination.
Given the remarkable properties of fluorine atoms, the late-stage
introduction of fluorine into arenes is significant but still faces recently reported by Sanford and co-workers.10 In light of the
challenges.1 The classic fluorination including Balz–Schiemann previous C–H bond fluorination studies, the coordinating
reaction2 and the Halex process3 is useful for the Caryl–fluorine bond ability of the N-ligand directing group is sensitive to this
construction from aryldiazonium salts and electron-deficient aryl type of transformation.8,9 We reasoned that the quinoxaline
chlorides (or nitroarenes), respectively. Deoxyfluorination of phenols directing group developed by our group in the C–H bond
developed by the Ritter group recently represents an alternative nitration11 might be a feasible directing group for C–H bond
efficient approach to prepare aryl fluorides.4 Despite the nucleophilic fluorination (Scheme 1).
attack process, electrophilic fluorination of aryl-lithium, -magnesium
We initiated our research by treating the model substrate
and -silicon reagents can also afford the corresponding fluoro- 2-phenyl quinoxaline (1a) with several fluorinating agents (A, B,
arenes.5 With much effort made in the past few years, C, D, and E), which were broadly used in the previous work,
transition metal catalysis exhibits high efficiency for the ipso- simple Pd(OAc)2 as the catalyst and trifluoroacetic acid (TFA) as
fluorination of aryl-halide, -silicon, -boron, -tin, -pseudohalide an additive in 1,2-chloroethane (DCE) in air. Unfortunately, only
and -nickel as well as other reagents.6 However, the use of a trace amount of desired product was formed after 12 hours at
prefunctionalized starting materials still limited the applica- 110 1C by using fluorinating agents A–D (Table 1, entries 1–4). To
tion of these strategies, the directed C–H bond fluorination our delight, when NFSI (N-fluorobenzenesulfonimide, E) was
potentially appears to be an improved approach.7
employed as the fluorine source (entry 5), the monofluorinated
While much remarkable achievements have been made in product (2a) and the difluorinated product (3a) were obtained in
ligand-directed C–H bond activation/functionalization in the recent 68% and 24% yields, respectively, with a trace amount of
decade, C–H bond fluorination is still rare and much less developed. acetoxylated by-product.12 After several solvents were screened
A pyridine directing group was employed by the Sanford group in (entries 6 and 7),13 we found that DCE and CH3NO2 effectively
their early studies of Pd(II)-catalyzed C–H bond fluorination.8 promoted the conversion of 1a while CH3CN provided better
Recently, Yu and co-workers reported two examples of amide- selectivity. This phenomenon led us to assume that a mixed
directed ortho-fluorination of C–H bonds, and selective mono- solvent of CH3NO2 (or DCE) and CH3CN could meet the
fluorination of benzoic amides was developed by tuning the demands of both conversion and selectivity. Gratifyingly, an
amide directing groups.9 In addition, C–H bond fluorination of optimized result was obtained as anticipated by adjusting the ratio
8-methylquinoline derivatives with nucleophilic fluoride was of the two types of solvents (entry 8). Various catalysts including
Pd(0) and Pd(II) were surveyed subsequently (entries 10–14),
Catalytic Hydrogenation Research Center, State Key Laboratory Breeding Base of
Pd(OAc)2 was found to exhibit the best efficiency and Pd(0) could
also accelerate the reaction albeit in lower yields (entries 13 and 14).
Green Chemistry-Synthesis Technology, Zhejiang University of Technology,
Hangzhou 310014, P. R. China. E-mail: greenchem@zjut.edu.cn;
Importantly, the additives played a crucial role in this transforma-
Fax: +86 571 8832 0066; Tel: +86 571 8832 0066
tion, and TFA14 performed the best among all the acidic additives
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc42220h
tested (entries 15–20). However, N-methyl pyrrolidone (NMP)
c
6218 Chem. Commun., 2013, 49, 6218--6220
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Table 1 Screening of the fluorination conditionsa
Table 2 Scope of quinoxaline-directed ortho-monofluorinationa
Entry Cat.
[F+] Add.
