Synthesis of new β-amidodehydroaminobutyric acid derivatives and of new tyrosine derivatives using copper catalyzed C-N and C-O coupling reactions

Article abstract of DOI:10.1007/s00726-012-1337-4

Several β-amidodehydroaminobutyric acid derivatives were prepared from N,C-diprotected β-bromodehydroaminobutyric acids and amides by a copper catalyzed C-N coupling reaction. The best reaction conditions include the use of a catalytic amount of CuI, N,N'-dimethylethylenediamine as ligand and K ₂CO₃ as base in toluene at 110 C. The stereochemistry of the products was determined using NOE difference experiments and the results obtained are in agreement with an E-stereochemistry. Thus, the stereochemistry is maintained in the case of the E-isomers of β-bromodehydroaminobutyric acid derivatives, but when the Z-isomers were used as substrates the reaction proceeds with inversion of configuration. The use of β- bromodehydrodipeptides as substrates was also tested. It was found that the reaction outcome depend on the stereochemistry of the β- bromodehydrodipeptide and on the nature of the first amino acid residue. The products isolated were the β-amidodehydrodipeptide derivatives and/or the corresponding dihydropyrazines. The same catalytic system (CuI/N,N'- dimethylethylene diamine) was used in the C-O coupling reactions between a tyrosine derivative and aryl bromides. The new O-aryltyrosine derivatives were isolated in moderate to good yields. The photophysical properties of two of these compounds were studied in four solvents of different polarity. The results show that these compounds after deprotection can be used as fluorescence markers.

Full text of DOI:10.1007/s00726-012-1337-4

Amino Acids (2013) 44:335–344
DOI 10.1007/s00726-012-1337-4
ORIGINAL ARTICLE
Synthesis of new b-amidodehydroaminobutyric acid derivatives
and of new tyrosine derivatives using copper catalyzed C–N
and C–O coupling reactions
•
G. Pereira H. Vilac¸a P. M. T. Ferreira
•
Received: 15 March 2012 / Accepted: 29 May 2012 / Published online: 20 June 2012
Ó Springer-Verlag 2012
Abstract Several b-amidodehydroaminobutyric acid
derivatives were prepared from N,C-diprotected b-bromo-
dehydroaminobutyric acids and amides by a copper cata-
lyzed C–N coupling reaction. The best reaction conditions
include the use of a catalytic amount of CuI, N,N0-
dimethylethylenediamine as ligand and K2CO3 as base in
toluene at 110 °C. The stereochemistry of the products was
determined using NOE difference experiments and the
results obtained are in agreement with an E-stereochemis-
try. Thus, the stereochemistry is maintained in the case of
the E-isomers of b-bromodehydroaminobutyric acid
derivatives, but when the Z-isomers were used as substrates
the reaction proceeds with inversion of configuration. The
use of b-bromodehydrodipeptides as substrates was also
tested. It was found that the reaction outcome depend on
the stereochemistry of the b-bromodehydrodipeptide and
on the nature of the first amino acid residue. The products
isolated were the b-amidodehydrodipeptide derivatives
and/or the corresponding dihydropyrazines. The same
catalytic system (CuI/N,N0-dimethylethylene diamine) was
used in the C–O coupling reactions between a tyrosine
derivative and aryl bromides. The new O-aryltyrosine
derivatives were isolated in moderate to good yields. The
photophysical properties of two of these compounds were
studied in four solvents of different polarity. The results
show that these compounds after deprotection can be used
as fluorescence markers.
Keywords Copper ꢀ N,N0-dimethylethylene diamine ꢀ
Cross-couplings ꢀ Dehydroamino acid derivatives ꢀ
Fluorescent amino acids
Introduction
Copper-catalyzed coupling reactions between aryl halides
and nucleophiles constitute an important method for the
formation of C–N and C–O bonds. The traditional copper-
assisted Ullmann reactions require harsh conditions,
namely high temperatures and the use of stoichiometric
amounts of copper, can only be applied to activated aryl
halides and give moderate yields (Beletskaya and Che-
prakov 2004). However, in the past few years the use of
bidentate ligands allowed this type of reaction to be per-
formed at much lower temperatures and in the presence of
copper as catalyst (Bao et al. 2005; Ma and Cai 2008;
Chen et al. 2008; Monnier and Taillefer 2009). Among
these chelating ligands the 1,2-diamines are used in the
efficient coupling of several types of substrates having a
free N–H or O–H. Most of the research work developed so
far in this area involves aromatic substrates; nevertheless,
there are several reports on the use of vinyl halides as
reagents. Thus, Shen et al. (2002), Shen and Porco (2000)
developed a copper (I) carboxylate-catalyzed coupling of
vinyl iodides and amides using cesium carbonate as base in
NMP or DMSO at 90 °C. Buchwald (Jiang et al. 2003;
Martin et al. 2007) described an efficient protocol for the
copper-catalyzed coupling of amides and carbamates with
vinyl halides using N,N0-dimethylethylenediamine
(DMED) as ligand and potassium or cesium carbonate as
base. The authors were able to prepare in good yields an
array of enamides from cyclic and acyclic primary amides
and cyclic secondary amides with differently substituted
G. Pereira ꢀ H. Vilac¸a ꢀ P. M. T. Ferreira (&)
´
Ferreira Centro de Quımica, University of Minho,
Gualtar, 4710-057 Braga, Portugal
e-mail: pmf@quimica.uminho.pt
123

336
G. Pereira et al.
vinyl bromides and iodides. Although Buchwald et al.
stated that N,N-dimethylglycine was much less effective
than N,N0-dimethylethylenediamine as ligand, Pan et al.
(2004) reported the CuI-catalyzed coupling reaction of
vinyl halides with amides using N,N-dimethylglycine as
ligand, cesium carbonate as base in dioxane. Furthermore,
the authors attributed Buchwald results with N,N-dimeth-
ylglycine to the use of toluene as solvent.
