Mild C - H halogenation of anilides and the isolation of an unusual palladium(I)-palladium(II) species

Article abstract of DOI:10.1002/anie.201101606

Reducing the load: A facile palladium-catalyzed ortho-selective bromination and chlorination of anilides occurs under aerobic conditions at room temperature when N-halosuccinimides (NXS) are used in the presence of p-toluenesulfonic acid (PTSA). The orthopalladated PTSA complex is not only catalytically competent but also undergoes a reductive process to yield an unusual Pd^I-Pd^II tetramer (see structure; Pdgreen, Ored, Syellow, Cgray). Copyright

Full text of DOI:10.1002/anie.201101606

Communications
DOI: 10.1002/anie.201101606
Synthetic Methods
À
Mild C H Halogenation of Anilides and the Isolation of an Unusual
Palladium(I)–Palladium(II) Species**
Robin B. Bedford,* Mairi F. Haddow, Charlotte J. Mitchell, and Ruth L. Webster
À
Palladium-catalyzed C H functionalization/halogenation is a
particularly useful method for producing halogenated aro-
matic products with selectivity that would not ordinarily be
obtained under simple electrophilic halogenation conditions
(Scheme 1).[1] A significant advance in this area was reported
using a remarkably simple system. This mild, operationally
simple methodology can also be readily extended to ortho-
selective chlorination.[4] Furthermore we report the isolation
of a highly intriguing, extremely fragile, mixed PdI–PdII
species that is formed under reaction conditions comparable
to those used in the catalytic reaction.
Inspired by de Vries and van Leeuwenꢀs use of p-tolue-
nesulfonic acid (PTSA) as an additive in the mild ortho-
vinylation of anilides,[5] we were delighted to find that
acetanilide, 1a, reacts with N-bromosuccinimide (NBS) and
0.5 equivalents of PTSA in the presence of 5 mol% Pd-
(OAc)2, at room temperature in toluene, to generate the 2-
brominated anilide 2a in 95% yield (spectroscopic) with no
para-Br product 3a and only trace amounts of the dibromi-
nated products 4a and 5a (Table 1, entry 1). Other solvents,
including 1,4-dioxane, also proved to be effective.[6] Lowering
À
Scheme 1. Directed ortho-selective C H functionalization/halogenation
versus electrophilic halogenation. DG=directing group.
Table 1: Reaction optimization.[a]
by Shi and co-workers who demonstrated that anilides could
be ortho chlorinated in good to excellent yields using Pd-
(OAc)2 as the catalyst and a mixture of CuCl2 and Cu(OAc)2
as the chloride source and the oxidant.[2]
Unfortunately these reactions require the use of industri-
ally disfavored 1,2-dichloroethane as a solvent and two days
heating at 908C for completion. Furthermore, contrary to the
original claims, we found that selective ortho bromination
cannot be obtained under these reaction conditions and only
para-selective electrophilic bromination is observed.[3] Since
aryl bromides are significantly more reactive than their
chloride congeners they represent profoundly more desirable
targets, therefore the selective ortho bromination of anilides
remained a synthetically highly important yet unmet goal.
Herein, we report that not only can ortho-selective
bromination be achieved, but that the reactions can be
performed under very mild reaction conditions: typically they
are complete within 1–4 hours at room temperature, under air
Yield [%][b]
Entry
Conditions
2a
3a
4a
5a
1
2
3
4
5
6
5 mol% Pd, 1 h, 50 mol% PTSA
1 mol% Pd, 30 min, 50 mol% PTSA
0 mol% Pd, 1 h, 50 mol% PTSA
5 mol% Pd, 2 h, 10 mol% PTSA
5 mol% Pd, 1 h, 50 mol% NaOTs
5 mol% [Pd(OTs)2(MeCN)2], 2 h,
no added acid
5 mol% [Pd(OTs)2(MeCN)2], 1 h,
50 mol% PTSA
5 mol% Pd, 1 h, 50 mol% CH3CO2H
5 mol% Pd, 1 h, 50 mol% CF3CO2H
5 mol% Pd, 1 h, 50 mol% H[BF4][c]
94
21
5
68
0
–
66
30
22
0
2.5
–
–
7
0
2.5
–
–
0
0
39
47
–
–
7
54
26
4
6
8
9
10
0
26
67
0
0
17
0
0
–
0
0
–
[a] Reaction conditions: 1a (0.5 mmol), NBS (0.52 mmol), additive as
specified, catalyst (5 mol%), toluene (2 mL), RT. [b] Determined by
1H NMR spectroscopy (1,3,5-C6H3(OMe)3 internal standard). [c] Yields
of isolated products. Ts=4-toluenesulfonyl.
