Regiospecific direct C-h arylation at the 2-position of l -histidine using arylboronic acids

Article abstract of DOI:10.1055/s-0031-1290381

The first regiospecific direct C-2 arylation procedure for histidine using arylboronic acids has been developed. The reaction allows a one-step synthesis of a large variety of 2-aryl-l-histidines using ammonium persulfate and catalytic silver nitrate in TFA and CHlH (1:1) at ambient temperature.

Full text of DOI:10.1055/s-0031-1290381

LETTER
▌1759
lRetteergiospecific Direct C–H Arylation at the 2-Position of L-Histidine Using
Arylboronic Acids
Direct C–H Arylation at the 2-Position of L-Histidine
Amit Mahindra, Rahul Jain*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062,
India
Fax +91(172)2214692; E-mail: rahuljain@niper.ac.in
Received: 16.04.2012; Accepted after revision: 26.04.2012
In recent years, direct C–H arylation reactions have
Abstract: The first regiospecific direct C-2 arylation procedure for
emerged as an alternative to cross-coupling reactions and
histidine using arylboronic acids has been developed. The reaction
have been used for multiple substitutions in diverse het-
allows a one-step synthesis of a large variety of 2-aryl-L-histidines
using ammonium persulfate and catalytic silver nitrate in TFA and
erocycles such as imidazole or quinoline.7 The major ad-
CH2Cl2/H2O (1:1) at ambient temperature.
vantage of C–H activation over cross-coupling reactions
is that it does not require different kinds of functionalized
starting materials.8 The direct C–H substitution reactions
also allow high functional-group tolerance and atom
economy.
Key words: regiospecific, arylation, histidine, arylboronic acids,
C–H activation
Modifications of the natural amino acids by derivatization
are imperative since their incorporation into biologically
active peptides may lead to peptidomimetics with im-
proved biological activity. These mimetics not only have
enhanced activity but also have high proteolytic stability
and receptor-subtype selectivity.1 Ring-substituted histi-
dines represent one such class of amino acids, and their in-
corporation into the peptides results in significant
improvement in biological activities.2 In the past several
years, the importance of the histidine residue in peptides
and proteins has received considerable attention, and its
presence is one of the foremost factors for the activity in
several instances.3 Even though ring-substituted histi-
dines are biologically important synthons, their prepara-
tion still remains a synthetic challenge for chemists.4
Recently, Baran and co-workers reported a method in
which electron-deficient heterocycles are arylated using
silver(I)-catalyzed addition of arylboronic acids.9 This net
C–H arylation employed to build up diaromatic systems
proceeds at ambient temperature and has a broad function-
al-group compatibility. This type of homolytic free-radi-
cal reaction was first reported by Minisci and co-workers
in which heterocycles are alkylated or acylated specifical-
ly at the most electron-deficient positions in the ring.10 In
contrast, Baran’s reaction accomplishes the direct aryla-
tion at electron-deficient positions of heterocycles with
arylboronic acids.
In this letter, we report the first direct C–H arylation of a
protected histidine resulting in the development of a meth-
od for the synthesis of 2-aryl-L-histidines, with diverse
aryl groups. The method is applicable for the arylation of
histidine in the presence of a reactive NH functional group
present in the imidazole ring.
Several synthetic methods are available in the literature
for the regiospecific arylation of imidazole at diverse po-
sitions.5 The method reported in the literature for the syn-
thesis of 5-arylhistidines is not direct.6 This protocol
requires the protection of the imidazole ring nitrogen of
histidine followed by electrophilic halogenation using N-
halosuccinimide and finally a palladium-catalyzed cross-
coupling reaction with arylboronic acids, resulting in 5-
aryl-L-histidines in five overall steps. Until now, to the
best of our knowledge, there is no method available in the
literature for the arylation of histidine at the C-2 position
of the imidazole ring.
To establish a protocol for the synthesis of 2-aryl-L-histi-
dines, the α-amino group on the side chain of L-histidine
methyl ester was protected. Of various groups used for
protecting the side-chain nitrogen (trifluoroacetyl, acetyl,
benzyloxycarbonyl, tert-butyloxycarbonyl), the first was
found to give best results. Later, the trifluoroacetyl group
could easily be removed by refluxing with dilute acid. The
commercially available L-histidine methyl ester dihydro-
AgNO3
(NH4)2S2O8
TFA
F3COCHN
MeO2C
F3COCHN
N
N
+
PhB(OH)2
Ph
MeO2C
CH2Cl2/H2O, r.t.
