Microwave-assisted synthesis of 2,5-piperazinediones under solvent-free conditions

Article abstract of DOI:10.1055/s-2005-918473

A general, efficient and environmentally friendly procedure for the synthesis of 2,5-piperazinediones is described, involving the microwave irradiation of N-Boc dipeptide esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918473

3412
PAPER
Microwave-Assisted Synthesis of 2,5-Piperazinediones under Solvent-Free
Conditions
M
icrowave-Assist
l
e
d
Synt
b
hesis of 2,5-
e
Piperazined
r
iones un
t
der Sol
o
vent-Free Conditio
L
ns ópez-Cobeñas, Pilar Cledera, J. Domingo Sánchez, Pilar López-Alvarado, M. Teresa Ramos,
Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@farm.ucm.es
Received 14 September 2005
This paper is dedicated to Professor Steven V. Ley on the occasion of his 60th birthday.
moieties.6 Due to their importance, the development of
Abstract: A general, efficient and environmentally friendly proce-
improved, environmentally benign routes to DKPs is of
dure for the synthesis of 2,5-piperazinediones is described, involv-
great interest.
ing the microwave irradiation of N-Boc dipeptide esters.
A variety of methods are available for the preparation of
DKPs.7 However, because they can be considered as
‘head to tail’ cyclic dipeptides, the simplest methods are
those that take advantage of the chirality and commercial
availability of amino acids, and normally involve the
preparation of a suitable linear dipeptide followed by N-
deprotection and cyclization. The cyclization step is nor-
mally carried out under basic8 or acidic9 conditions, and
epimerization is the most common undesired reaction.
Cyclization of dipeptide esters can also be carried out un-
der thermal conditions, normally by refluxing in high-
boiling solvents such as toluene or xylene for 24 hours,10
or, when starting from the formate salt of the dipeptide, in
toluene–sec-BuOH.11 In unfavorable cases, cyclization
sometimes requires hydrolysis of the ester group and
amide bond formation using peptide coupling methods.
Ideally, the choice of N-protecting group and cyclization
method should be such that deprotection takes place under
the same conditions as cyclization, leading to a one-step
preparation of the target DKP.
Key words: microwave irradiation, diketopiperazines, dipeptides,
cyclizations, heterocycles
Peptides are increasingly important in drug design, al-
though a number of problems, especially poor bioavail-
ability and stability, prevent their direct therapeutic use.
This has led to the concept of peptidomimetics, which can
be defined as non-peptidic compounds that behave as
ligands of peptide receptors. In this context, 2,5-pipera-
zinediones (2,5-diketopiperazines, DKPs) have often
been used to circumvent the limitations of peptides. Their
structure contains two hydrogen bond accepting centers
and two hydrogen donating sites, which are often neces-
sary for potential interactions between the lead compound
and its target. On the other hand, they are conformational-
ly restrained by the presence of a six-membered ring with
side chains that are orientated in a spatially defined man-
ner, allowing one to make easy and accurate conforma-
tional predictions. In contrast to classical linear peptides,
DKPs are very stable to hydrolysis, a very important fea-
ture when designing potential lead structures.
Since N-Boc groups can be deprotected under thermal
conditions and heating can also lead to cyclization of
dipeptides to DKPs, pyrolysis of N-Boc dipeptides can
provide a solvent-free synthesis of our target compounds.
One drawback of this approach is the potential for stereo-
center epimerization in sensitive cases due to the harsh re-
action conditions required. In this context, we reasoned
that, because N-Boc deprotection has been described un-
der microwave conditions, albeit not from dipeptides,12
perhaps Boc-protected dipeptides could be cyclized to
DKPs by microwave irradiation in one step under envi-
ronmentally benign conditions, provided that the intramo-
lecular amidation step can also be achieved under the
same conditions. We report here in full13 our results on
this subject, prompted by several synthetic projects in-
volving the construction of antitumour alkaloids from
DKPs. Microwave irradiation14 is considered as a green
technology because it normally allows solvent-free reac-
tions and its level of energy consumption is low compared
with more traditional methods.15 Although not related to
our work, two recent reports have been published where
preparation of 2,5-piperazinediones was assisted by mi-
crowave irradiation, namely an HBTU-induced dimeriza-
Natural products with the 2,5-piperazinedione skeleton
are quite common, and they have shown a wide variety of
biological activities.1 Unnatural DKPs have also been em-
ployed often in medicinal chemistry and show a broad
spectrum of interesting pharmacological properties.2 Su-
pramolecular chemistry is another field of where DKPs
have proved useful, and thus a class of artificial receptors
consisting of a rigid diketopiperazine backbone and pep-
tidic side chains has been developed that interact with
peptidic substrates with high specificity.3 Finally, 2,5-
piperazinediones have proven to be very useful synthetic
intermediates. Besides their well-known role as chiral
auxiliaries in the preparation of unnatural aminoacids us-
ing Schöllkopf-related chemistry,4 and Diels–Alder reac-
tions,5 they are useful starting materials for the synthesis
of many natural products containing nitrogen heterocyclic
SYNTHESIS 2005, No. 19, pp 3412–3422
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918473; Art ID: C06905SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of 2,5-Piperazinediones under Solvent-Free Conditions
3413
tion of a biologically active peptide to a DKP16 and the precaution of irradiating in short pulses was unnecessary,
microwave-assisted synthesis of DKP derivatives using since irradiations of up to five consecutive minutes at 600
the Ugi four-center, three-component reaction.17
W were tolerated without decomposition (e.g. entry 3).
Although the typical reaction scale for the results shown
in Table 1 was about 200–500 mg of starting material, mi-
crowave reactions were scaled-up with only slight yield
loss. For instance, the preparation of compound 5a in en-
try 2 could be performed in 91% yield starting from 1 g of
dipeptide and in 83% yield from 6 g of dipeptide. Similar-
ly, compound 5g was isolated in 97% yield from 1 g of
dipeptide and in 88% yield from 3 g of dipeptide.22 Be-
cause DKP ring formation is strongly sequence-depen-
dent, being particularly favored for Gly or Pro residues
acting as nucleophiles, but more difficult when hindered
amino acids like Val, Leu, Ile, Phe, Trp, Tyr, etc. are in-
volved,23 we also studied some of these cases, finding
yields only slightly lower than the one achieved with the
alanine derivative under similar conditions (entries 3–7).
Compound 5c (entry 4) has been recently isolated from
marine bacteria associated with the sponge Ircinia vari-
abilis.24 Regarding the N-substituted dipeptides, they re-
acted more slowly (e.g. R1 = Me, which required 8 min
irradiation, entry 8) or not at all (e.g. R1 = ArCH2 or
ArCH2CH2, entries 9 and 15) under our initial conditions
involving one-minute pulses. In these cases, we found that
addition of 10% silica gel to the reaction mixture acceler-
ated the reactions, and allowed to carry out the desired
transformations in five pulses (5 min total time), normally
with improved yields with regard to the thermal reaction
(entries 10, 13 and 17), although these reactions were not
completely solvent-free because of the need of extracting
the products from the silica gel. Under modified condi-
tions involving irradiation for up to three consecutive
minutes, addition of silica gel was unnecessary and the
DKPs were obtained in improved yields in all cases (en-
tries 11, 12, 14, 16, 18 and 19). Long pulses were advis-
able in the more difficult cases; for instance, during the
preparation of compound 5g a 66% yield was obtained af-
ter 6 pulses of two minutes, with intermediate two-minute
pauses, while three pulses of three–two–two minutes with
similar pauses led to a 98% yield.
The N-Boc protected dipeptide esters 3 required as start-
ing materials were prepared, normally as mixtures of rot-
amers, from the corresponding N-Boc protected amino
acids and amino acid ester hydrochlorides with prior
liberation of the free bases, in the presence of 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride
(EDC). With the exception of sarcosine, the N-substituted
glycine derivatives employed in these reactions (com-
pounds 1) were not commercially available, and were pre-
pared by reductive amination of the suitable aldehydes
with glycine ethyl ester hydrochloride in the presence of
sodium cyanoborohydride18 or, alternatively, by alkyla-
tion of the suitable arylalkylamines with ethyl bromoace-
tate,19 although in the latter case dialkylation products 2
could not be avoided (Scheme 1). Compound 1d, also pre-
pared by reductive amination or by alkylation of ethyl gly-
cinate with gramine, had been previously described by
us.20
O
EtO2C
R
EtO2C
NaCNBH3
R
H
NH
NH3
Cl
1
Comp.
1a
R
Yield, %
53
C6H5
1b
53
4-MeOC6H4
1c
1da
1e
1f
37
57
49
93
3,4-(MeO)2C6H3
3-indolyl
PhCH2
2-naphthyl
a Reference 20
EtO2C
R
N
CO2Et
2
Scheme 1 Preparation of some N-substituted glycine esters as star-
ting materials.
Besides yield and experimental convenience, stereochem-
ical integrity is also a very important aspect of the prepa-
ration of DKPs. In this regard, compound 5a (obtained
under thermal conditions) has been previously shown to
We show in Table 1 the comparison between the results
obtained in the preparation of variously substituted DKPs
from the corresponding N-Boc dipeptide esters 3 using
conventional and microwave heating, without isolation of
the intermediate N-deprotected derivatives 4. Regarding
simple derivatives substituted at the C-3 and/or N-1 posi-
tions (compounds 5a–n), the reactions were carried out in
two to eight minutes under microwave irradiation com-
pared to 2–4.5 hours at 200 °C for the conventional heat-
ing reactions, and yields were also normally higher for the
microwave-assisted reactions. We employed a domestic
microwave oven with the power set at 600 W, employing
an alumina heat sink.21 In our initial experiments we irra-
diated the reactions in one-minute pulses to prevent exces-
sive heating (e.g., entry 1, where six pulses were
required). Subsequent experimentation proved that the
1
be enantiomerically pure by H NMR in the presence of
Eu(hfc)3.25 As far as compounds bearing a single stereo-
center on the DKP framework are concerned, we have
found that samples of the valine derivative 5k prepared
according to three different procedures, namely thermal
and microwave cyclization of a N-Boc dipeptide ester and
hydrogenolysis of a N-Cbz dipeptide ester followed by cy-
clization, which is known to be safe from a stereochemical
point of view,10 were identical in all respects, including
optical rotation. Furthermore, none of these samples
showed splitting of any 1H NMR signal upon addition of
Eu(hfc)3, under conditions previously established on a
reference racemic sample of 5k prepared from ( )-Val.
