Atom-efficient synthesis of 2,6-diazacyclophane compounds through alcoholysis/reduction of 3-nitroarylmethylene-2,5-piperazinediones

Article abstract of DOI:10.1016/j.tet.2008.01.047

Readily available cyclic dehydrodipeptides are convenient starting materials for atom-efficient synthesis of different compounds. A one-pot ring-opening/alcoholysis/hydrolysis process with 3-nitroarylmethylene-2,5-piperazinediones yielded N-3-nitroarylpyr

Full text of DOI:10.1016/j.tet.2008.01.047

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2762e2771
www.elsevier.com/locate/tet
Atom-efficient synthesis of 2,6-diazacyclophane compounds through
alcoholysis/reduction of 3-nitroarylmethylene-2,5-piperazinediones
*
´
Juan Francisco Gonzalez, Elena de la Cuesta, Carmen Avendano
~
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 4 October 2007; received in revised form 9 January 2008; accepted 11 January 2008
Available online 16 January 2008
Abstract
Readily available cyclic dehydrodipeptides are convenient starting materials for atom-efficient synthesis of different compounds. A one-pot
ring-opening/alcoholysis/hydrolysis process with 3-nitroarylmethylene-2,5-piperazinediones yielded N-3-nitroarylpyruvoylamino esters, which
gave the corresponding amines by reduction of the nitro group. In the case of 2-nitroaryl compounds, an intramolecular reductive amination
afforded N-indole-2-carbonylamino esters, while the intermolecular reductive amination of 3- and 4-nitroaryl derivatives allowed the synthesis
of 2,6-diazacyclophanes. The amino compounds may be coupled with amino acids to get peptide-like derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclic dehydrodipeptides; Methanolysis; Azacyclophanes; Peptide-like compounds; Indoles; a-Ketoamides
1. Introduction
alcoholysis are the acid hydrolysis of 3-benzylidene-2,5-piper-
azinediones8 and azlactones9 to give N-pyruvoylamino acids
and 3-arylpyruvic acids, respectively. In the initial report of
this transformation, we gave an account of its extension to ni-
troarylmethylene derivatives that could give through reductive
processes other structures, such as 4 (Scheme 1).10
The a-ketoamide function generated in compounds 3 is
present in natural products such as the immunosuppressive mac-
rocyclic polyketides FK506 and rapamycin11 and the antitumor
antibiotic lankacidin,12 being also an important moiety of tran-
sition-state protease inhibitors.13 This function is usually pre-
pared by strategies that imply the DesseMartin periodinane
oxidation of a-hydroxyamides, oxidation of a-cyanoketones,
or amidation of a-keto acids.14e17 On the other hand, the in-
dole-2-carboxamide generated in compounds 4 is an important
moiety of biologically active compounds such as reverse tran-
scriptase inhibitors, peptide-like compounds, and antitumor
agents.18
3-Arylmethylene-2,5-piperazinediones may be obtained by
cyclization of N-haloacetyldehydroamino esters1 and, most gen-
erally, by an aldol-type reaction between an aromatic aldehyde
and N-acetyl or N,N0-diacetyl-2,5-piperazinediones.2 Many of
these compounds and their 3,6-bis-arylmethylene derivatives
are natural products with interesting biological activity,3 and
they are also versatile synthetic reagents used as chiral templates
in the synthesis of a-amino acids4 and as starting materials to an-
titumor antibiotics of the saframycins family.5
In the development of a synthetic procedure to obtain pyr-
azino[1,2-b]isoquinolines6 we observed that compounds 1 are
unstable in acidic alcohol solutions, giving first the N-deacetyl
derivatives 2 and, later, compounds 3. This one-pot three-step
process implies protonation of the enamine portion of 2, ring-
opening of N-acyliminium cations by addition of alcohol, and
imine hydrolysis in the reaction workup, being the reversal of
other methods applied for the synthesis of cyclic dehydrodi-
peptides.7 Related literature precedents of this acid-promoted
Given the ready access to compounds 1 and the novelty of
their one-pot transformation to compounds 3 and 4, a more
detailed optimization study exploration of more diverse struc-
tures was planned. We disclose here full details of our
investigation.
* Corresponding author. Tel.: þ34913941821; fax: þ34913941822.
~
E-mail address: avendano@farm.ucm.es (C. Avendano).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.047

J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
2763
O
O
O
O
NH
Ac
NH
H
H2O
N
HN
R'OH, H
HN
R
HN
R
R
O
2
R'OH
O
R
1
O
O
O
R
H
H2, Pd-C
N
H
HN
N
OR'
R = 2-NO2
CO2R'
4
O
3
Scheme 1.
2. Results and discussion
under thermal and/or microwave-assisted reaction conditions.
A detailed study of these reactions allowed the isolation in
some cases of the secondary products 5 and 6 (Table 1).
With the exception of compounds 1a and 1h, the yields of
the methanolysis products 3 were more satisfactory in MW-
assisted reactions (method C), varying from 50 to 90%. Di-
methyl ketals 5c and 5f and methyl 3-arylpyruvoyl esters 6
were also isolated. Compounds 6 exists exclusively as enol
forms in CDCl3 solution, and are the products of a second
acid-promoted methanolysis of compounds 3, which is favored
by the electron-withdrawing effect of the ketone into the am-
ide function.20 All compounds 3 exist as keto forms, with the
exception of 3g, in which the enol tautomer is exclusive per-
haps because it is stabilized through intramolecular hydrogen
bonding (Fig. 1).
The success of the ring-opening reaction of compounds 1 in
the previously studied examples10 required to avoid the precip-
itation of compounds 2, whose solubility is highly dependent
on the kind of the aryl substituent and the nature of the alcohol
employed. The best results were obtained for benzylic alcohol,
but the esters thus obtained (3, R0¼Bn) were usually unstable
when a subsequent catalytic reduction of the nitro groups was
required, giving the corresponding carboxylic acids (R0¼H).
Since improvement of yields with methanol (3, R0¼Me)
were envisaged in high diluted solutions assisted by micro-
wave irradiation,19 the methanolysis of compounds 1ae1h,
obtained by aldol-type condensation of 1,4-diacetylpipera-
zine-2,5-dione and commercial aldehydes, was performed
Table 1
Methanolysis of compounds 1
O2N
O
O
X
OH
H
H
N
Ac
MeOH,
HCl
O
N
O
Ar
N
Ar
Ar
OCH3
H
N
OMe
HN
OMe
O
O
O
O
1
3, X = O
5, X = (OMe)2
6
3g
Figure 1.
