Amine-Directed Palladium-Catalyzed C?H Halogenation of Phenylalanine Derivatives

Article abstract of DOI:10.1002/chem.202102411

An efficient primary-amine-directed, palladium-catalyzed C?H halogenation (X=I, Br, Cl) of phenylalanine derivatives is reported on a range of quaternary amino acid (AA) derivatives thanks to suitable conditions employing trifluoroacetic acid as additive. The extension of this original native functionality-directed ortho-selective halogenation was even demonstrated with the more challenging native phenylalanine as tertiary AA.

Full text of DOI:10.1002/chem.202102411

Accepted Article
Accepted Article
Title: Amine Directed Palladium Catalyzed C-H Halogenation of
Phenylalanine Derivatives
Authors: Alexia Ville, Julien Annibaletto, Sébastien Coufourier,
Christophe Hoarau, Rodolphe Tamion, Guillaume Journot,
Cédric Schneider, and Jean-François Brière
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To be cited as: Chem. Eur. J. 10.1002/chem.202102411
Link to VoR: https://doi.org/10.1002/chem.202102411
01/2020

10.1002/chem.202102411
Chemistry - A European Journal
COMMUNICATION
Amine Directed Palladium Catalyzed C-H Halogenation of
Phenylalanine Derivatives
Alexia Ville,[a,c] Julien Annibaletto,[a,c] Sébastien Coufourier,[a,b] Christophe Hoarau,[a]
Rodolphe Tamion,[b] Guillaume Journot,*[b] Cédric Schneider,*[a] Jean-François Brière*[a]
Dedication ((optional))
[a]
Dr. A. Ville, Dr. J. Annibaletto, Dr. S. Coufourier, Prof. C. Hoarau, Dr. C. Schneider and Dr. J.-F. Brière
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France.
E-mail: cedric.schneider@univ-rouen.fr and jean-francois.briere@insa-rouen.fr
Internet site: www.lab-cobra.fr/equipes/heterocycles/
[b]
[c]
Dr. G. Journot, Dr. R. Tamion
Industrial Research Centre–Oril Industrie, CS 60125, 76210 Bolbec, France
Email: guillaume.journot@servier.com
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: An efficient primary amine-directed palladium catalyzed C-
H halogenation (X = I, Br, Cl) of phenylalanine derivatives is reported
on a range of quaternary amino acid (AA) derivatives thanks to suited
conditions employing trifluoroacetic acid as additive. The extension of
this original native functionality-directed ortho-selective halogenation
was even demonstrated with the more challenging native
phenylalanine as tertiary AA.
carbonylation reaction of α,α-disubstituted R-NH2 quaternary Phe
(n = 1).[12] This catalytically more challenging C(sp2)-H activation
sequence, through the formation of a less favored six-membered
NH2-bond palladacycle,[13,14] was subsequently developed to the
coupling reactions of allenes,[13b] alkenes[13c] as well as aryl
partners,[13f,13h] and extended to the native Phe (α-
monosubstituted) in few cases.[13a,13d,13e,13g] During these
achievements, long-standing challenges were addressed to
overcome both the formation of stable (and poorly reactive) bis-
amino-PdII complexes and competitive β-H elimination events.[13]
These issues turned out to be intimately linked to the α-
substitution pattern of the amine substrate and the steric
hindrance of this native FG (usually beneficial to the process),[15]
while silver and acid reagents turned out to be key additives for
securing a successful transformation.[12,13] However, in spite of
previously reported insightful halogenation reactions of pre-
formed (stepwise and stoichiometric) six-membered ring NH2-
bond palladacycle like pioneered investigations by Vicente and
Saura-Llama (n = 1),[14,16] to the best of our knowledge, the Pd-
catalyzed NH2-directed C-H halogenation remains to be achieved.