Solvent
Yields of 2a/2aab (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
A
B
C
D
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
DCE
DCE
DCE
DCE
DCE
CH3CN
Trace/0
5/0
3/0
5/trace
68/24
53/1.5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OOCCF3)2
PdCl2
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
CH3NO2 54/33
MS 1c
MS 2
MS 1
MS 1
MS 1
MS 1
MS 1
78/3
60/2
73/2
Trace/0
58/2
32/trace
65/2
19/trace
18/trace
48/trace
64/15
56/5
70/3
7/trace
0/0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
Reaction conditions:
1 (0.2 mmol), Pd(OAc)2 (10 mol%), TFA
(2.0 equiv.), NFSI (1.5 equiv.), solvent (2.0 mL), 110 1C, in air, 12 h,
b
isolated yields, (unless otherwise noted). Solvent = [CH3NO2–CH3CN =
c
1 : 1 (v/v)] (2.0 mL). Solvent = [CH3NO2–CH3CN = 10 : 1 (v/v)] (2.0 mL).
d
e
Solvent = CH3NO2 (2.0 mL). Pd(OAc)2 (15 mol%), TFA (2.0 equiv.),
HOAc MS 1
PivOH MS 1
f
NFSI (2.0 equiv.), solvent = CH3NO2 (2.0 mL). Pd(OOCCF3)2 (15 mol%),
TFA (2.0 equiv.), NFSI (2.0 equiv.), solvent = CH3NO2 (2.0 mL).
HOTf
MSA
PTSA
TFAA
NMP
TFA
—
MS 1
MS 1
MS 1
MS 1
MS 1
MS 1
MS 1
MS 1
g
Pd(OAc)2 (15 mol%), TFA (2.0 equiv.), NFSI (3.0 equiv.), solvent =
[CH3NO2–CH3CN = 10 : 1 (v/v)] (2.0 mL).
to promote the fluorination of substrates containing strong electron-
withdrawing groups, such as nitro (2g), cyano (2h), and trifluoromethyl
(2i) substituents. ortho-Substituted substrates were monofluorinated
smoothly to provide the desired products in 86% to 87% yields
in the CH3NO2 system (2j, 2k, 2l). The heterocyclic ring was also
tolerated with elevated loading of catalyst (2m). In addition,
double-centered C–H fluorination occurred in a moderate iso-
lated yield for inseparable fluorinated side products (2n).9b
Substrates substituted on the quinoxaline side also took part in
the present protocol. Comparable results were obtained under
Pd(OAc)2
Pd(OOCCF3)2
10/2
55/3
—
a
Reaction conditions: 1a (0.1 mmol), [Pd] (10 mol%), additives (2.0
equiv.), [F+] (1.5 equiv.), solvent (1.0 mL), 110 1C, in air, 12 h (unless
otherwise noted), TFA = trifluoroacetic acid, MS1 = [CH3NO2–CH3CN =
1 : 1 (v/v)], MS2 = [DCE–CH3CN = 1 : 1 (v/v)], PivOH = pivalic acid, MSA =
methanesulfonic acid, PTSA = p-toluenesulfonic acid, TFAA = trifluor-
b
c
oacetic anhydride, NMP = N-methyl pyrrolidone. GC-MS yield. For
more detailed screening of mixed solvents, see the ESI.
used in Yu’s studies9 was inefficient in this case (entry 21). In suitable conditions (2o–2s). Notably, fluorination failed to proceed
addition, the reaction was sluggish in the absence of catalysts with the ortho-substituent at both the arene and quinoxaline
or additives (entries 22 and 23). Interestingly, when 10 mol% moieties of the substrate, presumably due to the increase in
Pd(TFA)2 was employed in place of Pd(OAc)2, a catalytic amount the steric hindrance which was unfavorable for the formation
of TFA that released in the C–H activation step7,12 notably promoted of palladacyclic intermediates (2t, 2u).15
the transformation and afforded monofluorinated product 2a
in 55% GC yield without external additives (entry 24). Finally, afforded in 84% yield when 3 equiv. of NFSI was utilized (Scheme 2).
palladium-catalyzed selective C–H bond monofluorination A series of different aryl-N-heterocycles other than quinoxaline
using NFSI as a fluorinating agent and TFA as a promoter were then investigated to examine the generality of this strategy.
under ambient conditions was disclosed. Through preliminary modification of the present conditions, pyr-
Meanwhile, the difluorinated product of 1a was successfully
The scope of the quinoxaline-directed ortho-monofluorination azole, benzo[d]oxazole, and pyrazine were determined to be practical
was explored with the optimal reaction conditions established directing groups (Table 3). In contrast, relatively strong coordinating
(Table 2). Notably, the ratio of the mixed solvent was sensitive groups, e.g., pyridine and quinoline, were ineffective in this directed
to the quinoxaline derivatives of various substituents. Substrates C–H bond fluorination.13
containing electron-donating functionalities (2b, 2c) were more
favorable in this transformation, more CH3CN was required in order
to inhibit difluorination of the arenes. On the other hand, substrates
bearing electron-withdrawing substituents fluorinated slowly under
standard conditions,13 thus a less amount of CH3CN was added
in these cases in order to obtain compromised yields (2d–2f).
