Copper-Promoted N-Arylation of the Imidazole Side Chain of Protected Histidine by Using Triarylbismuth Reagents

Article abstract of DOI:10.1002/chem.202102186

The N-arylation of the side chain of histidine by using triarylbismuthines is reported. The reaction is promoted by copper(II) acetate in dichloromethane at 40 °C under oxygen in the presence of diisopropylethylamine and 1,10-phenanthroline and allows the transfer of aryl groups with substituents at any position of the aromatic ring. The reaction shows excellent functional group tolerance and is applicable to dipeptides where the histidine is located at the N terminus. A histidine-guided backbone N?H arylation was observed in dipeptides where the histidine occupies the C terminus.

Full text of DOI:10.1002/chem.202102186

Communication
doi.org/10.1002/chem.202102186
Chemistry—A European Journal
Copper-Promoted N-Arylation of the Imidazole Side Chain
of Protected Histidine by Using Triarylbismuth Reagents
Hwai-Chien Chan,[a] Bianca Bueno,[a] Adrien Le Roch,[a] and Alexandre Gagnon*[a]
This paper is dedicated to our colleague and dear friend Prof. Victor Snieckus for his exceptional lifetime contribution to organic
chemistry.
Abstract: The N-arylation of the side chain of histidine by
using triarylbismuthines is reported. The reaction is pro-
Various methods have been reported for the N-arylation of
the side chain of histidine, usually in their N,O-diprotected
form. While the arylation can in principle occur at the proximal
N(π) or distal N(τ) atom of the imidazole ring in A, the vast
°
moted by copper(II) acetate in dichloromethane at 40 C
under oxygen in the presence of diisopropylethylamine and
1,10-phenanthroline and allows the transfer of aryl groups
with substituents at any position of the aromatic ring. The
majority of these methods result in the arylation of the sterically
more accessible N(τ) position to deliver product B (Scheme 1).[11]
reaction shows excellent functional group tolerance and is
The first procedures leading to the arylation of the side chain of
applicable to dipeptides where the histidine is located at
histidine relied on an SNAr reaction with aryl fluorides, as shown
first by Hanzlik[12] and then by Kelly.[13] However, like most SNAr
reactions, these methods require very high temperatures and/
or the presence of electron-withdrawing groups on the aryl
substrate. Hanzlik and Jain developed two copper(I)-catalyzed
protocols to arylate the side chain of histidine using aryl
bromides and iodides.[14] While their methods show excellent
scope, high temperatures are required. Using a Chan-Evans-Lam
approach, Campagne reported an efficient procedure to arylate
the imidazole side chain of histidine.[15] Although the reaction
operates under air at a moderate temperature, limited func-
tional groups were introduced on the aryl moiety. Histidine has
also been arylated using aryl lead triacetates, as shown by
Konopelski, but the toxicity associated with lead reagents
considerably limits the use of the method.[16] Recently, Nicewicz
performed the arylation of histidine according to a photoredox
protocol that involves an aryl methyl ether under irradiation at
the N terminus. A histidine-guided backbone NÀ H arylation
was observed in dipeptides where the histidine occupies
the C terminus.
Bismuth is the heaviest stable non-radioactive element of the
periodic table.[1] Contrary to its neighboring elements, this
heavy metal shows relatively low toxicity, as exemplified by
medicinal ingredients that contain inorganic bismuth salts.[2]
Due to its borderline behavior as a metal and a classic
pnictogen, bismuth compounds have served both as Lewis
acids and bases.[3]
Triarylbismuthines are versatile organometallic reagents
that have been used in a wide range of transition metal-
catalyzed reactions.[4] Our group reported a portfolio of copper-
catalyzed methods for the arylation of NH-containing
heterocycles,[5] phenols[6] and amino alcohols[7] that involve
triarylbismuthines. Recently, we transposed some of these
protocols to the arylation of the side chain of tryptophan[8] and
tyrosine.[9] In the course of our studies, we found that the side
chain of histidine was considerably reactive under those
conditions, resulting in the N-arylation of the imidazole
moiety.[9] This observation was in agreement with reports from
Finet and more recently Jadhav showing that imidazole can be
smoothly arylated by triarylbismuthines in the presence of
copper salts.[10] Motivated by these results, we decided to
further investigate this reaction.
[a] H.-C. Chan, B. Bueno, Dr. A. Le Roch, Prof. Dr. A. Gagnon
Université du Québec à Montréal
Département de chimie
C.P. 8888, Succursale Centre-Ville
Montréal, Québec, H3C 3P8 (Canada)
E-mail: gagnon.alexandre@uqam.ca
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202102186
Scheme 1. Methods for the N(τ)-arylation of the side chain of histidine.
