Synthesis of 5-arylhistidines via a Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1016/j.tet.2007.08.010

Microwave irradiation efficiently promoted the Suzuki-Miyaura reaction of a 5-bromohistidine with various arylboronic acids in the presence of a palladium catalyst. This methodology allowed the synthesis of histidines substituted at position 5 of the imid

Full text of DOI:10.1016/j.tet.2007.08.010

Tetrahedron 63 (2007) 10445–10453
Synthesis of 5-arylhistidines via a Suzuki–Miyaura cross-coupling
*
Vanessa Cerezo, Ana Afonso, Marta Planas and Lidia Feliu
Laboratori d’Innovacioꢀ en Processos i Productes de Sꢀıntesi Orgaꢁnica (LIPPSO), Departament de Quꢀımica,
Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain
Received 6 July 2007; revised 1 August 2007; accepted 2 August 2007
Available online 8 August 2007
Abstract—Microwave irradiation efficiently promoted the Suzuki–Miyaura reaction of a 5-bromohistidine with various arylboronic acids in
the presence of a palladium catalyst. This methodology allowed the synthesis of histidines substituted at position 5 of the imidazole ring with
a phenyl, a substituted phenyl, a pyridyl or a thienyl ring. The corresponding 5-arylhistidines were obtained in moderate to good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
comparison purposes, cross-coupling reactions under ther-
mal heating were also studied and will be discussed.
Unnatural amino acids are increasingly becoming important
substrates in modern drug design, synthesis, and discovery
research. Their incorporation into biologically active
peptides may lead to peptidomimetics with restricted confor-
mational flexibility, increased proteolytic stability, and
enhanced selectivity and biological activity.1,2 Among
them, biaryl amino acids have been the focus of intense syn-
thetic efforts owing to the broad spectrum of activities shown
by peptides containing biaryl motifs.3,4 In particular, arylhis-
tidines occur naturally in the active site of the heme–copper
oxidases and in cytotoxic and antifungal marine peptides.5–7
2. Results and discussion
2.1. Microwave-assisted arylation of an imidazole
derivative
The feasibility of the microwave-assisted Suzuki–Miyaura
reaction for the arylation of position 4(5) of an imidazole
ring was investigated using the 4(5)-methylimidazole (1)
as model system (Scheme 1). For this purpose, the com-
mercially available imidazole 1 was treated with NaH
(1.1 equiv) and BnCl (1 equiv),19 and then brominated
A method of choice for the preparation of unsymmetric
biaryl systems is the Suzuki–Miyaura cross-coupling of an
aryl halide with an arylboronic acid.8–13 It has been shown
that microwaves significantly enhance this reaction leading
to higher overall yields and purities as well as shorter reac-
tion times.14–18 Although a great variety of biarylic com-
pounds have been prepared following this approach, up to
now it has not been applied to the arylation of imidazole
rings.
1. NaH, DMSO
Br
2. BnCl (74%)
N
N
N
3. NBS, CH3CN (60%)
+
+
Br
N
H
N
N
Bn
2a
Bn
2b
1
PhB(OH)2
Pd(PPh3)4, Na2CO3
toluene, H2O, EtOH
Ph
N
N
In the course of our synthetic studies on biaryl amino acids,
we focused our interest on studying a methodology toward
the preparation of 5-arylhistidines. Here we report the aryla-
tion of an imidazole derivative via a microwave-assisted
Suzuki–Miyaura cross-coupling reaction, and the extension
of this methodology to the synthesis of 5-arylhistidines. For
Ph
N
Reflux: 24 h, 71%
or
MW: 110 ºC, 10 min, 70%
N
Bn
3a
Bn
3b
Na, liq NH3
t-BuOH, THF
68%
N
Ph
N
H
Keywords: Histidine; Arylation; Suzuki–Miyaura cross-coupling; Micro-
wave; Biaryl compounds.
4
* Corresponding author. Tel.: +34 972 418274; fax: +34 972 418150;
e-mail: lidia.feliu@udg.edu
Scheme 1. Synthesis of 4(5)-methyl-5(4)-phenylimidazole (4) via a Suzuki–
Miyaura cross-coupling.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.010

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V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
with NBS (1 equiv) to afford bromoimidazoles 2a and 2b
(Scheme 1).8 These regioisomers were separated by column
chromatography to be fully characterized. 1H and 13C NMR
as well as mass spectrometry clearly proved the assumption
of regioisomerism, and the unambiguous assignment was
achieved by HMBC (J1,3) and X-ray analysis. The HMBC
spectra of the isomer 2a showed that the signal of the meth-
ylene protons of the benzyl group correlated with the carbon
linked to the methyl substituent. In the spectra of the major
regioisomer 2b, the methylene protons of the protecting
group correlated with the carbon linked to the Br atom.
NBS (1.1 equiv) at 0 ꢀC in acetonitrile for 15 min led to
the 5-bromohistidine 5 (60% yield) along with the 2,5-dibro-
mohistidine derivative (13% yield).23 Alkylation of 5 with
SEMCl as described above gave a regioisomeric mixture
of the SEM-protected 5-bromohistidines 6a and 6b, which
were easily separated by column chromatography and ob-
tained in 24% and 49% yields, respectively. The unambigu-
ous assignment of each regioisomer was achieved by HMBC
(J1,3). The spectra of isomer 6a showed that the signal of the
methylene protons of the SEM N–CH2–O moiety correlated
with the imidazole carbon linked to the b-CH2. By contrast,
in the spectra of regioisomer 6b, the methylene protons of
this moiety correlated with the carbon linked to the Br atom.
The coupling of a regioisomeric mixture of 2a and 2b with
phenylboronic acid (1.1 equiv) was first attempted employ-
ing standard conditions, i.e., 5 mol % Pd(PPh3)4 as catalyst
and aqueous 2 M Na2CO3 as base (5 equiv), in toluene/
ethanol (Scheme 1). After heating at 110 ꢀC for 24 h, a mix-
ture of phenylimidazoles 3a and 3b was obtained in 71%
yield. The isomers were characterized by NMR spectros-
copy and mass spectrometry. Then, the Suzuki–Miyaura
reaction was performed under microwave irradiation em-
ploying the above reaction conditions. Even though phenyl-
imidazoles 3a and 3b were obtained in similar yield (70%),
the reaction time was considerably shortened, from 24 h to
just 10 min corresponding to a 144-fold rate increase. Final
debenzylation of 3a and 3b by sodium in liquid ammonia
afforded exclusively 4(5)-methyl-5(4)-phenylimidazole (4)
in 68% yield.20
With the properly functionalized 5-bromohistidines 6a and
6b in hand, we set out to examine the arylation of position
5 of the imidazole ring via a Suzuki–Miyaura cross-
coupling. The reaction conditions were standardized by
optimization of the coupling reaction of 6a and 6b with phe-
nylboronic acid (Table 1). No reaction took place when
either 6a or 6b was treated with phenylboronic acid
(1.1 equiv), 5 mol % Pd(PPh3)4, and aqueous 2 M Na2CO3
(2 equiv), in toluene/methanol under conventional heating
at 110 ꢀC for 24 h (entries 1 and 16). An increase of the cata-
lyst amount to 20 mol % did not lead either to the formation
of the 5-phenylhistidine 7b (entry 2). The use of other palla-
dium catalysts only afforded 7b in 26% yield (entries 3–5).
The arylation of 5-bromohistidine 6b was then attempted
under microwave heating (Table 1). The coupling was con-
ducted by employing the above reaction conditions using
Pd(PPh3)4 as catalyst (entries 6 and 7). When 20 mol % of
Pd(PPh3)4 was used, the 5-phenylhistidine 7b was obtained
in 63% yield after 30 min irradiation (entry 7). In entries
8–10 we investigated the catalyst. PdCl2(dppf) was not
effective for the reaction, producing a low yield of 7b
(20%). In the case of Pd2(dba)3, 7b was obtained in similar
yield as with Pd(PPh3)4 (58%) but using a lower amount of
catalyst (10 mol %) and in a shorter reaction time (10 min).
Based on these conditions we examined the influence of the
base (entries 11–15). KF was found to be the most effective,
furnishing 7b in 62% yield. The advantage of using KF as
base is clearly evident from the arylation of 5-bromohisti-
dine 6a, which led to 7a in 82% after 15 min irradiation
(entries 17–20).