N
H
N
2
H
1a
3a
Scheme 1
SYNLETT 2012, 23, 1759–1764
Advanced online publication: 21.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290381; Art ID: ST-2012-B0333-L
© Georg Thieme Verlag Stuttgart · New York

1760
A. Mahindra, R. Jain
LETTER
chloride (1) was reacted with trifluoroacetic anhydride to followed by rearomatization to give exclusive C-2 arylat-
give N-α-trifluoroacetyl-L-histidine methyl ester (1a).
ed product.9,10
The starting point of our study was the Baran’s observa-
tion that the reaction of the electron-deficient heterocycles
with various arylboronic acids could be performed in the
presence of AgNO3 and (NH4)2S2O8 under an air atmo-
sphere.9 With this in mind, we initially carried out a reac-
tion between 1a and phenylboronic acid (2), keeping the
reaction conditions intact (Scheme 1). To our delight, we
found that monoarylation of 1a took place in addition to
diarylation in the presence of a catalytic amount of
AgNO3 (0.2 equiv), (NH4)2S2O8 (3 equiv), PhB(OH)2 (1.5
equiv), and TFA (1 equiv) in 15% yield. The addition of a
second lot of reagents resulted in increased diarylation,
and the yield of monoarylated product further decreased.
a
Table 2 Solvent Effect on Arylation of 1a with PhB(OH)2
Entry Solvent
Temp
(°C)
Time
(min)
Yield
(%)
1
2
3
4
5
6
7
8
9
MeCN–H2O (1:1)
70–80
70–80
240
240
240
720
300
300
300
240
360
10
15
12
45
20
30
18
42
18
THF–H2O (1:1)
1,4-dioxane–H2O (1:1)
CH2Cl2/H2O (1:1)
DMF–H2O (1:1)
toluene/H2O (1:1)
DMSO–H2O (1:1)
DCE/H2O (1:1)
H2O
70–80
25–30
100–110
90–100
100–110
50–60
Table 1 Optimization of Reaction Conditions
Entry
AgNO3
(equiv)
PhB(OH)2 (NH4)2S2O8 TFA
Conv.
(equiv)
(equiv)
(equiv) (%)a
90–100
a Conditions: 1a (1 equiv), PhB(OH)2 (2.0 equiv), AgNO3 (0.2 equiv),
(NH4)2S2O8 (2 equiv), TFA (1.5 equiv).
1
2
3
4
5
6
7
0.2
0.2
0.2
0.2
0.2
0.4
0.4
1.5
2.5
2.0
2.0
2.0
2.0
2.0
3
3
3
2
2
2
3
1
60 (15)
90 (10)
80 (25)
85 (40)
92 (45)
95 (10)
90 (12)
1
1
It has been well established that the nature of the solvent
often modulates the rate of reaction and overall yield of
the product.11 To see the influence of solvents on the cou-
pling reaction between 1a and PhB(OH)2, a wide range of
solvent systems were tried (Table 2). We have observed
that reactions carried out in biphasic media are more effi-
cient than that in pure organic solvent. As also observed
by Baran, a biphasic system of CH2Cl2/H2O (1:1) provid-
ed the best results. We believe that the solvent effect was
related to the polarity of the solvent because switching
from nonpolar or polar aprotic to polar protic solvent led
to a substantially decreased yield of the product. This sug-
gests that polar solvents may be forming a complex with
the arylboronic acids, and as a result the reaction became
sluggish. Interestingly, the reaction also proceeded in wa-
ter at 90–100 °C to provide 3a in lower 18% yield (Table
2, entry 9).
1
1.5
1.5
1.5
a Isolated yield in parentheses in (%).
The reaction conditions for regiospecific C-2 arylation
were then established by optimization of the coupling of
1a with PhB(OH)2 (Table 1). In entry 1, the use of
PhB(OH)2 (1.5 equiv) resulted in only 60% conversion of
1a into 3a. The conversion was remarkably increased with
the increase of PhB(OH)2 (2.5 equiv), but the yield was
decreased because of undesired diarylation (Table 1, entry
2). However, the yield was almost doubled when
PhB(OH)2 (2 equiv) was used (Table 1, entry 3). In anoth-
er set of experiments, when the amount of (NH4)2S2O8
was decreased to (2 equiv) and the amount of TFA was in-
creased to (1.5 equiv), the yield of C-2 arylated product
was gradually increased to 45% (Table 1, entries 4 and 5).
