Copper-Promoted O-Arylation of the Phenol Side Chain of Tyrosine Using Triarylbismuthines

Article abstract of DOI:10.1002/ejoc.202000790

A general method for the O-arylation of the side chain of tyrosine using triarylbismuth reagents is reported. The reaction is mediated by copper diacetate, operates at 50 °C under oxygen in dichloromethane in the presence of pyridine, shows excellent functional group compatibility, and retains the integrity of the stereogenic center. The protocol was used to arylate the tyrosine residue of dipeptides and tripeptides.

Full text of DOI:10.1002/ejoc.202000790

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Copper-Promoted O-Arylation of the Phenol Side Chain of
Tyrosine using Triarylbismuthines
Authors: Adrien Le Roch, Martin Hébert, and Alexandre Gagnon
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000790
Link to VoR: https://doi.org/10.1002/ejoc.202000790
01/2020

10.1002/ejoc.202000790
European Journal of Organic Chemistry
COMMUNICATION
Copper-Promoted O-Arylation of the Phenol Side Chain of
Tyrosine using Triarylbismuthines
Adrien Le Roch,[a] Martin Hébert[a] and Alexandre Gagnon*[a]
[a]
A. Le Roch, M. Hébert, Prof. Dr. A. Gagnon
Université du Québec à Montréal
Département de chimie
C.P. 8888, Succursale Centre-Ville
Montréal, Québec, Canada, H3C 3P8
E-mail: gagnon.alexandre@uqam.ca
http://www.alexgagnonuqam.com
Supporting information for this article is given via a link at the end of the document.
Abstract: A general method for the O-arylation of the side chain of
tyrosine using triarylbismuth reagents is reported. The reaction is
mediated by copper diacetate, operates at 50 °C under oxygen in
dichloromethane in the presence of pyridine, shows excellent
functional group compatibility and retains the integrity of the
stereogenic center. The protocol was used to arylate the tyrosine
residue of dipeptides and tripeptides.
catalyzed reactions that involve trivalent organobismuth reagents
and that result in the transfer of alkyl,[10] cyclopropyl[11] and
aryl/heteroaryl[12] groups onto various scaffolds. In 2014, we
disclosed a highly efficient protocol for the O-arylation of phenols
using triarylbismuth reagents and hypothesized that the reaction
proceeds through a copper(III) species where the metal center is
simultaneously bound to the phenoxide and the aryl group
(Scheme 1d).[13] In contrast to Barton’s O-phenylation procedure,
this reaction operates directly from triarylbismuthines, a class of
reagents which can be easily prepared by the addition of Grignard
species to bismuth trichloride and where the functional groups can
be modified directly on the bismuth species.[14]
Bismuth occupies the 83rd position of the periodic table. This
heavy metal is the last natural member of the group 15 called the
pnictogens and the heaviest stable and non-radioactive element
of the periodic table.[1] Contrary to its immediate neighbors,
bismuth shows relatively low toxicity, thus allowing its
incorporation into therapeutic ingredients.[2] Organobismuth
compounds are organometallic species that contain one or
multiple C–Bi bonds and that can be subdivided into trivalent and
pentavalent species in which the bismuth is in the +3 or +5
oxidation state, respectively.[3] Due to unique properties such as
the ability to accommodate up to six ligands and to form
hypercoordinating interactions,[4] and a wide range of available
charge states from anionic to dicationic, organobismuths have
been used as catalysts[5] and reagents[3,6] in a wide range of
reactions.
The demonstration that organobismuth compounds can act as
arylating agents was made by Barton in 1980 when the oxidation
of quinine using triphenylbismuth carbonate unexpectedly
provided the corresponding a-phenyl keto derivative.[7a] The
ortho-phenylation of b-naphthol using various pentavalent
bismuth reagents was then reported and proposed to proceed
through a concerted mechanism (Scheme 1a).[7] In 1986, Barton
showed that triphenylbismuth diacetate reacts with phenols in the
presence of cupric acetate or metallic copper to give the product
of O-phenylation (Scheme 1b).[8] While these reports
demonstrated the value of organobismuth species in synthesis,
they showed limitations such as sensitivity to the reaction
conditions, a narrow scope and a reliance on pentavalent bismuth
species which require many steps for their preparation.
