Monoprotected l-Amino Acid (l-MPAA), Accelerated Bromination, Chlorination, and Iodination of C(sp2)?H Bonds by Iridium(III) Catalysis

Article abstract of DOI:10.1002/chem.201700280

Halogenated arenes are important structural motifs commonly found in biologically active molecules and used for a variety of transformations in organic synthesis. Herein, we report the mono-protected l-amino acid (l-MPAA) accelerated iridium(III)-catalyzed halogenation of (hetero)anilides at room temperature. This reaction constitutes the first example of an iridium(III)/l-MPAA-catalyzed general halogenation of (hetero)arenes through C(sp²)?H activation. Furthermore, we demonstrate the potential utility of our method through its use in the synthesis of a quinolone derivative.

Full text of DOI:10.1002/chem.201700280

A Journal of
Accepted Article
Title: Monoprotected L-Amino Acid (L-MPAA) Accelerated Bromination,
Chlorination, and Iodination of C(sp2)-H Bonds by Iridium(III)
Catalysis
Authors: Subban Kathiravan and Ian A Nicholls
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To be cited as: Chem. Eur. J. 10.1002/chem.201700280
Link to VoR: http://dx.doi.org/10.1002/chem.201700280
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Monoprotected L-Amino Acid (L-MPAA), Accelerated Bromination,
Chlorination, and Iodination of C(sp2)-H Bonds by Iridium(III)
catalysis
Subban Kathiravan,[a] and Ian A. Nicholls*[a] [b]
Abstract: Halogenated arenes are important structural motifs
commonly found in biologically active molecules and used for a
variety of transformations in organic synthesis. Herein, we
report the mono-protected L-amino acid (L-MPAA) accelerated
iridium(III) catalyzed halogenation of (hetero)anilides at room
temperature. This reaction constitutes the first example of an
iridium(III)/L-MPAA catalyzed general halogenation of
(hetero)arenes through C(sp2)-H activation. Furthermore, we
demonstrate the potential utility of our method through its use in
the synthesis a quinolone derivative.
mild conditions with a wide substrate scope are rare, making a
general method providing high yielding and selective formation
of valuable and versatile aryl halides (Cl, Br, and I) of significant
interest.
Introduction
Transition metal-catalyzed C-H functionalization of readily
accessible and structurally simple chemicals is an appealing
strategy for accessing molecularly diverse systems.1
Halogenated organic compounds are fundamental structural
motifs in a range of important drugs, agrochemicals, and natural
products.2 The aryl halides are one of the most useful functional
groups in organic synthesis, and can be readily transformed into
more functionalized structures.3 Furthermore, the use of chloro-,
bromo-, and iodo arenes in cross coupling reactions has
tremendously increased the utility of these building blocks in
organic synthesis.4 Classical approaches, including the
Sandmeyer or electrophilic aromatic halogenation or Finkelstein
reactions are the most established methods for the synthesis of
aryl halides.5 However, the utility of these transformations is
limited due to the need for stoichiometric amounts of toxic
halogens and harsh reaction conditions. Previously, the groups
of Sanford,6 Bedford,7 Shi,8 Yu,9 and others10 have made
extensive studies of the palladium-catalysed halogenation of C-
H bonds.11-21 Over more recent years the Rh(III),22 Co(III),23
Ru(II),24 Au,25 and Cu(I)26 catalysed halogenations of C-H bonds
have also been well described. Nonetheless, these approaches
are limited by their scope, efficiency, and they are generally
suitable for only one type of C-X bond formation (Scheme 1).
