Synthesis of conformationally constrained amino acid and peptide derivatives

Article abstract of DOI:10.1039/b108872f

6-Benzylpiperazine-2,3,5-trione 5, a cyclic phenylalanine derivative, can be selectively and sequentially alkylated at N⁴, C⁶ and N¹ to provide a range of conformationally constrained phenylalanine mimetics. Alkylation at C⁶, the α-carbon of the phenylalanine moiety is achieved under mild conditions and gives rise to Phe derivatives posessing a dialkylated α-carbon. Alkylation of piperazine 5 using methyl bromoacetate and ethyl bromopropionate gives access to peptoids 7 and 21 which are conformationally contrained Phe-Gly and Phe-Ala analogues respectively. The X-ray crystal structure of triallylated derivative 17 is also reported.

Full text of DOI:10.1039/b108872f

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Synthesis of conformationally constrained amino acid and peptide
derivatives
Patrick D. Bailey,a Neill Bannister,b Marine Bernad,b Sophie Blanchardb and Andrew N. Boa*b
1
a Department of Chemistry, University of Manchester Institute of Science & Technology,
Faraday Building, PO Box 88, Manchester, UK M60 1QD
b Department of Chemistry, University of Hull, Cottingham Road, Hull, UK HU6 7RX.
E-mail: a.n.boa@hull.ac.uk
Received (in Cambridge, UK) 1st October 2001, Accepted 26th October 2001
First published as an Advance Article on the web 22nd November 2001
6-Benzylpiperazine-2,3,5-trione 5, a cyclic phenylalanine derivative, can be selectively and sequentially alkylated at
N4, C6 and N1 to provide a range of conformationally constrained phenylalanine mimetics. Alkylation at C6, the
α-carbon of the phenylalanine moiety is achieved under mild conditions and gives rise to Phe derivatives posessing
a dialkylated α-carbon. Alkylation of piperazine 5 using methyl bromoacetate and ethyl bromopropionate gives
access to peptoids 7 and 21 which are conformationally contrained Phe-Gly and Phe-Ala analogues respectively.
The X-ray crystal structure of triallylated derivative 17 is also reported.
compound is a closer analogue of glutarimide, with which suc-
Introduction
cessful reaction had already been achieved, and which can be
readily made from phenylalaninamide and diethyl oxalate.2,3
Unlike the hydantoins used by Takeuchi et al. for essentially
the same purpose,4 this class of compound seemed an ideal
candidate for further modification. Some initial results5 indi-
During the course of a programme on the synthesis of α-fluoro-
glycine derivatives, we were searching for a suitably activated
amino acid amide derivative 1. Our interest was in constructing
peptides through O᎐CN CHR bond formation, as opposed
to the normal acylation at nitrogen O᎐C NCHR, allowing
access to peptides in which the free amino acid was considered
to be too unstable to use conventional coupling methods.1
With the derivatives 1 we wanted selectively to alkylate at the
amidic nitrogen with an α-fluoro-α-halocarboxamide, as a route
to access fluorodipeptides of the general structure 2 (Scheme 1).
Our initial studies1 had shown how simple nitrogen nucleo-
᎐
cated that the O᎐C3–N4 bond in 5 can be selectively cleaved at
᎐
᎐
a later date to give something which resembles more closely a
dipeptide (Scheme 3). Indeed Person and Le Corre3 have shown
Scheme 1
philes, such as succinimide and glutarimide, could be success-
fully used to displace iodide from α-fluoro-α-iodocarboxa-
mides. So we then started to look for suitable substrates (cf. 1)
that would ultimately give us access compounds such as 2 with
a true dipeptide skeleton. After some unsuccessful attempts to
utilise acyclic compounds as ‘amide anion equivalents’ (e.g. 3,
Scheme 2) our focus turned to piperazine-2,3,6-trione 5. This
Scheme 3 Reagents and conditions: i, (CO2Et)2, NaOEt–EtOH then
1 M HCl (aq) (63%); ii, alkylate; iii, H3Oϩ or OHϪ.
the 3-oxo group in 5 is sufficiently reactive to undergo selective
methylenation with Wittig reagents. Before progressing with
our work on α-fluoroglycine derivatives, trial alkylation
reactions of the piperazinetrione 5 were investigated.
N-Methylation of 5 was achieved using sodium hydride
(1 equiv.) and methyl iodide to give 6 (76%), but to our surprise
when the alkylating agent employed was methyl bromoacetate
(1.05 equiv.) we isolated the dialkylated species 8 (22%) as
well as the expected product 7 (60%). If potassium carbonate
was used as base trione 8, in which the α-carbon of the phenyl-
alanine residue has been alkylated, was the only product
obtained, with yields depending on the amount of electrophile
added (Scheme 4). Derivatives 7 and 8 are interesting as
they represent novel conformationally constrained Phe-Gly
dipeptide analogues. Modified amino acids, such as those
Scheme 2 Reagents and conditions: i, K2CO3, BrCH2CO2Me; ii, Pd–C/
H2.
DOI: 10.1039/b108872f
J. Chem. Soc., Perkin Trans. 1, 2001, 3245–3251
This journal is © The Royal Society of Chemistry 2001
3245

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Scheme 5 Reagents and conditions: i, K2CO3, DMF, 2.2 mol equiv.
RCH2Br.
(Scheme 5) reactions took place, giving moderate yields of the
dialkylated amino acid derivatives 8–11. In the cases of methyl
iodide and unactivated alkyl halides, however, no alkylation
products were isolated or identified. Sammes and co-workers
have previously found8 that α,β-unsaturated diketopiperazines
can be isolated as their aromatic ‘iminol’ tautomer from
basic conditions 13 or their amide tautomer 12 from acidic
conditions (Scheme 6).
Scheme 4 Reagents and conditions: i, NaH, DMF then MeI (76%);
ii, NaH, DMF then 1.05 mol equiv. BrCH2CO2Me (60% 7, 22% 8);
iii, K2CO3, DMF, 2.2 mol equiv. BrCH2CO2Me (61% 8).
containing dialkylated α-carbon atoms,6 and those that are
conformationally constrained by incorporation of the amino
acid into a ring,7 are currently receiving attention as synthetic
targets. Their use in the synthesis of peptides or other natural
products as replacements of a proteinogenic amino acid,
can not only result in marked changes in preferred molecular
conformation, but can also affect a compound’s susceptibility
to enzymatic hydrolysis. The synthesis and incorporation of α-
dialkylated α-amino acids into peptides is therefore an import-
ant goal for the medicinal chemist. In the light of our early
results5 we considered that alkylation of piperazinetriones
should give access to a wide range of conformationally con-
strained phenylalanine derivatives.