V-630 UV–Vis spectrophotometer. Fluorescence mea-
surements were performed using a HORIBA Jobin–Yvon
Fluoromax-4 spectrofluorimeter, equipped with a mono-
chromator in both excitation and emission, and a temper-
ature controlled cuvette holder. Fluorescence spectra were
corrected for the instrumental response of the system.
For fluorescence quantum yield determination, the
solutions were previously bubbled for 40 min with ultra-
pure nitrogen. The fluorescence quantum yields (Us) were
determined using the standard method (Eq. 1) (Demas and
Crosby 1971; Fery-Forgues and Lavabre 1999). 9,10-
diphenylanthracene in ethanol [Ur = 0.95 (Morris et al.
1976)], and naphthalene in cyclohexane [Ur = 0.23
(Berlman 1971)] were used as references.
On the basis of our previous work on the synthesis of
non-proteinogenic amino acids using palladium catalyzed
C–C and C–N coupling reactions (Abreu et al. 2003;
Ferreira et al. 2009) we have decided to apply copper-
catalyzed C–N and C–O couplings to the synthesis of new
amino acid derivatives. Thus, several methyl esters of
b-amidodehydroamino acids were prepared in good to high
yields from b-bromodehydroaminobutyric acid derivatives
and several amides using CuI as catalyst and of N,N0-
dimethyl ethylenediamine as ligand. The same catalytic
system was tested in the C–O coupling (Ma and Cai 2003;
Xia and Taillefer 2008) of a tyrosine derivative and aryl
halides to give new O-aryltyrosines. The photophysical
properties of two of the new amino acids prepared having a
pyrenyl and a biphenyl moiety were evaluated in four
solvents of different polarity.
ArFsn2
AsFrn2r
Us ¼
s Ur
ð1Þ
where A is the absorbance at the excitation wavelength,
F the integrated emission area, and n the refraction index of
the solvents used. Subscripts refer to the reference (r) or
sample (s) compound.
Synthesis of compounds Z-1 (Silva et al. 2002), E-1
(Silva et al. 2002), Z-3 (Ferreira et al. 2010b) and E-3
(Ferreira et al. 2010b). The synthesis of these compounds
was described elsewhere.
Materials and methods
General procedure for the synthesis of
b-amidodehydroamino acid derivatives
Melting points (oC) were determined in a Gallenkamp
1
apparatus and are uncorrected. H and 13C NMR spectra
An over-dried Schelenk tube was charged with CuI
(5.0 mol %), the b-bromodehydroaminobutyric acid
derivative, the amide (1.5 equiv.), K2CO3 (2 equiv.), and
N,N0-dimethylethylenediamine (20 mol %) followed by the
addition of dry toluene (1 mL). The tube was sealed, and
the reaction mixture was stirred at 110 °C for 5 h. After the
system had cooled to room temperature, the solvent was
evaporated. The reaction mixture was dissolved in ethyl
acetate (50 mL) and washed with water and brine
(2 9 30 mL each). After drying over MgSO4 the extract
was taken to dryness at reduced pressure. Crystallization
with ethyl acetate/petroleum ether afforded the corre-
sponding b-amidodehydroamino acid derivative.
were recorded on a Varian Unity Plus at 300 and
75.4 MHz, respectively, or on a Bruker Avance II? at 400
and 100.6 MHz, respectively. Heteronuclear correlations
(1H–13C, HMQC and HMBC) were also preformed.
Chemical shifts are given in ppm and coupling constants in
Hz. MS and HRMS data were recorded by the mass
spectrometry service of the University of Vigo, Spain;
elemental analysis was performed on a LECO CHNS 932
elemental analyser. The optical rotation was determined in
a ACTIVITY-AA-1000 polarimeter.
The reactions were monitored by thin layer chromatog-
raphy (TLC). Column chromatography was performed on
Macherey–Nagel silica gel 230–400 mesh. Petroleum ether
refers to the boiling range 40–60 °C. When solvent gradient
was used, the increase of polarity was made from neat
petroleum ether to mixtures of diethyl ether/petroleum
ether, increasing 10 % of diethyl ether each time until the
isolation of the product. All compounds were pure by NMR.
Synthesis of (E)-methyl 3-benzamido-2-(tert-
butoxycarbonylamino)but-2-enoate, E-2a
The general procedure described above was followed with
compound Z-1 (1 mmol, 294 mg) as substrate to give
compound E-2a (229 mg, 69 %) as a white solid. M.
p. 128.0–129.0 °C (from ethyl acetate/petroleum ether). 1H
NMR (400 MHz, CDCl3): 1.45 (s, 9 H, CH3 Boc), 2.62 (s,
3 H, cCH3), 3.77 (s, 3 H, OCH3), 5.54 (br s, 1 H, aNH),
7.48–7.56 (m, 3 H, ArH), 7.97 (d, J = 7.2 Hz, 2 H, ArH),
Spectroscopic measurements
All the solutions were prepared using spectroscopic grade
solvents. Absorption spectra were recorded in a Jasco
123

Synthesis of new b-amidodehydroaminobutyric acid derivatives
337
12.36 (br s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
CDCl3): 16.82 (cCH3), 28.24 [C(CH3)3], 52.06 (OCH3),
80.37 [OC(CH3)3], 105.53 (C), 127.63 (CH), 128.83 (CH),
132.38 (CH), 134.13 (C), 154.72 (C), 154.78 (C=O),
165.70 (C=O), 168.46 (C=O) ppm. C17H22N2O5 (334.37):
calcd. C 61.07, H 6.63, N 8.38; found C 60.78, H 6.911, N
8.354.