Scheme 2 Difluorination of 1a.
Furthermore, a single-component solvent of CH3NO2 was employed
c
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Table
3
ortho-Monofluorination using other aryl-N-heterocyclic directing
Notes and references
groupsa
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6 For selected transition metal-mediated or -catalyzed C–F bond
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See the ESI for detailed reaction conditions.
´
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7 For selected reviews on the C–H functionalization, see: (a) K. Godula
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Scheme 3 Proposed mechanism.
Preliminary mechanistic experiments were carried out to
obtain further insight into the directed C–H bond fluorination.
As monitored by kinetic studies, difluorination occurred as
soon as the monofluorinated arene was formed.13 A primary
kinetic isotope effect was observed both in the intramolecular
(kH/kD E 2.3) and intermolecular (kH/kD E 2.3) competition
experiments, suggesting that the aromatic C–H activation
might be involved in the rate-limiting step.13
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Mass spectrometry experiments were also employed to gain
a better understanding of the catalytic pathway of the present
transformation.16 The formation of cyclopalladation(II) inter-
mediates I, II (ESI-MS signal at m/z: 466, 517, 535) and reductive
eliminated Pd(II) intermediate IV (ESI-MS signal at m/z: 608,
626, 649, 667, 814, 832, 850; differed in the type of ligands that
coordinated to the Pd centre) was detected unambiguously
and assigned to the corresponding structures by MS/MS inter-
pretation.13 In addition, a competing coordination with Pd(II)
complex I between 1a and monofluorinated product 2a was also
observed (ESI-MS signal at m/z: 517 vs. 535), which led to the
generation of difluorinated 2aa.13 A plausible mechanism13
involving a Pd(II/IV) catalytic cycle was proposed based on the
abovementioned mechanistic experiments and previous litera-
tures12 (Scheme 3).13
10 K. B. McMurtrey, J. M. Racowski and M. S. Sanford, Org. Lett., 2012,
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valent palladium fluoride, see: (a) T. Furuya and T. Ritter, J. Am.
Chem. Soc., 2008, 130, 10060; (b) N. D. Ball and M. S. Sanford, J. Am.
Chem. Soc., 2009, 131, 3796; (c) L.-M. Xu, B.-J. Li, Z. Yang and
Z.-J. Shi, Chem. Soc. Rev., 2010, 39, 712; (d) T. Furuya, D. Benitez,
E. Tkatchouk, A. E. Strom, P. Tang, W. A. Goddard III and T. Ritter,
J. Am. Chem. Soc., 2010, 132, 3793; (e) K. M. Engle, T.-S. Mei, X. Wang
and J.-Q. Yu, Angew. Chem., Int. Ed., 2011, 50, 1478.
13 For detailed information, see the ESI†.
14 TFA is known to generate highly electrophilic palladium cations,
see: C. Jia, T. Kitamura and Y. Fujiwara, Acc. Chem. Res., 2001,
34, 633.
15 The increase in the steric hindrance made the formation of palla-
dacyclic intermediates sluggish.
In summary, we have developed a new facile Pd(II)–NFSI–
TFA system for the selective C–H bond monofluorination of
aromatics e.g., quinoxaline, pyrazole, benzo[d]oxazole, and
pyrazine derivatives. The present procedure features high
regio-selectivity, operational simplicity and special compatibility
with multi-heteroaromatics. ESI-MS/MS studies provided a clear
insight into the Pd(II/IV) catalytic cycle. Studies on the detailed
mechanism and expanded substrate variations are currently
underway in our lab.
16 (a) A. O. Aliprantis and J. W. Canary, J. Am. Chem. Soc., 1994,
116, 6985; (b) A. A. Sabino, A. H. L. Machado, C. R. D. Correia and
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c
6220 Chem. Commun., 2013, 49, 6218--6220
This journal is The Royal Society of Chemistry 2013