Entry
Ar in 1
Methoda
Products (% yield)
1
2-NO2-Phenyl
3-NO2-Phenyl
4-NO2-Phenyl
A
C
A
C
C
C
B
C
B
C
B
C
B
C
3a (59)10
3a (51)
2
Catalytic hydrogenation of the o-nitro group of compounds
3a, 3d, and 3e in ethyl acetate solutions afforded methyl N-
indole-2-carbonylamino esters 4a,10 4d, and 4e through a Reis-
sert-type synthesis (Scheme 2). This approach to compounds 4
differs from the most common N-acylation of amino esters
with 2-indolecarbonyl chloride21 or the palladium-mediated
carbonylation of 2-iodoindoles in the presence of an amine.22
Catalytic reduction of the nitro group in m- and p-nitrocom-
pounds 3f and 3g under similar reaction conditions gave the
corresponding aminoaryl derivatives 7f and 7g that exists, as
compound 3g, exclusively as the enol form. Compounds 3b
and 3c gave mixtures of the expected amino compounds 7b
and 7c, that were rather unstable and characterized by their
1H NMR spectra, with traces of other two new products (8
and 9). Structures of compounds 8 and 9 were assigned by
3
3b (8)10
4
3b (54)þ6b (13)
3c10 (63)bþ5c (7)
3d (90)
5
6
2,4-(NO2)2-Phenyl
1-NO2-2-Naphthyl
7
3e (33)þ6e (34)
3e (60)þ6e (10)
3f (41)þ5f (20)
3f (63)þ5f (8)
3gc (50)þ6g (10)
3gc (61)þ6g (24)
3h (70)þ6h (28)
3h (38)þ6h (25)
8
9
4-(4-NO2-Phenoxy)phenyl
6-(3-NO2-Phenyl)-2-pyridyl
3-NO2-2-Thienyl
10
11
12
13
14
a
Method A: reflux time 2.5 h, 0.12 M solutions of compounds 1 in methanol
containing 10% (v/v) of concd HCl; method B: reflux time 12 h, 0.03 M solu-
tions of compounds 1 in methanol containing 10% (v/v) of concd HCl; method
C: microwave irradiation time 5 min, 130 ꢀC, 0.003 M solutions of compounds
1 in methanol containing 10% (v/v) of concd HCl.
1
13C NMR and H NMR spectra that showed the disappearing
b
The corresponding benzyl ester was obtained in 50% yield under reflux
of the ketone signal and the presence of a eCHeCH2e por-
tion characterized by a double doublet one-proton signal
conditions.
c
As the enol tautomer.

2764
J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
O
OCH3
AcOEt, 10-2
M
O
N
H
H2, 10% Pd-C
92%
O
O
N
H
HN
NO2
CO2CH3
CO2CH3
4a
3a
O
AcOEt, 10-2
M
O
OCH3
H2, 16% Pd-C
82%
N
H
N
H
HN
H2N
O
O
O2N
NO2
4d
3d
O
AcOEt, 10-3 M
H2, 19% Pd-C
OCH3
O
N
H
O
NO2
O
64%
N
H
HN
CO2CH3
3e
4e
Scheme 2.
coupled to two benzylic methylene protons. These new prod-
ucts were identified as metacyclophane and paracyclophane
derivatives, which are formed through an intermolecular re-
ductive amination. As it was expected, they were nearly quan-
titatively obtained by performing the reduction of 3b and 3c at
higher concentrations (Scheme 3). No traces of other cyclo-
phanes were observed in the reduction of the rest of nitro-
derivatives studied here.
framework of their large cavities, primarily defined by aromatic
units, which are ready to accommodate charged or neutral guest
molecules.23
In order to determine the relative stereochemistry of cyclo-
phanes 8 and 9, after an initial semiempirical study using PM3
parameter set, we performed ab initio calculations using the 3-
21G(d) basis set at the HartreeeFock (HF) density functional
level in the gas phase.24 A representation of both possible di-
astereoisomers of metacyclophane 8 showed that the two ben-
zene rings are disposed quasi-parallel but not superimposed
Cyclophanes are important compounds in macrocyclic
and supramolecular chemistry mainly because of the rigid
H2N
AcOEt, 4x10-3 M
H2,10% Pd-C
O
O
O
3f
H
N
OMe
7f (69%)
OH
O
O
H
AcOEt, 2x10-3
H2, 26% Pd-C
M
H2N
N
OMe
N
3g
O
7g (55%)
O
O
O
NH
O
AcOEt, 2x10-3 M
H2, 10% Pd-C
O
H
N
H
H3CO
3b
N
OCH3
N
OMe
H2N
H2N
H
HN
O
O
+
O
7b (92%)
8 (6%)
AcOEt, 6x10-3
H2, 20% Pd-C
M
O
O
3c
H
N
NH
H3CO
O
OMe
H
N
H
N
O
+
O
HN
OCH3
O
7c (62%)
9 (9%)
AcOEt, 2x10-2
H2, 10% Pd-C
M
AcOEt, 2x10-2 M
H2, 10% Pd-C
3c
3b
8
9
93%
98%
Scheme 3.

J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
2765
while in paracyclophane 9 the two benzene rings are parallel and
that cis-8 is more stable than cis-9 (DH¼6.8 kcal molꢁ1
)
nearly superposed. The two tethers adopt in the cis-isomer of
compound 8 a boat-like conformation, while in the trans-isomer
they adopt a distorted chair-like conformation with the two side-
chains equatorially disposed in both cases. In the two diastereo-
isomers of 9 the two tethers adopt a boat-like conformation, but,
while the two side-chains are equatorially disposed in the
cis-isomer, in the trans-isomer one is equatorial and the other
is axial (Fig. 2). The calculated heat of formation values showed
that the cis-isomers are more stable than the trans-isomers
(DH¼3.7 kcal molꢁ1 for 8 and 1.2 kcal molꢁ1 for 9), and also
(Fig. 2). These data support a cis-stereochemistry for both
compounds.
Aminoaryl compounds 7b and 4d were coupled with N-
Boc-protected amino acids, under standard HOAteEDCe
NMO mediated conditions, to give compounds 10e14 (Table
2).
In conclusion, cyclic dehydrodipeptides 1, easily obtained
by aldol-type condensation of 1,4-diacetylpiperazine-2,5-di-
one and aromatic aldehydes, are convenient starting materials
for a one-pot atom-efficient synthesis of N-3-arylpyruvoyl-
amino esters 3 and a great array of structurally diverse
compounds. 2-Nitroaryl derivatives allow the synthesis of
N-indole-2-carbonylamino esters 4 through intramolecular
reductive amination. Reduction of the nitro groups in com-
pounds 3 afford the corresponding N-aminoarylpyruvoylamino
esters 7 or aminoindolecarbonylamino esters 4 that may be
coupled with amino acids to give peptide-like compounds
10e14. Alternatively, the intermolecular reductive amination
of m- or p-nitroaryl compounds 3b and 3c has been revealed
as a simple and very efficient route for the synthesis of 2,6-
diazacyclophanes 8 and 9.
H
H
H
R
Ha
H
H
R
N
N
H
R
N
Hb
Ha
Ha
Ha
Hb
R
N
H
Ha
Hb
H
trans-8
cis-8
R
H
H
H
Ha
Ha
R
R
R
N
H
N
H
Hb
H
Ha
Hb
H
Hb
N
Ha
Hb
N
H
trans-9
cis-9
3. Experimental
Calculated H-C-C-Ha and H-C-C-Hb dihedral angles
cis-8
170.7°/128.1° and 145.3°/97.8°
177.7°/61.6° and 172.2°/56.6°
175.1°/59.0° and 158.2°/85.2°
175.9°/60.5° and 69.2°/45.8°
3.1. General
cis-9
trans-8
trans-9
The reagents used were of commercial origin (Aldrich,
Fluka) and were employed without further purification. Solvents
(SDS, Scharlau) were purified and dried by standard procedures.
Figure 2. Side view of cis- and trans-diastereoisomer of metacyclophane (8)
and paracyclophane (9).
Table 2
Coupling reactions of compounds 7b and 4d with N-Boc-protected amino acids
O
O
O
H
N-Boc amino acid
H
N
BocNH
Linker
N
HN
Linker
H2N
OCH3
OCH3
HOAt, EDC, HCl, NMO,
dry DMF, 0 °C, 2 h, 4 °C, 16 h
R
O
O
Product
R
Yield
1010, 76%
BocHN
H3C
O
CH3
OCH3
N
H
11, 71%
12, 71%
13, 42%
O
O
BocHN
NHCOR
BocHN
H3C
CH3
BocHN
O
CH3
N
H
HN
RCONH
OCH3
H3C
14, 43%
O
BocHN

2766
J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
Reactions were monitored by thin-layer chromatography, using
Macherey-Nagel or Merck plates with fluorescent indicator.