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

3414
A. López-Cobeñas et al.
PAPER
However, the reaction in entry 5, involving (S,S)-Ile, chemical integrity, besides the improved yield and shorter
which is known to epimerize very easily,26 led to a 1:1 reaction time.
mixture of diastereomers under thermal conditions. In this
case, the microwave conditions afforded a 9:1 mixture of
diastereomers, showing an advantage in terms of stereo-
Table 1 Comparison of the Results Obtained in the Synthesis of 2,5-Piperazinediones Substituted at N-1, C-3, N-4 and C-6 from N-Boc
Dipeptide Esters under Conventional Thermal and Microwave-Assisted Conditions
O
R6
HN
R6
RO2C
R1
Boc
R4
R6
R4
R3
R4
R3
#
RO2C
R1
N
*
N
N
N
N
R1
R3
O
O
O
3
4
5
Entry Comp. R
R1
R6
R3
R4
Conf. Conf. Heating (200 °C)
at *
Microwave
(600 W)
at #
Time (h)
2
Yield (%) Time
Yield
(%) (dr)
(dr)
(min)
1
2
3
4
5
5a
5a
5b
5c
5d
Et
Et
Et
Et
Et
H
H
H
H
H
H
H
H
H
H
Me
Me
i-Pr
H
H
H
H
H
S
S
S
S
S
–
–
–
–
–
98
5a
65
6b
98
3.5
3
56
5b
87
i-Bu
81
2b
89
4.5
81 (1:1)
5b
91 (9:1)
Me
Me
6
7
5e
5f
Et
Et
H
H
H
H
Bn
H
H
S
S
–
–
4.5
3
72
69
2b
2b
82
92
N
H
8
5g
5h
5h
5h
5i
Me
Et
Et
Et
Et
Et
Et
Me
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–
S
S
S
–
S
S
–
–
–
–
–
–
–
3 (220 °C)
2
84
81
8c
5a
5d
3b
3b
5d
3b
98
0
9
Me
Me
Me
H
10
11
12
13
14
64
84
72
99
90
4-MeOBn
–
2
2
–
5j
3,4-(MeO)2Bn
Me
i-Pr
79
90
5k
N
H
15
16
17
18
19
5l
Et
Et
Et
Et
Et
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
H
H
H
H
H
H
H
H
H
H
H
–
–
S
S
S
–
–
–
–
–
2
80
5a
3b
5d
3b
5b
0
5l
H
99
65
90
81
5m
5m
5n
i-Pr
i-Pr
Me
2
–
2
81
–
79
20
21
5o
5p
Et
H
H
i-Pr
i-Pr
Bn
Bn
H
H
S
S
S
2
2
92 (1:1)
8a
98
98
Me
R
92 (2.6:1) 8a
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of 2,5-Piperazinediones under Solvent-Free Conditions
3415
Table 1 Comparison of the Results Obtained in the Synthesis of 2,5-Piperazinediones Substituted at N-1, C-3, N-4 and C-6 from N-Boc
Dipeptide Esters under Conventional Thermal and Microwave-Assisted Conditions (continued)
O
R6
HN
R6
RO2C
R1
Boc
R4
R6
R4
R3
R4
R3
#
RO2C
R1
N
*
N
N
N
N
R1
R3
O
O
O
3
4
5
Entry Comp. R
R1
R6
R3
R4
Conf. Conf. Heating (200 °C)
at *
Microwave
(600 W)
at #
Time (h)
Yield (%) Time
Yield
(dr)
(min)
(%) (dr)
22
23
24
5q
5r
5s
Et
H
H
H
i-Pr
i-Pr
4-MeOBn
4-MeOBn
(CH2)3
H
H
S
S
S
S
2
2
2
95 (3:1)
95 (3:1)
82 (2:1)
8a
98
Me
Me
R
R
8a
98
2b
95 (2:1)
N
H
25
26
5t
5t
Et
Et
H
H
i-Pr
i-Pr
(CH2)3
(CH2)3
R
R
S
S
2
0
5b,e
5b,e
76 (3:1)
99 (1:1)
a In cycles of 1-min irradiation followed by 1-min cooling.
b Irradiation without intermediate cooling,
c Three irradiations (3 + 3 + 2 min), with 2-min intermediate cooling periods.
d The starting dipeptide was mixed with 10% silica gel prior to irradiation using conditions a.
e The difference between entries 25 and 26 lies in the longer time of alumina preheating in the second case (12 min vs 8 min).
In order to extend the scope of our microwave-enhanced In conclusion, microwave irradiation of N-Boc dipeptide
method, we next examined the preparation of 3,6-disub- esters provides fast and efficient access to polysubstituted
stituted DKPs (compounds 5o–t), as shown in entries 20– 2,5-piperazinedione derivatives, normally in optically
26 of Table 1. Again, improved yields and shortened reac- pure form.
tion times were observed in all cases. An advantage of
these compounds is that, because they bear two stereo-
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
centers and therefore epimerization of one of them would
lead to a pair of diastereomers, they provide a simple way
to assess the course of the reactions in terms of stereo-
chemical integrity. As shown in entries 20–23, both the
S,S and S,R isomers of cyclo-(Phe-Val) and cyclo-(O-
MeTyr-Val) (compounds 5o–r) could be prepared in pure
form using the microwave-assisted conditions, while the
thermal reaction led to mixtures of diastereomers in all
cases. On the other hand, cyclo-(D-Trp-L-Pro), a natural
product isolated from strains of Aspergillus ustus,27 was
obtained as a 2:1 diastereomer mixture in both types of
conditions, although microwave irradiation led to an im-
proved yield (entry 24). Finally, because several cyclo-
(Pro-Val) diastereomers are natural products,28 some of
them with antibacterial activity,28b we studied the prepara-
tion of compound 5t. As shown in entry 25, this com-
pound was obtained in 76% yield and as a 3:1
diastereomer mixture under microwave irradiation, while
the thermal conditions failed to give any cyclization prod-
uct. An attempt to increase the yield by preheating the alu-
mina for 12 minutes prior to introduction of the reaction
mixture was successful (99% yield), but a 1:1 diastereo-
meric mixture was isolated in this case (entry 26).
were of commercial quality and were used as received. Some of the
N-Boc-protected amino acids were not commercially available, and
were prepared from the corresponding amino acids and tert-butyl
pyrocarbonate, under standard conditions.29 Microwave-enhanced
reactions were carried out on a Moulinex domestic microwave oven
operating at 600 W, employing as reaction vessels glass vials or
round-bottom flasks submerged into an alumina bath. Reactions
were monitored by TLC, on aluminium plates coated with silica gel
with fluorescent indicator (SDS CCM221254). Separations by flash
chromatography were performed on silica gel (SDS 60 ACC 40–63
mm). Melting points were measured on a Reichert 723 hot stage mi-
croscope, and are uncorrected. IR spectra were recorded on a Perkin
Elmer Paragon 1000 FT-IR spectrophotometer, with solid com-
pounds compressed into KBr pellets and liquid compounds exam-
ined as films on NaCl disks. NMR spectra were obtained on a
Bruker Avance 250 spectrometer operating at 250 MHz for 1H and
63 MHz for 13C (CAI de Resonancia Magnética Nuclear, Univer-
sidad Complutense). Polarimetric measurements were carried out
on a Perkin Elmer 240 polarimeter operating at the emission wave-
length of a sodium lamp; concentrations for these measurements are
given in g/100 mL. Elemental analyses were determined by the CAI
de Microanálisis Elemental, Universidad Complutense, using a
Leco 932 CHNS combustion microanalyzer.
Preparation of Compounds 1 by Reductive Amination (Method
A); General Procedure
A solution of the suitable aldehyde, aminoester hydrochloride and
NaCNBH3 in EtOH was stirred at r.t. for 24 h. The solvent was
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

3416
A. López-Cobeñas et al.
PAPER
evaporated under reduced pressure, the residue was dissolved in 2
M HCl (10 mL) and this solution was extracted with Et2O (2 × 10
mL). The aqueous phase was neutralized with sat. aq K2CO3 and it
was then extracted with CHCl3 (3 × 25 mL). The combined extracts
were dried over anhyd Na2SO4, filtered, evaporated under reduced
pressure and purified by flash column chromatography, eluting with
EtOAc).
1H NMR (250 MHz, CDCl3): d = 7.21 (d, J = 6.4 Hz, 2 H, H-2¢, H-
6¢), 6.80 (d, J = 6.4 Hz, 2 H, H-3¢, H-5¢), 4.11 (q, J = 6.9 Hz, 2 H,
OCH2CH3), 3.72 (s, 3 H, OCH3), 3.68 (s, 2 H, ArCH2N), 3.32 (s, 2
H, COCH2N), 1.85 (br s, 1 H, NH), 1.21 (t, J = 6.9 Hz, 3 H,
OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 172.39 (CO2Et), 158.70 (C-4),
131.13 (C-1¢), 129.43 (C-2¢, C-6¢), 113.73 (C-3¢, C-5¢), 60.64
(OCH2CH3), 55.16 (OCH3), 52.60 (NCH2CO), 49.91 (ArCH2N),
14.18 (OCH2CH3).
Preparation of Compounds 1 by Alkylation (Method B);
General Procedure
Anal. Calcd for C12H17NO3 (223): C, 64.55; H, 7.67; N, 6.27.
Found: C, 64.38; H, 7.79; N, 6.21.
To a solution of the suitable arylalkylamine in EtOH was dropwise
added ethyl bromoacetate. The mixture was stirred until the precip-
itation of solid amine hydrobromide was complete and was then fil-
tered. The filtrate was evaporated under reduced pressure and
purified by flash column chromatography, eluting with EtOAc,
affording, by order of elution, the di- and monoalkylated derivatives
of the starting amine.