a) Barton 1980s
H
X
Bi
O
X
OH
+
Bi
OH
Y
X,Y = CO3
X = Ph; Y = OAc or O2CCF3
X = Y = Ph, Cl or O2CCF3
ortho-arylation
b) Barton Tetrahedron Lett. 1986, 3619
OAc
O
O-arylation
Ar
Cu(OAc)2 or Cu(0)
OH
Bi
R
+
R
OAc
c) Ball Nature Chem. 2020, 260
O
O
H
Bi
Ar
O
S
S
O
OH
Ar
+
R
OH
Bi
R
O
mCBAO
+ mCPBA
ortho-arylation
d) Gagnon Chem. Eur. J. 2014, 2755
OAc
Bi
OH
+
O
O
Cu
L
Ar
Ar
R
R
Ar
R
Ar
Ar
+ Cu(OAc)2
O-arylation
Scheme 1. a) Ortho-phenylation of b-naphthol using pentavalent bismuth
reagents as reported by Barton in the 1980s. b) Copper-catalyzed O-
phenylation of phenols using triphenylbismuth diacetate as reported by Barton
in 1986. c) Ortho-arylation of phenols using a universal bismacycle as reported
by Ball in 2020. d) Copper diacetate-promoted O-arylation of phenols using
Recently, there has been a surge of interest for the chemistry of
bismuth as demonstrated by the elegant work of Ball where a
universal bismacycle was used in conjunction with meta-chloro
peroxybenzoic acid to ortho-arylate an impressive range of
phenols via a concerted mechanism (Scheme 1c).[9] Over the
past decade, our group has reported a repertoire of metal-
triarylbismuthines as reported by us in 2014. mCPBA
= meta-chloro
peroxybenzoic acid; mCBA = meta-chlorobenzoic acid.
1
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10.1002/ejoc.202000790
European Journal of Organic Chemistry
COMMUNICATION
Efficient methods that allow the modification of amino acids are
highly desirable, particularly for medicinal chemistry purposes.[15]
Tyrosine can be O-arylated using Buchwald-Hartwig[16] and Chan-
Evans-Lam protocols,[17] as demonstrated by Ma, Frost, Willis,
Arndt and Molander (Scheme 2a). Olofsson and Gaunt showed
that this reaction can also be performed using diaryliodonium
salts.[18] Although multiple methods exist to O-arylate the side
chain of tyrosine, many of them show limitations such as low
substrate scope, limited functional group tolerance, the need for
high temperatures or strong bases, or the necessity of having
specific substituents on the aryl moiety. Triphenylbismuth
diacetate has been used to arylate the terminal amino function of
amino acids.[19] However, to the best of our knowledge,
organobismuth reagents have never been used for the arylation
of the side chain of amino acids. Recently, we reported a protocol
for the N-arylation of the indole side chain of tryptophan that
operates directly from triarylbismuth reagents.[20] We now report
our results on the copper-promoted O-arylation of the side chain
of tyrosine using functionalized triarylbismuthines (Scheme 2b).
Table 1. Optimization of the reaction conditions for the copper-promoted O-
arylation of N-Boc tyrosine methyl ester 1a using tri(4-tolyl)bismuth 2a.[a]
Bi
O
O
H3C
CH3
BocHN
BocHN
OMe
OMe
2a (1.0 equiv)
Cu(OAc)2 (y equiv)
Base (3.0 equiv), CH2Cl2
50 °C, time, atmosphere
H3C
CH3
1a
3a
OH
O
Entry
Cu(OAc)2
(y equiv)
Base
Time
(h)
Atmosphere
Yield
(%)[b]
1
2
3
4
5
1.0
1.0
1.0
0.3
0.3
Et3N
3
air
air
air
air
O2
35
53
Et3N
16
16
16
16
Pyridine
Pyridine
Pyridine
77
75
99[c]
[a] The reaction was performed in a sealed tube placed in an oil bath at 50 °C.
[b] Yields of isolated pure product 3a. [c] The tube was sparged with pure
oxygen for 1 minute prior to the reaction.