Synthesis of (E)-methyl 2-(tert-butoxycarbonylamino)-
3-(4-nitrobenzamido)but-2-enoate, E-2d
The general procedure described above was followed with
compound Z-1 (0.25 mmol, 73 mg) as substrate to give
compound E-2d (22 mg, 23 %) as a white solid. M.
p. 179.0–184.0 °C (from ethyl acetate/petroleum ether). 1H
NMR (400 MHz, CDCl3): 1.49 (s, 9 H, CH3 Boc), 2.61 (s,
3 H, cCH3), 3.82 (s, 3 H, OCH3), 5.56 (br s, 1 H, aNH),
8.13 (d, J = 8.8 Hz, 2 H, ArH), 8.35 (d, J = 8.8 Hz, 2 H,
ArH), 12.55 (br s, 1 H, NH) ppm. 13C NMR (100.6 MHz,
CDCl3): 16.75 (cCH3), 28.22 [C(CH3)3], 52.32 (OCH3),
80.66 [OC(CH3)3], 106.73 (C), 124.02 (CH), 128.78 (CH),
139.61 (C), 150.03 (C), 153.85 (C), 154.59 (C=O), 163.50
(C=O), 168.59 (C=O) ppm. HRMS (micrOTOF): calcd. for
C17H21N3NaO7 402.12772; found 402.12717.
The general procedure described above was followed
with compound E-1 (0.25 mmol, 73.5 mg) as substrate to
give compound E-2a (55 mg, 64 %).
Synthesis of (E)-methyl 3-(4-bromobenzamido)-2-(tert-
butoxycarbonylamino)but-2-enoate, E-2b
The general procedure described above was followed with
compound Z-1 (0.5 mmol, 147 mg) as substrate and CuI
(10 mol %) to give compound E-2b (165 mg, 80 %) as a
white solid. M. p. 141.0–142.0 °C (from ethyl acetate/
The general procedure described above was followed
with compound E-1 (0.25 mmol, 73 mg) to give compound
E-2d (34 mg, 36 %).
1
petroleum ether). H NMR (300 MHz, CDCl3): 1.48 (s, 9
H, CH3 Boc), 2.59 (s, 3 H, cCH3), 3.80 (s, 3 H, OCH3),
5.54 (br s, 1 H, aNH), 7.63 (d, J = 8.4 Hz, 2 H, ArH), 7.83
Synthesis of (E)-methyl 3-acetamido-2-(tert-
butoxycarbonylamino)but-2-enoate, E-2e
(d, J = 8.4 Hz, 2 H, ArH), 12.39 (br s, 1 H, NH) ppm. 13
C
NMR (75.4 MHz, CDCl3): 16.77 (cCH3), 28.22 [C(CH3)3],
52.16 (OCH3), 80.46 [OC(CH3)3], 105.81 (C), 127.36 (C),
129.18 (CH), 132.10 (CH), 132.98 (C), 154.46 (C=O),
154.71 (C), 164.70 (C=O), 168.54 (C=O) ppm.
C17H21BrN2O5 (413.26): calcd. C 49.41, H 5.12, N 6.78;
found C 49.31, H 5.195, N 6.774.
The general procedure described above was followed with
compound Z-1 (0.5 mmol, 147 mg) as substrate, CuI
(10 mol %) and DMED (30 mol %) for 12 h to give
compound E-2e. Column chromatography using diethyl
ether/petroleum ether ((2:1) gave compound E-2e (97 mg,
71 %) as an oil. 1H NMR (300 MHz, CDCl3): 1.46 (s, 9 H,
CH3 Boc), 2.15 (s, 3 H, CH3), 2.46 (s, 3 H, cCH3), 3.76 (s,
3 H, OCH3), 5.44 (br s, 1 H, aNH), 11.42 (br s, 1 H, NH)
ppm. 13C NMR (75.4 MHz, CDCl3): 16.55 (cCH3), 25.53
(CH3), 28.22 [C(CH3)3], 51.91 (OCH3), 80.36 [OC(CH3)3],
104.71 (C), 154.36 (C), 154.79 (C=O), 168.19 (C=O),
169.19 (C=O) ppm. HRMS (micrOTOF): calcd. for
C12H20N2NaO5 295.12699; found 295.12644.
The general procedure described above was followed
with compound E-1 (0.5 mmol, 147 mg) as substrate to
give compound E-2b. Column chromatography using die-
thyl ether/petroleum ether (1:1) gave compound E-2b
(157 mg, 76 %).
Synthesis of (E)-methyl 2-(tert-butoxycarbonylamino)-
3-(4-methoxybenzamido)but-2-enoate, E-2c
Synthesis of (E)-methyl 2,3-bis(benzamido)but-2-
enoate, E-2f
The general procedure described above was followed with
compound Z-1 (0.25 mmol, 73 mg) as substrate and CuI
(10 mol %) to give compound E-2c (53 mg, 58 %) as an
1
The general procedure described above was followed with
compound E-3 (0.25 mmol, 75 mg) as substrate giving
compound 4 (31 mg, 58 %) and compound E-2f (30 mg,
37 %). Compound E-2f was obtained as a white solid, m.
oil. H NMR (400 MHz, CDCl3): 1.49 (s, 9 H, CH3 Boc),
2.61 (s, 3 H, cCH3), 3.80 (s, 3 H, OCH3), 3.88 (s, 3 H,
OCH3), 5.49 (br s, 1 H, aNH), 6.98 (d, J = 8.8 Hz, 2 H,
ArH), 7.95 (d, J = 8.8 Hz, 2 H, ArH), 12.32 (br s, 1 H,
NH) ppm. 13C NMR (100.6 MHz, CDCl3): 16.80 (cCH3),
28.26 [C(CH3)3], 52.02 (OCH3), 55.45 (OCH3), 80.34
[OC(CH3)3], 104.97 (C), 114.07 (CH), 126.47 (C), 129.69
(CH), 154.87 (C=O), 155.18 (C), 162.96 (C), 165.22
(C=O), 168.58 (C=O) ppm. HRMS (ESI): calcd. for
C18H24N2NaO6 387.15321; found 387.15282.