Diethyl (4-Methoxybenzyl)iminodiacetate (2b)
IR (NaCl): 3084, 2981, 1740, 1603, 1496, 1453, 1370 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.31–7.12 (m, 5 H, Ph), 4.14 (q,
J = 7.2 Hz, 4 H, OCH2CH3), 3.56 (s, 4 H, COCH2N), 2.90–2.80 (m,
4 H, ArCH2CH2N), 1.21 (t, J = 7.2 Hz, 6 H, OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 172.75 (CO2Et), 139.44 (C-1¢),
128.60, 128.26, 125.99 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 60.42
(OCH2CH3), 56.17 (ArCH2CH2N), 55.09 (NCH2CO), 50.70
(NCH2CO), 34.68 (ArCH2CH2N), 14.17 (OCH2CH3).
Ethyl N-Benzylglycinate (1a)
Method A: Starting from benzaldehyde (4.281 g, 40 mmol), ethyl
glycinate hydrochloride (16.701 g, 120 mmol) and NaCNBH3
(2.559 g, 40 mmol) in EtOH (100 mL), compound 1a (4.002 g,
53%) was obtained as a colorless oil.
Anal. Calcd for C16H23NO4 (293): C, 65.52; H, 7.90; N, 4.77.
Found: C, 65.30; H, 7.89; N, 4.94.
Method B: Starting from benzylamine (10.701 g, 100 mmol) and
ethyl bromoacetate (5.801 g, 35 mmol) in EtOH (250 mL), after stir-
ring for 48 h, the following products were obtained, by order of elu-
tion: diethyl benzyliminodiacetate (2a; 2.441 g, 25%) and ethyl N-
benzylglycinate (1a; 2.631 g, 39%), both as colorless oils.
Ethyl N-(3,4-Dimethoxybenzyl)glycinate (1c)
Starting from veratraldehyde (3.332 g, 20 mmol), ethyl glycinate
hydrochloride (8.350 g, 60 mmol) and NaCNBH3 (1.279 g, 20
mmol) in EtOH (50 mL), using Method A, compound 1c (1.851 g,
37%) was obtained as a colorless oil.
IR (NaCl): 3341, 3062, 2981, 2932, 1735, 1603, 1405 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.22–7.31 (m, 5 H, ArH), 4.17 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 3.78 (s, 2 H, PhCH2N), 3.38 (s, 2 H,
COCH2N), 1.89 (br s, 1 H, NH), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 172.37 (CO2Et), 139.46 (C-1¢),
128.39, 128.21, 127.09 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 60.89
(OCH2CH3), 53.57 (NCH2CO), 50.18 (ArCH2N), 14.34
(OCH2CH3).
IR (NaCl): 3342, 2936, 2834, 1737, 1591, 1514, 1464 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.72–6.98 (m, 3 H, ArH), 4.11 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 3.82 (s, 3 H, OCH3), 3.79 (s, 3 H,
OCH3), 3.67 (s, 2 H, ArCH2N), 3.33 (s, 2 H, COCH2N), 1.98 (br s,
1 H, NH), 1.20 (t, J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 172.28 (CO2Et), 148.75, 147.92
(C-3¢, C-4¢), 131.84 (C-1¢), 120.24 (C-6¢), 111.13, 110.68 (C-2¢, C-
5¢), 60.57 (OCH2CH3), 55.68, 55.61 (2 × OCH3), 52.87 (ArCH2N),
49.75 (NCH2CO), 14.05 (OCH2CH3).
Anal. Calcd for C11H15NO2 (193): C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.18; H, 7.99; N, 7.10.
Diethyl Benzyliminodiacetate (2a)
Anal. Calcd for C13H19NO4 (253): C, 61.64; H, 7.56; N, 5.53.
Found: C, 61.59; H, 7.38; N, 5.67.
IR (NaCl): 3062, 2983, 2935, 1737, 1604, 1405 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.31–7.22 (m, 5 H, Ph), 4.13 (q,
J = 7.1 Hz, 4 H, OCH2CH3), 3.89 (s, 2 H, PhCH2N), 3.52 (s, 4 H,
COCH2N), 1.24 (t, J = 7.1 Hz, 6 H, OCH2CH3).
Ethyl N-(3-Indolylmethyl)glycinate (1d)
This compound was prepared according to ref. 20.
13C NMR (63 MHz, CDCl3): d = 171.14 (CO2Et), 138.07 (C-1¢),
128.97, 128.27, 127.26 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 60.35
(OCH2CH3), 57.72 (NCH2CO), 54.11 (ArCH2N), 14.19
(OCH2CH3).
Ethyl N-(2-Phenylethyl)glycinate (1e)
Method A: Starting from 2-phenylacetaldehyde (2.401 g, 20 mmol),
ethyl glycinate hydrochloride (8.370 g, 60 mmol) and NaCNBH3
(1.28 g, 20 mmol) in EtOH (100 mL) compound 1e (2.042 g, 49%)
was obtained as a colorless oil.
Anal. Calcd for C15H21NO4 (279): C, 64.51; H, 7.52; N, 5.01.
Found: C, 64.78; H, 7.32; N, 5.25.
Method B: Starting from 2-phenylethylamine (6.051 g, 50 mmol)
and ethyl bromoacetate (3.322 g, 20 mmol) in EtOH (50 mL), stir-
ring for 24 h, the following products were obtained, by order of elu-
tion: diethyl 2-phenylethyliminodiacetate (2e; 0.882 g, 15%) and
ethyl N-(2-phenylethyl)glycinate (1e; 1.861 g, 45%), both as color-
less oils.
Ethyl N-(4-Methoxybenzyl)glycinate (1b)
Method A: Starting from anisaldehyde (5.441 g, 40 mmol), ethyl
glycinate hydrochloride (16.701 g, 120 mmol) and NaCNBH3
(2.559 g, 40 mmol) in EtOH (100 mL) compound 1b (4.721 g, 53%)
was obtained as a colorless oil.
IR (NaCl): 3335, 3025, 2950, 2935, 1733, 1603 cm–1.
Method B: Starting from 4-methoxybenzylamine (5.50 g, 50 mmol)
and ethyl bromoacetate (3.321 g, 20 mmol) in EtOH (250 mL), after
stirring for 24 h, the following products were obtained, by order of
elution: diethyl (4-methoxybenzyl)iminodiacetate (2b; 1.851 g,
30%) and 1b (1.670 g, 37%), both as colorless oils.
1H NMR (250 MHz, CDCl3): d = 7.15–7.35 (m, 5 H, ArH), 4.12 (q,
J = 7.1 Hz, 2 H, OCH2CH3), 3.36 (s, 2 H, COCH2N), 2.70–2.94 (m,
4 H, ArCH2CH2N), 1.80 (br s, 1 H, NH), 1.21 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 171.13 (CO2Et), 139.44 (C-1¢),
128.62, 128.48 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 60.52 (OCH2CH3),
IR (NaCl): 3341, 2981, 2835, 1733, 1611, 1585 cm–l.
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of 2,5-Piperazinediones under Solvent-Free Conditions
3417
50.70 (NCH2CO), 50.53 (ArCH2CH2N), 36.24 (ArCH2CH2N),
14.03 (OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 173.28 (CO2CH2CH3), 170.12 (CO
amide), 156.11 (CO carbamate), 80.44 [C(CH3)3], 61.83
(CO2CH2CH3), 56.34 (CHi-Bu), 41.58 (NCH2CO), 31.31
[CH2CH(CH3)2], 28.67 [C(CH3)3], 25.02 [CH2CH(CH3)2], 23.32,
22.11 [CH2CH(CH3)2], 14.48 (OCH2CH3).
Anal. Calcd for C12H17NO2 (207): C, 69.54; H, 8.27; N, 6.76.
Found: C, 69.18; H, 8.02; N, 7.09.
Diethyl (2-Phenylethyl)iminodiacetate (2e)
Anal. Calcd for C15H28N2O5 (316): C, 56.94; H, 8.92; N, 8.85.
Found: C, 57.10; H, 8.94; N, 8.99.
IR (NaCl): 3084, 2981, 1740, 1603, 1496, 1453, 1370 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.31–7.12 (m, 5 H, Ph), 4.14 (q,
J = 7.2 Hz, 4 H, OCH2CH3), 3.56 (s, 4 H, COCH2N), 2.90–2.80 (m,
4 H, ArCH2CH2N), 1.21 (t, J = 7.2 Hz, 6 H, OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 172.75 (CO2Et), 139.44 (C-1¢),
128.60, 128.26, 125.99 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 60.42
(OCH2CH3), 56.17 (ArCH2CH2N), 55.09 (NCH2CO), 50.70
(NCH2CO), 34.68 (ArCH2CH2N), 14.17 (OCH2CH3).
Ethyl N¢-(tert-Butoxycarbonyl)-L-isoleucylglycinate (3d)
Starting from ethyl glycinate (3.276 g, 31.8 mmol), compound 3d
(10.293 g, 100%) was obtained, as a rotamer mixture; [a]D26 –4.15
(c = 1.06, CH2Cl2).
IR (NaCl): 3313, 1745, 1702, 1664, 1171 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.71 (br s, 1 H, NHGly), 5.10–5.30
(m, 1 H, NHLeu), 4.22 (q, J = 6.9 Hz, 2 H, OCH2CH3), 4.40–4.55,
3.20–3.75 (2 × m, 1 H, CHs-Bu), 4.02–4.07 (m, 2 H, NCH2CO),
1.82–1.96 [m, 1 H, CH(CH3)CH2CH3], 1.44 [s, 9 H, C(CH3)3], 1.26
(t, J = 7.1 Hz, 3 H, OCH2CH3), 1.13–1.20 [m, 2 H,
CH(CH3)CH2CH3], 0.95–1.10 [m, 6 H, CH(CH3)CH2CH3].
13C NMR (63 MHz, CDCl3): d = 172.4 (CO2CH2CH3), 170.11 (CO
amide), 156.23 (CO carbamate), 80.32 [C(CH3)3], 61.89
(CO2CH2CH3), 59.45 (CHs-Bu), 41.71 (NCH2CO), 37.74
Anal. Calcd for C16H23NO4 (293): C, 65.52; H, 7.90; N, 4.77.