O
O
PGHN
PGHN
conditions
OR
OR
O-Arylation
Exploration of the scope of the reaction indicated that aryl groups
with substituents at any position can be transferred on 1a using
our optimized conditions (Table 2, entries 1 to 5). The process
showed no sensitivity to electronic effects, demonstrated
excellent functional group compatibility, allowed the installation of
a 2-naphthyl group and could be performed on Fmoc protected
tyrosine methyl ester 1b (entries 6 to 14).
Ar
OH
O
a)
Ma
Frost & Willis
Arndt
Molander Olofsson & Gaunt
X
I
Ar
Ar
Ar
Ar
Ar
Ar
(HO)2B
KF3B
X
X
CuI, Ligand Pd(OAc)2, Ligand
Cs2CO3
b) This work
Cu(OAc)2, Pyridine Cu(OAc)2•H2O
t-BuOK
• Simple and mild conditions
• Yields up to 99%
• Excellent aryl scope
• High functional group tolerance
• No racemization
• Applicable to dipeptides and tripeptides
• Good to excellent selectivity over other amino acids
Table 2. Triarylbismuth scope in the copper diacetate-promoted O-arylation of
Cu(OAc)2
Pyridine
CH2Cl2
Bi
the side chain of N-protected tyrosine methyl ester.[a]
Ar
Ar
O
O
Ar
PGHN
PGHN
Bi
OMe
OMe
conditions
+
Ar
Ar
Ar
Ar
3a–n
OH
O
Scheme 2. a) Existing methods for the O-arylation of the side chain of tyrosine.
b) O-Arylation of the side chain of tyrosine using triarylbismuths.
1a: PG = Boc
1b: PG = Fmoc
2
Entry
PG
Ar
Yield (%)[b]
99 (3a)
92 (3b)
83 (3c)
75 (3d)
99 (3e)
99 (3f)
99 (3g)
99 (3h)
65 (3i)
Using our conditions for the O-arylation of phenols,[13] N-Boc
tyrosine methyl ester 1a reacted to give the desired product 3a in
35% yield (Table 1, entry 1). Systematic optimization of the
reaction parameters (entries 2 to 4) indicated that a quantitative
yield could be obtained by using pyridine in the presence of 0.3
equivalents of copper acetate under oxygen at 50 °C for 16 hours
in non-anhydrous dichloromethane (entry 5). Reducing the
number of equivalents of the base or the bismuth reagent,
changing the solvent or running the reaction at room temperature
all had a detrimental effect on the yield. Gratifyingly, chiral HPLC
analysis indicated that the integrity of the stereogenic center is
maintained under our optimal conditions (see supplementary
material for details).
1
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
4-Tol
3-Tol
2-Tol
2
3
4
2,6-Me2C6H3
Ph
5
6
4-(MeO)C6H4
4-(CF3)C6H4
4-(THPO)C6H4
2-(CHO)C6H4
7
8
9
10
11
12
13
4-((MeO)2CH)C6H4
3-(NC)C6H4
4-BrC6H4
99 (3j)
74 (3k)
99 (3l)
2-Naphthyl
90 (3m)
2
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10.1002/ejoc.202000790
European Journal of Organic Chemistry
COMMUNICATION
Table 3. Copper diacetate-promoted arylation of tripeptides containing the most
reactive amino acids.[a]
14
Fmoc (1b)
4-Tol
99 (3n)
O
O
[a] Conditions: Ar3Bi (1.0 equiv), Cu(OAc)2 (0.3 equiv), Pyridine (3.0 equiv),
CH2Cl2, O2, 50 °C, 16 h. The reaction was performed in a sealed tube sparged
with pure oxygen and placed in an oil bath set at 50 °C. [b] Yields of isolated
pure products 3a–n.