Separations by flash liquid chromatography were performed us-
ing silica gel from SDS 60 ACC (230e400 mesh) or Merck (60,
40e63 mm) and aluminum oxide from Merck (90, 70e230
mesh).
3.2.3. 1-Acetyl-3-(2,4-dinitrophenylmethylene)-2,5-
piperazinedione (1d)
The crude residue was purified by flash column chromatog-
raphy (1:1 hexane/EtOAc) to provide compound 1d (98%
yield) as a yellow solid. Mp 239e240 ꢀC; IR (film) n 1695,
1
1633 cmꢁ1; H NMR (250 MHz, acetone-d6) d 8.91 (m, 1H),
Melting points are uncorrected, and were determined using
a Hoffler hot stage microscope. Spectroscopic data were ob-
tained with the following instruments: IR, PerkineElmer Para-
gon 1000 FT-IR; NMR, Bruker AC-250 (250 MHz for 1H and
63 MHz for 13C), Varian Unity 300 (300 MHz for 1H and
8.66 (d, J¼8.0 Hz, 1H), 8.13 (d, J¼8.0 Hz, 1H), 7.36 (s, 1H),
4.22 (s, 2H), 2.37 (s, 3H); 13C NMR (63 MHz, acetone-d6) d
173.6 (C), 164.6 (C), 161.0 (C), 158.7 (C), 150.7 (C), 138.2
(C), 134.5 (CH), 129.4 (CH), 127.6 (C), 121.7 (CH), 113.4
(CH), 47.4 (CH2), 27.7 (CH3). Anal. Calcd for C13H10N4O7:
C, 46.71; H, 3.02; N, 16.76. Found: C, 46.52; H, 2.94; N,
16.54.
1
75 MHz for 13C) or Varian Unity Inova 500 (500 MHz for H
and 125 MHz for 13C). Combustion elemental analyses were ob-
´
tained by the Servicio de Microanalisis Elemental, Universidad
Complutense, using a PerkineElmer 2400 CHN and a Leco
CHNS 932 microanalyzer.
3.2.4. 1-Acetyl-3-(1-nitro-2-naphthylmethylene)-2,5-
piperazinedione (1e)
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 1e (99% yield) as
3.2. Condensation procedure
a yellow solid. Mp 276e277 ꢀC; IR (film) n 1706, 1694 cmꢁ1
;
1H NMR (250 MHz, CDCl3) d 8.32 (br s, 1H), 8.10 (d, J¼
(d, J¼8.5 Hz, 1H), 7.22 (s, 1H), 4.44 (s, 2H), 2.84 (s, 3H); 13
ToasolutionofN,N0-diacetyl-2,5-piperazinedione (10 mmol)
in anhydrous THF (100 mL), under Ar atmosphere, were added
the corresponding aldehyde (11 mmol) and 1 equiv of a 1 M so-
lution of potassium tert-butoxide in tert-butyl alcohol. The reac-
tion was stirred at room temperature for 5 h. After the addition of
an aqueous solution of ammonium chloride (30 mL) and concen-
tration of the solvent the condensation product precipitated. The
filtratewas first washed with water (30 mL)and then with hexane
(30 mL) and the crude residue was purified by flash column
chromatography.
8.5 Hz, 1H), 7.98 (m, 1H), 7.85 (m, 1H), 7.72 (m, 2H), 7.49
C
NMR (63 MHz, CDCl3) d 172.3 (C), 162.9 (C), 158.6 (C),
147.6 (C), 133.6 (C), 132.0 (C), 129.6 (CH), 129.2 (CH),
128.5 (CH), 128.2 (CH), 124.7 (C), 124.1 (CH), 122.6 (C),
121.9 (CH), 113.4 (CH), 46.0 (CH2), 27.3 (CH3). Anal. Calcd
for C17H13N3O5: C, 60.18; H, 3.86; N, 12.38. Found: C,
59.93; H, 3.73; N, 12.06.
3.2.5. 1-Acetyl-3-(4-(4-nitrophenoxy)phenylmethylene)-2,5-
piperazinedione (1f)
3.2.1. 1-Acetyl-3-(3-nitrophenylmethylene)-2,5-
piperazinedione (1b)
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 1b (94% yield) as
a yellow solid. Mp 159e160 ꢀC; IR (film) n 1694, 1634 cmꢁ1
1H NMR (250 MHz, CDCl3) d 8.48 (br s, 1H), 8.33 (s, 1H),
8.27 (d, J¼7.8 Hz, 1H), 7.76 (d, J¼7.9 Hz, 1H), 7.68 (dd,
J¼7.9 and 7.8 Hz, 1H), 7.21 (s, 1H), 4.52 (s, 2H), 2.70 (s,
3H); 13C NMR (63 MHz, CDCl3) d 172.2 (C), 163.2 (C),
159.3 (C), 148.7 (C), 134.3 (CH), 134.1 (C), 130.5 (CH),
127.5 (C), 123.7 (CH), 123.4 (CH), 116.8 (CH), 45.9 (CH2),
27.2 (CH3). Anal. Calcd for C13H11N3O5: C, 53.98; H, 3.83;
N, 14.53. Found: C, 53.62; H, 3.77; N, 14.35.
The crude residue was purified by flash column chromatogra-
phy (3:7 hexane/EtOAc) to provide compound 1f (98% yield) as
a yellow solid. Mp 186e188 ꢀC; IR (film) n 1681, 1621 cmꢁ1
;
1H NMR (250 MHz, CDCl3) d 8.27 (d, J¼16.5 Hz, 2H), 8.13
(br s, 1H), 7.50 (d, J¼11.0 Hz, 2H), 7.20 (d, J¼16.5 Hz, 2H),
7.20 (s, 1H), 7.11 (d, J¼11.0 Hz, 2H), 4.56 (s, 2H), 2.69 (s,
3H); 13C NMR (63 MHz, CDCl3) d 170.7 (C), 163.0 (C),
162.1 (C), 159.8 (C), 155.6 (C), 143.2 (C), 130.7 (CH), 129.2
(C), 126.0 (CH), 125.6 (C), 121.0 (CH), 117.8 (CH), 117.8
(CH), 46.0 (CH2), 27.2 (CH3). Anal. Calcd for C19H15N3O6:
C, 59.84; H, 3.96; N, 11.02. Found: C, 59.75; H, 3.64; N, 10.87.
;
3.2.6. 1-Acetyl-3-(6-(3-nitrophenyl)-2-pyridylmethylene)-
2,5-piperazinedione (1g)
3.2.2. 1-Acetyl-3-(4-nitrophenylmethylene)-2,5-
piperazinedione (1c)
The crude residue was purified by flash column chromatogra-
phy (3:7 hexane/EtOAc) to provide compound 1g (93% yield) as
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 1c (92% yield) as
a yellow solid. Mp 210e211 ꢀC (lit25 212e214 ꢀC); IR (film) n
a yellow solid. Mp 250e251 ꢀC; IR (film) n 1693, 1633 cmꢁ1
;
1H NMR (250 MHz, CDCl3) d 8.63 (t, J¼1.7 Hz, 1H), 8.29
(m, 1H), 8.24 (m, 1H), 7.96 (m, 1H), 7.93 (m, 1H), 7.80e7.60
(m, 2H), 6.84 (s, 1H), 4.26 (s, 2H), 2.42 (s, 3H); 13C NMR
(63 MHz, CDCl3) d 172.6 (C), 163.1 (C), 159.6 (C), 154.9
(C), 153.8 (C), 148.9 (C), 140.1 (C), 139.7 (CH), 133.3 (CH),
132.0 (C), 131.2 (CH), 127.0 (CH), 124.7 (CH), 121.6 (CH),
121.1 (CH), 109.3 (CH), 46.9 (CH2), 27.5 (CH3). Anal. Calcd
for C18H14N4O5: C, 59.02; H, 3.85; N, 15.29. Found: C,
58.83; H, 3.61; N, 15.01.