It was immediately clear from the experiments (Table 1)
that the C-2 arylation reaction of 1a with PhB(OH)2 is best
achieved using the conditions described in entry 5 (Table
1). We have also observed that during the course of reac-
tion some unstable side products are formed arising due to
oxidative conditions, which could not be isolated and
characterized. Mechanistically, it has been proposed that
sulfate dianion and sulfate radical anion formed by sil-
ver(I)-catalyzed addition, upon reaction with arylboronic
acid generate an aryl radical. This aryl radical reacts with
protonated electron-deficient imidazole ring of histidine,
With the optimized conditions in hand, the new C-2 ary-
lation protocol was applied to synthesize several new ary-
lated-L-histidines (Scheme 2) as summarized in Table 3.
Various arylboronic acids bearing electron-donating or
electron-withdrawing substituents reacted with 1a to af-
ford the coupling products 3a–q in moderate to good
yields.12–14 The electronic variation of substitution on the
arylboronic acid substantially affected the yield of the
product (Table 3). In cases of electron-donating groups
AgNO3
(NH4)2S2O8
F3COCHN
HO
HO
TFA
N
1a
+
B
Ar
Ar
MeO2C
CH2Cl2/H2O, r.t.
N
H
3a–q
2a–q
Scheme 2
Synlett 2012, 23, 1759–1764
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct C–H Arylation at the 2-Position of L-Histidine
1761
such as methoxy or methyl the yields were higher (Table acid and phenanthreneboronic acid with 1a. The yield was
3, entries 4 and 7), whereas in the cases with electron- moderate in these cases, probably due to steric factors and
withdrawing groups such as bromo or fluoro the yield de- formation of dimeric byproducts. In the cases involving
creased (Table 3, entries 14–17). The reaction becomes electron-withdrawing group, ortho substitution, and bulky
sluggish in the cases of arylboronic acids are ortho-substi- arylboronic acids the lower yield of the product was ob-
tuted (Table 3, entries 6 and 9). We have also coupled tained because a substantial amount of unreacted starting
polyaromatic arylboronic acids such as naphthylboronic material was recovered even after longer reaction time.
Table 3 Regiospecific C-2 Arylation of 1a with Various Arylboronic Acidsa
Entry
1
2a–q
Time (h)
12
Product 3a–q
Yield (%)
45
F3COCHN
MeO2C
N
N
H
F3COCHN
MeO2C
N
2
10
55
N
H
F3COCHN
MeO2C
N
3
4
10
10
50
52
N
H
F3COCHN
MeO2C
N
N
H
F3COCHN
MeO2C
N
5
6
15
18
40
34
N
H
F3COCHN
MeO2C
N
N
H
F3COCHN
MeO2C
N
OMe
7
13
48
N
H
OMe
OMe
F3COCHN
MeO2C
N
8
9
15
17
40
32
N
H
OCH3
OMe
MeO
F3COCHN
MeO2C
N
N
H
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1759–1764

1762
A. Mahindra, R. Jain
LETTER
Table 3 Regiospecific C-2 Arylation of 1a with Various Arylboronic Acidsa (continued)
Entry
10
2a–q
Time (h)
16
Product 3a–q
Yield (%)
F3COCHN
MeO2C
N
23
N
H
F3COCHN
MeO2C
N
11
12
14
12
35
43
N
H
OMe
F3COCHN
MeO2C
N
MeO
N
H
F3COCHN
MeO2C
N
13
18
20
N
H
F3COCHN
MeO2C
N
Br
14
15
16
17
18
18
18
18
18
16
17
15
N
H
Br
Br
F3COCHN
MeO2C
N
N
H
Br
F3COCHN
MeO2C
N
F
N
H
F
F
F3COCHN
MeO2C
N
N
H
F
a Conditions: 1a (1 equiv), ArB(OH)2 (2.0 equiv), AgNO3 (0.2 equiv), NH4(S2O8)2 (2 equiv), TFA (1.5 equiv), CH2Cl2/H2O (1:1, v/v), 10–18
h, r.t.
Next, the removal of the protecting groups of 3a was synthesized 2-phenyl-D-histidine·2HCl to differentiate
achieved by refluxing it in 6 M HCl for 16–24 hours between the retention time of the two enantiomers. As ev-
(Scheme 3). The 2-phenyl-L-histidine dihydrochloride ident from the HPLC chromatograms of L-, D-histidine, 2-
(4a) was obtained by the evaporation of the solution in phenyl-L-histidine·2HCl and 2-phenyl-D-histidine·2HCl,
95% yield. By using the same acidic conditions, deprotec- we sum up that 2-phenyl-L-histidine·2HCl retained its chi-
tion of different N-α-trifluoroacetyl-2-aryl-L-histidine rality under the given reaction conditions, and the aryla-
methyl ester derivatives was achieved, resulting in the for-
mation of 2-aryl-L-histidines dihydrochloride (4a–f) in
high yields (Table 4).