H
H
conditions
N
N
BocHN
N
CO2Me
BocHN
N
CO2Me
CH3
H
H
O
O
A
H
A
Entry
Tripeptide
Yield (%)[b]
90 (16a)
63 (17)
Using stoichiometric amounts of copper diacetate, we next
evaluated the intrinsic reactivity of other N-protected amino acid
esters that possess a nucleophilic side chain under our conditions
(Scheme 3). Results show that N-Boc tryptophan methyl ester is
as reactive as N-Boc tyrosine methyl ester and that N-Boc
cysteine and histidine methyl esters are the third and fourth most
reactive amino acids (3a, 4–6). The high reactivity of N-protected
tryptophan, cysteine and histidine is easily explained by the fact
that triarylbismuthines are very efficient at arylating indoles,[12b]
thiols[21] and imidazoles.[22] N-Protected serine, lysine and
glutamine were much less reactive under these conditions (7–9).
These results are somewhat surprising since 1,2-
aminoalcohols,12c amines[23] and amides[24] can all be arylated
efficiently with triarylbismuthines. Therefore, they suggest that the
reactivity of these particular functional groups is impacted by the
presence of the proximal ester and carbamate moieties. Because
they possess a secondary alcohol and a carboxylic acid, two
groups that are difficult to arylate with organobismuth reagents,
N-protected threonine and glutamic acid were arylated in low
yields (10 and 11). No arylation was observed with N-Boc aspartic
acid and N-Boc asparagine. Last, N-Boc alanine methyl ester was
recovered intact, supporting the conclusion that the arylation of
amino acids 3a–11 proceeds on the side chain and not the NH-
carbamate.
1
2
3
4
Boc–Ala–Tyr–Val–OMe (12)
Boc–Ala–Trp–Val–OMe (13)
Boc–Ala–Cys–Val–OMe (14)
Boc–Ala–His–Val–OMe (15)
81 (18)
46 (19)
[a] Conditions: (4-Tol)3Bi (1.0 equiv), Cu(OAc)2 (1.0 equiv), Pyridine (3.0 equiv),
CH2Cl2, O2, 50 °C, 16 h. [b] Yields of isolated pure products.
Using conditions from Table 3, we then explored the triarylbismuth
scope in the arylation of Boc–Ala–Tyr–Val–OMe 12 (Scheme 4).
Our results show that the protocol allows the transfer of aryl
groups with substituents at any position of the aromatic ring (16a–
e) and substituted by electron withdrawing or donating groups
(16f–i). Excellent functional group compatibility was observed
(16j–r). Groups that would be reactive in arylation methods that
require strong bases or copper(I) or palladium(0) catalysts were
well tolerated (16k,n,q,s,t). Some of the examples were
performed with 0.3 equivalents of copper(II) acetate with no
impact on the yield (yields noted with an asterisk).
O
O
H
H
conditions
N
N
BocHN
N
CO2Me
BocHN
N
CO2Me
H
H
O
O
O
O
(4-Tol)3Bi (2a) (1.0 equiv)
Cu(OAc)2 (1.0 equiv)
Ar
PGHN
12
PGHN
16a–t
OMe
OMe
OH
O
Pyridine (3.0 equiv)
CH2Cl2, O2, 50 °C, 16 h
A
H
O
A
CH3
H3C
CH3
H3C
OCH3
O
O
S
O
CH3
BocHN
OMe
BocHN
CH3
BocHN
OMe
OMe
CH3
16d
(50%)
16a
(90%, 89%*)
16b
(99%)
16c
(79%)
16e
16f
CH3
(99%)
(92%)
CH3
N
4 (99%)
F
3a (99%)
5 (88%)
O
O
O
CH3
BocHN
BocHN
OMe
CbzHN
CF3
OCH3
F
OMe
N
OMe
H
16g
(95%)
16h
(35%)
16i
16j
(83%)
16k
(99%)
O
N
O
CH3
(83%)
8 (46%)
6 (82%)
7 (44%)
N
CH3
O
O
H
OEt
OEt
OH
O
O
O
O
BocHN
O
BocHN
CbzHN
16l
(99%)
16m
(93%)
16n
16o
CH3
OMe
OMe
OMe
(94%, 93%*)
(96%)
CH3
CH3
CH3
O
9 (34%)
11 (16%)
10 (21%)
Cl
Br
O
O
OMe
OH
O
N
H
CO2Et
16p
(92%, 92%*)
16q
(93%)
16r
(94%, 93%*)
16s
(99%, 98%*)
16t
(99%)
Scheme 3. Evaluation of the reactivity of amino acids containing a nucleophilic
side chain in the copper diacetate-promoted arylation using tri(4-tolyl)bismuth.