1
1693, 1633 cmꢁ1; H NMR (250 MHz, CDCl3) d 8.34 (d, J¼
8.4 Hz, 2H), 8.02 (br s, 1H), 7.61 (d, J¼8.4 Hz, 2H), 7.21 (s,
1H), 4.57 (s, 2H), 2.70 (s, 3H); 13C NMR (63 MHz, CDCl3)
d 172.3 (C), 162.3 (C), 159.1 (C), 147.6 (C), 139.0 (C), 129.4
(CH), 127.9 (C), 124.7 (CH), 116.4 (CH), 46.1 (CH2), 27.3
(CH3). Anal. Calcd for C13H11N3O5: C, 53.98; H, 3.83; N,
14.53. Found: C, 53.72; H, 3.64; N, 14.48.

J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
2767
3.2.7. 1-Acetyl-3-(3-nitro-2-thienylmethylene)-2,5-
piperazinedione (1h)
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 1h (96% yield) as
an orange solid. Mp 178e179 ꢀC; IR (film) n 1709, 1698 cmꢁ1
1H NMR (250 MHz, CDCl3) d 7.97 (d, J¼9.8 Hz, 1H), 7.25 (d,
J¼9.8 Hz, 1H), 4.60 (s, 2H), 2.69 (s, 3H); 13C NMR (63 MHz,
CDCl3) d 172.0 (C), 170.7 (C), 165.8 (C), 162.5 (C), 159.0
(C), 141.6 (C), 129.1 (CH), 128.7 (CH), 110.1 (CH), 47.1 (CH2),
26.7 (CH3). Anal. Calcd for C11H9N3O5S: C, 44.74; H, 3.07; N,
14.23. Found: C, 44.53; H, 2.94; N, 14.02.
1688 cmꢁ1; 1H NMR (250 MHz, CDCl3) d 8.18 (m, 1H), 7.57
(m, 2H), 7.38 (m, 2H), 4.39 (s, 2H), 4.14 (d, J¼5.7 Hz, 2H),
3.81 (s, 3H); 13C NMR (63 MHz, CDCl3) d 193.4 (C), 168.4
(C), 159.2 (C), 148.1 (C), 134.2 (C), 136.1 (CH), 129.5 (CH),
124.8 (CH), 122.5 (CH), 52.7 (CH3), 42.6 (CH2), 41.0 (CH2).
Anal. Calcd for C12H12N2O6: C, 51.43; H, 4.32; N, 10.00.
Found: C, 51.24; H, 4.08; N, 9.91.
;
3.5.3. Methyl N-(3-(2,4-dinitrophenyl)pyruvoyl)glycinate
(3d)
The crude residue was purified by flash column chromatogra-
phy (4:6 hexane/EtOAc) to provide compound 3d (method C,
90% yield) as a yellow solid. Mp 51e52 ꢀC; IR (film) n 1784,
1692 cmꢁ1; 1H NMR (250 MHz, CDCl3) d 9.06 (d, J¼3.4 Hz,
1H), 8.51 (dd, J¼8.4 and 3.4 Hz, 1H), 7.61 (d, J¼8.4 Hz, 1H),
7.42 (t, J¼5.6 Hz, 1H), 4.82 (s, 2H), 4.18 (d, J¼5.6 Hz, 2H),
3.84 (s, 3H); 13C NMR (63 MHz, CDCl3) d 192.0 (C), 168.9
(C), 159.2 (C), 148.6 (C), 147.4 (C), 136.2 (C), 135.0 (CH),
127.7 (CH), 120.9 (CH), 52.7 (CH3), 42.7 (CH2), 41.1 (CH2).
Anal. Calcd for C12H11N3O8: C, 44.32; H, 3.41; N, 12.92.
Found: C, 43.97; H, 3.02; N, 12.73.
3.3. Acid-promoted methanolysis: method A
A 0.12 M solution of the corresponding compound 1 in meth-
anol containing 10% (v/v) of concd HCl was refluxed for 2.5 h.
Then, the solvent was distilled in vacuo to dryness, and the solid
residue was purified by flash column chromatography.
3.4. Acid-promoted methanolysis: method B
A 0.03 M solution of the corresponding compound 1 in meth-
anol containing 10% (v/v) of concd HCl was refluxed for 12 h.
Then, the solvent was distilled in vacuo to dryness, and the solid
residue was purified by flash column chromatography.
3.5.4. Methyl N-(3-(1-nitro-2-naphthyl)pyruvoyl)glycinate
(3e)
The crude residue was purified by flash column chromatogra-
phy (7:3 hexane/EtOAc) to provide compound 3e (method C,
60% yield) as a brown solid. Mp 100e101 ꢀC, IR (film) n
1750, 1691 cmꢁ1 1H NMR (250 MHz, CDCl3) d 8.01 (d,
;
3.5. Acid-promoted methanolysis: method C
The microwave instrument used in this experiment was the
CEM Discover. A 0.003 M solution of the corresponding com-
pound 1 in methanol containing 10% (v/v) of concd HCl was
placed in a MW test tube (10 mL) containing a magnetic stir-
ring bar. The sealed tube was irradiated at 130 ꢀC for 5 min.
After cooling to room temperature, the solution was filtered
and the solvent evaporated in vacuo. EtOAc (50 mL) was
added to the residue, the organic solution was washed with
brine (50 mL), dried over sodium sulfate, filtered, and concen-
trated. The crude product was purified by flash column
chromatography.
J¼8.5 Hz, 1H), 7.95 (dd, J¼7.3 and 2.3 Hz, 1H), 7.88 (dd, J¼
8.5 and 1.2 Hz, 1H), 7.64 (m, 2H), 7.46 (t, J¼5.7 Hz, 1H),
7.37 (d, J¼8.5 Hz, 1H), 4.52 (s, 2H), 4.15 (d, J¼5.7 Hz, 2H),
3.81 (s, 3H); 13C NMR (63 MHz, CDCl3) d 192.9 (C), 169.0
(C), 159.4 (C), 147.9 (C), 133.2 (C), 131.5 (CH), 128.9 (CH),
128.7 (CH), 128.1 (CH), 127.4 (CH), 124.8 (C), 124.3 (C),
121.9 (CH), 52.6 (CH3), 41.0 (CH2), 40.5 (CH2). Anal. Calcd
for C16H14N2O6: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.93;
H, 3.94; N, 8.23.
3.5.5. Methyl N-(3-(4-(4-nitrophenoxy)phenyl)pyruvoyl)-
glycinate (3f)
3.5.1. Methyl N-(3-(2-nitrophenyl)pyruvoyl)glycinate (3a)
The crude residue was purified by flash column chromatogra-
phy (6:4 hexane/EtOAc) to provide compound 3a (method A,
59% yield) as a yellow solid. Mp 91e93 ꢀC; IR (film) n 1750,
The crude residue was purified by flash column chromatogra-
phy (7:3 hexane/EtOAc) to provide compound 3f (method C,
63% yield) as a yellow solid. Mp 107e108 ꢀC; IR (film) n
1753, 1689 cmꢁ1 1H NMR (250 MHz, CDCl3) d 8.13 (d,
;
1732, 1694 cmꢁ1
;
1H NMR (250 MHz, CDCl3) d 8.17 (d,
J¼7.1 Hz, 2H), 7.37 (t, J¼5.6 Hz, 1H), 6.98 (d, J¼7.1 Hz,
2H), 6.95 (d, J¼6.9 Hz, 2H), 4.18 (s, 2H), 4.04 (d, J¼5.6 Hz,
2H), 3.73 (s, 3H); 13C NMR (63 MHz, CDCl3) d 194.6 (C),
169.1 (C), 159.8 (C), 163.1 (C), 153.9 (C), 142.6 (C), 131.7
(CH), 129.5 (CH), 129.5 (C), 120.7 (CH), 117.1 (CH), 52.7
(CH3), 42.4 (CH2), 41.0 (CH2). Anal. Calcd for C18H16N2O7:
C, 58.06; H, 4.33; N, 7.52. Found: C, 57.87; H, 4.11; N, 7.43.