1
p. 98.0–99.0 °C (from ethyl acetate/petroleum ether). H
NMR (400 MHz, CDCl3): 2.64 (s, 3 H, cCH3), 3.79 (s, 3 H,
OCH3), 7.11 (br s, 1 H, aNH), 7.44–7.61 (m, 6 H, ArH),
7.90 (m, 2 H, ArH), 8.01 (d, J = 7.6 Hz, 2 H, ArH), 12.47
(br s, 1 H, NH) ppm. 13C NMR (100.6 MHz, CDCl3):
17.12 (cCH3), 52.26 (OCH3), 104.96 (C), 127.28 (CH),
127.70 (CH), 128.77 (CH), 128.89 (CH), 132.04 (CH),
132.49 (CH), 133.99 (C), 134.09 (C), 154.73 (C), 165.74
(C=O), 167.01 (C=O), 167.96 (C=O) ppm. HRMS
The general procedure described above was followed
with compound E-1 (0.25 mmol, 73 mg) to give compound
E-2c (61 mg, 67 %).
123

338
G. Pereira et al.
(micrOTOF): calcd. for C19H18N2NaO4 361.11643; found
361.11588.
(s, 3 H, OCH3), 4.68–4.73 (m, 1 H, CH), 5.26 (br s, 1 H,
NH) ppm. 13C NMR (75.4 MHz, CDCl3): 11.94 (CH3),
17.87 (CH3), 18.72 (CH3), 28.22 (CH3 Boc), 32.81 (CH),
51.92 (OCH3), 54.02 (CH), 79.84 [C(CH3)3], 127.17 (C),
155.33 (C=O), 156.21 (C), 162.10 (C=O), 162.63 (C=O)
ppm. HRMS (ESI): calcd. for C15H24NaN2O5 335.15774;
found 335.15763.
The general procedure described above was followed
with compound Z-3 (0.5 mmol, 149 mg) to give after
column chromatography using diethyl ether/petroleum
ether compound 4 (40 mg, 37 %) together with Bz-DAbu-
OMe 5 (Ferreira et al. 2008).
The general procedure described above was followed
with compound Z-7 (0.28 mmol, 110 mg) to give after
column chromatography using diethyl ether/petroleum
ether compound 10 (75 mg, 80 %).
Synthesis of methyl 3,4-dimethyl-6-oxo-1,4,5,6-
tetrahydropyrazine-2-carboxylate, 9
The general procedure described above was followed with
compound E-6 (0.25 mmol, 88 mg) as substrate giving
compound 9 (21 mg, 30 %) together with Boc-Gly-DAbu-
OMe (22 mg, 32 %). Compound 9 was obtained as a white
solid. M. p. 105.0–106.0 °C (from ethyl acetate/petroleum
General Procedure for the synthesis of O-aryltyrosine
derivatives
An over-dried Schelenk tube was charged with CuI
(15 mol %), N,N0-dimethylethylenediamine (50 mol %),
aryl halide (1 equiv.), Boc-L-Tyr-OMe (1.5 equiv.),
Cs2CO3 (1.5 equiv.) and followed by the addition of dry
toluene (1 mL). The tube was sealed, and the reaction mix-
ture was stirred at 100 °C. After the system had cooled to
room temperature, the solvent was evaporated. The reaction
mixture was dissolved in ethyl acetate (50 mL) and washed
with KHSO4 (1 M), NaHCO3 (1 M) and brine (30 mL each).
After drying over MgSO4 the extract was dried at reduced
pressure. The residue was submitted to column chromatog-
raphy using a solvent gradient from neat petroleum ether to
mixtures of ether/petroleum ether, increasing 10 % of ether
each time until the isolation of the product.
1
ether). H NMR (300 MHz, CDCl3): 1.44 (s, 9 H, CH3
Boc), 2.60 (s, 3 H, CH3), 3.89 (s, 3 H, OCH3), 4.41 (br s, 2
H, CH2), 5.22 (br s, 1 H, NH) ppm. 13C NMR (75.4 MHz,
CDCl3): 11.84 (CH3), 28.23 [C(CH3)3], 37.74 (CH2), 51.92
(OCH3), 80.20 [OC(CH3)3], 127.30 (C), 155.42 (C=O),
156.76 (C), 159.24 (C=O), 162.46 (C=O) ppm. HRMS
(ESI): calcd. for C12H18N2NaO5 293.11079; found
293.11091.
The general procedure described above was followed
with compound Z-6 (0.5 mmol, 176.0 mg) to give after
column chromatography using diethyl ether/petroleum
ether compound 9 (90 mg, 63 %).
Synthesis of E-methyl 7-isopropyl-3,11,11-trimethyl-
1,6,9-trioxo-1-phenyl-10-oxa-2,5,8-triazadodec-3-ene-
4-carboxylate, E-8 and of methyl 5-isopropyl-3,4-
dimethyl-6-oxo-1,4,5,6-tetrahydropyrazine-2-
carboxylate, 10
Synthesis of the methyl ester of N-(tert-
butoxycarbonyl)-O-(pyren-1-yl)-tyrosine, 11
The general procedure described above was followed with
1-bromopyrene (0.2 mmol, 56 mg) and Boc-Tyr-OMe
(0.3 mmol, 89 mg) for 24 h to afford compound 11
(35 mg, 35 %) as a white solid. M. p. 64.0–65.0 °C (from
ethyl acetate/petroleum ether). [a]D = -24.5 (c = 0.1,
The general procedure described above was followed with
compound E-7 (0.16 mmol, 62 mg) as substrate giving
compound E-8 (14 mg, 21 %) and compound 10 (14.5 mg,
29 %). Compound E-8 was obtained as oil. 1H NMR
(400 MHz, CDCl3): 0.99–1.06 (m, 6 H, CH3), 1.47 (s, 9 H,
CH3 Boc), 2.22–2.26 (m, 1 H, CH), 2.55 (s, 3 H, CH3), 3.76
(s, 3 H, OCH3), 3.98–4.02 (m, 1 H, CH), 7.01 (br s, 1 H,
NH), 7.44–7.52 (m, 2 H, ArH), 7.54–7.58 (m, 1 H, ArH),
7.96–7.99 (m, 2 H, ArH), 12.40 (br s, 1 H, NH) ppm. 13C
NMR (100.6 MHz, CDCl3): 16.91 (CH3), 19.30 (CH3),
19.35 (CH3), 28.29 [C(CH3)3], 30.31 (CH), 51.04 (OCH3),
60.36 (CH), 80.20 [OC(CH3)3], 104.50 (C), 127.67 (CH),
128.86 (CH), 132.47 (CH), 134.05 (C), 154.69 (C), 155.99
(C=O), 155.68 (C=O), 167.82 (C=O), 171.73 (C=O) ppm.