Yields of isolated pure products.
Scheme 4. Triarylbismuth scope in the copper diacetate-promoted O-arylation
of the side chain of tyrosine in Boc–Ala–Tyr–Val–OMe 12. Conditions: Ar3Bi (1.0
equiv), Cu(OAc)2 (1.0 equiv), Pyridine (3.0 equiv), CH2Cl2, O2, 50 °C, 16 h.
Asterisks indicate the yield of the reactions performed with 0.3 equiv Cu(OAc)2.
Yields of isolated pure products.
Next, we evaluated the reactivity of the four most reactive amino
acids in the context of tripeptides where they are flanked by two
inert residues and found that tyrosine and cysteine retain most of
their reactivity (Table 3, entry 1 and 3). Conversely, our results
indicate that tryptophan and histidine are much less reactive when
incorporated in a tripeptide (entry 2 and 4).
We next explored the applicability of our method to the arylation
of various tyrosine-containing dipeptides (Table 4). To amplify the
inherent differences in reactivity between each amino acid, 0.3
3
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10.1002/ejoc.202000790
European Journal of Organic Chemistry
COMMUNICATION
H3C
equivalents of copper diacetate were used. In addition, to prevent
the formation of diarylation products, some of the entries were
also performed at a higher dilution and in a shorter reaction time.
Our results indicate that dipeptides where the tyrosine is
connected to an inert amino acid such as valine or phenylalanine
can be efficiently arylated (entries 1 and 2). To examine the
chemoselectivity of the method vis-à-vis amino acids that possess
a nucleophilic side chain, we submitted 20c–f to our conditions
and obtained the products of O-arylation of tyrosine in yields
ranging between 64 and 83% (entries 3 to 6). As predicted by the
low reactivity of Boc–Ala–Trp–Val–OMe 13, the arylation of 20g
occurred regioselectively on the tyrosine residue, giving 21g in
78% yield (entry 7). The arylation of 20h proved challenging,
providing the product of O-arylation 21h in only 46% yield (entry
8). No diarylation product was detected for entries 4 to 8, the
unreacted starting material being the only other identifiable
material in those reactions. As anticipated by the high reactivity of
N-Boc cysteine methyl ester 5, the arylation of 20i afforded a
complex mixture of S and O-arylation products as well as S–S
disulfide formation from which 21i could nevertheless be isolated
in 50% yield (entry 9).
HN
N
N
N
H
H
N
CO2Me
N
CO2Me
conditions
BocHN
BocHN
O
O
CH3
20j
22: 60%
OH
O
Scheme 5. Copper diacetate-promoted arylation of Boc–His–Tyr–OMe 20j
using tri(4-tolyl)bismuth. Conditions: (4-Tol)3Bi (1.0 equiv), Cu(OAc)2 (0.3 equiv),
Pyridine (3.0 equiv), CH2Cl2, O2, 50 °C, 16 h.
Finally, to determine if the position of the tyrosine has an impact
on the chemoselectivity or if the reaction is driven uniquely by the
intrinsic reactivity of each amino acid, we submitted Boc–Tyr–
Trp–OMe 23 to our conditions and obtained the product of O-
arylation 24a in 73% yield accompanied by 13% of the diarylated
product 24b (Scheme 6). Since the complementary dipeptide
Boc–Trp–Tyr–OMe 20g did not provide any diarylation product,
these results suggest that the chemoselectivity is influenced by
the position of the tyrosine.