F3COCHN
H2N
N
N
reflux
Ar
Ar
MeO2C
6 M HCl
CO2H
4a–f
N
H
N
H
After deprotection of 3a into 4a, chiral HPLC studies
were performed using a ChiralPak-WH column to deter-
mine the optical integrity of the deprotected 2-aryl-L-his-
tidines. To confirm the chiral integrity of 4a, we have also
⋅2HCl
3a–f
Scheme 3
Synlett 2012, 23, 1759–1764
© Georg Thieme Verlag Stuttgart · New York

LETTER
Direct C–H Arylation at the 2-Position of L-Histidine
1763
Table 5 Boc Protection of 2-Aryl-L-histidine Dihydrochloridesa
tion protocol described herein did not result in any
racemization of the product.
Entry
1
5a–f Ar
Yield (%)
85
Table 4 Synthesis of 2-Aryl-L-histidine Dihydrochloridea
Entry
1
4a–f Ar
Yield (%)
95
OMe
2
3
4
80
84
80
OMe
2
3
4
90
96
91
5
81
5
6
95
90
6
85
a Conditions: 4a–f (1 mmol) was suspended in a mixture of H2O–
dioxane (1:2). A solution of 4 M NaOH was added, and the pH of the
reaction mixture was adjusted to 12. After 10 min, di-tert-butyl dicar-
bonate (3 mmol) was added to the reaction mixture.
a Conditions: 6 M HCl, reflux, 18–24 h.
Finally, 2-aryl-L-histidine·2HCl 4a–f were converted into
N-α-Boc-2-aryl-L-histidines 5a–f (Scheme 4) using di-
tert-butyl dicarbonate in a mixture of water–dioxane (2:3,
v/v) in 80–85% yield (Table 5). These enantiomerically
pure protected amino acid scaffolds are suitable for pep-
tide synthesis.
References and Notes
(1) (a) Rivier, J.; Vale, W.; Monahan, M.; Ling, N.; Burgus, R.
J. Med. Chem. 1972, 15, 479. (b) Jain, R.; Cohen, L. A.; El
Kadi, N. A.; King, M. M. Tetrahedron 1997, 53, 2365.
(c) Haug, B. E.; Stenson, W.; Stiberg, T.; Svendsen, J. S.
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Rajput, S.; Pawar, S.; Sharma, S. S.; Lu, X.; Gershengorn,
M. C.; Jain, R. ChemMedChem 2011, 6, 531.
(2) (a) Kaur, N.; Lu, X.; Gershengorn, M. C.; Jain, R. J. Med.
Chem. 2005, 48, 6162. (b) van Kan, E. J. M.; van der Bent,
A.; Demel, R. A.; de Kruijff, B. Biochemistry 2001, 40,
6398. (c) Delort, E.; Nguyen-Trung, N. Q.; Darbre, T.;
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R. K.; Reddy, R. P.; Tegge, W.; Jain, R. J. Med. Chem. 2009,
52, 7421.
H
H2N
N
Boc
N
N
Ar
Ar
CO2H
4a–f
CO2H
5a–f
N
H
N
H
•2HCl
Scheme 4
(3) (a) Maibaum, J.; Rich, D. H. J. Med. Chem. 1988, 31, 625.
(b) Samanen, J.; Brandeis, E.; Narindray, D.; Adams, W.;
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S. J. Org. Chem. 2005, 70, 3997. (b) Bellina, F.;
In conclusion, for the first time we report a regiospecific
synthesis of 2-aryl-L-histidine derivatives. This method
allowed direct regiospecific arylation at the C-2 position
of the imidazole ring of histidine under mild reaction con-
ditions, thus making the process simple and synthetically
desirable. This C–H functionalization approach offers an
advanced strategy for the synthesis of 2-aryl-L-histidines,
thus providing access to previously unknown scaffolds
that may have great importance in medicinal and peptide
chemistry.
Acknowledgment
Cauteruccio, S.; Mannina Bellina, F.; Cauteruccio, S.; Rossi,
R. Tetrahedron 2007, 63, 4571. (c) Shibahara, F.;
Yamaguchi, E.; Murai, T. J. Org. Chem. 2011, 76, 2680.
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(b) Cerezo, V.; Afonso, A.; Planas, M.; Feliu, L.