Accordingly, catalytic direct C-X bond formation remains a
daunting challenge, and catalytic systems that operate under
Scheme 1. Arene C-H activation and Ir(III)/L-MPAA catalysed C-
H activation
The use of mono-protected amino acid (MPAA) external ligands
for controlling the reactivity and selectivity of catalyst-driven
transformations has found broad scope in the development of C-
H activation reactions.27 The ready availability and ease of
handling of amino acids are further aspects that motivate their
use as ligands. The weak interaction of the MPAA ligand’s
functional groups with the metal centre is proposed to lower the
transition energy of the C-H activation step. This has been well
exploited, in particular in palladium catalysed C-C bond
formation, as demonstrated by the group of Yu and others.28-29
Dixneuf and co-workers reported a Ru(II)-catalyzed autocatalytic
process, where it was shown that carboxylic acid additives could
improve the catalytic activity of ruthenium by promoting the
dissociation of an acetate ligand from the metal acetate
species.30 In contrast, the use of this type of ligand system for
the synthesis of other C-X bond systems remains unexplored.
[a]
[b]
Dr. S. Kathiravan, and Prof. Ian A. Nicholls
Department of Chemistry & Biomedical Sciences
Linnaeus University Centre for Biomaterials chemistry
Linnaeus University, SE-391 82, Kalmar, Sweden
E-mail: ian.nicholls@lnu.se
In this study we envisioned the development of a ligand scaffold
that could promote C-H activation for the synthesis of various
aryl halides, a major class of synthetically useful compounds.
Due to the high reactivity of Ir(III) half sandwich complexes in
mild C-H transformations, we saw the potential of these
complexes in halogenation reactions.31 In particular, we
anticipated that an in situ generated cationic iridium(III) half
sandwich complex could be expected to coordinate an L-MPAA
Prof. Ian A. Nicholls
Department of Chemistry-BMC
Uppsala University, SE-751 23 Uppsala
Sweden
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization studiesa
through the carboxyl functionality and where the weakly
coordinating amide could occupy a further site.32
Herein, we report the first example of a highly selective Ir(III)/L-
MPAA catalysed halogenation of anilides. Anilide directed Ir(III)
catalysed C-H activation reactions are still rare,33 even though
this functional group has been frequently studied in other related
reactions catalysed by similar metals.34 Importantly, the
reactions feature an extraordinarily high mono-halogenation
(iodination, bromination, and chlorination) at room temperature
with very low catalyst loadings.
Results and Discussion
Optimization of reaction conditions
We began investigating the proposed strategy using the
coupling of acetanilide 1a with N-bromosuccinimide 2b in the
presence of 1 mol% IrCp*Cl22, 5 mol% AgNTf2, and 50 mol% of
pivalic acid. However, the formation of ortho-bromo acetanilide
3a was observed in only 12% yield, even at 120°C (Table 1,
entry 1). Importantly, we even observed some para-bromination
(10 % yield) resulted in the formation of the para-derivative. To
our delight, when we introduced 10 mol% of N-acetyl-L-
phenylalanine into the reaction mixture, the desired product was
obtained in 35% yield (Entry 2), though no reaction was
observed when using N-acetyl-L-tryphtophan (Entry 3).
Interestingly, the anticipated product was obtained in excellent
yield (89%) when N-Boc-L-phenyl alanine was used as
ligand/additive (Entry 4). In contrast, other N-protected amino
acids, N-Boc-L-proline and N-Boc-L-valine, resulted in reduced
yields (Entries 5-6). We then explored the role of the N-
protecting group on L-phenylalanine and some other amino
acids (Entries 7-16). Relative to Boc-L-phenylalanine, Piv-, 1-Ad,
COOMe and Fmoc- resulted in inferior performance. These
results suggest a future study on the influence of amino acid
side chain and protecting group on the reaction. Next, we
focused our attention on the screening of additives using
AgSbF6, AgOCOCF3, and AgBF4, all which gave lower to
modest product yields (Entries 17-19). Finally, when the catalyst
IrCp*Cl22 was replaced with RhCp*Cl22, (p-cymene)RuCl22
and even Cp*Co(CO)I2, the yield of the product was lower
(Entries 20-22).
aReaction conditions: 1 (0.36 mmol), 2 (0.36 mmol), IrCp*Cl22 (0.5
mol%), AgNTf2 (5 mol%), Boc-L-Phe-OH (10 mol%), DCE (1 mL), 4
h, N2, rt. bProduct yield corresponds to isolated yield. Ir(III) =
IrCp*Cl22, Rh(III) = (RhCp*Cl2)2, Ru(II) = (RuCl2(p-Cyemene)2,
Co(III) = CoCp*(CO)I2.