[*] Prof. R. B. Bedford, Dr. M. F. Haddow, R. L. Webster
School of Chemistry, University of Bristol
Cantocks Close, Bristol, BS8 1TS (UK)
E-mail: r.bedford@bristol.ac.uk
either the palladium or PTSA loading, or running the reaction
without palladium gave significant electrophilic bromination
(entries 2–4). The presence of acid was crucial, as neither the
addition of NaOTs nor the use of the preformed tosylate
complex [Pd(OTs)2(MeCN)2][7] alone were successful; while
the addition of PTSA to this catalyst gave significant electro-
philic bromination (Table 1, entries 5–7). Acetic acid showed
no reactivity and trifluoroacetic acid poor reactivity, whereas
C. J. Mitchell
GlaxoSmithKline
Stevenage, SG1 2NY (UK)
[**] We thank the EPSRC and GSK for funding under the collaborative
EPSRC Programme for Synthetic Organic Chemistry with AZ-GSK-
Pfizer.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101606.
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Angew. Chem. Int. Ed. 2011, 50, 5524 –5527

Table 2: Selected ortho bromination and chlorination of anilides.[a]
Entry
1
Anilide
Product(s)
Yield [%][b]
Entry
9
Anilide
Product(s)
Yield [%][b]
1a
1a
2a: 80 (94)
1 f
6 f: 92
2
3
4
5
6a: 73 (98)
6b: 52
10
11
12
13
1g
2g: 93
1b
1c
1c
1g
1h
1h
6g: 83
2c: 93
2h: 43[c,d]
6h: 80[c,d]
6c: 89
2d: 68
3d: 16
2i: 62 (81)[c]
7i: 6 (11)[c]
6
7
1d
1d
14
15
1i
1i
6d: 61 (82)
6i: 50 (83)[c]
6j: 87[c]
8j: 3[c]
8
1e
2e: 94
16
1j
9j: (3)[c]
[a] Selected data; see Table S1 for more comprehensive data,[8] Reaction conditions: Anilide (0.5 mmol), NXS (0.52 mmol), PTSA (0.25 mmol),
Pd(OAc)2 (5 mol%), toluene (2 mL), RT 1–4 h. [b] Yield of isolated products; yield determined by 1H NMR spectroscopy in parentheses (1,3,5-
C6H3(OMe)3 internal standard). [c] Run at 508C. [d] Run for 24 h. Piv=pivaloyl.
À
tetrafluoroboric acid gave some competitive electrophilic
bromination (entries 8–10).
have been proposed in a range of related oxidative C H
functionalization reactions.[10] Accordingly we prepared the
complexes 10a and b under reaction conditions that mimic
the catalytic process, but in the absence of NXS. Detailed
kinetic comparison of reactions catalyzed by Pd(OAc)2 or 10a
proved to be difficult because of the low solubility of PTSA.
However, in each case protracted induction periods of at least
20 minutes were observed (see Figure S3 in the Supporting
Information),[8] thus militating against direct intermediacy of
10a in the catalytic cycle. Meanwhile reaction of Pd(OAc)2
with PTSA alone gave the fragile palladacyclic complex 11.
This complex was not only catalytically competent, but
showed no induction period in the ortho chlorination of 1a
(Figure S3).[8]
With optimized reaction conditions in hand we next
examined the scope of the reaction (see selected results in
Table 2; full results in Table S1 of the Supporting Informa-
tion).[8] Good to excellent yields of both ortho brominated
and chlorinated anilides were obtained under very mild
reaction conditions and short reaction times with little or no
competitive electrophilic halogenation apparent in most
cases.
We next turned our attention to the possible mechanism
of the reaction. The function of the acid is presumably to
protonate a carbonyl group of the N-halosuccinimide (NXS),
thus rendering it a more effective source of X+.[9] The
halonium (or possibly HOX formed in situ) might be
expected to oxidatively add to an orthopalladated anilide
intermediate which then liberates the product by reductive
elimination. Such anilide-based palladacyclic intermediates
To the best of our knowledge complex 11 represents the
first example of a C H activated arylsulfonate ligand.