HRMS (M ? H): calcd. for C22H32N3O5 434.22856; found
1
CH3OH) H NMR (400 MHz, CDCl3): 1.44 (s, 9 H, CH3
Boc), 3.02–3.16 (m, 2 H, bCH2), 3.74 (s, 3 H, OCH3), 4.61
(q, J = 7.2 Hz, 1 H, aCH), 5.05 (d, J = 7.2 Hz, 1 H, NH),
6.98-7.00 (m, 2 H, ArH), 7.11 (d, J = 8.0 Hz, 2 H, ArH),
7.62 (d, J = 8.0 Hz, 1 H, ArH), 8.00–8.20 (m, 7 H, ArH),
8.35 (d, J = 9.2 Hz, 2 H, ArH) ppm. 13C NMR
(100.6 MHz, CDCl3): 28.29 [C(CH3)3], 37.66 (bCH2),
52.23 (OCH3), 54.47 (aCH), 79.95 [OC(CH3)3], 117.12
(CH), 117.97 (CH), 119.95 (CH), 121.06 (CH), 122.94 (C),
124.73 (C), 124.83 (CH), 125.01 (CH), 125.46 (CH),
125.99 (C), 126.29 (CH), 126.37 (CH), 127.10 (CH),
127.52 (CH), 127.77 (C), 130.48 (C), 130.68 (CH), 131.35
(C), 150.15 (C–O), 155.05 (C=O), 157.80 (C–O), 172.30
(C=O) ppm. C31H31NO5 (497.58): calcd. C 74.83, H 6.28,
N 2.81; found C 74.94, H 6.001, N 2.838.
1
434.22855. Compound 10 was obtained as oil. H NMR
(300 MHz, CDCl3): 0.88–0.92 (m, 6 H, CH3), 1.41 (s, 9 H,
CH3 Boc), 2.09–2.20 (m, 1 H, CH), 2.59 (s, 3 H, CH3), 3.89
123

Synthesis of new b-amidodehydroaminobutyric acid derivatives
339
Synthesis of the methyl ester of N-(tert-
butoxycarbonyl)-O-(4-nitrophenyl)-tyrosine, 12
conditions using the Z-isomer of the methyl ester of N-tert-
butoxycarbonyl-b-bromodehydroaminobutyric acid Z-1
(Silva et al. 2002) and benzamide as substrates (Scheme 1).
The conditions proposed by Pan et al. (2004), namely CuI
(10 mol %), N,N-dimethylglycine (20 mmol %), Cs2CO3
(2 equiv.) in dioxane at 80 °C failed to give the b-benza-
midodehydroaminobutyric acid derivative 2a. By changing
the solvent for toluene or the base for K2CO3 the only
compounds isolated were the reactants together with the
debrominated dehydroaminobutyric acid derivative. Using
Buchwald conditions (Jiang et al. 2003; Martin et al. 2007),
CuI (5 mol %), DMED (20 mol %), K2CO3 (2 equiv.) in
toluene at 110 °C, it was possible to isolate the methyl
ester of the b-amidodehydroaminobutyric acid 2a in 69 %
yield. Changing the base for Cs2CO3 or the solvent for
DMF failed to give the product. In view of these results,
Buchwald et al. conditions were applied to the synthesis of
several b-amidodehydroaminobutyric acid derivatives
(2a-e) (Scheme 1; Table 1) from the Z-1 and E-1 (Silva
et al. 2002) and aryl or alkyl primary amides. Compounds
Z-1 and E-1 were obtained from a threonine derivative by a
sequential dehydration reaction followed by halogenation
developed in our laboratories.(Ferreira et al. 2007).
The general procedure described above was followed with
1-bromo-4-nitrobenzene (0.2 mmol, 40.4 mg) and Boc-
Tyr-OMe (0.3 mmol, 89 mg) as substrate for 24 h to afford
compound 12 (48 mg, 58 %) as an oil [a]D = ?29.1
(c = 0.1, CH3OH). 1H NMR (400 MHz, CDCl3): 1.43 (s, 9
H, CH3 Boc), 3.00–3.06 (m, 1 H, bCH2), 3.15–3.20 (m, 1
H, bCH2), 3.75 (s, 3 H, OCH3), 4.61 (q, J = 7.0 Hz, 1 H,
aCH), 5.05 (d, J = 7.0 Hz, 1 H, NH), 6.99–7.03 (m, 4 H,
ArH), 7.20 (d, J = 8.4 Hz, 2 H, ArH), 8.20 (d, J = 9.2 Hz,
2 H, ArH) ppm. 13C NMR (100.6 MHz, CDCl3): 28.28
[C(CH3)3], 37.95 (bCH2), 52.33 (OCH3), 54.42 (aCH),
80.06 [OC(CH3)3], 117.09 (CH), 120.52 (CH), 125.92
(CH), 131.17 (CH), 133.42 (C), 142.67 (C), 153.73 (C–O),
155.00 (C=O), 163.27 (C–O), 172.15 (C=O) ppm. HRMS
(micrOTOF): calcd. for C21H24N2NaO7 439.14812; found
439.14757.
