Ligand Promoted meta-C-H Chlorination of Anilines and Phenols

Article abstract of DOI:10.1021/jacs.6b11055

Pd-catalyzed meta-C-H chlorination of anilines and phenols is developed using norbornene as the mediator. Heterocycles, including indole, thiophene, and indazole, are tolerated. The identification of a new pyridone-based ligand is crucial for the success of this meta-C-H chlorination reaction. Subsequent diverse transformations of the chlorinated products demonstrate the versatility of meta-C-H chlorination.

Full text of DOI:10.1021/jacs.6b11055

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Ligand Promoted meta-C–H Chlorination of Anilines and Phenols
Hang Shi, Peng Wang, Shin Suzuki, Marcus E. Farmer, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11055 • Publication Date (Web): 02 Nov 2016
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Ligand Promoted meta-C–H Chlorination of Anilines and Phenols
Hang Shi, Peng Wang, Shin Suzuki, Marcus E. Farmer and Jin-Quan Yu*
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
RECEIVED DATE (automatically inserted by publisher); yu200@scripps.edu
In the Catellani reaction, norbornene is used to relay palladium
Abstract: Pd-catalyzed meta-C–H chlorination of anilines
and phenols is developed using norbornene as the mediator.
The presence of heterocycles, including indole, thiophene
and indazole, are tolerated. The identification of a new
pyridone-based ligand is crucial for the success of this
meta-C–H chlorination reaction. Subsequent diverse
transformations of the chlorinated products demonstrate the
versatility of meta-C–H chlorination.
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from the ipso-position to ortho-position of aryl iodides via
carbopalladation of the norbornene double bond and subsequent
cyclopalladation.7 This reactivity has been exploited to develop a
variety of transformations analogous to the Catellani reaction (Eq
1).8 The ability of norbornene to relay palladium from one carbon
to the adjacent carbon of an arylpalladium species has recently
been exploited to achieve meta-C–H activation reactions initiated
by directed ortho-C–H palladation (Eq 2).5 Although the scope of
arenes has been substantially expanded by the development of
new ligands, many transformations demonstrated in ortho-C–H
functionalizations remain to be realized for meta-C–H bonds.5
Given that halides can be converted to various motifs through
subsequent transformations, development of meta-C–H
halogenation would facilitate the installation of a wide range of
functional groups at the meta-position of aromatics. However, the
compatibility of the Catellani relay step with halogenation has not
been demonstrated to date. In addition, the ortho-C–H palladation
in the catalytic cycle of the meta-C–H functionalization could lead
to ortho-C–H halogenation with all the well-known C–H
halogenating reagents
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The efficiency and scope of directed ortho-C–H
functionalization reactions of arenes has been substantially
improved in the past decade.1 In contrast, directed meta-C–H
activation remains a significant challenge due to the difficulty of
assembling a macrocyclic, cyclophane-like transition state. The
use of U-shaped directing templates to direct meta-C–H activation
reactions demonstrated the feasibility of overcoming the
constraint of distance and geometry. However, the scope of both
substrates and transformations remains significantly inferior to
ortho-C–H functionalizations.2 The Ru(II) catalyzed meta-C–H
functionalization via ortho-cyclometallation and subsequent
functionalization at the meta-position is also a promising and
elegant approach, though it has only been demonstrated with a
small set of substrates thus far.3 Several other approaches towards
the meta-C–H functionalization of aromatics have also been
reported, though the generality of these approaches remains to be
established.4 Recently, directed meta-C–H arylation5 and
alkylation5a,5c has been achieved by using norbornene as a
transient mediator. In general, a diverse range of meta-C–H
functionalizations via this approach remains to be demonstrated.
Herein we report the first example of meta-C–H chlorination
using this approach. The development of a new pyridone-based
ligand is crucial for the success of this reaction. The versatile
reactivity of aryl chlorides allows installation of a wide range of
functional groups to suit a broad range of synthetic applications.