A
series of halogen sources, N-halo succinimide and
phthalimide derivatives (2a-f) were also screened. For
bromination and iodination the corresponding N-
Synthetic scope
Iridium(III)/Boc-L-Phe-OH catalysed bromination
halosuccinimides 2b and 2d, respectively, afforded the product
in better yield than the corresponding phthalimides. For
chlorination, N-chlorophthalimide 2e provided product in good
yield, whereas reaction with N-chlorosuccinimide (2f) was not
observed.
With the optimized conditions in hand, we then investigated the
scope of bromination using various anilides (1a-y) with N-
bromosuccinimide (2b) (Table 2). To the best of our knowledge,
this is the first example of Cp*Ir(III) catalysed bromination at
room temperature. The reaction of
a variety of anilides
substituted with either a weak (3b) or a strong electron donating
group (3c-d) or various electron-withdrawing groups (3e-k)
proceeded efficiently affording the bromo anilides 3a-k with good
to excellent yields (60-92%) and selectivity. A variety of
functional groups such as fluoro (3e), chloro (3f), bromo (3g),
iodo (3h), cyano (3i), nitro (3j), and ester (3k) were well
tolerated, thus offering the opportunity for further synthetic
transformations. The reaction also worked for an array of multi-
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respectively. Importantly, no desired product was obtained in the
absence of Ir(III) catalyst. A study of the influence of catalyst
loading was undertaken, and the results suggest that amounts
as low as 0.01 mol% of the iridium(III) catalyst are effective,
providing 5a in 60% yield.
substituted anilides (1l-o) giving the products in good to
moderate yields (59-87%). Even the hydroxyl substituted anilide
3p afforded the corresponding product in moderate yields (51%).
A
meta-substituted anilide (3q) could also be selectively
brominated. Furthermore, the pyridine derivative afforded the
corresponding product (3r) in good yield (70%) when subjected
to the C-H activation derived bromination. The reaction was
found to have more limited applicability under these conditions
with some other anilides (3s-y).
Table 3. Iridium(III)/ Boc-L-Phe-OH catalysed iodinationa,b
Table 2. Iridium(III)/Boc-L-Phe-OH catalysed brominationa,b
aReaction conditions: 4a-o (0.25 mmol), 2d (0.39 mmol), (IrCp*Cl2)2
(0.5 mol%), AgNTf2 (5 mol%), Boc-L-Phe-OH (10 mol%), DCE (1
mL), 4 h, N2, rt. bProduct yield corresponds to isolated yield.
Iridium(III)/Boc-L-Phe-OH catalysed chlorination
The success of the bromination and iodination reactions led us
to extend this method to chlorination as there is yet no report of
chlorination via Ir(III) catalysed C-H activation. Gratifyingly, the
reaction proceeded, and gave various ortho-chlorinated anilides
in good to moderate yields (Table 4). No reaction occurred when
either Ir(III) or L-MPAA was omitted. Anilides substituted with
methyl and ethyl groups chlorinated to the corresponding
products 7a-b in 66 and 75% yields. Aryl halides underwent C-H
chlorination to afford the poly-halides 7c-f in 48-73% yields.
Anilides with Ester- (7g), ortho- (7h), pyridine- (7i), and multi-
substituted 7j-k anilides were found to be tolerated.
aReaction conditions: 1a-y (0.36 mmol), 2b (0.37 mmol), (IrCp*Cl2)2
(0.5 mol%), AgNTf2 (5 mol%), Boc-L-Phe-OH (10 mol%), DCE (1
mL), 4 h, N2, rt. bProduct yield corresponds to isolated yield. NR = no
reaction.
Iridium(III)/Boc-L-Phe-OH catalysed Iodination
It is noteworthy that attempts were made to apply the optimized
protocol to the fluorination of acetanilide (1a) with N-
fluorbenzenesulfonamide, though no fluorinated product was
observed, as was the case with studies performed at elevated
temperature (125 °C).