Found: C, 65.30; H, 7.89; N, 4.94.
Ethyl N-(2-Naphthylmethyl)glycinate (1f)
Starting from naphthalene-2-carbaldehyde (6.241 g, 40 mmol), eth-
yl glycinate hydrochloride (16.702 g, 120 mmol) and NaCNBH3
(2.559 g, 40 mmol) in EtOH (250 mL), using Method A, compound
1f (9.031 g, 93%) was obtained as a white solid.
[CH(CH3)CH2CH3],
[CH(CH3)CH2CH3],
[CH(CH3)CH2CH3].
28.78
15.89,
[C(CH3)3],
14.51,
25.32,
12.32,
25.04
11.93
IR (KBr): 3334, 3052, 1736, 1631, 1600 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.74–7.81 (m, 4 H, ArH), 7.42–
7.45 (m, 3 H, ArH), 4.16 (q, J = 7.2 Hz, 2 H, OCH2CH3), 3.95 (s, 2
H, CH2Ar), 3.42 (s, 2 H, NCH2CO), 1.82 (br s, 1 H, NH), 1.25 (t,
J = 7.2 Hz, 3 H, OCH2CH3).
Anal. Calcd for C15H28N2O5 (316): C, 56.94; H, 8.92; N, 8.85.
Found: C, 56.60; H, 8.82; N, 9.11.
13C NMR (63 MHz, CDCl3): d = 172.35 (CO2Et), 136.84, 133.26,
132.61, 128.06, 127.60, 127.53, 126.59, 126.48, 125.92, 125.54
(Ar), 60.67 (OCH2CH3), 53.25 (NCH2CO), 49.94 (ArCH2N), 14.12
(OCH2CH3).
Ethyl N¢-(tert-Butoxycarbonyl)-L-phenylalanylglycinate (3e)
Starting from ethyl glycinate (3.441 g, 33.4 mmol), compound 3e
(11.910 g, 100%) was obtained; [a]D26 +2.72 (c = 1.08, CH2Cl2).
IR (NaCl): 3314, 1748, 1702, 1666, 1170 cm–1.
Anal. Calcd for C15H17NO2 (243): C, 74.05; H, 7.04; N, 5.76.
Found: C, 73.86; H, 7.15; N, 5.85.
1H NMR (250 MHz, CDCl3): d = 7.22–7.29 (m, 5 H, ArH), 6.45 (br
s, 1 H, NHGly), 5.04 (br s, 1 H, NHPhe), 4.37–4.52 (m, 1 H, CHBn),
4.22 (q, J = 7.1 Hz, 2 H, OCH2CH3), 4.06 (dd, J = 18.5, 5.4 Hz, 1
H, CH2Ph), 3.94 (dd, J = 18.5, 5.4 Hz, 1 H, CH2Ph), 3.00–3.20 (m,
2 H, NCH2CO), 1.42 [s, 9 H, C(CH3)3], 1.30 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 171.86 (CO2CH2CH3), 169.88 (CO
amide), 155.13 (CO carbamate), 136.95 (C-1¢), 129.71, 129.09 (C-
2¢, C-3¢, C-5¢, C-6¢), 127.39 (C-4¢), 80.06 [C(CH3)3], 61.95
(OCH2CH3), 55.85 (CHCH2Ph), 41.75 (NCH2CO), 38.79 (CH2Ph),
28.65 [C(CH3)3], 14.55 (OCH2CH3).
Preparation of Dipeptides (3); General Procedure
Compounds 3a,25 3b,25 3f,33 and 3k20 were prepared using literature
conditions. Other dipeptides were prepared as follows: A solution
of the suitable commercially available amino ester hydrochloride
(30 mmol) in 20% aq K2CO3 (45 mL) was extracted with Et2O or
EtOAc (5 × 50 mL). The combined organic phases were dried
(Na2SO4) and evaporated (in the reactions starting from compounds
1a–f, this step was unnecessary, since they were obtained as free
bases). To the residue was added a solution of the suitable N-Boc
protected amino acid (1 equiv) and EDC hydrochloride (1 equiv) in
anhyd CH2Cl2 (60 mL), and the solution was stirred at r.t. for 24 h
under an Ar atmosphere. The solution was washed with 1 M aq HCl
(20 mL) and 1 M aq NaHCO3 (20 mL). Both aqueous layers were
extracted with CH2Cl2 (2 × 30 mL), and the combined organic ex-
tracts were dried (Na2SO4) and evaporated, to give the desired
dipeptides as thick colorless syrups that slowly solidified upon
standing at r.t. Conditions for the preparation of compounds 3h–n
and 3t were slightly different, and are specified below.
Anal. Calcd for C18H26N2O5 (350): C, 61.70; H, 7.48; N, 7.99.
Found: C, 61.65; H, 7.44; N, 8.25.
Methyl N¢-(tert-Butoxycarbonyl)glycylsarcosinate (3g)
Starting from methyl sarcosinate (3.322 g, 28.4 mmol), a yield of
8.094 g (93%) of compound 3g was obtained as a rotamer mixture.
IR (NaCl): 3350, 1747, 1714, 1661, 1168 cm–1.
1H NMR (250 MHz, CDCl3): d = 5.46 (br s, 1 H, NH), 4.15 (s, 2 H,
CH2NCH3), 4.00–4.05, 3.85–3.89 (2 × m, 2 H, NCH2CO), 3.78,
3.74 (2 × s, 3 H, CO2CH3), 3.04, 3.01 (2 × s, 3 H, NCH3), 1.45 [s, 9
H, C(CH3)3].
13C NMR (63 MHz, CDCl3): d = 169.91 (CO2CH3), 169.75 (CO
amide), 155.33 (CO carbamate), 80.24 [C(CH3)3], 52.70 (CO2CH3),
49.90 (NCH2CO2CH3), 42.64 (CH2NBoc), 35.70 (NCH3), 28.71,
28.22 [C(CH3)3].
Ethyl N¢-(tert-Butoxycarbonyl)-L-leucylglycinate (3c)
Starting from ethyl glycinate (1.278 g, 12.4 mmol), compound 3c
(4.060 g, 100%) was obtained; [a]D26 –24.19 (c = 1.68, CH2Cl2).
IR (NaCl): 3305, 1747, 1698, 1660, 1169 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.64 (t, J = 5.5 Hz, 1 H, NHGly),
4.88 (d, J = 6.9 Hz, 1 H, NHLeu), 4.21 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.11–4.25 (m, 1 H, CHi-Bu), 4.03 (d, J = 5.3 Hz, 2 H,
NCH2CO), 1.64–1.76 [m, 2 H, CH2CH(CH3)2], 1.48–1.56 [m, 1 H,
CH2CH(CH3)2], 1.44 [s, 9 H, C(CH3)3], 1.28 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 0.92–1.00 [m, 6 H, CH2CH(CH3)2].
Anal. Calcd for C11H20N2O5 (260): C, 50.76; H, 7.74; N, 10.76.
Found: C, 50.87; H, 7.61; N, 10.43.
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

3418
A. López-Cobeñas et al.
PAPER
Ethyl N¢-(tert-Butoxycarbonyl)-l-alanyl-N-benzylglycinate (3h)
Starting from ethyl N-benzylglycinate (1a; 0.41 g, 2.15 mmol), N-
Boc-L-alanine (0.44 g, 2.36 mmol) and EDC (0.62 g, 3.22 mmol),
compound 3i (0.54 g, 69%) was obtained as a colorless syrup (60:40
rotamer mixture); [a]D25 –2.2 (c = 0.18, CH2Cl2).
13C NMR (63 MHz, CDCl3): d = 169.18 (CO2Et), 168.71 (CO
amide), 155.78 (CO carbamate), 138.43, 137.30 (C-1¢), 128.80,
128.67, 128.48, 128.35, 127.90, 126.34 (C-2¢, C-3¢, C-4¢, C-5¢, C-
6¢), 79.73 [C(CH3)3], 62.03, 61.48 (OCH2CH3), 50.83, 49.95
(NCH2CO2Et), 49.46, 48.13 (ArCH2CH2N), 41.98 (NCH2CO),
35.25, 33.93 (ArCH2CH2N), 28.43 [C(CH3)3], 14.23 (OCH2CH3).
IR (NaCl): 3333, 1747, 1709, 1654, 1497, 1452, 1027 cm–1.
Anal. Calcd for C19H28N2O5 (364): C, 62.62; H, 7.74; N, 7.69.
Found: C, 62.48; H, 7.80; N, 7.97.
1H NMR (250 MHz, CDCl3): d = 7.12–7.35 (m, 5 H, ArH), 5.47,
5.40 (2 × d, J = 8.1 Hz, 1 H, NH), 3.62–5.30 (m, 7 H, OCH2CH3,
NCH2CO, CHCH3, ArCH2N), 1.38 [s, 9 H, C(CH3)3], 1.29–1.35 (m,
3 H, CHCH3), 1.05 (t, J = 7.2 Hz, 3 H, OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 174.04, 173.91 (CO2CH2CH3),
169.11, 168.94 (CO amide), 155.30, 115.06 (CO carbamate),
136.22, 135.41 (C-1¢), 129.15, 129.08, 128.76, 128.45, 128.23,
127.70, 127.36 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 79.78, 79.66
[C(CH3)3], 61.78, 61.32 (CO2CH2CH3), 54.30, 53.56 (NCH2CO),
51.89 (ArCH2N), 46.43, 46.26 (CHCH3), 28.42, 28.37 [C(CH3)3],
19.45, 19.03 (CHCH3), 14.19, 14.13 (OCH2CH3).
Ethyl N¢-(tert-Butoxycarbonyl)-L-valyl-N-(2-phenylethyl)glyci-
nate (3m)
Starting from ethyl N-(2-phenylethyl)glycinate (1e; 0.45g, 2.15
mmol), N-Boc-L-valine (0.51 g, 2.36 mmol) and EDC (0.44 g, 2.36
mmol) compound 3m (0.74 g, 85%) was obtained as a colorless oil
(80:20 rotamer mixture); [a]D25 –6.3 (c = 1.3, CH2Cl2).