Synthesis of the methyl ester of N-(tert-
butoxycarbonyl)-O-(biphenyl-4-yl)-tyrosine, 13
The general procedure described above was followed with
1-bromobiphenyl (0.2 mmol, 47 mg) and Boc-Tyr-OMe
(0.3 mmol, 89 mg) as substrate for 24 h to afford com-
pound 13 (30 mg, 34 %) as an oil.. [a]D = ?34.1 (c = 0.1,
CH3OH).1H NMR (400 MHz, CDCl3): 1.44 (s, 9 H, CH3
Boc), 3.01–3.06 (m, 1 H, bCH2), 3.10–3.15 (m, 1 H,
bCH2), 3.74 (s, 3 H, OCH3), 4.60 (dd, J = 6.8 Hz and
J = 6.0 Hz, 1 H, aCH), 5.02 (d, J = 6.8 Hz, 1 H, NH),
6.99 (d, J = 8.4 Hz, 2 H, ArH), 7.07 (d, 2 H, J = 8.4 Hz,
ArH), 7.12 (d, J = 8.8 Hz, 1 H, ArH), 7.32–7.36 (m, 1 H,
ArH), 7.42–7.46 (m, 2 H, ArH), 7.54–7.59 (m, 4 H, ArH)
ppm. 13C NMR (100.6 MHz, CDCl3): 28.29 [C(CH3)3],
37.72 (bCH2), 52.23 (OCH3), 54.46 (aCH), 79.96
[OC(CH3)3], 118.97 (CH), 119.05 (CH), 126.88 (CH),
127.03 (CH), 128.41 (CH), 128.76 (CH), 130.64 (CH),
130.97 (C), 136.34 (C), 125.99 (C), 126.29 (CH), 126.37
(CH), 127.10 (CH), 127.52 (CH), 127.77 (C), 140.50 (C),
155.04 (C=O), 156.23 (C–O), 156.72 (C–O), 172.29 (C=O)
ppm. HRMS (micrOTOF): calcd. for C27H29NNaO5
470.19434; found 470.19510.
The b-amidodehydroaminobutyric acid derivatives were
obtained in moderate to good yields (58–80 %) except
when 4-nitrobenzamide was used (23 and 36 % yield)
(Table 1). The results show a similar reactivity of both Z-
and E-isomers of the b-bromodehydroaminobutyric acid
derivative 1 and of aryl and alkylamides.
The stereochemistry of the b-amidodehydroaminobu-
tyric acid derivatives was determined by NOE difference
experiments by irradiating the a-NH and OCH3 protons and
observing NOE enhancements in the c-CH3 protons and in
the b-amide protons, respectively. This is in agreement with
an E-stereochemistry. Although it is reported that the cop-
per-catalyzed coupling between vinyl halides and amides
proceeds with maintenance of the geometry of the C–C
double bond in the case of the tetrasubstituted vinyl halides
Z-1 and E-1 it was found that the stereochemistry is
maintained in the case of the E-isomer, but when the
Z-isomer was used as substrate the coupling products have
an E-stereochemistry. This can be attributed to the steric
H
H
N
CO2CH3
N
CO2CH3
Boc
O
CuI / DMED
Boc
+
K2CO3,Toluene
Results and discussion
NH
R
R
NH2
Br
Z-1 or E-1
2a-e
O
In this work the copper-catalyzed vinylation of primary
amides with b-halo-b-substituted dehydroamino acids was
investigated. Considering the variety of conditions pro-
posed for the reaction between amides and vinyl halides we
have decided to screen the copper-catalyzed amidation of
b-bromodehydroamino acids under several reaction
H C
,d;
, e.
,c;O2N
3
R =
H CO
,b;
,a;
Br
3
Scheme 1 Synthesis of b-amidodehydroaminobutyric acid deriva-
tives 2a-e from the E- or Z-isomers of the methyl ester of N-tert-
butoxycarbonyl-b-bromodehydroaminobutyric acid and several
amides
123

340
G. Pereira et al.
bromodehydrophenylalanine and benzamide were the
reactants together with the debrominated dehydrophenyl-
alanine. Thus, the nature of the halogen and of the group
linked to the b-carbon atom are important issues to be
taken into consideration in this type of reactions involving
dehydroamino acid derivatives.
Table 1 Results obtained in synthesis of b-amidodehydroaminobu-
tyric acid derivatives
Substrate
Product
Yield (%)
69
Z-1
H
N
CO2CH3
NH
Boc
To evaluate the influence of other N-protecting groups
namely acyl protecting groups, the methyl esters of
N-benzoyl-b-bromodehydroaminobutyric acid (Z-3 and E-3)
(Ferreira et al. 2010b) were reacted with benzamide
(Scheme 2).
O
E-2a
E-1
Z-1
E-2a
64
80a
The coupled product E-2f [(E)-methyl 2,3-bis(benz-
amido)but-2-enoate] was isolated in 38 % yield together
with the trisubstituted oxazole 4 (Ferreira et al. 2008)
(58 % yield) using E-3 as substrate. When Z-3 was reacted
with benzamide the only products isolated were the cor-
responding oxazole 4 (Ferreira et al. 2008) (37 % yield)
together with the methyl ester of N-benzoyldehy-
droaminobutyric acid (5). These results were expected
since recently in our laboratories a new method was
developed for the synthesis of oxazoles from N-acyl-b-
bromodehydroaminobutyric acid derivatives by treatment
with base. The mechanism proposed for this reaction
involves the attack of the carbonyl oxygen on the b-carbon
atom of the dehydroaminobutyric acid with loss of the
halogen anion. As the reaction medium in the C–N cross-
coupling is basic the cyclization to give the oxazole can
also occur affecting the reaction outcome (Ferreira et al.
2010a). The 1H NMR spectra in CDCl3 of compounds
E-2a-f clearly show the presence of two broad singlets, one
between 11.42 and 12.55 ppm and the other between 5.34
and 7.11 ppm, originated from the b- and a-NH, respec-
tively (Table 2).
H
N
CO2CH3
NH
Boc
O
Br
E-2b
E-1
Z-1
E-2b
76
58a
H
N
CO2CH3
NH
Boc
O
OCH
3E-2c
E-1
Z-1
E-2c
67
23b
H
N
CO2CH3
NH
Boc
O
NO
2 E-2d
E-1
Z-1
E-2d
36b
71a
H
The high chemical shifts of the b-NH amide proton are
due to the conjugation with the a,b-unsaturated carbonyl
system of the dehydroamino acid. As expected, higher
values are observed for compounds E-2a-d and E-2f with
aromatic groups linked to the amide function and the
lowest value is observed for compound E-2e with a methyl
group linked to the amide. When comparing the chemical
N
CO2CH3
Boc
NH
O
E-2e
a
10 mol % of CuI
b
It was isolated Boc-DAbu-OMe
O
H
CO2CH3
N
Bz
OCH3
NH
N
+
hindrance of the Z-b-amidodehydroaminobutyric acid
derivatives.