Encouraged by these results, we explored the use of this
catalysis system for C-H iodination (Table 3).35 A variety of
anilides could be employed in the Ir(III)/L-MPAA catalysed C-H
iodination reaction. The substrate scope could be extended from
substituted to unsubstituted anilides. The anilides, with electron
donating (4b-d) or electron withdrawing (4e-j) substituents
afforded the desired products in good to excellent yields (50-
96%). Disubstituted anilides bearing methyl, iodo, and chloro
groups provided the iodinated products 5k-m in good yields. The
meta-substituted anilides also underwent reaction to form the
corresponding products 5n and 5o in 49 and 58% yields,
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Table 4. Iridium(III)/ Boc-L-Phe-OH catalysed chlorinationa,b
Scheme 2. Mechanistic studies and transformation of anilide
derivatives
Conclusions
In summary, we have developed the first iridium(III)
catalysed mono-N-protected amino acid (L-MPAA) accelerated
halogenation through C(sp2)-H activation. This enabled the
synthesis of a diverse array of halogenated anilides including
hetero variants at room temperature using commercially
available and less toxic halogen sources. These efficient
catalytic systems based upon readily available amino acid
derivatives may find application in other C-H activation
reactions. Moreover, we present the application of this
method in conjunction with an intramolecular C(sp3)-H
activation for the synthesis of a quinolinone derivative.
Finally, more detailed mechanistic studies and alternative
strategies for extension to the fluorination of aromatics are
currently being explored in our laboratory.
aReaction conditions: 6a-k (0.36 mmol), 2e (0.39 mmol), (IrCp*Cl2)2
(0.5 mol%), AgNTf2 (5 mol%), Boc-L-Phe-OH (10 mol%), DCE (1
mL), 4 h, N2, rt. bProduct yield corresponds to isolated yield. c80° C.
Mechanistic studies and Synthetic application
To gain insight into the mechanism of the C-H halogenation
reaction process, an H/D exchange study was performed using
1a in the presence of 2d, revealing 22% incorporation of D at the
ortho-position (Scheme 2a) suggesting reversible C-H activation.
To further probe the C-H activation process, the kinetic isotopic
effect was determined by intermolecular competition
experiments using an equimolar mixture of 1a and D5-1a. The
value of kH/kD (3.3) suggests that C-H bond cleavage is likely not
involved in the turnover-limiting step (Scheme 2b). The crucial
role of L-MPAA may be to generate a extremely reactive
Ir(III) catalyst with a vacant site for the amide coordination,
though amino acid activation of N-halo amides through
protonation, cannot be not discounted. Efforts to isolate the
metal complex were not successful. Moreover, to
demonstrate the synthetic utility of this method, we conducted
the C-H bromination of pivalimide (8) using our optimization
procedure. The product (9) was then subjected to a palladium
catalysed intramolecular C(sp3)-H activation to furnish 3,3-
dimethyl-3,4-dihydroquinolin-2-one (10) in 68% over two steps
(Scheme 2c), the quinolone moiety being a feature present in
some natural products and drug structures.36
Acknowledgements
We thank the Swedish Research Council (Vetenskapsrådet,
Grant 2014-4573) and Linnaeus University for financial support.
We also thank Dr Håkan S Andersson, Linnaeus University for
providing some of the amino acids used here.
Keywords: Iridium • L-MPAA • C-H activation • Halogenation •
Anilides
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Entry for the Table of Contents
FULL PAPER
Subban Kathiravan, Ian A. Nicholls*
Page No. – Page No.
Monoprotected L-Amino Acid (L-
MPAA) Accelerated Bromination,
Chlorination, and Iodination of C(sp2)-
H bonds by Iridium(III) Catalysis
Versatile mono protected amino acid promoted iridium(III) catalysed halogenation of
(hetero) anilides at room temperature was reported herein. The crucial role of L-MPAA
might be to generate a extremely reactive Ir(III) catalyst with a vacant site for amide
coordination. Variety of anilides could be efficiently converted into aryl halides and
their synthetic utility in heterocyclic synthesis was also demonstrated.
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