IR (NaCl): 3313, 3062, 1749, 1710, 1651, 1604 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.13–7.30 (m, 5 H, Ph), 5.19, 5.15
(2 × br s, 1 H, NHCO), 3.30–4.49 [m, 7 H, OCH2CH3, NCH2CO,
CHCH(CH3)2, ArCH2CH2N], 2.81–2.89 (m, 2 H, ArCH2CH2N),
1.88–1.99 [m, 1 H, CHCH(CH3)2], 1.40 [s, 9 H, C(CH3)3], 1.20–
1.30 (m, 3 H, OCH2CH3), 0.83–0.95 [m, 6 H, CHCH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 168.12 (CO2CH2CH3), 168.62 (CO
amide), 151.08 (CO carbamate), 138.00 (C-1¢), 128.92, 128.66,
126.91 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 79.00 [C(CH3)3], 61.35
(CO2CH2CH3), 55.04 [CHCH(CH3)2], 48.37 (ArCH2CH2N), 42.30,
42.10 (NCH2CO), 35.00 (ArCH2CH2N), 32.11 [CHCH(CH3)2],
28.44 [C(CH3)3], 19.02, 17.98 [CH(CH3)2], 14.20 (CO2CH2CH3).
Anal. Calcd for C19H28N2O5 (364): C, 62.62: H, 7.74; N, 7.69.
Found: C. 62.51; H, 7.47: N, 7.33.
Ethyl N¢-(tert-Butoxycarbonyl)glycyl-N-(4-methoxybenzyl)gly-
cinate (3i)
Starting from ethyl N-(4-methoxybenzyl)glycinate (1b; 3.192 g,
14.3 mmol), N-Boc-glycine (2.751 g, 15.7 mmol) and EDC (2.926
g, 15.3 mmol), compound 3i (4.56 g, 84%) was obtained as a color-
less syrup (65:35 rotamer mixture).
1H NMR (250 MHz, CDCl3): d = 7.10–7.20 (m, 2 H, ArH), 6.80–
6.90 (m, 2 H, ArH), 5.52 (br s, 1 H, NH), 3.85–4.59 (m, 8 H, 4 ×
CH2), 3.80, 3.79 (2 × s, 3 H, OCH3), 1.44 [s, 9 H, C(CH3)3], 1.20–
1.30 (m, 3 H, OCH2CH3).
Anal. Calcd for C22H34N2O5 (406): C, 65.00; H, 8.43; N, 6.89.
Found: C, 64.85; H, 8.52; N, 7.12.
Ethyl N¢-(tert-Butoxycarbonyl)-L-alanyl-N-(2-naphthyl-
methyl)glycinate (3n)
Starting from ethyl N-(2-naphthylmethyl)glycinate (1f; 0.52 g, 2.15
mmol), N-Boc-L-alanine (0.441 g, 2.36 mmol) and EDC (0.440 g,
2.36 mmol), compound 3n (0.802 g, 90%) was obtained as a color-
less syrup (60:40 rotamer mixture); [a]D25 +9.4 (c = 2.9, CHCl3).
Ethyl N¢-(tert-Butoxycarbonyl)-l-alanyl-N-(3,4-dimethoxyben-
zyl)glycinate (3j)
Starting from ethyl N-(3,4-dimethoxy)benzylglycinate (1c; 2.65 g,
10 mmol), N-Boc-L-alanine (1.89 g, 10 mmol) and EDC (1.91 g, 10
mmol), compound 3j (3.68 g, 87%) was obtained as a colorless syr-
up (60:40 rotamer mixture); [a]D25 –8.3 (c = 2.56, CHCl3).
IR (NaCl): 3328, 3054, 2978, 2934, 1746, 1709, 1657, 1602 cm–1.
IR (NaCl): 3334, 2979, 2935, 1746, 1707, 1654 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.29–7.87 (m, 7 H, ArH), 5.47,
5.39 (2 × d, J = 8.0 Hz, 1 H, NH), 3.80–4.98 (m, 7 H, OCH2CH3,
NCH2CO, CHCH3, ArCH2N), 1.20–1.42 [s, 12 H, C(CH3)3,
OCH2CH3], 1.10–1.20 (m, J = 7.1 Hz, 3 H, CHCH3).
13C NMR (63 MHz, CDCl3): d = 174.07 (CO2Et), 168.99 (CO
amide), 155.14 (CO carbamate), 133.70, 133.38, 133.31, 132.97,
132.83, 129.10, 128.67, 127.87, 127.23, 126.67, 126.39, 126.15,
125.06 (Ar), 79.85, 79.74 [C(CH3)3], 61.80, 61.35 (OCH2CH3),
52.11 (CHCH3), 48.35 (NCH2CO2Et), 46.36, 46.12 (ArCH2N),
28.44, 28.36 [C(CH3)3], 19.25, 19.07 [CH(CH3)], 14.20, 14.12
(OCH2CH3).
1H NMR (250 MHz, CDCl3): d = 6.72–6.83 (m, 3 H, ArH), 5.41,
5.38 (2 × d, J = 7.9 Hz, 1 H, NH), 3.60–4.84 (m, 13 H, OCH2CH3,
NCH2CO, CHCH3, 2 × OCH3, ArCH2N), 1.19–1.55 [m, 15 H,
C(CH3)3, CHCH3, OCH2CH3].
13C NMR (63 MHz, CDCl3): d = 173.70 (CO2CH2CH3), 168.83 (CO
amide), 155.04 (CO carbamate), 149.41 (C-4¢), 148.74 (C-3¢),
128.42, 127.48 (C-1¢), 119.74, 110.88, 110.75 (C-2¢, C-5¢, C-6¢),
79.52 [C(CH3)3], 61.57, 61.10 (OCH2CH3), 55.84, 55.80 (2 ×
OCH3), 51.47 (CHCH3), 49.59 (NCH2CO2Et), 46.35, 46.22
(ArCH2N), 28.20 [C(CH3)3], 18.99 (CHCH3), 14.00 (OCH2CH3).
Anal. Calcd for C21H32N2O7 (424): C, 59.42; H, 7.60; N, 6.60.
Found: C, 59.21; H, 7.91; N, 6.34.
Anal. Calcd for C23H30N2O5 (414): C, 66.65; H, 7.30; N, 6.76.
Found: C, 66.57; H, 7.04; N. 6.44.
Ethyl N¢-(tert-Butoxycarbonyl)glycyl-N-(2-phenylethyl)glyci-
nate (3l)
Starting from ethyl N-(2-phenylethyl)glycinate (1e; 0.440 g, 2.150
mmol), N-Boc-glycine (0.411 g, 2.361 mmol) and EDC (0.442 g,
2.361 mmol), compound 3l (0.702 g, 90%) was obtained as a color-
less syrup (55:45 rotamer mixture).
Ethyl N¢-(tert-Butoxycarbonyl)-L-phenylalanyl-L-valinate (3o)
Starting from ethyl L-valinate (1.550 g, 10.7 mmol) compound 3o
(3.813, 91%) was obtained; [a]D25 –61.8 (c = 0.165, CHCl3).
IR (KBr): 3300, 3122, 1742, 1683, 1652, 1174 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.08–7.27 (m, 5 H, ArH), 6.61 (d,
J = 8.4 Hz, 1 H, NH), 5.19 (br s, 1 H, NH), 4.39–4.47 (m, 2 H,
CHCH2Ar, CHi-Pr), 4.13 (q, 2 H, OCH2CH3), 2.99–3.07 (m, 2 H,
CH2Ar), 2.06–2.13 [m, 1 H, CH(CH3)2], 1.38 [s, 9 H, C(CH3)3],
1.23 (t, 3 H, OCH2CH3), 0.81–0.88 [m, 6 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 171.73, 171.53 (CO2CH2CH3, CO
amide), 155.82 (CO carbamate), 137.04 (C-1¢), 129.74, 129.05 (C-
2¢, C-6¢, C-3¢, C-5¢), 127.32 (C-4¢), 80.37 [C(CH3)3], 61.62
IR (NaCl): 3329, 2978, 1750, 1710, 1654, 1497, 1454, 1367 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.13–7.33 (m, 5 H, ArH), 5.35–
5.45 (2 × br s, 1 H, NH), 4.17 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.50–
4.00 (m, 6 H, NCH2CO, NCH2CO2Et, PhCH2CH2N), 2.94–2.84 (m,
2 H, PhCH2CH2N), 1.40 [s, 9 H, C(CH3)3], 1.24 (t, J = 7.1 Hz, 3 H,
OCH2CH3).
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Microwave-Assisted Synthesis of 2,5-Piperazinediones under Solvent-Free Conditions
3419
(CO2CH2CH3), 57.62 (CHi-Pr), 56.28 (CHCH2Ar), 31.74
(CHCH2Ar), 31.75 [CH(CH3)2], 28.67 [C(CH3)3], 19.22, 18.15
[CH(CH3)2], 14.63 (CO2CH2CH3).
Anal. Calcd for C21H32N2O6 (408): C, 61.75; H, 7.90; N, 6.86.
Found: C, 62.07; H, 7.90; N, 6.99.
Methyl N¢-(tert-Butoxycarbonyl)-L-prolyl-D-tryptophanate (3s)
Starting from methyl D-tryptophanate (4.443 g, 20.360 mmol),
compound 3s (8.375 g, 99%) was obtained; [a]D26 –40.6 (c = 1.15,
CH2Cl2).
Anal. Calcd for C21H32N2O5 (392): C, 64.26; H, 8.22; N, 7.14.
Found: C, 64.58; H, 7.98; N, 7.39.
Methyl N¢-(tert-Butoxycarbonyl)-L-phenylalanyl-D-valinate
(3p)
IR (KBr): 3276, 1750, 1672, 1163 cm–1.