Given the widespread use of non-proteinogenic amino acid (AA)
within bioactive molecules, the diversification of α-AA backbone
represents an active research field in medicinal chemistry and in
the development of synthetic methodologies.[1,2] Beside
numerous investigations of directing-group (DG) site-selective
metal-catalyzed C(sp3)-H activation of AAs,[2] the analogous
C(sp2)-H functionalization of phenylalanine (Phe) derivatives has
grown more recently as a powerful strategy for the regioselective
C-C and C-heteroatom bonds construction.[2,3] In this context, the
halogenated Phe derivatives are valuable building blocks and
versatile platforms for cross-coupling reactions allowing to
transform the C-X (X = I, Br, Cl) bonds into a myriad of useful
functionalities (Scheme 1A).[4] Based on the design of suited N-
directing-groups (DG) on Phe esters,[5] Yu[5a] and Correa[5b]
successfully applied the Pd-catalyzed ortho-iodination (triflimide
as DG) and bromination (picolinamide as DG) of Phe
derivatives.[6,7] On the other hand, Barluenga demonstrated the
metal-free ortho-iodination of Phe esters based on electrophilic
aromatic substitution (SEAr) using trifluoroacetamide as DG.[8]
This strategy overcomes the established moderate ortho- versus
para-regioselectivity issues from native-NH2 Phe upon usually
substrate-controlled pathways (depending on electronic and
steric factors).[9]
In line with atom- and step-economical strategies, exploiting
native-functional group (FG) as DG, the unprotected NH2-directed
palladium catalyzed C(sp2)-H activation emerged as
a
straightforward C-C bond formation method.[10] Beside the original
exploitation of thermodynamically favored five-membered
palladacycle intermediates from benzylamine precursors
(Scheme 1B, n = 0),[11] Garcia and Granell pioneered the
Scheme 1. NH2-directed C-H halogenation.
1
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We are pleased to report herein an ortho-selective C(sp2)-H
halogenation (X = I, Br, Cl) of Phe derivatives, highlighting the key
role of the amine topology and acid additive to achieve a catalytic
process while preventing the non-regioselective halogenation of
both the amine and arene moieties (Scheme 1C).
Table 2. Scope and limitation.
Table 1. Proof of principle and optimization.
Entry
Deviation from the standard conditions
Yield [%]
2a’, 2a
1
None
0, 78
22, 37
0, 0
2
Use of 1.1 equiv of NBS
3
Without palladium complex
4
Without CF3CO2H[a]
0, 0
5
AcOH, HCl, PivOH, PhCO2H instead of CF3CO2H[b]
Tf2NH or TfOH, instead of CF3CO2H [b]
40 °C instead of 50 °C
0, 0
6
16, 0
17, 28
11, 55
14, 64
0, 42
0, 64
14, 65
<26, 0
7
8
Pd(OAc)2 (5 mol%) instead of 10 mol%
Pd(TFA)2 instead of Pd(OAc)2
In CF3CO2H as solvent instead of CH2Cl2
In AcOH as solvent instead of CH2Cl2
In PhCF3 as solvent instead of CH2Cl2
In CPME or AcOEt as solvent instead of CH2Cl2
Reaction conditions: carried out with 1 (0.3 mmol) and NBS (2 equiv). Isolated
yields (%) after column chromatography. [a] The presence of starting material
(10%) and mono-halogenated products 3a’-19% and 4a’-13% were detected
on the crude mixture by 1H NMR. [b] Inseparable mixture. [c] Without Pd-catalyst
a mixture of ortho- and para-brominated products (28% and 29% respectively)
was obtained. [d] On 1 mmol scale. [e] With NXS (1.1 equiv). [f] In CH2Cl2/HFIP
giving slightly better results. [g] Remaining starting material 1e-10% (X = Br),
1e-13% (X = Cl), 1e-43% (X = I). [h] With NBS (1.1 equiv) 60/40 ratio of mono-
Br (5-position) and di-1,5-Br were obtained.
9
10
11
12
13
Reaction conditions: carried out with 1a-TFA (0.3 mmol) at CH2Cl2 as solvent
(0.1 M). Yields determined by 1H NMR with an internal standard. [a] Same
outcome in CH2Cl2/HFIP (1:1). [b] Carried out from the free amine 1a.
Then, we investigated these soft and ortho-selective C-H
bromination conditions to α-methyl phenylalanine ester
derivatives 1a-1o as free amine (Table 2). Starting from para-
substituted 1a-1c (para-Br, Cl and Me) and unsubstituted 1d
precursors, the ortho-dibrominated products 2a-c and 2d were
obtained in isolated yields ranging from 54% to 76%. In the case
of para-methyl substrate 1c traces of the mono-brominated 2c’
(6%) was also obtained. Interestingly, the α-methyl phenylalanine
ester 1d (electron-neutral Ar) furnished a mixture of ortho- and
para-brominated products in the absence of palladium. This
outcome shows that the Pd-catalyzed C-H halogenation
surpasses significantly the rate of the background reaction.