Results and discussion
The simple preparation of piperazinetriones from a range of
amino amides has been reported by Safir et al.,2 though we
found that the reported propensity towards rapid hydrolysis of
the intermediate N4-salts† meant that yields were often variable
(20–65%). Thus, during the reaction work-up the salt must
be isolated and protonation carried out promptly to avoid
excessive hydrolysis back to the acyclic oxamic acid. Also,
the natural inclination to use ethanol–sodium ethoxide for a
reaction using the diethyl ester of oxalic acid is, in this case,
definitely not as good as the methanol–methoxide system
employed by Person and Le Corre.3 The intermediate salt pre-
cipitates much more cleanly and in greater yield from methanol
in this particular case, though serious ‘bumping’ during the
latter period of heating is a problem. Even though our synthesis
of the trione 7 used enantiomerically pure phenylalaninamide,
the reaction was conducted under basic conditions. Checking
the specific rotation of 7 we found an [α]D of only ϩ2.1 (c = 0.1,
DMSO). Even though this value was slightly variable and the
analysis hampered by poor solubility, the near-zero value seems
to concur with the reports of Person and Le Corre that total
racemization occurs in the synthesis of piperazinetriones using
this method.
Scheme 6
Undoubtedly the facile C6-alkylation observed was due to the
increased acidity of C6-H due to the presence of the aromatic
tautomer 14a under the basic reaction conditions. We made
an attempt to isolate the TMS derivative 14b by heating 5
in hexamethydisilazane, however the experiment was unsuccess-
ful. To investigate this matter further, the N1-blocked trione 15
was synthesised from N-benzylphenylalaninamide (Scheme 7)
In addition to the early results mentioned above we also
observed by TLC that in a ‘blank run’ with potassium
carbonate–DMF only (no electrophile added) the trione was
consumed quickly to give just ‘baseline material’. Again the
hydrolysis of the anion of 5 is undoubtedly the competing
reaction in this system due to the difficulty of complete removal
of water from the DMF and the carbonate base. However,
in the presence of 2.2 equivalents of an activated electrophile
Scheme 7 Reagents and conditions: i, (a) PhCHO, azeotrope, cat. p-
TsOH; (b) NaBH4, MeOH, (73%, 2 steps); ii, (CO2Et)2, NaOEt–EtOH,
∆, then AcOH (43%); iii,
BrCH2CO2Me (83%).
3 equiv. K2CO3, DMF, 1.5 equiv.
† The parent piperazine 5 is named as a piperazine-2,3,5-trione using
the Chemical Abstracts system, but additional substituents can in
certain cases alter the numbering pattern. For clarity, reference to the
locants N1, N4 and C6 in the discussion are based on the parent piper-
azine 5. The correct numbering however is used in the Experimental
section.
and this compound underwent clean, rapid alkylation only at
N4 giving 16 (83%); no C6-alkylation was observed. The N1-
benzyl group prevents 15 from forming a stable conjugated
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tautomer and therefore presumably causes a significant drop in
the acidity of the C6-H.
derivatives 22–24. However, the yields of these reactions were
quite variable 40–78% (Scheme 9). Whereas the solubility of
In the case of alkylation of piperazinetrione 5 with allyl
bromide we noticed that alkylation at N1 could also be achieved
if left for longer times with sufficient electrophile present. The
rate of alkylation at N1 could be accelerated using the phase
transfer catalyst (PTC) tetra-n-butylammonium bromide. Thus
we were able to isolate and analyse the crystalline triallylated
product 17 using X-ray diffraction.5 However, if the PTC
was present from the beginning of the reaction and less than 3
equivalents of alkyl halide were present, then it was difficult to
isolate a single product in anything but modest yield.
Scheme 9 Reagents and conditions: i, 3 equiv. K2CO3, DMF, 1.2 equiv.
R2CH2Br, (40–80%).
trione 5 is quite low, the derivatives 7 and 18–21 are much more
soluble in DMF and so competing alkylation at N1 causes a
drop in the yield of the N4,C-dialkylated derivatives.
Knowing that we could alkylate at C6 using potassium
carbonate and DMF, and then promote further N1-alkylation
using a PTC, we speculated that with the right choice of con-
ditions and reaction time, we should be able to alkylate the
piperazinetrione selectively with up to three different groups.
We therefore next investigated a way of selectively alkylating at
N4 without concomitant reaction at C6, as had been observed
with sodium hydride and potassium carbonate. Use of the
non-nucleophilic DBU in both DMF and MeCN was unsuc-
cessful, and with stoichiometric amounts of triethylamine and
alkyl halide, competitive quaternization of the tertiary amine
reduced isolated yields of the desired product. However if the
substrate ratio was 1.0 equiv. trione, 1.2 equiv. base and 1.5
equiv. alkyl halide, moderate to good yields of the N4 alkylated
products were produced if the reaction was conducted at
room temperature or with warming (Scheme 8). Due to its
Given that all the piperazinetriones made so far can be
considered as conformationally constrained phenylalanine
analogues we thought that a modelling study may reveal
some trends in the preferred low-energy conformation of
these derivatives. Simple molecular modelling studies9 of the
dipeptide analogues 7, 8, 16 and 21 and the triallylated deriva-
tive 17 were therefore undertaken. In the cases of 7, 8, 16 and
17, which all bear an N4-CH2R group, the plane containing the
N4–C–C atoms was found to be near to perpendicular relative
to the approximate plane of the piperazine ring (Fig. 1). This
Fig. 1 Chem-3D® representation of the Phe-Gly dipeptide analogue
7.
was also seen in the single crystal X-ray structure10 of tri-
allylated derivative 17 (Fig. 2). From conformational analysis of
rotation about the N4–CH2 bond there seemed to be a distinct
preference for such conformations but with no great difference
in energy when the bulk of the N4 group was either syn or
anti to the C6 benzyl group.
Scheme 8 Reagents and conditions: i, 1.1 equiv. Et3N, MeCN–DMF,
1.5 equiv. R1RCHBr (65–75%, except 16% for 21).
In conclusion, we have reported a mild and versatile route
to conformationally constrained phenylalanine derivatives.
This method has allowed the preparation of a range of cyclic
piperazine derivatives containing a phenylalanine core, some
(9–11, 17, 22, 23) with and some (6, 15, 18–20) without an
alkylated α-carbon. In addition, conformationally constrained
analogues of the dipeptides Phe-Gly (7, 8, 16, 24) and Phe-Ala
(21) have been prepared (derivative 8 can also be considered as
an Asp-Gly analogue). Given that triketopiperazines from a
range of amino acids have been prepared, this methodology
should allow the preparation of larger numbers of novel
conformationally constrained amino acid and dipeptide
derivatives.
lower boiling point, acetonitrile proved easier to handle than
DMF, but the solubility of the trione in HPLC-grade or other
rigorously dried solvent was severely limited and hampered
progress of the reaction. So in certain cases some DMF was
added to the reaction mixture to aid solubility. In this way a
range of N4-derivatised piperazinetriones 18–21 were made,
and under these conditions no reaction at C6 was observed.
Alkylation with an unactivated alkyl bromide was even possible
under these conditions with heating (giving 20), and reaction
with ethyl 2-bromopropionate gave the Phe-Ala peptidomi-
metic 21 as a 1 : 1 mixture of diastereoisomers. However, in
this last case, even with extensive efforts at optimisation of the
reaction conditions, we could not get the yields of 21 above
15–20%. This is presumably because the reaction involves a
more hindered secondary bromide.