In addition, meta-chlorinated aryls are also found in many FDA
approved pharmaceuticals (Fig. 1).6
Our initial experimentation used N-chlorosuccinimide (NCS) as
the chlorination reagent. Only ortho-chlorinated product was
detected under various conditions when using this electrophile.9
These results indicated that NCS reacts with the ortho-aryl
palladium(II) intermediates faster than the norbornene. Following
this reasoning, we began to search for chlorinating reagents that
are less electrophilic, but could still serve as an oxidant in
Pd(II)/(IV) catalysis. Among various chlorinating reagents, we
found aryl chlorosulfate, initially utilized by the Buchwald group
for Pd-catalyzed chlorosulfonylation,10 is potentially suitable for
meta-C–H chlorination.11 In the presence of Pd(PhCN)2Cl2,
benzonitrile, NBE-CO2Me, and silver carbonate, the use of mono-
N-protected amino acid ligand Ac-Gly-OH12 gave the desired
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Figure 1. Selected pharmaceuticals containing the meta-chloro
aniline or phenol structure.
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product in 13% NMR yield (Table 1). While pyridine L2 is a poor
(2r), trifluoromethyl (2s), carbonyl (2t), and carboxyl (2u) are
ligand, pyridone derived ligands5e gave promising results (L3–6:
10-30% yields). Since tuning the N-protecting group on L3 did
not afford a noticeable improvement (see Supporting Information),
we focused on modification of the amide group of L6. Increasing
the acidity of the amide was found to improve the yield of the
reaction (L7, L8). Chloride substitution at the 5-position of the
pyridone further improved the yield to 70% (L9). Fluoride
substitution at the same position, however, is less effective (L10).
Replacing the CF3 in L9 by a CN group gave a similar result
(L11). Other norbornene derivatives gave significantly lower
yield (see supporting information).13 Although the necessity of
silver carbonate for the formation of the products led us to
propose that Ag+ promotes the activation of S–Cl bond of
chlorosulfate during the oxidation of palladium(II) intermediate. It
is possible that Ag+ also oxidizes Pd(0) or Pd(II) species in the
catalytic cycle by a one-electron transfer pathway.
also compatible with the reaction. A number of medicinally
important heterocyclic substrates were also smoothly converted to
the meta-chlorinated products 2w–2aa in good yields. Hydroxyl
group and pyridines are not compatible with current reaction
conditions. Unsubstituted aniline substrate, 1ab, was converted to
the di-substituted product in 77% yield (Eq 4). The feasibility of
extending this protocol to phenol substrates was also
demonstrated with modified conditions (Eq 5). A gram-scale
reaction was conducted and the product 2a was obtained in 87%
yield (Eq 6).
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Table 2. Substrate Scope of the C(sp2)–H Chlorination of
Anilines.a,b
Table 1. Ligand Screening of the meta-C–H Chlorination.a,b
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aReaction conditions: Pd(PhCN)2Cl2 (10 mol%), Ligand (10 mol%), PhCN (20
mol%), arene 1p (0.1 mmol), 2,6-diiPr-C6H3OSO2Cl (2.0 equiv.), NBE-CO2Me (1.5
equiv.), Ag2CO3 (2.0 equiv.), toluene (1 mL), cyclohexane (1 mL), 90 oC, 14 h, N2.
bThe yield was determined by 1H NMR analysis of the crude product using 1,1,2,2-
tetrachloroethane as an internal standard.
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With the optimized ligands (L9 and L11) and reaction
conditions in hand, a wide range of aniline substrates were
subjected to the standard meta-chlorination conditions (Table 2).
Meta-alkylated and arylated anilines gave the meta-chlorinated
products in excellent yields (2a–2f). Meta-chlorination of 1a
using 5 mol% catalyst also proceeded to give 2a in 72% yield (see
supporting information). Meta-chlorination of highly electron-rich
arenes containing Me2N, OMe and MeS groups also proceeded
smoothly without the formation of side products derived from the
electrophilic chlorination (2g–2k). The tolerance of alkynyl and
alkenyl groups (2l, 2m) is noteworthy as these functional groups
are known to react with electrophilic sources of chlorine, thus
demonstrating the mildness and selectivity of this transformation.
Intriguingly, aryl borate remained largely intact in the presence of
silver salts during the meta-chlorination (2n). Various electron-
withdrawing groups including fluoro (2o, 2p), chloro (2q), bromo
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aReaction conditions: Pd(PhCN)2Cl2 (10 mol%), Ligand 9 (10 mol%), PhCN (20
mol%), arene 1 (0.1 mmol), 2,6-diiPr-C6H3OSO2Cl (2.0 equiv.), NBE-CO2Me (1.5
equiv.), Ag2CO3 (2.0 equiv.), toluene (1 mL), cyclohexane (1 mL), 100 oC, 14 h, N2.
bIsolated yield. c110 oC. dLigand L11. ePd(PhCN)2Cl2 (15 mol%), Ligand (15 mol%).