Starting from methyl D-valinate (1.218 g, 9.3 mmol), compound 3p
1H NMR (250 MHz, CDCl3): d = 8.16 (br s, 1 H, Nindole-H), 7.54 (d,
J = 7.5 Hz, 1 H, H-4¢), 7.34 (d, J = 7.5 Hz, 1 H, H-7¢), 7.04–7.21 (m,
3 H, H-2¢, H-5¢, H-6¢), 6.55 (br s, 1 H, NH), 4.90 (br d, J = 6.1 Hz,
1 H, CHCH2indole), 4.08–4.38 (m, 1 H, NCHCO), 3.71 (s, 3 H,
CO2CH3), 3.12–3.51 (m, 4 H, CH2indole, NCH2CH2CH2), 1.79–
1.96 (m, 2 H, NCH2CH2CH2), 1.21–1.65 [m, 11 H, NCH2CH2CH2,
C(CH3)3].
13C NMR (63 MHz, CDCl3): d = 172.40 (CO2CH3, CO amide),
160.13 (CO carbamate), 136.56 (C-7¢a), 127.80 (C-3¢a), 122.51 (C-
2¢, C-6¢), 120.21 (C-5¢), 118.79 (C-4¢), 111.74 (C-7¢), 110.12 (C-3¢),
80.88 [C(CH3)3], 61.64 (NCHCO), 53.23 (CHCH2indole), 52.72
(CO2CH3), 47.50 (NCH2CH2CH2), 28.71 [C(CH3)3], 28.19
(NCH2CH2CH2), 25.86 (CH2indole), 24.78 (NCH2CH2CH2).
(3.212, 89%) was obtained; [a]D25 –37.8 (c = 0.405, CHCl3).
IR (KBr): 3337, 3028, 1739, 1685, 1666, 1169 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.10–7.27 (m, 5 H, ArH), 6.64 (d,
J = 7.8 Hz, 1 H, NH), 5.22 (d, J = 7.6 Hz, 1 H, NH), 4.30–4.49 (m,
2 H, CHCH2Ar, CHi-Pr), 3.66 (s, 3 H, OCH3), 2.95–3.10 (m, 2 H,
CH2Ar), 1.90–2.08 [m, 1 H, CH(CH3)2], 1.37 [s, 9 H, C(CH3)3],
0.71–0.76 [m, 6 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 172.45, 171.61 (CO2CH3, CO
amide), 156.25 (CO carbamate), 136.99 (C-1¢), 129.66, 129.16 (C-
2¢, C-3¢, C-5¢, C-6¢), 127.40 (C-4¢), 80.70 [C(CH3)3], 57.52 (CHi-
Pr), 56.50 (CHCH2Ar), 52.57 (CH3O), 38.70 (CHCH2Ar), 31.49
[CH(CH3)2], 28.65 [C(CH3)3], 19.19, 18.01 [CH(CH3)2].
Anal. Calcd for C22H29N3O5 (415): C, 63.60; H, 7.04; N, 10.11.
Found: C, 63.34; H, 7.07; N, 10.38.
Anal. Calcd for C20H30N2O5 (378): C, 63.47; H, 7.99; N, 7.40.
Found: C, 63.82; H, 7.71; N, 7.78.
Ethyl N¢-(tert-Butoxycarbonyl)-D-prolyl-L-valinate (3t)
Starting from ethyl l-valinate (1.136 g, 7.83 mmol), N-Boc-D-pro-
line (1.050 g, 4.878 mmol) and EDC (0.950 mg, 4.955 mmol), com-
pound 3t (1.538 g, 92%) of was obtained as a rotamer mixture;
[a]D25 –2.0 (c = 0.54, CHCl3).
Ethyl N¢-(tert-Butoxycarbonyl)-L-(O-methyltyrosyl)-L-valinate
(3q)
Starting from ethyl L-valinate (1.324 g, 9.1 mmol), compound 3q
(3.468 g, 90%) was obtained; [a]D25 –59.0 (c = 0.29, CHCl3).
IR (KBr): 3331, 3134, 1739, 1654, 1513, 1399, 1249, 1178 cm–1.
IR (KBr): 3287, 1736, 1699, 1661, 1395, 1162 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.03–7.14 (m, 2 H, ArH), 6.78–
6.84 (m, 2 H, ArH), 6.42 (d, J = 8.6 Hz, 1 H, NH), 5.03 (br s, 1 H,
NH), 4.43 (dd, J =8 .6, 5.0 Hz, 1 H, CHCH2Ar), 4.21–4.38 (m, 1 H,
CHi-Pr), 4.15 (q, J = 6.8 Hz, 2 H, OCH2CH3), 3.78 (s, 3 H, OCH3),
3.00 (d, J = 6.8 Hz, 2 H, CH2Ar), 2.00–2.20 [m, 1 H, CH(CH3)2],
1.41 [s, 9 H, C(CH3)3], 1.25 (t, J = 7.13 Hz, 3 H, OCH2CH3), 0.81–
0.91 [m, 6 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 171.73, 171.63 (CO2CH2CH3, CO
amide), 158.95 (C4¢OCH3), 155.84 (CO carbamate), 130.75 (C-2¢,
C-6¢), 128.95 (C-1¢), 114.44 (C-3¢, C-5¢), 80.50 [C(CH3)3], 61.60
(CO2CH2CH3), 57.62 (CHi-Pr), 56.38 (OCH3), 55.63 (CHCH2Ar),
37.63 (CHCH2Ar), 31.75 [CH(CH3)2], 28.67 [C(CH3)3], 19.22,
18.17 [CH(CH3)2], 14.61 (CO2CH2CH3).
1H NMR (250 MHz, CDCl3): d = 7.21, 6.56 (2 × br s, 1 H, NH),
4.46–4.67, 4.24–4.45 (2 × m, 2 H, CHi-Pr, NCHCO), 4.12–4.25 (m,
2 H, CO2CH2CH3), 2.21–2.67 (m, 2 H, NCH2CH2CH2), 2.11–2.43
[m, 3 H, NCH2CH2CH2, CH(CH3)2], 1.79–2.09 (m, 2 H,
NCH2CH2CH2), 1.48 [s, 9 H, C(CH3)3], 1.28 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 0.97 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.90 [d, J = 6.9
Hz, 3 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 172.87 (CO2CH2CH3), 171.90 (CO
amide), 154.72 (CO carbamate), 82.45 [C(CH3)3], 61.36
(CO2CH2CH3), 60.48 (NCHCO), 57.11 (CHi-Pr), 47.37
(NCH2CH2CH2), 28.59 [C(CH3)3], 24.65 (NCH2CH2CH2), 23.98
(NCH2CH2CH2), 19.33 [CH(CH3)2], 17.75 [CH(CH3)2], 14.46
(CO2CH2CH3).
Anal. Calcd for C22H34N2O6 (422): C, 62.54; H, 8.11; N, 6.63.
Found: C, 62.86; H, 7.91; N, 6.96.
Anal. Calcd for C17H30N2O5 (342): C, 59.63; H, 8.83; N, 8,18.
Found: C, 59.35; H, 8.57; N, 8.32.
Methyl N¢-(tert-Butoxycarbonyl)-L-(O-methyltyrosyl)-D-vali-
nate (3r)
Starting from methyl D-valinate (1.136 g, 8.67 mmol), compound
3r (3.183 g, 87%) was obtained as a rotamer mixture; [a]D25 = –54.1
(c = 0.365, CHCl3).
Preparation of Diketopiperazines (5) by Pyrolysis of Dipeptides
(3) under Thermal Conditions; General Procedure
The suitable dipeptide, neat and preferably as a syrup rather than in
crystalline form, was distributed as thinly as possible on the walls
of a round-bottom flask and then heated for 2 h in a poly(ethylene
glycol) bath at 200 °C (220 °C in the case of 3g), under an Ar atmo-
sphere, yielding the desired diketopiperazine.
IR (KBr): 3325, 3127, 1737, 1688, 1650, 1399, 1250, 1179 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.04–7.13 (m, 2 H, ArH), 6.78–
6.83 (m, 2 H, ArH), 6.50 (br s, 1 H, NH), 5.05 (br s, 1 H, NH), 4.46
(dd, J = 8.7, 4.9 Hz, 1 H, CHCH2Ar), 4.22–4.39 (m, 1 H, CHi-Pr),
3.77 (s, 3 H, OCH3), 3.69 (s, 3 H, CO2CH3), 2.90–3.00 (m, 2 H,
CH2Ar), 1.95–2.10 [m, 1 H, CH(CH3)2], 1.39 [s, 9 H, C(CH3)3],
0.76–0.81 [m, 6 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 172.48, 171.80 (CO2CH3, CO
amide), 158.96 (C4¢OCH3), 155.50 (CO carbamate), 130.68 (C-2¢,
C-6¢), 128.92 (C-1¢), 114.48 (C-3¢, C-5¢), 80.50 [C(CH3)3], 57.52
[CHi-Pr], 55.64 (CO2CH3), 52.52 (CHCH2Ar), 37.85 (CHCH2Ar),
31.47 [CH(CH3)2], 28.65 [C(CH3)3], 19.19, 18.16 [CH(CH3)2].
Preparation of Diketopiperazines (5) by Pyrolysis of Dipeptides
(3) under Microwave Irradiation; General Procedure
Methods A, B and C: The suitable dipeptide 3, neat and preferably
as a syrup rather than in crystalline form, was introduced in a glass
vial or distributed as thinly as possible on the walls of a round-bot-
tom flask, depending on the reaction scale. The vial or flask was
covered with an inverted glass funnel, in order to prevent projec-
tions, and submerged in a beaker containing alumina. The reaction
mixture was irradiated in a microwave oven at 600 W in 1-min puls-
es, with 1-min cooling periods (Method A), in 3- or 4-min pulses,
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3420
A. López-Cobeñas et al.
PAPER
with a 2-min cooling period (Method B), or for the times indicated
in Table 1, without intermediate cooling (Method C). The crude re-
action products were washed with EtOH, or recrystallized from
acetone or EtOH.
1H NMR (250 MHz, CDCl3): d = 7.21–7.36 (m, 5 H, ArH), 6.66 (s,
1 H, H-4), 4.57 (s, 2 H, ArCH2N), 4.10 (q, J = 7.0 Hz, 1 H, H-3),
3.82 (s, 2 H, H-6), 1.48 (d, J = 7.0 Hz, 3 H, CH3).