Experimental
Anhydrous N,N-dimethylformamide was stored over 4 Å
molecular sieves; methanol was dried by distillation from and
stored over calcium hydride. Triethylamine was dried and
Having now developed a route to N4-derivatised piper-
azinetriones, further reaction with a different alkyl halide was
possible. Using potassium carbonate in DMF, derivatives 7,
18, and 19 could be further alkylated selectively at C6 giving
J. Chem. Soc., Perkin Trans. 1, 2001, 3245–3251
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PhCH2), 4.59 (2 H, s, CH2), 3.72 (3 H, s, CO2Me); δC(22.5 MHz,
CDCl3) 172.3 (s), 169.1 (s), 154.1 (s), 136.0 (s), 134.2 (s), 131.5
(d), 128.3 (d), 128.1 (d), 127.9 (d), 68.9 (t), 52.3 (q), 46.5 (t);
νmax(CHCl3)/cmϪ1 1740, 1680; m/z FAB-MS 328 (MHϩ, 48%),
105 (29), 77 (100).
N-Benzoylglycine methyl ester, 4
The protected glycine derivative (113 mg, 0.35 mmol) was dis-
solved in methanol (10 cm3), and in this solution was suspended
a 10% palladium-on-charcoal catalyst (16 mg). The mixture
was then stirred under a hydrogen atmosphere for 16 h after
which the solution was diluted, filtered and then evaporated
to dryness. The resulting residue was purified by ‘filtration’
through a small pad of flash silica (eluent dichloromethane),
yielding 41 mg (61%) of the title compound. Rf 0.25 (CH2Cl2);
mp 72–82 ЊC (without further purification) (lit.11 85 ЊC);
δH(90 MHz, CDCl3) 7.87–7.30 (5 H, m, ArH), 6.90 (1 H, broad
s, NH), 4.22 (2 H, d, J 5.0, NHCH2), 3.77 (3 H, s, CO2Me);
δC(22.5 MHz, CDCl3) 169.5 (s), 166.6 (s), 132.6 (s), 130.7 (d),
127.5 (d), 126.1 (d), 51.4 (q), 40.7 (t); νmax(CHCl3)/cmϪ1 3440,
1745, 1660; m/z 193 (Mϩ, 11%), 161 (6), 134 (20), 105 (100), 77
(45).
Fig. 2 X-Ray crystal structure of derivative 17.
6-Benzylpiperazine-2,3,5-trione, 53
stored over potassium hydroxide. HPLC grade acetonitrile
and all other reagents were used as purchased. In reporting
1H NMR data for AB and ABX systems the chemical shift
of the centre of the pattern is quoted, followed by a ∆ value
(Hz) giving the spread of the outermost lines of the pattern.
The coupling constants for ABX systems are given with the
coupling constant JHa–Hb first, then JHa–X for the downfield
proton and lastly the JHb–X for the upfield proton. In the cases
where ∆ > 80 Hz (0.2 ppm at 400 MHz), the data are simply
quoted as being two separate doublets (or doublet of doublets).
()-Phenylalaninamide (1.0 g, 6.1 mmol) and diethyl oxalate
were dissolved in methanol (15 cm3), and heated at reflux for
0.25 h. Then, whilst refluxing was continued, 1.1 equivalents of
sodium methoxide in methanol were added dropwise over a
period of 0.25 h (353 mg of sodium was dissolved in 4.5ml of
methanol, and then 2 cm3 of this solution used). After addition
of the last portion of the sodium methoxide, refluxing was
continued for 0.3 h. Next the mixture was cooled in an ice bath,
before removal of the resulting precipitate by filtration. The
salt collected was added with stirring to 1 M hydrochloric acid
(6 cm3) to liberate the free trione. The suspension was filtered
immediately, and the solid dried under vacuum to yield 842 mg
(63%) of 5-benzylpiperazine-2,3,6-trione 5 as a white solid,
mp 230–240 ЊC (without further purification) [lit.4 264 ЊC
(H2O)]. Rf 0.11 [(1 : 1) chloroform–ethyl acetate]; δH(400 MHz,
d6-DMSO) 11.75 (1H, s, NH), 9.23 (1 H, broad s, NH), 7.29–
7.20 (3 H, m, Ph), 7.10–7.09 (2 H, m, Ph), 4.61 (1 H, t, J 3.5,
CH), 3.10 (2 H, ABX, ∆ = 41.5 Hz, J 13.8, 4.3 and 5.2, PhCH2);
δC(22.5MHz, d6-DMSO) 174.8 (s), 162.2 (s), 158.2 (s), 139.0 (s),
133.9 (d), 132.2 (d), 131.0 (d), 61.2 (d), 43.1 (t); νmax(Nujol)/
cmϪ1 3230, 1755, 1720–1680; m/z 218 (Mϩ, 2%), 91 (100).
N-(Benzyloxycarbonyl)benzamide, 3
Finely ground benzamide (3.0 g, 25 mmol) was suspended in
dry dichloromethane (40 cm3) under an argon atmosphere.
Next, to the vigorously stirred mixture at 0 ЊC, oxalyl chloride
(3.28 cm3, 38 mmol) in dichloromethane (20 cm3) was added
dropwise over a period of 45 minutes. The mixture was then
allowed to slowly warm to room temperature over 1.5 h and
heated at reflux for 22 h. After re-cooling to 0 ЊC benzyl alcohol
(12.9 cm3, 125 mmol) in dichloromethane (75 mmol) was added
dropwise to the solution over a period of 2.5 h. After stirring
at ambient temperature overnight, the solvent was removed
in vacuo, and the resulting sludge was washed thoroughly with
hexane. Recrystallization of the crude solid (CH2Cl2–hexane)
gave 6.04 g (95%) of the title compound as colourless plates. Rf
0.21 (CH2Cl2); Mp 112–114 ЊC (CH2Cl2–hexane); δH(90 MHz,
CDCl3) 7.90–7.70 and 7.50–7.30 (10 H, m, ArH), 8.57 (1 H, bs,
NH), 5.15 (2 H, s, CH2); δC(22.5 MHz, CDCl3) 165.1 (s), 151.0
(s), 135.0 (s), 132.8 (d), 128.7 (d), 128.5 (d), 127.8 (d), 67.7 (t);
νmax(CHCl3)/cmϪ1 3430, 1780, 1715; m/z 256 FAB-MS (NOBA)
(MHϩ, 60), 105 (19), 91 (100), 77 (9).
6-Benzyl-4-methylpiperazine-2,3,5-trione, 6
The piperazinetrione 5 (55 mg, 0.25 mmol) was dissolved in
DMF (1 cm3), and then added to a stirred suspension of
sodium hydride (7.5 mg, 0.25 mmol) in DMF (2 cm3) under
an argon atmosphere. After the solution had been stirred for
10 minutes, methyl iodide (25 µl, 1.5 equiv.) in DMF (2 cm3)
was added to the reaction vessel. After 8 h the DMF was
removed in vacuo to leave a residue, which was thoroughly
triturated with ethyl acetate (5 cm3). The fine white precipitate
that formed was collected by filtration, yielding 44 mg (76%) of
the methylated product 6. Rf 0.54 [(2 : 1 : 17) methanol–acetic
acid–chloroform); δH(d4-MeOH; 90 MHz) 7.40–7.20 (6 H, m,
Ph ϩ NH), 4.73 (1 H, t, J 4.6, CH), 3.25 (2 H, m, PhCH2), 2.98
(3 H, s, Me); δC(22.5 MHz, d6-DMSO) 169.0 (s), 156.9 (s), 152.6
(s), 134.5 (s), 129.6 (d), 128.1 (d), 127.1 (d), 56.6 (d), 39.9 (t),
26.1 (t); m/z 230 (Mϩ, 3%), 165 (10), 91 (100).