To demonstrate the utility of this meta-chlorination reaction, we
performed diversification of 2a using the meta-chloro group as a
synthetic handle (Scheme 1). Aniline 2a was converted into a
wide range of desirable synthons in good yields by known
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methods including amination14, cross-coupling15, α-arylation16,
norbornene insertion and metalation. We hypothesize that the
borylation17, methoxylation18, and alkynylation19. Notably, none
of the functional groups, shown in scheme 1, can currently be
installed through previously reported norbornene-mediated meta-
C–H activation methods. Furthermore, the pyridine directing
group was readily removed by treatment with hydrobromic acid in
excellent yield (see supporting information for details).
oxidation of b produces Pd(IV) intermediate c through palladium
insertion into the S–Cl bond of the aryl chlorosulfate. Reductive
elimination from this proposed intermediate would form the C–Cl
bond at the meta-position. Meanwhile, sulfate on palladium
(intermediate c) could be degraded into sulfur dioxide and
phenol.11,20 Norbornene is then released via β-carbon elimination,
which generates intermediate d. Protodemetalation of the aryl–
palladium bond yields the final product 2 and regenerates the
palladium catalyst.
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Scheme 2. KIE Studies and Competition Experiments.
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To gain insights into the two C–H activation steps of the
catalytic cycle, we measured the parallel kinetic isotope effects
(KIE) (Scheme 2). The results indicate that neither ortho- nor
meta-C–H cleavage is the rate-limiting step. The competition
experiments reveal that electron neutral substrate (1a) is more
reactive than both electron rich and deficient substrates (1ac, 1t).
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Scheme 1. Diversification of meta-Chloro Aniline.
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In summary, we have developed the first example of directed
meta-selective C(sp2)–H chlorination of arenes. The reaction,
promoted by a new pyridone ligand, displays outstanding
functional group tolerance. Meta-C(sp2)–H chlorination of other
classes of substrates will be reported in due course.
Scheme 3. Proposed Mechanism.
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Reaction conditions: aPd2(dba)3 (3 mol%), DavePhos (9 mol%), PhMeNH (1.5
equiv.), arene 2a (0.1 mmol), NaOtBu (1.4 equiv.), toluene (0.4 mL), 80 oC.
bPd(OAc)2 (4 mol%), XPhos (8 mol%), 3-Methyl-2-buten-2-ylboronic acid pinacol
ester (2.0 equiv.), arene 2a (0.1 mmol), K3PO4 (3.0 equiv.), THF (1 mL), 60 oC.
cPd(OAc)2 (5 mol%), MePhos (10 mol%), propiophenone (1.2 equiv.), arene 2a (0.1
mmol), NaOtBu (1.3 equiv.), toluene (0.2 mL), 80 oC. dPd(OAc)2 (5 mol%), XPhos
(10 mol%), B2Pin2 (2.0 equiv.), arene 2a (0.1 mmol), KOAc (3.0 equiv.), dioxane
t
(0.4 mL), 110 oC. ePd2(dba)3 (3 mol%), BuXPhos (12 mol%), MeOH (10 equiv.),
arene 2a (0.1 mmol), NaOtBu (1.4 equiv.), dioxane (0.4 mL), 100 oC. fPd(MeCN)2Cl2
(6 mol%), XPhos (18 mol%), tert-butylacetylene (1.4 equiv.), arene 2a (0.1 mmol),
Cs2CO3 (2.5 equiv.), MeCN (0.4 mL), 90 oC.
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Based on the previous work by our group and others, a
proposed catalytic cycle for the norbornene mediated meta-
chlorination is depicted in scheme 3. Key to the success of this
catalytic cycle is selective oxidation of palladacycle b by the
chlorosulfate. Intermediate b arises from intermediate a through
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(15) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Acknowledgements. We gratefully acknowledge The Scripps
Chem. Soc. 2005, 127, 4685.
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Research Institute and NIH (NIGMS, 2R01 GM102265).
Supporting Information Available:Experimental procedures
and spectral data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360.
(17) Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 5359.
(18) Cheung, C. W.; Buchwald, S. L. Org. Lett. 2013, 15, 3998.
(19) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993.
(20) 2,6-Diisopropylphenol was observed as the product from aryl
chlorosulfate:
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