A.M. thanks the CSIR, New Delhi for the award of Senior Research
Fellowship.
Tetrahedron 2007, 63, 10445.
(7) (a) Godula, K.; Sames, D. Science 2006, 312, 67.
(b) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1759–1764

1764
A. Mahindra, R. Jain
LETTER
S. Eur. J. Org. Chem. 2006, 693. (c) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48,
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Chem. Soc. 2011, 133, 3780.
followed by dilution with H2O, and extracted with EtOAc.
The layers were separated, and the organic layer was washed
with a mixture of H2O and brine. The resulting organic
solution was dried over Na2SO4 and filtered. The filtrate was
concentrated, and the residue was purified by flash column
chromatography to provide 3a–q.
(8) Skoumbourdis, A. P.; Moore, S.; Landsman, M.; Thomas,
C. J. Tetrahedron Lett. 2007, 48, 9140.
(13) Analytical Data of N-α-Trifluoroacetyl-2-phenyl-L-
histidine Methyl Ester (3a)
(9) (a) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc.
2010, 132, 13194. (b) Fujiwara, Y.; Domingo, V.; Seiple, I.
B.; Gianatassio, R.; Del Bel, M.; Baran, P. S. J. Am. Chem.
Soc. 2011, 133, 3295. (c) Ji, Y.; Brueckl, T.; Baxter, R. D.;
Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran,
P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 14411.
(10) (a) Minisci, F. Synthesis 1973, 1. (b) Minisci, F.; Vismara,
E.; Fontana, F. Heterocycles 1989, 28, 489. (c) Duncton, M.
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Yield 45%; yellow semisolid. 1H NMR (400 MHz, CDCl3):
δ = 9.87 (br s, 1 H), 7.72 (dd, J = 1.5, 8.0 Hz, 2 H), 7.34–7.26
(m, 3 H), 6.75 (s, 1 H), 4.78 (t, J = 4.5 Hz, 1 H), 3.61 (s, 3
H), 3.16 (dd, J = 4.8, 15.1 Hz, 1 H), 3.06 (dd, J = 4.6, 14.9
Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 170.4, 158.1,
146.7, 141.4, 135.7, 129.4, 127.6, 125.2, 120.2, 117.3,
115.4, 111.6, 52.9, 29.6, 27.9. IR (neat): ν = 3289, 1949,
1715, 1557, 1464, 1411, 1214, 967, 773, 698 cm–1. HRMS
(ESI-TOF): m/z calcd for [M + H+]: 342.1065; found:
342.1078.
(11) Heinisch, G.; Lotsch, G. Angew. Chem., Int. Ed. Engl. 1985,
24, 692.
(12) General Experimental Procedure
(14) Analytical Data of N-α-Trifluoroacetyl-2-(4-
methylphenyl)-L-histidine Methyl Ester (3d)
To a solution of 1a (1.89 mmol, 1.0 equiv) in CH2Cl2 (5 mL),
TFA (2.83 mmol, 1.5 equiv) was added. After 5 min a
solution of AgNO3 (0.37 mmol, 0.2 equiv) in H2O (5 mL)
was added, followed by arylboronic acid (3.77 mmol, 2
equiv). Ammonium persulfate (3.77 mmol, 2.0 equiv) was
then added in one portion, and the solution was stirred
vigorously at r.t. for 10–18 h and monitored by TLC analysis
of the organic layer. Upon the completion of reaction, the
reaction pH was adjusted around 11–12 by the addition of
NH3 solution. The residual CH2Cl2 was evaporated,
Yield 52%; yellow semisolid. 1H NMR (400 MHz, CDCl3):
δ = 9.79 (br s, 1 H), 7.62–7.61 (m, 2 H), 7.26–7.18 (m, 2 H),
6.76 (s, 1 H), 4.81 (s, 1 H), 3.66 (s, 3 H), 3.21 (dd, J = 4.4,
14.9 Hz, 1 H), 3.09 (dd, J = 0.8, 4.8, 15.0 Hz, 1 H), 2.35 (s,
3 H). 13C NMR (100 MHz, CDCl3): δ = 170.4, 158.0, 156.9,
146.9, 139.0, 136.0, 129.5, 126.6, 124.8, 117.4, 114.7,
111.7, 52.8, 52.7, 28.0, 21.2. IR (neat): ν = 3302, 2926, 1749,
1559, 1439, 1181, 821, 729 cm–1. HRMS (ESI-TOF): m/z
calcd for [M + H+]: 356.1222; found: 356.1220.
Synlett 2012, 23, 1759–1764
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