N-Benzoyl-N-(benzyloxycarbonyl)glycine methyl ester
The protected benzamide 3 (150 mg, 0.59 mmol) and anhydrous
potassium carbonate (406 mg, 5 equiv.) were mixed with DMF
(5 cm3) under argon. Next methyl bromoacetate (56 µl,
0.59 mmol) in DMF (3 cm3) was added and the mixture left
stirring at ambient temperature for 5 h. After this time the
DMF was removed in vacuo and the residue thoroughly tri-
turated chloroform. The chloroform washings were combined,
the solvent evaporated and the resulting residue purified
using silica flash chromatography (CH2Cl2) to yield the title
compound (170 mg, 67%) as a colourless oil. Rf 0.52 (CH2Cl2);
δH(90 MHz, CDCl3) 7.70–6.90 (10 H, m, ArH), 5.01 (2 H, s,
(3-Benzyl-2,5,6-trioxopiperazin-1-yl)acetic acid methyl ester 7
and (3-benzyl-3-methoxycarbonylmethyl-2,5,6-trioxopiperazin-
1-yl)acetic acid methyl ester, 8
Sodium hydride (13.8 mg, 0.46 mmol) was suspended in
DMF (2 cm3) under an argon atmosphere. Then trione 5
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(100 mg, 0.46 mmol) was added, and the solution stirred
for 10 minutes, after which effervescence had ceased and the
solution cleared. Methyl bromoacetate (46 µl, 0.48 mmol, 1.05
equiv.) in DMF (1 cm3) was added to the reaction flask, and the
mixture stirred for 6 h at room temperature. The DMF was then
removed in vacuo and the products separated and purified using
silica flash chromatography [(4 : 1) chloroform–ethyl acetate]
yielding 80 mg (60%) of 7; Rf 0.25 [(1 : 1) chloroform–ethyl
acetate]; found: MHϩ 291.0979. C14H15N2O5 requires M,
291.0981; δH(300 MHz, CDCl3) 8.30 (1 H, broad s, NH), 7.34–
7.25 and 7.15–7.12 (5 H, m, Ph), 4.77 (1 H, m, CH), 4.46 (2 H,
m, CH2N), 3.75 (3 H, s, CO2Me), 3.30 (2 H, ABX, ∆ = 46.1 Hz,
J 13.8, 4.5 and 6.3, PhCH2); δC(75 MHz, CDCl3) 167.7 (s),
166.9 (s), 155.9 (s), 153.6 (s), 133.3 (s), 129.8 (d), 129.0 (d), 128.1
(d), 57.7 (d), 52.8 (q), 41.3 (t), 41.2 (t); νmax(CHCl3)/cmϪ1 3380,
3230 (two broad, weak absorptions), 1750, 1710; m/z 291
(MHϩ, 100%). Also isolated was 8 (36 mg, 22%), mp 155–158
ЊC (chloroform–hexane); found: Mϩ 363.1200. C17H19N2O7
requires M, 363.1192; Rf 0.35 [(1 : 1) chloroform–ethyl acetate];
δH(300 MHz, CDCl3) 8.57 (1 H, broad s, NH), 7.31–7.26 and
7.10–7.07 (5 H, m, Ph), 4.39 (2 H, AB, ∆ = 40.8 Hz, J 16.7,
NCH2O2), 3.72 (3 H, s, CO2Me), 3.68 (3 H, s, CO2Me),
3.54 (1 H, d, J 17.4, one proton from PhCH2), 3.01 (1 H, d,
J 17.4, other proton from PhCH2), 3.23 (2 H, AB, ∆ = 53.4 Hz,
J 13.4, MeO2CCH2C); δC(75 MHz, CDCl3) 170.0 (s), 169.6 (s),
166.7 (s), 155.7 (s), 153.9 (s), 132.3 (s), 130.4 (d), 128.8 (d), 128.3
(d), 63.4 (s), 52.6 (q), 52.5 (q), 46.9 (t), 43.0 (t), 41.3 (t);
νmax(CHCl3)/cmϪ1 3370, 3230, 3100 (three broad, weak absorp-
tions), 1745–1710; m/z 363 (MHϩ, 100%).
6-Benzyl-4,6-bis[(E )-3-phenylallyl]piperazine-2,3,5-trione, 10
The piperazinetrione 5 (218 mg, 1 mmol), potassium carbonate
(690 mg, 5 equiv.), DMF (2 cm3) and (E)-cinnamyl bromide
(473 mg, 2.4 equiv.) gave after chromatographic purification
[(4 : 1) chloroform–ethyl acetate] the title compound (258 mg,
57%). Mp 239–240 ЊC (decomp.); Rf 0.55 [(4 : 1) chloroform–
ethyl acetate]; found: Mϩ 450.2040. C29H26N2O3 requires Mϩ,
450.1943; δH(400 MHz, d6-DMSO) 9.66 (1 H, s, NH), 7.31–7.15
(13 H, m, aromatics), 7.06–7.04 (2 H, m, aromatics), 6.51 (1 H,
d, J 15.7, PhCH᎐), 6.37 (1 H, d, J 16.1, PhCH᎐), 6.15 (1 H, dt,
᎐
᎐
J 15.7 and 7.8, CH᎐CH–CH ), 5.88 (1 H, dt, J 16.1 and 7.5,
᎐
2
CH᎐CH–CH ), 4.31–4.21 (2 H, m, NCH ), 3.30 (1 H, d, J 13.2,
᎐
2
2
PhCHH), 3.06 (1 H, dd, J 13.7 and 7.7, C–CHH–C᎐), 2.98
᎐
(1 H, d, J 13.2, PhCHH), 2.74 (1 H, dd, J 13.7 and 7.7,
C–CHH–C᎐); δ (100 MHz, d -DMSO) 170.1, 156.2, 152.8,
᎐
C
6
136.3, 135.8, 135.0, 134.2, 132.9, 130.1, 128.5(2), 128.4(9),
128.2, 127.8, 127.6, 127.3, 126.1(9), 126.1(6), 122.4, 122.2, 65.9,
46.0, 43.5, 41.5; m/z 450 (Mϩ, 0.2%), 306 (8), 191 (10), 117 (22),
91 (20), 28 (100).
4,6-Diallyl-6-benzylpiperazine-2,3,5-trione, 11
The piperazinetrione 5 (436 mg, 2 mmol), potassium carbonate
(1380 mg, 5 equiv.), DMF (4 cm3) and allyl bromide (400 µl,
2.2 equiv.) gave 340 mg (57%) of the title compound after
chromatographic purification [(6 : 1) chloroform–ethyl acetate].