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Chemistry—A European Journal
455 nm in the presence of an acridinium photosensitizer.[17]
However, a mixture of arylation products at N(π) and N(τ)
connected to the ortho and para position of anisole was
obtained.
ment in the yield of the reaction (entries 5 to 9). Using L4 as the
ligand, we verified the necessity of performing the reaction
under oxygen and found a considerable drop in the yield when
replacing it by air or argon (entry 10 and 11). Conducting the
reaction in other solvents led to the identification of THF and
acetonitrile as suitable replacements for dichloromethane
(entries 12 to 14). A complete loss of reactivity was observed
upon performing the reaction at room temperature, demon-
strating the importance of heat (entry 15). Minimal impact on
the yield was observed upon reducing the catalyst loading to
0.7 equivalent or lowering the reaction time to 4 h (entry 16
and 17).
We then investigated the scope of the reaction using
various triarylbismuth reagents (Scheme 2). To maximize the
yields, we used conditions from entry 8 in Table 1. Our results
show that the reaction tolerates substituents at any position of
the aromatic ring (3a–d), is unaffected by electronic effects
(3e–i), is compatible with a broad range of functional groups
(3j–q), allows the transfer of a naphthyl unit (3r) and functions
with Cbz and Fmoc protecting groups (3s, t). We performed
some entries in acetonitrile (yields indicated in brackets) and
observed that the transfer proceeded efficiently with the
electronically poor 4-fluorophenyl group (3f) but not with the
electronically rich 4-methoxyphenyl (3e) or sterically encum-
bered 2-tolyl (3c). Also, while the efficiency was preserved with
Cbz-protected histidine (3s), a dramatic drop was observed
with the Fmoc counterpart (3t).
There is an interest for general methods that lead to the
modification of amino acids, not only in medicinal chemistry
where peptides are used as lead compounds, but also in
chemical biology where arylated amino acids have been found
to play a role in biochemical processes.[18] Even though
procedures exist to arylate the side chain of histidine, additional
methods that operate under smooth conditions while offering
excellent functional group compatibility are still highly desir-
able. In this context, we would like to report herein our
investigation into the copper(II)-promoted arylation of histidine
using triarylbismuth reagents.
We commenced our work by optimizing the conditions for
the arylation of the imidazole side chain of Boc-protected
histidine methyl ester 1a with tri(4-tolyl)bismuth 2a (Table 1).
Using the conditions that we reported for the arylation of the
side chain of tyrosine,[9] we obtained the desired product in
81% yield (entry 1). After testing a few organic bases, we
identified N,N-diisopropylethylamine (DIPEA) as
a suitable
replacement for the undesirable pyridine and found that the
°
reaction could be performed at 40 C with only 1.0 equivalent
of DIPEA (entries 2 to 4). With the objective of improving the
yield, we added ligands L1–L5 and found that 1,10-phenanthro-
line L4 and bathophenanthroline L5 provided the best improve-
Table 1. Optimization of the reaction conditions for the copper-promoted N-arylation of the imidazole side chain of N-Boc histidine methyl ester 1a using
tri(4-tolyl)bismuth 2a.[a]
°
Cu(OAc)2 (x equiv)
Ligand (y equiv)
Base (z equiv)
Solvent
Atmosphere
T [ C]
t [h]
Yield 3a [%][b]
1
2
3
4
5
6
7
8
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
1.0 equiv
0.7 equiv
1.0 equiv
–
–
–
–
Pyridine (3.0 equiv)
Et3N (3.0 equiv)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
O2
O2
O2
O2
O2
O2
O2
O2
O2
Air
Ar
O2
O2
O2
O2
O2
O2
50
50
50
40
40
40
40
40
40
40
40
40
40
40
RT
40
40
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
4
81
72
82
84
37
72
85
99
99
88
42
87
99
98
0
DIPEA (3.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
DIPEA (1.0 equiv)
L1 (1.0 equiv)
L2 (1.0 equiv)
L3 (1.0 equiv)
L4 (1.0 equiv)
L5 (1.0 equiv)
L4 (1.0 equiv)
L4 (1.0 equiv)
L4 (1.0 equiv)
L4 (1.0 equiv)
L4 (1.0 equiv)
L4 (1.0 equiv)
L4 (0.7 equiv)
L4 (1.0 equiv)
9
10
11
12
13
14
15
16
17
THF
MeCN
MeCN
MeCN
MeCN
93
93
[a] Reaction performed in a sealed tube placed in an oil bath at the indicated temperature and under the specified atmosphere. [b] Yield of isolated pure
product. DMF=N,N-dimethylformamide. THF=tetrahydrofuran.