2.2. Microwave-assisted arylation of a histidine
derivative
The above methodology was applied to the synthesis of
5-arylhistidines. The commercially available Ac-His-OH was
chosen as the starting material, which was converted to the
methyl ester by treatment with SOCl2 in methanol (Scheme
2). The [2-(trimethylsilyl)ethoxy]methyl (SEM) group was
selected to protect the imidazole ring because it can be
more flexibly removed than the benzyl group, being more
suitable for solid-phase peptide synthesis.21,22 Imidazole de-
protonation of Ac-His-OMe with DBU (1.5 equiv) at 0 ꢀC
for 1.5 h in DMF under nitrogen, followed by the addition
of SEMCl (1 equiv) at 0 ꢀC, and stirring for 1.5 h produced
a regioisomeric mixture of Ac-His(p-SEM)-OMe and Ac-
His(t-SEM)-OMe in less than 5% yield. As an alternative,
the direct bromination of Ac-His-OMe followed by SEM
protection was attempted. Treatment of Ac-His-OMe with
Next, we explored the applicability of the Suzuki–Miyaura
reaction to the coupling of 5-bromohistidines 6a and 6b
with other arylboronic acids, possessing substituted benz-
ene, pyridine, and thiophene rings (Table 1, entries 21–28).
All reactions went to completion within 1 h giving rise
to the desired 5-arylhistidines 8–11 in moderate to good
yields. In general, the arylation of 5-bromohistidine 6a
proceeded smoother than that of 6b. These results could be
tentatively explained taking into account that in regioisomer
6b the SEM group is at N(t), which would increase the steric
hindrance, resulting in a more difficult reaction. Similar to
previous studies,24,25 coupling of 3-pyridylboronic acid
with 6a and 6b was found to be difficult, with a 40 mol %
of catalyst being necessary to promote the reaction (entries
25 and 26). The best result was obtained for the reaction
of 6a with 3-thienylboronic acid leading to 11a with 85%
yield (entry 28).
O
O
AcHN
AcHN
1. SOCl2, CH3OH (90%)
2. NBS, CH3CN (60%)
OH
OMe
Br
NH
NH
N
N
5
O
O
AcHN
AcHN
OMe
Br
OMe
5
1. DBU, DMF
2. SEMCl
Br
4
4
5
N
N
N
N
SEM
SEM
6a
2
2
6b
24%
Scheme 2. Synthesis of 5-bromohistidines 6a and 6b.
49%

V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
Table 1. Arylation of 5-bromohistidines 6a and 6b with various arylboronic acids
10447
O
O
O
ArB(OH)2
base, Pd0 cat.
toluene, H2O, MeOH
O
ArB(OH)2
base, Pd0 cat.
toluene, H2O, MeOH
AcHN
AcHN
AcHN
AcHN
OMe
Ar
OMe
Ar
OMe
Br
OMe
Br
Reflux or MW, 110 °C
Reflux or MW, 110 ºC
N
N
N
N
N
N
N
N
SEM
SEM
SEM
SEM
6b
7b-11b
6a
7a-11a
Entry Histidine 5 ArB(OH)2
ArB(OH)2 (equiv) Heatinga Catalyst
Catalyst (mol %) Base
Time
Product Yieldb (%)
1
2
3
4
5
6
7
1.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
Reflux
Reflux
Reflux
Reflux
Reflux
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
MWI
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
5
20
20
Na2CO3
24 h
24 h
24 h
24 h
24 h
30 min 7b
30 min 7b
20 min 7b
10 min 7b
15 min 7b
10 min 7b
10 min 7b
7b
7b
7b
7b
7b
0
0
12
26
0
22
63
20
58
45
10
27
35
47
62
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
PdCl2(dppf) 20
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
20
10
20
B(OH)2
8
9
6b
PdCl2(dppf) 20
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
10
20
10
10
10
10
10
10
11
12
13
14
15
Cs2CO3
NaHCO3 10 min 7b
10 min 7b
10 min 7b
K3PO4
KF
16
17
18
19
20
1.1
2.1
2.1
2.1
2.1
Reflux
MWI
MWI
MWI
MWI
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
5
10
10
15
10
Na2CO3
Na2CO3
Na2CO3
K3PO4
KF
24 h
7a
0
35
37
8
10 min 7a
15 min 7a
15 min 7a
15 min 7a
B(OH)2
B(OH)2
6a
82
21
22
6b
6a
2.1
2.1
MWI
MWI
Pd2(dba)3
Pd2(dba)3
10
10
KF
KF
1 h
1 h
8b
8a
36
54
OMe
B(OH)2
23
24
6b
6a
2.1
2.1
MWI
MWI
Pd2(dba)3
Pd2(dba)3
40
20
KF
KF
10 min 9b
1 h 9a
51
68
OMe
B(OH)2
25
26
6b
6a
2.1
2.1
MWI
MWI
Pd2(dba)3
Pd2(dba)3
40
40
KF
KF
10 min 10b
10 min 10a
33
40
N
B(OH)2
27
28
6b
6a
2.1
2.1
MWI
MWI
Pd2(dba)3
Pd2(dba)3
20
20
KF
KF
30 min 11b
15 min 11a
54
85
S
a
All experiments were performed at 110 ꢀC.
Isolated yields after chromatography.
b
Finally, the removal of the SEM group of arylhistidines was
examined (Table 2). The reaction conditions were first stud-
ied with phenylhistidine 7b. Disappointingly, treatment of
7b with TBAF (5 equiv) in THF at room temperature led
to a complex mixture of unidentified products. When the re-
action was performed with PPTS (1 equiv) in MeOH, the
starting material was recovered. Removal of the SEM group
could be accomplished by treatment with TFA/CH2Cl2 (2:1)
at room temperature for 1.5 h giving the 5-phenylhistidine
12 in 97% yield (entry 2). These conditions were then
applied to the deprotection of histidines 7a and 8–11 afford-
ing 5-arylhistidines 12–16 in high yields. Chiral HPLC stud-
ies were performed in order to analyze the optical integrity
of the deprotected 5-arylhistidines. Results showed that no
racemization occurred.
the Suzuki–Miyaura reaction of the corresponding 5-bromo-
histidine with phenyl, substituted phenyl, pyridyl, and
thienylboronic acids. This work constitutes the first Suzuki–
Miyaura coupling involving the imidazole ring of a histidine.
4. Experimental section
4.1. Synthesis of 4(5)-methyl-5(4)-phenylimidazole (4)
4.1.1. 1-Benzyl-4-bromo-5-methylimidazole (2a) and
1-benzyl-5-bromo-4-methylimidazole (2b). N-Bromosuc-
cinimide (420 mg, 2.4 mmol) was added to a solution of a
regioisomeric mixture of 1-benzyl-5-methylimidazole and
1-benzyl-4-methylimidazole (1:1.3)19 (422 mg, 2.4 mmol)
in dry acetonitrile (55 mL) at 0 ꢀC. The reaction mixture
was stirred for 30 min under N2 at this temperature. Pyridine
(4 mL) was added and the mixture was concentrated
in vacuo. Triethylamine (40 mL) was added to the con-
centrated solution. Removal of the solvent gave a residue,
which was purified by column chromatography. Elution
3. Conclusion
A straightforward approach has been established to the syn-
thesis of 5-arylhistidines. Microwave irradiation facilitates

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V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
Table 2. SEM group removal of 5-arylhistidines 7–11
24 h. After this time, the reaction mixture was extracted
with CH2Cl2 (25 mL), the organic layer was washed with
brine (25 mL), and dried. The solvent was evaporated leav-
ing an amber colored oil, which was purified by column
chromatography. Elution with hexane/EtOAc (1:2) afforded
a mixture of 3a and 3b (669 mg, 71%) as a yellow oil.
O
AcHN
OMe
Ar
O
TFA, CH2Cl2
AcHN
OMe
Ar
N
N
7a-11a
SEM
O
N
12-16
HN
Method B. A 30-mL vial containing a magnetic stir bar was
charged with a solution of 2a and 2b (1:1.2) (200 mg,
0.8 mmol) and Pd(PPh3)4 (46 mg, 5 mol %) in degassed
toluene (2 mL). Then, a degassed solution of phenylboronic
acid (110 mg, 0.9 mmol) in EtOH (1.25 mL) and aqueous
2 M Na2CO3 (2 mL, 4.0 mmol) were added. The vial was
sealed and heated under N2 in the microwave lab station.
Firstly, a microwave ramp (300 W maximum) was applied
for 7 min to reach 110 ꢀC. The reaction mixture was
irradiated at this temperature for 10 min. After this time,
upon cooling, the reaction mixture was extracted
with EtOAc (25 mL). The organic solution was washed
with water (25 mL) and brine (25 mL), dried over anhydrous
magnesium sulfate, and concentrated in vacuo. The
residue was purified by column chromatography. Elution
with hexane/EtOAc (3:1) afforded 3a as a colorless
oil (16 mg, 8%). Rf (EtOAc/NH3, 98:2) 0.48; 1H
NMR (200 MHz, CDCl3) d 2.22 (s, 3H, CH3), 5.04 (s, 2H,
CH2), 7.01–7.05 (m, 2H, o0-CHarom), 7.13–7.37 (m, 5H,
o-, m- and p-CHarom), 7.51 (s, 1H, CH-2imid), 7.56–7.62
(m, 3H, m0- and p0-CHarom); MS (ESI) m/z (%) 249.2 (100)
[M+H]+.