Mp 156.5–158.5 ЊC (CCl4–hexane); Rf 0.40 [(4 : 1) chloroform–
ethyl acetate]; found: C, 68.04; H, 6.11; N, 9.25%. C17H18N2O3
requires C, 68.44; H, 6.08; N, 9.39%; found: Mϩ 298.1318.
C17H18N2O3 requires Mϩ, 298.1317; δH(400 MHz, CDCl3) 9.31
(1 H, s, NH), 7.27–7.21 (3 H, m, aromatics), 7.08–7.06 (2 H, m,
General procedure for the dialkylation of 6-benzylpiperazine-
2,3,5-trione 5 using potassium carbonate
aromatics), 5.71–5.53 (2 H, m, 2 × C–CH᎐C), 5.24–5.09 (4 H,
᎐
m, 2 × C᎐CH ), 4.26 (2 H, dd, J 5.9 and 1.4, NCH ), 3.41 (1 H,
᎐
2
2
The alkyl halide (2.1 to 2.4 equiv.) was added to a stirred
suspension of the piperazinetrione 5 (1 equiv.) in dry DMF
[∼2 cm3 mmolϪ1 of 5] and anhydrous potassium carbonate
(5 equiv.). Stirring was continued for 2–3 h after which time
TLC indicated the disappearance of starting material. After
dilution with ethyl acetate and filtration to remove the in-
organic salts, the DMF was removed in vacuo and the resulting
oil purified using silica gel column chromatography (CH2Cl2 or
chloroform–ethyl acetate).
d, J 13.4, PhCHH), 3.05 (1 H, dd, J 13.4, PhCHH), 3.03 (1 H,
dd, J 13.9 and 7.3, C–CHH–C᎐), 2.65 (1 H, dd, J 13.9 and 7.6,
᎐
C–CHH–C᎐); δ (100 MHz, CDCl ) 169.9, 155.9, 155.0, 133.4,
᎐
C
3
130.3, 129.9 (2 × CH), 128.6, 127.9, 122.2, 119.2, 66.6, 47.0,
44.7, 42.8; m/z 298 (Mϩ, 40%), 257 (25), 207 (35), 91 (100), 50
(100). Also isolated in yields of around 10% was compound 17.
1,4,6-Triallyl-6-benzylpiperazine-2,3,5-trione, 17. Mp 100–
102 ЊC (chloroform–hexane); Rf 0.79 [(4 : 1) chloroform–ethyl
acetate]; found: C, 70.81; H, 6.60; N, 8.31%. C20H22N2O3
requires C, 70.99; H, 6.55; N, 8.28%; δH(400 MHz, CDCl3)
7.23–7.21 (3 H, m, aromatics), 6.96–6.94 (2 H, m, aromatics),
(3-Benzyl-3-methoxycarbonylmethyl-2,5,6-trioxopiperazin-1-
yl)acetic acid methyl ester, 8
6.09 (1 H, dddd, J 17.3, 10.0, 7.3 and 5.4, CH –CH᎐CH ), 5.62–
᎐
2
2
The piperazinetrione 5 (50 mg, 0.23 mmol), caesium carbonate
(374 mg, 5 equiv.), DMF (4 cm3) and methyl bromoacetate
(46 µl, 2.1 equiv.) gave 51 mg (61%) of the title compound 8 after
chromatographic purification [(2 : 1) chloroform–ethyl acetate].
The 1H, and 13C NMR, IR and mass spectra of this compound
were identical to those for the minor product isolated from the
previous reaction.
5.47 (2 H, m, 2 × CH –CH᎐CH ), 5.41 (1 H, d, J 17.3, CH᎐
᎐
᎐
2
2
CHH), 5.32 (1 H, d, J 10.0, CH᎐CHH), 5.20–5.08 (4 H, m,
᎐
2 × C᎐CH ), 4.59 (1 H, dd, J 14.8 and 5.5, NCHH), 4.21–4.19
᎐
2
(2 H, m, NCH2), 4.03 (1 H, dd, J 14.8 and 7.6, NCHH), 3.26
(2 H, ∆ = 55.7 Hz, J 13.9, PhCH2), 3.05 (1 H, dd, J 14.4 and 8.3,
C–CHH–C᎐), 2.83 (1 H, dd, J 14.9 and 5.9, C–CHH–C᎐);
᎐
᎐
δC(100 MHz, CDCl3) 169.4, 154.8, 153.7, 133.1, 129.9, 129.6,
129.5, 129.4, 128.9, 128.1, 121.7, 119.5, 119.3, 72.8, 47.2, 44.4,
42.8, 41.9.
4,6,6-Tribenzylpiperazine-2,3,5-trione, 9
The piperazinetrione 5 (218 mg, 1 mmol), potassium carbonate
(690 mg, 5 equiv.), DMF (2 cm3) and benzyl bromide (0.26 cm3,
2.2 equiv.) gave 234 mg (59%) of the dialkylated product 9 after
chromatographic purification [(6 : 1) chloroform–ethyl acetate].
Mp 253–254 ЊC (decomp.) (CHCl3–hexane); Rf 0.52 [(4 : 1)
chloroform–ethyl acetate]; found: C, 74.89; H, 5.54; N, 6.99%.
C25H22N2O3 requires C, 75.36; H, 5.56; N, 7.03%; δH(400 MHz,
d6-DMSO) 9.86 (1 H, s, NH), 7.25–7.14 (9 H, m, aromatics),
7.07–7.05 (4 H, m, aromatics), 6.72–6.69 (2 H, m, aromatics),
4.53 (2 H, s, NCH2), 3.48 (2 H, d, J 13.2, 2 × PhCHH), 3.08
(2 H, dd, J 13.2, 2 × PhCHH); δC(100 MHz, d6-DMSO) 170.1,
155.8, 152.2, 134.9, 134.3, 130.1, 128.3, 128.2, 127.2(9),
127.2(5), 127.2(0), 67.3, 46.1, 42.7; m/z 398 (Mϩ, 15%), 307 (45),
91 (100).