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Scheme 2. Scope of the N-arylation of the side chain of N-protected histidine methyl esters 1a–c. Yields are for isolated pure products; yields in brackets are
for reactions performed in MeCN instead of CH2Cl2.
ester 5 were almost equally reactive, followed by N-Boc cysteine
methyl ester 6 and N-Boc histidine methyl ester 1a (Figure 1,
white bars).[9] This lack of differentiation in reactivity was
expected to lead to issues of chemoselectivity during the
arylation of histidine-containing peptides. Under our new
conditions (Figure 1, black bars), a dramatic change in the order
of reactivity between the amino acids was observed: N-Boc
histidine methyl ester 1a was now the most reactive amino
acid, followed by N-Boc tyrosine methyl ester 4 and N-Boc
lysine methyl ester 8. N-Boc tryptophan methyl ester 5 and N-
Boc cysteine methyl ester 6 were found to be poorly reactive
under these new conditions: indeed, N-Boc tryptophan methyl
ester 5 gave the arylated product in only 12% yield with 88%
Figure 1. Arylation of amino acids possessing a nucleophilic side chain.
recovered starting material while N-Boc cysteine methyl ester 6
gave the desired product in 19% along with 59% recovered
starting material. N-Boc serine methyl ester 7, N-Boc glutamine
methyl ester 9, N-Boc threonine methyl ester 10 and N-Boc
glutamic acid mono methyl ester 11 were all recovered intact.
While it is difficult to explain this drastic change in ranking of
amino acids between the original and the new conditions, it
must be hypothesized that the lower reaction temperature
combined with the presence of the 1,10-phenanthroline ligand
are necessarily responsible for this phenomenon. Further
mechanistic and theoretical studies will be needed to better
Original conditions: amino acid N-Boc methyl ester (1.0 equiv), (p-Tol)3Bi
[9]
°
(1.0 equiv), Cu(OAc)2 (1.0 equiv), pyridine (3.0 equiv), CH2Cl2, O2, 50 C, 16 h.
New conditions: amino acid N-Boc methyl ester (1.0 equiv), (p-Tol)3Bi
(1.0 equiv), Cu(OAc)2 (1.0 equiv), DIPEA (1.0 equiv), 1,10-phen (1.0 equiv),
°
CH2Cl2, O2, 40 C, 16 h. Numbers refer to the N-Boc methyl ester amino acids
substrates.
Before transposing our protocol to histidine-containing
peptides, we sought to evaluate the relative reactivity of amino
acids possessing a nucleophilic side chain under our newly
optimized conditions (Figure 1). Under our original conditions,
N-Boc tyrosine methyl ester 4 and N-Boc tryptophan methyl
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Scheme 3. a) N-Arylation of histidine-containing dipeptides 12a–l. b) Double histidine and backbone N-arylation of “inverted” Boc-Ala-His-OMe. Yields of
isolated pure products. c) COSY spectra of product 15 and 16 (full spectra in Supporting Information).
chemoselectivity in the context of histidine-containing dipep-
tides where histidine occupies the N-terminal position (Sche-
me 3a). Thus, dipeptides 12a–l were prepared by conventional
methods (see the Supporting Information for details) and were
reacted with tri(4-tolyl)bismuth 2a under our optimized con-
ditions. In the event, good to excellent yields were obtained
with dipeptides where histidine is connected to an inert or
cyclic amino acid (13a–d). Lower yields were obtained when
the histidine is connected to an unsubstituted glycine residue
(13e), a copper-complexing methionine (13f) or an ester-
containing amino acid (13g). Using bathophenanthroline
instead of phenanthroline resulted in similar yields for 13a
(78%) and 13f (54%), motivating us to pursue with the simpler
phenanthroline ligand. The arylation of Boc-His-Thr-OMe and
Scheme 4. Histidine-directed NÀ H backbone arylation of Boc-Ala-His(Nτ-Trt)-
OMe 17. Yield of isolated pure products. [a] Performed at 40 C instead of
°
°
50 C.
understand the difference in reactivity under both sets of
conditions.