AcHN
OMe
Ar
TFA, CH2Cl2
N
N
7b-11b
SEM
Entry Arylhistidine Time (h) Yielda (%) Product
Ar
1
2
7a
7b
2.5
1.5
99
97
12
12
3
4
8a
8b
1.5
1.5
70
91
13
13
OMe
5
6
9a
9b
3.5
1.5
90
91
14
14
OMe
7
8
10a
10b
2.5
3.5
90
92
15
15
N
9
10
11a
11b
2.0
2.0
99
99
16
16
S
a
Gradient elution with hexane/EtOAc from 2:1 to 0:1 af-
forded 3b as a yellow oil (122 mg, 62%). Rf (EtOAc/NH3,
Isolated yields after chromatography.
1
98:2) 0.30; H NMR (200 MHz, CDCl3) d 2.15 (s, 3H,
with hexane/EtOAc/NH3 (83:16:1) afforded 2a as a yellow
solid (162 mg, 27%). Rf (EtOAc/NH3, 99:1) 0.60; IR
CH3), 4.93 (s, 2H, CH2), 6.86–6.91 (m, 2H, o0-CHarom),
7.09–7.31 (m, 5H, o-, m- and p-CHarom), 7.33–7.48 (m,
3H, m0- and p0-CHarom), 7.42 (s, 1H, CH-2imid); MS (ESI)
m/z (%) 249.2 (100) [M+H]+.
(neat) 2920, 1552, 1485, 1438, 1221, 735 cmꢁ1; H NMR
1
(200 MHz, CDCl3) d 2.11 (s, 3H, CH3), 5.09 (s, 2H, CH2),
7.09–7.13 (m, 2H, o-CHarom), 7.31–7.41 (m, 3H, m- and p-
CHarom), 7.44 (s, 1H, CH-2imid); 13C NMR (50 MHz,
CDCl3) d 8.96 (CH3), 49.60 (CH2), 114.55 (C-4imid),
125.25 (C-5imid), 126.68 (2ꢂo-CHarom), 128.23 (p-CHarom),
129.04 (2ꢂm-CHarom), 135.30 (Carom), 135.98 (CH-2imid);
MS (ESI) m/z (%) 250.9 (100) [M+H]+, 253.0 (96).
4.1.3. 4(5)-Methyl-5(4)-phenylimidazole (4). To a 100 mL
two-necked flask cooled to ꢁ78 ꢀC were added freshly cut
sodium metal (211 mg, 9.2 mmol) and liquid ammonia
(50 mL). When the solution became blue in color
(20 min), t-BuOH (440 mL, 4.6 mmol) in anhydrous THF
(8 mL) was added followed by a mixture of 3a and 3b
(669 mg, 2.69 mmol) in anhydrous THF (25 mL). The reac-
tion mixture was stirred at ꢁ78 ꢀC for 45 min; by then, all
the blue color had disappeared. Ammonia was evaporated
by replacing the cooling bath with a water bath (20–
30 ꢀC). The reaction mixture was then quenched with aque-
ous NH4Cl (2 mL) and extracted with EtOAc (25 mL). The
organic layer was dried over anhydrous magnesium sulfate
and the solvent was removed giving a residue, which was pu-
rified by column chromatography. Gradient elution with
hexane/EtOAc from 1:2 to 1:8 afforded 4 as a white solid
(286 mg, 68%). Rf (EtOAc/NH3, 98:2) 0.18; mp 186–
Elution with hexane/EtOAc/NH3 (79:20:1) afforded 2b as
a white solid (198 mg, 33%). Rf (EtOAc/NH3, 99:1) 0.50;
IR (neat) 2923, 1564, 1494, 1429, 1231, 723 cmꢁ1 1H
;
NMR (200 MHz, CDCl3) d 2.26 (s, 3H, CH3), 5.11 (s, 2H,
CH2), 7.15–7.20 (m, 2H, o-CHarom), 7.35–7.40 (m, 3H, m-
and p-CHarom), 7.55 (s, 1H, CH-2imid); 13C NMR (50 MHz,
CDCl3) d 13.15 (CH3), 49.82 (CH2), 100.89 (C-5imid),
127.16 (2ꢂo-CHarom), 128.15 (p-CHarom), 128.92 (2ꢂ
m-CHarom), 135.65 (Carom), 136.91 (CH-2imid), 137.20 (C-
4imid); MS (ESI) m/z (%) 250.9 (100) [M+H]+, 253.0 (96).
4.1.2. 1-Benzyl-5-methyl-4-phenylimidazole (3a) and
1-benzyl-4-methyl-5-phenylimidazole (3b). Method A. A
mixture of 2a and 2b (1:1.2) (966 mg, 3.8 mmol) and
Pd(PPh3)4 (225 mg, 5 mol %) was dissolved in degassed tol-
uene (9.3 mL). A degassed solution of phenylboronic acid
(534 mg, 4.2 mmol) in absolute ethanol (5.4 mL) and aque-
ous 2 M Na2CO3 (9.3 mL, 19 mmol) were added to the
above mixture. The reaction was heated at 110 ꢀC for
188 ꢀC; IR (neat) 1599, 1519, 1472, 952, 768, 699 cmꢁ1
;
1H NMR (200 MHz, DMSO-d6) d 2.47 (s, 3H, CH3), 7.30
(t, J¼7.4 Hz, 1H, p-CHarom), 7.48 (t, J¼7.4 Hz, 2H,
m-CHarom), 7.67 (s, 1H, CH-2imid), 7.71 (d, J¼7.4 Hz, 2H,
o-CHarom); 13C NMR (50 MHz, DMSO-d6) d 11.95 (CH3),
124.93 (C-5imid), 125.49 (p-CHarom), 125.77 (2ꢂo-CHarom),
128.30 (2ꢂm-CHarom), 132.34 (Carom), 133.68 (CH-2imid),
134.58 (C-4imid); MS (ESI) m/z (%) 159.1 (100) [M+H]+;

V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
10449
HRMS (ESI) m/z calcd for C10H11N2 [M+H]+ 159.091675,
found 159.091571.
[M+H]+. Anal. Calcd for C9H12BrN3O3: C, 37.26; H, 4.17;
N, 14.48. Found: C, 36.95; H, 4.53; N, 14.24.
4.2. Synthesis of 5-arylhistidines
4.2.2. Methyl N(a)-acetyl-5-bromo-N(p)-[2-(trimethylsi-
lyl)ethoxymethyl]-L-histidinate (6a) and methyl N(a)-
acetyl-5-bromo-N(t)-[2-(trimethylsilyl)ethoxymethyl]-L-
histidinate (6b). DBU (0.2 mL, 1.4 mmol) was added to
a solution of 5 (272 mg, 0.9 mmol) in dry DMF (1.8 mL)
at 0 ꢀC. The reaction mixture was stirred at this temperature
under N2 for 1.5 h. After this time, 2-(trimethylsilyl)ethoxy-
methyl chloride was added (0.2 mL, 0.9 mmol) and the reac-
tion mixture was stirred at 0 ꢀC under N2 for 1.5 h. Next the
crude product was poured into a mixture of water–ice
(150 mL) and the product was extracted with toluene/EtOAc
(1:1, 40 mL). The organic layer was washed with brine
(40 mL) and dried over anhydrous magnesium sulfate. Re-
moval of the solvent afforded an oil, which was purified
by column chromatography. Elution with hexane/EtOAc
(1:2) gave 6a as a colorless oil (96 mg, 24%). Rf (EtOAc/
MeOH, 5:1) 0.52; IR (neat) 2952, 1743, 1663, 1544, 1436,
4.2.1. Methyl N(a)-acetyl-5-bromo-L-histidinate (5) and
methyl N(a)-acetyl-2,5-dibromo-L-histidinate. Ac-His-
OH$H2O (5.5 g, 25.4 mmol) was added to a mixture of an-
hydrous methanol (51 mL) and thionyl chloride (3.5 mL,
48.2 mmol). The reaction mixture was stirred at room tem-
perature under N2 for 2 h. The solvent was then removed
in vacuo, H2O (40 mL) was added followed by the addition
of NaHCO3 until pH¼4–5. The solvent was removed afford-
ing a residue, which was purified by column chromato-
graphy. Elution with EtOAc/MeOH/NH3 (10:2:0.2) gave
methyl N(a)-acetyl-L-histidinate as a white solid (4.8 g,
90%). Rf (CHCl3/MeOH/HOAc, 5:3:1) 0.49; IR (neat)
3269, 3199, 1738, 1650, 1541, 1435, 1374, 1211,
1
1175 cmꢁ1; H NMR (200 MHz, DMSO-d6) d 1.92 (s, 3H,
CH3CO), 2.91 (dd, J¼8.0 and 14.6 Hz, 1H, CH2-b), 3.01
(dd, J¼5.8 and 14.6 Hz, 1H, CH2-b), 3.68 (s, 3H,
CO2CH3), 4.55 (ddd, J¼5.8, 8.0, and 7.4 Hz, 1H, CH-a),
6.89 (s, 1H, CH-5imid), 7.62 (s, 1H, CH-2imid), 8.31 (d,
J¼7.4 Hz, 1H, CONH); 13C NMR (50 MHz, DMSO-d6)
d 22.26 (CH3CO), 26.83 (CH2-b), 51.87 (CO2CH3), 52.03
(CH-a), 116.97 (CH-5imid), 130.47 (C-4imid), 134.06 (CH-
2imid), 169.60 (CONH), 171.52 (COO); MS (ESI) m/z (%)
212.2 (47) [M+H]+.