J¼7.4 Hz, 1H), 7.64 (d, J¼7.4 Hz, 1H), 7.51 (d, J¼7.4 Hz, 1H),
7.48 (br s, 1H), 7.32 (d, J¼7.4 Hz, 1H), 4.63 (s, 2H), 4.14 (d,
J¼5.7 Hz, 2H), 3.81 (s, 3H); 13C NMR (63 MHz, CDCl3)
d 193.2 (C), 169.1 (C), 159.7 (C), 148.3 (C), 133.8 (CH),
133.6 (CH), 129.4 (C), 128.7 (CH), 125.4 (CH), 52.5 (CH3),
42.5 (CH2), 41.0 (CH2). Anal. Calcd for C12H12N2O6: C,
51.43; H, 4.32; N, 10.00. Found: C, 51.32; H, 4.12; N, 9.89.
3.5.6. Methyl N-(3-(6-(3-nitrophenyl)-2-pyridyl)pyruvoyl)-
glycinate (3g)
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 3g (method C,
61% yield) as a yellow solid. Mp 94e96 ꢀC; IR (film) n 1748,
3.5.2. Methyl N-(3-(3-nitrophenyl)pyruvoyl)glycinate (3b)
The crude residue was purified by flash column chromatogra-
phy (6:4 hexane/EtOAc) to provide compound 3b (method C,
54% yield) as a yellow solid. Mp 80e81 ꢀC; IR (film) n 1750,

2768
J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
1674 cmꢁ1; H NMR (250 MHz, CDCl3) d 8.63 (t, J¼2.0 Hz,
1H), 8.27 (d, J¼8.2 Hz, 1H), 8.15 (dd, J¼7.8 and 1.6 Hz, 1H),
7.80 (t, J¼7.8 Hz, 1H), 7.66 (t, J¼8.0 Hz, 1H), 7.54 (dd, J¼
7.8 and 0.8 Hz, 1H), 7.42 (t, J¼5.5 Hz, 1H), 7.20 (d, J¼
7.8 Hz, 1H), 6.60 (s, 1H), 4.15 (d, J¼5.5 Hz, 2H), 3.73 (s, 3H);
13C NMR (63 MHz, CDCl3) d 169.9 (C), 163.1 (C), 157.3 (C),
153.9 (C), 151.9 (C), 148.8 (C), 139.4 (C), 138.8 (CH), 132.4
(CH), 130.3 (CH), 124.2 (CH), 123.1 (CH), 121.7 (CH), 118.6
(CH), 100.3 (CH), 52.5 (CH3), 41.1 (CH2). Anal. Calcd for
C17H15N3O6: C, 57.14; H, 4.23; N, 11.76. Found: C, 56.95; H,
4.07; N, 11.49.
13% yield) as a yellow solid. Mp 90e91 ꢀC; IR (film) n 3410,
1
1
1704, 1530 cmꢁ1; H NMR (250 MHz, CDCl3) d 8.56 (t, J¼
2.0 Hz, 1H), 8.05 (ddd, J¼8.2, 2.3, and 1.2 Hz, 1H), 7.96 (td, J¼
7.8 and 1.2 Hz, 1H), 7.45 (t, J¼8.0 Hz, 1H), 6.66 (d, J¼1.5 Hz,
1H), 6.47 (d, J¼1.1 Hz, 1H), 3.89 (s, 3H); 13C NMR (63 MHz,
CDCl3) d 166.4 (C), 148.8 (C), 141.3 (C), 136.1 (C), 135.8 (CH),
129.7 (CH), 124.7 (CH), 122.8 (CH), 108.8 (CH), 54.1 (CH3).
Anal. Calcd for C10H9NO5: C, 53.82; H, 4.06; N, 6.28. Found:
C, 53.61; H, 3.96; N, 5.97.
3.5.11. Methyl 2-hydroxy-3-(1-nitro-2-naphthyl)-2-
propenoate (6e)
3.5.7. Methyl N-(3-(3-nitro-2-thienyl)pyruvoyl)glycinate
(3h)
The crude residue was purified by flash column chromatogra-
phy (EtOAc) to provide compound 3h (method B, 70% yield) as
a brown solid. Mp 124e125 ꢀC; IR (film) n 1747, 1681 cmꢁ1
1H NMR (250 MHz, CDCl3) d 7.84 (d, J¼4.1 Hz, 1H), 7.53 (m,
1H), 6.94 (d, J¼4.1 Hz, 1H), 4.53 (s, 2H), 4.15 (d, J¼5.7 Hz,
2H), 3.82 (s, 3H); 13C NMR (63 MHz, CDCl3) d 191.9 (C),
169.0 (C), 159.1 (C), 143.6 (C), 141.8 (C), 128.4 (CH), 127.3
(CH), 52.7 (CH3), 41.0 (CH2), 37.9 (CH2). Anal. Calcd for
C10H10N2O6S: C, 41.96; H, 3.52; N, 9.79. Found: C, 41.77; H,
3.38; N, 9.45.
The crude residue was purified by flash column chromatogra-
phy (7:3 hexane/EtOAc) to provide compound 6e (method B,
34% yield) as a yellow solid. Mp 96e97 ꢀC; IR (film) n
1698 cmꢁ1; 1H NMR (250 MHz, CDCl3) d 8.43 (d, J¼8.8 Hz,
1H), 7.99 (d, J¼8.8 Hz, 1H), 7.72 (m, 1H), 7.65 (m, 1H),
7.62e7.57 (m, 2H), 6.84 (d, J¼1.2 Hz, 1H), 6.56 (s, 1H), 3.98
(s, 3H); 13C NMR (63 MHz, CDCl3) d 165.9 (C), 142.1 (C),
138.2 (C), 132.9 (C), 130.2 (CH), 128.7 (CH), 127.9 (CH),
127.6 (CH), 126.1 (CH), 124.3 (C), 123.5 (C), 121.8 (CH),
102.2 (CH), 53.8 (CH3). Anal. Calcd for C14H11NO5: C,
61.54; H, 4.06; N, 5.13. Found: C, 61.31; H, 3.92; N, 4.87.