Having established the order of reactivity of protected
amino acids under our arylating conditions, we explored the
Boc-His-Ser-OMe gave the products of histidine arylation 13h
and 13i in low yields, even though N-Boc threonine et serine
methyl esters were found to be unreactive under these
conditions in our amino acids study (Figure 1). The results
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Scheme 5. a) Attempted backbone NH arylation of tripeptides where histidine occupies the C-terminal position. b) Successful backbone NH-arylation of
tripeptides where histidine occupies the central position. c) Attempted backbone NH-arylation of tripeptide 21 where the histidine is replaced by a
nonchelating phenyl alanine residue. d) Proposed ATCUN models to explain the difference in reactivity between tripeptides 19a,b and 21. Yields are of
isolated pure products.
suggest that the arylation of amino acids in peptides greatly
depends on the immediate environment. However, as antici-
pated from our amino acid studies, Boc-His-Trp-OMe provided
exclusively product 13k from arylation on the histidine residue
while Boc-His-Tyr-OMe led to the diarylated product 13l.
To verify if the position of the histidine in the dipeptide has
an impact on the outcome of the reaction, Boc-Ala-His-OMe 14
was submitted to our arylation reaction (Scheme 3b). Firstly, we
found that the product of imidazole N-arylation 15 was formed
in lower yield than in the complementary dipeptide Boc-His-
Ala-OMe 13a, suggesting that the position of histidine in the
dipeptide affects the yield of the reaction. Secondly, product 16
where two aryl groups are transferred was isolated in 17%
yield. 2D NMR analysis showed that the second aryl group had
been introduced on the NÀ H backbone of alanine, thus the
amino acid preceding histidine (so-called n-1 residue; Sche-
me 3c). This type of NÀ H backbone arylation has previously
been reported by Ball in the copper- and nickel-catalyzed
arylation of peptides using boronic acids.[19] We sought to gain
some understanding about this copper-catalyzed histidine-
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sterically encumbered isopropyl residue at R2, we submitted the
“reverse” tripeptide Boc-Val-Ala-His(Trt)-OMe 19b to our con-
ditions but again, no reaction was observed. The histidine was
then moved to the central position, as shown in Boc-Ala-His
(Trt)-Val-OMe 21, and in this case, the product of arylation at
the n-1 position 22 was isolated in 83% yield (Scheme 5b).
Finally, to confirm our hypothesis that the imidazole ring acts as
a directing group, we prepared tripeptide 23 where the
histidine is replaced by a phenyl alanine (Scheme 5c). As
anticipated, product of arylation 24 could not be detected and
the starting peptide 23 was recovered in 83% yield. Altogether,
these results suggest that: 1) the arylation is guided by the
histidine; 2) the arylation proceeds at the n-1 position, that is,
one residue before the histidine; 3) the arylation occurs only if
the n-1 position is also the NHBoc terminus. These results can
be best explained by an ATCUN-like motif (amino terminal Cu
and Ni) where the copper center is chelated by the imidazole
moiety and the peptide backbone (Scheme 5d).[20] In the case of
19a or 19b, formation of the putative copper(III) species would
lead to a severe steric clash between the NHBoc and the aryl
group (complex i) thus preventing the arylation process. More-
over, the complex would not be able to avoid this steric
hindrance since rotation around the CÀ N or CÀ C bond would
lead to conformers with steric repulsion between R1 and R2
(species ii) or R1 and the Ar group (species iii). On the contrary,
in the case of 21, formation of an ATCUN-like intermediate iv
where the copper center is simultaneously chelated by the
imidazole, the internal amide, the terminal NBoc and the aryl
group would be less hindered and thus allowed, leading to the
arylation product 22.
Scheme 6. Proposed mechanism for the N-arylation of the imidazole side
chain of histidine. L=1,10-phenanthroline.
The proposed mechanism for the arylation of the imidazole
side chain of histidine begins by the complexation of cupric
acetate by phenanthroline to give species A (Scheme 6, step a).
Complexation of the triarylbismuth to this species would then
generate species B (step b) on which transmetalation of the aryl
group from Bi to CuII would occur (step c) to give species C
concomitantly with diarylbismuth acetate. Disproportion be-
tween the copper(II) complex C and copper(II) diacetate would
provide the copper(III) intermediate D along with copper(I)
acetate (step d). Complexation of the imidazole ring of histidine
to copper and deprotonation by DIPEA would then lead to the
key intermediate E where a copper(III) center is simultaneously
ligated to the imidazole ring, the aryl group and an acetate
(step e). Reductive elimination would provide the desired N-
arylated product along with cuprous acetate (species F, step f).