1
1371, 1235, 1207, 1086, 834 cmꢁ1; H NMR (200 MHz,
CDCl3) d 0.03 (s, 9H, (CH3)3Si), 0.93–1.02 (m, 2H, CH2Si),
2.00 (s, 3H, CH3CO), 3.09 (dd, J¼7.6 and 15.2 Hz, 1H, CH2-
b), 3.18 (dd, J¼6.8 and 15.2 Hz, 1H, CH2-b), 3.41–3.67 (m,
2H, CH2O), 3.78 (s, 3H, CO2CH3), 4.82–4.93 (m, 1H, CH-
a), 5.30 (d, J¼11.0 Hz, 1H, NCH2O), 5.43 (d, J¼11.0 Hz,
1H, NCH2O), 6.34 (d, J¼7.8 Hz, 1H, CONH), 7.49 (s,
1H, CH-2imid); 13C NMR (50 MHz, CDCl3) d ꢁ1.51
((CH3)3Si), 17.62 (CH2Si), 22.99 (CH3CO), 26.69 (CH2-
b), 51.35 (CO2CH3), 52.82 (CH-a), 66.49 (CH2O), 74.91
(NCH2O), 117.72 (C-5imid), 124.26 (C-4imid), 137.26 (CH-
2imid), 169.68 (CONH), 171.56 (COO); MS (ESI) m/z (%)
419.9 (91), 421.9 (100) [M+H]+. Anal. Calcd for
C15H26BrN3O4Si: C, 42.86; H, 6.23; N, 10.00. Found: C,
42.76; H, 6.60; N, 10.34.
N-Bromosuccinimide (4.4 g, 23.9 mmol) was added to a
solution of methyl N(a)-acetyl-L-histidinate (4.6 g,
21.8 mmol) in dry acetonitrile (125 mL) at 0 ꢀC. The reac-
tion mixture was stirred for 15 min at this temperature under
N2. Then, pyridine (40 mL) was added and the mixture was
concentrated in vacuo. Triethylamine (0.4 mL) was added
to the concentrated solution. Removal of the solvent gave
a residue, which was purified by column chromatography.
Elution with EtOAc/MeOH (99:1) gave methyl N(a)-
acetyl-2,5-dibromo-L-histidinate as a white solid (1.1 g,
13%). Rf (EtOAc/MeOH, 5:1) 0.70; mp 144–146 ꢀC; IR
(neat) 3064, 2969, 1701, 1644, 1535, 1431, 1371, 1177,
Elution with EtOAc/MeOH (99:1) afforded 6b as a colorless
oil (192 mg, 49%). Rf (EtOAc/MeOH, 5:1) 0.41; IR (neat)
2952, 1744, 1665, 1529, 1436, 1373, 1248, 1211, 1103,
835 cmꢁ1 1H NMR (200 MHz, CDCl3) d 0.01 (s, 9H,
;
(CH3)3Si), 0.93 (t, J¼8.0 Hz, 2H, CH2Si), 2.05 (s, 3H,
CH3CO), 3.00 (dd, J¼4.8 and 14.8 Hz, 1H, CH2-b), 3.16
(dd, J¼4.8 and 14.8 Hz, 1H, CH2-b), 3.54 (t, J¼8.0 Hz,
2H, CH2O), 3.72 (s, 3H, CO2CH3), 4.88 (dt, J¼4.8 and
8.0 Hz, 1H, CH-a), 5.26 (s, 2H, NCH2O), 7.02 (d,
J¼8.0 Hz, 1H, CONH), 7.65 (s, 1H, CH-2imid); 13C NMR
(50 MHz, CDCl3) d ꢁ1.38 ((CH3)3Si), 17.61 (CH2Si),
23.14 (CH3CO), 28.66 (CH2-b), 51.51 (CO2CH3), 52.25
(CH-a), 66.52 (CH2O), 74.78 (NCH2O), 102.11 (C-5imid),
136.51 (C-4imid), 138.08 (CH-2imid), 169.84 (CONH),
171.67 (COO); MS (ESI) m/z (%) 420.1 (100), 422.1 (87)
[M+H]+; HRMS (ESI) m/z calcd for C15H26BrN3NaO4Si
[M]+ 442.0774, 444.0753, found 442.0777, 444.0757.
971 cmꢁ1 1H NMR (200 MHz, CDCl3) d 2.13 (s, 3H,
;
CH3CO), 3.06 (dd, J¼6.6 and 15.4 Hz, 1H, CH2-b), 3.19
(dd, J¼6.4 and 15.4 Hz, 1H, CH2-b), 3.81 (s, 3H,
CO2CH3), 4.81–4.91 (m, 1H, CH-a), 6.56 (d, J¼7.8 Hz,
1H, CONH); 13C NMR (50 MHz, CDCl3) d 23.11
(CH3CO), 27.87 (CH2-b), 51.61 (CO2CH3), 53.01 (CH-a),
114.39 (C-5imid), 115.29 (C-2imid), 126.81 (C-4imid),
171.29 (CONH), 171.34 (COO); MS (ESI) m/z (%) 367.9
(59), 369.9 (100), 372.0 (44) [M+H]+.
Elution with EtOAc/MeOH/NH3 (90:9:1) afforded 5 as
a white solid (3.8 g, 60%). Rf (EtOAc/MeOH, 5:1) 0.18;
mp 165–167 ꢀC; IR (neat) 3321, 3277, 1730, 1661, 1544,
1434, 1371, 1177, 961 cmꢁ1; 1H NMR (200 MHz, DMSO-
d6) d 1.93 (s, 3H, CH3CO), 2.95 (dd, J¼7.4 and 14.8 Hz,
1H, CH2-b), 3.06 (dd, J¼7.4 and 14.8 Hz, 1H, CH2-b),
3.67 (s, 3H, CO2CH3), 4.52 (q, J¼7.4 Hz, 1H, CH-a), 7.66
(s, 1H, CH-2imid), 8.39 (d, J¼7.4 Hz, 1H, CONH); 13C
NMR (50 MHz, DMSO-d6) d 22.30 (CH3CO), 29.04
(CH2-b), 51.70 (CO2CH3), 52.45 (CH-a), 116.52 (C-5imid),
133.21 (C-4imid), 134.34 (CH-2imid), 169.28 (CONH),
172.24 (COO); MS (ESI) m/z (%) 290.0 (100), 291.9 (96)
4.2.3. General method for the arylation of histidines 6a
and 6b under microwave irradiation. A 30-mL vial con-
taining a magnetic stir bar was charged with a solution of
6a or 6b (1 mmol), Pd2(dba)3, and P(o-tolyl)3 in degassed
toluene (15 mL). Then, a degassed solution of the corre-
sponding arylboronic acid (2.1 mmol) in MeOH (10 mL)
and aqueous 2 M KF (2 mmol) were added. The vial was
sealed and heated under N2 in the microwave lab station.
Firstly, a microwave ramp (300 W maximum) was applied

10450
V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
for 7 min to reach 110 ꢀC. The reaction mixture was ir-
radiated at this temperature for periods of 10 or 15 min.
After the total reaction time, upon cooling, the solvent was
evaporated and the residue dissolved in EtOAc (50 mL).
The organic solution was washed with water (50 mL) and
brine (50 mL), dried over anhydrous magnesium sulfate,
and concentrated in vacuo. Products were isolated by
column chromatography.
