Direct Palladium-Catalyzed β-Arylation of Lactams

Article abstract of DOI:10.1002/anie.201800958

A direct and catalytic method is reported here for β-arylation of N-protected lactams with simple aryl iodides. The transformation is enabled by merging soft enolization of lactams, palladium-catalyzed desaturation, Ar?X bond activation, and aryl conjugate addition. The reaction is operated under mild reaction conditions, is scalable, and is chemoselective. Application of this method to concise syntheses of pharmaceutically relevant compounds is demonstrated.

Full text of DOI:10.1002/anie.201800958

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Accepted Article
Title: Direct Palladium-Catalyzed β-Arylation of Lactams
Authors: Ming Chen, Feipeng Liu, and Guangbin Dong
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10.1002/anie.201800958
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Direct Palladium-Catalyzed β-Arylation of Lactams
Ming Chen†, Feipeng Liu†,‡ and Guangbin Dong*,†
Abstract: A direct and catalytic method is reported here for β-
In 2013, we showed that direct β-arylation of ketones can be
realized via a Pd-catalyzed redox cascade process (Scheme 1b),
which involves Pd(II)-mediated ketone desaturation (step A),
Pd(0)-mediated Ar−X oxidative addition (step B), Pd(II)-aryl
conjugate addition (step C) and protonation of the resulting
Pd(II)-enolate (step D).[6] However, direct implementation of this
strategy for amide substrates is difficult, as amides do not easily
undergo α,β-desaturation under such reaction conditions.[7]
Recently, we developed a catalytic amide desaturation method
assisted by soft enolization, in which a bulky benzoquinone
serves as the optimal oxidant.[8] Despite the feasibility of
desaturating lactams (step A) in the proposed redox cascade,
three concerns remain to be addressed for successful β-
arylation of lactams. First, it is uncertain if the Lewis pair used in
the soft enolization would be compatible during the remaining
catalytic cycle, particularly in the C−C bond forming step.
Second, it is uncertain if aryl halides would substitute the bulky
benzoquinone and serve as an effective oxidant for Pd(0), as
electron-donating ligands cannot be used for lactam
desaturation,[8,9] which increases difficulty for the oxidative
addition step (step B). Third, the migratory insertion step (step C)
needs to be fast enough; otherwise, α-arylation side reaction[10]
would compete due to the presence of highly nucleophilic amide
enolates (vide infra, Table 3).
arylation of N-protected lactams with simple aryl iodides. The
transformation is enabled by merging soft enolization of lactams, Pd-
catalyzed desaturation, Ar−X bond activation and aryl conjugate
addition. The reaction is operated under mild conditions, scalable
and chemoselective. Application of this method to concise syntheses
of pharmaceutically relevant compounds is demonstrated.
Lactams with a β-aryl substituent are frequently found in
drugs and pharmaceutical intermediates (Figure 1).[1]
Conventionally, they are often prepared through conjugate
addition of an aryl nucleophile to an α,β-unsaturated lactam.[2]
This approach typically requires formation of an organometallic
reagent from an aryl halide and oxidative dehydrogenation of a
saturated lactam. Clearly, a more straightforward approach
would be directly coupling of an aryl halide at the β-position of a
saturated lactam, which remained an unmet challenge. Since
the seminal work by Daugulis,[3] β-arylation of amides has been
enabled using
a
directing group strategy (Scheme 1a).[4,5]
Unfortunately, such a strategy is not applicable to lactams, and
hence, the lack of chelation assistance in lactams calls for a
different mode of activation for β-arylation. Herein, we describe
the development of a Pd-catalyzed redox-cascade strategy for
direct arylation at lactam β-positions with readily available aryl
iodides (Scheme 1b). Compared with the conjugate addition
approach, this method avoids preparing unsaturated lactams
and aryl nucleophiles in advance.
Scheme 1. β-Arylation of Amides.
To examine the feasibility of the proposed strategy, our study
began with valerolactam 1a and 4-(CF3)-iodobenzene 2v as the
model substrates. After careful optimization, the use of Pd(TFA)2
as the pre-catalyst and AgTFA as the promoter ultimately
afforded the desired β-arylation product 3v in 73% yield at room
temperature via a boron-enolate intermediate. (Table 1). The
homo-coupling product HC-2v and the further oxidized product
DH-3v were formed in 6% and 8% yields, respectively, and no
desaturated 1a (DH-1a) remained. To understand the role of
each reactant, control experiments were conducted. Clearly, the
palladium pre-catalyst, the silver salt and the Lewis pair are all
critical for this transformation (entries 1-4). It was proposed that
the silver salt promoted iodide-carboxylate exchange to
regenerate the active Pd(II) catalyst. The Lewis acid/base pair
plays a pivotal role in forming the boron-enolate intermediate.