O
O
4
E-2f
E-3
CuI, DMED
K2CO3
Toluene, 110ºC
O
O
NH2
H
The use of a b-iododehydroaminobutyric acid derivative
was also tested and it was found that the reaction between
the Z-isomer of the methyl ester of N-tert-butoxycarbonyl-
b-iododehydroaminobutyric acid and benzamide gave the
coupled product, E-2a in 46 % yield together with a con-
siderable amount of the dehalogenated dehydroaminobu-
tyric acid derivative. The only products isolated from the
reaction of the methyl ester of N-(tert-butoxycarbonyl)-b-
N
Bz
OCH3
+
Br
CO2CH3
O
H
N
Z-3 or E-3
Z-3
N
Bz
OCH3
+
O
5
4
Scheme 2 Reaction between the E- and Z-isomers of the methyl ester
of N-benzoyl-b-bromodehydroaminobutyric acid and benzamide
123

Synthesis of new b-amidodehydroaminobutyric acid derivatives
341
Table 2 Chemical shifts in CDCl3 of the NH protons in compounds
E-2a-f
Table 3 Coupling products obtained from the reaction of b-bromo-
dehydroaminobutyric acid dipeptides and benzamide
Compound
a-NH (ppm)
b-NH (ppm)
Reagent
Products
E-2a
E-2b
E-2c
E-2d
E-2e
E-2f
5.34
5.54
5.49
5.56
5.44
7.11
12.36
12.39
12.32
12.55
11.42
12.47
Z-6
Boc
N
O
N
H
CO2CH3
9 (63 %)
E-6
Z-7
9 (30 %) ? Boc-Gly-DAbu-OMe (32 %)
Boc
N
shifts of the a-NH of compounds E-2a-e with that of
compounds E-1 (6.00 ppm) (Silva et al. 2002) and Z-1
(6.23 ppm) (Silva et al. 2002) it is possible to observe an
upfield effect probably because of the shielding of the
b-NH. The same effect was also found by comparing the
chemical shift of the a-NH of compound E-2f with those of
the a-NH of compounds E-3 (8.04 ppm) (Ferreira et al.
2010b).
O
N
CO2CH3
H
10 (80 %)
E-7
O
NH
O
H
N
Boc
N
CO2CH3
H
This reaction was also tested using b-bromodehyd-
roaminobutyric acid dipeptides [Z-6 (Ferreira et al. 2007),
E-6 (Ferreira et al. 2007), Z-7 (Ferreira et al. 2010b), and
E-7 (Ferreira et al. 2010b)] and benzamide as coupling
components (Scheme 3; Table 3).
E-8 (21 %) + 10 (29%)
and amides it was decided to prepare O-aryltyrosines using
C–O coupling reactions between tyrosine derivatives and
aryl bromides, namely 1-bromopyrene, 1-bromo-4-nitro-
benzene, and 4-bromobiphenyl (Scheme 4). The coupling
It was found that the products obtained in C–N coupling
reactions between dipeptides having a b-bromo-dehy-
droaminobutyric acid residue as the second amino acid and
benzamide depend on the stereochemistry of the dehydro-
dipeptide and on the nature of the first amino acid. Thus,
the formation of the b-benzamidodehydrodipeptide E-8
was only observed with the E-isomer of compound 7. The
intermolecular C–N coupling product E-8, was isolated
together with similar amounts of the pyrazine derivative
10. The pyrazine derivative was the only product obtained
from the reaction of Z-6 and E-6 with benzamide. The
dihydropyrazines 9 and 10 result from the intramolecular
C–N coupling between the a-NH of the first amino acid and
the vinyl halide moiety of the dehydroamino acid residue.
In order to test the versatility of the catalytic system
(CuI/N,N0-dimethylethylene diamine) used in the C–N
couplings between dehydroaminobutyric acid derivatives
O
H
N
Boc
OCH3
Br
11 (35%)
O
i)
O2N
O
H
N
Boc
OCH3
O2N
Br
12 (58 %)
Boc
O
i)
OH
Boc-L-Tyr-OMe
N
H3CO
H
O
i)
Br
Boc
O
O
NH2
Br
O
R
N
NH
CO2CH3
H
N
O
Boc
NH
+
H
N
i)
+
Boc
N
CO2CH3
O
H
O
N
H
CO2CH3
Boc
N
H
R
R
H3CO
13 (34 %)
R=H, 6
R=CH(CH3)2, 7
O
R=H, 9
R=CH(CH3)2, 10
R=CH(CH3)2, 8
i) CuI (15 mol%), N,N'-dimethylethylene diamine (50 mol%), Cs2CO3 (1.5 equiv.),
toluene, 100 ºC.
i) CuI (5 mol%), DMED (20 mol%), K2CO3 (2 eq.), toluene, 110 ºC.
Scheme 3 Reaction between the E- and Z-isomers of the methyl ester
of N-(tert-butoxycarbonyl)-b-bromodehydroaminobutyric acid dipep-
tides and benzamide
Scheme 4 Synthesis of new O-aryltyrosine derivatives obtained by
reacting a the methyl ester of N-tert-butoxycarbonyl-L-tyrosine with
aryl bromidesh
123

342
G. Pereira et al.
derivatives it is possible to use both catalytic systems with
similar results.
Since compounds 11 and 13 have a pyrenyl and a
biphenyl moiety, respectively, it was decided to study their
photophysical properties. Thus the absorption and fluores-
cence properties of these compounds were studied in four
solvents of different polarity (cyclohexane, ethyl acetate,
acetonitrile and ethanol). The normalized absorption and
fluorescence spectra of compounds 11 and 13 are presented
in Fig. 1. The maximum absorption (kabs) and emission
wavelengths (kem), molar absorption coefficients (e) and
fluorescence quantum yields (UF) for these compounds are
presented in Table 4.