Oxidation of this copper(I) species by oxygen would regenerate
the initial copper(II) catalyst. This mechanism is based on the
mechanism proposed for the Chan-Evans-Lam reaction and
involves a 2:1 ratio of Cu(OAc)2:Ar3Bi.[21] Based on our previous
results, we exclude a mechanism where copper diacetate
oxidizes the triarylbismuth species to its pentavalent triarylbis-
muth diacetate counterpart.[22] The mechanism for the arylation
of the NH backbone of peptides would presumably be similar
except that it would proceed through the ATCUN complex iv
presented in Scheme 5.
Scheme 7. Selective trityl removal in arylated peptide 22.
directed backbone NÀ H arylation involving triarylbismuth
reagents.
To prevent the arylation of the histidine, we prepared
dipeptide 17 where the imidazole ring is protected with a trityl
group (Scheme 4). When submitted to our arylation conditions,
peptide 17 provided the corresponding product of NÀ H
arylation 18a in a modest 68% yield. This yield was increased
°
to 84% simply by raising the temperature to 50 C. Rapid
investigation of the scope of this transformation indicated that
aryl groups with electron donating (18b) and withdrawing
(18c) substituents could be efficiently transferred using this
protocol. However, we found that the presence of a substituent
in ortho position was not accepted, possibly due to exacerbated
steric congestion generated by the tert-butyloxycarbonyl
protecting group (18d).
To determine if the reaction is guided by the histidine
residue or simply proceeds on the terminal NHBoc moiety, we
submitted Boc-Ala-Val-His(Trt)-OMe 19a to our conditions
where a histidine-directed process should lead to the arylation
of the central n-1 valine residue (Scheme 5a). In the event, no
reaction was observed and the starting material was recovered
intact. To make sure that the reaction was not inhibited by the
Finally, we verified that the trityl group could be chemo-
selectively removed under mild conditions, a process which was
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Chemistry—A European Journal
[3] a) A. Gagnon, E. Benoit, A. Le Roch, Sci. Synth. Knowl. Updates 2018, 4,
1–111; b) A. Gagnon, J. Dansereau, A. Le Roch, Synthesis 2017, 49, 1707–
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achieved by stirring 22 in a 9:1 mixture of acetic acid and water
°
at 60 C for 1.5 h to afford 25 in quantitative yield (Scheme 7).
In conclusion, we have developed a protocol to arylate the
imidazole side chain of histidine by using triarylbismuthines.
The reaction is promoted by cupric acetate, uses 1,10-phenan-
throline as a ligand and DIPEA as the base, and operates in
°
dichloromethane at 40 C under an oxygen atmosphere. The
reaction is insensitive to electronic or steric effects, shows
excellent functional group compatibility, and can be performed
with Boc, Cbz or Fmoc protecting groups. The protocol was
applied to histidine-containing dipeptides where histidine is at
the N terminus. Chemoselective arylation on the histidine
residue was obtained in most cases, except when histidine was
connected to a tyrosine. Dipeptides where the histidine is at
the C terminus resulted in imidazole and NÀ H backbone
arylation. Protection of the imidazole with a trityl group led to
exclusive backbone arylation. The arylation occurs at the n-1
position when this position is also the N-terminal position.
Chemoselective removal of the trityl group was accomplished
under mild conditions.
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This work was supported by the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC), by the Centre in Green
Chemistry and Catalysis (CGCC) and by Boehringer Ingelheim
Pharmaceuticals Inc. through a Scientific Advancement grant.
We would like to thank Prof. Steve Bourgault for useful
discussions and advice.
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Conflict of Interest
The authors declare no conflict of interest.
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Keywords: copper catalysis · histidine · imidazole · N-arylation ·
organobismuthines
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Manuscript received: June 18, 2021
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Chem. Eur. J. 2021, 27, 1–8
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COMMUNICATION
H.-C. Chan, B. Bueno, Dr. A. Le Roch,
Prof. Dr. A. Gagnon*
1 – 8
Copper-Promoted N-Arylation of the
Imidazole Side Chain of Protected
Histidine by Using Triarylbismuth
Reagents
Fine transfer protocol: A method for
the N-arylation of protected histidine
using triarylbismuth reagents is
reported. The reaction is promoted by
copper diacetate and proceeds under
smooth conditions, allowing the
transfer of aryl groups on the distal
nitrogen of the imidazole ring. A
histidine-directed backbone NÀ H
arylation was observed at the n-1
position of histidine-containing dipep-
tides.