Crystals of 11 were subjected to X-ray analysis, the results
of which supported the indicated connectivity (Figure S1);
À
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Communications
The formation of complex 12 is extraordinary in two
regards. Firstly 12 is a very rare example of a p-arene complex
where the arene is itself part of a metallacycle; indeed to the
best of our knowledge this is the first example of a metalla-
cycle supporting a PdI dimeric core. More importantly
though, the results show that a palladacycle can undergo
facile reduction to PdI under mild reaction conditions—even
under air![13] There has been considerable discussion as to
À
whether catalytic oxidative C H functionalization proceeds
by oxidation of PdII-based metallacycles to PdIV or PdIII
intermediates.[14] In contrast, the potential role(s) of PdI in
À
C H functionalization has yet to be established, an area that
we are currently exploring.[15]
however whole-molecule disorder meant that the data were
In conclusion ortho-selective halogenation of anilides can
be achieved under very mild, aerobic conditions. An anilide-
based palladacycle isolated under comparable conditions
does not appear to be directly involved in the catalytic
manifold. Conversely an unusual palladacycle based on
orthometalated PTSA, formed under conditions similar to
those employed in the catalytic reactions, is active and shows
no induction period. Furthermore this species can undergo a
facile reduction, under conditions similar to those used in the
catalysis, to generate a highly unusual PdI–PdII tetrameric
too poor in quality to comment on the structure further.[8]
Complex 11 was briefly stable in THF and DMSO, but in
most other donor solvents underwent rapid loss of PTSA,
even under anhydrous conditions, thus suggesting that
decomposition occurred by intramolecular protonolysis of
À
the Pd C bond by an aquo ligand. Solutions of 11 in 1,4-
dioxane under air gradually (hours) turned brown, thus taking
on the same coloration observed in the majority of the
catalytic reactions, which were performed under similar
conditions. In contrast, and somewhat surprisingly, the
brown solutions formed faster yet were far less stable under
a nitrogen atmosphere: the reactions deposited palladium
black within 45 minutes. NMR spectroscopic analysis of a
brown solution formed under air showed peaks for a mixture
of free PTSA and a new species 12, which is consistent with an
orthopalladated PTSA complex.[8] A crystal structure of 12
showed it to be a highly unusual complex wherein half of the
palladium had been reduced to give a PdI dimer supported by
À
complex. PTSA is used as an additive in a range of C H
functionalizations,[16] accordingly we are probing the potential
roles of these unique orthometalated PTSA complexes in
such processes.
Experimental Section
General procedure for the halogenation of anilides: A mixture of
anilide (0.5 mmol), TsOH·H2O (0.25 mmol), NXS (0.52 mmol), and
Pd(OAc)2 (5.6 mg, 0.025 mmol) in toluene (2 mL) was stirred under
air for the 1–4 h. The solution was then diluted with Et2O, washed
with NaHCO3 (aq) (10 mL) and then H2O (2 ꢂ 10 mL), after which
the organic extracts were dried over MgSO4 and the volatiles
removed under reduced pressure. The crude reaction mixture was
then purified by column chromatography (silica gel) eluting with
EtOAc/hexanes (1:1).
p coordination of two PdII palladacycles (Figure 1).[8] The Pd
À
Pd bond length (2.538(6) ꢁ) is typical of aryl-stabilized PdI
À
dimers where the ligand trans to the Pd Pd bond is a
moderately weakly coordinating anion.[11] Longer distances
(up to 2.727(4) ꢁ)[12] are seen for structures with phosphine
ligands in this position. The distance from the centroid of the
Preparation of palladacycle 11: TsOH·H2O (1 mmol) and Pd-
(OAc)2 (1 mmol) in toluene (2 mL) was stirred at RT for 1 h under
air. The supernatant was removed and the residue washed with cold
anhydrous EtOAc (4 ꢂ 2 mL) to give 11 as a yellow solid (66%).
Preparation palladacycle 12: A solution of 11 (ca. 10 mg) in
anhydrous 1,4-dioxane (1 mL, under air) in an NMR tube was layered
with anhydrous hexanes to give 12 as a brown, crystalline solid which
was characterized by X-ray analysis.[11] Solutions prepared in [D8]1,4-
dioxane were analyzed by NMR spectroscopy and showed mixtures of
12 and free PTSA in a 1:8 ratio within 3 h with an increase to 1:4 after
20 h. Pure samples of 12 could not be isolated as the crystals were
unstable in the absence of 1,4-dioxane, and decomposed rapidly (min)
into palladium black. In the presence of air and 1,4-dioxane, the
crystals were stable for approximately 1 week. When formed or
stored under nitrogen (in the presence of 1,4-dioxane), they decom-
posed into palladium black within 2 h.