Table 4. Copper diacetate-promoted O-arylation of tyrosine-containing
dipeptides using tri(4-tolyl)bismuth.[a]
HO
A
H
A
H
O
H
H
conditions
CO2Me
N
CO2Me
N
CO2Me
conditions
H3C
BocHN
BocHN
H
H
N
N
CO2Me
N
O
O
CH3
BocHN
BocHN
O
O
R
NH
OH
Dipeptide
O
23
24a: R = H (73%)
24b: R = 4-Tol (13%)
Entry
1
Yield (%)[b]
89 (21a)
87 (21b)
83 (21c)
73 (21d)
71 (21e)
64 (21f)
78 (21g)
46 (21h)
50 (21i)
Boc–Val–Tyr–OMe (20a)
Boc–Phe–Tyr–OMe (20b)
Boc–Met–Tyr–OMe (20c)
Boc–Thr–Tyr–OMe (20d)
Fmoc–Asn–Tyr–OMe (20e)
Fmoc–Asp–Tyr–OMe (20f)
Boc–Trp–Tyr–OMe (20g)
Fmoc–Lys–Tyr–OMe (20h)
Boc–Cys–Tyr–OMe (20i)
Scheme 6. Copper diacetate-promoted arylation of Boc–Tyr–Trp–OMe 23
using tri(4-tolyl)bismuth. Conditions: (4-Tol)3Bi (1.0 equiv), Cu(OAc)2 (0.3 equiv),
Pyridine (3.0 equiv), CH2Cl2, O2, 50 °C, 6 h, 0.02 M.
2
3
4[c]
5
In conclusion, we developed a mild protocol for the O-arylation of
the phenolic side chain of tyrosine using easily accessible
triarylbismuthines. The reaction operates in non-anhydrous
dichloromethane under oxygen at 50 °C and is catalyzed by
copper diacetate. Excellent functional group compatibility was
observed and no racemization was detected. N-Protected
tryptophan, cysteine and histidine were arylated under these
conditions. The arylation of tyrosine-containing dipeptides and
tripeptides was achieved. Transposition of this method to solid
support peptide chemistry is under investigation in our laboratory
and results will be reported in due course.
6[c]
7[c]
8[c]
9
[a] (4-Tol)3Bi (1.0 equiv), Cu(OAc)2 (0.3 equiv), Pyridine (3.0 equiv), CH2Cl2, O2,
50 °C, 16 h, 0.1M. [b] Yields of isolated pure products. [c] 6 h, 0.02 M.
We next studied the arylation of Boc–His–Tyr–OMe 20j. Although
N-Boc histidine methyl ester 6 is easily N-arylated under our
conditions, the reduced reactivity of Boc–Ala–His–Val–OMe 15
gave us hope that the arylation might proceed mainly on the
tyrosine residue. However, the reaction afforded exclusively the
product of diarylation 22 in 60% yield, suggesting that the
reactivity of histidine is considerably influenced by its immediate
environment (Scheme 5).
Acknowledgements
This work was supported by Boehringer Ingelheim
Pharmaceuticals Inc. through a Scientific Advancement grant, by
the Natural Sciences and Engineering Research Council of
Canada (NSERC), and by the Centre in Green Chemistry and
Catalysis (CGCC). We would like to thank Pr. Steve Bourgault for
useful discussions and advice regarding the synthesis of the
peptides. Hwai-Chien Chan is gratefully acknowledged for
proofreading the manuscript and the experimental section.
4
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10.1002/ejoc.202000790
European Journal of Organic Chemistry
COMMUNICATION
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Keywords: Triarylbismuthines • Tyrosine • Copper catalysis •
Amino acids • Arylation reaction
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000790
European Journal of Organic Chemistry
COMMUNICATION
Key Topic: Arylation reaction.
Copper-Promoted O-Arylation of the Phenol Side Chain of Tyrosine using Triarylbismuthines
Bi
O
O
Ar
Ar
PGHN
PGHN
Ar
OMe
OMe
Cu(OAc)2, Pyridine
DCM, 50 °C, O2, 16 h
Ar
OH
O
45 examples
up to 99% yield
• Simple conditions • Excellent scope and functional group compatibility
• No racemization
• Transposable to dipeptides and tripeptides
A procedure for the O-arylation of the side chain of tyrosine using triarylbismuth reagents is reported. The reaction is performed in
dichloromethane under oxygen at 50 °C in the presence of pyridine, is promoted by copper diacetate, shows excellent scope and
functional group tolerance and retains the integrity of the chiral center. The reactivity of other amino acids possessing a nucleophilic
side chain under these conditions is investigated. O-Arylation of tyrosine-containing dipeptides and tripeptides is achieved.
6
This article is protected by copyright. All rights reserved.