;
3.5.12. Methyl 2-hydroxy-3-(6-(3-nitrophenyl-2-pyridyl)-2-
propenoate (6g)
3.5.8. Methyl N-(2,2-dimethoxy-3-(4-nitrophenyl)propanoyl)-
glycinate (5c)
The crude residue was purified by flash column chromatogra-
phy (7:3 hexane/EtOAc) to provide compound 6g (method C,
24% yield) as a yellow solid. Mp 140e141 ꢀC; IR (film) n
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 5c (method C,
7% yield) as a yellow solid. Mp 126e127 ꢀC; IR (film) n
1
1714 cmꢁ1; H NMR (250 MHz, CDCl3) d 8.62 (t, J¼2.0 Hz,
1
1754, 1688 cmꢁ1; H NMR (250 MHz, CDCl3) d 7.90 (d, J¼
1H), 8.23 (m, 2H), 7.84 (t, J¼7.9 Hz, 1H), 7.62 (t, J¼8.0 Hz,
1H), 7.61 (dd, J¼7.9 and 0.8 Hz, 1H), 7.22 (dd, J¼7.9 and
0.8 Hz, 1H), 6.61 (s, 1H), 3.86 (s, 3H); 13C NMR (63 MHz,
CDCl3) d 164.0 (C), 156.8 (C), 152.3 (C), 151.6 (C), 148.7
(C), 139.3 (C), 138.9 (CH), 132.5 (CH), 130.3 (CH), 124.3
(CH), 123.1 (CH), 121.7 (CH), 119.1 (CH), 104.2 (CH), 52.7
(CH3). Anal. Calcd for C15H12N2O5: C, 60.00; H, 4.03; N,
9.33. Found: C, 59.77; H, 3.85; N, 9.06.
8.7 Hz, 2H), 7.14 (d, J¼8.7 Hz, 2H), 6.85 (d, J¼5.6 Hz, 1H),
3.70 (d, J¼5.6 Hz, 2H), 3.49 (s, 3H), 3.16 (s, 6H) 3.08 (s, 2H);
13C NMR (63 MHz, CDCl3) d 169.5 (C), 168.3 (C), 146.9 (C),
142.5 (C), 130.9 (CH), 123.3 (CH), 102.4 (C), 52.4 (CH3), 50.1
(CH3), 40.6 (CH2), 38.8 (CH2). Anal. Calcd for C14H18N2O7:
C, 51.53; H, 5.56; N, 8.59. Found: C, 51.39; H, 5.42; N, 8.38.
3.5.9. Methyl N-[2,2-dimethoxy-3-(4-(4-nitrophenoxy)-
phenyl)propanoyl]glycinate (5f)
3.5.13. Methyl 2-hydroxy-3-(3-nitro-2-thienyl)-2-
propenoate (6h)
The crude residue was purified by flash column chromatogra-
phy(1:1hexane/EtOAc) to providecompound 5f (method C, 8%
1
yield) as a yellow oil. IR (film) n 1755, 1682 cmꢁ1; H NMR
The crude residue was purified by flash column chromatogra-
phy (7:3 hexane/EtOAc) to provide compound 6h (method B,
28% yield) as a yellow solid. Mp 168e169 ꢀC; IR (film) n
1694 cmꢁ1; 1H NMR (250 MHz, CDCl3) d 7.89 (d, J¼4.3 Hz,
1H), 7.14 (d, J¼4.3 Hz, 1H), 6.97 (br s, 1H), 6.78 (s, 1H), 3.97
(s, 3H); 13C NMR (63 MHz, CDCl3) d 164.7 (C), 144.2 (C),
141.0 (C), 136.2 (C), 128.5 (CH), 127.2 (CH), 104.4 (CH),
53.7 (CH3). Anal. Calcd for C8H7NO5S: C, 41.92; H, 3.08; N,
6.11. Found: C, 41.76; H, 2.83; N, 6.02.
(250 MHz, CDCl3) d 8.19 (d, J¼5.5 Hz, 2H), 7.24 (d, J¼
4.6 Hz, 2H), 7.07 (t, J¼5.5 Hz, 1H), 7.02 (d, J¼5.5 Hz, 2H),
6.98 (d, J¼4.6 Hz, 2H), 3.95 (d, J¼5.5 Hz, 2H), 3.74 (s, 6H),
3.74 (s, 3H), 3.23 (s, 2H); 13C NMR (63 MHz, CDCl3) d
169.7 (C), 168.7 (C), 163.4 (C), 153.4 (C), 142.5 (C), 131.9 (C),
131.8 (CH), 125.9 (CH), 120.2 (CH), 116.9 (CH), 102.8 (C),
52.4 (CH3), 49.9 (CH3), 40.6 (CH2), 38.1 (CH2). Anal. Calcd
for C20H22N2O8: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.22;
H, 5.03; N, 6.41.
3.6. Catalytic reduction of compounds 3
3.5.10. Methyl 2-hydroxy-3-(3-nitrophenyl)-2-propenoate
(6b)
The crude residue was purified by flash column chromatogra-
phy (8:2 hexane/EtOAc) to provide compound 6b (method C,
A 10ꢁ2e10ꢁ3 M solution of compounds 3 in EtOAc with
a 10e26% PdeC was hydrogenated at room temperature for
5 h. After filtration over Celite and evaporation of the solvent

J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
2769
under reduced pressure, the solid residue was purified by flash
column chromatography.
chromatography (2:8 hexane/EtOAc) to provide compound 7c
(62% yield) as a yellow oil. IR (film) n 3352, 1746,
1679 cmꢁ1; 1H NMR (250 MHz, CDCl3) d 7.06 (d, J¼8.2 Hz,
2H), 6.67 (d, J¼8.2 Hz, 2H), 4.12 (s, 2H), 4.09 (s, 2H), 3.80
(s, 3H).
3.6.1. Methyl N-(1H-indole-2-carbonyl)glycinate (4a)
A 10ꢁ2 M solution of 3a in EtOAc with a 10% PdeC was
used. Thecruderesiduewaspurifiedbyflashcolumnchromatog-
raphy (1:1 hexane/EtOAc) to provide compound 4a (92% yield)
as a white solid. Mp 197e198 ꢀC; IR (film) n 3367, 3274,
1737 cmꢁ1; 1H NMR (250 MHz, CDCl3) d 7.61 (d, J¼8.0 Hz,
1H), 7.47 (d, J¼8.2 Hz, 1H), 7.22 (dd, J¼8.2 and 1.1 Hz, 1H),
7.10 (s, 1H), 7.06 (d, J¼8.0 Hz, 1H), 4.14 (s, 2H), 3.66 (s,
3H); 13C NMR (63 MHz, DMSO-d6) d 169.9 (C), 162.3 (C),
136.2 (C), 129.4 (C), 126.7 (C), 123.1 (CH), 120.7 (CH),
119.1 (CH), 110.0 (CH), 102.8 (CH), 50.6 (CH3), 39.8 (CH2).
Anal. CalcdforC12H12N2O3: C, 62.06; H, 5.21;N, 12.06. Found:
C, 61.97; H, 5.11; N, 11.93.
3.6.6. Methyl N-[3-(4-(4-aminophenoxy)phenyl)pyruvoyl]-
glycinate (7f)