(0.09 mmol), and 2-methoxy-5-methylphenylboronic acid,
after 1 h irradiation, elution with hexane/EtOAc (3:7) af-
forded 8a (45 mg, 54%) as a colorless oil. Rf (EtOAc/
MeOH, 10:1) 0.38; IR (neat) 2952, 1744, 1666, 1509,
1
1243, 1208, 1179, 1085, 1030, 858, 835 cmꢁ1; H NMR
(200 MHz, CDCl3) d ꢁ0.03 (s, 9H, (CH3)3Si), 0.95–1.03
(m, 2H, CH2Si), 1.74 (s, 3H, CH3CO), 2.33 (s, 3H, CH3),
3.19 (dd, J¼8.8 and 15.3 Hz, 1H, CH2-b), 3.32 (dd, J¼5.6
and 15.3 Hz, 1H, CH2-b), 3.55–3.63 (m, 2H, CH2O), 3.60
(s, 3H, CO2CH3), 3.83 (s, 3H, OCH3), 4.66–4.74 (m, 1H,
CH-a), 5.32 (s, 2H, NCH2O), 6.07 (d, J¼7.4 Hz, 1H,
CONH), 6.89 (d, J¼8.3 Hz, 1H, CH-3arom), 7.15 (dd,
J¼2.1 and 8.3 Hz, 1H, CH-4arom), 7.32 (d, J¼2.1 Hz, 1H,
CH-6arom), 7.63 (s, 1H, CH-2imid); 13C NMR (50 MHz,
CDCl3) d ꢁ1.50 ((CH3)3Si), 17.60 (CH2Si), 20.26 (CH3),
22.58 (CH3CO), 25.98 (CH2-b), 51.56 (CO2CH3), 52.20
(CH-a), 55.61 (OCH3), 66.20 (CH2O), 74.34 (NCH2O),
111.39 (CH-3arom), 123.46 (C-5imid), 123.63 (C-1arom), 129.44
(CH-6arom), 130.24 (C-5arom), 132.56 (CH-4arom), 137.85
(CH-2imid), 138.40 (C-4imid), 153.86 (C-2arom), 169.59
(CONH), 171.92 (COO); HRMS (ESI) m/z calcd for
C23H36N3O5Si [M]+ 462.241874, found 462.239847.
4.2.3.1. Methyl N(a)-acetyl-5-phenyl-N(p)-[2-(tri-
methylsilyl)ethoxymethyl]-L-histidinate (7a). From 6a
(100 mg, 0.24 mmol) following the general procedure using
Pd2(dba)3 (10 mol %), P(o-tolyl)3 (0.12 mmol), and phenyl-
boronic acid, after 15 min irradiation, elution with hexane/
EtOAc (1:1) afforded 7a (82 mg, 82%) as a colorless oil.
Rf (EtOAc/MeOH, 5:1) 0.48; IR (neat) 2952, 1742, 1662,
1
1504, 1438, 1367, 1248, 1200, 1081, 858, 835 cmꢁ1; H
NMR (200 MHz, CDCl3) d ꢁ0.06 (s, 9H, (CH3)3Si), 0.85–
0.94 (m, 2H, CH2Si), 1.66 (s, 3H, CH3CO), 3.33 (d,
J¼7.0 Hz, 2H, CH2-b), 3.44 (s, 3H, CO2CH3), 3.46–3.55
(m, 2H, CH2O), 4.70 (dt, J¼7.0 and 7.8 Hz, 1H, CH-a),
5.27 (s, 2H, NCH2O), 5.96 (d, J¼7.8 Hz, 1H, CONH), 7.21
(tt, J¼2.4 and 7.2 Hz, 1H, p-CHarom), 7.33 (td, J¼1.4 and
7.2 Hz, 2H, m-CHarom), 7.52 (s, 1H, CH-2imid), 7.55 (dt,
J¼2.4 and 7.2 Hz, 2H, o-CHarom); 13C NMR (50 MHz,
CDCl3) d ꢁ1.48 ((CH3)3Si), 17.65 (CH2Si), 22.70 (CH3CO),
26.38 (CH2-b), 51.83 (CO2CH3), 52.42 (CH-a), 66.24
(CH2O), 74.24 (NCH2O), 122.05 (C-5imid), 127.07 (p-
CHarom), 127.38 (2ꢂo-CHarom), 128.64 (2ꢂm-CHarom),
134.81 (Carom), 137.83 (CH-2imid), 141.29 (C-4imid), 169.61
(CONH), 171.70 (COO); HRMS (ESI) m/z calcd for
C21H32N3O4Si [M]+ 418.2157, found 418.2144; calcd for
C21H31N3NaO4Si [M]+ 440.1976, found 440.1958.
4.2.3.4. Methyl N(a)-acetyl-5-(2-methoxy-5-methyl-
phenyl)-N(t)-[2-(trimethylsilyl)ethoxymethyl]-L-histidi-
nate (8b). From 6b (75 mg, 0.18 mmol) following the
general procedure using Pd2(dba)3 (10 mol %), P(o-tolyl)3
(0.09 mmol), and 2-methoxy-5-methylphenylboronic acid,
after 1 h irradiation, elution with hexane/EtOAc (3:7) af-
forded 8b (30 mg, 36%) as a yellow oil. Rf (EtOAc/
MeOH, 10:1) 0.25; IR (neat) 2951, 1745, 1671, 1500,
1
1246, 1208, 1169, 1088, 1025, 858, 835 cmꢁ1; H NMR
(200 MHz, CDCl3) d ꢁ0.05 (s, 9H, (CH3)3Si), 0.74–0.82
(m, 2H, CH2Si), 2.02 (s, 1.5H, CH3CO), 2.04 (s, 1.5H,
CH3CO), 2.35 (s, 3H, CH3), 2.86–3.02 (m, 2H, CH2-b),
3.24–3.32 (m, 2H, CH2O), 3.51 (s, 1.5H, CO2CH3), 3.65
(s, 1.5H, CO2CH3), 3.78 (s, 3H, OCH3), 4.69–4.77 (m, 1H,
CH-a), 4.96–5.27 (m, 2H, NCH2O), 6.90 (d, J¼8.6 Hz,
1H, CH-3arom), 6.99 (d, J¼2.1 Hz, 1H, CH-6arom), 7.24
(dd, J¼2.1 and 8.6 Hz, 1H, CH-4arom), 7.32 (d, J¼7.0 Hz,
0.5H, CONH), 7.41 (d, J¼7.0 Hz, 0.5H, CONH), 7.66 (s,
1H, CH-2imid); 13C NMR (50 MHz, CDCl3) d ꢁ1.57
((CH3)3Si), 17.65 (CH2Si), 20.35 (CH3), 23.09 (CH3CO),
28.37 (CH2-b), (51.77, 52.31) (CO2CH3), 51.98 (CH-a),
55.48 (OCH3), 66.17 (CH2O), (74.38, 74.67) (NCH2O),
111.02 (CH-3arom), 117.23 (C-1arom), 126.53 (C-5arom),
(130.02, 130.25) (C-5imid), 130.99 (CH-6arom), 133.16
(CH-4arom), (135.01, 135.18) (C-4imid), 137.12 (CH-2imid),
155.33 (C-2arom), 169.92 (CONH), (171.91, 172.10)
(COO); HRMS (ESI) m/z calcd for C23H36N3O5Si [M]+
462.2419, found 462.2406; calcd for C23H35N3NaO5Si
[M]+ 484.2238, found 484.2211.
4.2.3.2. Methyl N(a)-acetyl-5-phenyl-N(t)-[2-(tri-
methylsilyl)ethoxymethyl]-L-histidinate (7b). From 6b
(75 mg, 0.18 mmol) following the general procedure using
Pd2(dba)3 (10 mol %), P(o-tolyl)3 (0.09 mmol), and phenyl-
boronic acid, after 10 min irradiation, gradient elution with
hexane/EtOAc from 3:7 to 0:1 afforded 7b (46 mg, 62%)
as a yellow oil. Rf (EtOAc/MeOH, 10:1) 0.45; IR (neat)
2952, 1742, 1667, 1526, 1493, 1371, 1247, 1205, 1174,
1085, 858, 835 cmꢁ1
;
1H NMR (200 MHz, CDCl3)
d ꢁ0.01 (s, 9H, (CH3)3Si), 0.83–0.91 (m, 2H, CH2Si), 2.04
(s, 3H, CH3CO), 3.02 (dd, J¼5.0 and 14.8 Hz, 1H, CH2-
b), 3.18 (dd, J¼5.0 and 14.8 Hz, 1H, CH2-b), 3.39–3.48
(m, 2H, CH2O), 3.55 (s, 3H, CO2CH3), 4.78 (dt, J¼5.0
and 7.6 Hz, 1H, CH-a), 5.14 (s, 2H, NCH2O), 7.34–7.39
(m, 2H, o-CHarom), 7.44–7.54 (m, 3H, m- and p-CHarom),
7.65 (s, 1H, CH-2imid); 13C NMR (50 MHz, CDCl3)
d ꢁ1.49 ((CH3)3Si), 17.69 (CH2Si), 23.16 (CH3CO), 28.23
(CH2-b), 51.95 (CO2CH3), 52.10 (CH-a), 66.31 (CH2O),
74.02 (NCH2O), 77.21 (C-5imid), 128.53 (p-CHarom),
128.74 (2ꢂo-CHarom), 130.26 (2ꢂm-CHarom), 135.06
(Carom), 135.18 (C-4imid), 137.26 (CH-2imid), 170.00
(CONH), 171.90 (COO); MS (ESI) m/z (%) 418.0 (100)
[M+H]+; HRMS (ESI) m/z calcd for C21H32N3O4Si [M]+
418.215659, found 418.215322.
4.2.3.5. Methyl N(a)-acetyl-5-(2-methoxyphenyl)-
N(p)-[2-(trimethylsilyl)ethoxymethyl]-L-histidinate (9a).