Although the sterically hindered meta-CF3 precursor 1e gave
selectively 2-brominated compound 2e in 55% yield (1.1 equiv of
NBS), the less sterically encumbered substrates (with m-F and m-
Me) led to the di-brominated products 2f and 2g in 70% and 60%
yields in the presence of 2 equivalents of NBS. Regardless of the
nature of the ortho-substituent on amino esters 1h-l, the
corresponding mono-brominated products 2h-2l were isolated in
52-80% yields. As expected, electron-rich methoxy-substituted
precursors 1m and 1n underwent a competitive SEAr-based
background pathway e.g. providing the brominated product 2n
(77%) at the para-position to the OMe at C2 position.
Nonetheless, starting from OTf derivative (1o) secured the Pd-
catalyzed ortho-bromination reaction to afford 2o in 79% yield.
Importantly, although full-conversion was not always reached in
similar conditions, the chlorinated (3a-54%, 3e-46%, 3l-60%) and
iodinated (4a-53%, 4e-29%, 4l-55%) products were also
synthesized by means of NCS and NIS, demonstrating thereby
Our investigation commenced with para-bromo-α-methyl
phenylalanine ester 1a as an ammonium trifluoroacetate 1a-TFA,
because no background halogenation took place in the presence
of N-bromosuccinimide (NBS) in CH2Cl2 at 50 °C (Table 1, entry
3).[17] To our delight the major ortho-dibrominated product 2a was
formed in 37% NMR yield along with 22% of the mono-brominated
counterpart 2a’ (entry 2) in the presence of 10 equivalents of
trifluoroacetic acid (CF3CO2H) and 1.1 equivalent of NBS, while 2
equivalents of NBS furnished exclusively 2a in an excellent 78%
yield (entry 1). In general, an excess of NBS led to lower yields.[17]
The key role of the acid additive is worthy of note (10 equivalents
is the optimal amount),[18] as no reaction took place in the absence
of CF3CO2H (entry 4), and other acids turned out to be ineffective
(entry 5) or to afford traces of 2a’ (like TfOH or Tf2NH, entry 6).
The amount of Pd(OAc)2 could be decreased to 5 mol % (entry
8), and Pd(TFA)2 (entry 9) could be used instead to furnish the
dibrominated product 2a (55-64%, entries 8-9), although the
obtained mono-brominated compound 2a’ (11-14%) was not
completely consumed in these conditions, likewise the reaction
temperature at 40 °C (entry 7). A screening of solvents showed
that the reaction could be carried out in pure CF3CO2H or acetic
acid (42% and 64% of 2a, entries 10-11), and in non-coordinating
solvents such as PhCF3 (2a’-14% and 2a-65% yields entries 12-
13), but none of them surpassed dichloromethane in the soft
50 °C conditions.
2
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the versatility of this C-H halogenation sequence towards
platforms with orthogonal substitution pattern for further cross-
coupling reactions.
protection. Interestingly, by carrying out the reaction in
trifluoroacetic acid as solvent (2 equiv of NBS and without
copper), a smooth dibromination occurred to provide exclusively
product 5u in 65% yield, showing that the second bromination is
even faster in this case.[21] These conditions were compatible with
phenylglycine precursor 7 (via a 5-membered Pd-cycle) furnishing
the dibrominated compound 8 in a descent yield of 47%.[6]
Eventually, the successful chlorination reaction of 1u-TFA was
also proven in CH2Cl2/HFIP solvent conditions at 60 °C for 24 h
giving a mixture of monochlorinated 6u’ (28%) and dichlorinated
6u (50%) products. This temperature secures a complete
consumption of the starting material while giving predominantly
the dichlorinated product 6u, contrariwise to the outcome at 50 °C
in 16 h (58% of 6u' and 29% of 6u).