À
Pd Pd bond to the plane of the phenyl ring is 2.125(12) ꢁ,
which is also typical for these systems. The structure contains
four 1,4-dioxane solvate molecules per molecule of dimer,
two of which are hydrogen bonded to the water ligand. This
solvation appeared to play a key role in the stability of the
complex: crystals of 12 underwent rapid decomposition in the
absence of extraneous 1,4-dioxane.
Received: March 4, 2011
Revised: April 11, 2011
Published online: May 12, 2011
À
Keywords: arenes · catalysis · C H functionalization ·
halogenation · palladium
Figure 1. X-ray crystal structure of 12 (1,4-dioxane solvate omitted for
clarity).
.
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[8] See the Supporting Information for details.
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[10] For selected recent examples see: a) R. Giri, J. K. Lam, J.-Q. Yu,
J. Am. Chem. Soc. 2010, 132, 686; b) M. Tobisu, Y. Ano, N.
Chatani, Org. Lett. 2009, 11, 3250; c) W. Rauf, A. L. Thompson,
J. M. Brown, Chem. Commun. 2009, 3874.
[11] Recent examples: a) M. Gorlov, A. Fischer, L. Kloo, Inorg.
Chim. Acta 2009, 362, 605; b) J. Akerstedt, M. Gorlvov, A.
Fischer, L. Kloo, J. Organomet. Chem. 2010, 695, 1513.
[12] P. Dotta, P. G. A. Kumar, P. S. Pregosin, A. Albinati, S. Rizzato,
Organometallics 2004, 23, 4247.
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Chem. Int. Ed. 2008, 47, 5215; i) X. Zhao, E. Dimitrijevic, V. M.
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Kochi, H. Mutsutani, N. Kobayashi, S. Urano, M. Sato, S.
Nishiyama, T. Tanabe, J. Am. Chem. Soc. 2009, 131, 11310; k) B.
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[2] X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang, Z. Shi, J. Am.
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[3] a) R. B. Bedford, C. J. Mitchell, R. L. Webster, Chem. Commun.
2010, 46, 3095; b) R. B. Bedford, J. U. Engelhart, M. F. Haddow,
C. J. Mitchell, R. L. Webster, Dalton Trans. 2010, 39, 10464.
[4] For two examples of chlorination of anilides using NCS under far
more forcing conditions (1008C, 12 h) see Ref. [1f].
[5] M. D. K. Boele, G. P. F. van Strijdonck, A. H. M. de Vries,
P. C. J. Kamer, J. G. de Vries, P. van Leeuwen, J. Am. Chem.
Soc. 2002, 124, 1586.
[6] Using THF, diethyl ether, or dichloromethane as the solvent led
to modest (11–14%) levels of competitive p-bromination. 1,4-
Dioxane gave 61% of 2a and 16% of 3a, whereas toluene/1,4-
dioxane (1:1) gave 73% of 2a, 14% of 3a, and 5% of 4a.
[7] C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G.
Tyler, M. R. Gagnꢃ, G. C. Lloyd-Jones, K. I. Booker-Milburn,
[13] As yet, we do not know what acts as the reductant in this
reaction.
[14] For recent examples see: a) D. C. Powers, D. Y. Xiao, M. A. L.
Geibel, T. Ritter, J. Am. Chem. Soc. 2010, 132, 14530; b) D. C.
Powers, T. Ritter, Nat. Chem. 2009, 1, 302; c) D. C. Powers,
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Soc. 2009, 131, 11234; e) S. R. Whitfield, M. S. Sanford, J. Am.
Chem. Soc. 2007, 129, 15142.
[15] Attempts to explore the precise role of 12 have so far been
hampered by the fact that it is not stable in the solid state in the
absence of 1,4-dioxane, but rather undergoes rapid (min)
decomposition. Conversely, 1,4-dioxane solutions of 12 contain
varying amounts of free PTSA and therefore must also contain
concomitant amounts of unidentified Pd species.
[16] For examples see: a) W. Rauf, J. M. Brown, Synlett 2009, 3103;
b) C. E. Houlden, C. D. Bailey, G. Ford, M. Gagnꢃ, G. C. Lloyd-
Jones, K. I. Booker-Milburn, J. Am. Chem. Soc. 2008, 130, 10066
and Refs. [7], [9a], and [9c].
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