From 6a (75 mg, 0.18 mmol) following the general proce-
dure using Pd2(dba)3 (20 mol %), P(o-tolyl)3 (0.18 mmol),
and 2-methoxyphenylboronic acid, after 1 h irradiation, elu-
tion with hexane/EtOAc (3:7) afforded 9a (54 mg, 68%) as
a colorless oil. Rf (EtOAc/MeOH, 10:1) 0.30; IR (neat)
2951, 1740, 1663, 1503, 1435, 1370, 1243, 1202, 1086,
4.2.3.3. Methyl N(a)-acetyl-5-(2-methoxy-5-methyl-
phenyl)-N(p)-[2-(trimethylsilyl)ethoxymethyl]-L-histidi-
nate (8a). From 6a (75 mg, 0.18 mmol) following the
general procedure using Pd2(dba)3 (10 mol %), P(o-tolyl)3
1
1025, 858, 836 cmꢁ1; H NMR (200 MHz, CDCl3) d 0.04
(s, 9H, (CH3)3Si), 0.95–1.03 (m, 2H, CH2Si), 1.74 (s, 3H,

V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
10451
CH3CO), 3.24 (dd, J¼7.0 and 15.6 Hz, 1H, CH2-b), 3.36
(dd, J¼5.8 and 15.6 Hz, 1H, CH2-b), 3.55–3.64 (m, 2H,
CH2O), 3.57 (s, 3H, CO2CH3), 3.86 (s, 3H, OCH3), 4.67–
4.77 (m, 1H, CH-a), 5.33 (s, 2H, NCH2O), 6.06 (d,
J¼7.2 Hz, 1H, CONH), 7.00 (dd, J¼0.9 and 7.6 Hz, 1H,
CH-3arom), 7.08 (td, J¼0.9 and 7.6 Hz, 1H, CH-5arom),
7.37 (td, J¼1.7 and 7.6 Hz, 1H, CH-4arom), 7.50 (dd,
J¼1.7 and 7.6 Hz, 1H, CH-6arom), 7.65 (s, 1H, CH-2imid);
13C NMR (50 MHz, CDCl3) d ꢁ1.49 ((CH3)3Si), 17.61
(CH2Si), 22.66 (CH3CO), 26.03 (CH2-b), 51.54
(CO2CH3), 52.25 (CH-a), 55.47 (OCH3), 66.24 (CH2O),
74.35 (NCH2O), 111.30 (CH-3arom), 121.05 (CH-5arom),
123.68 (C-5imid), 123.72 (C-1arom), 129.13 (CH-6arom),
132.03 (CH-4arom), 137.91 (CH-2imid), 138.23 (C-4imid),
156.01 (C-2arom), 169.64 (CONH), 171.88 (COO); HRMS
(ESI) m/z calcd for C22H34N3O5Si [M]+ 448.2262, found
448.2257.
(C-5imid, CH-5Py), 130.73 (C-3Py), 134.78 (CH-4Py), 137.96
(C-4imid), 138.39 (CH-2imid), 147.80 (CH-6Py), 148.00 (CH-
2Py), 169.68 (CONH), 171.47 (COO); HRMS (ESI) m/z
calcd for C20H31N4O4Si [M]+ 419.2109, found 419.2092;
calcd for C20H30N4NaO4Si [M]+ 441.1929, found 441.1902.
4.2.3.8. Methyl N(a)-acetyl-5-(3-pyridyl)-N(t)-[2-(tri-
methylsilyl)ethoxymethyl]-L-histidinate (10b). From 6b
(75 mg, 0.18 mmol) following the general procedure using
Pd2(dba)3 (40 mol %), P(o-tolyl)3 (0.36 mmol), and 3-pyri-
dylboronic acid, after 10 min irradiation, elution with
EtOAc/MeOH/NH3 (96:3:1) afforded 10b (25 mg, 33%) as
a yellow oil. Rf (EtOAc/MeOH, 5:1) 0.20; IR (neat) 2952,
1744, 1667, 1494, 1248, 1207, 1174, 1086, 858, 836 cmꢁ1
;
1H NMR (200 MHz, CDCl3) d 0.01 (s, 9H, (CH3)3Si),
0.86–0.94 (m, 2H, CH2Si), 2.05 (s, 3H, CH3CO), 3.01 (dd,
J¼5.0 and 15.0 Hz, 1H, CH2-b), 3.17 (dd, J¼5.0 and
15.0 Hz, 1H, CH2-b), 3.45–3.53 (m, 2H, CH2O), 3.58 (s,
3H, CO2CH3), 4.82 (dt, J¼5.0 and 7.8 Hz, 1H, CH-a),
5.13 (s, 2H, NCH2O), 7.44 (dd, J¼5.0 and 7.8 Hz, 1H,
CH-5Py), 7.46 (d, J¼7.8 Hz, 1H, CONH), 7.67 (s, 1H, CH-
2imid), 7.77 (dt, J¼2.0 and 7.8 Hz, 1H, CH-4Py), 8.63 (d,
J¼2.0 Hz, 1H, CH-2Py), 8.69 (dd, J¼2.0 and 5.0 Hz, 1H,
CH-6Py); 13C NMR (50 MHz, CDCl3) d ꢁ0.85 ((CH3)3Si),
18.34 (CH2Si), 23.80 (CH3CO), 28.89 (CH2-b), 52.56
(CO2CH3), 52.72 (CH-a), 67.07 (CH2O), 74.82 (NCH2O),
124.10 (CH-5Py), 125.74 (C-5imid), 127.46 (C-3Py), 137.40
(C-4imid), 138.24 (CH-4Py), 138.62 (CH-2imid), 150.28
(CH-6Py), 151.36 (CH-2Py), 170.62 (CONH), 172.43
(COO); HRMS (ESI) m/z calcd for C20H31N4O4Si [M]+
419.2109, found 419.2096; calcd for C20H30N4NaO4Si
[M]+ 441.1929, found 441.1915.
4.2.3.6. Methyl N(a)-acetyl-5-(2-methoxyphenyl)-
N(t)-[2-(trimethylsilyl)ethoxymethyl]-L-histidinate (9b).
From 6b (75 mg, 0.18 mmol) following the general proce-
dure using Pd2(dba)3 (40 mol %), P(o-tolyl)3 (0.36 mmol),
and 2-methoxyphenylboronic acid, after 10 min irradiation,
elution with hexane/EtOAc (4:6) afforded 9b (41 mg, 51%)
as a yellow oil. Rf (EtOAc/MeOH, 5:1) 0.33; IR (neat) 2952,
1745, 1668, 1526, 1493, 1435, 1247, 1207, 1173, 1088,
1023, 858, 836 cmꢁ1
;
1H NMR (200 MHz, CDCl3)
d ꢁ0.05 (s, 9H, (CH3)3Si), 0.73–0.81 (m, 2H, CH2Si), 2.01
(s, 3H, CH3CO), 2.89–3.15 (m, 2H, CH2-b), 3.24–3.33 (m,
2H, CH2O), 3.50 (s, 1.5H, CO2CH3), 3.63 (s, 1.5H,
CO2CH3), 3.82 (s, 3H, OCH3), 4.68–4.77 (m, 1H, CH-a),
4.97–5.33 (m, 2H, NCH2O), 7.00–7.10 (m, 2H, CH-3arom
and CH-5arom), 7.18 (br, 1H, CONH), 7.41–7.50 (m, 2H,
CH-4arom and CH-6arom), 7.67 (s, 1H, CH-2imid); 13C NMR
(50 MHz, CDCl3) d ꢁ1.57 ((CH3)3Si), 17.60 (CH2Si),
23.07 (CH3CO), 28.31 (CH2-b), (51.52, 52.27) (CO2CH3),
51.95 (CH-a), 55.34 (OCH3), 66.13 (CH2O), (74.35, 74.65)
(NCH2O), 111.03 (CH-3arom), 117.50 (C-1arom), (120.79,
121.00) (CH-5arom), (126.34, 126.57) (C-5imid), 130.63
(CH-6arom), 132.68 (CH-4arom), (135.10, 135.32) (C-4imid),
137.13 (CH-2imid), (157.18, 157.39) (C-2arom), 169.95
(CONH), (171.89, 172.05) (COO); HRMS (ESI) m/z calcd
for C22H34N3O5Si [M]+ 448.226224, found 448.224059.
4.2.3.9. Methyl N(a)-acetyl-5-(3-thienyl)-N(p)-[2-(tri-
methylsilyl)ethoxymethyl]-L-histidinate (11a). From 6a
(75 mg, 0.18 mmol) following the general procedure using
Pd2(dba)3 (20 mol %), P(o-tolyl)3 (0.18 mmol), and 3-thi-
enylboronic acid, after 15 min irradiation, elution with hex-
ane/EtOAc (4:6) afforded 11a (64 mg, 85%) as a yellow oil.