Next, we explored the diversity of the AA backbone (Table 3). The
use of the amino ester 1p, having a α-phenyl moiety, led to a
mixture likely due to competitive formation and reaction of 5 and
6-membered ring Pd-cycles. These phenomenons have been
discussed by Garcia, Granell and Ariza for the carbonylation
reaction.[12,13b] However, precursors with more hindered alkyl
groups such as i-Pr 1q and i-Bu 1r, and the precursor with ethyl
ester moiety 1t gave rise to the corresponding di-bromo
compounds 2q, 2r and 2t in respectively 66%, 70% and 87%
yields. Note of worthy, the tert-butyl-esters, and even the benzyl-
ester derivatives did not completely survive to these acidic
conditions. Interestingly, the dibenzyl-glycine precursor 1s
yielded uneventfully tetra-ortho-brominated product 2s in 63%
(even with less than 4 equivalents of NBS), highlighting an
efficient poly-halogenation process. Furthermore, the chlorinated
(3r-75% and 3s-66%) and, in lower yields, iodinated (4r-22% and
4s-28%) products were also accessible.
Table 3. Scope and structure-activity relationship.
Scheme 2. Reactivity investigation. Reaction conditions: [a] NBS (2 equiv/[Pd]),
CF3CO2H (10 equiv) in CH2Cl2, 50 °C, 16 h. 1H NMR yield determined with an
internal standard. [b] Same outcome in optimized conditions A in Table 3.
As long as the substrate topology is concerned, the replacement
of the CO2R by an amide function (9a) or the use of the α,α-
dimethyl amine 9b led to traces of products (unclean reaction,
Scheme 2A). Next, an unsubstituted phenethylamine 9c proved
to be moderately suited for these conditions giving the
monobrominated product 10c’ in 24% yield (See SI for details),
which shed light on the ester moiety as key element for the C-H
halogenation sequence. We also initiated some model test-
reactions (Scheme 2B). Although a slow background bromination
of the aryl moiety was observed for the ammonium salt 1d-TFA,
the free amine 1d underwent a rapid transformation in the
presence of NBS at room temperature, by forming a priori the N-
Br product 11d (structure observed in a NMR tube and analyzed
by MS-analysis). The subsequent addition of CF3CO2H triggered
Reaction conditions: carried out with 1p-1t, 1u-TFA, 7-TFA (0.3 mmol). Isolated
yields (%) after column chromatography. [a] Both benzyl moieties were ortho-
di-halogenated with NXS (4 equiv). [b] By 1H NMR with an internal standard: 2s-
95%, 3s-89%, 4s-56%. [c] 1H NMR yield of monoBr/diBr 2u’:2u amines before
benzoylation in various solvents gave 28:19 in CH2Cl2, 55:33 in CH2Cl2/HFIP,
67:34 in CH2Cl2/HFIP with Cu(OAc)2. Variations of conditions. [d] NBS (1.5
equiv), Cu(OAc)2 (1 equiv), CH2Cl2:HFIP (1:1), 50 °C, 16 h, and N-protection.
[e] NBS (1.5 for 8 and 2 equiv for 5u), Pd(OAc)2 (10 mol% for 8 and 20% mol%
for 5u), CF3CO2H as solvent. [f] NCS (1.5 equiv) at 60 °C, 24 h; 58% of 6u' and
29% of 6u at 50 °C.
+
We subsequently tackled the even more challenging
phenylalanine ester 1u, as an ammonium salt 1u-TFA which is
much easier to handle (Table 3). As a rule of thumb, the less
hindered secondary amines are more prone to both competitive
β-H elimination and pre-formation of unreactive bis-amino-PdII
complexes.[13a,13d,13e,13g] Although, the previously developed
conditions furnished a promising formation of mono- and
dibrominated amines 2u’ and 2u in 28% and 19% yields
the halogenation of the phenyl part (via a supposed -NH2 Br
species)[22] to afford a mixture of starting material 1d and several
derivatives from which the para-bromo 1a was the major product.