1,6-Dibenzylpiperazine-2,3,5-trione, 15
Phenylalaninamide (0.50 g, 3.05 mmol) and benzaldehyde
(310 µl, 3.05 mmol) were dissolved in sodium-dried benzene
(20 cm3) and refluxed for 1.5 h in a flask fitted with a Dean–
Stark trap and condenser. After cooling, the benzene was
removed in vacuo, and the resulting crude imine taken up in
methanol (20 cm3). Next sodium borohydride (58 mg,
1.5 mmol) was added portionwise to the solution, which was
subsequently left stirring for 1 h. After removal of the metha-
nol, the residue was partitioned between ethyl acetate (10 cm3)
and water (10 cm3), then the organic layer dried over
magnesium sulfate. Removal of the solvent yielded 564 mg
(73%) of N-benzylphenylalaninamide. A 490 mg (1.93 mmol)
J. Chem. Soc., Perkin Trans. 1, 2001, 3245–3251
3249

View Article Online
sample of the protected amino acid amide was cyclised in an
identical fashion to that described for 5, except for the following
modified work-up procedure: After the final period of reflux-
ing, the mixture was cooled in an ice–salt bath. No precipitate
formed, so 1 M acetic acid (2 cm3) was added directly to the
methanolic solution with stirring. The methanol was removed
in vacuo leaving a slurry, which was partitioned between ethyl
acetate (20 cm3) and water (20 cm3). The ethyl acetate was
separated, dried over magnesium sulfate, then evaporated to
dryness. The crude product was dissolved in a minimum of
ethyl acetate, then precipitated out with diethyl ether–hexane to
yield 271 mg (43%) of the 1,6-dibenzyl derivative 15 as a white
solid, mp 150–152 ЊC (ethyl acetate–hexane). Rf 0.49 [(1 : 1)
chloroform–ethyl acetate]; found: Mϩ 309.1237. C18H17N2O3
requires Mϩ, 309.1239; δH(300 MHz, d6-DMSO) 11.88 (1 H,
broad s, NH), 7.46–7.25 (8 H, m, Ph), 7.02–6.97 (2 H, m, ortho
protons from PhCH2N), 5.17 (1 H, d, J 14.9, one proton from
PhCH2N), 4.48 (1 H, d, J 14.9, other proton from PhCH2N),
4.50 (1 H, dd, J 5.1 and 3.2, PhCH2CH), 3.43 (1 H, dd, J 14.0
and 5.1, one proton from PhCH2CH), 3.10 (1 H, dd, J 14.0 and
3.2, other proton from PhCH2CH); δC(75 MHz, d6-DMSO)
168.9 (s), 155.9 (s), 153.4 (s), 135.5 (s), 133.7 (s), 129.7 (d), 128.5
(d), 128.4 (d), 128.3 (d), 127.6 (d), 127.4 (d), 61.4 (d), 47.2 (t),
37.4 (t); νmax(CHCl3)/cmϪ1 3490, 3360, 1675; m/z 309 (MHϩ,
70%), 107 (32), 91 (57).
(2 H, ABX, ∆ = 51.4 Hz, J 15.0, 5.6 and 5.1, NCH CH᎐), 3.24
᎐
2
(1 H, dd, J 13.6 and 3.9, PhCHH), 3.03 (1 H, dd, J 13.6 and 4.8,
PhCHH), δC(67.8 MHz, CDCl3) 167.9, 156.2, 154.3, 133.2,
130.1, 130.0, 128.9, 128.0, 119.5, 57.5, 42.9, 41.1; m/z 258 (Mϩ,
8%), 130 (18), 117 (20), 91 (100), 77 (22), 65 (30).
6-Benzyl-4-(4-bromobenzyl)piperazine-2,3,5-trione, 19
5-Benzylpiperazine-2,3,6-trione 5 (201 mg, 0.923 mmol),
acetonitrile (6 cm3), triethylamine (0.103 g, 0.14 cm3, 1.1 equiv.)
and p-bromobenzyl bromide (346 mg, 1.384 mmol, 1.5 equiv.)
gave the title compound as a white solid (231 mg, 65% yield).
Mp 188–190 ЊC; Rf 0.20 [(2 : 1) chloroform–ethyl acetate];
found: C, 55.68; H, 3.99; N, 7.16%. C18H15BrN2O3 requires C,
55.83; H, 3.90; N, 7.23%; δH(400 MHz, d6-DMSO) 9.44 (1 H,
s, NH), 7.43 (2 H, d, J 9.1, ArH × 2), 7.28–7.11 (4 H, m,
aromatic), 6.98–6.95 (4H, m, aromatic), 4.77 (1 H, m, CH), 4.66
(2 H, AB, ∆ = 44.4 Hz, J 14.6, NCH2), 3.23 (1 H, dd, J 13.9 and
3.8, PhCHH), 3.03 (1 H, dd, J 13.9 and 4.9, PhCHH); δC(67.8
MHz, CDCl3) 162.0, 150.2, 147.0, 127.7, 126.8, 124.7, 123.4,
122.1, 121.7, 50.7, 36.6, 34.3; m/z 388 (Mϩ, Br81 4%), 386 (Mϩ,
Br79, 4%), 360 (2), 358 (2), 162 (25), 91 (100).
6-Benzyl-4-(pent-4-enyl)piperazine-2,3,5-trione, 20
5-Benzylpiperazine-2,3,6-trione 5 (218 g, 1.0 mmol), triethyl-
amine (0.15 cm3, 1.1 equiv.), 5-bromopent-1-ene (0.20 cm3,
1.7 equiv.) in acetonitrile (6 cm3) after chromatographic purifi-
cation [(4 : 1) chloroform–ethyl acetate] gave the title compound
as a colourless oil which solidifed on standing (186 mg, 65%
yield). Mp 82–83 ЊC; Rf 0.38 [(1 : 1) chloroform–ethyl acetate];
δH(400 MHz, CDCl3) 9.03 (1 H, s, NH), 7.26–7.21 (3 H, m,
aromatic), 7.11–7.09 (2 H, m, aromatic), 5.77 (1 H, ddt, J 17.1,
(3,4-Dibenzyl-2,5,6-trioxopiperazin-1-yl)acetic acid methyl ester,
16
To anhydrous potassium carbonate (112 mg, 5 equiv.) and tri-
one 15 (50 mg, 0.16 mmol) in DMF (2 cm3) was added methyl
bromoacetate (16 µl, 1.05 equiv.) in DMF (1 cm3). The mixture
was stirred at ambient temperature for 3 h, the solvent was
removed in vacuo, and then the product purified using silica
flash chromatography [(1 : 1) chloroform–ethyl acetate] yielding
the title compound as a colourless oil (51 mg, 83%). Rf 0.63
[(1 : 1) chloroform–ethyl acetate]; found: Mϩ 381.1470.
C21H21N2O5 requires Mϩ 381.1450; δH(90 MHz, CDCl3) 7.45–
7.15 (1 H, broad s, NH), 7.05–6.85 (2 H, m, ortho protons from
PhCH2N), 5.51 (1 H, d, J 14.9, one proton from PhCH2N),
4.07 (1 H, d, J 14.9, other proton from PhCH2N), 4.51 (1 H, t,
J 4.3, PhCH2CH), 4.29 (2 H, s, CH2CO2Me), 3.70 (3 H, s,
CO2Me), 3.26 (2 H, m, PhCH2CH); δC(22.5 MHz, CDCl3) 167.6
(s), 166.7 (s), 155.4 (s), 152.9 (s), 134.0 (s), 132.9 (s), 129.4 (d),
129.3 (d), 129.1 (d), 128.8 (d), 128.3 (d), 60.9 (d), 52.7 (q), 48.3
(t), 41.0 (t), 39.2 (t); νmax(CH2Cl2)/cmϪ1 1740, 1690; m/z 381.2
(MHϩ, 100%).
10.5 and 6.6, CH –CH᎐CH ), 5.03 (1 H, br d, J ∼16, C᎐CHH),
᎐
᎐
2
2
5.03 (1 H, br d, J ∼12, C᎐CHH), 4.79 (1 H, br q, J 2.4,
᎐
HN–CH–CH2), 3.71–3.59 (2 H, m, NCH2), 3.29 (2 H, ABX,
∆ = 64.9 Hz, J 13.9, 4.4 and 4.4, PhCH2), 2.04–1.95 (2 H,
m, CH2), 1.58–1.40 (2 H, m, CH2); δC(67.8 MHz, CDCl3) 168.2,
156.5, 154.4, 137.0, 133.2, 130.0, 128.8, 127.9, 115.3, 57.4,
41.2, 40.5, 30.8, 26.1; m/z 286 (Mϩ, 5%), 91 (100), 43 (40);
νmax(Nujol)/cmϪ1 3550, 1686.