A 4ꢂ10ꢁ3 M solution of 3f in EtOAc with a 10% PdeC was
used. The crude residue was purified by flash column chroma-
tography (2:8 hexane/EtOAc) to provide compound 7f (69%
yield) as a yellow solid. Mp 87e88 ꢀC; IR (film) n 1748,
1
1682 cmꢁ1; H NMR (250 MHz, CDCl3) 7.45 (t, J¼6.1 Hz,
1H), 7.17 (d, J¼7.5 Hz, 2H), 6.90 (m, 4H), 6.70 (d, J¼8.6 Hz,
2H), 4.19 (s, 2H), 4.11 (d, J¼6.1 Hz, 2H), 3.80 (s, 3H); 13C
NMR (63 MHz, CDCl3) d 194.9 (C), 173.9 (C), 169.2 (C),
158.2 (C), 148.3 (C), 142.7 (C), 131.4 (CH), 125.6 (C), 121.7
(CH), 117.7 (CH), 116.7 (CH), 53.1 (CH3), 42.3 (CH2), 41.0
(CH2). Anal. Calcd for C18H18N2O5: C, 63.15; H, 5.30; N,
8.18. Found: C, 62.89; H, 4.96; N, 8.02.
3.6.2. Methyl N-(1H-6-aminoindole-2-carbonyl)glycinate
(4d)
A 10ꢁ2 M solution of 3d in EtOAc with a 16% PdeC was
used. The crude residue was purified by flash column chroma-
tography (2:8 hexane/EtOAc) to provide compound 4d (82%
3.6.7. Methyl N-[3-(6-(3-aminophenyl)pyridyl)pyruvoyl]-
glycinate (7g)
yield) as a brown solid. Mp 52e53 ꢀC; IR (film) n 1748 cmꢁ1
;
1H NMR (250 MHz, DMSO-d6) d 10.96 (br s, 1H), 8.64 (d,
J¼5.7 Hz, 1H), 7.26 (d, J¼8.5 Hz, 1H), 6.94 (s, 1H), 6.50 (s,
1H), 6.44 (d, J¼8.5 Hz, 1H), 5.06 (br s, 2H), 4.01(d,
J¼5.7 Hz, 1H), 3.60 (s, 3H); 13C NMR (63 MHz, DMSO-d6)
d 170.9, 162.0, 146.3, 138.8, 128.1, 122.0, 119.1, 111.7,
103.9, 94.4, 51.9, 40.3. Anal. Calcd for C12H13N3O3: C,
58.29; H, 5.30; N, 16.99. Found: C, 57.98; H, 5.04; N, 16.75.
A 2ꢂ10ꢁ3 M solution of 3g in EtOAc with a 26% PdeC was
used. The crude residue was purified by flash column chroma-
tography (aluminum oxide, H2O) to provide 7g (55% yield) as
a yellow oil. IR (film) n 1741, 1671 cmꢁ1
;
1H NMR
(250 MHz, CDCl3) d 7.76 (m, 2H), 7.52 (d, J¼8.0 Hz, 1H),
7.34 (m, 2H), 7.15 (d, J¼8.0 Hz, 1H), 6.84 (d, J¼7.8 Hz, 1H),
6.60 (s, 1H), 4.23 (d, J¼5.5 Hz, 2H), 3.82 (s, 3H); 13C NMR
(63 MHz, CDCl3) d 170.5 (C), 156.8 (C), 152.2 (C), 143.3
(C), 147.7 (C), 139.3 (CH), 138.2 (C), 130.6 (CH), 130.0
(CH), 122.0 (CH), 117.2 (CH), 114.5 (C), 113.1 (CH), 97.9
(CH), 52.3 (CH3), 41.6 (CH2). Anal. Calcd for C17H17N3O4:
C, 62.38; H, 5.23; N, 12.84. Found: C, 62.13; H, 5.08; N, 12.43.
3.6.3. Methyl N-(1H-benzo[g]indole-2-carbonyl)glycinate
(4e)
A10ꢁ3 M solutionof3einEtOAcwitha19%PdeCwasused.
The crude residue was purified by flash column chromatography
(1:1 hexane/EtOAc) to provide compound 4e (64% yield) as an
orange solid. Mp 200e201 ꢀC; IR (film) n 1748 cmꢁ1
;
1H
3.6.8. Methyl [2,6-diaza-1,5-bis(1,3)dibenzenacyclododeca-
phane]-3,7-bisylenecarbonyl glycinate (8)
NMR (250 MHz, CDCl3) d 8.18 (d, J¼8.2 Hz, 1H), 7.95 (d,
J¼7.3 Hz, 1H), 7.70 (d, J¼8.2 Hz, 1H), 7.57 (m, 3H), 7.10 (s,
A 2ꢂ10ꢁ2 M solution of 3b in EtOAc with a 10% PdeC was
used. The crude residue was purified by flash column chroma-
tography EtOAc to provide compound 8 (98% yield) as an or-
1H), 6.72 (br s, 1H), 4.36 (d, J¼5.0 Hz, 1H), 3.83 (s, 3H); 13
C
NMR (63 MHz, CDCl3) d 170.4 (C), 164.1 (C), 132.2 (C),
131.6 (C), 130.0 (C), 128.8 (C), 125.9 (CH), 125.3 (CH), 123.8
(C), 122.0 (CH), 121.8 (CH), 120.9 (CH), 120.5 (CH), 104.6
(CH), 52.6 (CH3), 41.4 (CH2). Anal. Calcd for C16H14N2O3: C,
68.07; H, 5.00; N, 9.92. Found: C, 67.94; H, 4.83; N, 9.76.
1
ange oil. IR (film) n 1748, 1652 cmꢁ1; H NMR (250 MHz,
CDCl3) d 7.26 (t, J¼5.5 Hz, 1H), 7.07 (dd, J¼5.6 and 3.1 Hz,
1H), 6.65 (d, J¼7.6 Hz, 1H), 6.57 (s, 1H), 6.55 (m, 1H), 4.29
(dd, J¼8.8 and 3.7 Hz, 1H), 4.02 (d, J¼5.6 Hz, 2H), 3.76 (s,
3H), 3.13 (dd, J¼13.4 and 8.8 Hz, 1H), 2.76 (dd, J¼13.4 and
3.7 Hz, 1H); 13C NMR (63 MHz, CDCl3) d 173.5 (C), 170.2
(C), 146.5 (C), 138.2 (C), 129.5 (CH), 119.8 (CH), 116.2 (CH),
113.8 (CH), 72.7 (CH), 52.3 (CH3), 40.7 (CH2), 40.6 (CH2).
Anal. Calcd for C24H28N4O6: C, 61.53; H, 6.02; N, 11.96.
Found: C, 61.22; H, 5.87; N, 11.75.
3.6.4. Methyl N-(3-(3-aminophenyl)pyruvoyl)glycinate (7b)
A 2ꢂ10ꢁ3 M solution of 3b in EtOAc with a 10% PdeC was
used. The crude residue was purified by flash column chroma-
tography (4:6 hexane/EtOAc) to provide compound 7b (92%
1
yield) as a yellow oil. IR (film) n 1748, 1682 cmꢁ1; H NMR
(250 MHz, CDCl3) d 7.35 (m, 1H), 7.13 (m, 1H), 7.04 (m,
2H), 4.05 (s, 2H), 4.10 (s, 2H), 3.98 (s, 3H).
3.6.9. Methyl [2,6-diaza-1,5-bis(1,4)dibenzenacyclotetra-
decaphan]-3,7-bisylenecarbonyl-glycinate (9)
A 2ꢂ10ꢁ2 M solution of 3c in EtOAc with a 10% PdeC was
used. The crude residue was purified by flash column chroma-
tography EtOAc to provide compound 9 (98% yield) as an
3.6.5. Methyl N-(3-(4-aminophenyl)pyruvoyl)glycinate (7c)
A 6ꢂ10ꢁ3 M solution of 3c in EtOAc with a 20% PdeC was
used. The crude residue was purified by flash column

2770
J.F. Gonza´lez et al. / Tetrahedron 64 (2008) 2762e2771
orange oil. IR (film) n 3374, 1742, 1667 cmꢁ1
;
1H NMR
3.7.3. Methyl N-(1H-6-tert-butoxycarbonyl-L-valylamino-
indole-2-carbonyl)glycinate (13)