Compounds 11 and 13 displayed low influence of the
solvent on the absorption and emission spectra. The two
compounds present absorption spectra with high molar
absorption coefficients (e [ 2.1 91 04 M-1 cm-1) at the
lowest energy maximum in all solvents studied (Table 4).
The high e values observed can indicate a predominance
of p–p* character in these compounds (Creed 1984;
Albinsson et al. 1989; Lippert et al. 2004). Compound 11
exhibits absorption and emission spectra that resemble
those of pyrene (Kalyanasundaram and Thomas 1977;
Winnik 1993) with well-defined vibrational structure
(Fig. 1) and presents high fluorescence quantum yields in
all solvents studied (Table 4) [UF = 0.58 for pyrene in
cyclohexane (Hissler et al. 1999)]. The fluorescence spec-
trum of biphenyl is structured, whereas the absorption
spectrum is broad and structureless which is characteristic
of a chromophore that is non-planar in the ground state and
more planar in its first excited singlet state. Unlike biphe-
nyl compound 13 presents a non-structured fluorescence
emission in all solvents (Fig. 1) and moderate fluorescence
quantum yields similar to those observed for biphenyl
(Table 4) [UF = 0.18 for biphenyl in cyclohexane (Valeur
Fig. 1 Normalized absorption and emission spectra of compounds 11
(kex 345 nm) and 13 (kex 270 nm) in four solvents of different
polarity
products 11, 12, and 13 were obtained in moderate yields
(34–58 %).
In order to increase the reaction yields Pan et al. (2004)
conditions (CuI as catalyst, N,N-dimethylglycine as ligand,
Cs2CO3 as base in dioxane at 80 °C) were used in the
coupling between the methyl ester of N-tert-butoxycar-
bonyl tyrosine and 4-bromobiphenyl. Compound 12 was
isolated in 32 % yield which indicates that in the case of
C–O couplings between aryl halides and tyrosine
Table 4 Maximum absorption (kabs) and emission wavelengths (kem), molar extinction coefficients (e) and fluorescence quantum yields (UF) for
compounds 11 (kex 345 nm) and 13 (kex 270 nm)
Solvent
kabs (nm) (e/104 M-1 cm-1
)
kem(nm)
UFa
11
13
11
13
11
13
Cyclohexane
382 (0.28), 361 (0.50), 343 (2.50), 328 (1.81), 317 (0.94, sh), 260 (2.33) 383, 389, 404, 426
277 (2.67), 269 (1.93), 243 (4.76), 238 (4.30, sh)
328 0.56 0.15
Ethyl acetate 382 (0.30), 361 (0.54), 342 (2.65), 328 (1.92), 317 (1.03, sh), 260 (2.55) 384, 389 (sh), 404, 427 325 0.38 0.15
277 (2.95), 268 (2.16)
Acetonitrile
382 (0.26), 361 (0.49), 342 (2.80), 327 (2.02), 317 (1.07, sh), 260 (2.36) 384, 389 (sh), 405, 427 326 0.37 0.20
277 (3.08), 267 (2.19), 242 (5.65), 237 (5.07, sh)
Ethanol
382 (0.28), 361 (0.49), 342 (2.30), 327 (1.69), 316 (0.92, sh), 260 (2.19) 383, 390 (sh), 404, 425 335 0.40 0.18
277 (2.64), 268 (1.92), 242 (4.55), 236 (3.85, sh)
Error about 10 %. Ethyl acetate cut-off: 260 nm. [11] and [13] = 1 9 10-6 M to measure the fluorescence quantum yields. [11] and
[13] = 2 9 10-5 M to determine the molar extinction coefficients
a
Relative to 9,10-diphenylanthracene in ethanol (U = 0.95 at 25 °C) (Morris et al. 1976) for 11; relative to naphthalene in cyclohexane
(U = 0.23) (Berlman 1971) for 13
123

Synthesis of new b-amidodehydroaminobutyric acid derivatives
343
2001; Lim and Li 1970; Bridges et al. 1965)]. In ethanol
can be detected a band enlargement together with a bath-
ochromic shift. This behavior points to an intramolecular
charge transfer (ICT) character of the excited state.
deprotection these compounds can be used as fluorescent
markers. The O-pyrenyltyrosine derivative can be partic-
ularly useful as a fluorescent marker for peptides and
proteins since it can be excited without simultaneous
excitation of other aromatic amino acids.
In solution tyrosine presents a maximum of fluorescence
emission between 303 and 305 nm as a non-structured
band (Lakowicz 1999; Eftink 2000). The introduction of a
biphenyl or a pyrenyl moiety in tyrosine results in a new
amino acid derivative with emission bands located at lower
energy and with higher fluorescent quantum yields
[UF = 0.14 for tyrosine in water (Lakowicz 1999)]. The
results obtained indicate that after deprotection these
compounds could be used as fluorescent markers. Com-
pound 11 can be use as a fluorescent probe in peptides and
proteins since this compound can be excited without
simultaneous excitation of other aromatic amino acids
(tyrosine, tryptophan and phenylalanine) that absorb light
at k \ 300 nm (Lakowicz 1999; Eftink 2000).
Acknowledgments This work was financed by FEDER through
‘‘Programa Operacional Factores de Competitividade’’—COMPETE
ˆ
and by FCT—‘‘Fundac¸a˜o para a Ciencia e Tecnologia’’ through
project ‘‘Projecto Estrategico—UI 686—2011-2012‘‘ Ref: PEst-C/
´
QUI/UI0686/2011. The NMR spectrometer is part of the National
NMR Network (RNRMN) and was purchased in the framework of the
National Programme for Scientific Re-equipment, contract REDE/
1517/RMN/2005, with funds from POCI 2010 (FEDER) and Fun-
ˆ
dac¸a˜o para a Ciencia e a Tecnologia (FCT) and is supported with
funds from FCT. G.P. acknowledges FCT for a PhD grant SFRH/BD/
38766/2007. H.V. acknowledges FCT for a PhD grant SFRH/BD/
7265/2010.
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