2-(3-Benzyl-2,5,6-trioxopiperazin-1-yl)propionic acid ethyl ester,
21
5-Benzylpiperazine-2,3,6-trione 5 (1.0 g, 4.58 mmol), aceto-
nitrile (20 cm3), triethylamine (0.75 cm3, 1.2 equiv.) and ethyl 2-
bromopropionate (1.0 cm3, 1.7 equiv.) gave a 1 : 1 mixture
of diastereoisomers of the title compound (226 mg, 16% yield)
as a colourless oil after chromatographic purification [(3 : 1)
chloroform–ethyl acetate]. δH (270 MHz, CDCl3) δ first isomer
[δ second isomer if resolved] 8.55 [8.45] (1 H, s, NH), 7.31–7.26
(3 H, m, ArH), 7.12–7.17 (2 H, m, ArH), 5.24 [5.13] (1 H, q, J 7,
CHCH2), 4.75 (1 H, m, CHCH3), 4.17 (2 H, q, J 7, CH2CH3),
3.31 (2 H, m, CH2Ph), 1.41 [1.34] (3 H, d, J 7, CHCH3), 1.23
(3 H, t, J 7, CH2CH3); δC(67.8 MHz, CDCl3) δ first isomer
(δ second isomer) 168.6, 167.5 (167.3), 155.8 (155.6), 153.9
(153.8), 133.3 (133.2), 130.1 (130.0), 129.1 (129.0), 128.1
(128.0), 61.9 (61.8), 57.6 (57.4), 50.2 (50.0), 41.3 (41.0), 14.1,
14.0 (13.9); m/z 318 (Mϩ, 4%), 275 (12), 201 (7), 146 (12), 120
(15), 91 (100).
General procedure for the mono N4-alkylation of the 5-benzyl-
piperazine-2,3,6-trione 5 using triethylamine
The piperazinetrione and acetonitrile were mixed, then triethyl-
amine followed by the halogenoalkane were added. The solu-
tion, with some DMF to aid dissolution if necessary, was
stirred whilst heating at reflux until TLC showed consumption
of starting material (2 to 3 h). After removal of the solvent the
crude mixture was purified by column chromatography [CH2Cl2
or chloroform–ethyl acetate] to give the product.
4-Allyl-6-benzylpiperazine-2,3,5-trione, 18
The piperazinetrione 5 (218 mg, 1 mmol), triethylamine
(0.7 cm3, 5 equiv.), MeCN (6 cm3) and allyl bromide (0.2 cm3,
2.2 equiv.) gave 198 mg (77%) of the title compound after
chromatographic purification [(5 : 1) chloroform–ethyl acetate].
Mp 105–110 ЊC (CH2Cl2–hexane); Rf 0.20 [(4 : 1) chloroform–
ethyl acetate]; found: Mϩ 258.1013. C14H14N2O5 requires Mϩ,
258.1004; δH(400 MHz, d6-DMSO) 9.40 (1 H, s, NH), 7.30–7.15
(3 H, m, aromatics), 7.10–7.00 (2 H, m, aromatics), 5.17 (1 H,
4-Allyl-6-benzyl-6-(4-bromobenzyl)piperazine-2,3,5-trione, 22
To potassium carbonate (0.481 g, 3 equiv.) and 4-allyl-6-benzyl-
piperazine-2,3,5-trione 18 (0.300 g, 1.163 mmol) in DMF–
acetonitrile (1 ϩ 4 cm3) was added 4-bromobenzyl bromide
(0.436 g, 1.5 equiv.). After stirring for several hours at room
temperature TLC indicated the consumption of starting
material. The mixture was then filtered and the solvent removed
in vacuo. The resulting residue was purified using silica
flash chromatography [(2 : 1) chloroform–ethyl acetate] to
ddt, J 17.1, 10.5 and 5.3, CH –CH᎐CH ), 4.99 (1 H, d, J 10.5,
᎐
2
2
C᎐CHH), 4.85 (1 H, d, J 17.1, C᎐CHH), 4.73 (1H, m, CH), 4.10
᎐
᎐
3250
J. Chem. Soc., Perkin Trans. 1, 2001, 3245–3251

View Article Online
yield the title compound (248 mg, 50%). Mp 241–245 ЊC
(dichloromethane–hexane); Rf 0.6 [(1 : 1) dichloromethane–
ethyl acetate]; found: C, 59.37; H, 4.61; N, 6.26%. C21H19-
BrN2O3 requires C, 59.03; H, 4.48; N, 6.56%; δH(400 MHz,
CDCl3) 7.59 (1 H, br s, NH), 7.41 (2 H, br d, J 8.4, ArH), 7.30–
7.29 (3 H, m, ArH), 7.11–7.09 (2 H, m, ArH), 6.99 (2 H, br d,
52.5 (q), 46.8 (t), 41.1 (t); νmax(CHCl3)/cmϪ1 3680, 1750, 1710;
m/z 381 (MHϩ).
Acknowledgements
We acknowledge gratefully the financial support of the EPSRC
(studentship to ANB), Pfizer (vacation studentship for MB)
and Hull University at various stages of this work. We also
would like to express our thanks to the following for their
contribution (NMR spectroscopy and mass spectrometry) to
this project: Mr A. D. Roberts and Mrs B. Worthington (Hull
University), and Dr R. Ferguson and Dr A. S. F. Boyd (Heriot-
Watt University, Edinburgh). We also acknowledge the use of
the EPSRC’s Chemical Database Service at Daresbury12 and
the EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea.
J 8.4, ArH), 5.46 (1 H, ddt, J 17.1, 10.2 and 6.1, CH –CH᎐
᎐
2
CH ), 5.10 (1 H, ddt, J 10.2, 1.2 and 1.0, CH –CH᎐CH H),
᎐
2
2
cis
4.97 (1 H, dtd, J 17.1, 1.4 and 1.2, CH –CH᎐CHHtrans), 4.62
᎐
2
(2 H, ddd, J 6.1, 1.4 and 1.0, NCH2), 3.55 (1 H, d, J 13.6,
PhCHH), 3.52 (1 H, d, J 13.7, ArCHH), 3.07 (1 H, d, J 13.7,
PhCHH), 3.01 (1 H, d, J 13.6, ArCHH); δC(100 MHz, CDCl3)
169.3, 155.3, 154.8, 133.1, 132.6, 132.0, 131.9, 130.3, 129.6,
128.8, 128.2, 122.2, 119.3, 67.6, 47.4, 45.9, 42.8; νmax(KBr)/cmϪ1
1695; m/z 428 (Mϩ, Br81 1%), 426 (Mϩ, Br79, 1), 257 (8), 171
(10), 91 (100).