(250 MHz, CDCl3) d 7.06 (d, J¼8.3 Hz, 2H), 7.05 (m, 1H),
6.68 (d, J¼8.3 Hz, 2H), 4.30 (dd, J¼8.6 and 4.1 Hz, 1H), 4.08
(d, J¼5.5 Hz, 2H), 3.78 (s, 3H), 3.17 (dd, J¼14.1 and 4.1 Hz,
1H), 2.81 (dd, J¼14.1 and 8.6 Hz, 1H); 13C NMR (63 MHz,
CDCl3) d 173.0 (C), 170.1 (C), 145.4 (C), 130.4 (CH), 126.0
(C), 115.5 (CH), 72.9 (CH), 52.3 (CH3), 40.7 (CH2), 39.8
(CH2). Anal. Calcd for C24H28N4O6: C, 61.53; H, 6.02; N,
11.96. Found: C, 61.31; H, 5.92; N, 11.69.
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 13 (42% yield) as
a yellow solid. Mp 112e113 ꢀC; IR (film) n 3292, 1746,
1
1668 cmꢁ1; H NMR (250 MHz, CDCl3) d 9.35 (br s, 1H),
8.68 (br s, 1H), 7.74 (s, 1H), 7.25 (d, J¼8.5 Hz, 1H), 7.13 (br
s, 1H), 6.85 (d, J¼8.0 Hz, 1H), 6.71 (s, 1H), 6.64 (s, 1H), 4.19
(d, J¼5.4 Hz, 2H), 4.00 (d, J¼6.7 Hz, 1H), 3.74 (s, 3H), 2.10
(m, 1H), 1.14 (s, 9H), 0.97 (d, J¼6.7 Hz, 6H); 13C NMR
(63 MHz, CDCl3) d 171.2 (C), 170.7 (C), 161.8 (C), 156.7
(C), 136.6 (C), 134.7 (C), 131.2 (C), 124.1 (C), 121.9 (CH),
114.3 (CH), 103.1 (CH), 102.9 (CH), 80.0 (C), 61.3 (CH),
52.6 (CH3), 41.2 (CH2), 30.6 (CH), 28.3 (CH3), 19.4 (CH3).
Anal. Calcd for C22H30N4O6: C, 59.18; H, 6.77; N, 12.55.
Found: C, 58.95; H, 6.52; N, 12.23.
3.7. N-Acylation of amino compounds
To a solution of the corresponding N-Boc-L-amino acid
(0.34 mmol), 1-hydroxy-7-azabenzotriazole(HOAt)(0.37 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydro-
chloride (0.41 mmol) and the amino derivatives 7b and 4d
(0.34 mmol) in anhydrous DMF (20 mL) under Ar atmosphere
at 0 ꢀC, was added 4-methylmorpholine (NMM) (1.02 mmol).
After being stirred at 0 ꢀC for 2 h, the reaction mixture was
kept in a freezer overnight (16 h) and it was then warmed at
room temperature. EtOAc (80 mL) was added and the organic
solution was washed with 5% H3PO4 (20 mL), a saturated aque-
ous solution of NaHCO3 (20 mL) and brine (20 mL), dried with
sodium sulfate, filtered, and concentrated. An analytical sample
was obtained through flash chromatography.
3.7.4. Methyl N-(1H-6-tert-butoxycarbonyl-L-leucylamino-
indole-2-carbonyl)glycinate (14)
The crude residue was purified by flash column chromatogra-
phy (1:1 hexane/EtOAc) to provide compound 14 (43% yield) as
a yellow solid. Mp 122e123 ꢀC, IR (film) n 3305, 1744,
1
1673 cmꢁ1; H NMR (250 MHz, CDCl3) d 9.64 (br s, 1H),
8.95 (br s, 1H), 7.80 (s, 1H), 7.26 (d, J¼8.7 Hz, 1H), 7.23 (br
s, 1H), 6.72 (d, J¼8.7 Hz, 1H), 6.70 (s, 1H), 5.86 (br s, 1H),
4.33 (m, 1H), 4.27 (d, J¼5.3 Hz, 2H), 3.85 (s, 3H), 1.61 (m,
2H), 1.40 (s, 9H), 1.25 (m, 1H), 1.01 (d, J¼6.3 Hz, 6H); 13C
NMR (63 MHz, CDCl3) d 171.6 (C), 171.3 (C), 161.9 (C),
159.5 (C), 136.8 (C), 135.0 (C), 129.7 (C), 124.0 (C), 121.8
(CH), 114.2 (CH), 103.2 (CH), 102.8 (CH), 80.2 (C), 54.1
(CH), 52.6 (CH3), 41.2 (CH2), 40.6 (CH2), 28.4 (CH3), 23.1
(CH), 16.4 (CH3). Anal. Calcd for C23H32N4O6: C, 59.99; H,
7.00; N, 12.17. Found: C, 59.82; H, 6.86; N, 11.94.
3.7.1. Methyl N-(3-(3-tert-butoxycarbonyl-L-valylamino-
phenyl)pyruvoyl)glycinate (11)
The crude residue was purified by flash column chromatogra-
phy (3:7 hexane/EtOAc) to provide compound 11 (71% yield) as
a yellow oil. IR (film) n 1748, 1662 cmꢁ1; 1H NMR (250 MHz,
CDCl3) d 8.19 (br s, 1H), 7.47 (m, 2H), 7.39 (s, 1H), 7.25 (m,
1H), 6.98 (d, J¼3.8 Hz, 1H), 4.19 (s, 2H), 4.11 (d, J¼3.0 Hz,
2H), 4.07 (m, 1H), 3.75 (s, 3H), 2.22 (m, 1H), 1.47 (s, 9H),
1.06 (d, J¼7.1 Hz, 6H); 13C NMR (63 MHz, CDCl3) d 194.7
(C), 170.2 (C), 169.2 (C), 160.0 (C), 156.2 (C), 137.8 (C),
133.3 (C), 129.1(CH), 125.8 (CH), 122.7 (CH), 118.9 (CH),
80.3 (C), 59.9 (CH), 52.5 (CH3), 42.9 (CH2), 41.0 (CH2), 30.6
(CH), 28.3 (CH3), 19.4 (CH3). Anal. Calcd for C22H31N3O7:
C, 58.78; H, 6.95; N, 9.35. Found: C, 58.63; H, 6.36; N, 9.02.
Acknowledgements
This work was supported by CICYT (CTQ2006-10930/
´
BQU project) and Comunidad Autonoma de Madrid (Group
920234).
References and notes
3.7.2. Methyl N-(1H-6-tert-butoxycarbonyl-L-phenylalanyl-
aminoindole-2-carbonyl)glycinate (12)
The crude residue was purified by flash column chromatogra-
phy (4:6 hexane/EtOAc) to provide compound 12 (71% yield) as
a brown solid. Mp 118e119 ꢀC; IR (film) n 3420, 1644 cmꢁ1
1H NMR (250 MHz, CDCl3) d 10.12 (br s, 1H), 9.02 (br s,
1H), 7.86 (m, 1H), 7.35 (m, 1H), 7.18 (m, 6H), 6.67 (s, 1H),
6.61 (m, 1H), 6.54 (br s, 1H), 4.68 (t, J¼5.9 Hz, 1H), 4.18 (d,
J¼4.3 Hz, 2H), 3.70 (s, 3H), 3.10 (m, 2H), 1.25 (s, 9H); 13C
NMR (63 MHz, CDCl3) d 171.3 (C), 170.8 (C), 162.3 (C),
156.8 (C), 137.3 (C), 136.9 (C), 134.6 (C), 129.3 (CH), 128.4
(CH), 126.5 (CH), 124.0 (C), 121.7 (CH), 114.1 (CH), 103.1
(CH), 103.4 (CH), 77.5 (C), 57.7 (CH), 53.0 (CH3), 41.4
(CH2), 38.4 (CH2), 28.2 (CH3). Anal. Calcd for C26H30N4O6:
C, 63.15; H, 6.11; N, 11.33. Found: C, 62.91; H, 6.01; N, 11.16.
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