Rf (EtOAc/MeOH, 10:1) 0.33; IR (neat) 2952, 1742, 1660,
1248, 1199, 1083, 857, 835 cmꢁ1 1H NMR (200 MHz,
;
CDCl3) d 0.02 (s, 9H, (CH3)3Si), 0.93–1.01 (m, 2H,
CH2Si), 1.82 (s, 3H, CH3CO), 3.37 (d, J¼7.4 Hz, 2H,
CH2-b), 3.54–3.62 (m, 2H, CH2O), 3.58 (s, 3H, CO2CH3),
4.84 (q, J¼7.4 Hz, 1H, CH-a), 5.35 (s, 2H, NCH2O), 6.41
(d, J¼7.4 Hz, 1H, CONH), 7.37 (dd, J¼2.8 and 5.1 Hz,
1H, CH-5thien), 7.45 (dd, J¼1.4 and 5.1 Hz, 1H, CH-4thien),
7.54 (dd, J¼1.4 and 2.8 Hz, 1H, CH-2thien), 7.68 (s, 1H, CH-
2imid); 13C NMR (50 MHz, CDCl3) d ꢁ1.55 ((CH3)3Si),
17.61 (CH2Si), 22.64 (CH3CO), 26.52 (CH2-b), 51.66
(CO2CH3), 52.45 (CH2-a), 66.33 (CH2O), 74.29
(NCH2O), 120.96 (CH-2thien), 121.83 (C-5imid), 125.90
(CH-5thien), 126.53 (CH-4thien), 134.87 (C-3thien), 136.61
(C-4imid), 137.40 (CH-2imid), 169.78 (CONH), 171.73
(COO); HRMS (ESI) m/z calcd for C19H30N3O4SSi [M]+
424.1721, found 424.1709.
4.2.3.7. Methyl N(a)-acetyl-5-(3-pyridyl)-N(p)-[2-(tri-
methylsilyl)ethoxymethyl]-L-histidinate (10a). From 6a
(116 mg, 0.28 mmol) following the general procedure using
Pd2(dba)3 (40 mol %), P(o-tolyl)3 (0.56 mmol), and 3-pyri-
dylboronic acid, after 10 min irradiation, gradient elution
with EtOAc/MeOH from 95:5 to 92:8 afforded 10a
(46 mg, 40%) as a colorless oil. Rf (EtOAc/MeOH, 5:1)
0.18; IR (neat) 2952, 1743, 1665, 1368, 1249, 1083, 858,
835 cmꢁ1 1H NMR (200 MHz, CDCl3) d 0.03 (s, 9H,
;
(CH3)3Si), 0.95–1.03 (m, 2H, CH2Si), 1.82 (s, 3H, CH3CO),
3.38–3.42 (m, 2H, CH2-b), 3.53 (s, 3H, CO2CH3), 3.56–3.65
(m, 2H, CH2O), 4.79–4.90 (m, 1H, CH-a), 5.32 (d, J¼
11.0 Hz, 1H, NCH2O), 5.41 (d, J¼11.0 Hz, 1H, NCH2O),
6.43 (d, J¼7.8 Hz, 1H, CONH), 7.34 (bb, 1H, CH-5Py), 7.66
(s, 1H, CH-2imid), 8.01 (d, J¼8.0 Hz, 1H, CH-4Py), 8.53
(bb, 1H, CH-6Py), 8.91 (bb, 1H, CH-2Py); 13C NMR
(50 MHz, CDCl3) d ꢁ1.50 ((CH3)3Si), 17.65 (CH2Si),
22.72 (CH3CO), 26.75 (CH2-b), 51.59 (CO2CH3),
52.48 (CH-a), 66.39 (CH2O), 74.37 (NCH2O), 123.36
4.2.3.10. Methyl N(a)-acetyl-5-(3-thienyl)-N(t)-[2-
(trimethylsilyl)ethoxymethyl]-L-histidinate (11b). From
6b (75 mg, 0.18 mmol) following the general procedure
using Pd2(dba)3 (20 mol %), P(o-tolyl)3 (0.18 mmol), and
3-thienylboronic acid, after 30 min irradiation, elution with
hexane/EtOAc (1:2) afforded 11b (41 mg, 54%) as a yellow

10452
V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
oil. Rf (EtOAc/MeOH, 5:1) 0.35; IR (neat) 2952, 1744, 1669,
1493, 1248, 1083, 858, 836 cmꢁ1 1H NMR (200 MHz,
J¼2.0 Hz, 1H, CH-6arom), 7.45 (d, J¼7.4 Hz, 1H, NHCO),
7.59 (s, 1H, CH-2imid); 13C NMR (50 MHz, CDCl3)
d 20.38 (CH3), 22.92 (CH3CO), 28.86 (CH2-b), 51.99
(CO2CH3), 52.18 (CH-a), 55.63 (OCH3), 111.33 (CH-
3arom), 118.69 (C-1arom), 125.61 (C-5imid), 129.45
(CH-6arom), 130.29 (CH-4arom), 130.39 (C-4imid), 132.30
(C-5arom), 133.71 (CH-2imid), 153.80 (C-2arom), 170.29
(CONH), 172.08 (COO); HRMS (ESI) m/z calcd for
C17H22N3O4 [M]+ 332.1605, found 332.1591; calcd for
C17H21N3NaO4 [M]+ 354.1424, found 354.1408.
;
CDCl3) d ꢁ0.01 (s, 9H, (CH3)3Si), 0.85–0.93 (m, 2H,
CH2Si), 2.00 (s, 3H, CH3CO), 3.00 (dd, J¼5.0 and
14.8 Hz, 1H, CH2-b), 3.21 (dd, J¼5.0 and 14.8 Hz, 1H,
CH2-b), 3.44–3.52 (m, 2H, CH2O), 3.57 (s, 3H, CO2CH3),
4.79 (dt, J¼5.0 and 10.0 Hz, 1H, CH-a), 5.14 (s, 2H,
NCH2O), 7.17–7.20 (m, 1H, CH-5thien), 7.43–7.49 (m, 3H,
CH-4thien, CH-2thien, CONH), 7.60 (s, 1H, CH-2imid); 13C
NMR (50 MHz, CDCl3) d ꢁ1.56 ((CH3)3Si), 17.64
(CH2Si), 23.02 (CH3CO), 28.45 (CH2-b), 51.93 (CO2CH3),
52.02 (CH-a), 66.14 (CH2O), 73.95 (NCH2O), 125.14
(CH-2thien), 125.45 (C-5imid), 126.19 (CH-5thien), 128.44
(CH-4thien), 128.54 (C-3thien), 135.35 (C-4imid), 137.20 (CH-
2imid), 169.93 (CONH), 171.84 (COO); HRMS (ESI) m/z
calcd for C19H30N3O4SSi [M]+ 424.1721, found 424.1737;
calcd for C19H29N3NaO4SSi [M]+ 446.1540, found
424.1548.
4.2.4.3. Methyl N(a)-acetyl-5-(2-methoxyphenyl)-
L-histidinate (14). From 9a (85 mg, 0.19 mmol) following
the general procedure after 3.5 h reaction, elution with
EtOAc/MeOH (99:1) afforded 14 (54 mg, 90%) as a pale
yellow solid. From 9b (85 mg, 0.19 mmol) following the
general procedure after 1.5 h reaction, elution with EtOAc/
MeOH (99:1) afforded 14 (55 mg, 91%) as a pale yellow
solid. Rf (EtOAc/MeOH, 10:3) 0.36; mp 50–51 ꢀC; [a]D19
9.55 (c 0.22, MeOH); IR (neat) 1740, 1661, 1435, 1375,
4.2.4. General method for the removal of the SEM group.
The corresponding arylhistidines 7–11 (1 mmol) were dis-
solved in TFA/CH2Cl2 (2:1, 24 mL) and stirred at room tem-
perature. After the total reaction time (Table 2), the solvent
was evaporated. Products were isolated by column chroma-
tography.
1246, 1200, 1178, 1127, 1022, 757 cmꢁ1
;
1H NMR
(200 MHz, CDCl3) d 1.92 (s, 3H, CH3CO), 3.21 (d,
J¼6.0 Hz, 2H, CH2-b), 3.56 (s, 3H, CO2CH3), 3.84 (s, 3H,
OCH3), 4.81 (dt, J¼6.0 and 7.8 Hz, 1H, CH-a), 6.98–7.07
(m, 2H, CH-3arom and CH-5arom), 7.33–7.42 (m, 2H, CH-
4arom and CH-6arom), 7.54 (d, J¼7.8 Hz, 1H, CONH), 7.81
(s, 1H, CH-2imid); 13C NMR (50 MHz, CDCl3) d 22.72
(CH3CO), 28.00 (CH2-b), 51.99 (CO2CH3), 52.22 (CH2-
a), 55.45 (OCH3), 111.35 (CH-3arom), 117.84 (C-1arom),
121.06 (CH-5arom), 126.70 (C-5imid), 129.71 (C-4imid),
130.10 (CH-6arom), 130.30 (CH-4arom), 133.24 (CH-2imid),
156.24 (C-2arom), 170.71 (CONH), 171.68 (COO); HRMS
(ESI) m/z calcd for C16H20N3O4 [M]+ 318.1448, found
318.1435; calcd for C16H19N3NaO4 [M]+ 340.1268, found
340.1250.