Figure 1. Bioactive lactams with β-aryl substituents
[†]Department of Chemistry, University of Chicago, Chicago, Illinois, 60637,
United States
[‡]Department of Applied Chemistry, China Agricultural University, 2 West
Yuanmingyuan Road, Beijing 100193, China
* Correspondence: gbdong@uchicago.edu (G. D.)
Supporting information for this article is given via a link at the end of the
document.
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Notably, no additional ligand was used in this reaction. A range
of phosphine, nitrogen and sulfur-based ligands have been
examined (entry 5). Sulfoxide type ligands were previously found
to be important in lactam dehydrogenation;[8] however, they led
to decreased yields in this reaction. The use of pyridine or
phosphine-based ligands dramatically shut down the reactivity.
Using Cy2BOTf instead of Bu2BOTf gave a lower yield (46%),
though formation of side products HC-2v and DH-3v also
diminished (entry 6). Replacing the trifluoroacetate counterion of
the palladium and the silver salt with OAc resulted in a
decreased yield (entry 7), in which significant amounts of homo-
coupling product HC-2v (17% yield) and desaturated lactam DH-
1a (12% yield) were formed. This indicates that trifluoroacetate
anion promotes the Pd-aryl species to undergo migratory
insertion into DH-1a, rather than a self-coupling. Attempts of
using Lewis acids to accelerate the protonation step (step D)
were unfruitful (entry 8). A survey of different solvents suggests
aromatic solvents, such as toluene and fluorobenzene, to be
optimal (entries 9-12), though 1,4-dioxane also delivered the
product in 60% yield; in contrast, more polar THF and CH3CN
gave no conversion of lactam 1a.
Subsequently, the substrate scope of aryl iodides was
investigated (Table 2). Aryl iodides bearing either electron-
donating or -withdrawing groups all participated to give the
corresponding β-arylated lactams in moderate to good yields.
The corresponding aryl bromides are not reactive. In addition,
substitutions at ortho, meta, or para positions all worked
comparably well (3a-d). A range of functional groups are
compatible, such as aryl esters (3x,[11] 3y), Weinreb amides (3j),
protected indoles (3k), amides (3l, 3m), ketones (3n, 3za)
fluorides (3r, 3t), chlorides (3q), bromides (3s), nitro (3u),
trifluoromethyl (3v, 3w), and sulfone moieties (3z). Acid sensitive
groups, e.g. silyl-ether (3i), or base sensitive groups, e.g.
phenolic ester (3h), are tolerated. When aryl iodides containing
additional enolizable tertiary amides (3l, 3m) or ketone (3n)
were employed, the β-arylation still occurred at the lactam
moiety. One key for such chemoselectivity is the order of
addition of the reagents: pre-mixing lactam substrates with
Bu2BOTf and DIPEA before adding aryl iodides allowed for
selective enolization of the lactam moiety. In all these examples,
the over-oxidation products were observed in 5-10% yields; no
α-arylation products were found.
Table 1. Selected Optimization Studies.[a]
Lactams with different ring sizes were also examined as
substrates (Table 3). 1,3-Difluorobenzene was found to be a
better solvent for other lactams than 1a. Surprisingly, the five-
membered lactam only afforded the α-arylation product (4a) in
60% yield, and the seven-membered lactam gave a 1:1 mixture
of the α- and β-arylation products (4b). We speculated that the
α-arylation products might come from a direct enolate arylation
pathway[12] as desaturation of five- and seven-membered
lactams were found to be slower than the six-membered ones.[8]
The benzofused six-membered lactams also only gave the α-
arylation products (4c, 4d); however, the benzofused seven and
eight-membered lactams all successfully delivered the desired
β-arylation products (4e-4l). Interestingly, the substrate with a γ-
substituent
furnished
product
4g
in
an
excellent
diastereoselectivity favoring the trans product. In the presence of
an enolizable ester group (4h), β-arylation still preferred to occur
at the lactam. In addition, eight-membered lactams with aryl or
cyclopropyl substituents (4j, 4k) are competent substrates.[13]
The oxazocine derivative also gave the desired product (4l).
To understand why benzofused six-membered lactams
preferred to give the α-arylation products, desaturation of
benzofused six-eight membered lactams was carried out.