Actually, this product 1a was hardly observed in the optimized Pd-
catalyzed conditions. In line with our previous observation with
phenylalanine ester 1u (giving 12u, Scheme 2C),[23]
a
straightforward synthesis and isolation of the palladacycle 12d as
a solid, likely as a dimeric species, was achieved from the free-
amine 1d in the presence of Pd(TFA)2 (likewise from 1d-TFA and
Pd(OAc)2).[17,24] This protocol conveniently complement the
seminal investigation of Vicente and Saura-Llama who observed
the facile palladation of triflate ammonium salt of phenylalanine
esters thanks to the electron-poor (and poorly coordinating)
1
(determined by H NMR with 1.5 equiv of NBS),[19] the use of
hexafluoroisopropanol (HFIP)[20] as solvent and copper additive
led to improved conversions (see Table 3). These conditions
allowed to isolate the corresponding products 5u’ and 5u in
respectively 46% and 38% yields, after the N-benzoylation
3
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triflate anion.[16b] To our surprise, no bromination took place on the
palladacycle 12u (R = H), even in optimized conditions (see Table
3). Contrariwise, the bis-bromination (66% of 2d) occurred on the
more hindered analogue 12d by NBS, but only in the presence of
CF3CO2H.
influence of both (1) steric hindrance (R = H vs Me)[15] and (2) an
external weakly coordinating ligand (L = CF3CO2H, NBS, etc.).
We assume likewise that the electron-poor and coordinated ester
group could balance the equilibrated steps 1 and 2 favorably in
the catalytic cycle.[13b]
In conclusion, this work reports an efficient and versatile primary
amine-directed palladium catalyzed C(sp2)-H halogenation (X = I,
Br, Cl) of phenylalanine (Phe) platforms. This strategy gives rise
to the formation of a large array of original halogenated Phe-
derivatives as non-proteinogenic-AA and highlights the use of
native functionality-NH2 as a DG, preventing thereby any N-
(de)protection sequences. The exploitation of this strategy to
introduce other functionalities is under investigation.
Acknowledgements
This work has been partially supported by University of Rouen
Normandy, INSA Rouen Normandy, the Centre National de la
Recherche
Scientifique
(CNRS),
European
Regional
Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-
0029), Carnot Institute I2C, the graduate school for research XL-
Chem (ANR-18-EURE-0020 XL CHEM) by Region Normandie
and by Oril Industrie, affiliated to “Les Laboratoires Servier”
through the aegis of the joint laboratory COBRA – Oril Industrie:
“IDECHEM”. We thank Dr Lucile Vaysse-Ludot and Dr Jean
Fournier for fruitful discussions and support.
Scheme 3. Proposed catalytic cycle.
In light of these preliminary investigations,[17] the Pd-catalyzed C-
H activation process and the subsequent halogenation events
seem to be finely balanced between reaction conditions and
substrate structure.[18,25,26] Then, we propose a postulated
catalytic cycle depicted in Scheme 3, in order to account these
outcomes. The more potent Pd(TFA)2 would be formed in situ
from Pd(OAc)2 and CF3CO2H to trigger the NH2-directed
palladation to give intermediate 14.[11a],[18] With regard to insightful
investigations on phenylglycine esters,[26] a type of concerted
metalation-deprotonation (CMD) mechanism would occur.
However, the rate of the second metalation significantly depends
on the conditions and substrates, leading to a more facile di-
halogenation of hindered quaternary amino esters (1, R  H) or
secondary aminoesters 1u and 7 in CF3CO2H as solvent,
contrariwise to phenylalanine ester 1u in HFIP/CH2Cl2.[25] The
halogenation of N-bonded Pd-cycle has been well-investigated
while revealing complex and various scenarios that also depend
on the nature of the halogenated reagent.[27] At that stage, we
hypothesize that the monomeric palladium complex 14 is the most
reactive species which undergoes a rapid oxidative insertion by
NBS, possibly pre-activated by CF3CO2H,[28] through the
previously proposed formation of a PdIV intermediate 15,[27a,29]
prior to the final reductive elimination furnishing the halogenated
product 2. Although the key role of reagents and additives
requires further investigations, one can suppose that the
trifluoroacetic acid additive also possesses the suited pKa value
to maintain the amino acid derivatives essentially in the
ammonium salt state (1-TFA). These conditions prevent thereby
the otherwise fast and unselective background bromination
Keywords: CH functionalization • halogenation • amino acids •
palladium • homogenous catalysis
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10.1002/chem.202102411
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A site-selective primary amine (as native NH2-functionality) directed palladium catalyzed C(sp2)-H halogenation (X = I, Br, Cl) of
phenylalanine (Phe) platforms was demonstrated and paves the way of the construction of original halogenated Phe-derivatives as
non-proteinogenic-AA
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