6-Allyl-6-benzyl-4-(4-bromobenzyl)piperazine-2,3,5-trione, 23
References
Following the method described above, potassium carbonate
(0.320 g, 3 equiv.), 1-(4-bromobenzyl)-6-benzylpiperazine-
2,3,5-trione 19 (0.300 g, 0.775 mmol), DMF–acetonitrile (1 ϩ
4 cm3) and allyl bromide (0.10 cm3, 1.5 equiv.) gave the title
compound (132 mg, 40%). Mp 197–199 ЊC (CH2Cl2–hexane);
Rf 0.57 (ethyl acetate); found: C, 58.74; H, 4.60; N, 6.21%.
C21H19BrN2O3 requires C, 59.03; H, 4.48; N, 6.56%; δH(400
MHz, d6-DMSO) 9.61 (1 H, s, NH), 7.28 (2 H, br d, J 8.3,
ArH × 2), 7.07 (1 H, br t, J 7.1, ArH), 6.98 (2 H, br t, J 7.3,
ArH × 2), 6.93 (2 H, br d, J 8.3, ArH × 2), 6.87 (2 H, br d, J 7.3,
1 (a) P. D. Bailey, A. N. Boa, G. A. Crofts, M. van Diepen,
M. Helliwell, R. E. Gammon and M. J. Harrison, Tetrahedron
Lett., 1989, 30, 7457; (b) P. D. Bailey and A. N. Boa, Amino Acids,
1991, 1, 163; (c) P. D. Bailey, S. R. Baker, A. N. Boa, J. Clayson and
G. M. Rosair, Tetrahedron Lett., 1998, 39, 7755.
2 S. R. Safir, J. J. Hlavka and J. H. Williams, J. Org. Chem., 1953,
18, 106.
3 D. Person and M. Le Corre, Bull. Soc. Chim. Fr., 1988(5), 673.
4 Y. Takeuchi, K. Kirihara, K. L. Kirk and N. Shibata, Chem.
Commun., 2000, 785.
5 P. D. Bailey, A. N. Boa, S. R. Baker, J. Clayson, E. J. Murray and
G. M. Rosair, Tetrahedron Lett., 1999, 40, 7557.
6 (a) D. Obrecht, C. Abrecht, M. Altorfer, U. Bohdal, A. Grieder,
M. Kleber, P. Pfyffer and K. Müller, Helv. Chim. Acta, 1996, 79,
1315; (b) T. Wirth, Angew. Chem., Int. Ed. Engl., 1997, 36, 225.
7 (a) Houben Weyl Methods of Organic Chemistry, Vol E2:2: Synthesis
of Peptides and Peptidomimetics, M. Goodman, A. Felix, L.
Moroder and C. Toniolo, Georg Thieme Edt., Stuttgart, 2001,
Ch. 11 and 12; (b) A. Giannis and T. Kolter, Angew. Chem., Int.
Ed. Engl., 1993, 32, 1244; (c) D. P. Fairlie, G. Abbenante and
D. R. March, Curr. Med. Chem., 1995, 2, 654.
ArH × 2), 5.57–5.46 (1 H, m, C–CH᎐C), 5.08–5.02 (2 H, m, C᎐
᎐
᎐
CH2), 4.62 (2 H, AB, ∆ = 45.9 Hz, J 14.0, NCH2), 3.19 (2 H, d,
J 13.4, PhCHH), 2.88 (2 H, d, J 13.4, PhCHH), 2.83 (2 H, dd,
J 13.7 and 6.1, CHH–C᎐C), 2.51 (2 H, dd, J 13.7 and 7.3,
᎐
CHH–C᎐C); δ (68.7 MHz, CDCl ) 170.0, 156.3, 154.9, 133.9,
᎐
C
3
133.1, 131.6, 131.3, 130.1, 129.7, 128.7, 127.9, 122.4, 122.2,
66.5, 47.0, 44.9, 43.5; m/z 428 (Mϩ, Br81 1%), 426 (Mϩ, Br79, 1),
91 (100).
8 (a) P. J. Machin, A. E. A. Porter and P. G. Sammes, J. Chem. Soc.,
Perkin Trans. 1, 1973, 404 See also J. Liebscher and S. Jin, Chem.
Soc. Rev., 1999, 28, 251 for a review of of ylidenepiperazine-2,5-
diones, cf. 12.
9 The PC software used for molecular modelling was CS Chem3D Pro
v 5.0, from CambridgeSoft Corporation, and Nemesis for Windows
v 2.0, from Oxford Molecular.
10 Crystal data for 17: colourless crystal (0.80 × 0.52 × 0.16 mm) from
ethyl acetate–hexane, coated with Nujol and mounted on a glass
fibre, C20H22N2O3, M = 338.40, monoclinic, space group P21/c,
a = 8.813(8), b = 11.418(12), c = 18.102(17) Å, β = 103.540(7)Њ,
V = 1770.9(4) Å3, Z = 4, Dc = 1.269 g cmϪ3, µ = 0.086 mmϪ1. R1 =
0.0372, for 2579 unique observed [I > 2σ(I )] data; R1 = 0.0476
wR2 = 0.1010 and goodness of fit 1.022 for all 3115 data and 226
parameters. Full data have been deposited with the Cambridge
Crystallographic Data Centre. CCDC reference number 135218. See
http://www.rsc.org/suppdata/p1/b1/b108872f/ for crystallographic
files in .cif or other electronic format.
(3,3-Dibenzyl-2,5,6-trioxopiperazin-1-yl)acetic acid methyl ester,
24
Anhydrous potassium carbonate (50 mg, 2 equiv.) and trione 7
(49 mg, 0.16 mmol) were dissolved in DMF (4 cm3) with
stirring, then benzyl bromide (32 µl, 0.27 mmol) was added.
After 0.25 h the solvent was removed in vacuo, and the
solid obtained was triturated thoroughly with chloroform
(2 × 5 ml). After combination of the organic fractions and
removal of the solvent the residue was purified using silica flash
chromatography [eluent (4 : 1) chloroform–ethyl acetate] to
yield 50 mg (78%) of the dibenzyl derivative 24. Mp 196–199 ЊC
(chloroform-hexane); Rf 0.53 [(1 : 1) chloroform-ethyl acetate];
Found: MHϩ 381.1460. C21H21N2O5 requires MHϩ, 381.1450;
δH(300 MHz, CDCl3) 9.15 (1 H, broad s, NH), 7.32–7.26 and
7.15–7.12 (10 H, m, Ph), 4.24 (2 H, s, NCH2), 3.65 (3 H, s,
CO2Me), 3.59 [2 H, d, J 13.6, two protons from (PhCH2)2C],
3.10 [1 H, dd, J 14.0 and 3.2, other two protons from
(PhCH2)2C]; δC(22.5 MHz, CDCl3) 169.7 (s), 166.3 (s), 155.3 (s),
154.3 (s), 133.4 (s), 130.3 (d), 128.7 (d), 128.0 (d), 67.9 (s),
11 Dictionary of Organic Compounds (Fifth Edition), Chapman and
Hall, London, 1982.
12 The United Kingdom Chemical Database Service: D. A. Fletcher,
R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput. Sci., 1996,
36, 746.
J. Chem. Soc., Perkin Trans. 1, 2001, 3245–3251
3251