The study showed that, while the seven- or eight-membered
lactams worked normally and delivered the desired products in
in good yields, the six-membered lactam surprisingly only gave
the deprotected product 5a. Due to the high aromaticity of 5a
aryl migratory insertion would be highly challenging. As a result,
such substrates would be problematic to afford the β-arylation
products; instead, the α-arylation pathway would then dominate.
[a] Each reaction was run on a 0.1 mmol scale in a sealed 4 mL vial for 48 h.
[b] Yields were determined by 1H NMR using CH2Br2 as the internal standard.
TFA = trifluoroacetate. [c] 17% yield of HC-2v and 12% yield of DH-1a. [d] 9%
yield of HC-2v and 10% yield of DH-3v. [e] 5% yield of HC-2v and 8% yield of
DH-3v. [f] 2% yield of HC-2v and 4% yield of DH-3v.
Table 2. Substrate Scope with Aryl Iodides[a,b]
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Table 3. Substrate Scope with Lactams[a,b]
[a] Each reaction was run on a 0.2 mmol scale in a sealed 8 mL vial for 24 h.
[b] Isolated yields. [c] 20 mol% Pd(TFA)2 was used. DFB=1,3-difluorobenzene.
Scheme 2. Dehydrogenation of Benzofused-lactams
10 mol% Pd(TFA)2
15 mol% Ph(SO)Me
20 mol% Zn(TFA)2
N
PGF
2,5-ditBu-BQ, Bu2BOTf, DIPEA
1,4-dioxane, 50 oC
N
PGF
O
O
N
PGF
N
PGF
O
N
H
O
O
5a, 58%
5b, 72%
5c, 60%
To test the practicality of this method, a gram-scale reaction
was carried out, which gave 64% yield and high recovery of
unreacted lactam 1a (Eq 1). Moreover, when the palladium
loading was reduced to 5, 2.5 and
1 mol%, though the
conversion was lower, up to 48 turnovers were obtained (Eq 2).
[a] Each reaction was run on a 0.2 mmol scale in a sealed 8 mL vial for 48 h.
[b] Isolated yields. Numbers in parenthesis are yields based on recovered
starting material. [c] 1.8 equiv 1a, 1.8 equiv Bu2BOTf and 1.8 equiv DIPEA
was used.
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To show the synthetic utility of this method, first, the acyl
protecting group was easily removed to reveal free lactams
under mild conditions (Scheme 3a).[14] Upon reduction with
LiAlH4, 6 was conveniently converted to γ-arylated piperidine 7
that is known to be a melanin-concentrating hormone (MCH)
antagonist.[15] In addition, using this β-arylation method followed
by deprotection, formal synthesis of paroxetine, an anti-
depression drug, was realized in a concise fashion (Scheme
3b).[16] Furthermore, a streamlined synthesis of antibacterial
compound 11 has been accomplished in a good overall yield
(Scheme 3c). Given that arylbromide is tolerated under the β-
arylation conditions, a highly chemoselective C−N coupling
between the arylbromide (9) and the oxazolinone (10) moieties
was enabled using copper catalysis.[17] Note that this
antibacterial compound is now made in only four steps from
inexpensive 2-pyrrolidinone; in contrast, the previous approach
took seven steps.[1f]
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Scheme 3. Synthetic Applications
In summary, an initial catalytic approach for direct β-arylation
of lactams is developed. This method tolerates a wide range of
functional groups, and shows promising scalability. It offers a
unique strategy to access β-arylated lactams and γ-arylated
piperidines, and streamlines synthesis of pharmaceutically
important compounds. Future work will involve minimizing side-
product formation through detailed mechanistic study as well as
developing an enantioselective version of this transformation.
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Acknowledgements
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crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
We thank University of Chicago for a startup fund. M.C. thanks
Shanghai Institute of Organic Chemistry for a postdoc fellowship.
F.L. is supported by a CSC fellowship. Mr. Chengpeng Wang is
acknowledged for checking the experiments.
Keywords: β-arylation • lactam • palladium catalysis • soft
enolization • C−C formation
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Entry for the Table of Contents
COMMUNICATION
Ming Chen†, Feipeng Liu†,‡ and
Guangbin Dong*,†
Page No. – Page No.
Direct β-arylation of N-protected lactams with simple aryl iodides is developed
through merging soft enolization and Pd-catalyzed redox cascade. The reaction is
operated under mild conditions, scalable and chemoselective.
Direct Palladium-Catalyzed β-
Arylation of Lactams
This article is protected by copyright. All rights reserved.