13C NMR (63 MHz, CDCl3): d = 165.98, 165.93 (C-2, C-5), 135.27
(C-1¢), 129.08, 128.45, 128.28 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 51.19
(C-3), 49.80, 49.14 (C-6, NCH2Ph), 20.30 (CCH3).
Method D: The suitable dipeptide 3 was thoroughly mixed with
silica gel (10% in weight) and irradiated as in Method A. The crude
reaction products were extracted with refluxing EtOH.
Data for compounds 5a,25 5b,10,25 5f,30 5s,30 and 5t31 were identical
to those found in the literature. Data for other compounds are given
below.
Anal. Calcd for C12H14N2O2 (218): C, 66.04; H, 6.47; N, 12.84.
Found: C, 65.82; H, 6.43; N, 12.65.
1-(4-Methoxybenzyl)-2,5-piperazinedione (5i)
1H NMR (250 MHz, CDCl3): d = 7.20–7.32 (m, 2 H, ArH), 6.85–
6.95 (m, 2 H, ArH), 6.07 (br s, 1 H, NH), 4.54 (s, 2 H, ArCH2), 4.08
(s, 2 H, H-3), 3.85 (s, 2 H, H-6), 3.81 (s, 3 H, OCH3).
(3S)-3-Isobutyl-2,5-piperazinedione (5c)
25
Mp 246–248 °C (EtOH) (lit.32 243–245 °C); [a]D –2.2 (c = 1.0,
DMSO) {lit.32 [a]D20 = +31.7 (c = 1.82, H2O}.
(3S)-1-(3,4-Dimethoxybenzyl)-3-methyl-2,5-piperazinedione
IR (KBr): 3434, 3196, 1679 cm–1.
(5j)
1H NMR (250 MHz, DMSO-d6): d = 8.26 (br s, 1 H, H-1), 7.99 (br
s, 1 H, H-4), 4.10–4.15 (m, 1 H, H-3), 3.82 (d, J = 17.4 Hz, 1 H, H-
6), 3.59 (d, J = 17.3 Hz, 1 H, H-6), 1.69–2.07 (m, 1 H, H-2¢), 1.45–
1.50 (m, 2 H, H-1¢), 0.87 (d, J = 6.7 Hz, 3 H, CH3), 0.85 (d, J = 6.7
Hz, 3 H, CH3).
13C NMR (63 MHz, DMSO-d6): d = 169.03 (C-2), 166.32 (C-5),
53.24 (C-3), 44.45 (C-6), 42.37 (C-1¢), 23.91, 23.22 (2 × CH3),
22.13 (C-2¢).
IR (KBr): 3273, 2927, 1684, 1659, 1590 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.06 (s, 1 H, H-4), 6.62–6.75 (m,
3 H, ArH), 4.50 (s, 2 H, ArCH2), 4.12 (q, J = 7.0 Hz, 1 H, H-3), 3.84
(s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.81 (s, 2 H, H-6), 1.49 (d, J =
7.0 Hz, 3 H, CCH3).
13C NMR (63 MHz, CDCl3): d = 166.73 (C-2), 166.19 (C-5), 149.45
(C-4¢), 149.05 (C-3¢), 127.10 (C-1¢), 121.13, 111.47, 111.17 (C-3¢,
C-5¢, C-6¢), 56.01 (2 × OCH3), 51.19 (C-3), 49.63, 48.93 (ArCH2N,
C-6), 20.31 (CCH3).
(3S,1¢S)-3-sec-Butyl-2,5-piperazinedione (5d)
IR (KBr): 3191, 3052, 1668, 1463, 1343 cm–1.
Anal. Calcd for C14H18N2O4 (278): C. 60.42; H, 6.52; N, 10.07.
Found: C, 60.25; H, 6.34; N, 10.29.
1H NMR (250 MHz, DMSO-d6): d = 8.17 (br s, 1 H, H-1), 8.01 (br
s, 1 H, H-4), 4.09–4.14 (m, 1 H, H-3), 3.80 (d, J = 17.8 Hz, 1 H, H-
6), 3.60 (dd, J = 17.7, 3.1 Hz, 1 H, H-6), 1.77–2.08 (m, 1 H, H-1¢),
1.36–1.42 (m, 1 H, H-2¢), 1.13–1.20 (m, 1 H, H-2¢), 0.74–0.93 (m,
6 H, 2 × CH3).
(3S)-1-(3-Indolylmethyl)-3-isopropyl-2,5-piperazinedione (5k)
Mp 228–229 °C; [a]D23 +6.0 (c = 0.40, MeOH).
IR (KBr): 3403, 3559, 1682, 1647, 742 cm–1.
13C NMR (63 MHz, DMSO-d6): d = 167.51 (C-2), 166.32 (C-5),
59.34 (C-3), 44.48 (C-6), 31.03 (C-1¢), 24.51 (C-2¢), 15.33, 11.89
(2 × CH3).
1H NMR (250 MHz, CDCl3): d = 8.23 (br s, 1 H, NHindole), 7.71 (d,
J = 7.5 Hz, 1 H, H-4¢), 7.37 (d, J = 8.0 Hz, 1 H, H-7¢), 7.09–7.20 (m,
3 H, H-2¢, H-5¢, H-6¢), 6.15 (br s, 1 H, H-4), 4.90 (d, J = 14.5 Hz, 1
H, ArCH2), 4.71 (d, J = 14.5 Hz, 1 H, ArCH2), 3.89–3.92 (m, 1 H,
H-3), 3.85 (s, 2 H, H-6), 2.51–2.41 [m, 1 H, CH(CH3)2], 1.00 [d,
J = 7.0 Hz, 3 H, CH(CH3)2], 0.82 (d, J = 7.0 Hz, 3 H, CH(CH3)2].
Anal. Calcd for C8H14N2O2 (170): C, 56.45; H, 8.29; N, 16.46.
Found: C, 56.33; H, 8.08; 16.22.
(3S)-3-Benzyl-2,5-piperazinedione (5e)
13C NMR (63 MHz, CDCl3): d = 166.3, 165.2 (2 × CO), 136.2 (C-
7a¢), 127.7 (C-3a¢), 124.7 (C-2¢), 122.8 (C-5¢), 120.3 (C-4¢), 119.2
(C-6¢), 111.4 (C-3¢), 110.1 (C-7¢), 61.0 (C-3), 48.3 (C-6), 40.8
(ArCH2), 33.0 [CH(CH3)2], 19.0 [CH(CH3)2], 16.1 [CH(CH3)2].
26
Mp 271–273 °C (EtOH) (lit.33 265.5 °C); [a]D +7.3 (c = 0.95,
DMSO).
IR (KBr): 3446, 3185, 1678 cm–1.
Anal. Calcd for C16H19N3O2 (285): C, 67.36; H, 6.66; N, 14.73.
Found: C, 66.92; H, 6.33; N, 14.53.
1H NMR (250 MHz, DMSO-d6): d = 8.16 (br s, 1 H, H-1), 7.90 (br
s, 1 H, H-4), 7.24–7.31 (m, 3 H, H-3¢, H-4¢, H-5¢), 7.13–7.21 (m, 2
H, H-2¢, H-6¢), 4.00–4.09 (m, 1 H, H-3), 3.34 (dd, J = 17.4, 2.8 Hz,
1 H, CH2Ar), 3.08 (dd, J = 13.5, 4.4 Hz, 1 H, H-6), 2.86 (dd, J =
13.5, 4.9 Hz, 1 H, H-6), 2.73 (d, J = 17.4 Hz, 1 H, CH2Ar).
13C NMR (63 MHz, DMSO-d6): d = 167.51 (C-2), 166.02 (C-5),
136.34 (C-1¢), 130.41 (C-3¢, C-5¢), 128.52 (C-2¢, C-6¢), 127.13 (C-
4¢), 55.78 (C-3), 44.01 (C-6), 31.02 (CH2Ar).
1-(2-Phenylethyl)-2,5-piperazinedione (5l)
Mp 225–227 °C.
IR (KBr): 3228, 2929, 1678, 1646, 1491 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.20–7.32 (m, 5 H, ArH), 6.13 (br
s, 1 H, H-4), 3.97 (s, 2 H, H-3), 3.77 (s, 2 H, H-6), 3.61 (t, J = 7.1
Hz, 2 H, ArCH2CH2N), 2.88 (t, J = 7.6 Hz, 2 H, ArCH2CH2N).
1-Methyl-2,5-piperazinedione (5g)
13C NMR (63 MHz, CDCl3): d = 167.00 (C-2), 165.00 (C-5), 138.05
(C-1¢), 128.90, 128.79, 126.97 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 50.43
(C-3), 48.51, 45.28 (ArCH2CH2N, C-6), 36.27 (ArCH2CH2N).
Mp 138–140 °C (EtOH) [lit.34 140–143 °C (EtOH–H2O)].
IR (KBr): 3392, 3192, 1672, 1659 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.76 (br s, 1 H, NH), 4.03, 3.99
(2 × s, 4 H, H-3, H-6), 3.00 (s, 3 H, NCH3).
Anal. Calcd for C12H14N2O2 (218): C, 66.04; H, 6.42; N, 12.84.
Found: C, 65.84; H, 6.31; N, 12.71.
13C NMR (63 MHz, DMSO-d6): d = 165.32, 164.33 (C-2, C-5),
51.41 (C-6), 44.62 (C-3), 33.12 (NMe).
(3S)-3-Isopropyl-1-(2-Phenylethyl)-2,5-piperazinadione (5m)
Mp 165–166 °C; [a]D25 +38.6 (c = 0.22, CH2Cl2).
(3S)-1-Benzyl-3-methyl-2,5-piperazinedione (5h)
Mp 110 °C; [a]D25 –38.1 (c = 0.31, CH2Cl2).
IR (KBr): 3274, 2979, 2935, 1694, 1662, 1495 cm–1.