4.2.4.1. Methyl N(a)-acetyl-5-phenyl-L-histidinate
(12). From 7a (81 mg, 0.19 mmol) following the general
procedure after 2.5 h reaction, elution with EtOAc/MeOH/
NH3 (98:1:1) afforded 12 (55 mg, 99%) as a colorless oil.
From 7b (108 mg, 0.26 mmol) following the general proce-
dure after 1.5 h reaction, elution with EtOAc/MeOH/NH3
(98:1:1) afforded 12 (72 mg, 97%) as a colorless oil. Rf
(EtOAc/MeOH/NH3, 98:1:1) 0.33; [a]2D0 9.74 (c 0.27,
MeOH); IR (neat) 1741, 1659, 1436, 1374, 1198, 1177,
1
1130 cmꢁ1; H NMR (200 MHz, CDCl3) d 1.95 (s, 3H,
CH3CO), 3.21 (dd, J¼5.2 and 15.4 Hz, 1H, CH2-b), 3.35
(dd, J¼5.2 and 15.4 Hz, 1H, CH2-b), 3.50 (s, 3H,
CO2CH3), 4.81 (dt, J¼5.2 and 7.8 Hz, 1H, CH-a), 7.26–
7.43 (m, 5H, CHarom), 7.53 (s, 1H, CH-2imid); 13C NMR
(50 MHz, CDCl3) d 22.06 (CH3CO), 27.56 (CH2-b), 51.14
(CO2CH3), 51.20 (CH-a), 126.14 (2ꢂo-CHarom), 126.45
(p-CHarom), 127.88 (2ꢂm-CHarom), 128.68, 129.72, 130.35
(C-4imid, C-5imid, C-1arom), 133.55 (CH-2imid), 169.43
(CONH), 170.99 (COO); HRMS (ESI) m/z calcd for
C15H18N3O3 [M]+ 288.1343, found 288.1339; calcd for
C15H17N3NaO3 [M]+ 310.11.62, found 310.1171.
4.2.4.4. Methyl N(a)-acetyl-5-(3-pyridyl)-L-histidinate
(15). From 10a (71 mg, 0.17 mmol) following the general
procedure after 2.5 h reaction, elution with EtOAc/MeOH/
NH3 (96:3:1) afforded 15 (44 mg, 90%) as a colorless oil.
From 10b (43 mg, 0.10 mmol) following the general proce-
dure after 3.5 h reaction, elution with EtOAc/MeOH/NH3
(96:3:1) afforded 15 (27 mg, 92%) as a colorless oil. Rf
(EtOAc/MeOH, 10:3) 0.1; [a]2D0 6.99 (c 0.27, MeOH); IR
1
(neat) 1740, 1658, 1199, 1177, 1130, 712 cmꢁ1; H NMR
(200 MHz, CDCl3) d 1.99 (s, 3H, CH3CO), 3.28 (dd,
J¼6.6 and 15.4 Hz, 1H, CH2-b), 3.41 (dd, J¼5.4 and
15.4 Hz, 1H, CH2-b), 3.63 (s, 3H, CO2CH3), 4.86 (ddd,
J¼5.4, 6.6, and 7.4 Hz, 1H, CH-a), 7.38 (d, J¼7.4 Hz, 1H,
CONH), 7.40 (dd, J¼4.8 and 8.0 Hz, 1H, CH-5Py), 7.85 (s,
1H, CH-2imid), 7.94 (dt, J¼1.8 and 8.0 Hz, 1H, CH-4Py),
8.54 (dd, J¼1.8 and 4.8 Hz, 1H, CH-6Py), 8.80 (d, J¼
1.8 Hz, 1H, CH-2Py); 13C NMR (50 MHz, CDCl3) d 22.89
(CH3CO), 28.41 (CH2-b), 52.08 (CO2CH3), 52.54 (CH-a),
4.2.4.2. Methyl N(a)-acetyl-5-(2-methoxy-5-methyl-
phenyl)-L-histidinate (13). From 8a (121 mg, 0.26 mmol)
following the general procedure after 1.5 h reaction, elution
with EtOAc afforded 13 (61 mg, 70%) as a pale yellow solid.
From 8b (49 mg, 0.11 mmol) following the general proce-
dure after 1.5 h reaction, elution with EtOAc afforded 13
(32 mg, 91%) as a pale yellow solid. Rf (EtOAc/MeOH,
10:3) 0.36; mp 50–51 ꢀC; [a]1D9 10.47 (c 0.28, MeOH); IR
123.86 (CH-5Py), 127.82, 128.46, 129.91 (C-3Py, C-4imid
,
C-5imid), 134.91 (CH-4Py), 135.31 (CH-2imid), 147.61 (CH-
6Py), 147.83 (CH-2Py), 170.86 (CONH), 171.61 (COO);
HRMS (ESI) m/z calcd for C14H17N4O3 [M]+ 289.1295,
found 289.1293; calcd for C14H16N4NaO3 [M]+ 311.1115,
found 311.1114.
1
(neat) 1742, 1658, 1502, 1437, 1241, 1026, 807 cmꢁ1; H
NMR (200 MHz, CDCl3) d 1.96 (s, 3H, CH3CO), 2.34 (s,
3H, CH3), 3.16 (dd, J¼4.7 and 14.8 Hz, 1H, CH2-b), 3.33
(dd, J¼6.2 and 14.8 Hz, 1H, CH2-b), 3.57 (s, 3H,
CO2CH3), 3.84 (s, 3H, OCH3), 4.82 (ddd, J¼4.7, 6.2, and
7.4 Hz, 1H, CH-a), 6.89 (d, J¼8.4 Hz, 1H, CH-3arom),
7.13 (dd, J¼2.0 and 8.4 Hz, 1H, CH-4arom), 7.21 (d,
4.2.4.5. Methyl N(a)-acetyl-5-(3-thienyl)-L-histidinate
(16). From 11a (121 mg, 0.29 mmol) following the general

V. Cerezo et al. / Tetrahedron 63 (2007) 10445–10453
10453
4. Moreno, E.; Nolasco, L. A.; Caggiano, L.; Jackson, R. F. W.
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procedure after 2.0 h reaction, gradient elution from EtOAc/
MeOH (99:1) to EtOAc/MeOH/NH3 (98:1:1) afforded 16
(83 mg, 99%) as a yellow solid. From 11b (84 mg,
0.20 mmol) following the general procedure after 2.0 h reac-
tion, gradient elution from EtOAc/MeOH (99:1) to EtOAc/
MeOH/NH3 (98:1:1) afforded 16 (57 mg, 99%) as a yellow
solid. Rf (EtOAc/MeOH, 10:3) 0.33; mp 49–50 ꢀC; [a]D19
7.55 (c 0.26, MeOH); IR (neat) 1739, 1660, 1198, 1177,
1
1129 cmꢁ1; H NMR (200 MHz, CDCl3) d 1.95 (s, 3H,
CH3CO), 3.25 (dd, J¼8.0 and 15.2 Hz, 1H, CH2-b), 3.38
(dd, J¼5.2 and 15.2 Hz, 1H, CH2-b), 3.64 (s, 3H,
CO2CH3), 4.78–4.88 (m, 1H, CH-a), 7.31 (d, J¼4.4 Hz,
1H, CH-4thien), 7.40 (dd, J¼2.8 and 4.4 Hz, 1H, CH-5thien),
7.50 (d, J¼2.8 Hz, 1H, CH-2thien), 7.60 (d, J¼8.0 Hz, 1H,
CONH), 7.87 (s, 1H, CH-2imid); 13C NMR (50 MHz, CDCl3)
d 22.71 (CH3CO), 27.98 (CH2-b), 52.14 (CO2CH3), 52.59
(CH-a), 122.42 (CH-2thien), 126.11 (CH-5thien), 126.56 (C-
5imid), 126.99 (CH-4thien), 127.35 (C-3thien), 129.94 (C-
4imid), 133.38 (CH-2imid), 171.16 (CONH), 171.44 (COO);
HRMS (ESI) m/z calcd for C13H16N3O3S [M]+ 294.0907,
found 294.0893; calcd for C13H15N3NaO3S [M]+
316.0726, found 316.0714.
13. Langhammer, I.; Erker, T. Heterocycles 2005, 65, 1975–1984.
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433–440.
We acknowledge the University of Girona for the financial
ꢁ
support. We are also grateful to the Serveis Tecnics de Re-
cerca (Dr. Matas and Mr. Fontrodona) of the University of
Girona.
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