IR (KBr): 3235, 3086, 2969, 1679, 1651, 1496 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.18–7.31 (m, 5 H, ArH), 6.68 (br
s, 1 H, H-4), 3.65–3.91 (m, 4 H, H-6, ArCH2CH2N, H-3), 3.42 (m,
1 H, ArCH2CH2N), 2.87 (t, J = 7.3 Hz, 2 H, ArCH2CH2N), 2.29–
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

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Microwave-Assisted Synthesis of 2,5-Piperazinediones under Solvent-Free Conditions
3421
2.41 [m, 1 H, CH(CH3)2], 0.95 [d, J = 7.1 Hz, 3 H, CH(CH3)2], 0.80
[d, J = 6.8 Hz, 3 H, CH(CH3)2].
13C NMR (63 MHz, CDCl3): d = 165.82 (C-2), 165.26 (C-5), 137.81
(C-1¢), 128.36, 128.59, 126.71 (C-2¢, C-3¢, C-4¢, C-5¢, C-6¢), 60.76
(C-3), 49.98 (C-6), 48.18 (ArCH2CH2N), 33.08, 32.77
[ArCH2CH2N, CH(CH3)2], 18.77 [CH(CH3)2], 16.08 [CH(CH3)2].
Hz, 2 H, H-3¢, H-5¢), 4.07 (m, 1 H, H-3), 3.65 (s, 3 H, OCH3), 3.48
(m, 1 H, H-6), 3.03 (dd, J = 13.4, 5.1 Hz, 1 H, CH2Ar), 2.77 (dd, J =
13.4, 5.1 Hz, 1 H, CH2Ar), 1.60 [m, 1 H, CH(CH3)2], 0.61 [d, J =
7.0 Hz, 3 H, CH(CH3)2], 0.23 (d, J = 7.0 Hz, 3 H, CH(CH3)2].
13C NMR (63 MHz, DMSO-d6): d = 166.92, 166.73 (2 × CO),
158.52 (C-4¢), 131.71 (C-2¢, C-6¢), 128.48 (C-1¢), 113.97 (C-3¢, C-
5¢), 59.47 (C-6), 55.48, 55.36 (OCH3, C-3), 37.25 (CH2Ar), 31.34
[CH(CH3)2], 18.58, 16.48 [CH(CH3)2].
Anal. Calcd for C15H20N2O2 (260): C, 69.20; H, 7.74; N, 10.76.
Found: C, 68.90; H, 7.70; N, 10.70.
Anal. Calcd for C15H20N2O3 (276): C, 65.20; H, 7.30; N, 10.14.
Found: C, 65.48; H, 7.65; N, 9.93.
(3S)-1-(2-Naphthylmethyl)-3-methyl-2,5-piperazinedione (5n)
Mp 132–134 °C; [a]D25 –33.3 (c = 0.15, CH2Cl2).
(3S,6R)-6-Isopropyl-3-(4-methoxybenzyl)-2,5-piperazinedione
(5r)35
IR (KBr): 3239, 2931, 1688, 1658, 1508 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.78–7.74 (m, 3 H, ArH), 7.65 (s,
1 H, H-1¢), 7.48–7.23 (m, 3 H, ArH), 7.21 (br s, 1 H, H-4), 4.75 (d,
J = 15.3 Hz, 1 H, ArCH2N), 4.69 (d, J = 15.3 Hz, 1 H, ArCH2N),
4.12 (q, J = 7.0 Hz, 1 H, H-3), 3.84 (s, 2 H, H-6), 1.48 (d, J = 7.0
Hz, 3 H, CH3).
13C NMR (63 MHz, CDCl3): d = 166.81 (C-2), 165.99 (C-5),
133.09, 132.51, 132.80, 129.15, 127.84, 127.71, 126.70, 126.64,
126.44, 125.99 (Ar), 51.17 (C-3), 49.70, 48.90 (C-6, NCH2Ar),
19.95 (CCH3).
Mp 230–232 °C; [a]D25 –48.6 (c = 0.51, DMSO).
IR (KBr): 1662, 1514 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.13 (br s, 1 H, NH), 7.96 (br
s, 1 H, NH), 7.15 (d, J = 8.5 Hz, 2 H, H-2¢, H-6¢), 6.8 (d, J = 8.5 Hz,
2 H, H-3¢, H-5¢), 4.10 (m, 1 H, H-3), 3.69 (s, 3 H, OCH3), 3.07 (dd,
J = 13.8, 4.3 Hz, 1 H, CH2Ar), 2.97 (m, 1 H, H-6), 2.77 (dd, J = 13.6,
4.5 Hz, 1 H, CH2Ar), 2.02 [m, 1 H, CH(CH3)2], 0.81 [d, J = 7.0 Hz,
3 H, CH(CH3)2], 0.74 [d, J = 7.0 Hz, 3 H, CH(CH3)2].
13C NMR (63 MHz, DMSO-d6): d = 167.62, 167.41 (2 × CO),
158.36 (C-4¢), 131.53 (C-2¢, C-6¢), 128.11 (C-1¢), 113.97 (C-3¢, C-
5¢), 59.28 (C-6), 55.30, 55.26 (OCH3, C-3), 37.30 (CH2Ar), 31.96
[CH(CH3)2], 18.50, 16.90 [CH(CH3)2].
Anal. Calcd for C16H16N2O2 (268): C, 71.62; H, 6.01; N, 10.42.
Found: C, 71.52; H, 6.13; N, 10.31.
(3S,6S)-3-Benzyl-6-isopropyl-2,5-piperazinedione (5o)
Mp 176–178 °C; [a]D25 –43.30 (c = 0.27, DMSO).
IR (KBr): 1663, 1452 cm–1.
Anal. Calcd for C15H20N2O3 (276): C, 65.20; H, 7.30; N, 10.14.
Found: 64.98; H, 7.42; N, 9.83.
1H NMR (250 MHz, DMSO-d6): d = 8.14 (br s, 1 H, NH), 7.93 (br
s, 1 H, NH), 7.15–7.30 (m, 5 H, ArH), 4.19 (m, 1 H, H-3), 3.38 (m,
1 H, H-6, overlapped with the H2O resonance), 3.13 (dd, J = 13.4,
4.2 Hz, 1 H, CH2Ar), 2.84 (dd, J = 13.4, 4.2 Hz, 1 H, CH2Ar), 1.50–
1.75 [m, 1 H, CH(CH3)2], 0.61 [d, J = 7.0 Hz, 3 H, CH(CH3)2], 0.21
(d, J = 7.0 Hz, 3 H, CH(CH3)2].
Acknowledgment
We thank CICYT for financial support of this research through
grant SAF 2003-03141. A studentship to ALC (Beca FPU, from Mi-
nisterio de Educación y Ciencia) is also gratefully acknowledged.
13C NMR (63 MHz, DMSO-d6): d = 164.89, 164.78 (2 × CO),
134.66 (C-1¢), 128.69 (C-3¢, C-5¢), 126.30 (C-2¢, C-6¢), 124.86 (C-
4¢), 57.50 (C-6), 53.37 (C-3), 36.10 (CH2Ar), 29.34 [CH(CH3)2],
16.59, 14.45 [CH(CH3)2].
References
(1) See, for instance: (a)Antibacterial activity (avrainvillamide,
CJ-17,665): Sugie, Y.; Hirai, H.; Inagaki, T.; Ishiguro, M.;
Kim, Y.-J.; Kojima, Y.; Sakakibara, T.; Sakemi, S.; Sugiura,
A.; Suzuki, Y.; Brennan, L.; Duignan, J.; Huang, L. H.;
Sutcliffe, J.; Kojima, N. J. Antibiot. 2001, 54, 911.
(b) MDR reversal activity(ardeemins): Chou, T.-C.; Depew,
K. M.; Zheng, Y.-H.; Safer, M. L.; Chan, D.; Helfrich, B.;
Zatorska, D.; Zatorski, A.; Bornmann, W.; Danishefsky, S.
J. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8369. (c) Cell
cycle inhibition at the G2/M phase (fumitremorgins,
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Osada, H. J. Antibiot. 1996, 49, 527. (d) Microtubule
binding(phenylahistin): Kanoh, K.; Kohno, S.; Katada, J.;
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Anal. Calcd for C14H18N2O2 (246): C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.02; H, 7.23; N, 11.12.
(3S,6R)-3-Benzyl-6-isopropyl-2,5-piperazinedione (5p)
Mp 269–271 °C; [a]D25 –70.98 (c = 0.355, DMSO).
IR (KBr): 1674, 1453 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.14 (br s, 1 H, NH), 7.93 (br
s, 1 H, NH), 7.05–7.30 (m, 5 H, ArH), 4.16 (m, 1 H, H-3), 3.14 (dd,
J = 13.6, 3.7 Hz, 1 H, CH2Ar), 2.92 (m, 1 H, H-6), 2.86 (dd, J = 13.6,
3.7 Hz, 1 H, CH2Ar), 1.90–2.10 [m, 1 H, CH(CH3)2], 0.79 [d, J =
7.0 Hz, 3 H, CH(CH3)2], 0.72 (d, J = 7.0 Hz, 3 H, CH(CH3)2].
13C NMR (63 MHz, DMSO-d6): d = 167.11, 166.81 (2 × CO),
135.79 (C-1¢), 129.92 (C-3¢, C-5¢), 125.95 (C-2¢, C-6¢), 126.33 (C-
4¢), 58.63 (C-6), 54.45 (C-3), 37.63 (CH2Ar), 31.24 [CH(CH3)2],
17.89, 16.28 [CH(CH3)2].
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resistance to antitumor agents: Dale, I. L.; Tuffley, W.;
Callaghan, R.; Holmes, J. A.; Martin, K.; Luscombe, M.;
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Found: C, 67.98; H, 7.63; N, 11.01.
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(3S,6S)-6-Isopropyl-3-(4-methoxybenzyl)-2,5-piperazinedione
(5q)
Mp 182–184 °C; [a]D25 –37.9 (c = 0.14, DMSO).35
IR (KBr): 1668, 1514 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.13 (br s, 1 H, NH), 7.96 (br
s, 1 H, NH), 7.05 (d, J = 8.5 Hz, 2 H, H-2¢, H-6¢), 6.78 (d, J = 8.5
Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York

3422
A. López-Cobeñas et al.
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Synthesis 2005, No. 19, 3412–3422 © Thieme Stuttgart · New York